- About
- Home
- Introduction
- Statistics
- Programs
- Dignet
- Gene
- GenePair
- BioSummarAI
- Help & Docs
- Documents
- Help
- FAQs
- Links
- Acknowledge
- Disclaimer
- Contact Us
Gene Information
Gene symbol: IRS1
Gene name: insulin receptor substrate 1
HGNC ID: 6125
Synonyms: HIRS-1
Related Genes
Related Sentences
| # | PMID | Sentence |
| 1 | 1312712 | YMXM motifs of IRS-1 define substrate specificity of the insulin receptor kinase. |
| 2 | 1316358 | Non-tyrosine kinase pathways that could signal insulin effects through the insulin receptor include non-covalent activation of G proteins, phospholipase Cs, or docking proteins such as IRS-1. |
| 3 | 1320027 | The level of biological function approximately paralleled the insulin-stimulated tyrosine kinase activity in the intact cell as estimated by tyrosine phosphorylation of the insulin receptor and its endogenous substrate pp 185/IRS-1. |
| 4 | 1320027 | The data are consistent with a requirement for the receptor tyrosine kinase either as an obligatory step or a modulator, in both metabolic and growth responses, and demonstrate the important role of the level of insulin receptor kinase domain autophosphorylation in regulating insulin sensitivity. |
| 5 | 1331176 | In the present study we have examined the levels of IRS-1 and the phosphorylation state of insulin receptor and IRS-1 in liver and muscle after insulin stimulation in vivo in two rat models of insulin resistance, i.e., insulinopenic diabetes and fasting, and a mouse model of non-insulin-dependent diabetes mellitus (ob/ob) by immunoblotting with anti-peptide antibodies to IRS-1 and anti-phosphotyrosine antibodies. |
| 6 | 1331176 | The tyrosyl phosphorylation of IRS-1 after insulin stimulation reflected an amplification of the receptor phosphorylation in liver and muscle of hypoinsulinemic animals (fasting and STZ diabetes) with a twofold increase, and showed a significant reduction (approximately 50%) in liver and muscle of ob/ob mouse. |
| 7 | 1331176 | By contrast, the levels of IRS-1 protein showed a tissue specific regulation with a decreased level in muscle and an increased level in liver in hypoinsulinemic states of insulin resistance, and decreased levels in liver in the hyperinsulinemic ob/ob mouse. |
| 8 | 1331176 | These data indicate that: (a) IRS-1 protein levels are differentially regulated in liver and muscle; (b) insulin levels may play a role in this differential regulation of IRS-1; (c) IRS-1 phosphorylation depends more on insulin receptor kinase activity than IRS-1 protein levels; and (d) reduced IRS-1 phosphorylation in liver and muscle may play a role in insulin-resistant states, especially of the ob/ob mice. |
| 9 | 1331176 | In the present study we have examined the levels of IRS-1 and the phosphorylation state of insulin receptor and IRS-1 in liver and muscle after insulin stimulation in vivo in two rat models of insulin resistance, i.e., insulinopenic diabetes and fasting, and a mouse model of non-insulin-dependent diabetes mellitus (ob/ob) by immunoblotting with anti-peptide antibodies to IRS-1 and anti-phosphotyrosine antibodies. |
| 10 | 1331176 | The tyrosyl phosphorylation of IRS-1 after insulin stimulation reflected an amplification of the receptor phosphorylation in liver and muscle of hypoinsulinemic animals (fasting and STZ diabetes) with a twofold increase, and showed a significant reduction (approximately 50%) in liver and muscle of ob/ob mouse. |
| 11 | 1331176 | By contrast, the levels of IRS-1 protein showed a tissue specific regulation with a decreased level in muscle and an increased level in liver in hypoinsulinemic states of insulin resistance, and decreased levels in liver in the hyperinsulinemic ob/ob mouse. |
| 12 | 1331176 | These data indicate that: (a) IRS-1 protein levels are differentially regulated in liver and muscle; (b) insulin levels may play a role in this differential regulation of IRS-1; (c) IRS-1 phosphorylation depends more on insulin receptor kinase activity than IRS-1 protein levels; and (d) reduced IRS-1 phosphorylation in liver and muscle may play a role in insulin-resistant states, especially of the ob/ob mice. |
| 13 | 1331176 | In the present study we have examined the levels of IRS-1 and the phosphorylation state of insulin receptor and IRS-1 in liver and muscle after insulin stimulation in vivo in two rat models of insulin resistance, i.e., insulinopenic diabetes and fasting, and a mouse model of non-insulin-dependent diabetes mellitus (ob/ob) by immunoblotting with anti-peptide antibodies to IRS-1 and anti-phosphotyrosine antibodies. |
| 14 | 1331176 | The tyrosyl phosphorylation of IRS-1 after insulin stimulation reflected an amplification of the receptor phosphorylation in liver and muscle of hypoinsulinemic animals (fasting and STZ diabetes) with a twofold increase, and showed a significant reduction (approximately 50%) in liver and muscle of ob/ob mouse. |
| 15 | 1331176 | By contrast, the levels of IRS-1 protein showed a tissue specific regulation with a decreased level in muscle and an increased level in liver in hypoinsulinemic states of insulin resistance, and decreased levels in liver in the hyperinsulinemic ob/ob mouse. |
| 16 | 1331176 | These data indicate that: (a) IRS-1 protein levels are differentially regulated in liver and muscle; (b) insulin levels may play a role in this differential regulation of IRS-1; (c) IRS-1 phosphorylation depends more on insulin receptor kinase activity than IRS-1 protein levels; and (d) reduced IRS-1 phosphorylation in liver and muscle may play a role in insulin-resistant states, especially of the ob/ob mice. |
| 17 | 1331176 | In the present study we have examined the levels of IRS-1 and the phosphorylation state of insulin receptor and IRS-1 in liver and muscle after insulin stimulation in vivo in two rat models of insulin resistance, i.e., insulinopenic diabetes and fasting, and a mouse model of non-insulin-dependent diabetes mellitus (ob/ob) by immunoblotting with anti-peptide antibodies to IRS-1 and anti-phosphotyrosine antibodies. |
| 18 | 1331176 | The tyrosyl phosphorylation of IRS-1 after insulin stimulation reflected an amplification of the receptor phosphorylation in liver and muscle of hypoinsulinemic animals (fasting and STZ diabetes) with a twofold increase, and showed a significant reduction (approximately 50%) in liver and muscle of ob/ob mouse. |
| 19 | 1331176 | By contrast, the levels of IRS-1 protein showed a tissue specific regulation with a decreased level in muscle and an increased level in liver in hypoinsulinemic states of insulin resistance, and decreased levels in liver in the hyperinsulinemic ob/ob mouse. |
| 20 | 1331176 | These data indicate that: (a) IRS-1 protein levels are differentially regulated in liver and muscle; (b) insulin levels may play a role in this differential regulation of IRS-1; (c) IRS-1 phosphorylation depends more on insulin receptor kinase activity than IRS-1 protein levels; and (d) reduced IRS-1 phosphorylation in liver and muscle may play a role in insulin-resistant states, especially of the ob/ob mice. |
| 21 | 1332046 | IRS-1 activates phosphatidylinositol 3'-kinase by associating with src homology 2 domains of p85. |
| 22 | 1332046 | IRS-1 is an insulin receptor substrate that undergoes tyrosine phosphorylation and associates with the phosphatidylinositol (PtdIns) 3'-kinase immediately after insulin stimulation. |
| 23 | 1332046 | Recombinant IRS-1 protein was tyrosine phosphorylated by the insulin receptor in vitro and associated with the PtdIns 3'-kinase from lysates of quiescent 3T3 fibroblasts. |
| 24 | 1332046 | Bacterial fusion proteins containing the src homology 2 domains (SH2 domains) of the 85-kDa subunit (p85) of the PtdIns 3'-kinase bound quantitatively to tyrosine phosphorylated, but not unphosphorylated, IRS-1, and this association was blocked by phosphotyrosine-containing synthetic peptides. |
| 25 | 1332046 | These data suggest that the interaction between PtdIns 3'-kinase and IRS-1 is mediated by tyrosine phosphorylated motifs on IRS-1 and the SH2 domains of p85, and IRS-1 activates PtdIns 3'-kinase by binding to the SH2 domains of p85. |
| 26 | 1332046 | Thus, IRS-1 likely serves to transmit the insulin signal by binding and regulating intracellular enzymes containing SH2 domains. |
| 27 | 1332046 | IRS-1 activates phosphatidylinositol 3'-kinase by associating with src homology 2 domains of p85. |
| 28 | 1332046 | IRS-1 is an insulin receptor substrate that undergoes tyrosine phosphorylation and associates with the phosphatidylinositol (PtdIns) 3'-kinase immediately after insulin stimulation. |
| 29 | 1332046 | Recombinant IRS-1 protein was tyrosine phosphorylated by the insulin receptor in vitro and associated with the PtdIns 3'-kinase from lysates of quiescent 3T3 fibroblasts. |
| 30 | 1332046 | Bacterial fusion proteins containing the src homology 2 domains (SH2 domains) of the 85-kDa subunit (p85) of the PtdIns 3'-kinase bound quantitatively to tyrosine phosphorylated, but not unphosphorylated, IRS-1, and this association was blocked by phosphotyrosine-containing synthetic peptides. |
| 31 | 1332046 | These data suggest that the interaction between PtdIns 3'-kinase and IRS-1 is mediated by tyrosine phosphorylated motifs on IRS-1 and the SH2 domains of p85, and IRS-1 activates PtdIns 3'-kinase by binding to the SH2 domains of p85. |
| 32 | 1332046 | Thus, IRS-1 likely serves to transmit the insulin signal by binding and regulating intracellular enzymes containing SH2 domains. |
| 33 | 1332046 | IRS-1 activates phosphatidylinositol 3'-kinase by associating with src homology 2 domains of p85. |
| 34 | 1332046 | IRS-1 is an insulin receptor substrate that undergoes tyrosine phosphorylation and associates with the phosphatidylinositol (PtdIns) 3'-kinase immediately after insulin stimulation. |
| 35 | 1332046 | Recombinant IRS-1 protein was tyrosine phosphorylated by the insulin receptor in vitro and associated with the PtdIns 3'-kinase from lysates of quiescent 3T3 fibroblasts. |
| 36 | 1332046 | Bacterial fusion proteins containing the src homology 2 domains (SH2 domains) of the 85-kDa subunit (p85) of the PtdIns 3'-kinase bound quantitatively to tyrosine phosphorylated, but not unphosphorylated, IRS-1, and this association was blocked by phosphotyrosine-containing synthetic peptides. |
| 37 | 1332046 | These data suggest that the interaction between PtdIns 3'-kinase and IRS-1 is mediated by tyrosine phosphorylated motifs on IRS-1 and the SH2 domains of p85, and IRS-1 activates PtdIns 3'-kinase by binding to the SH2 domains of p85. |
| 38 | 1332046 | Thus, IRS-1 likely serves to transmit the insulin signal by binding and regulating intracellular enzymes containing SH2 domains. |
| 39 | 1332046 | IRS-1 activates phosphatidylinositol 3'-kinase by associating with src homology 2 domains of p85. |
| 40 | 1332046 | IRS-1 is an insulin receptor substrate that undergoes tyrosine phosphorylation and associates with the phosphatidylinositol (PtdIns) 3'-kinase immediately after insulin stimulation. |
| 41 | 1332046 | Recombinant IRS-1 protein was tyrosine phosphorylated by the insulin receptor in vitro and associated with the PtdIns 3'-kinase from lysates of quiescent 3T3 fibroblasts. |
| 42 | 1332046 | Bacterial fusion proteins containing the src homology 2 domains (SH2 domains) of the 85-kDa subunit (p85) of the PtdIns 3'-kinase bound quantitatively to tyrosine phosphorylated, but not unphosphorylated, IRS-1, and this association was blocked by phosphotyrosine-containing synthetic peptides. |
| 43 | 1332046 | These data suggest that the interaction between PtdIns 3'-kinase and IRS-1 is mediated by tyrosine phosphorylated motifs on IRS-1 and the SH2 domains of p85, and IRS-1 activates PtdIns 3'-kinase by binding to the SH2 domains of p85. |
| 44 | 1332046 | Thus, IRS-1 likely serves to transmit the insulin signal by binding and regulating intracellular enzymes containing SH2 domains. |
| 45 | 1332046 | IRS-1 activates phosphatidylinositol 3'-kinase by associating with src homology 2 domains of p85. |
| 46 | 1332046 | IRS-1 is an insulin receptor substrate that undergoes tyrosine phosphorylation and associates with the phosphatidylinositol (PtdIns) 3'-kinase immediately after insulin stimulation. |
| 47 | 1332046 | Recombinant IRS-1 protein was tyrosine phosphorylated by the insulin receptor in vitro and associated with the PtdIns 3'-kinase from lysates of quiescent 3T3 fibroblasts. |
| 48 | 1332046 | Bacterial fusion proteins containing the src homology 2 domains (SH2 domains) of the 85-kDa subunit (p85) of the PtdIns 3'-kinase bound quantitatively to tyrosine phosphorylated, but not unphosphorylated, IRS-1, and this association was blocked by phosphotyrosine-containing synthetic peptides. |
| 49 | 1332046 | These data suggest that the interaction between PtdIns 3'-kinase and IRS-1 is mediated by tyrosine phosphorylated motifs on IRS-1 and the SH2 domains of p85, and IRS-1 activates PtdIns 3'-kinase by binding to the SH2 domains of p85. |
| 50 | 1332046 | Thus, IRS-1 likely serves to transmit the insulin signal by binding and regulating intracellular enzymes containing SH2 domains. |
| 51 | 1332046 | IRS-1 activates phosphatidylinositol 3'-kinase by associating with src homology 2 domains of p85. |
| 52 | 1332046 | IRS-1 is an insulin receptor substrate that undergoes tyrosine phosphorylation and associates with the phosphatidylinositol (PtdIns) 3'-kinase immediately after insulin stimulation. |
| 53 | 1332046 | Recombinant IRS-1 protein was tyrosine phosphorylated by the insulin receptor in vitro and associated with the PtdIns 3'-kinase from lysates of quiescent 3T3 fibroblasts. |
| 54 | 1332046 | Bacterial fusion proteins containing the src homology 2 domains (SH2 domains) of the 85-kDa subunit (p85) of the PtdIns 3'-kinase bound quantitatively to tyrosine phosphorylated, but not unphosphorylated, IRS-1, and this association was blocked by phosphotyrosine-containing synthetic peptides. |
| 55 | 1332046 | These data suggest that the interaction between PtdIns 3'-kinase and IRS-1 is mediated by tyrosine phosphorylated motifs on IRS-1 and the SH2 domains of p85, and IRS-1 activates PtdIns 3'-kinase by binding to the SH2 domains of p85. |
| 56 | 1332046 | Thus, IRS-1 likely serves to transmit the insulin signal by binding and regulating intracellular enzymes containing SH2 domains. |
| 57 | 1380456 | Phosphatidylinositol 3'-kinase is activated by association with IRS-1 during insulin stimulation. |
| 58 | 1380456 | IRS-1 undergoes rapid tyrosine phosphorylation during insulin stimulation and forms a stable complex containing the 85 kDa subunit (p85) of the phosphatidylinositol (PtdIns) 3'-kinase, but p85 is not tyrosyl phosphorylated. |
| 59 | 1380456 | Formation of the IRS-1-PtdIns 3'-kinase complex in vitro is inhibited by synthetic peptides containing phosphorylated YXXM motifs, suggesting that the binding of PtdIns 3'-kinase to IRS-1 is mediated through the SH2 (src homology-2) domains of p85. |
| 60 | 1380456 | Furthermore, overexpression of IRS-1 potentiates the activation of PtdIns 3-kinase in insulin-stimulated cells, and tyrosyl phosphorylated IRS-1 or peptides containing phosphorylated YXXM motifs activate PtdIns 3'-kinase in vitro. |
| 61 | 1380456 | We conclude that the binding of tyrosyl phosphorylated IRS-1 to the SH2 domains of p85 is the critical step that activates PtdIns 3'-kinase during insulin stimulation. |
| 62 | 1380456 | Phosphatidylinositol 3'-kinase is activated by association with IRS-1 during insulin stimulation. |
| 63 | 1380456 | IRS-1 undergoes rapid tyrosine phosphorylation during insulin stimulation and forms a stable complex containing the 85 kDa subunit (p85) of the phosphatidylinositol (PtdIns) 3'-kinase, but p85 is not tyrosyl phosphorylated. |
| 64 | 1380456 | Formation of the IRS-1-PtdIns 3'-kinase complex in vitro is inhibited by synthetic peptides containing phosphorylated YXXM motifs, suggesting that the binding of PtdIns 3'-kinase to IRS-1 is mediated through the SH2 (src homology-2) domains of p85. |
| 65 | 1380456 | Furthermore, overexpression of IRS-1 potentiates the activation of PtdIns 3-kinase in insulin-stimulated cells, and tyrosyl phosphorylated IRS-1 or peptides containing phosphorylated YXXM motifs activate PtdIns 3'-kinase in vitro. |
| 66 | 1380456 | We conclude that the binding of tyrosyl phosphorylated IRS-1 to the SH2 domains of p85 is the critical step that activates PtdIns 3'-kinase during insulin stimulation. |
| 67 | 1380456 | Phosphatidylinositol 3'-kinase is activated by association with IRS-1 during insulin stimulation. |
| 68 | 1380456 | IRS-1 undergoes rapid tyrosine phosphorylation during insulin stimulation and forms a stable complex containing the 85 kDa subunit (p85) of the phosphatidylinositol (PtdIns) 3'-kinase, but p85 is not tyrosyl phosphorylated. |
| 69 | 1380456 | Formation of the IRS-1-PtdIns 3'-kinase complex in vitro is inhibited by synthetic peptides containing phosphorylated YXXM motifs, suggesting that the binding of PtdIns 3'-kinase to IRS-1 is mediated through the SH2 (src homology-2) domains of p85. |
| 70 | 1380456 | Furthermore, overexpression of IRS-1 potentiates the activation of PtdIns 3-kinase in insulin-stimulated cells, and tyrosyl phosphorylated IRS-1 or peptides containing phosphorylated YXXM motifs activate PtdIns 3'-kinase in vitro. |
| 71 | 1380456 | We conclude that the binding of tyrosyl phosphorylated IRS-1 to the SH2 domains of p85 is the critical step that activates PtdIns 3'-kinase during insulin stimulation. |
| 72 | 1380456 | Phosphatidylinositol 3'-kinase is activated by association with IRS-1 during insulin stimulation. |
| 73 | 1380456 | IRS-1 undergoes rapid tyrosine phosphorylation during insulin stimulation and forms a stable complex containing the 85 kDa subunit (p85) of the phosphatidylinositol (PtdIns) 3'-kinase, but p85 is not tyrosyl phosphorylated. |
| 74 | 1380456 | Formation of the IRS-1-PtdIns 3'-kinase complex in vitro is inhibited by synthetic peptides containing phosphorylated YXXM motifs, suggesting that the binding of PtdIns 3'-kinase to IRS-1 is mediated through the SH2 (src homology-2) domains of p85. |
| 75 | 1380456 | Furthermore, overexpression of IRS-1 potentiates the activation of PtdIns 3-kinase in insulin-stimulated cells, and tyrosyl phosphorylated IRS-1 or peptides containing phosphorylated YXXM motifs activate PtdIns 3'-kinase in vitro. |
| 76 | 1380456 | We conclude that the binding of tyrosyl phosphorylated IRS-1 to the SH2 domains of p85 is the critical step that activates PtdIns 3'-kinase during insulin stimulation. |
| 77 | 1380456 | Phosphatidylinositol 3'-kinase is activated by association with IRS-1 during insulin stimulation. |
| 78 | 1380456 | IRS-1 undergoes rapid tyrosine phosphorylation during insulin stimulation and forms a stable complex containing the 85 kDa subunit (p85) of the phosphatidylinositol (PtdIns) 3'-kinase, but p85 is not tyrosyl phosphorylated. |
| 79 | 1380456 | Formation of the IRS-1-PtdIns 3'-kinase complex in vitro is inhibited by synthetic peptides containing phosphorylated YXXM motifs, suggesting that the binding of PtdIns 3'-kinase to IRS-1 is mediated through the SH2 (src homology-2) domains of p85. |
| 80 | 1380456 | Furthermore, overexpression of IRS-1 potentiates the activation of PtdIns 3-kinase in insulin-stimulated cells, and tyrosyl phosphorylated IRS-1 or peptides containing phosphorylated YXXM motifs activate PtdIns 3'-kinase in vitro. |
| 81 | 1380456 | We conclude that the binding of tyrosyl phosphorylated IRS-1 to the SH2 domains of p85 is the critical step that activates PtdIns 3'-kinase during insulin stimulation. |
| 82 | 1382584 | Recently, we purified and cloned IRS-1, one of the phosphoproteins that binds to alpha PY and migrates near 180 kDa following insulin stimulation of rat liver [Sun, X. |
| 83 | 1382584 | IRS-1 and pp185 undergo tyrosine phosphorylation immediately after insulin stimulation and show an insulin dose response similar to that of insulin receptor autophosphorylation. |
| 84 | 1382584 | Moreover, the phosphatidylinositol 3'-kinase and its 85-kDa associated protein (p85) bound to IRS-1 in Fao cells, but weakly or not at all to HMW-pp185. |
| 85 | 1382584 | Our results show that Fao cells contain at least two insulin receptor substrates, IRS-1 and HMW-pp185, which may play unique roles in insulin signal transmission. |
| 86 | 1382584 | Recently, we purified and cloned IRS-1, one of the phosphoproteins that binds to alpha PY and migrates near 180 kDa following insulin stimulation of rat liver [Sun, X. |
| 87 | 1382584 | IRS-1 and pp185 undergo tyrosine phosphorylation immediately after insulin stimulation and show an insulin dose response similar to that of insulin receptor autophosphorylation. |
| 88 | 1382584 | Moreover, the phosphatidylinositol 3'-kinase and its 85-kDa associated protein (p85) bound to IRS-1 in Fao cells, but weakly or not at all to HMW-pp185. |
| 89 | 1382584 | Our results show that Fao cells contain at least two insulin receptor substrates, IRS-1 and HMW-pp185, which may play unique roles in insulin signal transmission. |
| 90 | 1382584 | Recently, we purified and cloned IRS-1, one of the phosphoproteins that binds to alpha PY and migrates near 180 kDa following insulin stimulation of rat liver [Sun, X. |
| 91 | 1382584 | IRS-1 and pp185 undergo tyrosine phosphorylation immediately after insulin stimulation and show an insulin dose response similar to that of insulin receptor autophosphorylation. |
| 92 | 1382584 | Moreover, the phosphatidylinositol 3'-kinase and its 85-kDa associated protein (p85) bound to IRS-1 in Fao cells, but weakly or not at all to HMW-pp185. |
| 93 | 1382584 | Our results show that Fao cells contain at least two insulin receptor substrates, IRS-1 and HMW-pp185, which may play unique roles in insulin signal transmission. |
| 94 | 1382584 | Recently, we purified and cloned IRS-1, one of the phosphoproteins that binds to alpha PY and migrates near 180 kDa following insulin stimulation of rat liver [Sun, X. |
| 95 | 1382584 | IRS-1 and pp185 undergo tyrosine phosphorylation immediately after insulin stimulation and show an insulin dose response similar to that of insulin receptor autophosphorylation. |
| 96 | 1382584 | Moreover, the phosphatidylinositol 3'-kinase and its 85-kDa associated protein (p85) bound to IRS-1 in Fao cells, but weakly or not at all to HMW-pp185. |
| 97 | 1382584 | Our results show that Fao cells contain at least two insulin receptor substrates, IRS-1 and HMW-pp185, which may play unique roles in insulin signal transmission. |
| 98 | 1385396 | Insulin stimulation of phosphatidylinositol 3-kinase activity and association with insulin receptor substrate 1 in liver and muscle of the intact rat. |
| 99 | 1385403 | Expression and function of IRS-1 in insulin signal transmission. |
| 100 | 1385403 | IRS-1 is a major insulin receptor substrate which may play an important role in insulin signal transmission. |
| 101 | 1385403 | IRS-1 was phosphorylated strongly on serine residues and weakly on threonine residues before insulin stimulation. |
| 102 | 1385403 | Insulin immediately stimulated tyrosine phosphorylation of IRS-1, and after 10-30 min with insulin its apparent molecular mass increased to 175-180 kDa. |
| 103 | 1385403 | Expression of the human insulin receptor and rat IRS-1 together in CHO/IR/IRS-1 cells increased the basal serine phosphorylation of IRS-1 and strongly increased tyrosine phosphorylation during insulin stimulation. |
| 104 | 1385403 | Purified insulin receptors directly phosphorylated baculovirus-produced IRS-1 exclusively on tyrosine residues. |
| 105 | 1385403 | By immunofluorescence, IRS-1 was absent from the nucleus, but otherwise distributed uniformly before and after insulin stimulation. |
| 106 | 1385403 | Some IRS-1 associated with the insulin receptor during insulin stimulation. |
| 107 | 1385403 | In addition, a phosphatidylinositol 3'-kinase associated with IRS-1 during insulin stimulation, and this association was more sensitive to insulin in CHO cells overexpressing the insulin receptor (CHO/IR cells), more responsive to insulin to CHO/IRS-1 cells, and both sensitive and responsive in CHO/IR/IRS-1 cells. |
| 108 | 1385403 | Similarly, insulin-stimulated DNA synthesis was more sensitive to insulin in CHO/IR cells, and more responsive in CHO/IRS-1 cells; however, insulin-stimulated DNA synthesis was sensitive but poorly responsive to insulin in CHO/IR/IRS-1 cells. |
| 109 | 1385403 | Together, these results suggest that IRS-1 is a direct physiologic substrate of the insulin receptor and may play an important role in insulin signal transmission. |
| 110 | 1385403 | Expression and function of IRS-1 in insulin signal transmission. |
| 111 | 1385403 | IRS-1 is a major insulin receptor substrate which may play an important role in insulin signal transmission. |
| 112 | 1385403 | IRS-1 was phosphorylated strongly on serine residues and weakly on threonine residues before insulin stimulation. |
| 113 | 1385403 | Insulin immediately stimulated tyrosine phosphorylation of IRS-1, and after 10-30 min with insulin its apparent molecular mass increased to 175-180 kDa. |
| 114 | 1385403 | Expression of the human insulin receptor and rat IRS-1 together in CHO/IR/IRS-1 cells increased the basal serine phosphorylation of IRS-1 and strongly increased tyrosine phosphorylation during insulin stimulation. |
| 115 | 1385403 | Purified insulin receptors directly phosphorylated baculovirus-produced IRS-1 exclusively on tyrosine residues. |
| 116 | 1385403 | By immunofluorescence, IRS-1 was absent from the nucleus, but otherwise distributed uniformly before and after insulin stimulation. |
| 117 | 1385403 | Some IRS-1 associated with the insulin receptor during insulin stimulation. |
| 118 | 1385403 | In addition, a phosphatidylinositol 3'-kinase associated with IRS-1 during insulin stimulation, and this association was more sensitive to insulin in CHO cells overexpressing the insulin receptor (CHO/IR cells), more responsive to insulin to CHO/IRS-1 cells, and both sensitive and responsive in CHO/IR/IRS-1 cells. |
| 119 | 1385403 | Similarly, insulin-stimulated DNA synthesis was more sensitive to insulin in CHO/IR cells, and more responsive in CHO/IRS-1 cells; however, insulin-stimulated DNA synthesis was sensitive but poorly responsive to insulin in CHO/IR/IRS-1 cells. |
| 120 | 1385403 | Together, these results suggest that IRS-1 is a direct physiologic substrate of the insulin receptor and may play an important role in insulin signal transmission. |
| 121 | 1385403 | Expression and function of IRS-1 in insulin signal transmission. |
| 122 | 1385403 | IRS-1 is a major insulin receptor substrate which may play an important role in insulin signal transmission. |
| 123 | 1385403 | IRS-1 was phosphorylated strongly on serine residues and weakly on threonine residues before insulin stimulation. |
| 124 | 1385403 | Insulin immediately stimulated tyrosine phosphorylation of IRS-1, and after 10-30 min with insulin its apparent molecular mass increased to 175-180 kDa. |
| 125 | 1385403 | Expression of the human insulin receptor and rat IRS-1 together in CHO/IR/IRS-1 cells increased the basal serine phosphorylation of IRS-1 and strongly increased tyrosine phosphorylation during insulin stimulation. |
| 126 | 1385403 | Purified insulin receptors directly phosphorylated baculovirus-produced IRS-1 exclusively on tyrosine residues. |
| 127 | 1385403 | By immunofluorescence, IRS-1 was absent from the nucleus, but otherwise distributed uniformly before and after insulin stimulation. |
| 128 | 1385403 | Some IRS-1 associated with the insulin receptor during insulin stimulation. |
| 129 | 1385403 | In addition, a phosphatidylinositol 3'-kinase associated with IRS-1 during insulin stimulation, and this association was more sensitive to insulin in CHO cells overexpressing the insulin receptor (CHO/IR cells), more responsive to insulin to CHO/IRS-1 cells, and both sensitive and responsive in CHO/IR/IRS-1 cells. |
| 130 | 1385403 | Similarly, insulin-stimulated DNA synthesis was more sensitive to insulin in CHO/IR cells, and more responsive in CHO/IRS-1 cells; however, insulin-stimulated DNA synthesis was sensitive but poorly responsive to insulin in CHO/IR/IRS-1 cells. |
| 131 | 1385403 | Together, these results suggest that IRS-1 is a direct physiologic substrate of the insulin receptor and may play an important role in insulin signal transmission. |
| 132 | 1385403 | Expression and function of IRS-1 in insulin signal transmission. |
| 133 | 1385403 | IRS-1 is a major insulin receptor substrate which may play an important role in insulin signal transmission. |
| 134 | 1385403 | IRS-1 was phosphorylated strongly on serine residues and weakly on threonine residues before insulin stimulation. |
| 135 | 1385403 | Insulin immediately stimulated tyrosine phosphorylation of IRS-1, and after 10-30 min with insulin its apparent molecular mass increased to 175-180 kDa. |
| 136 | 1385403 | Expression of the human insulin receptor and rat IRS-1 together in CHO/IR/IRS-1 cells increased the basal serine phosphorylation of IRS-1 and strongly increased tyrosine phosphorylation during insulin stimulation. |
| 137 | 1385403 | Purified insulin receptors directly phosphorylated baculovirus-produced IRS-1 exclusively on tyrosine residues. |
| 138 | 1385403 | By immunofluorescence, IRS-1 was absent from the nucleus, but otherwise distributed uniformly before and after insulin stimulation. |
| 139 | 1385403 | Some IRS-1 associated with the insulin receptor during insulin stimulation. |
| 140 | 1385403 | In addition, a phosphatidylinositol 3'-kinase associated with IRS-1 during insulin stimulation, and this association was more sensitive to insulin in CHO cells overexpressing the insulin receptor (CHO/IR cells), more responsive to insulin to CHO/IRS-1 cells, and both sensitive and responsive in CHO/IR/IRS-1 cells. |
| 141 | 1385403 | Similarly, insulin-stimulated DNA synthesis was more sensitive to insulin in CHO/IR cells, and more responsive in CHO/IRS-1 cells; however, insulin-stimulated DNA synthesis was sensitive but poorly responsive to insulin in CHO/IR/IRS-1 cells. |
| 142 | 1385403 | Together, these results suggest that IRS-1 is a direct physiologic substrate of the insulin receptor and may play an important role in insulin signal transmission. |
| 143 | 1385403 | Expression and function of IRS-1 in insulin signal transmission. |
| 144 | 1385403 | IRS-1 is a major insulin receptor substrate which may play an important role in insulin signal transmission. |
| 145 | 1385403 | IRS-1 was phosphorylated strongly on serine residues and weakly on threonine residues before insulin stimulation. |
| 146 | 1385403 | Insulin immediately stimulated tyrosine phosphorylation of IRS-1, and after 10-30 min with insulin its apparent molecular mass increased to 175-180 kDa. |
| 147 | 1385403 | Expression of the human insulin receptor and rat IRS-1 together in CHO/IR/IRS-1 cells increased the basal serine phosphorylation of IRS-1 and strongly increased tyrosine phosphorylation during insulin stimulation. |
| 148 | 1385403 | Purified insulin receptors directly phosphorylated baculovirus-produced IRS-1 exclusively on tyrosine residues. |
| 149 | 1385403 | By immunofluorescence, IRS-1 was absent from the nucleus, but otherwise distributed uniformly before and after insulin stimulation. |
| 150 | 1385403 | Some IRS-1 associated with the insulin receptor during insulin stimulation. |
| 151 | 1385403 | In addition, a phosphatidylinositol 3'-kinase associated with IRS-1 during insulin stimulation, and this association was more sensitive to insulin in CHO cells overexpressing the insulin receptor (CHO/IR cells), more responsive to insulin to CHO/IRS-1 cells, and both sensitive and responsive in CHO/IR/IRS-1 cells. |
| 152 | 1385403 | Similarly, insulin-stimulated DNA synthesis was more sensitive to insulin in CHO/IR cells, and more responsive in CHO/IRS-1 cells; however, insulin-stimulated DNA synthesis was sensitive but poorly responsive to insulin in CHO/IR/IRS-1 cells. |
| 153 | 1385403 | Together, these results suggest that IRS-1 is a direct physiologic substrate of the insulin receptor and may play an important role in insulin signal transmission. |
| 154 | 1385403 | Expression and function of IRS-1 in insulin signal transmission. |
| 155 | 1385403 | IRS-1 is a major insulin receptor substrate which may play an important role in insulin signal transmission. |
| 156 | 1385403 | IRS-1 was phosphorylated strongly on serine residues and weakly on threonine residues before insulin stimulation. |
| 157 | 1385403 | Insulin immediately stimulated tyrosine phosphorylation of IRS-1, and after 10-30 min with insulin its apparent molecular mass increased to 175-180 kDa. |
| 158 | 1385403 | Expression of the human insulin receptor and rat IRS-1 together in CHO/IR/IRS-1 cells increased the basal serine phosphorylation of IRS-1 and strongly increased tyrosine phosphorylation during insulin stimulation. |
| 159 | 1385403 | Purified insulin receptors directly phosphorylated baculovirus-produced IRS-1 exclusively on tyrosine residues. |
| 160 | 1385403 | By immunofluorescence, IRS-1 was absent from the nucleus, but otherwise distributed uniformly before and after insulin stimulation. |
| 161 | 1385403 | Some IRS-1 associated with the insulin receptor during insulin stimulation. |
| 162 | 1385403 | In addition, a phosphatidylinositol 3'-kinase associated with IRS-1 during insulin stimulation, and this association was more sensitive to insulin in CHO cells overexpressing the insulin receptor (CHO/IR cells), more responsive to insulin to CHO/IRS-1 cells, and both sensitive and responsive in CHO/IR/IRS-1 cells. |
| 163 | 1385403 | Similarly, insulin-stimulated DNA synthesis was more sensitive to insulin in CHO/IR cells, and more responsive in CHO/IRS-1 cells; however, insulin-stimulated DNA synthesis was sensitive but poorly responsive to insulin in CHO/IR/IRS-1 cells. |
| 164 | 1385403 | Together, these results suggest that IRS-1 is a direct physiologic substrate of the insulin receptor and may play an important role in insulin signal transmission. |
| 165 | 1385403 | Expression and function of IRS-1 in insulin signal transmission. |
| 166 | 1385403 | IRS-1 is a major insulin receptor substrate which may play an important role in insulin signal transmission. |
| 167 | 1385403 | IRS-1 was phosphorylated strongly on serine residues and weakly on threonine residues before insulin stimulation. |
| 168 | 1385403 | Insulin immediately stimulated tyrosine phosphorylation of IRS-1, and after 10-30 min with insulin its apparent molecular mass increased to 175-180 kDa. |
| 169 | 1385403 | Expression of the human insulin receptor and rat IRS-1 together in CHO/IR/IRS-1 cells increased the basal serine phosphorylation of IRS-1 and strongly increased tyrosine phosphorylation during insulin stimulation. |
| 170 | 1385403 | Purified insulin receptors directly phosphorylated baculovirus-produced IRS-1 exclusively on tyrosine residues. |
| 171 | 1385403 | By immunofluorescence, IRS-1 was absent from the nucleus, but otherwise distributed uniformly before and after insulin stimulation. |
| 172 | 1385403 | Some IRS-1 associated with the insulin receptor during insulin stimulation. |
| 173 | 1385403 | In addition, a phosphatidylinositol 3'-kinase associated with IRS-1 during insulin stimulation, and this association was more sensitive to insulin in CHO cells overexpressing the insulin receptor (CHO/IR cells), more responsive to insulin to CHO/IRS-1 cells, and both sensitive and responsive in CHO/IR/IRS-1 cells. |
| 174 | 1385403 | Similarly, insulin-stimulated DNA synthesis was more sensitive to insulin in CHO/IR cells, and more responsive in CHO/IRS-1 cells; however, insulin-stimulated DNA synthesis was sensitive but poorly responsive to insulin in CHO/IR/IRS-1 cells. |
| 175 | 1385403 | Together, these results suggest that IRS-1 is a direct physiologic substrate of the insulin receptor and may play an important role in insulin signal transmission. |
| 176 | 1385403 | Expression and function of IRS-1 in insulin signal transmission. |
| 177 | 1385403 | IRS-1 is a major insulin receptor substrate which may play an important role in insulin signal transmission. |
| 178 | 1385403 | IRS-1 was phosphorylated strongly on serine residues and weakly on threonine residues before insulin stimulation. |
| 179 | 1385403 | Insulin immediately stimulated tyrosine phosphorylation of IRS-1, and after 10-30 min with insulin its apparent molecular mass increased to 175-180 kDa. |
| 180 | 1385403 | Expression of the human insulin receptor and rat IRS-1 together in CHO/IR/IRS-1 cells increased the basal serine phosphorylation of IRS-1 and strongly increased tyrosine phosphorylation during insulin stimulation. |
| 181 | 1385403 | Purified insulin receptors directly phosphorylated baculovirus-produced IRS-1 exclusively on tyrosine residues. |
| 182 | 1385403 | By immunofluorescence, IRS-1 was absent from the nucleus, but otherwise distributed uniformly before and after insulin stimulation. |
| 183 | 1385403 | Some IRS-1 associated with the insulin receptor during insulin stimulation. |
| 184 | 1385403 | In addition, a phosphatidylinositol 3'-kinase associated with IRS-1 during insulin stimulation, and this association was more sensitive to insulin in CHO cells overexpressing the insulin receptor (CHO/IR cells), more responsive to insulin to CHO/IRS-1 cells, and both sensitive and responsive in CHO/IR/IRS-1 cells. |
| 185 | 1385403 | Similarly, insulin-stimulated DNA synthesis was more sensitive to insulin in CHO/IR cells, and more responsive in CHO/IRS-1 cells; however, insulin-stimulated DNA synthesis was sensitive but poorly responsive to insulin in CHO/IR/IRS-1 cells. |
| 186 | 1385403 | Together, these results suggest that IRS-1 is a direct physiologic substrate of the insulin receptor and may play an important role in insulin signal transmission. |
| 187 | 1385403 | Expression and function of IRS-1 in insulin signal transmission. |
| 188 | 1385403 | IRS-1 is a major insulin receptor substrate which may play an important role in insulin signal transmission. |
| 189 | 1385403 | IRS-1 was phosphorylated strongly on serine residues and weakly on threonine residues before insulin stimulation. |
| 190 | 1385403 | Insulin immediately stimulated tyrosine phosphorylation of IRS-1, and after 10-30 min with insulin its apparent molecular mass increased to 175-180 kDa. |
| 191 | 1385403 | Expression of the human insulin receptor and rat IRS-1 together in CHO/IR/IRS-1 cells increased the basal serine phosphorylation of IRS-1 and strongly increased tyrosine phosphorylation during insulin stimulation. |
| 192 | 1385403 | Purified insulin receptors directly phosphorylated baculovirus-produced IRS-1 exclusively on tyrosine residues. |
| 193 | 1385403 | By immunofluorescence, IRS-1 was absent from the nucleus, but otherwise distributed uniformly before and after insulin stimulation. |
| 194 | 1385403 | Some IRS-1 associated with the insulin receptor during insulin stimulation. |
| 195 | 1385403 | In addition, a phosphatidylinositol 3'-kinase associated with IRS-1 during insulin stimulation, and this association was more sensitive to insulin in CHO cells overexpressing the insulin receptor (CHO/IR cells), more responsive to insulin to CHO/IRS-1 cells, and both sensitive and responsive in CHO/IR/IRS-1 cells. |
| 196 | 1385403 | Similarly, insulin-stimulated DNA synthesis was more sensitive to insulin in CHO/IR cells, and more responsive in CHO/IRS-1 cells; however, insulin-stimulated DNA synthesis was sensitive but poorly responsive to insulin in CHO/IR/IRS-1 cells. |
| 197 | 1385403 | Together, these results suggest that IRS-1 is a direct physiologic substrate of the insulin receptor and may play an important role in insulin signal transmission. |
| 198 | 1385403 | Expression and function of IRS-1 in insulin signal transmission. |
| 199 | 1385403 | IRS-1 is a major insulin receptor substrate which may play an important role in insulin signal transmission. |
| 200 | 1385403 | IRS-1 was phosphorylated strongly on serine residues and weakly on threonine residues before insulin stimulation. |
| 201 | 1385403 | Insulin immediately stimulated tyrosine phosphorylation of IRS-1, and after 10-30 min with insulin its apparent molecular mass increased to 175-180 kDa. |
| 202 | 1385403 | Expression of the human insulin receptor and rat IRS-1 together in CHO/IR/IRS-1 cells increased the basal serine phosphorylation of IRS-1 and strongly increased tyrosine phosphorylation during insulin stimulation. |
| 203 | 1385403 | Purified insulin receptors directly phosphorylated baculovirus-produced IRS-1 exclusively on tyrosine residues. |
| 204 | 1385403 | By immunofluorescence, IRS-1 was absent from the nucleus, but otherwise distributed uniformly before and after insulin stimulation. |
| 205 | 1385403 | Some IRS-1 associated with the insulin receptor during insulin stimulation. |
| 206 | 1385403 | In addition, a phosphatidylinositol 3'-kinase associated with IRS-1 during insulin stimulation, and this association was more sensitive to insulin in CHO cells overexpressing the insulin receptor (CHO/IR cells), more responsive to insulin to CHO/IRS-1 cells, and both sensitive and responsive in CHO/IR/IRS-1 cells. |
| 207 | 1385403 | Similarly, insulin-stimulated DNA synthesis was more sensitive to insulin in CHO/IR cells, and more responsive in CHO/IRS-1 cells; however, insulin-stimulated DNA synthesis was sensitive but poorly responsive to insulin in CHO/IR/IRS-1 cells. |
| 208 | 1385403 | Together, these results suggest that IRS-1 is a direct physiologic substrate of the insulin receptor and may play an important role in insulin signal transmission. |
| 209 | 1385403 | Expression and function of IRS-1 in insulin signal transmission. |
| 210 | 1385403 | IRS-1 is a major insulin receptor substrate which may play an important role in insulin signal transmission. |
| 211 | 1385403 | IRS-1 was phosphorylated strongly on serine residues and weakly on threonine residues before insulin stimulation. |
| 212 | 1385403 | Insulin immediately stimulated tyrosine phosphorylation of IRS-1, and after 10-30 min with insulin its apparent molecular mass increased to 175-180 kDa. |
| 213 | 1385403 | Expression of the human insulin receptor and rat IRS-1 together in CHO/IR/IRS-1 cells increased the basal serine phosphorylation of IRS-1 and strongly increased tyrosine phosphorylation during insulin stimulation. |
| 214 | 1385403 | Purified insulin receptors directly phosphorylated baculovirus-produced IRS-1 exclusively on tyrosine residues. |
| 215 | 1385403 | By immunofluorescence, IRS-1 was absent from the nucleus, but otherwise distributed uniformly before and after insulin stimulation. |
| 216 | 1385403 | Some IRS-1 associated with the insulin receptor during insulin stimulation. |
| 217 | 1385403 | In addition, a phosphatidylinositol 3'-kinase associated with IRS-1 during insulin stimulation, and this association was more sensitive to insulin in CHO cells overexpressing the insulin receptor (CHO/IR cells), more responsive to insulin to CHO/IRS-1 cells, and both sensitive and responsive in CHO/IR/IRS-1 cells. |
| 218 | 1385403 | Similarly, insulin-stimulated DNA synthesis was more sensitive to insulin in CHO/IR cells, and more responsive in CHO/IRS-1 cells; however, insulin-stimulated DNA synthesis was sensitive but poorly responsive to insulin in CHO/IR/IRS-1 cells. |
| 219 | 1385403 | Together, these results suggest that IRS-1 is a direct physiologic substrate of the insulin receptor and may play an important role in insulin signal transmission. |
| 220 | 1457763 | Tyrosine phosphorylation of insulin receptor and of IRS-1 have been implicated in insulin signal transmission based on studies with insulin receptor mutants. |
| 221 | 1457763 | In the study presented here, the levels and phosphorylation state of the insulin receptor and IRS-1 in liver and muscle after insulin stimulation in vivo have been examined in spontaneously hypertensive rats (SHR) by immunoblotting with antipeptide antibodies to insulin receptor and IRS-1 and antiphosphotyrosine antibodies. |
| 222 | 1457763 | It was found that the levels of insulin receptor and IRS-1 protein in liver and muscle are similar in controls (Wistar-Kyoto rats) and SHR. |
| 223 | 1457763 | Tyrosine phosphorylation of insulin receptor and of IRS-1 have been implicated in insulin signal transmission based on studies with insulin receptor mutants. |
| 224 | 1457763 | In the study presented here, the levels and phosphorylation state of the insulin receptor and IRS-1 in liver and muscle after insulin stimulation in vivo have been examined in spontaneously hypertensive rats (SHR) by immunoblotting with antipeptide antibodies to insulin receptor and IRS-1 and antiphosphotyrosine antibodies. |
| 225 | 1457763 | It was found that the levels of insulin receptor and IRS-1 protein in liver and muscle are similar in controls (Wistar-Kyoto rats) and SHR. |
| 226 | 1457763 | Tyrosine phosphorylation of insulin receptor and of IRS-1 have been implicated in insulin signal transmission based on studies with insulin receptor mutants. |
| 227 | 1457763 | In the study presented here, the levels and phosphorylation state of the insulin receptor and IRS-1 in liver and muscle after insulin stimulation in vivo have been examined in spontaneously hypertensive rats (SHR) by immunoblotting with antipeptide antibodies to insulin receptor and IRS-1 and antiphosphotyrosine antibodies. |
| 228 | 1457763 | It was found that the levels of insulin receptor and IRS-1 protein in liver and muscle are similar in controls (Wistar-Kyoto rats) and SHR. |
| 229 | 1648180 | Structure of the insulin receptor substrate IRS-1 defines a unique signal transduction protein. |
| 230 | 1648180 | During insulin stimulation, the IRS-1 protein undergoes tyrosine phosphorylation and binds phosphatidylinositol 3-kinase, suggesting that IRS-1 acts as a multisite 'docking' protein to bind signal-transducing molecules containing Src-homology 2 and Src-homology-3 domains. |
| 231 | 1648180 | Thus IRS-1 may link the insulin receptor kinase and enzymes regulating cellular growth and metabolism. |
| 232 | 1648180 | Structure of the insulin receptor substrate IRS-1 defines a unique signal transduction protein. |
| 233 | 1648180 | During insulin stimulation, the IRS-1 protein undergoes tyrosine phosphorylation and binds phosphatidylinositol 3-kinase, suggesting that IRS-1 acts as a multisite 'docking' protein to bind signal-transducing molecules containing Src-homology 2 and Src-homology-3 domains. |
| 234 | 1648180 | Thus IRS-1 may link the insulin receptor kinase and enzymes regulating cellular growth and metabolism. |
| 235 | 1648180 | Structure of the insulin receptor substrate IRS-1 defines a unique signal transduction protein. |
| 236 | 1648180 | During insulin stimulation, the IRS-1 protein undergoes tyrosine phosphorylation and binds phosphatidylinositol 3-kinase, suggesting that IRS-1 acts as a multisite 'docking' protein to bind signal-transducing molecules containing Src-homology 2 and Src-homology-3 domains. |
| 237 | 1648180 | Thus IRS-1 may link the insulin receptor kinase and enzymes regulating cellular growth and metabolism. |
| 238 | 7485492 | Phosphorylated IRS-1 then interacts with the p85 alpha subunit of phosphatidylinositol 3-kinase (PI3K), Nck, growth factor receptor-bound protein 2 (GRB2), and Syp, thus branching insulin's signal for both mitogenic and metabolic responses. |
| 239 | 7485492 | IR and PI3K p85 alpha protein levels were significantly lower in KKAy mice than in control nondiabetic mice, whereas IRS-1 protein levels were not altered. |
| 240 | 7485492 | In contrast, the protein levels of GRB2, Nck, Syp, and GLUT-1 were dramatically elevated in KKAy fat, with less striking changes in liver. |
| 241 | 7485492 | Phosphorylated IRS-1 then interacts with the p85 alpha subunit of phosphatidylinositol 3-kinase (PI3K), Nck, growth factor receptor-bound protein 2 (GRB2), and Syp, thus branching insulin's signal for both mitogenic and metabolic responses. |
| 242 | 7485492 | IR and PI3K p85 alpha protein levels were significantly lower in KKAy mice than in control nondiabetic mice, whereas IRS-1 protein levels were not altered. |
| 243 | 7485492 | In contrast, the protein levels of GRB2, Nck, Syp, and GLUT-1 were dramatically elevated in KKAy fat, with less striking changes in liver. |
| 244 | 7486683 | Autophosphorylation sites in the PDGFr directly bind SH2 proteins, whereas activation of the insulin receptor leads to phosphorylation of IRS-1, which in turn binds SH2 proteins. |
| 245 | 7486683 | In HIR 3.5 cells, which contain similar numbers of PDGF and insulin receptors, insulin, but not PDGF, stimulated tyrosyl phosphorylation of IRS-1. |
| 246 | 7486683 | Similarly, insulin, but not PDGF, treatment of HIR 3.5 stimulated the association of IRS-1 with PtdIns 3'-kinase, although PDGF stimulated the association of PtdIns 3'-kinase with the tyrosine-phosphorylated PDGFr. |
| 247 | 7486683 | Whereas the PDGFr associated with PtdIns 3'-kinase, ras-GAP, GRB-2, and phospholipase C gamma, only GRB-2 and PtdIns 3'-kinase associated with IRS-1. |
| 248 | 7486683 | Moreover, PDGF, but not insulin, caused tyrosine phosphorylation of phospholipase C gamma in HIR 3.5 cells. |
| 249 | 7486683 | Thus, the insulin signal differs from that of PDGF by the insertion of a cytosolic, nonreceptor SH2 domain docking protein (IRS-1). |
| 250 | 7486683 | These results support the hypothesis that IRS-1 differentiates the signals generated by the insulin receptor and PDGFr tyrosine kinases by binding and regulating a specific subset of SH2 domain-containing signaling molecules. |
| 251 | 7486683 | Autophosphorylation sites in the PDGFr directly bind SH2 proteins, whereas activation of the insulin receptor leads to phosphorylation of IRS-1, which in turn binds SH2 proteins. |
| 252 | 7486683 | In HIR 3.5 cells, which contain similar numbers of PDGF and insulin receptors, insulin, but not PDGF, stimulated tyrosyl phosphorylation of IRS-1. |
| 253 | 7486683 | Similarly, insulin, but not PDGF, treatment of HIR 3.5 stimulated the association of IRS-1 with PtdIns 3'-kinase, although PDGF stimulated the association of PtdIns 3'-kinase with the tyrosine-phosphorylated PDGFr. |
| 254 | 7486683 | Whereas the PDGFr associated with PtdIns 3'-kinase, ras-GAP, GRB-2, and phospholipase C gamma, only GRB-2 and PtdIns 3'-kinase associated with IRS-1. |
| 255 | 7486683 | Moreover, PDGF, but not insulin, caused tyrosine phosphorylation of phospholipase C gamma in HIR 3.5 cells. |
| 256 | 7486683 | Thus, the insulin signal differs from that of PDGF by the insertion of a cytosolic, nonreceptor SH2 domain docking protein (IRS-1). |
| 257 | 7486683 | These results support the hypothesis that IRS-1 differentiates the signals generated by the insulin receptor and PDGFr tyrosine kinases by binding and regulating a specific subset of SH2 domain-containing signaling molecules. |
| 258 | 7486683 | Autophosphorylation sites in the PDGFr directly bind SH2 proteins, whereas activation of the insulin receptor leads to phosphorylation of IRS-1, which in turn binds SH2 proteins. |
| 259 | 7486683 | In HIR 3.5 cells, which contain similar numbers of PDGF and insulin receptors, insulin, but not PDGF, stimulated tyrosyl phosphorylation of IRS-1. |
| 260 | 7486683 | Similarly, insulin, but not PDGF, treatment of HIR 3.5 stimulated the association of IRS-1 with PtdIns 3'-kinase, although PDGF stimulated the association of PtdIns 3'-kinase with the tyrosine-phosphorylated PDGFr. |
| 261 | 7486683 | Whereas the PDGFr associated with PtdIns 3'-kinase, ras-GAP, GRB-2, and phospholipase C gamma, only GRB-2 and PtdIns 3'-kinase associated with IRS-1. |
| 262 | 7486683 | Moreover, PDGF, but not insulin, caused tyrosine phosphorylation of phospholipase C gamma in HIR 3.5 cells. |
| 263 | 7486683 | Thus, the insulin signal differs from that of PDGF by the insertion of a cytosolic, nonreceptor SH2 domain docking protein (IRS-1). |
| 264 | 7486683 | These results support the hypothesis that IRS-1 differentiates the signals generated by the insulin receptor and PDGFr tyrosine kinases by binding and regulating a specific subset of SH2 domain-containing signaling molecules. |
| 265 | 7486683 | Autophosphorylation sites in the PDGFr directly bind SH2 proteins, whereas activation of the insulin receptor leads to phosphorylation of IRS-1, which in turn binds SH2 proteins. |
| 266 | 7486683 | In HIR 3.5 cells, which contain similar numbers of PDGF and insulin receptors, insulin, but not PDGF, stimulated tyrosyl phosphorylation of IRS-1. |
| 267 | 7486683 | Similarly, insulin, but not PDGF, treatment of HIR 3.5 stimulated the association of IRS-1 with PtdIns 3'-kinase, although PDGF stimulated the association of PtdIns 3'-kinase with the tyrosine-phosphorylated PDGFr. |
| 268 | 7486683 | Whereas the PDGFr associated with PtdIns 3'-kinase, ras-GAP, GRB-2, and phospholipase C gamma, only GRB-2 and PtdIns 3'-kinase associated with IRS-1. |
| 269 | 7486683 | Moreover, PDGF, but not insulin, caused tyrosine phosphorylation of phospholipase C gamma in HIR 3.5 cells. |
| 270 | 7486683 | Thus, the insulin signal differs from that of PDGF by the insertion of a cytosolic, nonreceptor SH2 domain docking protein (IRS-1). |
| 271 | 7486683 | These results support the hypothesis that IRS-1 differentiates the signals generated by the insulin receptor and PDGFr tyrosine kinases by binding and regulating a specific subset of SH2 domain-containing signaling molecules. |
| 272 | 7486683 | Autophosphorylation sites in the PDGFr directly bind SH2 proteins, whereas activation of the insulin receptor leads to phosphorylation of IRS-1, which in turn binds SH2 proteins. |
| 273 | 7486683 | In HIR 3.5 cells, which contain similar numbers of PDGF and insulin receptors, insulin, but not PDGF, stimulated tyrosyl phosphorylation of IRS-1. |
| 274 | 7486683 | Similarly, insulin, but not PDGF, treatment of HIR 3.5 stimulated the association of IRS-1 with PtdIns 3'-kinase, although PDGF stimulated the association of PtdIns 3'-kinase with the tyrosine-phosphorylated PDGFr. |
| 275 | 7486683 | Whereas the PDGFr associated with PtdIns 3'-kinase, ras-GAP, GRB-2, and phospholipase C gamma, only GRB-2 and PtdIns 3'-kinase associated with IRS-1. |
| 276 | 7486683 | Moreover, PDGF, but not insulin, caused tyrosine phosphorylation of phospholipase C gamma in HIR 3.5 cells. |
| 277 | 7486683 | Thus, the insulin signal differs from that of PDGF by the insertion of a cytosolic, nonreceptor SH2 domain docking protein (IRS-1). |
| 278 | 7486683 | These results support the hypothesis that IRS-1 differentiates the signals generated by the insulin receptor and PDGFr tyrosine kinases by binding and regulating a specific subset of SH2 domain-containing signaling molecules. |
| 279 | 7486683 | Autophosphorylation sites in the PDGFr directly bind SH2 proteins, whereas activation of the insulin receptor leads to phosphorylation of IRS-1, which in turn binds SH2 proteins. |
| 280 | 7486683 | In HIR 3.5 cells, which contain similar numbers of PDGF and insulin receptors, insulin, but not PDGF, stimulated tyrosyl phosphorylation of IRS-1. |
| 281 | 7486683 | Similarly, insulin, but not PDGF, treatment of HIR 3.5 stimulated the association of IRS-1 with PtdIns 3'-kinase, although PDGF stimulated the association of PtdIns 3'-kinase with the tyrosine-phosphorylated PDGFr. |
| 282 | 7486683 | Whereas the PDGFr associated with PtdIns 3'-kinase, ras-GAP, GRB-2, and phospholipase C gamma, only GRB-2 and PtdIns 3'-kinase associated with IRS-1. |
| 283 | 7486683 | Moreover, PDGF, but not insulin, caused tyrosine phosphorylation of phospholipase C gamma in HIR 3.5 cells. |
| 284 | 7486683 | Thus, the insulin signal differs from that of PDGF by the insertion of a cytosolic, nonreceptor SH2 domain docking protein (IRS-1). |
| 285 | 7486683 | These results support the hypothesis that IRS-1 differentiates the signals generated by the insulin receptor and PDGFr tyrosine kinases by binding and regulating a specific subset of SH2 domain-containing signaling molecules. |
| 286 | 7493944 | The role of the tyrosine kinase domain of the insulin-like growth factor-I receptor in intracellular signaling, cellular proliferation, and tumorigenesis. |
| 287 | 7493944 | Insulin and insulin-like growth factor (IGF-I) receptors are heterotetrameric proteins consisting of two alpha-and two beta-subunits and members of the transmembrane tyrosine kinase receptors. |
| 288 | 7493944 | Previous studies have shown that substitutions of these three tyrosines by phenylalanines of both insulin and IGF-I receptors practically abolish any activation of cellular signaling pathways. |
| 289 | 7493944 | We have studied the effect of double tyrosine mutations on IGF-I induced receptor autophosphorylation, activation of Shc and IRS-1 pathways, and cell proliferation and tumorigenicity. |
| 290 | 7493944 | Nevertheless, all the cells expressing IGF-I receptors with double tyrosine substitutions demonstrated markedly reduced signaling through Shc and IRS-1 pathways. |
| 291 | 7493944 | The role of the tyrosine kinase domain of the insulin-like growth factor-I receptor in intracellular signaling, cellular proliferation, and tumorigenesis. |
| 292 | 7493944 | Insulin and insulin-like growth factor (IGF-I) receptors are heterotetrameric proteins consisting of two alpha-and two beta-subunits and members of the transmembrane tyrosine kinase receptors. |
| 293 | 7493944 | Previous studies have shown that substitutions of these three tyrosines by phenylalanines of both insulin and IGF-I receptors practically abolish any activation of cellular signaling pathways. |
| 294 | 7493944 | We have studied the effect of double tyrosine mutations on IGF-I induced receptor autophosphorylation, activation of Shc and IRS-1 pathways, and cell proliferation and tumorigenicity. |
| 295 | 7493944 | Nevertheless, all the cells expressing IGF-I receptors with double tyrosine substitutions demonstrated markedly reduced signaling through Shc and IRS-1 pathways. |
| 296 | 7499194 | PTB domains of IRS-1 and Shc have distinct but overlapping binding specificities. |
| 297 | 7499194 | By serial truncation, we show that a 174-residue region of Shc p52 (33-206) has full PTB activity. |
| 298 | 7499194 | Phosphopeptide assays developed to compare PTB domain specificities show that the Shc PTB domain binds with highest affinity to psi XN beta 1 beta 2 pY motifs derived from middle T (mT), TrkA, ErbB4, or epidermal growth factor receptors (psi = hydrophobic, beta = beta-turn forming); the IRS-1 PTB domain does not bind with this motif. |
| 299 | 7499194 | In contrast, both the Shc and IRS-1 PTB domains bind psi psi psi XXN beta 1 beta 2pY sequences derived from insulin and interleukin 4 receptors, although specificities vary in detail. |
| 300 | 7499194 | Shc and IRS-1 are phosphorylated by distinct but overlapping sets of receptor-linked tyrosine kinases. |
| 301 | 7499194 | PTB domains of IRS-1 and Shc have distinct but overlapping binding specificities. |
| 302 | 7499194 | By serial truncation, we show that a 174-residue region of Shc p52 (33-206) has full PTB activity. |
| 303 | 7499194 | Phosphopeptide assays developed to compare PTB domain specificities show that the Shc PTB domain binds with highest affinity to psi XN beta 1 beta 2 pY motifs derived from middle T (mT), TrkA, ErbB4, or epidermal growth factor receptors (psi = hydrophobic, beta = beta-turn forming); the IRS-1 PTB domain does not bind with this motif. |
| 304 | 7499194 | In contrast, both the Shc and IRS-1 PTB domains bind psi psi psi XXN beta 1 beta 2pY sequences derived from insulin and interleukin 4 receptors, although specificities vary in detail. |
| 305 | 7499194 | Shc and IRS-1 are phosphorylated by distinct but overlapping sets of receptor-linked tyrosine kinases. |
| 306 | 7499194 | PTB domains of IRS-1 and Shc have distinct but overlapping binding specificities. |
| 307 | 7499194 | By serial truncation, we show that a 174-residue region of Shc p52 (33-206) has full PTB activity. |
| 308 | 7499194 | Phosphopeptide assays developed to compare PTB domain specificities show that the Shc PTB domain binds with highest affinity to psi XN beta 1 beta 2 pY motifs derived from middle T (mT), TrkA, ErbB4, or epidermal growth factor receptors (psi = hydrophobic, beta = beta-turn forming); the IRS-1 PTB domain does not bind with this motif. |
| 309 | 7499194 | In contrast, both the Shc and IRS-1 PTB domains bind psi psi psi XXN beta 1 beta 2pY sequences derived from insulin and interleukin 4 receptors, although specificities vary in detail. |
| 310 | 7499194 | Shc and IRS-1 are phosphorylated by distinct but overlapping sets of receptor-linked tyrosine kinases. |
| 311 | 7499194 | PTB domains of IRS-1 and Shc have distinct but overlapping binding specificities. |
| 312 | 7499194 | By serial truncation, we show that a 174-residue region of Shc p52 (33-206) has full PTB activity. |
| 313 | 7499194 | Phosphopeptide assays developed to compare PTB domain specificities show that the Shc PTB domain binds with highest affinity to psi XN beta 1 beta 2 pY motifs derived from middle T (mT), TrkA, ErbB4, or epidermal growth factor receptors (psi = hydrophobic, beta = beta-turn forming); the IRS-1 PTB domain does not bind with this motif. |
| 314 | 7499194 | In contrast, both the Shc and IRS-1 PTB domains bind psi psi psi XXN beta 1 beta 2pY sequences derived from insulin and interleukin 4 receptors, although specificities vary in detail. |
| 315 | 7499194 | Shc and IRS-1 are phosphorylated by distinct but overlapping sets of receptor-linked tyrosine kinases. |
| 316 | 7504175 | Pleiotropic insulin signals are engaged by multisite phosphorylation of IRS-1. |
| 317 | 7504175 | Tyrosine-phosphorylated IRS-1 binds specifically to various cellular proteins containing Src homology 2 (SH2) domains (SH2 proteins). |
| 318 | 7504175 | We identified some of the tyrosine residues of IRS-1 that undergo insulin-stimulated phosphorylation by the purified insulin receptor and in intact cells during insulin stimulation. |
| 319 | 7504175 | These results extend the notion that IRS-1 is a multisite docking protein that engages various downstream regulatory elements during insulin signal transmission. |
| 320 | 7504175 | Pleiotropic insulin signals are engaged by multisite phosphorylation of IRS-1. |
| 321 | 7504175 | Tyrosine-phosphorylated IRS-1 binds specifically to various cellular proteins containing Src homology 2 (SH2) domains (SH2 proteins). |
| 322 | 7504175 | We identified some of the tyrosine residues of IRS-1 that undergo insulin-stimulated phosphorylation by the purified insulin receptor and in intact cells during insulin stimulation. |
| 323 | 7504175 | These results extend the notion that IRS-1 is a multisite docking protein that engages various downstream regulatory elements during insulin signal transmission. |
| 324 | 7504175 | Pleiotropic insulin signals are engaged by multisite phosphorylation of IRS-1. |
| 325 | 7504175 | Tyrosine-phosphorylated IRS-1 binds specifically to various cellular proteins containing Src homology 2 (SH2) domains (SH2 proteins). |
| 326 | 7504175 | We identified some of the tyrosine residues of IRS-1 that undergo insulin-stimulated phosphorylation by the purified insulin receptor and in intact cells during insulin stimulation. |
| 327 | 7504175 | These results extend the notion that IRS-1 is a multisite docking protein that engages various downstream regulatory elements during insulin signal transmission. |
| 328 | 7504175 | Pleiotropic insulin signals are engaged by multisite phosphorylation of IRS-1. |
| 329 | 7504175 | Tyrosine-phosphorylated IRS-1 binds specifically to various cellular proteins containing Src homology 2 (SH2) domains (SH2 proteins). |
| 330 | 7504175 | We identified some of the tyrosine residues of IRS-1 that undergo insulin-stimulated phosphorylation by the purified insulin receptor and in intact cells during insulin stimulation. |
| 331 | 7504175 | These results extend the notion that IRS-1 is a multisite docking protein that engages various downstream regulatory elements during insulin signal transmission. |
| 332 | 7505252 | In cell culture and in vitro, phosphorylated IRS-1 associates with the lipid-metabolizing enzyme phosphatidylinositol 3-kinase (PI 3-kinase), resulting in activation of this enzyme. |
| 333 | 7505252 | Thus, the insulin receptor, IRS-1 and PI-3 kinase represent three of the earliest steps in insulin action at the cellular level. |
| 334 | 7505252 | We have recently demonstrated that insulin is capable of stimulating PI 3-kinase activity in liver and muscle in vivo in animals and that IRS-1 phosphorylation may play a significant role in the association/activation with PI 3-kinase in vivo. |
| 335 | 7505252 | In cell culture and in vitro, phosphorylated IRS-1 associates with the lipid-metabolizing enzyme phosphatidylinositol 3-kinase (PI 3-kinase), resulting in activation of this enzyme. |
| 336 | 7505252 | Thus, the insulin receptor, IRS-1 and PI-3 kinase represent three of the earliest steps in insulin action at the cellular level. |
| 337 | 7505252 | We have recently demonstrated that insulin is capable of stimulating PI 3-kinase activity in liver and muscle in vivo in animals and that IRS-1 phosphorylation may play a significant role in the association/activation with PI 3-kinase in vivo. |
| 338 | 7505252 | In cell culture and in vitro, phosphorylated IRS-1 associates with the lipid-metabolizing enzyme phosphatidylinositol 3-kinase (PI 3-kinase), resulting in activation of this enzyme. |
| 339 | 7505252 | Thus, the insulin receptor, IRS-1 and PI-3 kinase represent three of the earliest steps in insulin action at the cellular level. |
| 340 | 7505252 | We have recently demonstrated that insulin is capable of stimulating PI 3-kinase activity in liver and muscle in vivo in animals and that IRS-1 phosphorylation may play a significant role in the association/activation with PI 3-kinase in vivo. |
| 341 | 7508874 | Maturity-onset diabetes of the young (MODY) is a model for genetic studies of non-insulin-dependent diabetes mellitus. |
| 342 | 7508874 | We have identified 15 MODY families in which diabetes is not the result of mutations in the glucokinase gene. |
| 343 | 7508874 | Nine other candidate genes potentially implicated in insulin secretion or insulin action have been tested for linkage with MODY in these families, including glucokinase regulatory protein, hexokinase II, insulin receptor substrate 1, fatty acid-binding protein 2, glucagon-like peptide-1 receptor, apolipoprotein C-II, glycogen synthase, adenosine deaminase (a marker for the MODY gene on chromosome 20), and phosphoenolpyruvate carboxykinase. |
| 344 | 7510688 | Two alternatively spliced forms of the human insulin-like growth factor I receptor have distinct biological activities and internalization kinetics. |
| 345 | 7510688 | Two alternatively spliced human insulin-like growth factor I (IGF I) receptor mRNA transcripts have been described that differ by three nucleotides (CAG) starting at position 2829. |
| 346 | 7510688 | The two receptors bound IGF I with similar affinity (Kd approximately 1.7 nM), but the CAG- form exhibited an approximately 2-fold increase in IGF I stimulation of receptor autophosphorylation, insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation, thymidine incorporation, and IRS-1-associated phosphatidylinositol 3-kinase activity. |
| 347 | 7520127 | Regulation of insulin receptor, insulin receptor substrate-1 and phosphatidylinositol 3-kinase in 3T3-F442A adipocytes. |
| 348 | 7520127 | Insulin rapidly stimulates tyrosine kinase activity of its receptor resulting in phosphorylation of its cytosolic substrate insulin receptor substrate 1 (IRS-1), which in turn associates with and activates the enzyme phosphatidylinositol 3-kinase (PI 3-kinase). |
| 349 | 7520127 | The differentiation of 3T3-F442A cells was characterized by a 13-fold increase in insulin receptor protein, a 9-fold increase in IRS-1, and a 10- and 4.5-fold increase in their insulin-stimulated phosphorylation, respectively. |
| 350 | 7520127 | The expression of insulin receptor mRNA was unchanged, but the expression of IRS-1 mRNA was decreased by approximately 75% after dexamethasone. |
| 351 | 7520127 | Chronic treatment with 100 nM insulin induced a time- and dose-dependent decrease in insulin receptor and IRS-1 protein levels reaching a nadir of 34 +/- 5% (P < 0.005) and 39 +/- 5% (P < 0.01) of control levels after 24 h, respectively. |
| 352 | 7520127 | Chronic insulin treatment also produced a 30% decrease in PI 3-kinase protein levels and a approximately 50% decrease in the association/activation between IRS-1/PI 3-kinase. |
| 353 | 7520127 | The expression of insulin receptor and IRS-1 mRNA was unchanged during chronic insulin treatment. |
| 354 | 7520127 | Regulation of insulin receptor, insulin receptor substrate-1 and phosphatidylinositol 3-kinase in 3T3-F442A adipocytes. |
| 355 | 7520127 | Insulin rapidly stimulates tyrosine kinase activity of its receptor resulting in phosphorylation of its cytosolic substrate insulin receptor substrate 1 (IRS-1), which in turn associates with and activates the enzyme phosphatidylinositol 3-kinase (PI 3-kinase). |
| 356 | 7520127 | The differentiation of 3T3-F442A cells was characterized by a 13-fold increase in insulin receptor protein, a 9-fold increase in IRS-1, and a 10- and 4.5-fold increase in their insulin-stimulated phosphorylation, respectively. |
| 357 | 7520127 | The expression of insulin receptor mRNA was unchanged, but the expression of IRS-1 mRNA was decreased by approximately 75% after dexamethasone. |
| 358 | 7520127 | Chronic treatment with 100 nM insulin induced a time- and dose-dependent decrease in insulin receptor and IRS-1 protein levels reaching a nadir of 34 +/- 5% (P < 0.005) and 39 +/- 5% (P < 0.01) of control levels after 24 h, respectively. |
| 359 | 7520127 | Chronic insulin treatment also produced a 30% decrease in PI 3-kinase protein levels and a approximately 50% decrease in the association/activation between IRS-1/PI 3-kinase. |
| 360 | 7520127 | The expression of insulin receptor and IRS-1 mRNA was unchanged during chronic insulin treatment. |
| 361 | 7520127 | Regulation of insulin receptor, insulin receptor substrate-1 and phosphatidylinositol 3-kinase in 3T3-F442A adipocytes. |
| 362 | 7520127 | Insulin rapidly stimulates tyrosine kinase activity of its receptor resulting in phosphorylation of its cytosolic substrate insulin receptor substrate 1 (IRS-1), which in turn associates with and activates the enzyme phosphatidylinositol 3-kinase (PI 3-kinase). |
| 363 | 7520127 | The differentiation of 3T3-F442A cells was characterized by a 13-fold increase in insulin receptor protein, a 9-fold increase in IRS-1, and a 10- and 4.5-fold increase in their insulin-stimulated phosphorylation, respectively. |
| 364 | 7520127 | The expression of insulin receptor mRNA was unchanged, but the expression of IRS-1 mRNA was decreased by approximately 75% after dexamethasone. |
| 365 | 7520127 | Chronic treatment with 100 nM insulin induced a time- and dose-dependent decrease in insulin receptor and IRS-1 protein levels reaching a nadir of 34 +/- 5% (P < 0.005) and 39 +/- 5% (P < 0.01) of control levels after 24 h, respectively. |
| 366 | 7520127 | Chronic insulin treatment also produced a 30% decrease in PI 3-kinase protein levels and a approximately 50% decrease in the association/activation between IRS-1/PI 3-kinase. |
| 367 | 7520127 | The expression of insulin receptor and IRS-1 mRNA was unchanged during chronic insulin treatment. |
| 368 | 7520127 | Regulation of insulin receptor, insulin receptor substrate-1 and phosphatidylinositol 3-kinase in 3T3-F442A adipocytes. |
| 369 | 7520127 | Insulin rapidly stimulates tyrosine kinase activity of its receptor resulting in phosphorylation of its cytosolic substrate insulin receptor substrate 1 (IRS-1), which in turn associates with and activates the enzyme phosphatidylinositol 3-kinase (PI 3-kinase). |
| 370 | 7520127 | The differentiation of 3T3-F442A cells was characterized by a 13-fold increase in insulin receptor protein, a 9-fold increase in IRS-1, and a 10- and 4.5-fold increase in their insulin-stimulated phosphorylation, respectively. |
| 371 | 7520127 | The expression of insulin receptor mRNA was unchanged, but the expression of IRS-1 mRNA was decreased by approximately 75% after dexamethasone. |
| 372 | 7520127 | Chronic treatment with 100 nM insulin induced a time- and dose-dependent decrease in insulin receptor and IRS-1 protein levels reaching a nadir of 34 +/- 5% (P < 0.005) and 39 +/- 5% (P < 0.01) of control levels after 24 h, respectively. |
| 373 | 7520127 | Chronic insulin treatment also produced a 30% decrease in PI 3-kinase protein levels and a approximately 50% decrease in the association/activation between IRS-1/PI 3-kinase. |
| 374 | 7520127 | The expression of insulin receptor and IRS-1 mRNA was unchanged during chronic insulin treatment. |
| 375 | 7520127 | Regulation of insulin receptor, insulin receptor substrate-1 and phosphatidylinositol 3-kinase in 3T3-F442A adipocytes. |
| 376 | 7520127 | Insulin rapidly stimulates tyrosine kinase activity of its receptor resulting in phosphorylation of its cytosolic substrate insulin receptor substrate 1 (IRS-1), which in turn associates with and activates the enzyme phosphatidylinositol 3-kinase (PI 3-kinase). |
| 377 | 7520127 | The differentiation of 3T3-F442A cells was characterized by a 13-fold increase in insulin receptor protein, a 9-fold increase in IRS-1, and a 10- and 4.5-fold increase in their insulin-stimulated phosphorylation, respectively. |
| 378 | 7520127 | The expression of insulin receptor mRNA was unchanged, but the expression of IRS-1 mRNA was decreased by approximately 75% after dexamethasone. |
| 379 | 7520127 | Chronic treatment with 100 nM insulin induced a time- and dose-dependent decrease in insulin receptor and IRS-1 protein levels reaching a nadir of 34 +/- 5% (P < 0.005) and 39 +/- 5% (P < 0.01) of control levels after 24 h, respectively. |
| 380 | 7520127 | Chronic insulin treatment also produced a 30% decrease in PI 3-kinase protein levels and a approximately 50% decrease in the association/activation between IRS-1/PI 3-kinase. |
| 381 | 7520127 | The expression of insulin receptor and IRS-1 mRNA was unchanged during chronic insulin treatment. |
| 382 | 7520127 | Regulation of insulin receptor, insulin receptor substrate-1 and phosphatidylinositol 3-kinase in 3T3-F442A adipocytes. |
| 383 | 7520127 | Insulin rapidly stimulates tyrosine kinase activity of its receptor resulting in phosphorylation of its cytosolic substrate insulin receptor substrate 1 (IRS-1), which in turn associates with and activates the enzyme phosphatidylinositol 3-kinase (PI 3-kinase). |
| 384 | 7520127 | The differentiation of 3T3-F442A cells was characterized by a 13-fold increase in insulin receptor protein, a 9-fold increase in IRS-1, and a 10- and 4.5-fold increase in their insulin-stimulated phosphorylation, respectively. |
| 385 | 7520127 | The expression of insulin receptor mRNA was unchanged, but the expression of IRS-1 mRNA was decreased by approximately 75% after dexamethasone. |
| 386 | 7520127 | Chronic treatment with 100 nM insulin induced a time- and dose-dependent decrease in insulin receptor and IRS-1 protein levels reaching a nadir of 34 +/- 5% (P < 0.005) and 39 +/- 5% (P < 0.01) of control levels after 24 h, respectively. |
| 387 | 7520127 | Chronic insulin treatment also produced a 30% decrease in PI 3-kinase protein levels and a approximately 50% decrease in the association/activation between IRS-1/PI 3-kinase. |
| 388 | 7520127 | The expression of insulin receptor and IRS-1 mRNA was unchanged during chronic insulin treatment. |
| 389 | 7520127 | Regulation of insulin receptor, insulin receptor substrate-1 and phosphatidylinositol 3-kinase in 3T3-F442A adipocytes. |
| 390 | 7520127 | Insulin rapidly stimulates tyrosine kinase activity of its receptor resulting in phosphorylation of its cytosolic substrate insulin receptor substrate 1 (IRS-1), which in turn associates with and activates the enzyme phosphatidylinositol 3-kinase (PI 3-kinase). |
| 391 | 7520127 | The differentiation of 3T3-F442A cells was characterized by a 13-fold increase in insulin receptor protein, a 9-fold increase in IRS-1, and a 10- and 4.5-fold increase in their insulin-stimulated phosphorylation, respectively. |
| 392 | 7520127 | The expression of insulin receptor mRNA was unchanged, but the expression of IRS-1 mRNA was decreased by approximately 75% after dexamethasone. |
| 393 | 7520127 | Chronic treatment with 100 nM insulin induced a time- and dose-dependent decrease in insulin receptor and IRS-1 protein levels reaching a nadir of 34 +/- 5% (P < 0.005) and 39 +/- 5% (P < 0.01) of control levels after 24 h, respectively. |
| 394 | 7520127 | Chronic insulin treatment also produced a 30% decrease in PI 3-kinase protein levels and a approximately 50% decrease in the association/activation between IRS-1/PI 3-kinase. |
| 395 | 7520127 | The expression of insulin receptor and IRS-1 mRNA was unchanged during chronic insulin treatment. |
| 396 | 7523453 | We have previously demonstrated that tumor necrosis factor-alpha produced by adipose tissue is a key mediator of insulin resistance in animal models of obesity-diabetes. |
| 397 | 7523453 | However, the mechanism by which TNF-alpha interferes with insulin action is not known. |
| 398 | 7523453 | Since a defective insulin receptor (IR) tyrosine kinase activity has been observed in obesity and NIDDM, we measured the IR tyrosine kinase activity in the Zucker (fa/fa) rat model of obesity and insulin resistance after neutralizing TNF-alpha with a soluble TNF receptor (TNFR)-lgG fusion protein. |
| 399 | 7523453 | This neutralization resulted in a marked increase in insulin-stimulated autophosphorylation of the IR, as well as phosphorylation of insulin receptor substrate 1 (IRS-1) in muscle and fat tissues of the fa/fa rats, restoring them to near control (lean) levels. |
| 400 | 7523453 | In contrast, no significant changes were observed in insulin-stimulated tyrosine phosphorylations of IR and IRS-1 in liver. |
| 401 | 7523453 | These results demonstrate that TNF-alpha participates in obesity-related systemic insulin resistance by inhibiting the IR tyrosine kinase in the two tissues mainly responsible for insulin-stimulated glucose uptake: muscle and fat. |
| 402 | 7523453 | We have previously demonstrated that tumor necrosis factor-alpha produced by adipose tissue is a key mediator of insulin resistance in animal models of obesity-diabetes. |
| 403 | 7523453 | However, the mechanism by which TNF-alpha interferes with insulin action is not known. |
| 404 | 7523453 | Since a defective insulin receptor (IR) tyrosine kinase activity has been observed in obesity and NIDDM, we measured the IR tyrosine kinase activity in the Zucker (fa/fa) rat model of obesity and insulin resistance after neutralizing TNF-alpha with a soluble TNF receptor (TNFR)-lgG fusion protein. |
| 405 | 7523453 | This neutralization resulted in a marked increase in insulin-stimulated autophosphorylation of the IR, as well as phosphorylation of insulin receptor substrate 1 (IRS-1) in muscle and fat tissues of the fa/fa rats, restoring them to near control (lean) levels. |
| 406 | 7523453 | In contrast, no significant changes were observed in insulin-stimulated tyrosine phosphorylations of IR and IRS-1 in liver. |
| 407 | 7523453 | These results demonstrate that TNF-alpha participates in obesity-related systemic insulin resistance by inhibiting the IR tyrosine kinase in the two tissues mainly responsible for insulin-stimulated glucose uptake: muscle and fat. |
| 408 | 7525562 | In addition, we demonstrate the association of the phosphorylated Leu323 mutant receptor with insulin receptor substrate-1 and with phosphatidylinositol 3-kinase. |
| 409 | 7525562 | These findings indicate that insulin binding is not required for phosphorylation of the Leu323 mutant receptor, that the phosphorylation of the Leu323 mutant receptor occurs by an intermolecular transphosphorylation mechanism, and, finally, that the Leu323 mutant receptor, once phosphorylated, can associate with insulin receptor substrate-1 and phosphatidylinositol 3-kinase. |
| 410 | 7525562 | In addition, we demonstrate the association of the phosphorylated Leu323 mutant receptor with insulin receptor substrate-1 and with phosphatidylinositol 3-kinase. |
| 411 | 7525562 | These findings indicate that insulin binding is not required for phosphorylation of the Leu323 mutant receptor, that the phosphorylation of the Leu323 mutant receptor occurs by an intermolecular transphosphorylation mechanism, and, finally, that the Leu323 mutant receptor, once phosphorylated, can associate with insulin receptor substrate-1 and phosphatidylinositol 3-kinase. |
| 412 | 7525563 | Insulin receptor substrate 1 mediates the stimulatory effect of insulin on GLUT4 translocation in transfected rat adipose cells. |
| 413 | 7525563 | We have now investigated the possible role of IRS-1 in mediating the effect of insulin to stimulate glucose transport in a physiologically relevant insulin target tissue. |
| 414 | 7525563 | Expression of the ribozyme in these cells caused a 4.4-fold increase in the concentration of insulin required to achieve half-maximal stimulation of the translocation of cotransfected epitope-tagged GLUT4 without changing the maximal insulin response. |
| 415 | 7525563 | Overexpression of human IRS-1 increased the basal cell surface GLUT4 to nearly the maximal level in the absence of insulin. |
| 416 | 7525563 | When the ribozyme (specific to rat IRS-1) was cotransfected along with human IRS-1, the insulin dose-response curve was shifted to the left when compared with cells transfected with the ribozyme alone. |
| 417 | 7525563 | These data provide strong support for the hypothesis that IRS-1 plays a role in insulin-stimulated glucose transport in insulin-responsive cells. |
| 418 | 7525563 | Insulin receptor substrate 1 mediates the stimulatory effect of insulin on GLUT4 translocation in transfected rat adipose cells. |
| 419 | 7525563 | We have now investigated the possible role of IRS-1 in mediating the effect of insulin to stimulate glucose transport in a physiologically relevant insulin target tissue. |
| 420 | 7525563 | Expression of the ribozyme in these cells caused a 4.4-fold increase in the concentration of insulin required to achieve half-maximal stimulation of the translocation of cotransfected epitope-tagged GLUT4 without changing the maximal insulin response. |
| 421 | 7525563 | Overexpression of human IRS-1 increased the basal cell surface GLUT4 to nearly the maximal level in the absence of insulin. |
| 422 | 7525563 | When the ribozyme (specific to rat IRS-1) was cotransfected along with human IRS-1, the insulin dose-response curve was shifted to the left when compared with cells transfected with the ribozyme alone. |
| 423 | 7525563 | These data provide strong support for the hypothesis that IRS-1 plays a role in insulin-stimulated glucose transport in insulin-responsive cells. |
| 424 | 7525563 | Insulin receptor substrate 1 mediates the stimulatory effect of insulin on GLUT4 translocation in transfected rat adipose cells. |
| 425 | 7525563 | We have now investigated the possible role of IRS-1 in mediating the effect of insulin to stimulate glucose transport in a physiologically relevant insulin target tissue. |
| 426 | 7525563 | Expression of the ribozyme in these cells caused a 4.4-fold increase in the concentration of insulin required to achieve half-maximal stimulation of the translocation of cotransfected epitope-tagged GLUT4 without changing the maximal insulin response. |
| 427 | 7525563 | Overexpression of human IRS-1 increased the basal cell surface GLUT4 to nearly the maximal level in the absence of insulin. |
| 428 | 7525563 | When the ribozyme (specific to rat IRS-1) was cotransfected along with human IRS-1, the insulin dose-response curve was shifted to the left when compared with cells transfected with the ribozyme alone. |
| 429 | 7525563 | These data provide strong support for the hypothesis that IRS-1 plays a role in insulin-stimulated glucose transport in insulin-responsive cells. |
| 430 | 7525563 | Insulin receptor substrate 1 mediates the stimulatory effect of insulin on GLUT4 translocation in transfected rat adipose cells. |
| 431 | 7525563 | We have now investigated the possible role of IRS-1 in mediating the effect of insulin to stimulate glucose transport in a physiologically relevant insulin target tissue. |
| 432 | 7525563 | Expression of the ribozyme in these cells caused a 4.4-fold increase in the concentration of insulin required to achieve half-maximal stimulation of the translocation of cotransfected epitope-tagged GLUT4 without changing the maximal insulin response. |
| 433 | 7525563 | Overexpression of human IRS-1 increased the basal cell surface GLUT4 to nearly the maximal level in the absence of insulin. |
| 434 | 7525563 | When the ribozyme (specific to rat IRS-1) was cotransfected along with human IRS-1, the insulin dose-response curve was shifted to the left when compared with cells transfected with the ribozyme alone. |
| 435 | 7525563 | These data provide strong support for the hypothesis that IRS-1 plays a role in insulin-stimulated glucose transport in insulin-responsive cells. |
| 436 | 7525563 | Insulin receptor substrate 1 mediates the stimulatory effect of insulin on GLUT4 translocation in transfected rat adipose cells. |
| 437 | 7525563 | We have now investigated the possible role of IRS-1 in mediating the effect of insulin to stimulate glucose transport in a physiologically relevant insulin target tissue. |
| 438 | 7525563 | Expression of the ribozyme in these cells caused a 4.4-fold increase in the concentration of insulin required to achieve half-maximal stimulation of the translocation of cotransfected epitope-tagged GLUT4 without changing the maximal insulin response. |
| 439 | 7525563 | Overexpression of human IRS-1 increased the basal cell surface GLUT4 to nearly the maximal level in the absence of insulin. |
| 440 | 7525563 | When the ribozyme (specific to rat IRS-1) was cotransfected along with human IRS-1, the insulin dose-response curve was shifted to the left when compared with cells transfected with the ribozyme alone. |
| 441 | 7525563 | These data provide strong support for the hypothesis that IRS-1 plays a role in insulin-stimulated glucose transport in insulin-responsive cells. |
| 442 | 7526222 | Alternative pathway of insulin signalling in mice with targeted disruption of the IRS-1 gene. |
| 443 | 7526222 | The principal substrate for the insulin and insulin-like growth factor-1 (IGF-1) receptors is the cytoplasmic protein insulin-receptor substrate-1 (IRS-1/pp185). |
| 444 | 7526222 | To elucidate the role of IRS-1 in insulin/IGF-1 action, we created IRS-1-deficient mice by targeted gene mutation. |
| 445 | 7526222 | The residual insulin/IGF-1 action correlated with the appearance of a new tyrosine-phosphorylated protein (IRS-2) which binds to PI(3)K, but is slightly larger than and immunologically distinct from IRS-1. |
| 446 | 7526222 | Our results provide evidence for IRS-1-dependent and IRS-1-independent pathways of insulin/IGF-1 signalling and for the existence of an alternative substrate of these receptor kinases. |
| 447 | 7526222 | Alternative pathway of insulin signalling in mice with targeted disruption of the IRS-1 gene. |
| 448 | 7526222 | The principal substrate for the insulin and insulin-like growth factor-1 (IGF-1) receptors is the cytoplasmic protein insulin-receptor substrate-1 (IRS-1/pp185). |
| 449 | 7526222 | To elucidate the role of IRS-1 in insulin/IGF-1 action, we created IRS-1-deficient mice by targeted gene mutation. |
| 450 | 7526222 | The residual insulin/IGF-1 action correlated with the appearance of a new tyrosine-phosphorylated protein (IRS-2) which binds to PI(3)K, but is slightly larger than and immunologically distinct from IRS-1. |
| 451 | 7526222 | Our results provide evidence for IRS-1-dependent and IRS-1-independent pathways of insulin/IGF-1 signalling and for the existence of an alternative substrate of these receptor kinases. |
| 452 | 7526222 | Alternative pathway of insulin signalling in mice with targeted disruption of the IRS-1 gene. |
| 453 | 7526222 | The principal substrate for the insulin and insulin-like growth factor-1 (IGF-1) receptors is the cytoplasmic protein insulin-receptor substrate-1 (IRS-1/pp185). |
| 454 | 7526222 | To elucidate the role of IRS-1 in insulin/IGF-1 action, we created IRS-1-deficient mice by targeted gene mutation. |
| 455 | 7526222 | The residual insulin/IGF-1 action correlated with the appearance of a new tyrosine-phosphorylated protein (IRS-2) which binds to PI(3)K, but is slightly larger than and immunologically distinct from IRS-1. |
| 456 | 7526222 | Our results provide evidence for IRS-1-dependent and IRS-1-independent pathways of insulin/IGF-1 signalling and for the existence of an alternative substrate of these receptor kinases. |
| 457 | 7526222 | Alternative pathway of insulin signalling in mice with targeted disruption of the IRS-1 gene. |
| 458 | 7526222 | The principal substrate for the insulin and insulin-like growth factor-1 (IGF-1) receptors is the cytoplasmic protein insulin-receptor substrate-1 (IRS-1/pp185). |
| 459 | 7526222 | To elucidate the role of IRS-1 in insulin/IGF-1 action, we created IRS-1-deficient mice by targeted gene mutation. |
| 460 | 7526222 | The residual insulin/IGF-1 action correlated with the appearance of a new tyrosine-phosphorylated protein (IRS-2) which binds to PI(3)K, but is slightly larger than and immunologically distinct from IRS-1. |
| 461 | 7526222 | Our results provide evidence for IRS-1-dependent and IRS-1-independent pathways of insulin/IGF-1 signalling and for the existence of an alternative substrate of these receptor kinases. |
| 462 | 7537758 | Insulin receptor phosphorylation, insulin receptor substrate-1 phosphorylation, and phosphatidylinositol 3-kinase activity are decreased in intact skeletal muscle strips from obese subjects. |
| 463 | 7537758 | To determine whether the impaired insulin-stimulated glucose uptake in obese individuals is associated with altered insulin receptor signaling, we measured both glucose uptake and early steps in the insulin action pathway in intact strips of human skeletal muscle. |
| 464 | 7537758 | In the lean subjects, tyrosine phosphorylation of the insulin receptor and insulin receptor substrate-1 (IRS-1), measured by immunoblotting with anti-phosphotyrosine antibodies, was significantly increased by insulin at all time points. |
| 465 | 7537758 | In the skeletal muscle from the obese subjects, insulin was less effective in stimulating tyrosine phosphorylation (maximum receptor and IRS-1 phosphorylation decreased by 35 and 38%, respectively). |
| 466 | 7537758 | Insulin stimulation of IRS-1 immunoprecipitable phosphatidylinositol 3-kinase (PI 3-kinase) activity also was markedly lower in obese subjects compared with controls (10- vs 35-fold above basal, respectively). |
| 467 | 7537758 | In addition, the obese subjects had a lower abundance of the insulin receptor, IRS-1, and the p85 subunit of PI 3-kinase (55, 54, and 64% of nonobese, respectively). |
| 468 | 7537758 | We conclude that impaired insulin-stimulated glucose uptake in skeletal muscle from severely obese subjects is accompanied by a deficiency in insulin receptor signaling, which may contribute to decreased insulin action. |
| 469 | 7537758 | Insulin receptor phosphorylation, insulin receptor substrate-1 phosphorylation, and phosphatidylinositol 3-kinase activity are decreased in intact skeletal muscle strips from obese subjects. |
| 470 | 7537758 | To determine whether the impaired insulin-stimulated glucose uptake in obese individuals is associated with altered insulin receptor signaling, we measured both glucose uptake and early steps in the insulin action pathway in intact strips of human skeletal muscle. |
| 471 | 7537758 | In the lean subjects, tyrosine phosphorylation of the insulin receptor and insulin receptor substrate-1 (IRS-1), measured by immunoblotting with anti-phosphotyrosine antibodies, was significantly increased by insulin at all time points. |
| 472 | 7537758 | In the skeletal muscle from the obese subjects, insulin was less effective in stimulating tyrosine phosphorylation (maximum receptor and IRS-1 phosphorylation decreased by 35 and 38%, respectively). |
| 473 | 7537758 | Insulin stimulation of IRS-1 immunoprecipitable phosphatidylinositol 3-kinase (PI 3-kinase) activity also was markedly lower in obese subjects compared with controls (10- vs 35-fold above basal, respectively). |
| 474 | 7537758 | In addition, the obese subjects had a lower abundance of the insulin receptor, IRS-1, and the p85 subunit of PI 3-kinase (55, 54, and 64% of nonobese, respectively). |
| 475 | 7537758 | We conclude that impaired insulin-stimulated glucose uptake in skeletal muscle from severely obese subjects is accompanied by a deficiency in insulin receptor signaling, which may contribute to decreased insulin action. |
| 476 | 7537758 | Insulin receptor phosphorylation, insulin receptor substrate-1 phosphorylation, and phosphatidylinositol 3-kinase activity are decreased in intact skeletal muscle strips from obese subjects. |
| 477 | 7537758 | To determine whether the impaired insulin-stimulated glucose uptake in obese individuals is associated with altered insulin receptor signaling, we measured both glucose uptake and early steps in the insulin action pathway in intact strips of human skeletal muscle. |
| 478 | 7537758 | In the lean subjects, tyrosine phosphorylation of the insulin receptor and insulin receptor substrate-1 (IRS-1), measured by immunoblotting with anti-phosphotyrosine antibodies, was significantly increased by insulin at all time points. |
| 479 | 7537758 | In the skeletal muscle from the obese subjects, insulin was less effective in stimulating tyrosine phosphorylation (maximum receptor and IRS-1 phosphorylation decreased by 35 and 38%, respectively). |
| 480 | 7537758 | Insulin stimulation of IRS-1 immunoprecipitable phosphatidylinositol 3-kinase (PI 3-kinase) activity also was markedly lower in obese subjects compared with controls (10- vs 35-fold above basal, respectively). |
| 481 | 7537758 | In addition, the obese subjects had a lower abundance of the insulin receptor, IRS-1, and the p85 subunit of PI 3-kinase (55, 54, and 64% of nonobese, respectively). |
| 482 | 7537758 | We conclude that impaired insulin-stimulated glucose uptake in skeletal muscle from severely obese subjects is accompanied by a deficiency in insulin receptor signaling, which may contribute to decreased insulin action. |
| 483 | 7537758 | Insulin receptor phosphorylation, insulin receptor substrate-1 phosphorylation, and phosphatidylinositol 3-kinase activity are decreased in intact skeletal muscle strips from obese subjects. |
| 484 | 7537758 | To determine whether the impaired insulin-stimulated glucose uptake in obese individuals is associated with altered insulin receptor signaling, we measured both glucose uptake and early steps in the insulin action pathway in intact strips of human skeletal muscle. |
| 485 | 7537758 | In the lean subjects, tyrosine phosphorylation of the insulin receptor and insulin receptor substrate-1 (IRS-1), measured by immunoblotting with anti-phosphotyrosine antibodies, was significantly increased by insulin at all time points. |
| 486 | 7537758 | In the skeletal muscle from the obese subjects, insulin was less effective in stimulating tyrosine phosphorylation (maximum receptor and IRS-1 phosphorylation decreased by 35 and 38%, respectively). |
| 487 | 7537758 | Insulin stimulation of IRS-1 immunoprecipitable phosphatidylinositol 3-kinase (PI 3-kinase) activity also was markedly lower in obese subjects compared with controls (10- vs 35-fold above basal, respectively). |
| 488 | 7537758 | In addition, the obese subjects had a lower abundance of the insulin receptor, IRS-1, and the p85 subunit of PI 3-kinase (55, 54, and 64% of nonobese, respectively). |
| 489 | 7537758 | We conclude that impaired insulin-stimulated glucose uptake in skeletal muscle from severely obese subjects is accompanied by a deficiency in insulin receptor signaling, which may contribute to decreased insulin action. |
| 490 | 7537758 | Insulin receptor phosphorylation, insulin receptor substrate-1 phosphorylation, and phosphatidylinositol 3-kinase activity are decreased in intact skeletal muscle strips from obese subjects. |
| 491 | 7537758 | To determine whether the impaired insulin-stimulated glucose uptake in obese individuals is associated with altered insulin receptor signaling, we measured both glucose uptake and early steps in the insulin action pathway in intact strips of human skeletal muscle. |
| 492 | 7537758 | In the lean subjects, tyrosine phosphorylation of the insulin receptor and insulin receptor substrate-1 (IRS-1), measured by immunoblotting with anti-phosphotyrosine antibodies, was significantly increased by insulin at all time points. |
| 493 | 7537758 | In the skeletal muscle from the obese subjects, insulin was less effective in stimulating tyrosine phosphorylation (maximum receptor and IRS-1 phosphorylation decreased by 35 and 38%, respectively). |
| 494 | 7537758 | Insulin stimulation of IRS-1 immunoprecipitable phosphatidylinositol 3-kinase (PI 3-kinase) activity also was markedly lower in obese subjects compared with controls (10- vs 35-fold above basal, respectively). |
| 495 | 7537758 | In addition, the obese subjects had a lower abundance of the insulin receptor, IRS-1, and the p85 subunit of PI 3-kinase (55, 54, and 64% of nonobese, respectively). |
| 496 | 7537758 | We conclude that impaired insulin-stimulated glucose uptake in skeletal muscle from severely obese subjects is accompanied by a deficiency in insulin receptor signaling, which may contribute to decreased insulin action. |
| 497 | 7540574 | Glucose-induced insulin receptor tyrosine phosphorylation in insulin-secreting beta-cells. |
| 498 | 7540574 | In the beta TC3 insulin-secreting beta-cell line, glucose rapidly induces the tyrosine phosphorylation of the 97-kDa insulin receptor beta-subunit. |
| 499 | 7540574 | In addition, functional insulin-like growth factor I (IGF-I) receptors are also expressed by these beta-cells, as indicated by IGF-I-induced receptor tyrosine phosphorylation (ED50 = 5 x 10(-9) mol/l) and also by detection of hybrid insulin/IGF-I receptor autophosphorylation at 10(-7) mol/l IGF-I. |
| 500 | 7540574 | Both glucose and insulin stimulate the tyrosine phosphorylation of the insulin receptor substrate (IRS) IRS-1 and increase by two- to fivefold the rapid association of IRS-1 with the 85-kDa alpha-subunit of the phosphatidylinositol-3-kinase, as determined by co-immunoprecipitation assays. |
| 501 | 7542745 | Phosphatidylinositol 3-kinase (PI-3 kinase) is implicated in the regulation of diverse cellular processes, including insulin-stimulated glucose transport. |
| 502 | 7542745 | Here, we describe p55PIK, a new regulatory subunit that was isolated by screening expression libraries with tyrosine-phosphorylated insulin receptor substrate 1 (IRS-1). p55PIK is composed of a unique 30-residue NH2 terminus followed by a proline-rich motif and two Src homology 2 (SH2) domains with significant sequence identify to those in p85. p55PIK mRNA is expressed early during development, remains abundant in adult mouse brain and testis tissue, and is detectable in adult adipocytes and heart and kidney tissues. p55PIK forms a stable complex with p110, and it associates with IRS-1 during insulin stimulation. |
| 503 | 7544790 | Osmotic loading of neutralizing antibodies demonstrates a role for protein-tyrosine phosphatase 1B in negative regulation of the insulin action pathway. |
| 504 | 7544790 | To explore whether PTP1B, a widely expressed, non-receptor-type PTPase, regulates insulin signaling, we used osmotic shock to load rat KRC-7 hepatoma cells with affinity-purified neutralizing antibodies that immunoprecipitate and inactivate the enzymatic activity of recombinant rat PTP1B in vitro. |
| 505 | 7544790 | In cells loaded with PTP1B antibody, insulin-stimulated DNA synthesis and phosphatidylinositol 3'-kinase activity were increased by 42% and 38%, respectively, compared with control cells loaded with preimmune IgG (p < 0.005). |
| 506 | 7544790 | In order to characterize the potential site(s) of action of PTP1B in insulin signaling, we also determined that insulin-stimulated receptor autophosphorylation and insulin receptor substrate 1 tyrosine phosphorylation were increased 2.2- and 2.0-fold, respectively, and that insulin-stimulated receptor kinase activity toward an exogenous peptide substrate was increased by 57% in the PTP1B antibody-loaded cells. |
| 507 | 7544790 | These studies demonstrate that PTP1B has a role in the negative regulation of insulin signaling and acts, at least in part, directly at the level of the insulin receptor. |
| 508 | 7544807 | Dexamethasone enhances insulin-like growth factor-I effects on skeletal muscle cell proliferation. |
| 509 | 7544807 | IGF-I stimulation of cell proliferation and c-Fos expression in skeletal muscle cells is markedly enhanced by dexamethasone. |
| 510 | 7544807 | The effect of dexamethasone is not mediated by changes in IGF-binding proteins, as evidenced by similar effects of dexamethasone on the actions of insulin, PDGF-BB, and the IGF-I analogue long R3IGF-I. |
| 511 | 7544807 | In dexamethasone-treated cells, the levels of IGF-I receptor tyrosine phosphorylation and receptor-associated phosphatidylinositol 3-kinase activity were increased. |
| 512 | 7544807 | In contrast, dexamethasone decreased both tyrosine phosphorylation and expression of insulin receptor substrate 1 (IRS-1) and IRS-1-associated phosphatidylinositol 3-kinase activity. |
| 513 | 7544807 | Potentiation of IGF-I action correlates with increased IGF-I receptor-associated phosphatidylinositol 3-kinase activity and tyrosine phosphorylation of Shc, but appears to be independent of activation of the IRS-1/phosphatidylinositol 3-kinase signaling pathway. |
| 514 | 7544807 | Dexamethasone enhances insulin-like growth factor-I effects on skeletal muscle cell proliferation. |
| 515 | 7544807 | IGF-I stimulation of cell proliferation and c-Fos expression in skeletal muscle cells is markedly enhanced by dexamethasone. |
| 516 | 7544807 | The effect of dexamethasone is not mediated by changes in IGF-binding proteins, as evidenced by similar effects of dexamethasone on the actions of insulin, PDGF-BB, and the IGF-I analogue long R3IGF-I. |
| 517 | 7544807 | In dexamethasone-treated cells, the levels of IGF-I receptor tyrosine phosphorylation and receptor-associated phosphatidylinositol 3-kinase activity were increased. |
| 518 | 7544807 | In contrast, dexamethasone decreased both tyrosine phosphorylation and expression of insulin receptor substrate 1 (IRS-1) and IRS-1-associated phosphatidylinositol 3-kinase activity. |
| 519 | 7544807 | Potentiation of IGF-I action correlates with increased IGF-I receptor-associated phosphatidylinositol 3-kinase activity and tyrosine phosphorylation of Shc, but appears to be independent of activation of the IRS-1/phosphatidylinositol 3-kinase signaling pathway. |
| 520 | 7559579 | Insulin receptor substrate-1 (IRS-1) is the major cytoplasmic substrate of the insulin and insulin-like growth factor (IGF)-1 receptors. |
| 521 | 7559579 | Transgenic mice lacking IRS-1 are resistant to insulin and IGF-1, but exhibit significant residual insulin action which corresponds to the presence of an alternative high molecular weight substrate in liver and muscle. |
| 522 | 7559579 | F. (1995) Nature 377, 173-177) purified and cloned 4PS, the major substrate of the IL-4 receptor-associated tyrosine kinase in myeloid cells, which has significant structural similarity to IRS-1. |
| 523 | 7559579 | Following insulin stimulation, 4PS is rapidly phosphorylated in liver and muscle, binds to the p85 subunit of PI 3-kinase, and activates the enzyme. |
| 524 | 7559579 | IRS-2, which plays a major role in physiologic insulin signal transduction via both PI 3-kinase activation and Grb 2/Sos association. |
| 525 | 7559579 | In IRS-1-deficient mice, 4PS/IRS-2 provides signal transduction to these two major pathways of insulin signaling. |
| 526 | 7559579 | Insulin receptor substrate-1 (IRS-1) is the major cytoplasmic substrate of the insulin and insulin-like growth factor (IGF)-1 receptors. |
| 527 | 7559579 | Transgenic mice lacking IRS-1 are resistant to insulin and IGF-1, but exhibit significant residual insulin action which corresponds to the presence of an alternative high molecular weight substrate in liver and muscle. |
| 528 | 7559579 | F. (1995) Nature 377, 173-177) purified and cloned 4PS, the major substrate of the IL-4 receptor-associated tyrosine kinase in myeloid cells, which has significant structural similarity to IRS-1. |
| 529 | 7559579 | Following insulin stimulation, 4PS is rapidly phosphorylated in liver and muscle, binds to the p85 subunit of PI 3-kinase, and activates the enzyme. |
| 530 | 7559579 | IRS-2, which plays a major role in physiologic insulin signal transduction via both PI 3-kinase activation and Grb 2/Sos association. |
| 531 | 7559579 | In IRS-1-deficient mice, 4PS/IRS-2 provides signal transduction to these two major pathways of insulin signaling. |
| 532 | 7559579 | Insulin receptor substrate-1 (IRS-1) is the major cytoplasmic substrate of the insulin and insulin-like growth factor (IGF)-1 receptors. |
| 533 | 7559579 | Transgenic mice lacking IRS-1 are resistant to insulin and IGF-1, but exhibit significant residual insulin action which corresponds to the presence of an alternative high molecular weight substrate in liver and muscle. |
| 534 | 7559579 | F. (1995) Nature 377, 173-177) purified and cloned 4PS, the major substrate of the IL-4 receptor-associated tyrosine kinase in myeloid cells, which has significant structural similarity to IRS-1. |
| 535 | 7559579 | Following insulin stimulation, 4PS is rapidly phosphorylated in liver and muscle, binds to the p85 subunit of PI 3-kinase, and activates the enzyme. |
| 536 | 7559579 | IRS-2, which plays a major role in physiologic insulin signal transduction via both PI 3-kinase activation and Grb 2/Sos association. |
| 537 | 7559579 | In IRS-1-deficient mice, 4PS/IRS-2 provides signal transduction to these two major pathways of insulin signaling. |
| 538 | 7559625 | In this report, we demonstrate that in 3T3-L1 adipocytes: 1) cytosolic beta' is generated by chronic insulin administration to the cells, and that E64 inhibits the production of beta'; 2) chronic administration of insulin to the adipocytes leads to an insulin-resistant state, as measured by lipogenesis and glycogen synthesis, and E64 totally prevents the generation of this insulin-induced cellular insulin resistance; 3) E64 has no effect on the insulin-induced down-regulation of insulin receptor substrate-1, and therefore insulin resistance is not mediated by the down-regulation of insulin receptor substrate-1; 4) under in vitro conditions, partially purified beta' stoichiometrically inhibits the insulin-induced autophosphorylation of the insulin receptor beta subunit; and 5) administration of E64 to obese Zucker fatty rats improves the insulin resistance of the rats compared to saline-treated animals. |
| 539 | 7559625 | These data indicate that beta' is a mediator of insulin resistance, and the mechanism of action of beta' is the inhibition of the insulin-induced autophosphorylation of the beta subunit of the insulin receptor. |
| 540 | 7588225 | Single tyrosine substitution in the insulin-like growth factor I receptor inhibits ligand-induced receptor autophosphorylation and internalization, but not mitogenesis. |
| 541 | 7588225 | The tyrosine kinase domains of the insulin and insulin-like growth factor I (IGF-I) receptors play an essential role in signal transduction. |
| 542 | 7588225 | This mutation significantly reduced IGF-I-induced beta-subunit autophosphorylation, whereas phosphorylation of the endogenous substrate IRS-1 was unaffected. |
| 543 | 7589821 | Loci included the insulin-responsive (GLUT4) glucose transporter, hexokinase 2, glucagon, growth hormone, insulin receptor substrate 1 (IRS1), phosphoenolpyruvate carboxykinase, hepatic and muscle forms of pyruvate kinase, hepatic phosphofructokinase, the apolipoprotein B and the apolipoprotein A2 cluster, lipoprotein lipase, hepatic triglyceride lipase, the very-low-density-lipoprotein receptor, and the Pima insulin resistance locus on chromosome 4. |
| 544 | 7623569 | Non-obese carriers of either polymorphism had similar insulin sensitivity and pancreatic beta-cell function to non-obese wild-type subjects (no known variants of IRS-1). |
| 545 | 7623569 | Our results suggest that the codon-972 IRS-1 gene variant may interact with obesity in the pathogenesis of common insulin-resistant disorders. |
| 546 | 7623569 | Non-obese carriers of either polymorphism had similar insulin sensitivity and pancreatic beta-cell function to non-obese wild-type subjects (no known variants of IRS-1). |
| 547 | 7623569 | Our results suggest that the codon-972 IRS-1 gene variant may interact with obesity in the pathogenesis of common insulin-resistant disorders. |
| 548 | 7626133 | Tyrosine-phosphorylation of IRS-1 causes it to associate with the src-homology-2 (SH2) domains of at least four other proteins: phosphatidylinositol 3'-kinase (PI3K), growth factor receptor-bound protein-2 (GRB2), Nck, and Syp. |
| 549 | 7626133 | In liver tissue of diabetic rats, the levels of Nck and Syp were significantly decreased to 71 +/- 6% and 61 +/- 4% control, respectively, while in fat tissue only the Syp levels were significantly reduced to 72 +/- 9% control. |
| 550 | 7675087 | Role of IRS-2 in insulin and cytokine signalling. |
| 551 | 7675087 | The protein IRS-1 acts as an interface between signalling proteins with Src-homology-2 domains (SH2 proteins) and the receptors for insulin, IGF-1, growth hormone, several interleukins (IL-4, IL-9, IL-13) and other cytokines. |
| 552 | 7675087 | We purified and cloned a likely candidate called 4PS from myeloid progenitor cells and, because of its resemblance to IRS-1, we designate it IRS-2. |
| 553 | 7675087 | Alignment of the sequences of IRS-2 and IRS-1 revealed a highly conserved amino terminus containing a pleckstrin-homology domain and a phosphotyrosine-binding domain, and a poorly conserved carboxy terminus containing several tyrosine phosphorylation motifs. |
| 554 | 7675087 | Role of IRS-2 in insulin and cytokine signalling. |
| 555 | 7675087 | The protein IRS-1 acts as an interface between signalling proteins with Src-homology-2 domains (SH2 proteins) and the receptors for insulin, IGF-1, growth hormone, several interleukins (IL-4, IL-9, IL-13) and other cytokines. |
| 556 | 7675087 | We purified and cloned a likely candidate called 4PS from myeloid progenitor cells and, because of its resemblance to IRS-1, we designate it IRS-2. |
| 557 | 7675087 | Alignment of the sequences of IRS-2 and IRS-1 revealed a highly conserved amino terminus containing a pleckstrin-homology domain and a phosphotyrosine-binding domain, and a poorly conserved carboxy terminus containing several tyrosine phosphorylation motifs. |
| 558 | 7675087 | Role of IRS-2 in insulin and cytokine signalling. |
| 559 | 7675087 | The protein IRS-1 acts as an interface between signalling proteins with Src-homology-2 domains (SH2 proteins) and the receptors for insulin, IGF-1, growth hormone, several interleukins (IL-4, IL-9, IL-13) and other cytokines. |
| 560 | 7675087 | We purified and cloned a likely candidate called 4PS from myeloid progenitor cells and, because of its resemblance to IRS-1, we designate it IRS-2. |
| 561 | 7675087 | Alignment of the sequences of IRS-2 and IRS-1 revealed a highly conserved amino terminus containing a pleckstrin-homology domain and a phosphotyrosine-binding domain, and a poorly conserved carboxy terminus containing several tyrosine phosphorylation motifs. |
| 562 | 7683695 | Glucocorticoid regulation of insulin receptor and substrate IRS-1 tyrosine phosphorylation in rat skeletal muscle in vivo. |
| 563 | 7683695 | To test the hypothesis that glucocorticoid-induced insulin resistance might originate from abnormalities in insulin receptor signaling, we investigated the effects of glucocorticoids on in vivo tyrosine phosphorylation of the insulin receptor and the insulin receptor substrate IRS-1 in rat skeletal muscle. |
| 564 | 7683695 | Insulin receptors and substrate IRS-1 were identified and quantified with specific antibodies. |
| 565 | 7683695 | Treatment with protein phosphatase-2A reduced IRS-1 M(r) in control but not in glucocorticoid-treated muscle indicating that the lower M(r) likely results from lower phosphoserine and/or phosphothreonine content. |
| 566 | 7683695 | Subsequent treatment with cortisone for 5 d had no effects on insulin levels, tyrosine phosphorylation of insulin receptors or IRS-1, or the M(r) of IRS-1. |
| 567 | 7683695 | In conclusion, glucocorticoid-treated skeletal muscle is characterized by: (a) decreased total tyrosine phosphorylation of insulin receptors as a result of a reduction in the pool of receptors undergoing tyrosine phosphorylation; (b) decreased IRS-1 content and reduced serine and/or threonine phosphorylation of IRS-1. |
| 568 | 7683695 | Glucocorticoid regulation of insulin receptor and substrate IRS-1 tyrosine phosphorylation in rat skeletal muscle in vivo. |
| 569 | 7683695 | To test the hypothesis that glucocorticoid-induced insulin resistance might originate from abnormalities in insulin receptor signaling, we investigated the effects of glucocorticoids on in vivo tyrosine phosphorylation of the insulin receptor and the insulin receptor substrate IRS-1 in rat skeletal muscle. |
| 570 | 7683695 | Insulin receptors and substrate IRS-1 were identified and quantified with specific antibodies. |
| 571 | 7683695 | Treatment with protein phosphatase-2A reduced IRS-1 M(r) in control but not in glucocorticoid-treated muscle indicating that the lower M(r) likely results from lower phosphoserine and/or phosphothreonine content. |
| 572 | 7683695 | Subsequent treatment with cortisone for 5 d had no effects on insulin levels, tyrosine phosphorylation of insulin receptors or IRS-1, or the M(r) of IRS-1. |
| 573 | 7683695 | In conclusion, glucocorticoid-treated skeletal muscle is characterized by: (a) decreased total tyrosine phosphorylation of insulin receptors as a result of a reduction in the pool of receptors undergoing tyrosine phosphorylation; (b) decreased IRS-1 content and reduced serine and/or threonine phosphorylation of IRS-1. |
| 574 | 7683695 | Glucocorticoid regulation of insulin receptor and substrate IRS-1 tyrosine phosphorylation in rat skeletal muscle in vivo. |
| 575 | 7683695 | To test the hypothesis that glucocorticoid-induced insulin resistance might originate from abnormalities in insulin receptor signaling, we investigated the effects of glucocorticoids on in vivo tyrosine phosphorylation of the insulin receptor and the insulin receptor substrate IRS-1 in rat skeletal muscle. |
| 576 | 7683695 | Insulin receptors and substrate IRS-1 were identified and quantified with specific antibodies. |
| 577 | 7683695 | Treatment with protein phosphatase-2A reduced IRS-1 M(r) in control but not in glucocorticoid-treated muscle indicating that the lower M(r) likely results from lower phosphoserine and/or phosphothreonine content. |
| 578 | 7683695 | Subsequent treatment with cortisone for 5 d had no effects on insulin levels, tyrosine phosphorylation of insulin receptors or IRS-1, or the M(r) of IRS-1. |
| 579 | 7683695 | In conclusion, glucocorticoid-treated skeletal muscle is characterized by: (a) decreased total tyrosine phosphorylation of insulin receptors as a result of a reduction in the pool of receptors undergoing tyrosine phosphorylation; (b) decreased IRS-1 content and reduced serine and/or threonine phosphorylation of IRS-1. |
| 580 | 7683695 | Glucocorticoid regulation of insulin receptor and substrate IRS-1 tyrosine phosphorylation in rat skeletal muscle in vivo. |
| 581 | 7683695 | To test the hypothesis that glucocorticoid-induced insulin resistance might originate from abnormalities in insulin receptor signaling, we investigated the effects of glucocorticoids on in vivo tyrosine phosphorylation of the insulin receptor and the insulin receptor substrate IRS-1 in rat skeletal muscle. |
| 582 | 7683695 | Insulin receptors and substrate IRS-1 were identified and quantified with specific antibodies. |
| 583 | 7683695 | Treatment with protein phosphatase-2A reduced IRS-1 M(r) in control but not in glucocorticoid-treated muscle indicating that the lower M(r) likely results from lower phosphoserine and/or phosphothreonine content. |
| 584 | 7683695 | Subsequent treatment with cortisone for 5 d had no effects on insulin levels, tyrosine phosphorylation of insulin receptors or IRS-1, or the M(r) of IRS-1. |
| 585 | 7683695 | In conclusion, glucocorticoid-treated skeletal muscle is characterized by: (a) decreased total tyrosine phosphorylation of insulin receptors as a result of a reduction in the pool of receptors undergoing tyrosine phosphorylation; (b) decreased IRS-1 content and reduced serine and/or threonine phosphorylation of IRS-1. |
| 586 | 7683695 | Glucocorticoid regulation of insulin receptor and substrate IRS-1 tyrosine phosphorylation in rat skeletal muscle in vivo. |
| 587 | 7683695 | To test the hypothesis that glucocorticoid-induced insulin resistance might originate from abnormalities in insulin receptor signaling, we investigated the effects of glucocorticoids on in vivo tyrosine phosphorylation of the insulin receptor and the insulin receptor substrate IRS-1 in rat skeletal muscle. |
| 588 | 7683695 | Insulin receptors and substrate IRS-1 were identified and quantified with specific antibodies. |
| 589 | 7683695 | Treatment with protein phosphatase-2A reduced IRS-1 M(r) in control but not in glucocorticoid-treated muscle indicating that the lower M(r) likely results from lower phosphoserine and/or phosphothreonine content. |
| 590 | 7683695 | Subsequent treatment with cortisone for 5 d had no effects on insulin levels, tyrosine phosphorylation of insulin receptors or IRS-1, or the M(r) of IRS-1. |
| 591 | 7683695 | In conclusion, glucocorticoid-treated skeletal muscle is characterized by: (a) decreased total tyrosine phosphorylation of insulin receptors as a result of a reduction in the pool of receptors undergoing tyrosine phosphorylation; (b) decreased IRS-1 content and reduced serine and/or threonine phosphorylation of IRS-1. |
| 592 | 7683695 | Glucocorticoid regulation of insulin receptor and substrate IRS-1 tyrosine phosphorylation in rat skeletal muscle in vivo. |
| 593 | 7683695 | To test the hypothesis that glucocorticoid-induced insulin resistance might originate from abnormalities in insulin receptor signaling, we investigated the effects of glucocorticoids on in vivo tyrosine phosphorylation of the insulin receptor and the insulin receptor substrate IRS-1 in rat skeletal muscle. |
| 594 | 7683695 | Insulin receptors and substrate IRS-1 were identified and quantified with specific antibodies. |
| 595 | 7683695 | Treatment with protein phosphatase-2A reduced IRS-1 M(r) in control but not in glucocorticoid-treated muscle indicating that the lower M(r) likely results from lower phosphoserine and/or phosphothreonine content. |
| 596 | 7683695 | Subsequent treatment with cortisone for 5 d had no effects on insulin levels, tyrosine phosphorylation of insulin receptors or IRS-1, or the M(r) of IRS-1. |
| 597 | 7683695 | In conclusion, glucocorticoid-treated skeletal muscle is characterized by: (a) decreased total tyrosine phosphorylation of insulin receptors as a result of a reduction in the pool of receptors undergoing tyrosine phosphorylation; (b) decreased IRS-1 content and reduced serine and/or threonine phosphorylation of IRS-1. |
| 598 | 7685118 | Insulin receptor substrate 1 mediates insulin and insulin-like growth factor I-stimulated maturation of Xenopus oocytes. |
| 599 | 7685118 | Insulin and insulin-like growth factor I (IGF-I) initiate cellular functions by activating their homologous tyrosine kinase receptors. |
| 600 | 7685118 | We have developed a reconstitution system to study the role of IRS-1 in insulin and IGF-I signaling, taking advantage of the fact that Xenopus oocytes possess endogenous IGF-I receptors but have little or no IRS-1, as determined by immunoblotting with anti-IRS-1 and antiphosphotyrosine antibodies. |
| 601 | 7685118 | After microinjection of IRS-1 protein produced in a baculovirus expression system, tyrosyl phosphorylation of injected IRS-1 is stimulated by both insulin and IGF-I in a concentration-dependent manner, with IGF-I more potent than insulin. |
| 602 | 7685118 | By contrast, overexpression of human insulin receptors in the Xenopus oocytes does not enhance either IRS-1 phosphorylation or oocyte maturation response upon insulin stimulation. |
| 603 | 7685118 | These results demonstrate that IRS-1 serves a critical role in linking IGF-I and insulin to their final cellular responses. |
| 604 | 7685118 | Insulin receptor substrate 1 mediates insulin and insulin-like growth factor I-stimulated maturation of Xenopus oocytes. |
| 605 | 7685118 | Insulin and insulin-like growth factor I (IGF-I) initiate cellular functions by activating their homologous tyrosine kinase receptors. |
| 606 | 7685118 | We have developed a reconstitution system to study the role of IRS-1 in insulin and IGF-I signaling, taking advantage of the fact that Xenopus oocytes possess endogenous IGF-I receptors but have little or no IRS-1, as determined by immunoblotting with anti-IRS-1 and antiphosphotyrosine antibodies. |
| 607 | 7685118 | After microinjection of IRS-1 protein produced in a baculovirus expression system, tyrosyl phosphorylation of injected IRS-1 is stimulated by both insulin and IGF-I in a concentration-dependent manner, with IGF-I more potent than insulin. |
| 608 | 7685118 | By contrast, overexpression of human insulin receptors in the Xenopus oocytes does not enhance either IRS-1 phosphorylation or oocyte maturation response upon insulin stimulation. |
| 609 | 7685118 | These results demonstrate that IRS-1 serves a critical role in linking IGF-I and insulin to their final cellular responses. |
| 610 | 7685118 | Insulin receptor substrate 1 mediates insulin and insulin-like growth factor I-stimulated maturation of Xenopus oocytes. |
| 611 | 7685118 | Insulin and insulin-like growth factor I (IGF-I) initiate cellular functions by activating their homologous tyrosine kinase receptors. |
| 612 | 7685118 | We have developed a reconstitution system to study the role of IRS-1 in insulin and IGF-I signaling, taking advantage of the fact that Xenopus oocytes possess endogenous IGF-I receptors but have little or no IRS-1, as determined by immunoblotting with anti-IRS-1 and antiphosphotyrosine antibodies. |
| 613 | 7685118 | After microinjection of IRS-1 protein produced in a baculovirus expression system, tyrosyl phosphorylation of injected IRS-1 is stimulated by both insulin and IGF-I in a concentration-dependent manner, with IGF-I more potent than insulin. |
| 614 | 7685118 | By contrast, overexpression of human insulin receptors in the Xenopus oocytes does not enhance either IRS-1 phosphorylation or oocyte maturation response upon insulin stimulation. |
| 615 | 7685118 | These results demonstrate that IRS-1 serves a critical role in linking IGF-I and insulin to their final cellular responses. |
| 616 | 7685118 | Insulin receptor substrate 1 mediates insulin and insulin-like growth factor I-stimulated maturation of Xenopus oocytes. |
| 617 | 7685118 | Insulin and insulin-like growth factor I (IGF-I) initiate cellular functions by activating their homologous tyrosine kinase receptors. |
| 618 | 7685118 | We have developed a reconstitution system to study the role of IRS-1 in insulin and IGF-I signaling, taking advantage of the fact that Xenopus oocytes possess endogenous IGF-I receptors but have little or no IRS-1, as determined by immunoblotting with anti-IRS-1 and antiphosphotyrosine antibodies. |
| 619 | 7685118 | After microinjection of IRS-1 protein produced in a baculovirus expression system, tyrosyl phosphorylation of injected IRS-1 is stimulated by both insulin and IGF-I in a concentration-dependent manner, with IGF-I more potent than insulin. |
| 620 | 7685118 | By contrast, overexpression of human insulin receptors in the Xenopus oocytes does not enhance either IRS-1 phosphorylation or oocyte maturation response upon insulin stimulation. |
| 621 | 7685118 | These results demonstrate that IRS-1 serves a critical role in linking IGF-I and insulin to their final cellular responses. |
| 622 | 7685118 | Insulin receptor substrate 1 mediates insulin and insulin-like growth factor I-stimulated maturation of Xenopus oocytes. |
| 623 | 7685118 | Insulin and insulin-like growth factor I (IGF-I) initiate cellular functions by activating their homologous tyrosine kinase receptors. |
| 624 | 7685118 | We have developed a reconstitution system to study the role of IRS-1 in insulin and IGF-I signaling, taking advantage of the fact that Xenopus oocytes possess endogenous IGF-I receptors but have little or no IRS-1, as determined by immunoblotting with anti-IRS-1 and antiphosphotyrosine antibodies. |
| 625 | 7685118 | After microinjection of IRS-1 protein produced in a baculovirus expression system, tyrosyl phosphorylation of injected IRS-1 is stimulated by both insulin and IGF-I in a concentration-dependent manner, with IGF-I more potent than insulin. |
| 626 | 7685118 | By contrast, overexpression of human insulin receptors in the Xenopus oocytes does not enhance either IRS-1 phosphorylation or oocyte maturation response upon insulin stimulation. |
| 627 | 7685118 | These results demonstrate that IRS-1 serves a critical role in linking IGF-I and insulin to their final cellular responses. |
| 628 | 7688476 | Substitution of the erbB-2 oncoprotein transmembrane domain activates the insulin receptor and modulates the action of insulin and insulin-receptor substrate 1. |
| 629 | 7688476 | This activity results in an increase in the level of insulin-receptor substrate 1 phosphorylation but a down-regulation in insulin-receptor substrate 1 protein and desensitization to insulin stimulation of glycogen synthesis. |
| 630 | 7688476 | Over-expression of chimeric insulin receptors containing the c-erbB-2 TM domain or a single point mutation in the insulin receptor TM domain of Val-938-->Asp, on the other hand, shows none of these alterations. |
| 631 | 7688476 | Substitution of the erbB-2 oncoprotein transmembrane domain activates the insulin receptor and modulates the action of insulin and insulin-receptor substrate 1. |
| 632 | 7688476 | This activity results in an increase in the level of insulin-receptor substrate 1 phosphorylation but a down-regulation in insulin-receptor substrate 1 protein and desensitization to insulin stimulation of glycogen synthesis. |
| 633 | 7688476 | Over-expression of chimeric insulin receptors containing the c-erbB-2 TM domain or a single point mutation in the insulin receptor TM domain of Val-938-->Asp, on the other hand, shows none of these alterations. |
| 634 | 7691886 | Regulation of phosphatidylinositol 3-kinase activity in liver and muscle of animal models of insulin-resistant and insulin-deficient diabetes mellitus. |
| 635 | 7691886 | Insulin stimulates tyrosine phosphorylation of insulin receptor substrate 1 (IRS-1), which in turn binds to and activates phosphatidylinositol 3-kinase (PI 3-kinase). |
| 636 | 7691886 | After in vivo insulin stimulation, there was a 60-80% decrease in IRS-1 phosphorylation in liver and muscle of the ob/ob mouse. |
| 637 | 7691886 | There was no insulin stimulation of PI 3-kinase (85 kD subunit) association with IRS-1, and IRS-1-associated PI 3-kinase activity was reduced 90%. |
| 638 | 7691886 | By contrast, in the streptozotocin diabetic rat, IRS-1 phosphorylation increased 50% in muscle, IRS-1-associated PI 3-kinase activity was increased two- to threefold in liver and muscle, and there was a 50% increase in the p85 associated with IRS-1 after insulin stimulation in muscle. |
| 639 | 7691886 | In conclusion, (a) IRS-1-associated PI 3-kinase activity is differentially regulated in hyperinsulinemic and hypoinsulinemic diabetic states; (b) PI 3-kinase activation closely correlates with IRS-1 phosphorylation; and (c) reduced PI 3-kinase activity may play a role in the pathophysiology of insulin resistant diabetic states, such as that seen in the ob/ob mouse. |
| 640 | 7691886 | Regulation of phosphatidylinositol 3-kinase activity in liver and muscle of animal models of insulin-resistant and insulin-deficient diabetes mellitus. |
| 641 | 7691886 | Insulin stimulates tyrosine phosphorylation of insulin receptor substrate 1 (IRS-1), which in turn binds to and activates phosphatidylinositol 3-kinase (PI 3-kinase). |
| 642 | 7691886 | After in vivo insulin stimulation, there was a 60-80% decrease in IRS-1 phosphorylation in liver and muscle of the ob/ob mouse. |
| 643 | 7691886 | There was no insulin stimulation of PI 3-kinase (85 kD subunit) association with IRS-1, and IRS-1-associated PI 3-kinase activity was reduced 90%. |
| 644 | 7691886 | By contrast, in the streptozotocin diabetic rat, IRS-1 phosphorylation increased 50% in muscle, IRS-1-associated PI 3-kinase activity was increased two- to threefold in liver and muscle, and there was a 50% increase in the p85 associated with IRS-1 after insulin stimulation in muscle. |
| 645 | 7691886 | In conclusion, (a) IRS-1-associated PI 3-kinase activity is differentially regulated in hyperinsulinemic and hypoinsulinemic diabetic states; (b) PI 3-kinase activation closely correlates with IRS-1 phosphorylation; and (c) reduced PI 3-kinase activity may play a role in the pathophysiology of insulin resistant diabetic states, such as that seen in the ob/ob mouse. |
| 646 | 7691886 | Regulation of phosphatidylinositol 3-kinase activity in liver and muscle of animal models of insulin-resistant and insulin-deficient diabetes mellitus. |
| 647 | 7691886 | Insulin stimulates tyrosine phosphorylation of insulin receptor substrate 1 (IRS-1), which in turn binds to and activates phosphatidylinositol 3-kinase (PI 3-kinase). |
| 648 | 7691886 | After in vivo insulin stimulation, there was a 60-80% decrease in IRS-1 phosphorylation in liver and muscle of the ob/ob mouse. |
| 649 | 7691886 | There was no insulin stimulation of PI 3-kinase (85 kD subunit) association with IRS-1, and IRS-1-associated PI 3-kinase activity was reduced 90%. |
| 650 | 7691886 | By contrast, in the streptozotocin diabetic rat, IRS-1 phosphorylation increased 50% in muscle, IRS-1-associated PI 3-kinase activity was increased two- to threefold in liver and muscle, and there was a 50% increase in the p85 associated with IRS-1 after insulin stimulation in muscle. |
| 651 | 7691886 | In conclusion, (a) IRS-1-associated PI 3-kinase activity is differentially regulated in hyperinsulinemic and hypoinsulinemic diabetic states; (b) PI 3-kinase activation closely correlates with IRS-1 phosphorylation; and (c) reduced PI 3-kinase activity may play a role in the pathophysiology of insulin resistant diabetic states, such as that seen in the ob/ob mouse. |
| 652 | 7691886 | Regulation of phosphatidylinositol 3-kinase activity in liver and muscle of animal models of insulin-resistant and insulin-deficient diabetes mellitus. |
| 653 | 7691886 | Insulin stimulates tyrosine phosphorylation of insulin receptor substrate 1 (IRS-1), which in turn binds to and activates phosphatidylinositol 3-kinase (PI 3-kinase). |
| 654 | 7691886 | After in vivo insulin stimulation, there was a 60-80% decrease in IRS-1 phosphorylation in liver and muscle of the ob/ob mouse. |
| 655 | 7691886 | There was no insulin stimulation of PI 3-kinase (85 kD subunit) association with IRS-1, and IRS-1-associated PI 3-kinase activity was reduced 90%. |
| 656 | 7691886 | By contrast, in the streptozotocin diabetic rat, IRS-1 phosphorylation increased 50% in muscle, IRS-1-associated PI 3-kinase activity was increased two- to threefold in liver and muscle, and there was a 50% increase in the p85 associated with IRS-1 after insulin stimulation in muscle. |
| 657 | 7691886 | In conclusion, (a) IRS-1-associated PI 3-kinase activity is differentially regulated in hyperinsulinemic and hypoinsulinemic diabetic states; (b) PI 3-kinase activation closely correlates with IRS-1 phosphorylation; and (c) reduced PI 3-kinase activity may play a role in the pathophysiology of insulin resistant diabetic states, such as that seen in the ob/ob mouse. |
| 658 | 7691886 | Regulation of phosphatidylinositol 3-kinase activity in liver and muscle of animal models of insulin-resistant and insulin-deficient diabetes mellitus. |
| 659 | 7691886 | Insulin stimulates tyrosine phosphorylation of insulin receptor substrate 1 (IRS-1), which in turn binds to and activates phosphatidylinositol 3-kinase (PI 3-kinase). |
| 660 | 7691886 | After in vivo insulin stimulation, there was a 60-80% decrease in IRS-1 phosphorylation in liver and muscle of the ob/ob mouse. |
| 661 | 7691886 | There was no insulin stimulation of PI 3-kinase (85 kD subunit) association with IRS-1, and IRS-1-associated PI 3-kinase activity was reduced 90%. |
| 662 | 7691886 | By contrast, in the streptozotocin diabetic rat, IRS-1 phosphorylation increased 50% in muscle, IRS-1-associated PI 3-kinase activity was increased two- to threefold in liver and muscle, and there was a 50% increase in the p85 associated with IRS-1 after insulin stimulation in muscle. |
| 663 | 7691886 | In conclusion, (a) IRS-1-associated PI 3-kinase activity is differentially regulated in hyperinsulinemic and hypoinsulinemic diabetic states; (b) PI 3-kinase activation closely correlates with IRS-1 phosphorylation; and (c) reduced PI 3-kinase activity may play a role in the pathophysiology of insulin resistant diabetic states, such as that seen in the ob/ob mouse. |
| 664 | 7691892 | Modulation of insulin receptor, insulin receptor substrate-1, and phosphatidylinositol 3-kinase in liver and muscle of dexamethasone-treated rats. |
| 665 | 7691892 | Insulin rapidly stimulates tyrosine kinase activity of its receptor resulting in phosphorylation of its cytosolic substrate, insulin receptor substrate-1 (IRS-1), which in turn associates with phosphatidylinositol 3-kinase (PI 3-kinase), thus activating the enzyme. |
| 666 | 7691892 | In the present study we have examined the levels and phosphorylation state of the insulin receptor and IRS-1, as well as the association/activation between IRS-1 and PI 3-kinase in the liver and muscle of rats treated with dexamethasone. |
| 667 | 7691892 | By contrast, IRS-1 phosphorylation was decreased by 31.3 +/- 10.9% (P < 0.05), and insulin stimulated PI 3-kinase activity in anti-IRS-1 immunoprecipitates was decreased by 79.5 +/- 11.2% (P < 0.02). |
| 668 | 7691892 | IRS-1 phosphorylation showed no significant change in muscle, but insulin-stimulated IRS-1 associated PI 3-kinase was decreased by 41%. |
| 669 | 7691892 | Modulation of insulin receptor, insulin receptor substrate-1, and phosphatidylinositol 3-kinase in liver and muscle of dexamethasone-treated rats. |
| 670 | 7691892 | Insulin rapidly stimulates tyrosine kinase activity of its receptor resulting in phosphorylation of its cytosolic substrate, insulin receptor substrate-1 (IRS-1), which in turn associates with phosphatidylinositol 3-kinase (PI 3-kinase), thus activating the enzyme. |
| 671 | 7691892 | In the present study we have examined the levels and phosphorylation state of the insulin receptor and IRS-1, as well as the association/activation between IRS-1 and PI 3-kinase in the liver and muscle of rats treated with dexamethasone. |
| 672 | 7691892 | By contrast, IRS-1 phosphorylation was decreased by 31.3 +/- 10.9% (P < 0.05), and insulin stimulated PI 3-kinase activity in anti-IRS-1 immunoprecipitates was decreased by 79.5 +/- 11.2% (P < 0.02). |
| 673 | 7691892 | IRS-1 phosphorylation showed no significant change in muscle, but insulin-stimulated IRS-1 associated PI 3-kinase was decreased by 41%. |
| 674 | 7691892 | Modulation of insulin receptor, insulin receptor substrate-1, and phosphatidylinositol 3-kinase in liver and muscle of dexamethasone-treated rats. |
| 675 | 7691892 | Insulin rapidly stimulates tyrosine kinase activity of its receptor resulting in phosphorylation of its cytosolic substrate, insulin receptor substrate-1 (IRS-1), which in turn associates with phosphatidylinositol 3-kinase (PI 3-kinase), thus activating the enzyme. |
| 676 | 7691892 | In the present study we have examined the levels and phosphorylation state of the insulin receptor and IRS-1, as well as the association/activation between IRS-1 and PI 3-kinase in the liver and muscle of rats treated with dexamethasone. |
| 677 | 7691892 | By contrast, IRS-1 phosphorylation was decreased by 31.3 +/- 10.9% (P < 0.05), and insulin stimulated PI 3-kinase activity in anti-IRS-1 immunoprecipitates was decreased by 79.5 +/- 11.2% (P < 0.02). |
| 678 | 7691892 | IRS-1 phosphorylation showed no significant change in muscle, but insulin-stimulated IRS-1 associated PI 3-kinase was decreased by 41%. |
| 679 | 7691892 | Modulation of insulin receptor, insulin receptor substrate-1, and phosphatidylinositol 3-kinase in liver and muscle of dexamethasone-treated rats. |
| 680 | 7691892 | Insulin rapidly stimulates tyrosine kinase activity of its receptor resulting in phosphorylation of its cytosolic substrate, insulin receptor substrate-1 (IRS-1), which in turn associates with phosphatidylinositol 3-kinase (PI 3-kinase), thus activating the enzyme. |
| 681 | 7691892 | In the present study we have examined the levels and phosphorylation state of the insulin receptor and IRS-1, as well as the association/activation between IRS-1 and PI 3-kinase in the liver and muscle of rats treated with dexamethasone. |
| 682 | 7691892 | By contrast, IRS-1 phosphorylation was decreased by 31.3 +/- 10.9% (P < 0.05), and insulin stimulated PI 3-kinase activity in anti-IRS-1 immunoprecipitates was decreased by 79.5 +/- 11.2% (P < 0.02). |
| 683 | 7691892 | IRS-1 phosphorylation showed no significant change in muscle, but insulin-stimulated IRS-1 associated PI 3-kinase was decreased by 41%. |
| 684 | 7691892 | Modulation of insulin receptor, insulin receptor substrate-1, and phosphatidylinositol 3-kinase in liver and muscle of dexamethasone-treated rats. |
| 685 | 7691892 | Insulin rapidly stimulates tyrosine kinase activity of its receptor resulting in phosphorylation of its cytosolic substrate, insulin receptor substrate-1 (IRS-1), which in turn associates with phosphatidylinositol 3-kinase (PI 3-kinase), thus activating the enzyme. |
| 686 | 7691892 | In the present study we have examined the levels and phosphorylation state of the insulin receptor and IRS-1, as well as the association/activation between IRS-1 and PI 3-kinase in the liver and muscle of rats treated with dexamethasone. |
| 687 | 7691892 | By contrast, IRS-1 phosphorylation was decreased by 31.3 +/- 10.9% (P < 0.05), and insulin stimulated PI 3-kinase activity in anti-IRS-1 immunoprecipitates was decreased by 79.5 +/- 11.2% (P < 0.02). |
| 688 | 7691892 | IRS-1 phosphorylation showed no significant change in muscle, but insulin-stimulated IRS-1 associated PI 3-kinase was decreased by 41%. |
| 689 | 7713316 | The beta-cell/liver glucose transporter (GLUT2) gene was screened for mutations using single-strand conformation polymorphism analysis (SSCP) in 30 Japanese subjects with non-insulin dependent diabetes mellitus (NIDDM). |
| 690 | 7713316 | The GLUT2 and IRS1 amino acid polymorphisms did not show a simple pattern of co-inheritance with NIDDM in the families of these subjects suggesting that neither polymorphism is sufficient to cause NIDDM but may increase diabetes-susceptibility through their interaction with other loci and environmental factors. |
| 691 | 7744813 | During insulin stimulation, IRS-1 delta PH is poorly tyrosine-phosphorylated in CHO cells, but undergoes serine/threonine phosphorylation. |
| 692 | 7744813 | Similarly, IRS-1 delta PH fails to undergo insulin-stimulated tyrosine phosphorylation in 32D cells, which uncouples the activation of phosphatidylinositol 3'-kinase and p70s6k from the endogenous insulin receptors. |
| 693 | 7744813 | Overexpression of the insulin receptor in 32DIR cells, however, restores tyrosine phosphorylation of IRS-1 delta PH and rescues insulin responses including mitogenesis. |
| 694 | 7744813 | Thus, while the PH domain is not required for the engagement of downstream signals, it is one of the elements in the NH2 terminus of IRS-1 that is needed for a sensitive coupling to insulin receptors, especially at ordinary receptor levels found in most cells and tissues. |
| 695 | 7744813 | During insulin stimulation, IRS-1 delta PH is poorly tyrosine-phosphorylated in CHO cells, but undergoes serine/threonine phosphorylation. |
| 696 | 7744813 | Similarly, IRS-1 delta PH fails to undergo insulin-stimulated tyrosine phosphorylation in 32D cells, which uncouples the activation of phosphatidylinositol 3'-kinase and p70s6k from the endogenous insulin receptors. |
| 697 | 7744813 | Overexpression of the insulin receptor in 32DIR cells, however, restores tyrosine phosphorylation of IRS-1 delta PH and rescues insulin responses including mitogenesis. |
| 698 | 7744813 | Thus, while the PH domain is not required for the engagement of downstream signals, it is one of the elements in the NH2 terminus of IRS-1 that is needed for a sensitive coupling to insulin receptors, especially at ordinary receptor levels found in most cells and tissues. |
| 699 | 7744813 | During insulin stimulation, IRS-1 delta PH is poorly tyrosine-phosphorylated in CHO cells, but undergoes serine/threonine phosphorylation. |
| 700 | 7744813 | Similarly, IRS-1 delta PH fails to undergo insulin-stimulated tyrosine phosphorylation in 32D cells, which uncouples the activation of phosphatidylinositol 3'-kinase and p70s6k from the endogenous insulin receptors. |
| 701 | 7744813 | Overexpression of the insulin receptor in 32DIR cells, however, restores tyrosine phosphorylation of IRS-1 delta PH and rescues insulin responses including mitogenesis. |
| 702 | 7744813 | Thus, while the PH domain is not required for the engagement of downstream signals, it is one of the elements in the NH2 terminus of IRS-1 that is needed for a sensitive coupling to insulin receptors, especially at ordinary receptor levels found in most cells and tissues. |
| 703 | 7744813 | During insulin stimulation, IRS-1 delta PH is poorly tyrosine-phosphorylated in CHO cells, but undergoes serine/threonine phosphorylation. |
| 704 | 7744813 | Similarly, IRS-1 delta PH fails to undergo insulin-stimulated tyrosine phosphorylation in 32D cells, which uncouples the activation of phosphatidylinositol 3'-kinase and p70s6k from the endogenous insulin receptors. |
| 705 | 7744813 | Overexpression of the insulin receptor in 32DIR cells, however, restores tyrosine phosphorylation of IRS-1 delta PH and rescues insulin responses including mitogenesis. |
| 706 | 7744813 | Thus, while the PH domain is not required for the engagement of downstream signals, it is one of the elements in the NH2 terminus of IRS-1 that is needed for a sensitive coupling to insulin receptors, especially at ordinary receptor levels found in most cells and tissues. |
| 707 | 7762655 | Insulin stimulates signaling reactions that include insulin receptor autophosphorylation and tyrosine kinase activation, insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation, and phosphatidylinositol 3-kinase (PI 3-kinase) activation. |
| 708 | 7762655 | Insulin increased tyrosine phosphorylation of the insulin receptor and IRS-1, whereas contraction alone had no effect. |
| 709 | 7762655 | Contraction before insulin injection decreased the insulin effect on receptor and IRS-1 phosphorylation by 20-25%. |
| 710 | 7762655 | Contraction alone had little effect on PI 3-kinase activity, but contraction markedly blunted the insulin-stimulated activation of IRS-1 and insulin receptor-immunoprecipitable PI 3-kinase. |
| 711 | 7762655 | Insulin stimulates signaling reactions that include insulin receptor autophosphorylation and tyrosine kinase activation, insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation, and phosphatidylinositol 3-kinase (PI 3-kinase) activation. |
| 712 | 7762655 | Insulin increased tyrosine phosphorylation of the insulin receptor and IRS-1, whereas contraction alone had no effect. |
| 713 | 7762655 | Contraction before insulin injection decreased the insulin effect on receptor and IRS-1 phosphorylation by 20-25%. |
| 714 | 7762655 | Contraction alone had little effect on PI 3-kinase activity, but contraction markedly blunted the insulin-stimulated activation of IRS-1 and insulin receptor-immunoprecipitable PI 3-kinase. |
| 715 | 7762655 | Insulin stimulates signaling reactions that include insulin receptor autophosphorylation and tyrosine kinase activation, insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation, and phosphatidylinositol 3-kinase (PI 3-kinase) activation. |
| 716 | 7762655 | Insulin increased tyrosine phosphorylation of the insulin receptor and IRS-1, whereas contraction alone had no effect. |
| 717 | 7762655 | Contraction before insulin injection decreased the insulin effect on receptor and IRS-1 phosphorylation by 20-25%. |
| 718 | 7762655 | Contraction alone had little effect on PI 3-kinase activity, but contraction markedly blunted the insulin-stimulated activation of IRS-1 and insulin receptor-immunoprecipitable PI 3-kinase. |
| 719 | 7762655 | Insulin stimulates signaling reactions that include insulin receptor autophosphorylation and tyrosine kinase activation, insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation, and phosphatidylinositol 3-kinase (PI 3-kinase) activation. |
| 720 | 7762655 | Insulin increased tyrosine phosphorylation of the insulin receptor and IRS-1, whereas contraction alone had no effect. |
| 721 | 7762655 | Contraction before insulin injection decreased the insulin effect on receptor and IRS-1 phosphorylation by 20-25%. |
| 722 | 7762655 | Contraction alone had little effect on PI 3-kinase activity, but contraction markedly blunted the insulin-stimulated activation of IRS-1 and insulin receptor-immunoprecipitable PI 3-kinase. |
| 723 | 7852347 | The amino acid sequence of the tyrosine kinase domain of the insulin-like growth factor-I (IGF-I) receptor is 84% identical to the sequence of the analogous region of the insulin receptor. |
| 724 | 7852347 | Phosphorylation of insulin receptor substrate (IRS)-1 in intact cells by the mutant IGF-I receptors was similar to the level of IRS-1 phosphorylation seen in the parental NIH-3T3 cells, but there was no obvious dominant-negative effect on IRS-1 phosphorylation. |
| 725 | 7852347 | Wheat germ agglutinin-purified mutant receptors were as active in phosphorylating poly-(Glu,Tyr) 4:1 as wild-type IGF-I receptors, suggesting that, in intact cells, additional factors are necessary in order for the IGF-I receptor to phosphorylate IRS-1. |
| 726 | 7852347 | The amino acid sequence of the tyrosine kinase domain of the insulin-like growth factor-I (IGF-I) receptor is 84% identical to the sequence of the analogous region of the insulin receptor. |
| 727 | 7852347 | Phosphorylation of insulin receptor substrate (IRS)-1 in intact cells by the mutant IGF-I receptors was similar to the level of IRS-1 phosphorylation seen in the parental NIH-3T3 cells, but there was no obvious dominant-negative effect on IRS-1 phosphorylation. |
| 728 | 7852347 | Wheat germ agglutinin-purified mutant receptors were as active in phosphorylating poly-(Glu,Tyr) 4:1 as wild-type IGF-I receptors, suggesting that, in intact cells, additional factors are necessary in order for the IGF-I receptor to phosphorylate IRS-1. |
| 729 | 7895667 | Insulin and dexamethasone regulate insulin receptors, insulin receptor substrate-1, and phosphatidylinositol 3-kinase in Fao hepatoma cells. |
| 730 | 7895667 | Insulin rapidly stimulates tyrosine kinase activity of its receptor, resulting in phosphorylation of the cytosolic substrate, insulin receptor substrate-1 (IRS-1), which, in turn, associates with phosphatidylinositol 3-kinase (PI 3-kinase), thus activating the enzyme. |
| 731 | 7895667 | Prolonged insulin treatment induced a time- and dose-dependent decrease in insulin receptor and IRS-1 protein levels, reaching nadirs of 40 +/- 4% (P < 0.01) and 15 +/- 6% (P < 0.005) of control levels, respectively, after 24 h with 100 nM insulin. |
| 732 | 7895667 | There was also a decrease in the phosphorylation of insulin receptors and IRS-1, a marked decrease in the association between IRS-1 and PI 3-kinase, and an 82% decrease in insulin-stimulated PI 3-kinase activity without a significant change in PI 3-kinase protein levels. |
| 733 | 7895667 | When cells were exposed to both insulin and dexamethasone, the effect of insulin to reduce insulin receptor and IRS-1 levels and insulin-stimulated IRS-1 phosphorylation dominated. |
| 734 | 7895667 | These data suggest that regulation of the insulin receptor, IRS-1, and PI 3-kinase contributes significantly to the insulin resistance induced by chronic hyperinsulinemia, but that glucocorticoid-induced insulin resistance is located beyond these early steps in insulin action. |
| 735 | 7895667 | Insulin and dexamethasone regulate insulin receptors, insulin receptor substrate-1, and phosphatidylinositol 3-kinase in Fao hepatoma cells. |
| 736 | 7895667 | Insulin rapidly stimulates tyrosine kinase activity of its receptor, resulting in phosphorylation of the cytosolic substrate, insulin receptor substrate-1 (IRS-1), which, in turn, associates with phosphatidylinositol 3-kinase (PI 3-kinase), thus activating the enzyme. |
| 737 | 7895667 | Prolonged insulin treatment induced a time- and dose-dependent decrease in insulin receptor and IRS-1 protein levels, reaching nadirs of 40 +/- 4% (P < 0.01) and 15 +/- 6% (P < 0.005) of control levels, respectively, after 24 h with 100 nM insulin. |
| 738 | 7895667 | There was also a decrease in the phosphorylation of insulin receptors and IRS-1, a marked decrease in the association between IRS-1 and PI 3-kinase, and an 82% decrease in insulin-stimulated PI 3-kinase activity without a significant change in PI 3-kinase protein levels. |
| 739 | 7895667 | When cells were exposed to both insulin and dexamethasone, the effect of insulin to reduce insulin receptor and IRS-1 levels and insulin-stimulated IRS-1 phosphorylation dominated. |
| 740 | 7895667 | These data suggest that regulation of the insulin receptor, IRS-1, and PI 3-kinase contributes significantly to the insulin resistance induced by chronic hyperinsulinemia, but that glucocorticoid-induced insulin resistance is located beyond these early steps in insulin action. |
| 741 | 7895667 | Insulin and dexamethasone regulate insulin receptors, insulin receptor substrate-1, and phosphatidylinositol 3-kinase in Fao hepatoma cells. |
| 742 | 7895667 | Insulin rapidly stimulates tyrosine kinase activity of its receptor, resulting in phosphorylation of the cytosolic substrate, insulin receptor substrate-1 (IRS-1), which, in turn, associates with phosphatidylinositol 3-kinase (PI 3-kinase), thus activating the enzyme. |
| 743 | 7895667 | Prolonged insulin treatment induced a time- and dose-dependent decrease in insulin receptor and IRS-1 protein levels, reaching nadirs of 40 +/- 4% (P < 0.01) and 15 +/- 6% (P < 0.005) of control levels, respectively, after 24 h with 100 nM insulin. |
| 744 | 7895667 | There was also a decrease in the phosphorylation of insulin receptors and IRS-1, a marked decrease in the association between IRS-1 and PI 3-kinase, and an 82% decrease in insulin-stimulated PI 3-kinase activity without a significant change in PI 3-kinase protein levels. |
| 745 | 7895667 | When cells were exposed to both insulin and dexamethasone, the effect of insulin to reduce insulin receptor and IRS-1 levels and insulin-stimulated IRS-1 phosphorylation dominated. |
| 746 | 7895667 | These data suggest that regulation of the insulin receptor, IRS-1, and PI 3-kinase contributes significantly to the insulin resistance induced by chronic hyperinsulinemia, but that glucocorticoid-induced insulin resistance is located beyond these early steps in insulin action. |
| 747 | 7895667 | Insulin and dexamethasone regulate insulin receptors, insulin receptor substrate-1, and phosphatidylinositol 3-kinase in Fao hepatoma cells. |
| 748 | 7895667 | Insulin rapidly stimulates tyrosine kinase activity of its receptor, resulting in phosphorylation of the cytosolic substrate, insulin receptor substrate-1 (IRS-1), which, in turn, associates with phosphatidylinositol 3-kinase (PI 3-kinase), thus activating the enzyme. |
| 749 | 7895667 | Prolonged insulin treatment induced a time- and dose-dependent decrease in insulin receptor and IRS-1 protein levels, reaching nadirs of 40 +/- 4% (P < 0.01) and 15 +/- 6% (P < 0.005) of control levels, respectively, after 24 h with 100 nM insulin. |
| 750 | 7895667 | There was also a decrease in the phosphorylation of insulin receptors and IRS-1, a marked decrease in the association between IRS-1 and PI 3-kinase, and an 82% decrease in insulin-stimulated PI 3-kinase activity without a significant change in PI 3-kinase protein levels. |
| 751 | 7895667 | When cells were exposed to both insulin and dexamethasone, the effect of insulin to reduce insulin receptor and IRS-1 levels and insulin-stimulated IRS-1 phosphorylation dominated. |
| 752 | 7895667 | These data suggest that regulation of the insulin receptor, IRS-1, and PI 3-kinase contributes significantly to the insulin resistance induced by chronic hyperinsulinemia, but that glucocorticoid-induced insulin resistance is located beyond these early steps in insulin action. |
| 753 | 7895667 | Insulin and dexamethasone regulate insulin receptors, insulin receptor substrate-1, and phosphatidylinositol 3-kinase in Fao hepatoma cells. |
| 754 | 7895667 | Insulin rapidly stimulates tyrosine kinase activity of its receptor, resulting in phosphorylation of the cytosolic substrate, insulin receptor substrate-1 (IRS-1), which, in turn, associates with phosphatidylinositol 3-kinase (PI 3-kinase), thus activating the enzyme. |
| 755 | 7895667 | Prolonged insulin treatment induced a time- and dose-dependent decrease in insulin receptor and IRS-1 protein levels, reaching nadirs of 40 +/- 4% (P < 0.01) and 15 +/- 6% (P < 0.005) of control levels, respectively, after 24 h with 100 nM insulin. |
| 756 | 7895667 | There was also a decrease in the phosphorylation of insulin receptors and IRS-1, a marked decrease in the association between IRS-1 and PI 3-kinase, and an 82% decrease in insulin-stimulated PI 3-kinase activity without a significant change in PI 3-kinase protein levels. |
| 757 | 7895667 | When cells were exposed to both insulin and dexamethasone, the effect of insulin to reduce insulin receptor and IRS-1 levels and insulin-stimulated IRS-1 phosphorylation dominated. |
| 758 | 7895667 | These data suggest that regulation of the insulin receptor, IRS-1, and PI 3-kinase contributes significantly to the insulin resistance induced by chronic hyperinsulinemia, but that glucocorticoid-induced insulin resistance is located beyond these early steps in insulin action. |
| 759 | 7895667 | Insulin and dexamethasone regulate insulin receptors, insulin receptor substrate-1, and phosphatidylinositol 3-kinase in Fao hepatoma cells. |
| 760 | 7895667 | Insulin rapidly stimulates tyrosine kinase activity of its receptor, resulting in phosphorylation of the cytosolic substrate, insulin receptor substrate-1 (IRS-1), which, in turn, associates with phosphatidylinositol 3-kinase (PI 3-kinase), thus activating the enzyme. |
| 761 | 7895667 | Prolonged insulin treatment induced a time- and dose-dependent decrease in insulin receptor and IRS-1 protein levels, reaching nadirs of 40 +/- 4% (P < 0.01) and 15 +/- 6% (P < 0.005) of control levels, respectively, after 24 h with 100 nM insulin. |
| 762 | 7895667 | There was also a decrease in the phosphorylation of insulin receptors and IRS-1, a marked decrease in the association between IRS-1 and PI 3-kinase, and an 82% decrease in insulin-stimulated PI 3-kinase activity without a significant change in PI 3-kinase protein levels. |
| 763 | 7895667 | When cells were exposed to both insulin and dexamethasone, the effect of insulin to reduce insulin receptor and IRS-1 levels and insulin-stimulated IRS-1 phosphorylation dominated. |
| 764 | 7895667 | These data suggest that regulation of the insulin receptor, IRS-1, and PI 3-kinase contributes significantly to the insulin resistance induced by chronic hyperinsulinemia, but that glucocorticoid-induced insulin resistance is located beyond these early steps in insulin action. |
| 765 | 7895862 | After phosphorylation by the insulin receptor, IRS-1 binds to the specific molecules which possess SH2 (src homology 2) domain such as 85 kDa subunit of phosphatidylinositol 3 kinase and may mediate insulin signals. |
| 766 | 7895862 | The regulation of IRS-1 has been analyzed in animal models of insulin resistance, and its mechanism has been studied in culture cells. |
| 767 | 7895862 | In animal models of insulin resistance, phosphorylation of IRS-1 was mainly regulated by the insulin receptor tyrosine kinase both in liver and muscle. |
| 768 | 7895862 | In cultured cell such as 3T3-L1 or 3T3-F442A adipocytes, IRS-1 was negatively regulated both by insulin and dexamethasone by different mechanisms. |
| 769 | 7895862 | Insulin regulates the IRS-1 expression at protein level mainly by decreasing the half life of IRS-1 protein, and dexamethasone regulates it at mRNA level mainly by decreasing the half life of IRS-1 mRNA. |
| 770 | 7895862 | After phosphorylation by the insulin receptor, IRS-1 binds to the specific molecules which possess SH2 (src homology 2) domain such as 85 kDa subunit of phosphatidylinositol 3 kinase and may mediate insulin signals. |
| 771 | 7895862 | The regulation of IRS-1 has been analyzed in animal models of insulin resistance, and its mechanism has been studied in culture cells. |
| 772 | 7895862 | In animal models of insulin resistance, phosphorylation of IRS-1 was mainly regulated by the insulin receptor tyrosine kinase both in liver and muscle. |
| 773 | 7895862 | In cultured cell such as 3T3-L1 or 3T3-F442A adipocytes, IRS-1 was negatively regulated both by insulin and dexamethasone by different mechanisms. |
| 774 | 7895862 | Insulin regulates the IRS-1 expression at protein level mainly by decreasing the half life of IRS-1 protein, and dexamethasone regulates it at mRNA level mainly by decreasing the half life of IRS-1 mRNA. |
| 775 | 7895862 | After phosphorylation by the insulin receptor, IRS-1 binds to the specific molecules which possess SH2 (src homology 2) domain such as 85 kDa subunit of phosphatidylinositol 3 kinase and may mediate insulin signals. |
| 776 | 7895862 | The regulation of IRS-1 has been analyzed in animal models of insulin resistance, and its mechanism has been studied in culture cells. |
| 777 | 7895862 | In animal models of insulin resistance, phosphorylation of IRS-1 was mainly regulated by the insulin receptor tyrosine kinase both in liver and muscle. |
| 778 | 7895862 | In cultured cell such as 3T3-L1 or 3T3-F442A adipocytes, IRS-1 was negatively regulated both by insulin and dexamethasone by different mechanisms. |
| 779 | 7895862 | Insulin regulates the IRS-1 expression at protein level mainly by decreasing the half life of IRS-1 protein, and dexamethasone regulates it at mRNA level mainly by decreasing the half life of IRS-1 mRNA. |
| 780 | 7895862 | After phosphorylation by the insulin receptor, IRS-1 binds to the specific molecules which possess SH2 (src homology 2) domain such as 85 kDa subunit of phosphatidylinositol 3 kinase and may mediate insulin signals. |
| 781 | 7895862 | The regulation of IRS-1 has been analyzed in animal models of insulin resistance, and its mechanism has been studied in culture cells. |
| 782 | 7895862 | In animal models of insulin resistance, phosphorylation of IRS-1 was mainly regulated by the insulin receptor tyrosine kinase both in liver and muscle. |
| 783 | 7895862 | In cultured cell such as 3T3-L1 or 3T3-F442A adipocytes, IRS-1 was negatively regulated both by insulin and dexamethasone by different mechanisms. |
| 784 | 7895862 | Insulin regulates the IRS-1 expression at protein level mainly by decreasing the half life of IRS-1 protein, and dexamethasone regulates it at mRNA level mainly by decreasing the half life of IRS-1 mRNA. |
| 785 | 7895862 | After phosphorylation by the insulin receptor, IRS-1 binds to the specific molecules which possess SH2 (src homology 2) domain such as 85 kDa subunit of phosphatidylinositol 3 kinase and may mediate insulin signals. |
| 786 | 7895862 | The regulation of IRS-1 has been analyzed in animal models of insulin resistance, and its mechanism has been studied in culture cells. |
| 787 | 7895862 | In animal models of insulin resistance, phosphorylation of IRS-1 was mainly regulated by the insulin receptor tyrosine kinase both in liver and muscle. |
| 788 | 7895862 | In cultured cell such as 3T3-L1 or 3T3-F442A adipocytes, IRS-1 was negatively regulated both by insulin and dexamethasone by different mechanisms. |
| 789 | 7895862 | Insulin regulates the IRS-1 expression at protein level mainly by decreasing the half life of IRS-1 protein, and dexamethasone regulates it at mRNA level mainly by decreasing the half life of IRS-1 mRNA. |
| 790 | 7901717 | Insulin receptor substrate (IRS-1) gene polymorphisms in French NIDDM families. |
| 791 | 7926300 | Recent data have suggested a key role for tumor necrosis factor (TNF)-alpha in the insulin resistance of obesity and non-insulin-dependent diabetes mellitus (NIDDM). |
| 792 | 7926300 | Neutralization of TNF-alpha in one of these models improves insulin sensitivity by increasing the activity of the insulin receptor tyrosine kinase, specifically in muscle and fat tissues. |
| 793 | 7926300 | On a cellular level, TNF-alpha is a potent inhibitor of the insulin-stimulated tyrosine phosphorylations on the beta-chain of the insulin receptor and insulin receptor substrate-1, suggesting a defect at or near the tyrosine kinase activity of the insulin receptor. |
| 794 | 7926300 | Given the clear link between obesity, insulin resistance, and diabetes, these results strongly suggest that TNF-alpha may play a crucial role in the systemic insulin resistance of NIDDM. |
| 795 | 7926303 | The expressed receptor was able to mediate an insulin-stimulated increase in both anti-phosphotyrosine-precipitable and anti-insulin receptor substrate 1-precipitable phosphatidylinositol 3-kinase activity. |
| 796 | 7948013 | An area of recent investigation is in insulin-stimulated phosphorylation of intracellular substrates such as IRS-1 which activates insulin specific cellular signaling molecules [245]. |
| 797 | 7948013 | Candidate molecules to study insulin action on apo B include IRS-1 and SH2-containing signaling molecules. |
| 798 | 7948013 | An area of recent investigation is in insulin-stimulated phosphorylation of intracellular substrates such as IRS-1 which activates insulin specific cellular signaling molecules [245]. |
| 799 | 7948013 | Candidate molecules to study insulin action on apo B include IRS-1 and SH2-containing signaling molecules. |
| 800 | 7961682 | Interactive roles of Ras, insulin receptor substrate-1, and proteins with Src homology-2 domains in insulin signaling in Xenopus oocytes. |
| 801 | 7961682 | Insulin receptor substrate-1 (IRS-1) serves as the major immediate substrate of insulin/insulin-like growth factor (IGF)-1 receptors and following tyrosine phosphorylation binds to specific Src homology-2 (SH2) domain-containing proteins including the p85 subunit of phosphatidylinositol (PI) 3-kinase and GRB2, a molecule believed to link IRS-1 to the Ras pathway. |
| 802 | 7961682 | To investigate how these SH2-containing signaling molecules interact to regulate insulin/IGF-1 action, IRS-1, glutathione S-transferase (GST)-SH2 domain fusion proteins and Ras proteins were microinjected into Xenopus oocytes. |
| 803 | 7961682 | We found that pleiotropic insulin actions are mediated by IRS-1 through two independent, but convergent, pathways involving PI 3-kinase and GRB2. |
| 804 | 7961682 | Thus, microinjection of GST-fusion proteins of either p85 or GRB2 inhibited IRS-1-dependent activation of mitogen-activated protein (MAP) and S6 kinases and oocyte maturation, although only the GST-SH2 of p85 reduced insulin-stimulated PI 3-kinase activation. |
| 805 | 7961682 | Co-injection of a dominant negative Ras (S17N) with IRS-1 inhibited insulin-stimulated MAP and S6 kinase activation. |
| 806 | 7961682 | Micro-injection of activated [Arg12,Thr59]Ras increased basal MAP and S6 kinase activities and sensitized the oocytes to insulin-stimulated maturation without altering insulin-stimulated PI 3-kinase. |
| 807 | 7961682 | These data strongly suggest that IRS-1 can mediate many of insulin's actions on cellular enzyme activation and cell cycle progression requires binding and activation of multiple different SH2-domain proteins. |
| 808 | 7961682 | Interactive roles of Ras, insulin receptor substrate-1, and proteins with Src homology-2 domains in insulin signaling in Xenopus oocytes. |
| 809 | 7961682 | Insulin receptor substrate-1 (IRS-1) serves as the major immediate substrate of insulin/insulin-like growth factor (IGF)-1 receptors and following tyrosine phosphorylation binds to specific Src homology-2 (SH2) domain-containing proteins including the p85 subunit of phosphatidylinositol (PI) 3-kinase and GRB2, a molecule believed to link IRS-1 to the Ras pathway. |
| 810 | 7961682 | To investigate how these SH2-containing signaling molecules interact to regulate insulin/IGF-1 action, IRS-1, glutathione S-transferase (GST)-SH2 domain fusion proteins and Ras proteins were microinjected into Xenopus oocytes. |
| 811 | 7961682 | We found that pleiotropic insulin actions are mediated by IRS-1 through two independent, but convergent, pathways involving PI 3-kinase and GRB2. |
| 812 | 7961682 | Thus, microinjection of GST-fusion proteins of either p85 or GRB2 inhibited IRS-1-dependent activation of mitogen-activated protein (MAP) and S6 kinases and oocyte maturation, although only the GST-SH2 of p85 reduced insulin-stimulated PI 3-kinase activation. |
| 813 | 7961682 | Co-injection of a dominant negative Ras (S17N) with IRS-1 inhibited insulin-stimulated MAP and S6 kinase activation. |
| 814 | 7961682 | Micro-injection of activated [Arg12,Thr59]Ras increased basal MAP and S6 kinase activities and sensitized the oocytes to insulin-stimulated maturation without altering insulin-stimulated PI 3-kinase. |
| 815 | 7961682 | These data strongly suggest that IRS-1 can mediate many of insulin's actions on cellular enzyme activation and cell cycle progression requires binding and activation of multiple different SH2-domain proteins. |
| 816 | 7961682 | Interactive roles of Ras, insulin receptor substrate-1, and proteins with Src homology-2 domains in insulin signaling in Xenopus oocytes. |
| 817 | 7961682 | Insulin receptor substrate-1 (IRS-1) serves as the major immediate substrate of insulin/insulin-like growth factor (IGF)-1 receptors and following tyrosine phosphorylation binds to specific Src homology-2 (SH2) domain-containing proteins including the p85 subunit of phosphatidylinositol (PI) 3-kinase and GRB2, a molecule believed to link IRS-1 to the Ras pathway. |
| 818 | 7961682 | To investigate how these SH2-containing signaling molecules interact to regulate insulin/IGF-1 action, IRS-1, glutathione S-transferase (GST)-SH2 domain fusion proteins and Ras proteins were microinjected into Xenopus oocytes. |
| 819 | 7961682 | We found that pleiotropic insulin actions are mediated by IRS-1 through two independent, but convergent, pathways involving PI 3-kinase and GRB2. |
| 820 | 7961682 | Thus, microinjection of GST-fusion proteins of either p85 or GRB2 inhibited IRS-1-dependent activation of mitogen-activated protein (MAP) and S6 kinases and oocyte maturation, although only the GST-SH2 of p85 reduced insulin-stimulated PI 3-kinase activation. |
| 821 | 7961682 | Co-injection of a dominant negative Ras (S17N) with IRS-1 inhibited insulin-stimulated MAP and S6 kinase activation. |
| 822 | 7961682 | Micro-injection of activated [Arg12,Thr59]Ras increased basal MAP and S6 kinase activities and sensitized the oocytes to insulin-stimulated maturation without altering insulin-stimulated PI 3-kinase. |
| 823 | 7961682 | These data strongly suggest that IRS-1 can mediate many of insulin's actions on cellular enzyme activation and cell cycle progression requires binding and activation of multiple different SH2-domain proteins. |
| 824 | 7961682 | Interactive roles of Ras, insulin receptor substrate-1, and proteins with Src homology-2 domains in insulin signaling in Xenopus oocytes. |
| 825 | 7961682 | Insulin receptor substrate-1 (IRS-1) serves as the major immediate substrate of insulin/insulin-like growth factor (IGF)-1 receptors and following tyrosine phosphorylation binds to specific Src homology-2 (SH2) domain-containing proteins including the p85 subunit of phosphatidylinositol (PI) 3-kinase and GRB2, a molecule believed to link IRS-1 to the Ras pathway. |
| 826 | 7961682 | To investigate how these SH2-containing signaling molecules interact to regulate insulin/IGF-1 action, IRS-1, glutathione S-transferase (GST)-SH2 domain fusion proteins and Ras proteins were microinjected into Xenopus oocytes. |
| 827 | 7961682 | We found that pleiotropic insulin actions are mediated by IRS-1 through two independent, but convergent, pathways involving PI 3-kinase and GRB2. |
| 828 | 7961682 | Thus, microinjection of GST-fusion proteins of either p85 or GRB2 inhibited IRS-1-dependent activation of mitogen-activated protein (MAP) and S6 kinases and oocyte maturation, although only the GST-SH2 of p85 reduced insulin-stimulated PI 3-kinase activation. |
| 829 | 7961682 | Co-injection of a dominant negative Ras (S17N) with IRS-1 inhibited insulin-stimulated MAP and S6 kinase activation. |
| 830 | 7961682 | Micro-injection of activated [Arg12,Thr59]Ras increased basal MAP and S6 kinase activities and sensitized the oocytes to insulin-stimulated maturation without altering insulin-stimulated PI 3-kinase. |
| 831 | 7961682 | These data strongly suggest that IRS-1 can mediate many of insulin's actions on cellular enzyme activation and cell cycle progression requires binding and activation of multiple different SH2-domain proteins. |
| 832 | 7961682 | Interactive roles of Ras, insulin receptor substrate-1, and proteins with Src homology-2 domains in insulin signaling in Xenopus oocytes. |
| 833 | 7961682 | Insulin receptor substrate-1 (IRS-1) serves as the major immediate substrate of insulin/insulin-like growth factor (IGF)-1 receptors and following tyrosine phosphorylation binds to specific Src homology-2 (SH2) domain-containing proteins including the p85 subunit of phosphatidylinositol (PI) 3-kinase and GRB2, a molecule believed to link IRS-1 to the Ras pathway. |
| 834 | 7961682 | To investigate how these SH2-containing signaling molecules interact to regulate insulin/IGF-1 action, IRS-1, glutathione S-transferase (GST)-SH2 domain fusion proteins and Ras proteins were microinjected into Xenopus oocytes. |
| 835 | 7961682 | We found that pleiotropic insulin actions are mediated by IRS-1 through two independent, but convergent, pathways involving PI 3-kinase and GRB2. |
| 836 | 7961682 | Thus, microinjection of GST-fusion proteins of either p85 or GRB2 inhibited IRS-1-dependent activation of mitogen-activated protein (MAP) and S6 kinases and oocyte maturation, although only the GST-SH2 of p85 reduced insulin-stimulated PI 3-kinase activation. |
| 837 | 7961682 | Co-injection of a dominant negative Ras (S17N) with IRS-1 inhibited insulin-stimulated MAP and S6 kinase activation. |
| 838 | 7961682 | Micro-injection of activated [Arg12,Thr59]Ras increased basal MAP and S6 kinase activities and sensitized the oocytes to insulin-stimulated maturation without altering insulin-stimulated PI 3-kinase. |
| 839 | 7961682 | These data strongly suggest that IRS-1 can mediate many of insulin's actions on cellular enzyme activation and cell cycle progression requires binding and activation of multiple different SH2-domain proteins. |
| 840 | 7961682 | Interactive roles of Ras, insulin receptor substrate-1, and proteins with Src homology-2 domains in insulin signaling in Xenopus oocytes. |
| 841 | 7961682 | Insulin receptor substrate-1 (IRS-1) serves as the major immediate substrate of insulin/insulin-like growth factor (IGF)-1 receptors and following tyrosine phosphorylation binds to specific Src homology-2 (SH2) domain-containing proteins including the p85 subunit of phosphatidylinositol (PI) 3-kinase and GRB2, a molecule believed to link IRS-1 to the Ras pathway. |
| 842 | 7961682 | To investigate how these SH2-containing signaling molecules interact to regulate insulin/IGF-1 action, IRS-1, glutathione S-transferase (GST)-SH2 domain fusion proteins and Ras proteins were microinjected into Xenopus oocytes. |
| 843 | 7961682 | We found that pleiotropic insulin actions are mediated by IRS-1 through two independent, but convergent, pathways involving PI 3-kinase and GRB2. |
| 844 | 7961682 | Thus, microinjection of GST-fusion proteins of either p85 or GRB2 inhibited IRS-1-dependent activation of mitogen-activated protein (MAP) and S6 kinases and oocyte maturation, although only the GST-SH2 of p85 reduced insulin-stimulated PI 3-kinase activation. |
| 845 | 7961682 | Co-injection of a dominant negative Ras (S17N) with IRS-1 inhibited insulin-stimulated MAP and S6 kinase activation. |
| 846 | 7961682 | Micro-injection of activated [Arg12,Thr59]Ras increased basal MAP and S6 kinase activities and sensitized the oocytes to insulin-stimulated maturation without altering insulin-stimulated PI 3-kinase. |
| 847 | 7961682 | These data strongly suggest that IRS-1 can mediate many of insulin's actions on cellular enzyme activation and cell cycle progression requires binding and activation of multiple different SH2-domain proteins. |
| 848 | 7961833 | Insulin receptor substrate-1 mediates phosphatidylinositol 3'-kinase and p70S6k signaling during insulin, insulin-like growth factor-1, and interleukin-4 stimulation. |
| 849 | 7961833 | Insulin Receptor Substrate-1 (IRS-1) is an endogenous cellular protein that is tyrosine phosphorylated during stimulation of cells with insulin, IGF-1, and interleukin 4 (IL-4). |
| 850 | 7961833 | The 32D myeloid progenitor cell line contains few insulin receptors and no detectable IRS-1. |
| 851 | 7961833 | Expression of the insulin receptor alone partially mediates insulin-stimulated microtubule-associated protein (MAP) kinase activation, and the addition of IRS-1 enhances this effect (Myers, M. |
| 852 | 7961833 | Expression of IRS-1 alone in 32D cells mediates the stimulation of p70S6k by insulin, IGF-1, or IL-4; addition of insulin receptor to these cells increases the sensitivity of the insulin response. |
| 853 | 7961833 | In contrast, full insulin stimulation of PI 3'-kinase requires both the insulin receptor and IRS-1, suggesting that a high level of IRS-1 phosphorylation is required for insulin-stimulated PI 3'-kinase activation, whereas a low level of IRS-1 tyrosine phosphorylation transmits an essential signal to p70S6k. |
| 854 | 7961833 | Both insulin receptors and IRS-1 are required for mitogenic signaling in 32D cells suggesting that MAP kinase or p70S6k alone are not sufficient, and that both or additional unknown IRS-1-mediated signals are necessary. |
| 855 | 7961833 | Insulin receptor substrate-1 mediates phosphatidylinositol 3'-kinase and p70S6k signaling during insulin, insulin-like growth factor-1, and interleukin-4 stimulation. |
| 856 | 7961833 | Insulin Receptor Substrate-1 (IRS-1) is an endogenous cellular protein that is tyrosine phosphorylated during stimulation of cells with insulin, IGF-1, and interleukin 4 (IL-4). |
| 857 | 7961833 | The 32D myeloid progenitor cell line contains few insulin receptors and no detectable IRS-1. |
| 858 | 7961833 | Expression of the insulin receptor alone partially mediates insulin-stimulated microtubule-associated protein (MAP) kinase activation, and the addition of IRS-1 enhances this effect (Myers, M. |
| 859 | 7961833 | Expression of IRS-1 alone in 32D cells mediates the stimulation of p70S6k by insulin, IGF-1, or IL-4; addition of insulin receptor to these cells increases the sensitivity of the insulin response. |
| 860 | 7961833 | In contrast, full insulin stimulation of PI 3'-kinase requires both the insulin receptor and IRS-1, suggesting that a high level of IRS-1 phosphorylation is required for insulin-stimulated PI 3'-kinase activation, whereas a low level of IRS-1 tyrosine phosphorylation transmits an essential signal to p70S6k. |
| 861 | 7961833 | Both insulin receptors and IRS-1 are required for mitogenic signaling in 32D cells suggesting that MAP kinase or p70S6k alone are not sufficient, and that both or additional unknown IRS-1-mediated signals are necessary. |
| 862 | 7961833 | Insulin receptor substrate-1 mediates phosphatidylinositol 3'-kinase and p70S6k signaling during insulin, insulin-like growth factor-1, and interleukin-4 stimulation. |
| 863 | 7961833 | Insulin Receptor Substrate-1 (IRS-1) is an endogenous cellular protein that is tyrosine phosphorylated during stimulation of cells with insulin, IGF-1, and interleukin 4 (IL-4). |
| 864 | 7961833 | The 32D myeloid progenitor cell line contains few insulin receptors and no detectable IRS-1. |
| 865 | 7961833 | Expression of the insulin receptor alone partially mediates insulin-stimulated microtubule-associated protein (MAP) kinase activation, and the addition of IRS-1 enhances this effect (Myers, M. |
| 866 | 7961833 | Expression of IRS-1 alone in 32D cells mediates the stimulation of p70S6k by insulin, IGF-1, or IL-4; addition of insulin receptor to these cells increases the sensitivity of the insulin response. |
| 867 | 7961833 | In contrast, full insulin stimulation of PI 3'-kinase requires both the insulin receptor and IRS-1, suggesting that a high level of IRS-1 phosphorylation is required for insulin-stimulated PI 3'-kinase activation, whereas a low level of IRS-1 tyrosine phosphorylation transmits an essential signal to p70S6k. |
| 868 | 7961833 | Both insulin receptors and IRS-1 are required for mitogenic signaling in 32D cells suggesting that MAP kinase or p70S6k alone are not sufficient, and that both or additional unknown IRS-1-mediated signals are necessary. |
| 869 | 7961833 | Insulin receptor substrate-1 mediates phosphatidylinositol 3'-kinase and p70S6k signaling during insulin, insulin-like growth factor-1, and interleukin-4 stimulation. |
| 870 | 7961833 | Insulin Receptor Substrate-1 (IRS-1) is an endogenous cellular protein that is tyrosine phosphorylated during stimulation of cells with insulin, IGF-1, and interleukin 4 (IL-4). |
| 871 | 7961833 | The 32D myeloid progenitor cell line contains few insulin receptors and no detectable IRS-1. |
| 872 | 7961833 | Expression of the insulin receptor alone partially mediates insulin-stimulated microtubule-associated protein (MAP) kinase activation, and the addition of IRS-1 enhances this effect (Myers, M. |
| 873 | 7961833 | Expression of IRS-1 alone in 32D cells mediates the stimulation of p70S6k by insulin, IGF-1, or IL-4; addition of insulin receptor to these cells increases the sensitivity of the insulin response. |
| 874 | 7961833 | In contrast, full insulin stimulation of PI 3'-kinase requires both the insulin receptor and IRS-1, suggesting that a high level of IRS-1 phosphorylation is required for insulin-stimulated PI 3'-kinase activation, whereas a low level of IRS-1 tyrosine phosphorylation transmits an essential signal to p70S6k. |
| 875 | 7961833 | Both insulin receptors and IRS-1 are required for mitogenic signaling in 32D cells suggesting that MAP kinase or p70S6k alone are not sufficient, and that both or additional unknown IRS-1-mediated signals are necessary. |
| 876 | 7961833 | Insulin receptor substrate-1 mediates phosphatidylinositol 3'-kinase and p70S6k signaling during insulin, insulin-like growth factor-1, and interleukin-4 stimulation. |
| 877 | 7961833 | Insulin Receptor Substrate-1 (IRS-1) is an endogenous cellular protein that is tyrosine phosphorylated during stimulation of cells with insulin, IGF-1, and interleukin 4 (IL-4). |
| 878 | 7961833 | The 32D myeloid progenitor cell line contains few insulin receptors and no detectable IRS-1. |
| 879 | 7961833 | Expression of the insulin receptor alone partially mediates insulin-stimulated microtubule-associated protein (MAP) kinase activation, and the addition of IRS-1 enhances this effect (Myers, M. |
| 880 | 7961833 | Expression of IRS-1 alone in 32D cells mediates the stimulation of p70S6k by insulin, IGF-1, or IL-4; addition of insulin receptor to these cells increases the sensitivity of the insulin response. |
| 881 | 7961833 | In contrast, full insulin stimulation of PI 3'-kinase requires both the insulin receptor and IRS-1, suggesting that a high level of IRS-1 phosphorylation is required for insulin-stimulated PI 3'-kinase activation, whereas a low level of IRS-1 tyrosine phosphorylation transmits an essential signal to p70S6k. |
| 882 | 7961833 | Both insulin receptors and IRS-1 are required for mitogenic signaling in 32D cells suggesting that MAP kinase or p70S6k alone are not sufficient, and that both or additional unknown IRS-1-mediated signals are necessary. |
| 883 | 7961833 | Insulin receptor substrate-1 mediates phosphatidylinositol 3'-kinase and p70S6k signaling during insulin, insulin-like growth factor-1, and interleukin-4 stimulation. |
| 884 | 7961833 | Insulin Receptor Substrate-1 (IRS-1) is an endogenous cellular protein that is tyrosine phosphorylated during stimulation of cells with insulin, IGF-1, and interleukin 4 (IL-4). |
| 885 | 7961833 | The 32D myeloid progenitor cell line contains few insulin receptors and no detectable IRS-1. |
| 886 | 7961833 | Expression of the insulin receptor alone partially mediates insulin-stimulated microtubule-associated protein (MAP) kinase activation, and the addition of IRS-1 enhances this effect (Myers, M. |
| 887 | 7961833 | Expression of IRS-1 alone in 32D cells mediates the stimulation of p70S6k by insulin, IGF-1, or IL-4; addition of insulin receptor to these cells increases the sensitivity of the insulin response. |
| 888 | 7961833 | In contrast, full insulin stimulation of PI 3'-kinase requires both the insulin receptor and IRS-1, suggesting that a high level of IRS-1 phosphorylation is required for insulin-stimulated PI 3'-kinase activation, whereas a low level of IRS-1 tyrosine phosphorylation transmits an essential signal to p70S6k. |
| 889 | 7961833 | Both insulin receptors and IRS-1 are required for mitogenic signaling in 32D cells suggesting that MAP kinase or p70S6k alone are not sufficient, and that both or additional unknown IRS-1-mediated signals are necessary. |
| 890 | 7961833 | Insulin receptor substrate-1 mediates phosphatidylinositol 3'-kinase and p70S6k signaling during insulin, insulin-like growth factor-1, and interleukin-4 stimulation. |
| 891 | 7961833 | Insulin Receptor Substrate-1 (IRS-1) is an endogenous cellular protein that is tyrosine phosphorylated during stimulation of cells with insulin, IGF-1, and interleukin 4 (IL-4). |
| 892 | 7961833 | The 32D myeloid progenitor cell line contains few insulin receptors and no detectable IRS-1. |
| 893 | 7961833 | Expression of the insulin receptor alone partially mediates insulin-stimulated microtubule-associated protein (MAP) kinase activation, and the addition of IRS-1 enhances this effect (Myers, M. |
| 894 | 7961833 | Expression of IRS-1 alone in 32D cells mediates the stimulation of p70S6k by insulin, IGF-1, or IL-4; addition of insulin receptor to these cells increases the sensitivity of the insulin response. |
| 895 | 7961833 | In contrast, full insulin stimulation of PI 3'-kinase requires both the insulin receptor and IRS-1, suggesting that a high level of IRS-1 phosphorylation is required for insulin-stimulated PI 3'-kinase activation, whereas a low level of IRS-1 tyrosine phosphorylation transmits an essential signal to p70S6k. |
| 896 | 7961833 | Both insulin receptors and IRS-1 are required for mitogenic signaling in 32D cells suggesting that MAP kinase or p70S6k alone are not sufficient, and that both or additional unknown IRS-1-mediated signals are necessary. |
| 897 | 7965046 | Insulin receptor substrate 1 (IRS-1) is the primary cytosolic substrate of the insulin and insulin-like growth factor-I (IGF-I) receptors. |
| 898 | 7965046 | Using biochemical and immunocytochemical techniques, we have mapped the distribution of IRS-1 in the CNS of the adult rat and compared it with that of insulin and IGF-I receptors and phosphatidylinositol 3-kinase (PI-3 kinase), a signaling molecule functionally related to IRS-1. |
| 899 | 7965046 | Immunoprecipitation and Western blotting experiments demonstrate the presence of substantial amounts of IRS-1, insulin receptor, and PI-3 kinase in the brain. |
| 900 | 7965046 | In these areas most of the neurons immunoreactive for IRS-1 are also stained by either anti-insulin receptor or anti-IGF-I receptor antibodies as well as PI-3 kinase antiserum. |
| 901 | 7965046 | IRS-1 immunostaining was very weak or totally absent in neurons of the olfactory bulb, the supraoptic and paraventricular nuclei, the mesencephalic trigeminal nucleus, and the granule cell layer of the cerebellum, despite the fact that these areas were immunolabeled with antibodies against insulin or IGF-I receptors and/or PI-3 kinase. |
| 902 | 7965046 | These results show that neurons in the adult rat CNS are endowed with some of the components of the early signaling pathway for growth factors of the insulin/IGF-I family, although IRS-1 has a distribution distinct from that of the two receptors. |
| 903 | 7965046 | Insulin receptor substrate 1 (IRS-1) is the primary cytosolic substrate of the insulin and insulin-like growth factor-I (IGF-I) receptors. |
| 904 | 7965046 | Using biochemical and immunocytochemical techniques, we have mapped the distribution of IRS-1 in the CNS of the adult rat and compared it with that of insulin and IGF-I receptors and phosphatidylinositol 3-kinase (PI-3 kinase), a signaling molecule functionally related to IRS-1. |
| 905 | 7965046 | Immunoprecipitation and Western blotting experiments demonstrate the presence of substantial amounts of IRS-1, insulin receptor, and PI-3 kinase in the brain. |
| 906 | 7965046 | In these areas most of the neurons immunoreactive for IRS-1 are also stained by either anti-insulin receptor or anti-IGF-I receptor antibodies as well as PI-3 kinase antiserum. |
| 907 | 7965046 | IRS-1 immunostaining was very weak or totally absent in neurons of the olfactory bulb, the supraoptic and paraventricular nuclei, the mesencephalic trigeminal nucleus, and the granule cell layer of the cerebellum, despite the fact that these areas were immunolabeled with antibodies against insulin or IGF-I receptors and/or PI-3 kinase. |
| 908 | 7965046 | These results show that neurons in the adult rat CNS are endowed with some of the components of the early signaling pathway for growth factors of the insulin/IGF-I family, although IRS-1 has a distribution distinct from that of the two receptors. |
| 909 | 7965046 | Insulin receptor substrate 1 (IRS-1) is the primary cytosolic substrate of the insulin and insulin-like growth factor-I (IGF-I) receptors. |
| 910 | 7965046 | Using biochemical and immunocytochemical techniques, we have mapped the distribution of IRS-1 in the CNS of the adult rat and compared it with that of insulin and IGF-I receptors and phosphatidylinositol 3-kinase (PI-3 kinase), a signaling molecule functionally related to IRS-1. |
| 911 | 7965046 | Immunoprecipitation and Western blotting experiments demonstrate the presence of substantial amounts of IRS-1, insulin receptor, and PI-3 kinase in the brain. |
| 912 | 7965046 | In these areas most of the neurons immunoreactive for IRS-1 are also stained by either anti-insulin receptor or anti-IGF-I receptor antibodies as well as PI-3 kinase antiserum. |
| 913 | 7965046 | IRS-1 immunostaining was very weak or totally absent in neurons of the olfactory bulb, the supraoptic and paraventricular nuclei, the mesencephalic trigeminal nucleus, and the granule cell layer of the cerebellum, despite the fact that these areas were immunolabeled with antibodies against insulin or IGF-I receptors and/or PI-3 kinase. |
| 914 | 7965046 | These results show that neurons in the adult rat CNS are endowed with some of the components of the early signaling pathway for growth factors of the insulin/IGF-I family, although IRS-1 has a distribution distinct from that of the two receptors. |
| 915 | 7965046 | Insulin receptor substrate 1 (IRS-1) is the primary cytosolic substrate of the insulin and insulin-like growth factor-I (IGF-I) receptors. |
| 916 | 7965046 | Using biochemical and immunocytochemical techniques, we have mapped the distribution of IRS-1 in the CNS of the adult rat and compared it with that of insulin and IGF-I receptors and phosphatidylinositol 3-kinase (PI-3 kinase), a signaling molecule functionally related to IRS-1. |
| 917 | 7965046 | Immunoprecipitation and Western blotting experiments demonstrate the presence of substantial amounts of IRS-1, insulin receptor, and PI-3 kinase in the brain. |
| 918 | 7965046 | In these areas most of the neurons immunoreactive for IRS-1 are also stained by either anti-insulin receptor or anti-IGF-I receptor antibodies as well as PI-3 kinase antiserum. |
| 919 | 7965046 | IRS-1 immunostaining was very weak or totally absent in neurons of the olfactory bulb, the supraoptic and paraventricular nuclei, the mesencephalic trigeminal nucleus, and the granule cell layer of the cerebellum, despite the fact that these areas were immunolabeled with antibodies against insulin or IGF-I receptors and/or PI-3 kinase. |
| 920 | 7965046 | These results show that neurons in the adult rat CNS are endowed with some of the components of the early signaling pathway for growth factors of the insulin/IGF-I family, although IRS-1 has a distribution distinct from that of the two receptors. |
| 921 | 7965046 | Insulin receptor substrate 1 (IRS-1) is the primary cytosolic substrate of the insulin and insulin-like growth factor-I (IGF-I) receptors. |
| 922 | 7965046 | Using biochemical and immunocytochemical techniques, we have mapped the distribution of IRS-1 in the CNS of the adult rat and compared it with that of insulin and IGF-I receptors and phosphatidylinositol 3-kinase (PI-3 kinase), a signaling molecule functionally related to IRS-1. |
| 923 | 7965046 | Immunoprecipitation and Western blotting experiments demonstrate the presence of substantial amounts of IRS-1, insulin receptor, and PI-3 kinase in the brain. |
| 924 | 7965046 | In these areas most of the neurons immunoreactive for IRS-1 are also stained by either anti-insulin receptor or anti-IGF-I receptor antibodies as well as PI-3 kinase antiserum. |
| 925 | 7965046 | IRS-1 immunostaining was very weak or totally absent in neurons of the olfactory bulb, the supraoptic and paraventricular nuclei, the mesencephalic trigeminal nucleus, and the granule cell layer of the cerebellum, despite the fact that these areas were immunolabeled with antibodies against insulin or IGF-I receptors and/or PI-3 kinase. |
| 926 | 7965046 | These results show that neurons in the adult rat CNS are endowed with some of the components of the early signaling pathway for growth factors of the insulin/IGF-I family, although IRS-1 has a distribution distinct from that of the two receptors. |
| 927 | 7965046 | Insulin receptor substrate 1 (IRS-1) is the primary cytosolic substrate of the insulin and insulin-like growth factor-I (IGF-I) receptors. |
| 928 | 7965046 | Using biochemical and immunocytochemical techniques, we have mapped the distribution of IRS-1 in the CNS of the adult rat and compared it with that of insulin and IGF-I receptors and phosphatidylinositol 3-kinase (PI-3 kinase), a signaling molecule functionally related to IRS-1. |
| 929 | 7965046 | Immunoprecipitation and Western blotting experiments demonstrate the presence of substantial amounts of IRS-1, insulin receptor, and PI-3 kinase in the brain. |
| 930 | 7965046 | In these areas most of the neurons immunoreactive for IRS-1 are also stained by either anti-insulin receptor or anti-IGF-I receptor antibodies as well as PI-3 kinase antiserum. |
| 931 | 7965046 | IRS-1 immunostaining was very weak or totally absent in neurons of the olfactory bulb, the supraoptic and paraventricular nuclei, the mesencephalic trigeminal nucleus, and the granule cell layer of the cerebellum, despite the fact that these areas were immunolabeled with antibodies against insulin or IGF-I receptors and/or PI-3 kinase. |
| 932 | 7965046 | These results show that neurons in the adult rat CNS are endowed with some of the components of the early signaling pathway for growth factors of the insulin/IGF-I family, although IRS-1 has a distribution distinct from that of the two receptors. |
| 933 | 7983060 | Demonstration that the p85 subunit binds directly to the COOH terminus of the insulin receptor in intact cells. |
| 934 | 7983060 | Phosphorylated IRS-1 binds to SH2 domains in the p85 regulatory subunit of phosphatidyl inositol (PI) 3-kinase, thereby stimulating the catalytic activity of PI 3-kinase. |
| 935 | 7983060 | For most growth factor receptor tyrosine kinases (including receptors for epidermal growth factor and platelet-derived growth factor), the p85 regulatory subunit of PI 3-kinase binds directly to phosphorylated YXXM motifs contained in the cytoplasmic domain of the receptor itself. |
| 936 | 7983060 | Previous studies in cell-free systems have shown that the phosphorylated YHTM sequence (amino acid residues 1322-1325) in the COOH terminus of the insulin receptor has the ability to bind to the p85 subunit of PI 3-kinase, thereby activating the enzyme. |
| 937 | 7983060 | Subsequent to insulin-stimulated phosphorylation of the insulin receptor, a complex is formed that contains the insulin receptor and PI 3-kinase. |
| 938 | 7983060 | This complex can be immunoprecipitated by antibodies directed against either the insulin receptor or the p85 subunit of PI 3-kinase. |
| 939 | 7983060 | The delta 43 mutant insulin receptor that lacks 43 amino acids at the COOH terminus does not bind p85. |
| 940 | 7983060 | Thus, by binding directly to p85, the phosphorylated YHTM motif in the COOH terminus of the insulin receptor contributes partially to mediating the effect of insulin to activate PI 3-kinase. |
| 941 | 7989470 | To search for genetic defects causing NIDDM, we have screened for mutations in the gene encoding insulin receptor substrate-1 (IRS-1), an intracellular protein that is phosphorylated by the insulin receptor and is thought to play an important role in mediating insulin action. |
| 942 | 8037748 | We studied a simple tandem repeat DNA polymorphism in the glycogen synthase gene and polymorphisms at codon 513 (Ala-->Pro) and 972 (Gly-->Arg) in the insulin receptor substrate-1 (IRS-1) gene in 197 non-insulin-dependent diabetes mellitus (NIDDM) and 178 control subjects in Japan. |
| 943 | 8048169 | Insulin-receptor substrate 1 (IRS-1) is a principal substrate of the receptor tyrosine kinase for insulin and insulin-like growth factor 1, and a substrate for a tyrosine kinase activated by interleukin 4. |
| 944 | 8048169 | IRS-1 undergoes multisite tyrosine phosphorylation and mediates downstream signals by 'docking' various proteins that contain Src homology 2 domains. |
| 945 | 8048169 | Insulin-receptor substrate 1 (IRS-1) is a principal substrate of the receptor tyrosine kinase for insulin and insulin-like growth factor 1, and a substrate for a tyrosine kinase activated by interleukin 4. |
| 946 | 8048169 | IRS-1 undergoes multisite tyrosine phosphorylation and mediates downstream signals by 'docking' various proteins that contain Src homology 2 domains. |
| 947 | 8049217 | We found that, despite the deletion of most of the tyrosine kinase domain and all of the C-terminal domain of the beta-subunit of the insulin receptor, the delta 1000 mutant receptors were processed normally and were transported to the plasma membrane where they bind insulin with high affinity. |
| 948 | 8049217 | However, they fail to undergo insulin-stimulated internalization, do not regulate the phosphorylation of insulin receptor substrate 1, and are unable to mediate an insulin-stimulated increase in DNA synthesis and c-jun and c-fos expression. |
| 949 | 8058065 | The level of insulin receptor tyrosine kinase activity modulates the activities of phosphatidylinositol 3-kinase, microtubule-associated protein, and S6 kinases. |
| 950 | 8058065 | The role of insulin receptor tyrosine kinase activity in stimulation of intracellular enzymes linked to insulin action [phosphatidylinositol 3-kinase (PtdIns 3-kinase), microtubule-associated protein (MAP) kinase, and S6 kinases] was studied in Chinese hamster ovary cells which overexpress wild type human insulin receptors, receptors with reduced kinase activity due to substitution of Phe for Tyr1146 (single-Phe), Tyr1150,1151 (double-Phe), and Tyr1146,1150,1151 (triple-Phe), or kinase-inactive receptors with a substitution of Ala for Lys1018 in the ATP binding site (A1018). |
| 951 | 8058065 | Overexpression of the wild type insulin receptor increased both maximal insulin receptor substrate-1-associated and total insulin-stimulated PtdIns 3-kinase activity, as well as S6 and MAP kinase activities 2.0- to 3.6-fold. |
| 952 | 8058065 | Expression of the single- and double-Phe mutant receptors also enhanced maximal PtdIns 3-kinase activity, but had no effect on insulin sensitivity, whereas expression of either the triple-Phe or kinase-inactive receptors did not enhance insulin stimulation or increase insulin sensitivity as compared to the control cells. |
| 953 | 8058065 | When comparing the mutant and wild type receptors, differences in insulin sensitivity were least for insulin-stimulated MAP kinase and greatest for S6 kinase; with the latter there was greater than a 1000-fold difference in insulin sensitivity when cells that overexpress wild type vs. kinase-inactive insulin receptors were compared. |
| 954 | 8068015 | Staurosporine inhibits phorbol 12-myristate 13-acetate- and insulin-stimulated translocation of GLUT1 and GLUT4 glucose transporters in rat adipose cells. |
| 955 | 8068015 | Staurosporine, a widely used protein kinase C inhibitor, completely inhibited both phorbol 12-myristate 13-acetate (PMA)- and insulin-stimulated glucose transport activity in isolated rat adipocytes. |
| 956 | 8068015 | The inhibition was non-competitive and was attributed to a blockade of the PMA- and insulin-induced translocation of both GLUT1 and GLUT4 glucose transporters. |
| 957 | 8068015 | Staurosporine (30 microM) was able to block insulin's ability to stimulate glucose transport, whether added before or after insulin, by a mechanism that did not alter the rate of GLUT4 internalization. |
| 958 | 8068015 | In intact adipose cells, staurosporine (30 microM) induced a slight (30%) decrease in the maximal insulin-induced receptor autophosphorylation and a similar decrease in the tyrosine phosphorylation of pp60 and pp160 (insulin-receptor substrate-1: 'IRS-1'), but was without effect on insulin binding to its receptor. |
| 959 | 8083355 | Insulin receptor substrate-1 (IRS-1) plays an important role in insulin-stimulated signaling mechanisms. |
| 960 | 8087096 | IRS-1 fulfills the criteria of a direct substrate of the insulin receptor, and tyrosine phosphorylation of IRS-1 leads to another step in insulin action, i.e., an association of phosphorylated IRS-1 with the enzyme PI3-kinase activating this enzyme. |
| 961 | 8087096 | Using antipeptide antibodies to insulin receptor, to IRS-1 and to PI 3-kinase together with anti-phosphotyrosine antibodies it is possible to study insulin-stimulated insulin receptor phosphorylation, IRS-1 phosphorylation and the association/activation of IRS-1/PI 3-kinase. 2. |
| 962 | 8087096 | IRS-1 fulfills the criteria of a direct substrate of the insulin receptor, and tyrosine phosphorylation of IRS-1 leads to another step in insulin action, i.e., an association of phosphorylated IRS-1 with the enzyme PI3-kinase activating this enzyme. |
| 963 | 8087096 | Using antipeptide antibodies to insulin receptor, to IRS-1 and to PI 3-kinase together with anti-phosphotyrosine antibodies it is possible to study insulin-stimulated insulin receptor phosphorylation, IRS-1 phosphorylation and the association/activation of IRS-1/PI 3-kinase. 2. |
| 964 | 8088704 | A model of insulin resistance has recently been described in which the insulin receptor is expressed in Chinese hamster ovary cells along with the phospholipid- and calcium-activated serine/threonine kinase called protein kinase C. |
| 965 | 8088704 | In this model system, activation of protein kinase C is shown to interfere with insulin receptor signalling by inhibiting tyrosine phosphorylation of IRS-1 and its subsequent binding by phosphatidylinositol 3-kinase. |
| 966 | 8104271 | Since relative or absolute insulin deficiency and insulin insensitivity are involved in the aetiology of non-insulin-dependent diabetes mellitus (NIDDM), we examined whether patients with NIDDM exhibit genetic variability in the coding region of insulin receptor substrate-1 (IRS-1), a candidate gene that is ubiquitous in insulin-sensitive and insulin-like growth factor 1 (IGF1) sensitive tissues, including those that determine glucose production and clearance and those with regulatory effects on pancreatic beta-cell function. |
| 967 | 8104271 | IRS-1 has a central role as an adaptor molecule that links the insulin-receptor and IGF1-receptor kinases with enzymes that regulate cellular metabolism and growth. |
| 968 | 8104271 | Both aminoacid substitutions were located close to tyrosine phosphorylation motifs that are putative recognition sites for insulin and IGF1 signal transmission proteins. |
| 969 | 8104271 | Analysis of the phenotypes showed that patients with NIDDM who had IRS-1 variants did not differ in their degree of insulin resistance compared with patients without known IRS-1 polymorphisms. |
| 970 | 8104271 | Since relative or absolute insulin deficiency and insulin insensitivity are involved in the aetiology of non-insulin-dependent diabetes mellitus (NIDDM), we examined whether patients with NIDDM exhibit genetic variability in the coding region of insulin receptor substrate-1 (IRS-1), a candidate gene that is ubiquitous in insulin-sensitive and insulin-like growth factor 1 (IGF1) sensitive tissues, including those that determine glucose production and clearance and those with regulatory effects on pancreatic beta-cell function. |
| 971 | 8104271 | IRS-1 has a central role as an adaptor molecule that links the insulin-receptor and IGF1-receptor kinases with enzymes that regulate cellular metabolism and growth. |
| 972 | 8104271 | Both aminoacid substitutions were located close to tyrosine phosphorylation motifs that are putative recognition sites for insulin and IGF1 signal transmission proteins. |
| 973 | 8104271 | Analysis of the phenotypes showed that patients with NIDDM who had IRS-1 variants did not differ in their degree of insulin resistance compared with patients without known IRS-1 polymorphisms. |
| 974 | 8104271 | Since relative or absolute insulin deficiency and insulin insensitivity are involved in the aetiology of non-insulin-dependent diabetes mellitus (NIDDM), we examined whether patients with NIDDM exhibit genetic variability in the coding region of insulin receptor substrate-1 (IRS-1), a candidate gene that is ubiquitous in insulin-sensitive and insulin-like growth factor 1 (IGF1) sensitive tissues, including those that determine glucose production and clearance and those with regulatory effects on pancreatic beta-cell function. |
| 975 | 8104271 | IRS-1 has a central role as an adaptor molecule that links the insulin-receptor and IGF1-receptor kinases with enzymes that regulate cellular metabolism and growth. |
| 976 | 8104271 | Both aminoacid substitutions were located close to tyrosine phosphorylation motifs that are putative recognition sites for insulin and IGF1 signal transmission proteins. |
| 977 | 8104271 | Analysis of the phenotypes showed that patients with NIDDM who had IRS-1 variants did not differ in their degree of insulin resistance compared with patients without known IRS-1 polymorphisms. |
| 978 | 8112298 | Despite the absence of alpha 2 beta beta mut hybrids, expression of the Ile1153 mutant receptor inhibited the ability of the delta 43 truncated receptor to mediate insulin-stimulated phosphorylation of insulin receptor substrate-1 (IRS-1). |
| 979 | 8144631 | SH-PTP2/Syp SH2 domain binding specificity is defined by direct interactions with platelet-derived growth factor beta-receptor, epidermal growth factor receptor, and insulin receptor substrate-1-derived phosphopeptides. |
| 980 | 8144631 | The cytoplasmic phosphotyrosine phosphatase SH-PTP2 (Syp, PTP 1D, PTP-2C) contains two SH2 domains (N and C) which mediate its association with and activation by the platelet-derived growth factor (PDGF) and epidermal growth factor receptors and IRS-1. |
| 981 | 8144631 | The sequence surrounding Tyr1009 bound with greatest affinity (ID50 = 14 microM) of eight PDGF receptor-derived phosphopeptides tested. |
| 982 | 8144631 | These findings are consistent with recent mutational analyses of the PDGF receptor and predict site-specific interactions between SH-PTP2 and each of these phosphoproteins. |
| 983 | 8144631 | SH-PTP2/Syp SH2 domain binding specificity is defined by direct interactions with platelet-derived growth factor beta-receptor, epidermal growth factor receptor, and insulin receptor substrate-1-derived phosphopeptides. |
| 984 | 8144631 | The cytoplasmic phosphotyrosine phosphatase SH-PTP2 (Syp, PTP 1D, PTP-2C) contains two SH2 domains (N and C) which mediate its association with and activation by the platelet-derived growth factor (PDGF) and epidermal growth factor receptors and IRS-1. |
| 985 | 8144631 | The sequence surrounding Tyr1009 bound with greatest affinity (ID50 = 14 microM) of eight PDGF receptor-derived phosphopeptides tested. |
| 986 | 8144631 | These findings are consistent with recent mutational analyses of the PDGF receptor and predict site-specific interactions between SH-PTP2 and each of these phosphoproteins. |
| 987 | 8193539 | IRS-1 is a principal substrate of the insulin receptor tyrosine kinase. |
| 988 | 8193539 | Interleukin-4 also stimulates IRS-1 phosphorylation, and it is suspected that a few more growth factors or cytokines will be added to form a select group of receptors that utilize the IRS-1 signaling pathway. |
| 989 | 8193539 | IRS-1 is a principal substrate of the insulin receptor tyrosine kinase. |
| 990 | 8193539 | Interleukin-4 also stimulates IRS-1 phosphorylation, and it is suspected that a few more growth factors or cytokines will be added to form a select group of receptors that utilize the IRS-1 signaling pathway. |
| 991 | 8196603 | GRB-2 is a small SH2- and SH3 domain-containing adapter protein that associates with the mammalian SOS homolog to regulate p21ras during growth factor signaling. |
| 992 | 8196603 | During insulin stimulation, GRB-2 binds to the phosphorylated Y895VNI motif of IRS-1. |
| 993 | 8196603 | The myeloid progenitor cell line, 32-D, is insensitive to insulin because it contains few insulin receptors and no IRS-1. |
| 994 | 8196603 | Coexpression of IRS-1 or IRS-1F-895 with the insulin receptor was required for insulin-stimulated mitogenesis in 32-D cells, while expression of the insulin receptor alone was sufficient to mediate insulin-stimulated tyrosine phosphorylation of Shc and activation of p21ras and mitogen-activated protein (MAP) kinase. |
| 995 | 8196603 | The Shc-GRB-2 complex formed during insulin stimulation is a possible mediator of p21ras and MAP kinase activation in IRS-1-deficient 32-D cells. |
| 996 | 8196603 | Interestingly, IRS-1, but not IRS-1F-895, enhanced the stimulation of MAP kinase by insulin in 32-D cells expressing insulin receptors. |
| 997 | 8196603 | Thus, IRS-1 contributes to the stimulation of MAP kinase by insulin, probably through formation of the IRS-1-GRB-2 complex at Tyr-895. |
| 998 | 8196603 | Our results suggest that the Shc-GRB-2 complex and the activation of p21ras-dependent signaling pathways, including MAP kinase, are insufficient for insulin-stimulated mitogenesis and that the essential function(s) of IRS-1 in proliferative signaling is largely unrelated to IRS-1-GRB-2 complex formation. |
| 999 | 8196603 | GRB-2 is a small SH2- and SH3 domain-containing adapter protein that associates with the mammalian SOS homolog to regulate p21ras during growth factor signaling. |
| 1000 | 8196603 | During insulin stimulation, GRB-2 binds to the phosphorylated Y895VNI motif of IRS-1. |
| 1001 | 8196603 | The myeloid progenitor cell line, 32-D, is insensitive to insulin because it contains few insulin receptors and no IRS-1. |
| 1002 | 8196603 | Coexpression of IRS-1 or IRS-1F-895 with the insulin receptor was required for insulin-stimulated mitogenesis in 32-D cells, while expression of the insulin receptor alone was sufficient to mediate insulin-stimulated tyrosine phosphorylation of Shc and activation of p21ras and mitogen-activated protein (MAP) kinase. |
| 1003 | 8196603 | The Shc-GRB-2 complex formed during insulin stimulation is a possible mediator of p21ras and MAP kinase activation in IRS-1-deficient 32-D cells. |
| 1004 | 8196603 | Interestingly, IRS-1, but not IRS-1F-895, enhanced the stimulation of MAP kinase by insulin in 32-D cells expressing insulin receptors. |
| 1005 | 8196603 | Thus, IRS-1 contributes to the stimulation of MAP kinase by insulin, probably through formation of the IRS-1-GRB-2 complex at Tyr-895. |
| 1006 | 8196603 | Our results suggest that the Shc-GRB-2 complex and the activation of p21ras-dependent signaling pathways, including MAP kinase, are insufficient for insulin-stimulated mitogenesis and that the essential function(s) of IRS-1 in proliferative signaling is largely unrelated to IRS-1-GRB-2 complex formation. |
| 1007 | 8196603 | GRB-2 is a small SH2- and SH3 domain-containing adapter protein that associates with the mammalian SOS homolog to regulate p21ras during growth factor signaling. |
| 1008 | 8196603 | During insulin stimulation, GRB-2 binds to the phosphorylated Y895VNI motif of IRS-1. |
| 1009 | 8196603 | The myeloid progenitor cell line, 32-D, is insensitive to insulin because it contains few insulin receptors and no IRS-1. |
| 1010 | 8196603 | Coexpression of IRS-1 or IRS-1F-895 with the insulin receptor was required for insulin-stimulated mitogenesis in 32-D cells, while expression of the insulin receptor alone was sufficient to mediate insulin-stimulated tyrosine phosphorylation of Shc and activation of p21ras and mitogen-activated protein (MAP) kinase. |
| 1011 | 8196603 | The Shc-GRB-2 complex formed during insulin stimulation is a possible mediator of p21ras and MAP kinase activation in IRS-1-deficient 32-D cells. |
| 1012 | 8196603 | Interestingly, IRS-1, but not IRS-1F-895, enhanced the stimulation of MAP kinase by insulin in 32-D cells expressing insulin receptors. |
| 1013 | 8196603 | Thus, IRS-1 contributes to the stimulation of MAP kinase by insulin, probably through formation of the IRS-1-GRB-2 complex at Tyr-895. |
| 1014 | 8196603 | Our results suggest that the Shc-GRB-2 complex and the activation of p21ras-dependent signaling pathways, including MAP kinase, are insufficient for insulin-stimulated mitogenesis and that the essential function(s) of IRS-1 in proliferative signaling is largely unrelated to IRS-1-GRB-2 complex formation. |
| 1015 | 8196603 | GRB-2 is a small SH2- and SH3 domain-containing adapter protein that associates with the mammalian SOS homolog to regulate p21ras during growth factor signaling. |
| 1016 | 8196603 | During insulin stimulation, GRB-2 binds to the phosphorylated Y895VNI motif of IRS-1. |
| 1017 | 8196603 | The myeloid progenitor cell line, 32-D, is insensitive to insulin because it contains few insulin receptors and no IRS-1. |
| 1018 | 8196603 | Coexpression of IRS-1 or IRS-1F-895 with the insulin receptor was required for insulin-stimulated mitogenesis in 32-D cells, while expression of the insulin receptor alone was sufficient to mediate insulin-stimulated tyrosine phosphorylation of Shc and activation of p21ras and mitogen-activated protein (MAP) kinase. |
| 1019 | 8196603 | The Shc-GRB-2 complex formed during insulin stimulation is a possible mediator of p21ras and MAP kinase activation in IRS-1-deficient 32-D cells. |
| 1020 | 8196603 | Interestingly, IRS-1, but not IRS-1F-895, enhanced the stimulation of MAP kinase by insulin in 32-D cells expressing insulin receptors. |
| 1021 | 8196603 | Thus, IRS-1 contributes to the stimulation of MAP kinase by insulin, probably through formation of the IRS-1-GRB-2 complex at Tyr-895. |
| 1022 | 8196603 | Our results suggest that the Shc-GRB-2 complex and the activation of p21ras-dependent signaling pathways, including MAP kinase, are insufficient for insulin-stimulated mitogenesis and that the essential function(s) of IRS-1 in proliferative signaling is largely unrelated to IRS-1-GRB-2 complex formation. |
| 1023 | 8196603 | GRB-2 is a small SH2- and SH3 domain-containing adapter protein that associates with the mammalian SOS homolog to regulate p21ras during growth factor signaling. |
| 1024 | 8196603 | During insulin stimulation, GRB-2 binds to the phosphorylated Y895VNI motif of IRS-1. |
| 1025 | 8196603 | The myeloid progenitor cell line, 32-D, is insensitive to insulin because it contains few insulin receptors and no IRS-1. |
| 1026 | 8196603 | Coexpression of IRS-1 or IRS-1F-895 with the insulin receptor was required for insulin-stimulated mitogenesis in 32-D cells, while expression of the insulin receptor alone was sufficient to mediate insulin-stimulated tyrosine phosphorylation of Shc and activation of p21ras and mitogen-activated protein (MAP) kinase. |
| 1027 | 8196603 | The Shc-GRB-2 complex formed during insulin stimulation is a possible mediator of p21ras and MAP kinase activation in IRS-1-deficient 32-D cells. |
| 1028 | 8196603 | Interestingly, IRS-1, but not IRS-1F-895, enhanced the stimulation of MAP kinase by insulin in 32-D cells expressing insulin receptors. |
| 1029 | 8196603 | Thus, IRS-1 contributes to the stimulation of MAP kinase by insulin, probably through formation of the IRS-1-GRB-2 complex at Tyr-895. |
| 1030 | 8196603 | Our results suggest that the Shc-GRB-2 complex and the activation of p21ras-dependent signaling pathways, including MAP kinase, are insufficient for insulin-stimulated mitogenesis and that the essential function(s) of IRS-1 in proliferative signaling is largely unrelated to IRS-1-GRB-2 complex formation. |
| 1031 | 8196603 | GRB-2 is a small SH2- and SH3 domain-containing adapter protein that associates with the mammalian SOS homolog to regulate p21ras during growth factor signaling. |
| 1032 | 8196603 | During insulin stimulation, GRB-2 binds to the phosphorylated Y895VNI motif of IRS-1. |
| 1033 | 8196603 | The myeloid progenitor cell line, 32-D, is insensitive to insulin because it contains few insulin receptors and no IRS-1. |
| 1034 | 8196603 | Coexpression of IRS-1 or IRS-1F-895 with the insulin receptor was required for insulin-stimulated mitogenesis in 32-D cells, while expression of the insulin receptor alone was sufficient to mediate insulin-stimulated tyrosine phosphorylation of Shc and activation of p21ras and mitogen-activated protein (MAP) kinase. |
| 1035 | 8196603 | The Shc-GRB-2 complex formed during insulin stimulation is a possible mediator of p21ras and MAP kinase activation in IRS-1-deficient 32-D cells. |
| 1036 | 8196603 | Interestingly, IRS-1, but not IRS-1F-895, enhanced the stimulation of MAP kinase by insulin in 32-D cells expressing insulin receptors. |
| 1037 | 8196603 | Thus, IRS-1 contributes to the stimulation of MAP kinase by insulin, probably through formation of the IRS-1-GRB-2 complex at Tyr-895. |
| 1038 | 8196603 | Our results suggest that the Shc-GRB-2 complex and the activation of p21ras-dependent signaling pathways, including MAP kinase, are insufficient for insulin-stimulated mitogenesis and that the essential function(s) of IRS-1 in proliferative signaling is largely unrelated to IRS-1-GRB-2 complex formation. |
| 1039 | 8227156 | The insulin receptor substrate protein 1 (IRS-1) could not be detected in the nucleus by immunoblotting. |
| 1040 | 8382612 | An example of such phosphoprotein-effector coupling is provided by the association of phosphatidylinositol 3-kinase (PI 3-kinase) with specific phosphorylation sites within the PDGF receptor, the c-Src/polyoma virus middle T antigen complex and the insulin receptor substrate IRS-1. |
| 1041 | 8382612 | To investigate how phosphoprotein binding to the p85 SH2 domain stimulates p110 catalytic activation, we have examined the differential effects of phosphotyrosine and PDGF receptor-, IRS-1- and c-Src-derived phosphopeptides on the conformation of an isolated SH2 domain of PI 3-kinase. |
| 1042 | 8384986 | IRS-1 is a common element in insulin and insulin-like growth factor-I signaling to the phosphatidylinositol 3'-kinase. |
| 1043 | 8384986 | IRS-1 is a unique cytosolic protein that becomes tyrosine phosphorylated during insulin stimulation of intact cells and immediately associates with the phosphatidylinositol 3'-kinase (PtdIns 3'-kinase). |
| 1044 | 8384986 | The insulin-like growth factor-I (IGF-I) receptor also mediated the tyrosine phosphorylation of IRS-1 and increased the amount of PtdIns 3'-kinase activity bound to IRS-1 in Chinese hamster ovary cells. |
| 1045 | 8384986 | Purified insulin receptor and IGF-I receptor phosphorylated recombinant baculovirus-produced IRS-1 on similar sites in vitro, and phosphorylated baculovirus-produced IRS-1 bound PtdIns 3'-kinase activity from lysates of quiescent cells. |
| 1046 | 8384986 | Treatment of cells with IGF-I activated the PtdIns 3'-kinase, suggesting that IGF-I activates the PtdIns 3'-kinase through IRS-1 binding to p85 in a manner similar to insulin. |
| 1047 | 8384986 | These data demonstrate that IRS-1 is a common element for signal transmission by the IGF-I and insulin receptors. |
| 1048 | 8384986 | IRS-1 is a common element in insulin and insulin-like growth factor-I signaling to the phosphatidylinositol 3'-kinase. |
| 1049 | 8384986 | IRS-1 is a unique cytosolic protein that becomes tyrosine phosphorylated during insulin stimulation of intact cells and immediately associates with the phosphatidylinositol 3'-kinase (PtdIns 3'-kinase). |
| 1050 | 8384986 | The insulin-like growth factor-I (IGF-I) receptor also mediated the tyrosine phosphorylation of IRS-1 and increased the amount of PtdIns 3'-kinase activity bound to IRS-1 in Chinese hamster ovary cells. |
| 1051 | 8384986 | Purified insulin receptor and IGF-I receptor phosphorylated recombinant baculovirus-produced IRS-1 on similar sites in vitro, and phosphorylated baculovirus-produced IRS-1 bound PtdIns 3'-kinase activity from lysates of quiescent cells. |
| 1052 | 8384986 | Treatment of cells with IGF-I activated the PtdIns 3'-kinase, suggesting that IGF-I activates the PtdIns 3'-kinase through IRS-1 binding to p85 in a manner similar to insulin. |
| 1053 | 8384986 | These data demonstrate that IRS-1 is a common element for signal transmission by the IGF-I and insulin receptors. |
| 1054 | 8384986 | IRS-1 is a common element in insulin and insulin-like growth factor-I signaling to the phosphatidylinositol 3'-kinase. |
| 1055 | 8384986 | IRS-1 is a unique cytosolic protein that becomes tyrosine phosphorylated during insulin stimulation of intact cells and immediately associates with the phosphatidylinositol 3'-kinase (PtdIns 3'-kinase). |
| 1056 | 8384986 | The insulin-like growth factor-I (IGF-I) receptor also mediated the tyrosine phosphorylation of IRS-1 and increased the amount of PtdIns 3'-kinase activity bound to IRS-1 in Chinese hamster ovary cells. |
| 1057 | 8384986 | Purified insulin receptor and IGF-I receptor phosphorylated recombinant baculovirus-produced IRS-1 on similar sites in vitro, and phosphorylated baculovirus-produced IRS-1 bound PtdIns 3'-kinase activity from lysates of quiescent cells. |
| 1058 | 8384986 | Treatment of cells with IGF-I activated the PtdIns 3'-kinase, suggesting that IGF-I activates the PtdIns 3'-kinase through IRS-1 binding to p85 in a manner similar to insulin. |
| 1059 | 8384986 | These data demonstrate that IRS-1 is a common element for signal transmission by the IGF-I and insulin receptors. |
| 1060 | 8384986 | IRS-1 is a common element in insulin and insulin-like growth factor-I signaling to the phosphatidylinositol 3'-kinase. |
| 1061 | 8384986 | IRS-1 is a unique cytosolic protein that becomes tyrosine phosphorylated during insulin stimulation of intact cells and immediately associates with the phosphatidylinositol 3'-kinase (PtdIns 3'-kinase). |
| 1062 | 8384986 | The insulin-like growth factor-I (IGF-I) receptor also mediated the tyrosine phosphorylation of IRS-1 and increased the amount of PtdIns 3'-kinase activity bound to IRS-1 in Chinese hamster ovary cells. |
| 1063 | 8384986 | Purified insulin receptor and IGF-I receptor phosphorylated recombinant baculovirus-produced IRS-1 on similar sites in vitro, and phosphorylated baculovirus-produced IRS-1 bound PtdIns 3'-kinase activity from lysates of quiescent cells. |
| 1064 | 8384986 | Treatment of cells with IGF-I activated the PtdIns 3'-kinase, suggesting that IGF-I activates the PtdIns 3'-kinase through IRS-1 binding to p85 in a manner similar to insulin. |
| 1065 | 8384986 | These data demonstrate that IRS-1 is a common element for signal transmission by the IGF-I and insulin receptors. |
| 1066 | 8384986 | IRS-1 is a common element in insulin and insulin-like growth factor-I signaling to the phosphatidylinositol 3'-kinase. |
| 1067 | 8384986 | IRS-1 is a unique cytosolic protein that becomes tyrosine phosphorylated during insulin stimulation of intact cells and immediately associates with the phosphatidylinositol 3'-kinase (PtdIns 3'-kinase). |
| 1068 | 8384986 | The insulin-like growth factor-I (IGF-I) receptor also mediated the tyrosine phosphorylation of IRS-1 and increased the amount of PtdIns 3'-kinase activity bound to IRS-1 in Chinese hamster ovary cells. |
| 1069 | 8384986 | Purified insulin receptor and IGF-I receptor phosphorylated recombinant baculovirus-produced IRS-1 on similar sites in vitro, and phosphorylated baculovirus-produced IRS-1 bound PtdIns 3'-kinase activity from lysates of quiescent cells. |
| 1070 | 8384986 | Treatment of cells with IGF-I activated the PtdIns 3'-kinase, suggesting that IGF-I activates the PtdIns 3'-kinase through IRS-1 binding to p85 in a manner similar to insulin. |
| 1071 | 8384986 | These data demonstrate that IRS-1 is a common element for signal transmission by the IGF-I and insulin receptors. |
| 1072 | 8384986 | IRS-1 is a common element in insulin and insulin-like growth factor-I signaling to the phosphatidylinositol 3'-kinase. |
| 1073 | 8384986 | IRS-1 is a unique cytosolic protein that becomes tyrosine phosphorylated during insulin stimulation of intact cells and immediately associates with the phosphatidylinositol 3'-kinase (PtdIns 3'-kinase). |
| 1074 | 8384986 | The insulin-like growth factor-I (IGF-I) receptor also mediated the tyrosine phosphorylation of IRS-1 and increased the amount of PtdIns 3'-kinase activity bound to IRS-1 in Chinese hamster ovary cells. |
| 1075 | 8384986 | Purified insulin receptor and IGF-I receptor phosphorylated recombinant baculovirus-produced IRS-1 on similar sites in vitro, and phosphorylated baculovirus-produced IRS-1 bound PtdIns 3'-kinase activity from lysates of quiescent cells. |
| 1076 | 8384986 | Treatment of cells with IGF-I activated the PtdIns 3'-kinase, suggesting that IGF-I activates the PtdIns 3'-kinase through IRS-1 binding to p85 in a manner similar to insulin. |
| 1077 | 8384986 | These data demonstrate that IRS-1 is a common element for signal transmission by the IGF-I and insulin receptors. |
| 1078 | 8385139 | Association of IRS-1 with the insulin receptor and the phosphatidylinositol 3'-kinase. |
| 1079 | 8385139 | Insulin stimulates the formation of binary and ternary signaling complexes between the phosphatidylinositol (PtdIns) 3'-kinase, IRS-1, and the insulin receptor in vivo. |
| 1080 | 8385139 | Binary complex formation between IRS-1 and the PtdIns 3'-kinase occurs in intact cells and requires the tyrosyl phosphorylation IRS-1, as mutant insulin receptors which weakly phosphorylate IRS-1 in vivo do not mediate formation of IRS-1/PtdIns 3'-kinase complexes in transfected CHO cells. |
| 1081 | 8385139 | Insulin also stimulates the formation of ternary signaling complexes, as both IRS-1 and the PtdIns 3'-kinase are present in anti-insulin receptor immunoprecipitates from insulin-stimulated cells. |
| 1082 | 8385139 | Overexpression of IRS-1 in CHO cells increases the amount of PtdIns 3'-kinase activity in alpha IR immunoprecipitates, and IRS-1 markedly increases the in vitro binding of p85 alpha and PtdIns 3-kinase activity to anti-receptor immunoprecipitates. |
| 1083 | 8385139 | The mechanism for this association is unknown, but appears to involve the binding of IRS-1/PtdIns 3'-kinase complexes to the insulin receptor. |
| 1084 | 8385139 | The formation of binary and ternary complexes between the insulin receptor, IRS-1 and the PtdIns 3'-kinase may play a critical role in transmission of the insulin signal. |
| 1085 | 8385139 | Association of IRS-1 with the insulin receptor and the phosphatidylinositol 3'-kinase. |
| 1086 | 8385139 | Insulin stimulates the formation of binary and ternary signaling complexes between the phosphatidylinositol (PtdIns) 3'-kinase, IRS-1, and the insulin receptor in vivo. |
| 1087 | 8385139 | Binary complex formation between IRS-1 and the PtdIns 3'-kinase occurs in intact cells and requires the tyrosyl phosphorylation IRS-1, as mutant insulin receptors which weakly phosphorylate IRS-1 in vivo do not mediate formation of IRS-1/PtdIns 3'-kinase complexes in transfected CHO cells. |
| 1088 | 8385139 | Insulin also stimulates the formation of ternary signaling complexes, as both IRS-1 and the PtdIns 3'-kinase are present in anti-insulin receptor immunoprecipitates from insulin-stimulated cells. |
| 1089 | 8385139 | Overexpression of IRS-1 in CHO cells increases the amount of PtdIns 3'-kinase activity in alpha IR immunoprecipitates, and IRS-1 markedly increases the in vitro binding of p85 alpha and PtdIns 3-kinase activity to anti-receptor immunoprecipitates. |
| 1090 | 8385139 | The mechanism for this association is unknown, but appears to involve the binding of IRS-1/PtdIns 3'-kinase complexes to the insulin receptor. |
| 1091 | 8385139 | The formation of binary and ternary complexes between the insulin receptor, IRS-1 and the PtdIns 3'-kinase may play a critical role in transmission of the insulin signal. |
| 1092 | 8385139 | Association of IRS-1 with the insulin receptor and the phosphatidylinositol 3'-kinase. |
| 1093 | 8385139 | Insulin stimulates the formation of binary and ternary signaling complexes between the phosphatidylinositol (PtdIns) 3'-kinase, IRS-1, and the insulin receptor in vivo. |
| 1094 | 8385139 | Binary complex formation between IRS-1 and the PtdIns 3'-kinase occurs in intact cells and requires the tyrosyl phosphorylation IRS-1, as mutant insulin receptors which weakly phosphorylate IRS-1 in vivo do not mediate formation of IRS-1/PtdIns 3'-kinase complexes in transfected CHO cells. |
| 1095 | 8385139 | Insulin also stimulates the formation of ternary signaling complexes, as both IRS-1 and the PtdIns 3'-kinase are present in anti-insulin receptor immunoprecipitates from insulin-stimulated cells. |
| 1096 | 8385139 | Overexpression of IRS-1 in CHO cells increases the amount of PtdIns 3'-kinase activity in alpha IR immunoprecipitates, and IRS-1 markedly increases the in vitro binding of p85 alpha and PtdIns 3-kinase activity to anti-receptor immunoprecipitates. |
| 1097 | 8385139 | The mechanism for this association is unknown, but appears to involve the binding of IRS-1/PtdIns 3'-kinase complexes to the insulin receptor. |
| 1098 | 8385139 | The formation of binary and ternary complexes between the insulin receptor, IRS-1 and the PtdIns 3'-kinase may play a critical role in transmission of the insulin signal. |
| 1099 | 8385139 | Association of IRS-1 with the insulin receptor and the phosphatidylinositol 3'-kinase. |
| 1100 | 8385139 | Insulin stimulates the formation of binary and ternary signaling complexes between the phosphatidylinositol (PtdIns) 3'-kinase, IRS-1, and the insulin receptor in vivo. |
| 1101 | 8385139 | Binary complex formation between IRS-1 and the PtdIns 3'-kinase occurs in intact cells and requires the tyrosyl phosphorylation IRS-1, as mutant insulin receptors which weakly phosphorylate IRS-1 in vivo do not mediate formation of IRS-1/PtdIns 3'-kinase complexes in transfected CHO cells. |
| 1102 | 8385139 | Insulin also stimulates the formation of ternary signaling complexes, as both IRS-1 and the PtdIns 3'-kinase are present in anti-insulin receptor immunoprecipitates from insulin-stimulated cells. |
| 1103 | 8385139 | Overexpression of IRS-1 in CHO cells increases the amount of PtdIns 3'-kinase activity in alpha IR immunoprecipitates, and IRS-1 markedly increases the in vitro binding of p85 alpha and PtdIns 3-kinase activity to anti-receptor immunoprecipitates. |
| 1104 | 8385139 | The mechanism for this association is unknown, but appears to involve the binding of IRS-1/PtdIns 3'-kinase complexes to the insulin receptor. |
| 1105 | 8385139 | The formation of binary and ternary complexes between the insulin receptor, IRS-1 and the PtdIns 3'-kinase may play a critical role in transmission of the insulin signal. |
| 1106 | 8385139 | Association of IRS-1 with the insulin receptor and the phosphatidylinositol 3'-kinase. |
| 1107 | 8385139 | Insulin stimulates the formation of binary and ternary signaling complexes between the phosphatidylinositol (PtdIns) 3'-kinase, IRS-1, and the insulin receptor in vivo. |
| 1108 | 8385139 | Binary complex formation between IRS-1 and the PtdIns 3'-kinase occurs in intact cells and requires the tyrosyl phosphorylation IRS-1, as mutant insulin receptors which weakly phosphorylate IRS-1 in vivo do not mediate formation of IRS-1/PtdIns 3'-kinase complexes in transfected CHO cells. |
| 1109 | 8385139 | Insulin also stimulates the formation of ternary signaling complexes, as both IRS-1 and the PtdIns 3'-kinase are present in anti-insulin receptor immunoprecipitates from insulin-stimulated cells. |
| 1110 | 8385139 | Overexpression of IRS-1 in CHO cells increases the amount of PtdIns 3'-kinase activity in alpha IR immunoprecipitates, and IRS-1 markedly increases the in vitro binding of p85 alpha and PtdIns 3-kinase activity to anti-receptor immunoprecipitates. |
| 1111 | 8385139 | The mechanism for this association is unknown, but appears to involve the binding of IRS-1/PtdIns 3'-kinase complexes to the insulin receptor. |
| 1112 | 8385139 | The formation of binary and ternary complexes between the insulin receptor, IRS-1 and the PtdIns 3'-kinase may play a critical role in transmission of the insulin signal. |
| 1113 | 8385139 | Association of IRS-1 with the insulin receptor and the phosphatidylinositol 3'-kinase. |
| 1114 | 8385139 | Insulin stimulates the formation of binary and ternary signaling complexes between the phosphatidylinositol (PtdIns) 3'-kinase, IRS-1, and the insulin receptor in vivo. |
| 1115 | 8385139 | Binary complex formation between IRS-1 and the PtdIns 3'-kinase occurs in intact cells and requires the tyrosyl phosphorylation IRS-1, as mutant insulin receptors which weakly phosphorylate IRS-1 in vivo do not mediate formation of IRS-1/PtdIns 3'-kinase complexes in transfected CHO cells. |
| 1116 | 8385139 | Insulin also stimulates the formation of ternary signaling complexes, as both IRS-1 and the PtdIns 3'-kinase are present in anti-insulin receptor immunoprecipitates from insulin-stimulated cells. |
| 1117 | 8385139 | Overexpression of IRS-1 in CHO cells increases the amount of PtdIns 3'-kinase activity in alpha IR immunoprecipitates, and IRS-1 markedly increases the in vitro binding of p85 alpha and PtdIns 3-kinase activity to anti-receptor immunoprecipitates. |
| 1118 | 8385139 | The mechanism for this association is unknown, but appears to involve the binding of IRS-1/PtdIns 3'-kinase complexes to the insulin receptor. |
| 1119 | 8385139 | The formation of binary and ternary complexes between the insulin receptor, IRS-1 and the PtdIns 3'-kinase may play a critical role in transmission of the insulin signal. |
| 1120 | 8385139 | Association of IRS-1 with the insulin receptor and the phosphatidylinositol 3'-kinase. |
| 1121 | 8385139 | Insulin stimulates the formation of binary and ternary signaling complexes between the phosphatidylinositol (PtdIns) 3'-kinase, IRS-1, and the insulin receptor in vivo. |
| 1122 | 8385139 | Binary complex formation between IRS-1 and the PtdIns 3'-kinase occurs in intact cells and requires the tyrosyl phosphorylation IRS-1, as mutant insulin receptors which weakly phosphorylate IRS-1 in vivo do not mediate formation of IRS-1/PtdIns 3'-kinase complexes in transfected CHO cells. |
| 1123 | 8385139 | Insulin also stimulates the formation of ternary signaling complexes, as both IRS-1 and the PtdIns 3'-kinase are present in anti-insulin receptor immunoprecipitates from insulin-stimulated cells. |
| 1124 | 8385139 | Overexpression of IRS-1 in CHO cells increases the amount of PtdIns 3'-kinase activity in alpha IR immunoprecipitates, and IRS-1 markedly increases the in vitro binding of p85 alpha and PtdIns 3-kinase activity to anti-receptor immunoprecipitates. |
| 1125 | 8385139 | The mechanism for this association is unknown, but appears to involve the binding of IRS-1/PtdIns 3'-kinase complexes to the insulin receptor. |
| 1126 | 8385139 | The formation of binary and ternary complexes between the insulin receptor, IRS-1 and the PtdIns 3'-kinase may play a critical role in transmission of the insulin signal. |
| 1127 | 8387037 | The recently discovered insulin receptor substrate, IRS-1, provides an innovative and simple way to think about this problem: IRS-1 may mediate the control of various cellular processes by insulin. |
| 1128 | 8387037 | Overexpression of IRS-1 enhances insulin-stimulated DNA synthesis in Chinese hamster ovary cells, and microinjection of IRS-1 protein potentiates the maturation of Xenopus oocytes. |
| 1129 | 8387037 | We suspect that insulin signals are enabled when the activated insulin receptor kinase phosphorylates specific tyrosine residues in IRS-1. |
| 1130 | 8387037 | The recently discovered insulin receptor substrate, IRS-1, provides an innovative and simple way to think about this problem: IRS-1 may mediate the control of various cellular processes by insulin. |
| 1131 | 8387037 | Overexpression of IRS-1 enhances insulin-stimulated DNA synthesis in Chinese hamster ovary cells, and microinjection of IRS-1 protein potentiates the maturation of Xenopus oocytes. |
| 1132 | 8387037 | We suspect that insulin signals are enabled when the activated insulin receptor kinase phosphorylates specific tyrosine residues in IRS-1. |
| 1133 | 8387037 | The recently discovered insulin receptor substrate, IRS-1, provides an innovative and simple way to think about this problem: IRS-1 may mediate the control of various cellular processes by insulin. |
| 1134 | 8387037 | Overexpression of IRS-1 enhances insulin-stimulated DNA synthesis in Chinese hamster ovary cells, and microinjection of IRS-1 protein potentiates the maturation of Xenopus oocytes. |
| 1135 | 8387037 | We suspect that insulin signals are enabled when the activated insulin receptor kinase phosphorylates specific tyrosine residues in IRS-1. |
| 1136 | 8393870 | In CHO-Y960F cells, tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1), the activation of phosphatidylinositol 3-kinase in the anti-phosphotyrosine and anti-IRS-1 immunoprecipitates, the activation of mitogen-activated protein (MAP) kinase, and biological actions were also impaired. |
| 1137 | 8393870 | In addition, although the deletion of residues 954-965 severely impaired insulin internalization, the deletion of NPXY (957-960), the internalization signal of the low density lipoprotein receptor, did not affect internalization. |
| 1138 | 8393870 | These data suggest that: 1) Tyr960 is important for the recognition of pp185/IRS-1, the association of phosphatidylinositol 3-kinase with pp185/IRS-1, and the activation of MAP kinase; 2) MAP kinase may lie downstream of pp185/IRS-1 in insulin's signal transduction; and 3) the juxtamembrane domain, but not NPXY or individual tyrosines, is important for insulin internalization. |
| 1139 | 8393870 | In CHO-Y960F cells, tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1), the activation of phosphatidylinositol 3-kinase in the anti-phosphotyrosine and anti-IRS-1 immunoprecipitates, the activation of mitogen-activated protein (MAP) kinase, and biological actions were also impaired. |
| 1140 | 8393870 | In addition, although the deletion of residues 954-965 severely impaired insulin internalization, the deletion of NPXY (957-960), the internalization signal of the low density lipoprotein receptor, did not affect internalization. |
| 1141 | 8393870 | These data suggest that: 1) Tyr960 is important for the recognition of pp185/IRS-1, the association of phosphatidylinositol 3-kinase with pp185/IRS-1, and the activation of MAP kinase; 2) MAP kinase may lie downstream of pp185/IRS-1 in insulin's signal transduction; and 3) the juxtamembrane domain, but not NPXY or individual tyrosines, is important for insulin internalization. |
| 1142 | 8413261 | Insulin-stimulated oocyte maturation requires insulin receptor substrate 1 and interaction with the SH2 domains of phosphatidylinositol 3-kinase. |
| 1143 | 8413261 | Xenopus oocytes from unprimed frogs possess insulin-like growth factor I (IGF-I) receptors but lack insulin and IGF-I receptor substrate 1 (IRS-1), the endogenous substrate of this kinase, and fail to show downstream responses to hormonal stimulation. |
| 1144 | 8413261 | Microinjection of recombinant IRS-1 protein enhances insulin-stimulated phosphatidylinositol (PtdIns) 3-kinase activity and restores the germinal vesicle breakdown response. |
| 1145 | 8413261 | Activation of PtdIns 3-kinase results from formation of a complex between phosphorylated IRS-1 and the p85 subunit of PtdIns 3-kinase. |
| 1146 | 8413261 | Microinjection of a phosphonopeptide containing a pYMXM motif with high affinity for the src homology 2 (SH2) domain of PtdIns 3-kinase p85 inhibits IRS-1 association with and activation of the PtdIns 3-kinase. |
| 1147 | 8413261 | Formation of the IRS-1-PtdIns 3-kinase complex and insulin-stimulated PtdIns 3-kinase activation are also inhibited by microinjection of a glutathione S-transferase fusion protein containing the SH2 domain of p85. |
| 1148 | 8413261 | These inhibitory effects are specific and are not mimicked by glutathione S-transferase fusion proteins expressing the SH2 domains of ras-GAP or phospholipase C gamma. |
| 1149 | 8413261 | Moreover, injection of the SH2 domains of p85, ras-GAP, and phospholipase C gamma do not interfere with progesterone-induced oocyte maturation. |
| 1150 | 8413261 | These data demonstrate that phosphorylation of IRS-1 plays an essential role in IGF-I and insulin signaling in oocyte maturation and that this effect occurs through interactions of the phosphorylated YMXM/YXXM motifs of IRS-1 with SH2 domains of PtdIns 3-kinase or some related molecules. |
| 1151 | 8413261 | Insulin-stimulated oocyte maturation requires insulin receptor substrate 1 and interaction with the SH2 domains of phosphatidylinositol 3-kinase. |
| 1152 | 8413261 | Xenopus oocytes from unprimed frogs possess insulin-like growth factor I (IGF-I) receptors but lack insulin and IGF-I receptor substrate 1 (IRS-1), the endogenous substrate of this kinase, and fail to show downstream responses to hormonal stimulation. |
| 1153 | 8413261 | Microinjection of recombinant IRS-1 protein enhances insulin-stimulated phosphatidylinositol (PtdIns) 3-kinase activity and restores the germinal vesicle breakdown response. |
| 1154 | 8413261 | Activation of PtdIns 3-kinase results from formation of a complex between phosphorylated IRS-1 and the p85 subunit of PtdIns 3-kinase. |
| 1155 | 8413261 | Microinjection of a phosphonopeptide containing a pYMXM motif with high affinity for the src homology 2 (SH2) domain of PtdIns 3-kinase p85 inhibits IRS-1 association with and activation of the PtdIns 3-kinase. |
| 1156 | 8413261 | Formation of the IRS-1-PtdIns 3-kinase complex and insulin-stimulated PtdIns 3-kinase activation are also inhibited by microinjection of a glutathione S-transferase fusion protein containing the SH2 domain of p85. |
| 1157 | 8413261 | These inhibitory effects are specific and are not mimicked by glutathione S-transferase fusion proteins expressing the SH2 domains of ras-GAP or phospholipase C gamma. |
| 1158 | 8413261 | Moreover, injection of the SH2 domains of p85, ras-GAP, and phospholipase C gamma do not interfere with progesterone-induced oocyte maturation. |
| 1159 | 8413261 | These data demonstrate that phosphorylation of IRS-1 plays an essential role in IGF-I and insulin signaling in oocyte maturation and that this effect occurs through interactions of the phosphorylated YMXM/YXXM motifs of IRS-1 with SH2 domains of PtdIns 3-kinase or some related molecules. |
| 1160 | 8413261 | Insulin-stimulated oocyte maturation requires insulin receptor substrate 1 and interaction with the SH2 domains of phosphatidylinositol 3-kinase. |
| 1161 | 8413261 | Xenopus oocytes from unprimed frogs possess insulin-like growth factor I (IGF-I) receptors but lack insulin and IGF-I receptor substrate 1 (IRS-1), the endogenous substrate of this kinase, and fail to show downstream responses to hormonal stimulation. |
| 1162 | 8413261 | Microinjection of recombinant IRS-1 protein enhances insulin-stimulated phosphatidylinositol (PtdIns) 3-kinase activity and restores the germinal vesicle breakdown response. |
| 1163 | 8413261 | Activation of PtdIns 3-kinase results from formation of a complex between phosphorylated IRS-1 and the p85 subunit of PtdIns 3-kinase. |
| 1164 | 8413261 | Microinjection of a phosphonopeptide containing a pYMXM motif with high affinity for the src homology 2 (SH2) domain of PtdIns 3-kinase p85 inhibits IRS-1 association with and activation of the PtdIns 3-kinase. |
| 1165 | 8413261 | Formation of the IRS-1-PtdIns 3-kinase complex and insulin-stimulated PtdIns 3-kinase activation are also inhibited by microinjection of a glutathione S-transferase fusion protein containing the SH2 domain of p85. |
| 1166 | 8413261 | These inhibitory effects are specific and are not mimicked by glutathione S-transferase fusion proteins expressing the SH2 domains of ras-GAP or phospholipase C gamma. |
| 1167 | 8413261 | Moreover, injection of the SH2 domains of p85, ras-GAP, and phospholipase C gamma do not interfere with progesterone-induced oocyte maturation. |
| 1168 | 8413261 | These data demonstrate that phosphorylation of IRS-1 plays an essential role in IGF-I and insulin signaling in oocyte maturation and that this effect occurs through interactions of the phosphorylated YMXM/YXXM motifs of IRS-1 with SH2 domains of PtdIns 3-kinase or some related molecules. |
| 1169 | 8413261 | Insulin-stimulated oocyte maturation requires insulin receptor substrate 1 and interaction with the SH2 domains of phosphatidylinositol 3-kinase. |
| 1170 | 8413261 | Xenopus oocytes from unprimed frogs possess insulin-like growth factor I (IGF-I) receptors but lack insulin and IGF-I receptor substrate 1 (IRS-1), the endogenous substrate of this kinase, and fail to show downstream responses to hormonal stimulation. |
| 1171 | 8413261 | Microinjection of recombinant IRS-1 protein enhances insulin-stimulated phosphatidylinositol (PtdIns) 3-kinase activity and restores the germinal vesicle breakdown response. |
| 1172 | 8413261 | Activation of PtdIns 3-kinase results from formation of a complex between phosphorylated IRS-1 and the p85 subunit of PtdIns 3-kinase. |
| 1173 | 8413261 | Microinjection of a phosphonopeptide containing a pYMXM motif with high affinity for the src homology 2 (SH2) domain of PtdIns 3-kinase p85 inhibits IRS-1 association with and activation of the PtdIns 3-kinase. |
| 1174 | 8413261 | Formation of the IRS-1-PtdIns 3-kinase complex and insulin-stimulated PtdIns 3-kinase activation are also inhibited by microinjection of a glutathione S-transferase fusion protein containing the SH2 domain of p85. |
| 1175 | 8413261 | These inhibitory effects are specific and are not mimicked by glutathione S-transferase fusion proteins expressing the SH2 domains of ras-GAP or phospholipase C gamma. |
| 1176 | 8413261 | Moreover, injection of the SH2 domains of p85, ras-GAP, and phospholipase C gamma do not interfere with progesterone-induced oocyte maturation. |
| 1177 | 8413261 | These data demonstrate that phosphorylation of IRS-1 plays an essential role in IGF-I and insulin signaling in oocyte maturation and that this effect occurs through interactions of the phosphorylated YMXM/YXXM motifs of IRS-1 with SH2 domains of PtdIns 3-kinase or some related molecules. |
| 1178 | 8413261 | Insulin-stimulated oocyte maturation requires insulin receptor substrate 1 and interaction with the SH2 domains of phosphatidylinositol 3-kinase. |
| 1179 | 8413261 | Xenopus oocytes from unprimed frogs possess insulin-like growth factor I (IGF-I) receptors but lack insulin and IGF-I receptor substrate 1 (IRS-1), the endogenous substrate of this kinase, and fail to show downstream responses to hormonal stimulation. |
| 1180 | 8413261 | Microinjection of recombinant IRS-1 protein enhances insulin-stimulated phosphatidylinositol (PtdIns) 3-kinase activity and restores the germinal vesicle breakdown response. |
| 1181 | 8413261 | Activation of PtdIns 3-kinase results from formation of a complex between phosphorylated IRS-1 and the p85 subunit of PtdIns 3-kinase. |
| 1182 | 8413261 | Microinjection of a phosphonopeptide containing a pYMXM motif with high affinity for the src homology 2 (SH2) domain of PtdIns 3-kinase p85 inhibits IRS-1 association with and activation of the PtdIns 3-kinase. |
| 1183 | 8413261 | Formation of the IRS-1-PtdIns 3-kinase complex and insulin-stimulated PtdIns 3-kinase activation are also inhibited by microinjection of a glutathione S-transferase fusion protein containing the SH2 domain of p85. |
| 1184 | 8413261 | These inhibitory effects are specific and are not mimicked by glutathione S-transferase fusion proteins expressing the SH2 domains of ras-GAP or phospholipase C gamma. |
| 1185 | 8413261 | Moreover, injection of the SH2 domains of p85, ras-GAP, and phospholipase C gamma do not interfere with progesterone-induced oocyte maturation. |
| 1186 | 8413261 | These data demonstrate that phosphorylation of IRS-1 plays an essential role in IGF-I and insulin signaling in oocyte maturation and that this effect occurs through interactions of the phosphorylated YMXM/YXXM motifs of IRS-1 with SH2 domains of PtdIns 3-kinase or some related molecules. |
| 1187 | 8413261 | Insulin-stimulated oocyte maturation requires insulin receptor substrate 1 and interaction with the SH2 domains of phosphatidylinositol 3-kinase. |
| 1188 | 8413261 | Xenopus oocytes from unprimed frogs possess insulin-like growth factor I (IGF-I) receptors but lack insulin and IGF-I receptor substrate 1 (IRS-1), the endogenous substrate of this kinase, and fail to show downstream responses to hormonal stimulation. |
| 1189 | 8413261 | Microinjection of recombinant IRS-1 protein enhances insulin-stimulated phosphatidylinositol (PtdIns) 3-kinase activity and restores the germinal vesicle breakdown response. |
| 1190 | 8413261 | Activation of PtdIns 3-kinase results from formation of a complex between phosphorylated IRS-1 and the p85 subunit of PtdIns 3-kinase. |
| 1191 | 8413261 | Microinjection of a phosphonopeptide containing a pYMXM motif with high affinity for the src homology 2 (SH2) domain of PtdIns 3-kinase p85 inhibits IRS-1 association with and activation of the PtdIns 3-kinase. |
| 1192 | 8413261 | Formation of the IRS-1-PtdIns 3-kinase complex and insulin-stimulated PtdIns 3-kinase activation are also inhibited by microinjection of a glutathione S-transferase fusion protein containing the SH2 domain of p85. |
| 1193 | 8413261 | These inhibitory effects are specific and are not mimicked by glutathione S-transferase fusion proteins expressing the SH2 domains of ras-GAP or phospholipase C gamma. |
| 1194 | 8413261 | Moreover, injection of the SH2 domains of p85, ras-GAP, and phospholipase C gamma do not interfere with progesterone-induced oocyte maturation. |
| 1195 | 8413261 | These data demonstrate that phosphorylation of IRS-1 plays an essential role in IGF-I and insulin signaling in oocyte maturation and that this effect occurs through interactions of the phosphorylated YMXM/YXXM motifs of IRS-1 with SH2 domains of PtdIns 3-kinase or some related molecules. |
| 1196 | 8477879 | Since post-receptor defects in the insulin signalling pathway are a common feature of Type 2 (non-insulin-dependent) diabetes mellitus, we have cloned the human IRS-1 gene in order to study the role of genetic variation in this gene in the pathogenesis of diabetes mellitus. |
| 1197 | 8513971 | We have now cloned the IRS-1 cDNA from human skeletal muscle, one of the most important target tissues of insulin action, localized and cloned the human IRS-1 gene, and studied the expression of the protein in Chinese hamster ovary cells. |
| 1198 | 8513971 | When human IRS-1 cDNA was expressed in Chinese hamster ovary cells, the protein migrated between 170,000-180,000 M(r) in sodium dodecyl sulfate-polyacrylamide gel electrophoresis and was rapidly Tyr phosphorylated upon insulin stimulation. |
| 1199 | 8513971 | We have now cloned the IRS-1 cDNA from human skeletal muscle, one of the most important target tissues of insulin action, localized and cloned the human IRS-1 gene, and studied the expression of the protein in Chinese hamster ovary cells. |
| 1200 | 8513971 | When human IRS-1 cDNA was expressed in Chinese hamster ovary cells, the protein migrated between 170,000-180,000 M(r) in sodium dodecyl sulfate-polyacrylamide gel electrophoresis and was rapidly Tyr phosphorylated upon insulin stimulation. |
| 1201 | 8518461 | Insulin-receptor substrate 1 may be central to phosphorylation reactions through a role in serine and threonine kinase activity. |
| 1202 | 8518461 | Important roles for insulin-receptor kinase, glucose transporters, insulin-receptor substrate 1, and various intracellular enzymes in the actions of insulin have been demonstrated; nonetheless, the formulation of potential therapeutic strategies directed at particular stages of the insulin action cascade will require further elucidation of its components. |
| 1203 | 8518461 | Insulin-receptor substrate 1 may be central to phosphorylation reactions through a role in serine and threonine kinase activity. |
| 1204 | 8518461 | Important roles for insulin-receptor kinase, glucose transporters, insulin-receptor substrate 1, and various intracellular enzymes in the actions of insulin have been demonstrated; nonetheless, the formulation of potential therapeutic strategies directed at particular stages of the insulin action cascade will require further elucidation of its components. |
| 1205 | 8522061 | There was a selective decrease in GLUT4 (54 +/- 5% of high-carbohydrate) in epididymal fat from rats on the high-fat diet for 3 weeks, but englitazone treatment did not reverse the defect in GLUT4 (43 +/- 8% of high-carbohydrate) or increase GLUT1 (81 +/- 12% of high-carbohydrate). |
| 1206 | 8522061 | Englitazone did not reverse this decrease in IRS-1 and PI-3-kinase levels in fat from high-fat-fed rats (there was a further 25-30% decrease, P < 0.05), nor did it increase PI-3-kinase activity in 3T3-L1 adipocytes under conditions (48 h incubation) where it stimulated 2-DG uptake sixfold or enhanced insulin-stimulated 2-DG uptake. |
| 1207 | 8530404 | Insulin-induced phosphorylation of insulin receptors and insulin receptor substrate-1 displaces phosphorylated platelet-derived growth factor receptors from binding sites on PI 3-kinase. |
| 1208 | 8530404 | The p85 regulatory subunit of PI 3-kinase binds to phosphotyrosine residues of various phosphoproteins including the platelet-derived growth factor (PDGF) receptor, the insulin receptor, and insulin receptor substrate-1 (IRS-1). |
| 1209 | 8530404 | Using NIH-3T3 cells overexpressing the human insulin receptor, we demonstrate that the p85 regulatory subunit of PI 3-kinase binds to phosphorylated PDGF receptor in cells incubated in the absence of insulin. |
| 1210 | 8530404 | When insulin is added, p85 is released from phosphorylated PDGF receptors and binds to phosphorylated insulin receptors and insulin receptor substrate-1. |
| 1211 | 8530404 | Moreover, insulin-induced dissociation of PDGF receptors from binding sites on PI 3-kinase requires a functional insulin receptor and is not prevented by vanadate treatment. |
| 1212 | 8530404 | In contrast, insulin activation does not displace PDGF receptors from binding sites on Ras GTPase-activating protein. |
| 1213 | 8530404 | This competition for binding to PI 3-kinase provides a mechanism for cross-talk among signaling pathways initiated by distinct peptide hormones and growth factors such as insulin and PDGF. |
| 1214 | 8530404 | Insulin-induced phosphorylation of insulin receptors and insulin receptor substrate-1 displaces phosphorylated platelet-derived growth factor receptors from binding sites on PI 3-kinase. |
| 1215 | 8530404 | The p85 regulatory subunit of PI 3-kinase binds to phosphotyrosine residues of various phosphoproteins including the platelet-derived growth factor (PDGF) receptor, the insulin receptor, and insulin receptor substrate-1 (IRS-1). |
| 1216 | 8530404 | Using NIH-3T3 cells overexpressing the human insulin receptor, we demonstrate that the p85 regulatory subunit of PI 3-kinase binds to phosphorylated PDGF receptor in cells incubated in the absence of insulin. |
| 1217 | 8530404 | When insulin is added, p85 is released from phosphorylated PDGF receptors and binds to phosphorylated insulin receptors and insulin receptor substrate-1. |
| 1218 | 8530404 | Moreover, insulin-induced dissociation of PDGF receptors from binding sites on PI 3-kinase requires a functional insulin receptor and is not prevented by vanadate treatment. |
| 1219 | 8530404 | In contrast, insulin activation does not displace PDGF receptors from binding sites on Ras GTPase-activating protein. |
| 1220 | 8530404 | This competition for binding to PI 3-kinase provides a mechanism for cross-talk among signaling pathways initiated by distinct peptide hormones and growth factors such as insulin and PDGF. |
| 1221 | 8530404 | Insulin-induced phosphorylation of insulin receptors and insulin receptor substrate-1 displaces phosphorylated platelet-derived growth factor receptors from binding sites on PI 3-kinase. |
| 1222 | 8530404 | The p85 regulatory subunit of PI 3-kinase binds to phosphotyrosine residues of various phosphoproteins including the platelet-derived growth factor (PDGF) receptor, the insulin receptor, and insulin receptor substrate-1 (IRS-1). |
| 1223 | 8530404 | Using NIH-3T3 cells overexpressing the human insulin receptor, we demonstrate that the p85 regulatory subunit of PI 3-kinase binds to phosphorylated PDGF receptor in cells incubated in the absence of insulin. |
| 1224 | 8530404 | When insulin is added, p85 is released from phosphorylated PDGF receptors and binds to phosphorylated insulin receptors and insulin receptor substrate-1. |
| 1225 | 8530404 | Moreover, insulin-induced dissociation of PDGF receptors from binding sites on PI 3-kinase requires a functional insulin receptor and is not prevented by vanadate treatment. |
| 1226 | 8530404 | In contrast, insulin activation does not displace PDGF receptors from binding sites on Ras GTPase-activating protein. |
| 1227 | 8530404 | This competition for binding to PI 3-kinase provides a mechanism for cross-talk among signaling pathways initiated by distinct peptide hormones and growth factors such as insulin and PDGF. |
| 1228 | 8544845 | To evaluate the potential for regulation of the insulin receptor substrate IRS-1, we have cloned the mouse IRS-1 gene, identified its promoter, and analyzed promoter activity in the basal state and in response to stimulation. |
| 1229 | 8544845 | The 5'-region of the mouse IRS-1 gene lacks typical CAAT and TATA boxes but contains nine potential Sp1 binding sites consistent with a housekeeping gene. |
| 1230 | 8544845 | The 5'-region of the IRS-1 gene also has significant regions of homology with the promoters of the progesterone receptor gene, the insulin-like growth factor I receptor gene, and the androgen receptor gene. |
| 1231 | 8544845 | By gel shift assay, a nuclear factor was identified in CHO cells which binds to -1606 and -1586 sequence in the negative regulatory element and appears to be distinct from C/EBP, CREB, and AP-1. |
| 1232 | 8544845 | Insulin also decreased IRS-1 protein by approximately 60% within 9 h but did so without altering IRS-1 mRNA levels or chloramphenicol acetyl transferase activity. |
| 1233 | 8544845 | Thus, both insulin and dexamethasone down-regulate IRS-1 expression at the posttranscriptional level; with insulin this is probably due to an effect on protein half-life, whereas with dexamethasone the effect is due to a change in the half-life of IRS-1 mRNA. |
| 1234 | 8544845 | To evaluate the potential for regulation of the insulin receptor substrate IRS-1, we have cloned the mouse IRS-1 gene, identified its promoter, and analyzed promoter activity in the basal state and in response to stimulation. |
| 1235 | 8544845 | The 5'-region of the mouse IRS-1 gene lacks typical CAAT and TATA boxes but contains nine potential Sp1 binding sites consistent with a housekeeping gene. |
| 1236 | 8544845 | The 5'-region of the IRS-1 gene also has significant regions of homology with the promoters of the progesterone receptor gene, the insulin-like growth factor I receptor gene, and the androgen receptor gene. |
| 1237 | 8544845 | By gel shift assay, a nuclear factor was identified in CHO cells which binds to -1606 and -1586 sequence in the negative regulatory element and appears to be distinct from C/EBP, CREB, and AP-1. |
| 1238 | 8544845 | Insulin also decreased IRS-1 protein by approximately 60% within 9 h but did so without altering IRS-1 mRNA levels or chloramphenicol acetyl transferase activity. |
| 1239 | 8544845 | Thus, both insulin and dexamethasone down-regulate IRS-1 expression at the posttranscriptional level; with insulin this is probably due to an effect on protein half-life, whereas with dexamethasone the effect is due to a change in the half-life of IRS-1 mRNA. |
| 1240 | 8544845 | To evaluate the potential for regulation of the insulin receptor substrate IRS-1, we have cloned the mouse IRS-1 gene, identified its promoter, and analyzed promoter activity in the basal state and in response to stimulation. |
| 1241 | 8544845 | The 5'-region of the mouse IRS-1 gene lacks typical CAAT and TATA boxes but contains nine potential Sp1 binding sites consistent with a housekeeping gene. |
| 1242 | 8544845 | The 5'-region of the IRS-1 gene also has significant regions of homology with the promoters of the progesterone receptor gene, the insulin-like growth factor I receptor gene, and the androgen receptor gene. |
| 1243 | 8544845 | By gel shift assay, a nuclear factor was identified in CHO cells which binds to -1606 and -1586 sequence in the negative regulatory element and appears to be distinct from C/EBP, CREB, and AP-1. |
| 1244 | 8544845 | Insulin also decreased IRS-1 protein by approximately 60% within 9 h but did so without altering IRS-1 mRNA levels or chloramphenicol acetyl transferase activity. |
| 1245 | 8544845 | Thus, both insulin and dexamethasone down-regulate IRS-1 expression at the posttranscriptional level; with insulin this is probably due to an effect on protein half-life, whereas with dexamethasone the effect is due to a change in the half-life of IRS-1 mRNA. |
| 1246 | 8544845 | To evaluate the potential for regulation of the insulin receptor substrate IRS-1, we have cloned the mouse IRS-1 gene, identified its promoter, and analyzed promoter activity in the basal state and in response to stimulation. |
| 1247 | 8544845 | The 5'-region of the mouse IRS-1 gene lacks typical CAAT and TATA boxes but contains nine potential Sp1 binding sites consistent with a housekeeping gene. |
| 1248 | 8544845 | The 5'-region of the IRS-1 gene also has significant regions of homology with the promoters of the progesterone receptor gene, the insulin-like growth factor I receptor gene, and the androgen receptor gene. |
| 1249 | 8544845 | By gel shift assay, a nuclear factor was identified in CHO cells which binds to -1606 and -1586 sequence in the negative regulatory element and appears to be distinct from C/EBP, CREB, and AP-1. |
| 1250 | 8544845 | Insulin also decreased IRS-1 protein by approximately 60% within 9 h but did so without altering IRS-1 mRNA levels or chloramphenicol acetyl transferase activity. |
| 1251 | 8544845 | Thus, both insulin and dexamethasone down-regulate IRS-1 expression at the posttranscriptional level; with insulin this is probably due to an effect on protein half-life, whereas with dexamethasone the effect is due to a change in the half-life of IRS-1 mRNA. |
| 1252 | 8544845 | To evaluate the potential for regulation of the insulin receptor substrate IRS-1, we have cloned the mouse IRS-1 gene, identified its promoter, and analyzed promoter activity in the basal state and in response to stimulation. |
| 1253 | 8544845 | The 5'-region of the mouse IRS-1 gene lacks typical CAAT and TATA boxes but contains nine potential Sp1 binding sites consistent with a housekeeping gene. |
| 1254 | 8544845 | The 5'-region of the IRS-1 gene also has significant regions of homology with the promoters of the progesterone receptor gene, the insulin-like growth factor I receptor gene, and the androgen receptor gene. |
| 1255 | 8544845 | By gel shift assay, a nuclear factor was identified in CHO cells which binds to -1606 and -1586 sequence in the negative regulatory element and appears to be distinct from C/EBP, CREB, and AP-1. |
| 1256 | 8544845 | Insulin also decreased IRS-1 protein by approximately 60% within 9 h but did so without altering IRS-1 mRNA levels or chloramphenicol acetyl transferase activity. |
| 1257 | 8544845 | Thus, both insulin and dexamethasone down-regulate IRS-1 expression at the posttranscriptional level; with insulin this is probably due to an effect on protein half-life, whereas with dexamethasone the effect is due to a change in the half-life of IRS-1 mRNA. |
| 1258 | 8571133 | IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-induced insulin resistance. |
| 1259 | 8571133 | Tumor necrosis factor-alpha (TNF-alpha) is an important mediator of insulin resistance in obesity and diabetes through its ability to decrease the tyrosine kinase activity of the insulin receptor (IR). |
| 1260 | 8571133 | Treatment of cultured murine adipocytes with TNF-alpha was shown to induce serine phosphorylation of insulin receptor substrate 1 (IRS-1) and convert IRS-1 into an inhibitor of the IR tyrosine kinase activity in vitro. |
| 1261 | 8571133 | Myeloid 32D cells, which lack endogenous IRS-1, were resistant to TNF-alpha-mediated inhibition of IR signaling, whereas transfected 32D cells that express IRS-1 were very sensitive to this effect of TNF-alpha. |
| 1262 | 8571133 | These results indicate that TNF-alpha induces insulin resistance through an unexpected action of IRS-1 to attenuate insulin receptor signaling. |
| 1263 | 8571133 | IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-induced insulin resistance. |
| 1264 | 8571133 | Tumor necrosis factor-alpha (TNF-alpha) is an important mediator of insulin resistance in obesity and diabetes through its ability to decrease the tyrosine kinase activity of the insulin receptor (IR). |
| 1265 | 8571133 | Treatment of cultured murine adipocytes with TNF-alpha was shown to induce serine phosphorylation of insulin receptor substrate 1 (IRS-1) and convert IRS-1 into an inhibitor of the IR tyrosine kinase activity in vitro. |
| 1266 | 8571133 | Myeloid 32D cells, which lack endogenous IRS-1, were resistant to TNF-alpha-mediated inhibition of IR signaling, whereas transfected 32D cells that express IRS-1 were very sensitive to this effect of TNF-alpha. |
| 1267 | 8571133 | These results indicate that TNF-alpha induces insulin resistance through an unexpected action of IRS-1 to attenuate insulin receptor signaling. |
| 1268 | 8571133 | IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-induced insulin resistance. |
| 1269 | 8571133 | Tumor necrosis factor-alpha (TNF-alpha) is an important mediator of insulin resistance in obesity and diabetes through its ability to decrease the tyrosine kinase activity of the insulin receptor (IR). |
| 1270 | 8571133 | Treatment of cultured murine adipocytes with TNF-alpha was shown to induce serine phosphorylation of insulin receptor substrate 1 (IRS-1) and convert IRS-1 into an inhibitor of the IR tyrosine kinase activity in vitro. |
| 1271 | 8571133 | Myeloid 32D cells, which lack endogenous IRS-1, were resistant to TNF-alpha-mediated inhibition of IR signaling, whereas transfected 32D cells that express IRS-1 were very sensitive to this effect of TNF-alpha. |
| 1272 | 8571133 | These results indicate that TNF-alpha induces insulin resistance through an unexpected action of IRS-1 to attenuate insulin receptor signaling. |
| 1273 | 8587610 | G ialpha2 deficiency increases protein-tyrosine phosphatase activity and attenuates insulin-stimulated tyrosine phosphorylation of IRS (insulin-receptor substrate 1) in vivo. |
| 1274 | 8593783 | Tumorigenic and mitogenic capacities are reduced in transfected fibroblasts expressing mutant insulin-like growth factor (IGF)-I receptors. |
| 1275 | 8593783 | The insulin-like growth factor-I (IGF-I) receptor contains three tyrosine residues in the carboxy-terminal domain at positions 1250, 1251, and 1316. |
| 1276 | 8593783 | The yyFH mutation results in an IGF-I receptor with the amino acids found in the homologous position of the human insulin receptor. |
| 1277 | 8593783 | The ability of yyFH mutant IGF-I receptors to autophosphorylate the beta-subunit or phosphorylate insulin receptor substrate-1 was not significantly different from wild-type type IGF-I receptors. |
| 1278 | 8607861 | Insulin receptor substrate-1 (IRS-1) is a multisite docking protein implicated in mitogenic signaling following activation of the insulin and insulin-like growth factor I receptors. |
| 1279 | 8607861 | Analysis of RNA isolated from normal and cancerous human pancreatic tissues indicated that 7 of 16 pancreatic cancer samples overexpressed IRS-1 mRNA transcripts by comparison with the normal pancreas and that insulin mRNA levels were abundant in many tumors. |
| 1280 | 8607861 | Insulin receptor substrate-1 (IRS-1) is a multisite docking protein implicated in mitogenic signaling following activation of the insulin and insulin-like growth factor I receptors. |
| 1281 | 8607861 | Analysis of RNA isolated from normal and cancerous human pancreatic tissues indicated that 7 of 16 pancreatic cancer samples overexpressed IRS-1 mRNA transcripts by comparison with the normal pancreas and that insulin mRNA levels were abundant in many tumors. |
| 1282 | 8621530 | Interaction between the Grb10 SH2 domain and the insulin receptor carboxyl terminus. |
| 1283 | 8621530 | We identified and isolated the Grb10 SH2 domain based on its interaction with the intracellular domain of the insulin receptor beta-subunit using the yeast two-hybrid system. |
| 1284 | 8621530 | The interaction was specific for the insulin receptor and the insulin-like growth factor-1 receptor, and it required a catalytically active receptor kinase domain and an intact Grb10 SH2 domain. |
| 1285 | 8621530 | Glutathione S-transferase fusion proteins containing the Grb10 SH2 domain associated in an insulin-dependent manner with insulin receptors from cell lysates and with purified insulin receptors. |
| 1286 | 8621530 | Co-precipitation experiments revealed the association of cellular Grb10 with hormone-stimulated insulin receptors in cell extracts. |
| 1287 | 8621530 | The Grb10 SH2 domain did not bind to an insulin receptor lacking 43 amino acids at the carboxyl terminus, and it exhibited highest affinity for a phosphopeptide containing Tyr(P)-1322. |
| 1288 | 8621530 | Unlike p85 and Syp, which also bind to Tyr(P)-1322, Grb10 was not found to associate with insulin receptor substrate-1. |
| 1289 | 8621530 | These results suggest that Grb10 is a novel insulin receptor interactive protein and provide direct evidence for an insulin receptor substrate-1-independent function of the insulin receptor carboxyl terminus in protein binding. |
| 1290 | 8621530 | Interaction between the Grb10 SH2 domain and the insulin receptor carboxyl terminus. |
| 1291 | 8621530 | We identified and isolated the Grb10 SH2 domain based on its interaction with the intracellular domain of the insulin receptor beta-subunit using the yeast two-hybrid system. |
| 1292 | 8621530 | The interaction was specific for the insulin receptor and the insulin-like growth factor-1 receptor, and it required a catalytically active receptor kinase domain and an intact Grb10 SH2 domain. |
| 1293 | 8621530 | Glutathione S-transferase fusion proteins containing the Grb10 SH2 domain associated in an insulin-dependent manner with insulin receptors from cell lysates and with purified insulin receptors. |
| 1294 | 8621530 | Co-precipitation experiments revealed the association of cellular Grb10 with hormone-stimulated insulin receptors in cell extracts. |
| 1295 | 8621530 | The Grb10 SH2 domain did not bind to an insulin receptor lacking 43 amino acids at the carboxyl terminus, and it exhibited highest affinity for a phosphopeptide containing Tyr(P)-1322. |
| 1296 | 8621530 | Unlike p85 and Syp, which also bind to Tyr(P)-1322, Grb10 was not found to associate with insulin receptor substrate-1. |
| 1297 | 8621530 | These results suggest that Grb10 is a novel insulin receptor interactive protein and provide direct evidence for an insulin receptor substrate-1-independent function of the insulin receptor carboxyl terminus in protein binding. |
| 1298 | 8621590 | Modulation by insulin growth factor-I (IGF) and enhanced IGF-I signaling. |
| 1299 | 8621590 | The Crk proto-oncogene product is an SH2 and SH3 domain-containing adaptor protein which we have previously shown to become rapidly tyrosine phosphorylated in response to stimulation with insulin-like growth factor I (IGF-I) in NIH-3T3 cells. |
| 1300 | 8621590 | Stimulation with IGF-I resulted in a dissociation of Crk protein from IRS-1. |
| 1301 | 8621590 | In contrast, the association of the related adaptor protein Grb2 with IRS-1 was enhanced by IGF-I stimulation. |
| 1302 | 8621590 | In these cells, IRS-1 and 4PS both associated with Crk, and this association was also decreased by IGF-I treatment, whereas the association of Grb2 with IRS-1 and 4PS was enhanced by IGF-I. |
| 1303 | 8621590 | These results suggest that Crk is a positive effector of IGF-I signaling, and may mediate its effects via interaction with IRS-1 and/or 4PS. |
| 1304 | 8621590 | Modulation by insulin growth factor-I (IGF) and enhanced IGF-I signaling. |
| 1305 | 8621590 | The Crk proto-oncogene product is an SH2 and SH3 domain-containing adaptor protein which we have previously shown to become rapidly tyrosine phosphorylated in response to stimulation with insulin-like growth factor I (IGF-I) in NIH-3T3 cells. |
| 1306 | 8621590 | Stimulation with IGF-I resulted in a dissociation of Crk protein from IRS-1. |
| 1307 | 8621590 | In contrast, the association of the related adaptor protein Grb2 with IRS-1 was enhanced by IGF-I stimulation. |
| 1308 | 8621590 | In these cells, IRS-1 and 4PS both associated with Crk, and this association was also decreased by IGF-I treatment, whereas the association of Grb2 with IRS-1 and 4PS was enhanced by IGF-I. |
| 1309 | 8621590 | These results suggest that Crk is a positive effector of IGF-I signaling, and may mediate its effects via interaction with IRS-1 and/or 4PS. |
| 1310 | 8621590 | Modulation by insulin growth factor-I (IGF) and enhanced IGF-I signaling. |
| 1311 | 8621590 | The Crk proto-oncogene product is an SH2 and SH3 domain-containing adaptor protein which we have previously shown to become rapidly tyrosine phosphorylated in response to stimulation with insulin-like growth factor I (IGF-I) in NIH-3T3 cells. |
| 1312 | 8621590 | Stimulation with IGF-I resulted in a dissociation of Crk protein from IRS-1. |
| 1313 | 8621590 | In contrast, the association of the related adaptor protein Grb2 with IRS-1 was enhanced by IGF-I stimulation. |
| 1314 | 8621590 | In these cells, IRS-1 and 4PS both associated with Crk, and this association was also decreased by IGF-I treatment, whereas the association of Grb2 with IRS-1 and 4PS was enhanced by IGF-I. |
| 1315 | 8621590 | These results suggest that Crk is a positive effector of IGF-I signaling, and may mediate its effects via interaction with IRS-1 and/or 4PS. |
| 1316 | 8621590 | Modulation by insulin growth factor-I (IGF) and enhanced IGF-I signaling. |
| 1317 | 8621590 | The Crk proto-oncogene product is an SH2 and SH3 domain-containing adaptor protein which we have previously shown to become rapidly tyrosine phosphorylated in response to stimulation with insulin-like growth factor I (IGF-I) in NIH-3T3 cells. |
| 1318 | 8621590 | Stimulation with IGF-I resulted in a dissociation of Crk protein from IRS-1. |
| 1319 | 8621590 | In contrast, the association of the related adaptor protein Grb2 with IRS-1 was enhanced by IGF-I stimulation. |
| 1320 | 8621590 | In these cells, IRS-1 and 4PS both associated with Crk, and this association was also decreased by IGF-I treatment, whereas the association of Grb2 with IRS-1 and 4PS was enhanced by IGF-I. |
| 1321 | 8621590 | These results suggest that Crk is a positive effector of IGF-I signaling, and may mediate its effects via interaction with IRS-1 and/or 4PS. |
| 1322 | 8628286 | Insulin receptor substrate 1 binds two novel splice variants of the regulatory subunit of phosphatidylinositol 3-kinase in muscle and brain. |
| 1323 | 8628286 | We have identified two novel alternatively spliced forms of the p85alpha regulatory subunit of phosphatidylinositol (PI) 3-kinase by expression screening of a human skeletal muscle library with phosphorylated baculovirus- produced human insulin receptor substrate 1. |
| 1324 | 8628286 | Both p85 and p85/AS53 bind to p110 in coprecipitation experiments, but p85alpha itself appears to have preferential binding to insulin receptor substrate 1 following insulin stimulation. |
| 1325 | 8628286 | Insulin receptor substrate 1 binds two novel splice variants of the regulatory subunit of phosphatidylinositol 3-kinase in muscle and brain. |
| 1326 | 8628286 | We have identified two novel alternatively spliced forms of the p85alpha regulatory subunit of phosphatidylinositol (PI) 3-kinase by expression screening of a human skeletal muscle library with phosphorylated baculovirus- produced human insulin receptor substrate 1. |
| 1327 | 8628286 | Both p85 and p85/AS53 bind to p110 in coprecipitation experiments, but p85alpha itself appears to have preferential binding to insulin receptor substrate 1 following insulin stimulation. |
| 1328 | 8628286 | Insulin receptor substrate 1 binds two novel splice variants of the regulatory subunit of phosphatidylinositol 3-kinase in muscle and brain. |
| 1329 | 8628286 | We have identified two novel alternatively spliced forms of the p85alpha regulatory subunit of phosphatidylinositol (PI) 3-kinase by expression screening of a human skeletal muscle library with phosphorylated baculovirus- produced human insulin receptor substrate 1. |
| 1330 | 8628286 | Both p85 and p85/AS53 bind to p110 in coprecipitation experiments, but p85alpha itself appears to have preferential binding to insulin receptor substrate 1 following insulin stimulation. |
| 1331 | 8628319 | Insulin stimulated tyrosine autophosphorylation of the human insulin receptor and hDIR, and both receptors mediated tyrosine phosphorylation of Shc and activated mitogen-activated protein kinase. |
| 1332 | 8628319 | IRS-1 was required by the human insulin receptor to activate PI 3-kinase and p70s6k, whereas hDIR associated with PI 3-kinase and activated p70s6k without IRS-1. |
| 1333 | 8628319 | However, both receptors required IRS-1 to mediate insulin-stimulated mitogenesis. |
| 1334 | 8628319 | These data demonstrate that the DIR possesses additional signaling capabilities compared with its mammalian counterpart but still requires IRS-1 for the complete insulin response in mammalian cells. |
| 1335 | 8628319 | Insulin stimulated tyrosine autophosphorylation of the human insulin receptor and hDIR, and both receptors mediated tyrosine phosphorylation of Shc and activated mitogen-activated protein kinase. |
| 1336 | 8628319 | IRS-1 was required by the human insulin receptor to activate PI 3-kinase and p70s6k, whereas hDIR associated with PI 3-kinase and activated p70s6k without IRS-1. |
| 1337 | 8628319 | However, both receptors required IRS-1 to mediate insulin-stimulated mitogenesis. |
| 1338 | 8628319 | These data demonstrate that the DIR possesses additional signaling capabilities compared with its mammalian counterpart but still requires IRS-1 for the complete insulin response in mammalian cells. |
| 1339 | 8628319 | Insulin stimulated tyrosine autophosphorylation of the human insulin receptor and hDIR, and both receptors mediated tyrosine phosphorylation of Shc and activated mitogen-activated protein kinase. |
| 1340 | 8628319 | IRS-1 was required by the human insulin receptor to activate PI 3-kinase and p70s6k, whereas hDIR associated with PI 3-kinase and activated p70s6k without IRS-1. |
| 1341 | 8628319 | However, both receptors required IRS-1 to mediate insulin-stimulated mitogenesis. |
| 1342 | 8628319 | These data demonstrate that the DIR possesses additional signaling capabilities compared with its mammalian counterpart but still requires IRS-1 for the complete insulin response in mammalian cells. |
| 1343 | 8631859 | The Fyn tyrosine kinase binds Irs-1 and forms a distinct signaling complex during insulin stimulation. |
| 1344 | 8631859 | Irs-proteins link the receptors for insulin/IGF-1, growth hormones, and several interleukins and interferons to signaling proteins that contain Src homology-2 (SH2). |
| 1345 | 8631859 | Mutation of p59fyn at the COOH-terminal tyrosine phosphorylation site (Tyr531) enhanced its binding to Irs-1 during insulin stimulation. |
| 1346 | 8631859 | Binding experiments with various SH2 protein revealed that Grb-2 was largely excluded from Irs-1 complexes containing p59fyn, whereas Grb-2 and p85 occurred in the same Irs-1 complex. |
| 1347 | 8631859 | By comparison with the insulin receptor, p59fyn kinase phosphorylated a unique cohort of tyrosine residues in Irs-1. |
| 1348 | 8631859 | The Fyn tyrosine kinase binds Irs-1 and forms a distinct signaling complex during insulin stimulation. |
| 1349 | 8631859 | Irs-proteins link the receptors for insulin/IGF-1, growth hormones, and several interleukins and interferons to signaling proteins that contain Src homology-2 (SH2). |
| 1350 | 8631859 | Mutation of p59fyn at the COOH-terminal tyrosine phosphorylation site (Tyr531) enhanced its binding to Irs-1 during insulin stimulation. |
| 1351 | 8631859 | Binding experiments with various SH2 protein revealed that Grb-2 was largely excluded from Irs-1 complexes containing p59fyn, whereas Grb-2 and p85 occurred in the same Irs-1 complex. |
| 1352 | 8631859 | By comparison with the insulin receptor, p59fyn kinase phosphorylated a unique cohort of tyrosine residues in Irs-1. |
| 1353 | 8631859 | The Fyn tyrosine kinase binds Irs-1 and forms a distinct signaling complex during insulin stimulation. |
| 1354 | 8631859 | Irs-proteins link the receptors for insulin/IGF-1, growth hormones, and several interleukins and interferons to signaling proteins that contain Src homology-2 (SH2). |
| 1355 | 8631859 | Mutation of p59fyn at the COOH-terminal tyrosine phosphorylation site (Tyr531) enhanced its binding to Irs-1 during insulin stimulation. |
| 1356 | 8631859 | Binding experiments with various SH2 protein revealed that Grb-2 was largely excluded from Irs-1 complexes containing p59fyn, whereas Grb-2 and p85 occurred in the same Irs-1 complex. |
| 1357 | 8631859 | By comparison with the insulin receptor, p59fyn kinase phosphorylated a unique cohort of tyrosine residues in Irs-1. |
| 1358 | 8631859 | The Fyn tyrosine kinase binds Irs-1 and forms a distinct signaling complex during insulin stimulation. |
| 1359 | 8631859 | Irs-proteins link the receptors for insulin/IGF-1, growth hormones, and several interleukins and interferons to signaling proteins that contain Src homology-2 (SH2). |
| 1360 | 8631859 | Mutation of p59fyn at the COOH-terminal tyrosine phosphorylation site (Tyr531) enhanced its binding to Irs-1 during insulin stimulation. |
| 1361 | 8631859 | Binding experiments with various SH2 protein revealed that Grb-2 was largely excluded from Irs-1 complexes containing p59fyn, whereas Grb-2 and p85 occurred in the same Irs-1 complex. |
| 1362 | 8631859 | By comparison with the insulin receptor, p59fyn kinase phosphorylated a unique cohort of tyrosine residues in Irs-1. |
| 1363 | 8635642 | Since IRS-1 links several cell surface receptors, including those for insulin and IGF-I, to distal signal transduction pathways, our observations indicate that hormonal regulation of islet beta-cells potentially involves the same signal transduction pathway that mediates insulin and growth factor signaling in peripheral insulin target tissue cell types. |
| 1364 | 8641117 | The function and position of IRS-1 within the insulin signalling pathway make it a prime candidate gene for the development of insulin resistance and NIDDM. |
| 1365 | 8647950 | Insulin receptor substrates-1 (IRS-1) is the major cytoplasmic substrate of the insulin and IGF-1 receptors. |
| 1366 | 8647950 | Recent studies have identified multiple sequence variants of IRS-1, especially in patients with non-insulin-dependent diabetes mellitus. |
| 1367 | 8647950 | In the present study, we have examined insulin-stimulated processes in 32D(IR) cells, a myeloid progenitor cell stably overexpressing the insulin receptor, transfected with wild-type human-IRS-1 or the most common human variant of IRS-1 in which glycine 972 is replaced by arginine. |
| 1368 | 8647950 | As compared to wild-type IRS-1, insulin stimulation of cells transfected with mutant IRS-1 exhibited a 32% decrease in incorporation of [3H]thymidine into DNA (P = 0.002), a 36% decrease in IRS-1 associated phosphatidylinositol (PI) 3-kinase activity (P = 0.004) and a 25% decrease in binding of the p85 regulatory subunit of PI 3-kinase to IRS-1 (P = 0.002). |
| 1369 | 8647950 | There was also a tendency for a decrease in Grb2 binding to IRS-1 and insulin-stimulated mitogen-activated protein kinase activity, however, these were not statistically significant. |
| 1370 | 8647950 | The changes occurred with no change in insulin receptor or IRS-1 tyrosine phosphorylation. |
| 1371 | 8647950 | These data indicate that the mutation in codon 972 in IRS-1 impairs insulin-stimulated signaling, especially along the PI 3-kinase pathway, and may contribute to insulin resistance in normal and diabetic populations. |
| 1372 | 8647950 | Insulin receptor substrates-1 (IRS-1) is the major cytoplasmic substrate of the insulin and IGF-1 receptors. |
| 1373 | 8647950 | Recent studies have identified multiple sequence variants of IRS-1, especially in patients with non-insulin-dependent diabetes mellitus. |
| 1374 | 8647950 | In the present study, we have examined insulin-stimulated processes in 32D(IR) cells, a myeloid progenitor cell stably overexpressing the insulin receptor, transfected with wild-type human-IRS-1 or the most common human variant of IRS-1 in which glycine 972 is replaced by arginine. |
| 1375 | 8647950 | As compared to wild-type IRS-1, insulin stimulation of cells transfected with mutant IRS-1 exhibited a 32% decrease in incorporation of [3H]thymidine into DNA (P = 0.002), a 36% decrease in IRS-1 associated phosphatidylinositol (PI) 3-kinase activity (P = 0.004) and a 25% decrease in binding of the p85 regulatory subunit of PI 3-kinase to IRS-1 (P = 0.002). |
| 1376 | 8647950 | There was also a tendency for a decrease in Grb2 binding to IRS-1 and insulin-stimulated mitogen-activated protein kinase activity, however, these were not statistically significant. |
| 1377 | 8647950 | The changes occurred with no change in insulin receptor or IRS-1 tyrosine phosphorylation. |
| 1378 | 8647950 | These data indicate that the mutation in codon 972 in IRS-1 impairs insulin-stimulated signaling, especially along the PI 3-kinase pathway, and may contribute to insulin resistance in normal and diabetic populations. |
| 1379 | 8647950 | Insulin receptor substrates-1 (IRS-1) is the major cytoplasmic substrate of the insulin and IGF-1 receptors. |
| 1380 | 8647950 | Recent studies have identified multiple sequence variants of IRS-1, especially in patients with non-insulin-dependent diabetes mellitus. |
| 1381 | 8647950 | In the present study, we have examined insulin-stimulated processes in 32D(IR) cells, a myeloid progenitor cell stably overexpressing the insulin receptor, transfected with wild-type human-IRS-1 or the most common human variant of IRS-1 in which glycine 972 is replaced by arginine. |
| 1382 | 8647950 | As compared to wild-type IRS-1, insulin stimulation of cells transfected with mutant IRS-1 exhibited a 32% decrease in incorporation of [3H]thymidine into DNA (P = 0.002), a 36% decrease in IRS-1 associated phosphatidylinositol (PI) 3-kinase activity (P = 0.004) and a 25% decrease in binding of the p85 regulatory subunit of PI 3-kinase to IRS-1 (P = 0.002). |
| 1383 | 8647950 | There was also a tendency for a decrease in Grb2 binding to IRS-1 and insulin-stimulated mitogen-activated protein kinase activity, however, these were not statistically significant. |
| 1384 | 8647950 | The changes occurred with no change in insulin receptor or IRS-1 tyrosine phosphorylation. |
| 1385 | 8647950 | These data indicate that the mutation in codon 972 in IRS-1 impairs insulin-stimulated signaling, especially along the PI 3-kinase pathway, and may contribute to insulin resistance in normal and diabetic populations. |
| 1386 | 8647950 | Insulin receptor substrates-1 (IRS-1) is the major cytoplasmic substrate of the insulin and IGF-1 receptors. |
| 1387 | 8647950 | Recent studies have identified multiple sequence variants of IRS-1, especially in patients with non-insulin-dependent diabetes mellitus. |
| 1388 | 8647950 | In the present study, we have examined insulin-stimulated processes in 32D(IR) cells, a myeloid progenitor cell stably overexpressing the insulin receptor, transfected with wild-type human-IRS-1 or the most common human variant of IRS-1 in which glycine 972 is replaced by arginine. |
| 1389 | 8647950 | As compared to wild-type IRS-1, insulin stimulation of cells transfected with mutant IRS-1 exhibited a 32% decrease in incorporation of [3H]thymidine into DNA (P = 0.002), a 36% decrease in IRS-1 associated phosphatidylinositol (PI) 3-kinase activity (P = 0.004) and a 25% decrease in binding of the p85 regulatory subunit of PI 3-kinase to IRS-1 (P = 0.002). |
| 1390 | 8647950 | There was also a tendency for a decrease in Grb2 binding to IRS-1 and insulin-stimulated mitogen-activated protein kinase activity, however, these were not statistically significant. |
| 1391 | 8647950 | The changes occurred with no change in insulin receptor or IRS-1 tyrosine phosphorylation. |
| 1392 | 8647950 | These data indicate that the mutation in codon 972 in IRS-1 impairs insulin-stimulated signaling, especially along the PI 3-kinase pathway, and may contribute to insulin resistance in normal and diabetic populations. |
| 1393 | 8647950 | Insulin receptor substrates-1 (IRS-1) is the major cytoplasmic substrate of the insulin and IGF-1 receptors. |
| 1394 | 8647950 | Recent studies have identified multiple sequence variants of IRS-1, especially in patients with non-insulin-dependent diabetes mellitus. |
| 1395 | 8647950 | In the present study, we have examined insulin-stimulated processes in 32D(IR) cells, a myeloid progenitor cell stably overexpressing the insulin receptor, transfected with wild-type human-IRS-1 or the most common human variant of IRS-1 in which glycine 972 is replaced by arginine. |
| 1396 | 8647950 | As compared to wild-type IRS-1, insulin stimulation of cells transfected with mutant IRS-1 exhibited a 32% decrease in incorporation of [3H]thymidine into DNA (P = 0.002), a 36% decrease in IRS-1 associated phosphatidylinositol (PI) 3-kinase activity (P = 0.004) and a 25% decrease in binding of the p85 regulatory subunit of PI 3-kinase to IRS-1 (P = 0.002). |
| 1397 | 8647950 | There was also a tendency for a decrease in Grb2 binding to IRS-1 and insulin-stimulated mitogen-activated protein kinase activity, however, these were not statistically significant. |
| 1398 | 8647950 | The changes occurred with no change in insulin receptor or IRS-1 tyrosine phosphorylation. |
| 1399 | 8647950 | These data indicate that the mutation in codon 972 in IRS-1 impairs insulin-stimulated signaling, especially along the PI 3-kinase pathway, and may contribute to insulin resistance in normal and diabetic populations. |
| 1400 | 8647950 | Insulin receptor substrates-1 (IRS-1) is the major cytoplasmic substrate of the insulin and IGF-1 receptors. |
| 1401 | 8647950 | Recent studies have identified multiple sequence variants of IRS-1, especially in patients with non-insulin-dependent diabetes mellitus. |
| 1402 | 8647950 | In the present study, we have examined insulin-stimulated processes in 32D(IR) cells, a myeloid progenitor cell stably overexpressing the insulin receptor, transfected with wild-type human-IRS-1 or the most common human variant of IRS-1 in which glycine 972 is replaced by arginine. |
| 1403 | 8647950 | As compared to wild-type IRS-1, insulin stimulation of cells transfected with mutant IRS-1 exhibited a 32% decrease in incorporation of [3H]thymidine into DNA (P = 0.002), a 36% decrease in IRS-1 associated phosphatidylinositol (PI) 3-kinase activity (P = 0.004) and a 25% decrease in binding of the p85 regulatory subunit of PI 3-kinase to IRS-1 (P = 0.002). |
| 1404 | 8647950 | There was also a tendency for a decrease in Grb2 binding to IRS-1 and insulin-stimulated mitogen-activated protein kinase activity, however, these were not statistically significant. |
| 1405 | 8647950 | The changes occurred with no change in insulin receptor or IRS-1 tyrosine phosphorylation. |
| 1406 | 8647950 | These data indicate that the mutation in codon 972 in IRS-1 impairs insulin-stimulated signaling, especially along the PI 3-kinase pathway, and may contribute to insulin resistance in normal and diabetic populations. |
| 1407 | 8647950 | Insulin receptor substrates-1 (IRS-1) is the major cytoplasmic substrate of the insulin and IGF-1 receptors. |
| 1408 | 8647950 | Recent studies have identified multiple sequence variants of IRS-1, especially in patients with non-insulin-dependent diabetes mellitus. |
| 1409 | 8647950 | In the present study, we have examined insulin-stimulated processes in 32D(IR) cells, a myeloid progenitor cell stably overexpressing the insulin receptor, transfected with wild-type human-IRS-1 or the most common human variant of IRS-1 in which glycine 972 is replaced by arginine. |
| 1410 | 8647950 | As compared to wild-type IRS-1, insulin stimulation of cells transfected with mutant IRS-1 exhibited a 32% decrease in incorporation of [3H]thymidine into DNA (P = 0.002), a 36% decrease in IRS-1 associated phosphatidylinositol (PI) 3-kinase activity (P = 0.004) and a 25% decrease in binding of the p85 regulatory subunit of PI 3-kinase to IRS-1 (P = 0.002). |
| 1411 | 8647950 | There was also a tendency for a decrease in Grb2 binding to IRS-1 and insulin-stimulated mitogen-activated protein kinase activity, however, these were not statistically significant. |
| 1412 | 8647950 | The changes occurred with no change in insulin receptor or IRS-1 tyrosine phosphorylation. |
| 1413 | 8647950 | These data indicate that the mutation in codon 972 in IRS-1 impairs insulin-stimulated signaling, especially along the PI 3-kinase pathway, and may contribute to insulin resistance in normal and diabetic populations. |
| 1414 | 8662948 | 3S-peptide-I is a synthetic tris-sulfotyrosyl dodecapeptide corresponding to the major site of insulin receptor autophosphorylation that potently inhibits dephosphorylation of the insulin receptor in a cell-free system and in digitonin-permeabilized Chinese hamster ovary (CHO) cells overexpressing the human insulin receptors (CHO/HIRc cells) (Liotta, A. |
| 1415 | 8662948 | In the present study, we found that 3S-peptide-I was not capable of inhibiting dephosphorylation of the epidermal growth factor (EGF) receptors in digitonin-permeabilized CHO cells that overexpress human EGF receptors (CHO/EGF-R cells). |
| 1416 | 8662948 | Moreover, the addition of a N-stearyl derivative of 3S-peptide-I to intact CHO/HIRc cells caused a concentration-dependent increase in insulin-stimulated phosphorylation of the insulin receptor, with a maximum effect (approximately 2.7-fold) at 50 microM. |
| 1417 | 8662948 | In contrast, ligand-stimulated EGF receptor phosphorylation in CHO/EGF-R cells was not affected by the presence of stearyl 3S-peptide-I. |
| 1418 | 8662948 | Furthermore, treatment of CHO/HIRc cells with this N-stearyl peptide led to a significant enhancement of the insulin-induced association of phosphatidylinositol (PI) 3-kinase activity with insulin receptor substrate 1 and the activation of mitogen-activated protein kinase. |
| 1419 | 8662948 | However, stearyl 3S-peptide-I had no effect on the EGF-stimulated activation of PI-3-kinase and mitogen-activated protein kinase in CHO/EGF-R cells. |
| 1420 | 8663361 | Okadaic acid exerts a full insulin-like effect on glucose transport and glucose transporter 4 translocation in human adipocytes. |
| 1421 | 8663361 | The effects of the serine/threonine phosphatase inhibitor, okadaic acid, and insulin on glucose transport activity, glucose transporter 4 translocation to the plasma membrane, and the signaling pathway of insulin were examined in human adipocytes. |
| 1422 | 8663361 | Both insulin alone and okadaic acid alone stimulated the translocation of glucose transporter 4 to the plasma membrane. |
| 1423 | 8663361 | Insulin, but not okadaic acid, stimulated phosphatidylinositol 3-kinase (PI 3-kinase) activity, and wortmannin completely inhibited the effect of insulin on glucose transport. |
| 1424 | 8663361 | When the cells were incubated with both agents, okadaic acid inhibited insulin-stimulated PI 3-kinase activity but did not block the association of the p85 or p110 subunits of PI 3-kinase with insulin receptor substrate 1. |
| 1425 | 8663361 | Insulin-stimulated tyrosine phosphorylation of insulin receptor substrate 1 was only slightly reduced (15-30%) by okadaic acid. |
| 1426 | 8663361 | Okadaic acid exerts a full insulin-like effect on glucose transport and glucose transporter 4 translocation in human adipocytes. |
| 1427 | 8663361 | The effects of the serine/threonine phosphatase inhibitor, okadaic acid, and insulin on glucose transport activity, glucose transporter 4 translocation to the plasma membrane, and the signaling pathway of insulin were examined in human adipocytes. |
| 1428 | 8663361 | Both insulin alone and okadaic acid alone stimulated the translocation of glucose transporter 4 to the plasma membrane. |
| 1429 | 8663361 | Insulin, but not okadaic acid, stimulated phosphatidylinositol 3-kinase (PI 3-kinase) activity, and wortmannin completely inhibited the effect of insulin on glucose transport. |
| 1430 | 8663361 | When the cells were incubated with both agents, okadaic acid inhibited insulin-stimulated PI 3-kinase activity but did not block the association of the p85 or p110 subunits of PI 3-kinase with insulin receptor substrate 1. |
| 1431 | 8663361 | Insulin-stimulated tyrosine phosphorylation of insulin receptor substrate 1 was only slightly reduced (15-30%) by okadaic acid. |
| 1432 | 8665940 | Effect of tumor necrosis factor-alpha on insulin-stimulated mitogen-activated protein kinase cascade in cultured rat skeletal muscle cells. |
| 1433 | 8665940 | Tumor necrosis factor-alpha (TNF-alpha) is a proposed mediator of insulin resistance in obese/diabetic animals through its effects on tyrosine phosphorylation of the insulin receptor and its substrate, insulin receptor substrate-1. |
| 1434 | 8665940 | In this study, the acute effects of TNF-alpha on the mitogen-activated protein kinase (MAPK) signalling cascade were examined in cultured rat skeletal muscle cell line, L6. |
| 1435 | 8665940 | Insulin treatment of L6 cells resulted in a rapid increase in MAPK activity (> twofold in 5 min with 10 nM insulin). |
| 1436 | 8665940 | Prior treatment with TNF-alpha for 60 min blocked subsequent insulin-induced activation of MAPK in a dose- and time-dependent manner. |
| 1437 | 8665940 | Metabolic labelling studies with inorganic [32P]phosphate followed by immuno-precipitation of MAPK and its upstream activator, mitogen-activated protein kinase kinase, indicated decreased phosphorylation of MAPK and its kinase in response to insulin in cells exposed to TNF-alpha. |
| 1438 | 8665940 | This effect of TNF-alpha was not due to inhibition of insulin-stimulated p21ras-GTP loading or Raf-1 phosphorylation. |
| 1439 | 8665940 | Low concentrations (2 nM) of okadaic acid, a serine/threonine phosphatase inhibitor, prevented TNF-alpha-induced inhibition of MAPK and restored insulin's effect on MAPK activity, while orthovanadate (a tyrosine phosphatase inhibitor), inhibitor 2 (phosphatase-1 inhibitor) and FK506 (phosphatase-2B inhibitor) were ineffective. |
| 1440 | 8665940 | These results suggested an involvement of an okadaic-acid-sensitive serine/threonine phosphatase in TNF-alpha-induced blockade of insulin's effect on MAPK and/or its kinase. |
| 1441 | 8665940 | Therefore, we examined the effect of TNF-alpha on protein phosphatase-1 (PP-1) and protein phosphatase-2A (PP-2A) activities. |
| 1442 | 8665940 | As reported by us earlier, insulin rapidly stimulated PP-1 and concomitantly inhibited PP-2A activities in control cells. |
| 1443 | 8665940 | TNF-alpha treatment blocked insulin-induced activation of PP-1. |
| 1444 | 8665940 | In contrast to PP-1, TNF-alpha caused a 60% increase in PP-2A activity and insulin failed to prevent this TNF-alpha effect. |
| 1445 | 8665940 | The time course of PP-2A activation by TNF-alpha preceded the kinetics of inhibition of MAPK. |
| 1446 | 8665940 | Cell-permeable ceramide analogs mimicked the TNF-alpha effect on MAPK inhibition and PP-2A activation. |
| 1447 | 8665940 | We conclude that TNF-alpha abrogates the insulin effect on MAPK activation by increasing dephosphorylation of MAPK kinase via an activated phosphatase. |
| 1448 | 8690802 | Acute regulation by insulin of phosphatidylinositol-3-kinase, Rad, Glut 4, and lipoprotein lipase mRNA levels in human muscle. |
| 1449 | 8690802 | Using reverse transcription-competitive PCR, we have measured the mRNAs encoding the two insulin receptor variants, the insulin receptor substrate-1, the p85alpha subunit of phosphatidylinositol-3-kinase, Ras associated to diabetes (Rad), the glucose transporter Glut 4, glycogen synthase, 6-phosphofructo-l-kinase, lipoprotein lipase, and the hormone-sensitive lipase. |
| 1450 | 8690802 | Insulin infusion induced a significant increase in the mRNA level of Glut 4 (+56 +/- 13%), Rad (+96 +/- 25%), the p85alpha subunit of phosphatidylinositol-3-kinase (+92 +/- 18%) and a decrease in the lipoprotein lipase mRNA level (-49 +/- 5%), while the abundance of the other mRNAs was unaffected. |
| 1451 | 8690802 | These results demonstrate an acute coordinated regulation by insulin of the expression of genes coding key proteins involved in its action in human skeletal muscle and suggest that Rad and the p85alpha regulatory subunit of phosphatidylinositol-3-kinase can be added to the list of the genes controlled by insulin. |
| 1452 | 8712800 | Specific genetic defects have been identified for rate monogenic forms of NIDDM: maturity-onset diabetes of the young, or MODY (which is due to glucokinase mutations in about 40% of families), syndromes of extreme insulin resistance (which often involve the insulin receptor), and diabetes-deafness syndromes (with defects in mitochondrial genes). |
| 1453 | 8712800 | Some evidence of involvement has been produced for insulin-receptor substrate-1, glycogen synthase, the glucagon receptor, a ras-related protein (Rad), histocompatibility antigens, PC-1, and fatty acid binding protein, but the contributions of these genes to NIDDM is probably small. |
| 1454 | 8739921 | Since the insulin receptor substrate-1 (IRS-1) is the major substrate of the insulin receptor tyrosine kinase and has been shown to activate phosphatidylinositol (PI) 3-kinase and promote GLUT4 translocation, the IRS-1 gene is a potential candidate for development of non-insulin-dependent diabetes mellitus (NIDDM). |
| 1455 | 8739921 | Although the prevalence of each of these polymorphisms was not statistically different between NIDDM and control subjects, the prevalence of the four IRS-1 polymorphisms with an amino acid substitution together was significantly higher in NIDDM than in control subjects (23.4 vs 8.5%, p < 0.05), and two substitutions (Met 209 --> Thr and Ser809 --> Phe) were found only in NIDDM patients. |
| 1456 | 8739921 | Thus, IRS-1 polymorphisms may contribute in part to the insulin resistance and development of NIDDM in Japanese subjects; however, they do not account for the major part of the decrease in insulin-stimulated glucose uptake which is observed in subjects with clinically apparent NIDDM. |
| 1457 | 8739921 | Since the insulin receptor substrate-1 (IRS-1) is the major substrate of the insulin receptor tyrosine kinase and has been shown to activate phosphatidylinositol (PI) 3-kinase and promote GLUT4 translocation, the IRS-1 gene is a potential candidate for development of non-insulin-dependent diabetes mellitus (NIDDM). |
| 1458 | 8739921 | Although the prevalence of each of these polymorphisms was not statistically different between NIDDM and control subjects, the prevalence of the four IRS-1 polymorphisms with an amino acid substitution together was significantly higher in NIDDM than in control subjects (23.4 vs 8.5%, p < 0.05), and two substitutions (Met 209 --> Thr and Ser809 --> Phe) were found only in NIDDM patients. |
| 1459 | 8739921 | Thus, IRS-1 polymorphisms may contribute in part to the insulin resistance and development of NIDDM in Japanese subjects; however, they do not account for the major part of the decrease in insulin-stimulated glucose uptake which is observed in subjects with clinically apparent NIDDM. |
| 1460 | 8739921 | Since the insulin receptor substrate-1 (IRS-1) is the major substrate of the insulin receptor tyrosine kinase and has been shown to activate phosphatidylinositol (PI) 3-kinase and promote GLUT4 translocation, the IRS-1 gene is a potential candidate for development of non-insulin-dependent diabetes mellitus (NIDDM). |
| 1461 | 8739921 | Although the prevalence of each of these polymorphisms was not statistically different between NIDDM and control subjects, the prevalence of the four IRS-1 polymorphisms with an amino acid substitution together was significantly higher in NIDDM than in control subjects (23.4 vs 8.5%, p < 0.05), and two substitutions (Met 209 --> Thr and Ser809 --> Phe) were found only in NIDDM patients. |
| 1462 | 8739921 | Thus, IRS-1 polymorphisms may contribute in part to the insulin resistance and development of NIDDM in Japanese subjects; however, they do not account for the major part of the decrease in insulin-stimulated glucose uptake which is observed in subjects with clinically apparent NIDDM. |
| 1463 | 8754813 | Tyrosine phosphorylation of insulin receptor substrate 1 (IRS-1) by the activated receptors for insulin, IGF-1, and various cytokines creates binding sites for signaling proteins with Src homology 2 domains (SH2 proteins). |
| 1464 | 8754813 | Determining the role of specific SH2 proteins during insulin signaling has been difficult because IRS-1 possesses as many as 18 potential tyrosine phosphorylation sites, several of which contain redundant motifs. |
| 1465 | 8754813 | Using 32D cells, which contain no endogenous IRS proteins, we compared the signaling ability of an IRS-1 molecule in which 18 potential tyrosine phosphorylation sites were replaced by phenylalanine (IRS-1(F18)) with two derivative molecules which retained three YMXM motifs (IRS-1(3YMXM)) or the two COOH-terminal SHP2-Fyn binding sites (IRS-1(YCT)). |
| 1466 | 8754813 | During insulin stimulation, IRS-1(F18) failed to undergo tyrosine phosphorylation or mediate activation of the phosphotidylinositol (PI) 3'-kinase or p70(s6k); IRS-1(YCT) was tyrosine phosphorylated but also failed to mediate these signaling events. |
| 1467 | 8754813 | IRS-1(F18) and IRS-1(YCT) partially mediated similar levels of insulin-stimulated mitogenesis at high insulin concentrations, however, suggesting that IRS-1 contains phosphotyrosine-independent elements which effect mitogenic signals, and that the sites in IRS-l(YCT) do not augment this signal. |
| 1468 | 8754813 | IRS-1(3YMXM) mediated the maximal mitogenic response to insulin, although the response to insulin was more sensitive with wild-type IRS-1. |
| 1469 | 8754813 | By contrast, the association of IRS-1(3YMXM) with PI 3'-kinase was more sensitive to insulin than the association with IRS-1. |
| 1470 | 8754813 | Tyrosine phosphorylation of insulin receptor substrate 1 (IRS-1) by the activated receptors for insulin, IGF-1, and various cytokines creates binding sites for signaling proteins with Src homology 2 domains (SH2 proteins). |
| 1471 | 8754813 | Determining the role of specific SH2 proteins during insulin signaling has been difficult because IRS-1 possesses as many as 18 potential tyrosine phosphorylation sites, several of which contain redundant motifs. |
| 1472 | 8754813 | Using 32D cells, which contain no endogenous IRS proteins, we compared the signaling ability of an IRS-1 molecule in which 18 potential tyrosine phosphorylation sites were replaced by phenylalanine (IRS-1(F18)) with two derivative molecules which retained three YMXM motifs (IRS-1(3YMXM)) or the two COOH-terminal SHP2-Fyn binding sites (IRS-1(YCT)). |
| 1473 | 8754813 | During insulin stimulation, IRS-1(F18) failed to undergo tyrosine phosphorylation or mediate activation of the phosphotidylinositol (PI) 3'-kinase or p70(s6k); IRS-1(YCT) was tyrosine phosphorylated but also failed to mediate these signaling events. |
| 1474 | 8754813 | IRS-1(F18) and IRS-1(YCT) partially mediated similar levels of insulin-stimulated mitogenesis at high insulin concentrations, however, suggesting that IRS-1 contains phosphotyrosine-independent elements which effect mitogenic signals, and that the sites in IRS-l(YCT) do not augment this signal. |
| 1475 | 8754813 | IRS-1(3YMXM) mediated the maximal mitogenic response to insulin, although the response to insulin was more sensitive with wild-type IRS-1. |
| 1476 | 8754813 | By contrast, the association of IRS-1(3YMXM) with PI 3'-kinase was more sensitive to insulin than the association with IRS-1. |
| 1477 | 8754813 | Tyrosine phosphorylation of insulin receptor substrate 1 (IRS-1) by the activated receptors for insulin, IGF-1, and various cytokines creates binding sites for signaling proteins with Src homology 2 domains (SH2 proteins). |
| 1478 | 8754813 | Determining the role of specific SH2 proteins during insulin signaling has been difficult because IRS-1 possesses as many as 18 potential tyrosine phosphorylation sites, several of which contain redundant motifs. |
| 1479 | 8754813 | Using 32D cells, which contain no endogenous IRS proteins, we compared the signaling ability of an IRS-1 molecule in which 18 potential tyrosine phosphorylation sites were replaced by phenylalanine (IRS-1(F18)) with two derivative molecules which retained three YMXM motifs (IRS-1(3YMXM)) or the two COOH-terminal SHP2-Fyn binding sites (IRS-1(YCT)). |
| 1480 | 8754813 | During insulin stimulation, IRS-1(F18) failed to undergo tyrosine phosphorylation or mediate activation of the phosphotidylinositol (PI) 3'-kinase or p70(s6k); IRS-1(YCT) was tyrosine phosphorylated but also failed to mediate these signaling events. |
| 1481 | 8754813 | IRS-1(F18) and IRS-1(YCT) partially mediated similar levels of insulin-stimulated mitogenesis at high insulin concentrations, however, suggesting that IRS-1 contains phosphotyrosine-independent elements which effect mitogenic signals, and that the sites in IRS-l(YCT) do not augment this signal. |
| 1482 | 8754813 | IRS-1(3YMXM) mediated the maximal mitogenic response to insulin, although the response to insulin was more sensitive with wild-type IRS-1. |
| 1483 | 8754813 | By contrast, the association of IRS-1(3YMXM) with PI 3'-kinase was more sensitive to insulin than the association with IRS-1. |
| 1484 | 8754813 | Tyrosine phosphorylation of insulin receptor substrate 1 (IRS-1) by the activated receptors for insulin, IGF-1, and various cytokines creates binding sites for signaling proteins with Src homology 2 domains (SH2 proteins). |
| 1485 | 8754813 | Determining the role of specific SH2 proteins during insulin signaling has been difficult because IRS-1 possesses as many as 18 potential tyrosine phosphorylation sites, several of which contain redundant motifs. |
| 1486 | 8754813 | Using 32D cells, which contain no endogenous IRS proteins, we compared the signaling ability of an IRS-1 molecule in which 18 potential tyrosine phosphorylation sites were replaced by phenylalanine (IRS-1(F18)) with two derivative molecules which retained three YMXM motifs (IRS-1(3YMXM)) or the two COOH-terminal SHP2-Fyn binding sites (IRS-1(YCT)). |
| 1487 | 8754813 | During insulin stimulation, IRS-1(F18) failed to undergo tyrosine phosphorylation or mediate activation of the phosphotidylinositol (PI) 3'-kinase or p70(s6k); IRS-1(YCT) was tyrosine phosphorylated but also failed to mediate these signaling events. |
| 1488 | 8754813 | IRS-1(F18) and IRS-1(YCT) partially mediated similar levels of insulin-stimulated mitogenesis at high insulin concentrations, however, suggesting that IRS-1 contains phosphotyrosine-independent elements which effect mitogenic signals, and that the sites in IRS-l(YCT) do not augment this signal. |
| 1489 | 8754813 | IRS-1(3YMXM) mediated the maximal mitogenic response to insulin, although the response to insulin was more sensitive with wild-type IRS-1. |
| 1490 | 8754813 | By contrast, the association of IRS-1(3YMXM) with PI 3'-kinase was more sensitive to insulin than the association with IRS-1. |
| 1491 | 8754813 | Tyrosine phosphorylation of insulin receptor substrate 1 (IRS-1) by the activated receptors for insulin, IGF-1, and various cytokines creates binding sites for signaling proteins with Src homology 2 domains (SH2 proteins). |
| 1492 | 8754813 | Determining the role of specific SH2 proteins during insulin signaling has been difficult because IRS-1 possesses as many as 18 potential tyrosine phosphorylation sites, several of which contain redundant motifs. |
| 1493 | 8754813 | Using 32D cells, which contain no endogenous IRS proteins, we compared the signaling ability of an IRS-1 molecule in which 18 potential tyrosine phosphorylation sites were replaced by phenylalanine (IRS-1(F18)) with two derivative molecules which retained three YMXM motifs (IRS-1(3YMXM)) or the two COOH-terminal SHP2-Fyn binding sites (IRS-1(YCT)). |
| 1494 | 8754813 | During insulin stimulation, IRS-1(F18) failed to undergo tyrosine phosphorylation or mediate activation of the phosphotidylinositol (PI) 3'-kinase or p70(s6k); IRS-1(YCT) was tyrosine phosphorylated but also failed to mediate these signaling events. |
| 1495 | 8754813 | IRS-1(F18) and IRS-1(YCT) partially mediated similar levels of insulin-stimulated mitogenesis at high insulin concentrations, however, suggesting that IRS-1 contains phosphotyrosine-independent elements which effect mitogenic signals, and that the sites in IRS-l(YCT) do not augment this signal. |
| 1496 | 8754813 | IRS-1(3YMXM) mediated the maximal mitogenic response to insulin, although the response to insulin was more sensitive with wild-type IRS-1. |
| 1497 | 8754813 | By contrast, the association of IRS-1(3YMXM) with PI 3'-kinase was more sensitive to insulin than the association with IRS-1. |
| 1498 | 8754813 | Tyrosine phosphorylation of insulin receptor substrate 1 (IRS-1) by the activated receptors for insulin, IGF-1, and various cytokines creates binding sites for signaling proteins with Src homology 2 domains (SH2 proteins). |
| 1499 | 8754813 | Determining the role of specific SH2 proteins during insulin signaling has been difficult because IRS-1 possesses as many as 18 potential tyrosine phosphorylation sites, several of which contain redundant motifs. |
| 1500 | 8754813 | Using 32D cells, which contain no endogenous IRS proteins, we compared the signaling ability of an IRS-1 molecule in which 18 potential tyrosine phosphorylation sites were replaced by phenylalanine (IRS-1(F18)) with two derivative molecules which retained three YMXM motifs (IRS-1(3YMXM)) or the two COOH-terminal SHP2-Fyn binding sites (IRS-1(YCT)). |
| 1501 | 8754813 | During insulin stimulation, IRS-1(F18) failed to undergo tyrosine phosphorylation or mediate activation of the phosphotidylinositol (PI) 3'-kinase or p70(s6k); IRS-1(YCT) was tyrosine phosphorylated but also failed to mediate these signaling events. |
| 1502 | 8754813 | IRS-1(F18) and IRS-1(YCT) partially mediated similar levels of insulin-stimulated mitogenesis at high insulin concentrations, however, suggesting that IRS-1 contains phosphotyrosine-independent elements which effect mitogenic signals, and that the sites in IRS-l(YCT) do not augment this signal. |
| 1503 | 8754813 | IRS-1(3YMXM) mediated the maximal mitogenic response to insulin, although the response to insulin was more sensitive with wild-type IRS-1. |
| 1504 | 8754813 | By contrast, the association of IRS-1(3YMXM) with PI 3'-kinase was more sensitive to insulin than the association with IRS-1. |
| 1505 | 8754813 | Tyrosine phosphorylation of insulin receptor substrate 1 (IRS-1) by the activated receptors for insulin, IGF-1, and various cytokines creates binding sites for signaling proteins with Src homology 2 domains (SH2 proteins). |
| 1506 | 8754813 | Determining the role of specific SH2 proteins during insulin signaling has been difficult because IRS-1 possesses as many as 18 potential tyrosine phosphorylation sites, several of which contain redundant motifs. |
| 1507 | 8754813 | Using 32D cells, which contain no endogenous IRS proteins, we compared the signaling ability of an IRS-1 molecule in which 18 potential tyrosine phosphorylation sites were replaced by phenylalanine (IRS-1(F18)) with two derivative molecules which retained three YMXM motifs (IRS-1(3YMXM)) or the two COOH-terminal SHP2-Fyn binding sites (IRS-1(YCT)). |
| 1508 | 8754813 | During insulin stimulation, IRS-1(F18) failed to undergo tyrosine phosphorylation or mediate activation of the phosphotidylinositol (PI) 3'-kinase or p70(s6k); IRS-1(YCT) was tyrosine phosphorylated but also failed to mediate these signaling events. |
| 1509 | 8754813 | IRS-1(F18) and IRS-1(YCT) partially mediated similar levels of insulin-stimulated mitogenesis at high insulin concentrations, however, suggesting that IRS-1 contains phosphotyrosine-independent elements which effect mitogenic signals, and that the sites in IRS-l(YCT) do not augment this signal. |
| 1510 | 8754813 | IRS-1(3YMXM) mediated the maximal mitogenic response to insulin, although the response to insulin was more sensitive with wild-type IRS-1. |
| 1511 | 8754813 | By contrast, the association of IRS-1(3YMXM) with PI 3'-kinase was more sensitive to insulin than the association with IRS-1. |
| 1512 | 8770909 | Growth hormone stimulates tyrosine phosphorylation of JAK2 and STAT5, but not insulin receptor substrate-1 or SHC proteins in liver and skeletal muscle of normal rats in vivo. |
| 1513 | 8770909 | GH has been shown to stimulate tyrosine phosphorylation of JAK2, several STAT proteins, insulin receptor substrate-1 (IRS-1), and SHC proteins in cultured cells. |
| 1514 | 8770909 | Although basal tyrosine phosphorylation of IRS-1 and SHC was evident, GH did not stimulate tyrosine phosphorylation of either of these proteins in liver or skeletal muscle. |
| 1515 | 8770909 | In conclusion, GH stimulates the tyrosine phosphorylation of JAK2 and STAT5, but not IRS-1, SHC, or other STAT proteins in liver and skeletal muscle of normal rats. |
| 1516 | 8770909 | Growth hormone stimulates tyrosine phosphorylation of JAK2 and STAT5, but not insulin receptor substrate-1 or SHC proteins in liver and skeletal muscle of normal rats in vivo. |
| 1517 | 8770909 | GH has been shown to stimulate tyrosine phosphorylation of JAK2, several STAT proteins, insulin receptor substrate-1 (IRS-1), and SHC proteins in cultured cells. |
| 1518 | 8770909 | Although basal tyrosine phosphorylation of IRS-1 and SHC was evident, GH did not stimulate tyrosine phosphorylation of either of these proteins in liver or skeletal muscle. |
| 1519 | 8770909 | In conclusion, GH stimulates the tyrosine phosphorylation of JAK2 and STAT5, but not IRS-1, SHC, or other STAT proteins in liver and skeletal muscle of normal rats. |
| 1520 | 8770909 | Growth hormone stimulates tyrosine phosphorylation of JAK2 and STAT5, but not insulin receptor substrate-1 or SHC proteins in liver and skeletal muscle of normal rats in vivo. |
| 1521 | 8770909 | GH has been shown to stimulate tyrosine phosphorylation of JAK2, several STAT proteins, insulin receptor substrate-1 (IRS-1), and SHC proteins in cultured cells. |
| 1522 | 8770909 | Although basal tyrosine phosphorylation of IRS-1 and SHC was evident, GH did not stimulate tyrosine phosphorylation of either of these proteins in liver or skeletal muscle. |
| 1523 | 8770909 | In conclusion, GH stimulates the tyrosine phosphorylation of JAK2 and STAT5, but not IRS-1, SHC, or other STAT proteins in liver and skeletal muscle of normal rats. |
| 1524 | 8770909 | Growth hormone stimulates tyrosine phosphorylation of JAK2 and STAT5, but not insulin receptor substrate-1 or SHC proteins in liver and skeletal muscle of normal rats in vivo. |
| 1525 | 8770909 | GH has been shown to stimulate tyrosine phosphorylation of JAK2, several STAT proteins, insulin receptor substrate-1 (IRS-1), and SHC proteins in cultured cells. |
| 1526 | 8770909 | Although basal tyrosine phosphorylation of IRS-1 and SHC was evident, GH did not stimulate tyrosine phosphorylation of either of these proteins in liver or skeletal muscle. |
| 1527 | 8770909 | In conclusion, GH stimulates the tyrosine phosphorylation of JAK2 and STAT5, but not IRS-1, SHC, or other STAT proteins in liver and skeletal muscle of normal rats. |
| 1528 | 8798677 | The pleckstrin homology domain is the principal link between the insulin receptor and IRS-1. |
| 1529 | 8798677 | Interaction domains located in the NH2 terminus of IRS-1 mediate its recognition by the insulin receptor. |
| 1530 | 8798677 | Alignment of IRS-1 and IRS-2 reveals two homology regions: the IH1(PH) contains a pleckstrin homology (PH) domain, and the IH2(PTB) contains a phosphotyrosine binding (PTB) domain. |
| 1531 | 8798677 | Peptide competition experiments demonstrated that the IH2(PTB) in IRS-2, like the corresponding domain in IRS-1, binds directly to peptides containing NPXY motifs. |
| 1532 | 8798677 | In 32D cells the IH1(PH) was essential for insulin-stimulated tyrosine phosphorylation of IRS-1 and insulin-stimulated phosphatidylinositol 3-kinase activity and p70(s6k) phosphorylation. |
| 1533 | 8798677 | In contrast, the IH2(PTB) and the SAIN regions were not required for these insulin actions; however, the IH2(PTB) improved the coupling between IRS-1 and the insulin receptor. |
| 1534 | 8798677 | Overexpression of the insulin receptor in 32DIR cells increased IRS-1 tyrosine phosphorylation and mediated insulin-stimulated DNA synthesis. |
| 1535 | 8798677 | Thus, the PH and PTB domains equally couple IRS-1 to high levels of insulin receptor normally expressed in most cells, whereas at low levels of insulin receptors the PTB domain is inefficient and the PH domain is essential for a productive interaction. |
| 1536 | 8798677 | The pleckstrin homology domain is the principal link between the insulin receptor and IRS-1. |
| 1537 | 8798677 | Interaction domains located in the NH2 terminus of IRS-1 mediate its recognition by the insulin receptor. |
| 1538 | 8798677 | Alignment of IRS-1 and IRS-2 reveals two homology regions: the IH1(PH) contains a pleckstrin homology (PH) domain, and the IH2(PTB) contains a phosphotyrosine binding (PTB) domain. |
| 1539 | 8798677 | Peptide competition experiments demonstrated that the IH2(PTB) in IRS-2, like the corresponding domain in IRS-1, binds directly to peptides containing NPXY motifs. |
| 1540 | 8798677 | In 32D cells the IH1(PH) was essential for insulin-stimulated tyrosine phosphorylation of IRS-1 and insulin-stimulated phosphatidylinositol 3-kinase activity and p70(s6k) phosphorylation. |
| 1541 | 8798677 | In contrast, the IH2(PTB) and the SAIN regions were not required for these insulin actions; however, the IH2(PTB) improved the coupling between IRS-1 and the insulin receptor. |
| 1542 | 8798677 | Overexpression of the insulin receptor in 32DIR cells increased IRS-1 tyrosine phosphorylation and mediated insulin-stimulated DNA synthesis. |
| 1543 | 8798677 | Thus, the PH and PTB domains equally couple IRS-1 to high levels of insulin receptor normally expressed in most cells, whereas at low levels of insulin receptors the PTB domain is inefficient and the PH domain is essential for a productive interaction. |
| 1544 | 8798677 | The pleckstrin homology domain is the principal link between the insulin receptor and IRS-1. |
| 1545 | 8798677 | Interaction domains located in the NH2 terminus of IRS-1 mediate its recognition by the insulin receptor. |
| 1546 | 8798677 | Alignment of IRS-1 and IRS-2 reveals two homology regions: the IH1(PH) contains a pleckstrin homology (PH) domain, and the IH2(PTB) contains a phosphotyrosine binding (PTB) domain. |
| 1547 | 8798677 | Peptide competition experiments demonstrated that the IH2(PTB) in IRS-2, like the corresponding domain in IRS-1, binds directly to peptides containing NPXY motifs. |
| 1548 | 8798677 | In 32D cells the IH1(PH) was essential for insulin-stimulated tyrosine phosphorylation of IRS-1 and insulin-stimulated phosphatidylinositol 3-kinase activity and p70(s6k) phosphorylation. |
| 1549 | 8798677 | In contrast, the IH2(PTB) and the SAIN regions were not required for these insulin actions; however, the IH2(PTB) improved the coupling between IRS-1 and the insulin receptor. |
| 1550 | 8798677 | Overexpression of the insulin receptor in 32DIR cells increased IRS-1 tyrosine phosphorylation and mediated insulin-stimulated DNA synthesis. |
| 1551 | 8798677 | Thus, the PH and PTB domains equally couple IRS-1 to high levels of insulin receptor normally expressed in most cells, whereas at low levels of insulin receptors the PTB domain is inefficient and the PH domain is essential for a productive interaction. |
| 1552 | 8798677 | The pleckstrin homology domain is the principal link between the insulin receptor and IRS-1. |
| 1553 | 8798677 | Interaction domains located in the NH2 terminus of IRS-1 mediate its recognition by the insulin receptor. |
| 1554 | 8798677 | Alignment of IRS-1 and IRS-2 reveals two homology regions: the IH1(PH) contains a pleckstrin homology (PH) domain, and the IH2(PTB) contains a phosphotyrosine binding (PTB) domain. |
| 1555 | 8798677 | Peptide competition experiments demonstrated that the IH2(PTB) in IRS-2, like the corresponding domain in IRS-1, binds directly to peptides containing NPXY motifs. |
| 1556 | 8798677 | In 32D cells the IH1(PH) was essential for insulin-stimulated tyrosine phosphorylation of IRS-1 and insulin-stimulated phosphatidylinositol 3-kinase activity and p70(s6k) phosphorylation. |
| 1557 | 8798677 | In contrast, the IH2(PTB) and the SAIN regions were not required for these insulin actions; however, the IH2(PTB) improved the coupling between IRS-1 and the insulin receptor. |
| 1558 | 8798677 | Overexpression of the insulin receptor in 32DIR cells increased IRS-1 tyrosine phosphorylation and mediated insulin-stimulated DNA synthesis. |
| 1559 | 8798677 | Thus, the PH and PTB domains equally couple IRS-1 to high levels of insulin receptor normally expressed in most cells, whereas at low levels of insulin receptors the PTB domain is inefficient and the PH domain is essential for a productive interaction. |
| 1560 | 8798677 | The pleckstrin homology domain is the principal link between the insulin receptor and IRS-1. |
| 1561 | 8798677 | Interaction domains located in the NH2 terminus of IRS-1 mediate its recognition by the insulin receptor. |
| 1562 | 8798677 | Alignment of IRS-1 and IRS-2 reveals two homology regions: the IH1(PH) contains a pleckstrin homology (PH) domain, and the IH2(PTB) contains a phosphotyrosine binding (PTB) domain. |
| 1563 | 8798677 | Peptide competition experiments demonstrated that the IH2(PTB) in IRS-2, like the corresponding domain in IRS-1, binds directly to peptides containing NPXY motifs. |
| 1564 | 8798677 | In 32D cells the IH1(PH) was essential for insulin-stimulated tyrosine phosphorylation of IRS-1 and insulin-stimulated phosphatidylinositol 3-kinase activity and p70(s6k) phosphorylation. |
| 1565 | 8798677 | In contrast, the IH2(PTB) and the SAIN regions were not required for these insulin actions; however, the IH2(PTB) improved the coupling between IRS-1 and the insulin receptor. |
| 1566 | 8798677 | Overexpression of the insulin receptor in 32DIR cells increased IRS-1 tyrosine phosphorylation and mediated insulin-stimulated DNA synthesis. |
| 1567 | 8798677 | Thus, the PH and PTB domains equally couple IRS-1 to high levels of insulin receptor normally expressed in most cells, whereas at low levels of insulin receptors the PTB domain is inefficient and the PH domain is essential for a productive interaction. |
| 1568 | 8798677 | The pleckstrin homology domain is the principal link between the insulin receptor and IRS-1. |
| 1569 | 8798677 | Interaction domains located in the NH2 terminus of IRS-1 mediate its recognition by the insulin receptor. |
| 1570 | 8798677 | Alignment of IRS-1 and IRS-2 reveals two homology regions: the IH1(PH) contains a pleckstrin homology (PH) domain, and the IH2(PTB) contains a phosphotyrosine binding (PTB) domain. |
| 1571 | 8798677 | Peptide competition experiments demonstrated that the IH2(PTB) in IRS-2, like the corresponding domain in IRS-1, binds directly to peptides containing NPXY motifs. |
| 1572 | 8798677 | In 32D cells the IH1(PH) was essential for insulin-stimulated tyrosine phosphorylation of IRS-1 and insulin-stimulated phosphatidylinositol 3-kinase activity and p70(s6k) phosphorylation. |
| 1573 | 8798677 | In contrast, the IH2(PTB) and the SAIN regions were not required for these insulin actions; however, the IH2(PTB) improved the coupling between IRS-1 and the insulin receptor. |
| 1574 | 8798677 | Overexpression of the insulin receptor in 32DIR cells increased IRS-1 tyrosine phosphorylation and mediated insulin-stimulated DNA synthesis. |
| 1575 | 8798677 | Thus, the PH and PTB domains equally couple IRS-1 to high levels of insulin receptor normally expressed in most cells, whereas at low levels of insulin receptors the PTB domain is inefficient and the PH domain is essential for a productive interaction. |
| 1576 | 8798677 | The pleckstrin homology domain is the principal link between the insulin receptor and IRS-1. |
| 1577 | 8798677 | Interaction domains located in the NH2 terminus of IRS-1 mediate its recognition by the insulin receptor. |
| 1578 | 8798677 | Alignment of IRS-1 and IRS-2 reveals two homology regions: the IH1(PH) contains a pleckstrin homology (PH) domain, and the IH2(PTB) contains a phosphotyrosine binding (PTB) domain. |
| 1579 | 8798677 | Peptide competition experiments demonstrated that the IH2(PTB) in IRS-2, like the corresponding domain in IRS-1, binds directly to peptides containing NPXY motifs. |
| 1580 | 8798677 | In 32D cells the IH1(PH) was essential for insulin-stimulated tyrosine phosphorylation of IRS-1 and insulin-stimulated phosphatidylinositol 3-kinase activity and p70(s6k) phosphorylation. |
| 1581 | 8798677 | In contrast, the IH2(PTB) and the SAIN regions were not required for these insulin actions; however, the IH2(PTB) improved the coupling between IRS-1 and the insulin receptor. |
| 1582 | 8798677 | Overexpression of the insulin receptor in 32DIR cells increased IRS-1 tyrosine phosphorylation and mediated insulin-stimulated DNA synthesis. |
| 1583 | 8798677 | Thus, the PH and PTB domains equally couple IRS-1 to high levels of insulin receptor normally expressed in most cells, whereas at low levels of insulin receptors the PTB domain is inefficient and the PH domain is essential for a productive interaction. |
| 1584 | 8798677 | The pleckstrin homology domain is the principal link between the insulin receptor and IRS-1. |
| 1585 | 8798677 | Interaction domains located in the NH2 terminus of IRS-1 mediate its recognition by the insulin receptor. |
| 1586 | 8798677 | Alignment of IRS-1 and IRS-2 reveals two homology regions: the IH1(PH) contains a pleckstrin homology (PH) domain, and the IH2(PTB) contains a phosphotyrosine binding (PTB) domain. |
| 1587 | 8798677 | Peptide competition experiments demonstrated that the IH2(PTB) in IRS-2, like the corresponding domain in IRS-1, binds directly to peptides containing NPXY motifs. |
| 1588 | 8798677 | In 32D cells the IH1(PH) was essential for insulin-stimulated tyrosine phosphorylation of IRS-1 and insulin-stimulated phosphatidylinositol 3-kinase activity and p70(s6k) phosphorylation. |
| 1589 | 8798677 | In contrast, the IH2(PTB) and the SAIN regions were not required for these insulin actions; however, the IH2(PTB) improved the coupling between IRS-1 and the insulin receptor. |
| 1590 | 8798677 | Overexpression of the insulin receptor in 32DIR cells increased IRS-1 tyrosine phosphorylation and mediated insulin-stimulated DNA synthesis. |
| 1591 | 8798677 | Thus, the PH and PTB domains equally couple IRS-1 to high levels of insulin receptor normally expressed in most cells, whereas at low levels of insulin receptors the PTB domain is inefficient and the PH domain is essential for a productive interaction. |
| 1592 | 8803477 | To further delineate the TNF-alpha signal transduction pathway mediating glucose metabolism, we utilized L6 rat myoblasts which contain the receptors for the insulin-like growth factor-I (IGF-I) and TNF-alpha, and the ability of both ligands to stimulate glucose uptake was compared. |
| 1593 | 8803477 | IGF-I (6.5 nM) maximally stimulated glucose uptake 7-fold after 24 h incubation, while 23 nM TNF-alpha maximally stimulated glucose uptake 3-fold only after 48 h incubation. |
| 1594 | 8803477 | IGF-I receptor beta-subunit, insulin receptor substrate-1 (IRS-1), and mitogen-activated protein (MAP) kinase were all phosphorylated in response to 6.5 nM IGF-I after 10 min incubation. |
| 1595 | 8803477 | In contrast, the treatment with 23 nM TNF-alpha failed to phosphorylate either IGF-I receptor beta-subunit or IRS-1 but did phosphorylate MAP kinase as much as IGF-I did. |
| 1596 | 8803477 | Despite a similar extent to which TNF-alpha induced MAP kinase phosphorylation as IGF-I did, TNF-alpha stimulated glucose uptake less compared to IGF-I. |
| 1597 | 8803477 | The results indicate that MAP kinase phosphorylation is not sufficient for glucose uptake in L6 myoblasts. |
| 1598 | 8803477 | TNF-alpha-elicited signal transduction to glucose uptake may utilize a different pathway from that seen with IGF-I. |
| 1599 | 8803477 | To further delineate the TNF-alpha signal transduction pathway mediating glucose metabolism, we utilized L6 rat myoblasts which contain the receptors for the insulin-like growth factor-I (IGF-I) and TNF-alpha, and the ability of both ligands to stimulate glucose uptake was compared. |
| 1600 | 8803477 | IGF-I (6.5 nM) maximally stimulated glucose uptake 7-fold after 24 h incubation, while 23 nM TNF-alpha maximally stimulated glucose uptake 3-fold only after 48 h incubation. |
| 1601 | 8803477 | IGF-I receptor beta-subunit, insulin receptor substrate-1 (IRS-1), and mitogen-activated protein (MAP) kinase were all phosphorylated in response to 6.5 nM IGF-I after 10 min incubation. |
| 1602 | 8803477 | In contrast, the treatment with 23 nM TNF-alpha failed to phosphorylate either IGF-I receptor beta-subunit or IRS-1 but did phosphorylate MAP kinase as much as IGF-I did. |
| 1603 | 8803477 | Despite a similar extent to which TNF-alpha induced MAP kinase phosphorylation as IGF-I did, TNF-alpha stimulated glucose uptake less compared to IGF-I. |
| 1604 | 8803477 | The results indicate that MAP kinase phosphorylation is not sufficient for glucose uptake in L6 myoblasts. |
| 1605 | 8803477 | TNF-alpha-elicited signal transduction to glucose uptake may utilize a different pathway from that seen with IGF-I. |
| 1606 | 8826975 | Protein tyrosine phosphatase 1B interacts with the activated insulin receptor. |
| 1607 | 8826975 | Protein tyrosine phosphatase 1B (PTP1B) is a protein tyrosine phosphatase of unknown function, although increasing evidence supports a role for this phosphatase in insulin action. |
| 1608 | 8826975 | We have investigated the interaction of PTP1B with the insulin receptor using a PTP1B glutathione S-transferase (GST) fusion protein with a point mutation in the enzyme's catalytic domain. |
| 1609 | 8826975 | The activated insulin receptor was precipitated from purified receptor preparations and whole-cell lysates by the inactive PTP1B-GST, demonstrating a direct association between the insulin receptor and PTP1B. |
| 1610 | 8826975 | A p120 of unknown identity was also precipitated from whole-cell lysates by the PTP1B fusion protein, but IRS-1 (pp185) was not. |
| 1611 | 8826975 | A catalytically inactive [35S]PTP1B-fusion protein bound directly to immobilized insulin receptor kinase domains and was displaced in a concentration-dependent manner. |
| 1612 | 8826975 | Finally, tyrosine-phosphorylated PTP1B was precipitated from whole-cell lysates by an anti-insulin receptor antibody after insulin stimulation. |
| 1613 | 8826975 | The site of interaction between PTP1B and the insulin receptor was studied using phosphopeptides modeled after the receptor's kinase domain, the NPXY domain, and the COOH-terminal. |
| 1614 | 8826975 | Study of mutant insulin receptors demonstrated that activation of the kinase domain is necessary for the PTP1B:insulin receptor interaction, but receptors with deletion of the NPXY domain or of the COOH-terminal can still bind to the PTP1B-GST. |
| 1615 | 8826975 | We conclude that PTP1B can associate directly with the activated insulin receptor at multiple different phosphotyrosine sites and that dephosphorylation by PTP1B may play a significant role in insulin receptor signal transduction. |
| 1616 | 8899293 | Signaling via the insulin-like growth factor-I receptor: does it differ from insulin receptor signaling? |
| 1617 | 8899293 | The insulin and insulin-like growth factor (IGF-I) receptors while similar in structure and function serve different physiological functions in vivo. |
| 1618 | 8899293 | In non-disease states the insulin receptor is primarily involved in metabolic functions whereas the IGF-I receptor mediates growth and differentiation. |
| 1619 | 8899293 | Modulation of the binding of the ligands insulin or IGF-I and IGF-II to their respective receptors by the local environment of the cell also offers signaling specificity mediated via the receptors. |
| 1620 | 8899293 | Furthermore IGF-binding proteins are specific for IGF-I and IGF-II thereby modulating the binding of the IGFs to the IGF-I receptor. |
| 1621 | 8899293 | While a number of known endogenous substrates such as IRS-1, IRS-2 and She are utilized by both receptors, the structural differences in the beta subunits of the two receptors has lead investigators to suggest that certain substrates may be unique to each receptor. |
| 1622 | 8899293 | Full eludication of the specificities of the insulin and IGF-I signaling pathways is of interest of course for a better understanding of intercellular communication. |
| 1623 | 8899293 | In addition, because the closely related proteins insulin and IGF-I are used clinically, a clear understanding of the pathways activated by these agents is essential if more specific therapeutic modalities are to be developed for use in disease states. |
| 1624 | 8910437 | We have reported previously that substitution of the transmembrane domain of the insulin receptor with that of the erbB-2 oncogene (IRerbV-->E) results in constitutive activation of the insulin receptor kinase. |
| 1625 | 8910437 | Compared to NIH3T3 cells overexpressing wild-type insulin receptors (IRwt), cells overexpressing IRerbV-->E displayed a decrease in IRS-1 protein content by 55%, but basal tyrosine phosphorylation of IRS-1 was increased. |
| 1626 | 8910437 | This resulted in an increased association of IRS-1 with the p85 subunit of phosphatidylinositol 3-kinase, increased phosphatidylinositol 3-kinase activity in anti-IRS-1 immunoprecipitates, constitutive activation of p70 S6 protein kinase, and an increased association of Grb2 with Shc in the absence of ligand. |
| 1627 | 8910437 | However, Grb2 association with IRS-1 could not be detected in the basal or insulin-stimulated states, and mitogen-activated protein kinase (MAPK) activity could not be stimulated by insulin, epidermal growth factor, or platelet-derived growth factor. |
| 1628 | 8910437 | With decreased IRS-1 content, tyrosine phosphorylation of IRS-1 was decreased by over 75%, leading to decreased IRS-1-associated PI 3-kinase and Grb2. |
| 1629 | 8910437 | In addition, Grb2 association with Shc and activation of MAPK and the p70 S6 kinase were insensitive to insulin stimulation. |
| 1630 | 8910437 | By contrast, association of Grb2 with Shc and activation of MAPK, but not the p70 S6 kinase, could be stimulated by epidermal growth factor or platelet-derived growth factor. |
| 1631 | 8910437 | We have reported previously that substitution of the transmembrane domain of the insulin receptor with that of the erbB-2 oncogene (IRerbV-->E) results in constitutive activation of the insulin receptor kinase. |
| 1632 | 8910437 | Compared to NIH3T3 cells overexpressing wild-type insulin receptors (IRwt), cells overexpressing IRerbV-->E displayed a decrease in IRS-1 protein content by 55%, but basal tyrosine phosphorylation of IRS-1 was increased. |
| 1633 | 8910437 | This resulted in an increased association of IRS-1 with the p85 subunit of phosphatidylinositol 3-kinase, increased phosphatidylinositol 3-kinase activity in anti-IRS-1 immunoprecipitates, constitutive activation of p70 S6 protein kinase, and an increased association of Grb2 with Shc in the absence of ligand. |
| 1634 | 8910437 | However, Grb2 association with IRS-1 could not be detected in the basal or insulin-stimulated states, and mitogen-activated protein kinase (MAPK) activity could not be stimulated by insulin, epidermal growth factor, or platelet-derived growth factor. |
| 1635 | 8910437 | With decreased IRS-1 content, tyrosine phosphorylation of IRS-1 was decreased by over 75%, leading to decreased IRS-1-associated PI 3-kinase and Grb2. |
| 1636 | 8910437 | In addition, Grb2 association with Shc and activation of MAPK and the p70 S6 kinase were insensitive to insulin stimulation. |
| 1637 | 8910437 | By contrast, association of Grb2 with Shc and activation of MAPK, but not the p70 S6 kinase, could be stimulated by epidermal growth factor or platelet-derived growth factor. |
| 1638 | 8910437 | We have reported previously that substitution of the transmembrane domain of the insulin receptor with that of the erbB-2 oncogene (IRerbV-->E) results in constitutive activation of the insulin receptor kinase. |
| 1639 | 8910437 | Compared to NIH3T3 cells overexpressing wild-type insulin receptors (IRwt), cells overexpressing IRerbV-->E displayed a decrease in IRS-1 protein content by 55%, but basal tyrosine phosphorylation of IRS-1 was increased. |
| 1640 | 8910437 | This resulted in an increased association of IRS-1 with the p85 subunit of phosphatidylinositol 3-kinase, increased phosphatidylinositol 3-kinase activity in anti-IRS-1 immunoprecipitates, constitutive activation of p70 S6 protein kinase, and an increased association of Grb2 with Shc in the absence of ligand. |
| 1641 | 8910437 | However, Grb2 association with IRS-1 could not be detected in the basal or insulin-stimulated states, and mitogen-activated protein kinase (MAPK) activity could not be stimulated by insulin, epidermal growth factor, or platelet-derived growth factor. |
| 1642 | 8910437 | With decreased IRS-1 content, tyrosine phosphorylation of IRS-1 was decreased by over 75%, leading to decreased IRS-1-associated PI 3-kinase and Grb2. |
| 1643 | 8910437 | In addition, Grb2 association with Shc and activation of MAPK and the p70 S6 kinase were insensitive to insulin stimulation. |
| 1644 | 8910437 | By contrast, association of Grb2 with Shc and activation of MAPK, but not the p70 S6 kinase, could be stimulated by epidermal growth factor or platelet-derived growth factor. |
| 1645 | 8910437 | We have reported previously that substitution of the transmembrane domain of the insulin receptor with that of the erbB-2 oncogene (IRerbV-->E) results in constitutive activation of the insulin receptor kinase. |
| 1646 | 8910437 | Compared to NIH3T3 cells overexpressing wild-type insulin receptors (IRwt), cells overexpressing IRerbV-->E displayed a decrease in IRS-1 protein content by 55%, but basal tyrosine phosphorylation of IRS-1 was increased. |
| 1647 | 8910437 | This resulted in an increased association of IRS-1 with the p85 subunit of phosphatidylinositol 3-kinase, increased phosphatidylinositol 3-kinase activity in anti-IRS-1 immunoprecipitates, constitutive activation of p70 S6 protein kinase, and an increased association of Grb2 with Shc in the absence of ligand. |
| 1648 | 8910437 | However, Grb2 association with IRS-1 could not be detected in the basal or insulin-stimulated states, and mitogen-activated protein kinase (MAPK) activity could not be stimulated by insulin, epidermal growth factor, or platelet-derived growth factor. |
| 1649 | 8910437 | With decreased IRS-1 content, tyrosine phosphorylation of IRS-1 was decreased by over 75%, leading to decreased IRS-1-associated PI 3-kinase and Grb2. |
| 1650 | 8910437 | In addition, Grb2 association with Shc and activation of MAPK and the p70 S6 kinase were insensitive to insulin stimulation. |
| 1651 | 8910437 | By contrast, association of Grb2 with Shc and activation of MAPK, but not the p70 S6 kinase, could be stimulated by epidermal growth factor or platelet-derived growth factor. |
| 1652 | 8943287 | Transcriptional regulation of insulin receptor substrate 1 by protein kinase C. |
| 1653 | 8943287 | Targeted disruption of IRS-1 leads to insulin resistance and hyperglycemia in mice, which suggests that altered IRS-1 expression could contribute to the insulin resistance seen in non-insulin-dependent diabetes mellitus. |
| 1654 | 8943287 | In vitro studies using phorbol esters have implicated the protein kinase C (PKC) pathway as being involved in the pathogenesis of insulin resistance. |
| 1655 | 8943287 | In an MCF-7 cell line (MCF-7-PKC-alpha) that exhibits multiple alterations in PKC isoform expression, IRS-1 content was reduced to negligible levels relative to parental MCF-7 cells. |
| 1656 | 8943287 | Transcriptional regulation of insulin receptor substrate 1 by protein kinase C. |
| 1657 | 8943287 | Targeted disruption of IRS-1 leads to insulin resistance and hyperglycemia in mice, which suggests that altered IRS-1 expression could contribute to the insulin resistance seen in non-insulin-dependent diabetes mellitus. |
| 1658 | 8943287 | In vitro studies using phorbol esters have implicated the protein kinase C (PKC) pathway as being involved in the pathogenesis of insulin resistance. |
| 1659 | 8943287 | In an MCF-7 cell line (MCF-7-PKC-alpha) that exhibits multiple alterations in PKC isoform expression, IRS-1 content was reduced to negligible levels relative to parental MCF-7 cells. |
| 1660 | 8943287 | Transcriptional regulation of insulin receptor substrate 1 by protein kinase C. |
| 1661 | 8943287 | Targeted disruption of IRS-1 leads to insulin resistance and hyperglycemia in mice, which suggests that altered IRS-1 expression could contribute to the insulin resistance seen in non-insulin-dependent diabetes mellitus. |
| 1662 | 8943287 | In vitro studies using phorbol esters have implicated the protein kinase C (PKC) pathway as being involved in the pathogenesis of insulin resistance. |
| 1663 | 8943287 | In an MCF-7 cell line (MCF-7-PKC-alpha) that exhibits multiple alterations in PKC isoform expression, IRS-1 content was reduced to negligible levels relative to parental MCF-7 cells. |
| 1664 | 8960833 | UKPDS 19: heterogeneity in NIDDM: separate contributions of IRS-1 and beta 3-adrenergic-receptor mutations to insulin resistance and obesity respectively with no evidence for glycogen synthase gene mutations. |
| 1665 | 8960833 | Insulin receptor substrate-1 (IRS-1), beta 3-adrenergic-receptor (beta 3-AR) and glycogen synthase (GS) genes are candidate genes for non-insulin-dependent diabetes mellitus (NIDDM), insulin resistance, dyslipidaemia and obesity. |
| 1666 | 8960833 | The IRS-1 972 mutation was significantly different between the four groups with increased prevalence in the insulin resistant and dyslipidaemia subjects (18 and 26% compared with 11% in control subjects; p < 0.0005). |
| 1667 | 8960833 | Those with or without IRS-1 mutations had similar clinical characteristics and impaired insulin sensitivity. beta 3-AR 64 mutation was not significantly different between the four groups but those with the mutation were more obese, with a test for linear association between number of alleles and degree of obesity in an analysis of variance showing a significant association (p = 0.029). |
| 1668 | 8960833 | In conclusion, IRS-1 972 had an increased prevalence in subjects with insulin resistance, with or without dyslipidaemia. beta 3-AR 64 was associated with increased obesity but not with insulin resistance or dyslipidaemia. |
| 1669 | 8960833 | UKPDS 19: heterogeneity in NIDDM: separate contributions of IRS-1 and beta 3-adrenergic-receptor mutations to insulin resistance and obesity respectively with no evidence for glycogen synthase gene mutations. |
| 1670 | 8960833 | Insulin receptor substrate-1 (IRS-1), beta 3-adrenergic-receptor (beta 3-AR) and glycogen synthase (GS) genes are candidate genes for non-insulin-dependent diabetes mellitus (NIDDM), insulin resistance, dyslipidaemia and obesity. |
| 1671 | 8960833 | The IRS-1 972 mutation was significantly different between the four groups with increased prevalence in the insulin resistant and dyslipidaemia subjects (18 and 26% compared with 11% in control subjects; p < 0.0005). |
| 1672 | 8960833 | Those with or without IRS-1 mutations had similar clinical characteristics and impaired insulin sensitivity. beta 3-AR 64 mutation was not significantly different between the four groups but those with the mutation were more obese, with a test for linear association between number of alleles and degree of obesity in an analysis of variance showing a significant association (p = 0.029). |
| 1673 | 8960833 | In conclusion, IRS-1 972 had an increased prevalence in subjects with insulin resistance, with or without dyslipidaemia. beta 3-AR 64 was associated with increased obesity but not with insulin resistance or dyslipidaemia. |
| 1674 | 8960833 | UKPDS 19: heterogeneity in NIDDM: separate contributions of IRS-1 and beta 3-adrenergic-receptor mutations to insulin resistance and obesity respectively with no evidence for glycogen synthase gene mutations. |
| 1675 | 8960833 | Insulin receptor substrate-1 (IRS-1), beta 3-adrenergic-receptor (beta 3-AR) and glycogen synthase (GS) genes are candidate genes for non-insulin-dependent diabetes mellitus (NIDDM), insulin resistance, dyslipidaemia and obesity. |
| 1676 | 8960833 | The IRS-1 972 mutation was significantly different between the four groups with increased prevalence in the insulin resistant and dyslipidaemia subjects (18 and 26% compared with 11% in control subjects; p < 0.0005). |
| 1677 | 8960833 | Those with or without IRS-1 mutations had similar clinical characteristics and impaired insulin sensitivity. beta 3-AR 64 mutation was not significantly different between the four groups but those with the mutation were more obese, with a test for linear association between number of alleles and degree of obesity in an analysis of variance showing a significant association (p = 0.029). |
| 1678 | 8960833 | In conclusion, IRS-1 972 had an increased prevalence in subjects with insulin resistance, with or without dyslipidaemia. beta 3-AR 64 was associated with increased obesity but not with insulin resistance or dyslipidaemia. |
| 1679 | 8960833 | UKPDS 19: heterogeneity in NIDDM: separate contributions of IRS-1 and beta 3-adrenergic-receptor mutations to insulin resistance and obesity respectively with no evidence for glycogen synthase gene mutations. |
| 1680 | 8960833 | Insulin receptor substrate-1 (IRS-1), beta 3-adrenergic-receptor (beta 3-AR) and glycogen synthase (GS) genes are candidate genes for non-insulin-dependent diabetes mellitus (NIDDM), insulin resistance, dyslipidaemia and obesity. |
| 1681 | 8960833 | The IRS-1 972 mutation was significantly different between the four groups with increased prevalence in the insulin resistant and dyslipidaemia subjects (18 and 26% compared with 11% in control subjects; p < 0.0005). |
| 1682 | 8960833 | Those with or without IRS-1 mutations had similar clinical characteristics and impaired insulin sensitivity. beta 3-AR 64 mutation was not significantly different between the four groups but those with the mutation were more obese, with a test for linear association between number of alleles and degree of obesity in an analysis of variance showing a significant association (p = 0.029). |
| 1683 | 8960833 | In conclusion, IRS-1 972 had an increased prevalence in subjects with insulin resistance, with or without dyslipidaemia. beta 3-AR 64 was associated with increased obesity but not with insulin resistance or dyslipidaemia. |
| 1684 | 8960833 | UKPDS 19: heterogeneity in NIDDM: separate contributions of IRS-1 and beta 3-adrenergic-receptor mutations to insulin resistance and obesity respectively with no evidence for glycogen synthase gene mutations. |
| 1685 | 8960833 | Insulin receptor substrate-1 (IRS-1), beta 3-adrenergic-receptor (beta 3-AR) and glycogen synthase (GS) genes are candidate genes for non-insulin-dependent diabetes mellitus (NIDDM), insulin resistance, dyslipidaemia and obesity. |
| 1686 | 8960833 | The IRS-1 972 mutation was significantly different between the four groups with increased prevalence in the insulin resistant and dyslipidaemia subjects (18 and 26% compared with 11% in control subjects; p < 0.0005). |
| 1687 | 8960833 | Those with or without IRS-1 mutations had similar clinical characteristics and impaired insulin sensitivity. beta 3-AR 64 mutation was not significantly different between the four groups but those with the mutation were more obese, with a test for linear association between number of alleles and degree of obesity in an analysis of variance showing a significant association (p = 0.029). |
| 1688 | 8960833 | In conclusion, IRS-1 972 had an increased prevalence in subjects with insulin resistance, with or without dyslipidaemia. beta 3-AR 64 was associated with increased obesity but not with insulin resistance or dyslipidaemia. |
| 1689 | 8972717 | The serine/threonine phosphatase inhibitor, okadaic acid (OA), exerted several insulin-like effects in rat adipose cells and was, in part, synergistic with insulin. |
| 1690 | 8972717 | OA stimulated glucose transport activity, altered the electrophoretic mobility of IRS-1, increased the phosphorylation of the MAP-kinases ERK 1 and 2 on tyrosine sites, markedly increased MAP kinase activity and also acted synergistically with insulin in activating these enzymes. |
| 1691 | 8972717 | Staurosporine virtually completely inhibited the insulin-stimulated glucose transport and MAP kinase activation in spite of a maintained high PI 3-kinase activity. |
| 1692 | 8983814 | IRS-1 binds several Src homology 2 (SH2) proteins through its multiple tyrosine phosphorylation sites: phosphatidylinositol 3-kinase (PI 3-kinase), the Ras guanine-nucleotide-releasing complex Grb2-SOS, the tyrosine phosphatase Syp, and the adapter protein Nck. |
| 1693 | 8983814 | IRS-1 is essential for many, but not all of the insulin's biological responses. |
| 1694 | 8983814 | IRS-1 binds several Src homology 2 (SH2) proteins through its multiple tyrosine phosphorylation sites: phosphatidylinositol 3-kinase (PI 3-kinase), the Ras guanine-nucleotide-releasing complex Grb2-SOS, the tyrosine phosphatase Syp, and the adapter protein Nck. |
| 1695 | 8983814 | IRS-1 is essential for many, but not all of the insulin's biological responses. |
| 1696 | 8985654 | Indication for genetic linkage of the phosphoenolpyruvate carboxykinase (PCK1) gene region on chromosome 20q to non-insulin-dependent diabetes mellitus. |
| 1697 | 8985654 | No significant results were obtained with glycogen synthase (GSY), insulin receptor substrate-1 (IRS-1) and apolipoprotein C-II (APOC-II) genes. |
| 1698 | 8995390 | Tumor necrosis factor-alpha-induced insulin resistance in 3T3-L1 adipocytes is accompanied by a loss of insulin receptor substrate-1 and GLUT4 expression without a loss of insulin receptor-mediated signal transduction. |
| 1699 | 8995390 | A number of studies have demonstrated that tumor necrosis factor-alpha (TNF-alpha) is associated with profound insulin resistance in adipocytes and may also play a critical role in the insulin resistance of obesity and non-insulin-dependent diabetes mellitus. |
| 1700 | 8995390 | GLUT4 down-regulation has been implicated as a possible cause of insulin resistance as has been the reduced kinase function of the insulin receptor. |
| 1701 | 8995390 | Here we examine the effects of tumor necrosis factor on the protein components thought to be involved in insulin-stimulated glucose transport in adipocytes, namely the insulin receptor, its major substrate IRS-1, and the insulin responsive glucose transporter GLUT4. |
| 1702 | 8995390 | Prolonged exposure (72-96 h) of 3T3-L1 adipocytes to TNF-alpha causes a substantial reduction (>80%) in IRS-1 and GLUT4 mRNA and protein as well as a lesser reduction (>50%) in the amount of the insulin receptor. |
| 1703 | 8995390 | Both the insulin receptor and IRS-1 are tyrosine-phosphorylated to the same extent in response to acute insulin stimulation following cellular TNF-alpha exposure. |
| 1704 | 8995390 | Furthermore, the ability of the insulin receptor to phosphorylate exogenous substrate in the test tube is also normal following its isolation from TNF-alpha-treated cells. |
| 1705 | 8995390 | These results are confirmed by the reduced but obvious level of insulin-dependent glucose transport and GLUT4 translocation observed in TNF-alpha-treated adipocytes. |
| 1706 | 8995390 | We conclude that the insulin resistance of glucose transport in 3T3-L1 adipocytes exposed to TNF-alpha for 72-96 h results from a reduced amount in requisite proteins involved in insulin action. |
| 1707 | 8995390 | These results are consistent with earlier studies indicating that TNF-alpha reduces the transcriptional activity of the GLUT4 gene in murine adipocytes, and reduced mRNA transcription of a number of relevant genes may be the general mechanism by which TNF-alpha causes insulin resistance in adipocytes. |
| 1708 | 8995390 | Tumor necrosis factor-alpha-induced insulin resistance in 3T3-L1 adipocytes is accompanied by a loss of insulin receptor substrate-1 and GLUT4 expression without a loss of insulin receptor-mediated signal transduction. |
| 1709 | 8995390 | A number of studies have demonstrated that tumor necrosis factor-alpha (TNF-alpha) is associated with profound insulin resistance in adipocytes and may also play a critical role in the insulin resistance of obesity and non-insulin-dependent diabetes mellitus. |
| 1710 | 8995390 | GLUT4 down-regulation has been implicated as a possible cause of insulin resistance as has been the reduced kinase function of the insulin receptor. |
| 1711 | 8995390 | Here we examine the effects of tumor necrosis factor on the protein components thought to be involved in insulin-stimulated glucose transport in adipocytes, namely the insulin receptor, its major substrate IRS-1, and the insulin responsive glucose transporter GLUT4. |
| 1712 | 8995390 | Prolonged exposure (72-96 h) of 3T3-L1 adipocytes to TNF-alpha causes a substantial reduction (>80%) in IRS-1 and GLUT4 mRNA and protein as well as a lesser reduction (>50%) in the amount of the insulin receptor. |
| 1713 | 8995390 | Both the insulin receptor and IRS-1 are tyrosine-phosphorylated to the same extent in response to acute insulin stimulation following cellular TNF-alpha exposure. |
| 1714 | 8995390 | Furthermore, the ability of the insulin receptor to phosphorylate exogenous substrate in the test tube is also normal following its isolation from TNF-alpha-treated cells. |
| 1715 | 8995390 | These results are confirmed by the reduced but obvious level of insulin-dependent glucose transport and GLUT4 translocation observed in TNF-alpha-treated adipocytes. |
| 1716 | 8995390 | We conclude that the insulin resistance of glucose transport in 3T3-L1 adipocytes exposed to TNF-alpha for 72-96 h results from a reduced amount in requisite proteins involved in insulin action. |
| 1717 | 8995390 | These results are consistent with earlier studies indicating that TNF-alpha reduces the transcriptional activity of the GLUT4 gene in murine adipocytes, and reduced mRNA transcription of a number of relevant genes may be the general mechanism by which TNF-alpha causes insulin resistance in adipocytes. |
| 1718 | 8995390 | Tumor necrosis factor-alpha-induced insulin resistance in 3T3-L1 adipocytes is accompanied by a loss of insulin receptor substrate-1 and GLUT4 expression without a loss of insulin receptor-mediated signal transduction. |
| 1719 | 8995390 | A number of studies have demonstrated that tumor necrosis factor-alpha (TNF-alpha) is associated with profound insulin resistance in adipocytes and may also play a critical role in the insulin resistance of obesity and non-insulin-dependent diabetes mellitus. |
| 1720 | 8995390 | GLUT4 down-regulation has been implicated as a possible cause of insulin resistance as has been the reduced kinase function of the insulin receptor. |
| 1721 | 8995390 | Here we examine the effects of tumor necrosis factor on the protein components thought to be involved in insulin-stimulated glucose transport in adipocytes, namely the insulin receptor, its major substrate IRS-1, and the insulin responsive glucose transporter GLUT4. |
| 1722 | 8995390 | Prolonged exposure (72-96 h) of 3T3-L1 adipocytes to TNF-alpha causes a substantial reduction (>80%) in IRS-1 and GLUT4 mRNA and protein as well as a lesser reduction (>50%) in the amount of the insulin receptor. |
| 1723 | 8995390 | Both the insulin receptor and IRS-1 are tyrosine-phosphorylated to the same extent in response to acute insulin stimulation following cellular TNF-alpha exposure. |
| 1724 | 8995390 | Furthermore, the ability of the insulin receptor to phosphorylate exogenous substrate in the test tube is also normal following its isolation from TNF-alpha-treated cells. |
| 1725 | 8995390 | These results are confirmed by the reduced but obvious level of insulin-dependent glucose transport and GLUT4 translocation observed in TNF-alpha-treated adipocytes. |
| 1726 | 8995390 | We conclude that the insulin resistance of glucose transport in 3T3-L1 adipocytes exposed to TNF-alpha for 72-96 h results from a reduced amount in requisite proteins involved in insulin action. |
| 1727 | 8995390 | These results are consistent with earlier studies indicating that TNF-alpha reduces the transcriptional activity of the GLUT4 gene in murine adipocytes, and reduced mRNA transcription of a number of relevant genes may be the general mechanism by which TNF-alpha causes insulin resistance in adipocytes. |
| 1728 | 8995390 | Tumor necrosis factor-alpha-induced insulin resistance in 3T3-L1 adipocytes is accompanied by a loss of insulin receptor substrate-1 and GLUT4 expression without a loss of insulin receptor-mediated signal transduction. |
| 1729 | 8995390 | A number of studies have demonstrated that tumor necrosis factor-alpha (TNF-alpha) is associated with profound insulin resistance in adipocytes and may also play a critical role in the insulin resistance of obesity and non-insulin-dependent diabetes mellitus. |
| 1730 | 8995390 | GLUT4 down-regulation has been implicated as a possible cause of insulin resistance as has been the reduced kinase function of the insulin receptor. |
| 1731 | 8995390 | Here we examine the effects of tumor necrosis factor on the protein components thought to be involved in insulin-stimulated glucose transport in adipocytes, namely the insulin receptor, its major substrate IRS-1, and the insulin responsive glucose transporter GLUT4. |
| 1732 | 8995390 | Prolonged exposure (72-96 h) of 3T3-L1 adipocytes to TNF-alpha causes a substantial reduction (>80%) in IRS-1 and GLUT4 mRNA and protein as well as a lesser reduction (>50%) in the amount of the insulin receptor. |
| 1733 | 8995390 | Both the insulin receptor and IRS-1 are tyrosine-phosphorylated to the same extent in response to acute insulin stimulation following cellular TNF-alpha exposure. |
| 1734 | 8995390 | Furthermore, the ability of the insulin receptor to phosphorylate exogenous substrate in the test tube is also normal following its isolation from TNF-alpha-treated cells. |
| 1735 | 8995390 | These results are confirmed by the reduced but obvious level of insulin-dependent glucose transport and GLUT4 translocation observed in TNF-alpha-treated adipocytes. |
| 1736 | 8995390 | We conclude that the insulin resistance of glucose transport in 3T3-L1 adipocytes exposed to TNF-alpha for 72-96 h results from a reduced amount in requisite proteins involved in insulin action. |
| 1737 | 8995390 | These results are consistent with earlier studies indicating that TNF-alpha reduces the transcriptional activity of the GLUT4 gene in murine adipocytes, and reduced mRNA transcription of a number of relevant genes may be the general mechanism by which TNF-alpha causes insulin resistance in adipocytes. |
| 1738 | 9000697 | High-fat feeding impairs insulin-stimulated GLUT4 recruitment via an early insulin-signaling defect. |
| 1739 | 9000697 | GLUT4 expression in soleus muscle from the high-fat-fed mice was also normal, but the insulin-stimulated cell surface recruitment of GLUT4 assessed by exofacial photolabeling with [3H]-ATB bis-mannose was reduced by 50% (P < 0.001). |
| 1740 | 9000697 | Insulin-receptor substrate 1 (IRS-1) associated phosphatidylinositol (PI) 3-kinase activity stimulated by insulin was also reduced by 36% (P < 0.001), and expression of p85 and p110b subunits of PI 3-kinase was normal. |
| 1741 | 9000697 | In conclusion, high-fat feeding selectively impairs insulin-stimulated, but not contraction-pathway-mediated, glucose transport by reducing GLUT4 translocation to the plasma membrane. |
| 1742 | 9003010 | Roles of insulin receptor substrate-1 and Shc on insulin-like growth factor I receptor signaling in early passages of cultured human fibroblasts. |
| 1743 | 9003010 | Insulin-like growth factor-I (IGF-I) improves glucose metabolism and growth in patients with leprechaunism. |
| 1744 | 9003010 | We investigated signal transduction through IGF-I receptor in comparison with epidermal growth factor (EGF) receptor in early passages of cultured skin fibroblasts from a normal subject and a patient with leprechaunism whose insulin receptor tyrosine kinase was almost nonexistent. |
| 1745 | 9003010 | Insulin receptor substrate-1 (IRS-1) became tyrosine-phosphorylated and bound growth factor receptor-bound protein 2 (GRB2) quickly by IGF-I. |
| 1746 | 9003010 | The association of Shc with GRB2 by IGF-I was detected by immunoblot with anti-Shc antibody but was hardly visible with antiphosphotyrosine antibody, which was in marked contrast to efficient tyrosine phosphorylation of Shc by EGF. |
| 1747 | 9003010 | However, the potency of IGF-I for DNA synthesis was far stronger than EGF, which was not parallel with the potency of these growth factors to activate Shc or MAP kinase. |
| 1748 | 9003010 | Rather, phosphatidylinositol (PI) 3-kinase activity, which was activated by IGF-I about 5- to 10-fold more strongly than EGF, appeared to correlate with mitogenesis. |
| 1749 | 9003010 | Signal transduction pathways following IGF-I receptor or EGF receptor activation were indistinguishable between the normal subject and the patient. |
| 1750 | 9003010 | Our results strongly suggest that in human skin fibroblasts, which represent a more physiological cell culture: 1) IRS-1, rather than Shc, is the major tyrosine-phosphorylated protein binding GRB2 in initial phase of IGF-I signaling; 2) mitogenic potency of receptor tyrosine kinases such as IGF-I receptor and EGF receptor may not be determined solely by the amount of Shc-GRB2 complex or the activity of MAP kinase; and 3) in contrast to previous reports, IGF-I and EGF receptor signalings are not defective in leprechaunism. |
| 1751 | 9003010 | Roles of insulin receptor substrate-1 and Shc on insulin-like growth factor I receptor signaling in early passages of cultured human fibroblasts. |
| 1752 | 9003010 | Insulin-like growth factor-I (IGF-I) improves glucose metabolism and growth in patients with leprechaunism. |
| 1753 | 9003010 | We investigated signal transduction through IGF-I receptor in comparison with epidermal growth factor (EGF) receptor in early passages of cultured skin fibroblasts from a normal subject and a patient with leprechaunism whose insulin receptor tyrosine kinase was almost nonexistent. |
| 1754 | 9003010 | Insulin receptor substrate-1 (IRS-1) became tyrosine-phosphorylated and bound growth factor receptor-bound protein 2 (GRB2) quickly by IGF-I. |
| 1755 | 9003010 | The association of Shc with GRB2 by IGF-I was detected by immunoblot with anti-Shc antibody but was hardly visible with antiphosphotyrosine antibody, which was in marked contrast to efficient tyrosine phosphorylation of Shc by EGF. |
| 1756 | 9003010 | However, the potency of IGF-I for DNA synthesis was far stronger than EGF, which was not parallel with the potency of these growth factors to activate Shc or MAP kinase. |
| 1757 | 9003010 | Rather, phosphatidylinositol (PI) 3-kinase activity, which was activated by IGF-I about 5- to 10-fold more strongly than EGF, appeared to correlate with mitogenesis. |
| 1758 | 9003010 | Signal transduction pathways following IGF-I receptor or EGF receptor activation were indistinguishable between the normal subject and the patient. |
| 1759 | 9003010 | Our results strongly suggest that in human skin fibroblasts, which represent a more physiological cell culture: 1) IRS-1, rather than Shc, is the major tyrosine-phosphorylated protein binding GRB2 in initial phase of IGF-I signaling; 2) mitogenic potency of receptor tyrosine kinases such as IGF-I receptor and EGF receptor may not be determined solely by the amount of Shc-GRB2 complex or the activity of MAP kinase; and 3) in contrast to previous reports, IGF-I and EGF receptor signalings are not defective in leprechaunism. |
| 1760 | 9003010 | Roles of insulin receptor substrate-1 and Shc on insulin-like growth factor I receptor signaling in early passages of cultured human fibroblasts. |
| 1761 | 9003010 | Insulin-like growth factor-I (IGF-I) improves glucose metabolism and growth in patients with leprechaunism. |
| 1762 | 9003010 | We investigated signal transduction through IGF-I receptor in comparison with epidermal growth factor (EGF) receptor in early passages of cultured skin fibroblasts from a normal subject and a patient with leprechaunism whose insulin receptor tyrosine kinase was almost nonexistent. |
| 1763 | 9003010 | Insulin receptor substrate-1 (IRS-1) became tyrosine-phosphorylated and bound growth factor receptor-bound protein 2 (GRB2) quickly by IGF-I. |
| 1764 | 9003010 | The association of Shc with GRB2 by IGF-I was detected by immunoblot with anti-Shc antibody but was hardly visible with antiphosphotyrosine antibody, which was in marked contrast to efficient tyrosine phosphorylation of Shc by EGF. |
| 1765 | 9003010 | However, the potency of IGF-I for DNA synthesis was far stronger than EGF, which was not parallel with the potency of these growth factors to activate Shc or MAP kinase. |
| 1766 | 9003010 | Rather, phosphatidylinositol (PI) 3-kinase activity, which was activated by IGF-I about 5- to 10-fold more strongly than EGF, appeared to correlate with mitogenesis. |
| 1767 | 9003010 | Signal transduction pathways following IGF-I receptor or EGF receptor activation were indistinguishable between the normal subject and the patient. |
| 1768 | 9003010 | Our results strongly suggest that in human skin fibroblasts, which represent a more physiological cell culture: 1) IRS-1, rather than Shc, is the major tyrosine-phosphorylated protein binding GRB2 in initial phase of IGF-I signaling; 2) mitogenic potency of receptor tyrosine kinases such as IGF-I receptor and EGF receptor may not be determined solely by the amount of Shc-GRB2 complex or the activity of MAP kinase; and 3) in contrast to previous reports, IGF-I and EGF receptor signalings are not defective in leprechaunism. |
| 1769 | 9015760 | Tumor necrosis factor-alpha (TNF-alpha) can modulate the signalling capacity of tyrosine kinase receptors; in particular, TNF-alpha has been shown to mediate the insulin resistance associated with animal models of obesity and noninsulin-dependent diabetes mellitus. |
| 1770 | 9015760 | In order to determine whether the effects of TNF-alpha might involve alterations in the expression of specific protein-tyrosine phosphatases (PTPases) that have been implicated in the regulation of growth factor receptor signalling, KRC-7 rat hepatoma cells were treated with TNF-alpha, and changes in overall tissue PTPase activity and the abundance of three major hepatic PTPases (LAR, PTP1B, and SH-PTP2) were measured in addition to effects of TNF-alpha on ligand-stimulated autophosphorylation of insulin and epidermal growth factor (EGF) receptors and insulin-stimulated insulin receptor substrate-1 (IRS-1) phosphorylation. |
| 1771 | 9015760 | TNF-alpha caused a dose-dependent decrease in insulin-stimulated IRS-1 phosphorylation and EGF-stimulated receptor autophosphorylation to 47-50% of control. |
| 1772 | 9015760 | However, immunoblot analysis showed that TNF-alpha treatment resulted in a 2.5-fold increase in the abundance of SH-PTP2, a 49% decrease in the transmembrane PTPase LAR, and no evident change in the expression of PTP1B. |
| 1773 | 9015760 | Since SH-PTP2 has been shown to interact directly with both the EGF receptor and IRS-1, increased abundance of this PTPase, may mediate the TNF-alpha effect to inhibit signalling through these proteins. |
| 1774 | 9015760 | Furthermore, decreased abundance of the LAR PTPase, which has been implicated in the regulation of insulin receptor phosphorylation, may account for the less marked effect of TNF-alpha on the autophosphorylation state of the insulin receptor while postreceptor actions of insulin are inhibited. |
| 1775 | 9015760 | Tumor necrosis factor-alpha (TNF-alpha) can modulate the signalling capacity of tyrosine kinase receptors; in particular, TNF-alpha has been shown to mediate the insulin resistance associated with animal models of obesity and noninsulin-dependent diabetes mellitus. |
| 1776 | 9015760 | In order to determine whether the effects of TNF-alpha might involve alterations in the expression of specific protein-tyrosine phosphatases (PTPases) that have been implicated in the regulation of growth factor receptor signalling, KRC-7 rat hepatoma cells were treated with TNF-alpha, and changes in overall tissue PTPase activity and the abundance of three major hepatic PTPases (LAR, PTP1B, and SH-PTP2) were measured in addition to effects of TNF-alpha on ligand-stimulated autophosphorylation of insulin and epidermal growth factor (EGF) receptors and insulin-stimulated insulin receptor substrate-1 (IRS-1) phosphorylation. |
| 1777 | 9015760 | TNF-alpha caused a dose-dependent decrease in insulin-stimulated IRS-1 phosphorylation and EGF-stimulated receptor autophosphorylation to 47-50% of control. |
| 1778 | 9015760 | However, immunoblot analysis showed that TNF-alpha treatment resulted in a 2.5-fold increase in the abundance of SH-PTP2, a 49% decrease in the transmembrane PTPase LAR, and no evident change in the expression of PTP1B. |
| 1779 | 9015760 | Since SH-PTP2 has been shown to interact directly with both the EGF receptor and IRS-1, increased abundance of this PTPase, may mediate the TNF-alpha effect to inhibit signalling through these proteins. |
| 1780 | 9015760 | Furthermore, decreased abundance of the LAR PTPase, which has been implicated in the regulation of insulin receptor phosphorylation, may account for the less marked effect of TNF-alpha on the autophosphorylation state of the insulin receptor while postreceptor actions of insulin are inhibited. |
| 1781 | 9015760 | Tumor necrosis factor-alpha (TNF-alpha) can modulate the signalling capacity of tyrosine kinase receptors; in particular, TNF-alpha has been shown to mediate the insulin resistance associated with animal models of obesity and noninsulin-dependent diabetes mellitus. |
| 1782 | 9015760 | In order to determine whether the effects of TNF-alpha might involve alterations in the expression of specific protein-tyrosine phosphatases (PTPases) that have been implicated in the regulation of growth factor receptor signalling, KRC-7 rat hepatoma cells were treated with TNF-alpha, and changes in overall tissue PTPase activity and the abundance of three major hepatic PTPases (LAR, PTP1B, and SH-PTP2) were measured in addition to effects of TNF-alpha on ligand-stimulated autophosphorylation of insulin and epidermal growth factor (EGF) receptors and insulin-stimulated insulin receptor substrate-1 (IRS-1) phosphorylation. |
| 1783 | 9015760 | TNF-alpha caused a dose-dependent decrease in insulin-stimulated IRS-1 phosphorylation and EGF-stimulated receptor autophosphorylation to 47-50% of control. |
| 1784 | 9015760 | However, immunoblot analysis showed that TNF-alpha treatment resulted in a 2.5-fold increase in the abundance of SH-PTP2, a 49% decrease in the transmembrane PTPase LAR, and no evident change in the expression of PTP1B. |
| 1785 | 9015760 | Since SH-PTP2 has been shown to interact directly with both the EGF receptor and IRS-1, increased abundance of this PTPase, may mediate the TNF-alpha effect to inhibit signalling through these proteins. |
| 1786 | 9015760 | Furthermore, decreased abundance of the LAR PTPase, which has been implicated in the regulation of insulin receptor phosphorylation, may account for the less marked effect of TNF-alpha on the autophosphorylation state of the insulin receptor while postreceptor actions of insulin are inhibited. |
| 1787 | 9032089 | Cell-specific regulation of IRS-1 gene expression: role of E box and C/EBP binding site in HepG2 cells and CHO cells. |
| 1788 | 9032089 | CAT assays using promoters mutated at the E box or at the C/EBP binding site revealed that these sequences were responsible for cell-specific regulation of the IRS-1 gene. |
| 1789 | 9032089 | We therefore concluded that the two nuclear proteins that bind to the E box regulate IRS-1 gene expression positively in HepG2 cells and the two nuclear proteins that bind to the C/EBP binding site regulate it negatively in CHO cells. |
| 1790 | 9032089 | Cell-specific regulation of IRS-1 gene expression: role of E box and C/EBP binding site in HepG2 cells and CHO cells. |
| 1791 | 9032089 | CAT assays using promoters mutated at the E box or at the C/EBP binding site revealed that these sequences were responsible for cell-specific regulation of the IRS-1 gene. |
| 1792 | 9032089 | We therefore concluded that the two nuclear proteins that bind to the E box regulate IRS-1 gene expression positively in HepG2 cells and the two nuclear proteins that bind to the C/EBP binding site regulate it negatively in CHO cells. |
| 1793 | 9032089 | Cell-specific regulation of IRS-1 gene expression: role of E box and C/EBP binding site in HepG2 cells and CHO cells. |
| 1794 | 9032089 | CAT assays using promoters mutated at the E box or at the C/EBP binding site revealed that these sequences were responsible for cell-specific regulation of the IRS-1 gene. |
| 1795 | 9032089 | We therefore concluded that the two nuclear proteins that bind to the E box regulate IRS-1 gene expression positively in HepG2 cells and the two nuclear proteins that bind to the C/EBP binding site regulate it negatively in CHO cells. |
| 1796 | 9032113 | Insulin receptor substrate-1 phosphorylation and phosphatidylinositol 3-kinase activity in skeletal muscle from NIDDM subjects after in vivo insulin stimulation. |
| 1797 | 9032113 | A rise in serum insulin levels from approximately 60 to approximately 650 pmol/l increased IRS-1 tyrosine phosphorylation sixfold over basal levels in control muscle (P < 0.01), whereas no significant increase was noted in NIDDM muscle. |
| 1798 | 9032113 | The present findings couple both reduced insulin-stimulated IRS-1 tyrosine phosphorylation and PI 3-kinase activity to the impaired insulin-stimulated glucose transport in skeletal muscle from lean-to-moderately obese NIDDM subjects. |
| 1799 | 9032113 | Insulin receptor substrate-1 phosphorylation and phosphatidylinositol 3-kinase activity in skeletal muscle from NIDDM subjects after in vivo insulin stimulation. |
| 1800 | 9032113 | A rise in serum insulin levels from approximately 60 to approximately 650 pmol/l increased IRS-1 tyrosine phosphorylation sixfold over basal levels in control muscle (P < 0.01), whereas no significant increase was noted in NIDDM muscle. |
| 1801 | 9032113 | The present findings couple both reduced insulin-stimulated IRS-1 tyrosine phosphorylation and PI 3-kinase activity to the impaired insulin-stimulated glucose transport in skeletal muscle from lean-to-moderately obese NIDDM subjects. |
| 1802 | 9032113 | Insulin receptor substrate-1 phosphorylation and phosphatidylinositol 3-kinase activity in skeletal muscle from NIDDM subjects after in vivo insulin stimulation. |
| 1803 | 9032113 | A rise in serum insulin levels from approximately 60 to approximately 650 pmol/l increased IRS-1 tyrosine phosphorylation sixfold over basal levels in control muscle (P < 0.01), whereas no significant increase was noted in NIDDM muscle. |
| 1804 | 9032113 | The present findings couple both reduced insulin-stimulated IRS-1 tyrosine phosphorylation and PI 3-kinase activity to the impaired insulin-stimulated glucose transport in skeletal muscle from lean-to-moderately obese NIDDM subjects. |
| 1805 | 9032245 | Shc and insulin receptor substrate 1 (IRS-1) are cytoplasmic substrates of tyrosine kinase receptors that engage, localize, and activate downstream SH2 enzymes. |
| 1806 | 9032245 | We have designed high-affinity, cellular inhibitors of the Shc PTB domain by incorporating nonnatural, phosphatase-resistant amino acids into short peptides. |
| 1807 | 9032245 | None of the inhibitors bind the IRS-1 PTB domain, consistent with distinct specificities for domains. |
| 1808 | 9032245 | The best inhibitor of the Shc domain was introduced by electroporation into Rat1 fibroblasts that express human insulin receptors. |
| 1809 | 9032245 | Insulin-stimulated phosphorylation of Shc was inhibited, with no effect on IRS-1, and downstream effects on mitogen-activated protein kinase and DNA synthesis were both inhibited. |
| 1810 | 9032245 | The PTB domain inhibitor had less influence on epidermal growth factor-induced effects and essentially no impact on serum- or phorbol ester-induced effects. |
| 1811 | 9032245 | We conclude that the PTB domain of Shc is critical for its phosphorylation by the insulin receptor, that Shc is an important mediator of insulin's mitogenic effects, and that Shc is not central to insulin receptor cycling in these cells. |
| 1812 | 9032245 | Shc and insulin receptor substrate 1 (IRS-1) are cytoplasmic substrates of tyrosine kinase receptors that engage, localize, and activate downstream SH2 enzymes. |
| 1813 | 9032245 | We have designed high-affinity, cellular inhibitors of the Shc PTB domain by incorporating nonnatural, phosphatase-resistant amino acids into short peptides. |
| 1814 | 9032245 | None of the inhibitors bind the IRS-1 PTB domain, consistent with distinct specificities for domains. |
| 1815 | 9032245 | The best inhibitor of the Shc domain was introduced by electroporation into Rat1 fibroblasts that express human insulin receptors. |
| 1816 | 9032245 | Insulin-stimulated phosphorylation of Shc was inhibited, with no effect on IRS-1, and downstream effects on mitogen-activated protein kinase and DNA synthesis were both inhibited. |
| 1817 | 9032245 | The PTB domain inhibitor had less influence on epidermal growth factor-induced effects and essentially no impact on serum- or phorbol ester-induced effects. |
| 1818 | 9032245 | We conclude that the PTB domain of Shc is critical for its phosphorylation by the insulin receptor, that Shc is an important mediator of insulin's mitogenic effects, and that Shc is not central to insulin receptor cycling in these cells. |
| 1819 | 9032245 | Shc and insulin receptor substrate 1 (IRS-1) are cytoplasmic substrates of tyrosine kinase receptors that engage, localize, and activate downstream SH2 enzymes. |
| 1820 | 9032245 | We have designed high-affinity, cellular inhibitors of the Shc PTB domain by incorporating nonnatural, phosphatase-resistant amino acids into short peptides. |
| 1821 | 9032245 | None of the inhibitors bind the IRS-1 PTB domain, consistent with distinct specificities for domains. |
| 1822 | 9032245 | The best inhibitor of the Shc domain was introduced by electroporation into Rat1 fibroblasts that express human insulin receptors. |
| 1823 | 9032245 | Insulin-stimulated phosphorylation of Shc was inhibited, with no effect on IRS-1, and downstream effects on mitogen-activated protein kinase and DNA synthesis were both inhibited. |
| 1824 | 9032245 | The PTB domain inhibitor had less influence on epidermal growth factor-induced effects and essentially no impact on serum- or phorbol ester-induced effects. |
| 1825 | 9032245 | We conclude that the PTB domain of Shc is critical for its phosphorylation by the insulin receptor, that Shc is an important mediator of insulin's mitogenic effects, and that Shc is not central to insulin receptor cycling in these cells. |
| 1826 | 9032279 | Differential signaling by insulin receptor substrate 1 (IRS-1) and IRS-2 in IRS-1-deficient cells. |
| 1827 | 9032279 | Mice made insulin receptor substrate 1 (IRS-1) deficient by targeted gene knockout exhibit growth retardation and abnormal glucose metabolism due to resistance to the actions of insulin-like growth factor 1 (IGF-1) and insulin (E. |
| 1828 | 9032279 | Embryonic fibroblasts and 3T3 cell lines derived from IRS-1-deficient embryos exhibit no IGF-1-stimulated IRS-1 phosphorylation or IRS-1-associated phosphatidylinositol 3-kinase (PI 3-kinase) activity but exhibit normal phosphorylation of IRS-2 and Shc and normal IRS-2-associated PI 3-kinase activity. |
| 1829 | 9032279 | IRS-1 deficiency results in a 70 to 80% reduction in IGF-1-stimulated cell growth and parallel decreases in IGF-1-stimulated S-phase entry, PI 3-kinase activity, and induction of the immediate-early genes c-fos and egr-1 but unaltered activation of the mitogen-activated protein kinases ERK 1 and ERK 2. |
| 1830 | 9032279 | Expression of IRS-1 in IRS-1-deficient cells by retroviral gene transduction restores IGF-1-stimulated mitogenesis, PI 3-kinase activation, and c-fos and egr-1 induction in proportion to the level of reconstitution. |
| 1831 | 9032279 | Increasing the level of IRS-2 in these cells by using a retrovirus reconstitutes IGF-1 activation of PI 3-kinase and immediate-early gene expression to the same degree as expression of IRS-1; however, IRS-2 overexpression has only a minor effect on IGF-1 stimulation of cell cycle progression. |
| 1832 | 9032279 | These results indicate that IRS-1 is not necessary for activation of ERK 1 and ERK 2 and that activation of ERK 1 and ERK 2 is not sufficient for IGF-1-stimulated activation of c-fos and egr-1. |
| 1833 | 9032279 | These data also provide evidence that IRS-1 and IRS-2 are not functionally interchangeable signaling intermediates for stimulation of mitogenesis despite their highly conserved structure and many common functions such as activating PI 3-kinase and early gene expression. |
| 1834 | 9032279 | Differential signaling by insulin receptor substrate 1 (IRS-1) and IRS-2 in IRS-1-deficient cells. |
| 1835 | 9032279 | Mice made insulin receptor substrate 1 (IRS-1) deficient by targeted gene knockout exhibit growth retardation and abnormal glucose metabolism due to resistance to the actions of insulin-like growth factor 1 (IGF-1) and insulin (E. |
| 1836 | 9032279 | Embryonic fibroblasts and 3T3 cell lines derived from IRS-1-deficient embryos exhibit no IGF-1-stimulated IRS-1 phosphorylation or IRS-1-associated phosphatidylinositol 3-kinase (PI 3-kinase) activity but exhibit normal phosphorylation of IRS-2 and Shc and normal IRS-2-associated PI 3-kinase activity. |
| 1837 | 9032279 | IRS-1 deficiency results in a 70 to 80% reduction in IGF-1-stimulated cell growth and parallel decreases in IGF-1-stimulated S-phase entry, PI 3-kinase activity, and induction of the immediate-early genes c-fos and egr-1 but unaltered activation of the mitogen-activated protein kinases ERK 1 and ERK 2. |
| 1838 | 9032279 | Expression of IRS-1 in IRS-1-deficient cells by retroviral gene transduction restores IGF-1-stimulated mitogenesis, PI 3-kinase activation, and c-fos and egr-1 induction in proportion to the level of reconstitution. |
| 1839 | 9032279 | Increasing the level of IRS-2 in these cells by using a retrovirus reconstitutes IGF-1 activation of PI 3-kinase and immediate-early gene expression to the same degree as expression of IRS-1; however, IRS-2 overexpression has only a minor effect on IGF-1 stimulation of cell cycle progression. |
| 1840 | 9032279 | These results indicate that IRS-1 is not necessary for activation of ERK 1 and ERK 2 and that activation of ERK 1 and ERK 2 is not sufficient for IGF-1-stimulated activation of c-fos and egr-1. |
| 1841 | 9032279 | These data also provide evidence that IRS-1 and IRS-2 are not functionally interchangeable signaling intermediates for stimulation of mitogenesis despite their highly conserved structure and many common functions such as activating PI 3-kinase and early gene expression. |
| 1842 | 9032279 | Differential signaling by insulin receptor substrate 1 (IRS-1) and IRS-2 in IRS-1-deficient cells. |
| 1843 | 9032279 | Mice made insulin receptor substrate 1 (IRS-1) deficient by targeted gene knockout exhibit growth retardation and abnormal glucose metabolism due to resistance to the actions of insulin-like growth factor 1 (IGF-1) and insulin (E. |
| 1844 | 9032279 | Embryonic fibroblasts and 3T3 cell lines derived from IRS-1-deficient embryos exhibit no IGF-1-stimulated IRS-1 phosphorylation or IRS-1-associated phosphatidylinositol 3-kinase (PI 3-kinase) activity but exhibit normal phosphorylation of IRS-2 and Shc and normal IRS-2-associated PI 3-kinase activity. |
| 1845 | 9032279 | IRS-1 deficiency results in a 70 to 80% reduction in IGF-1-stimulated cell growth and parallel decreases in IGF-1-stimulated S-phase entry, PI 3-kinase activity, and induction of the immediate-early genes c-fos and egr-1 but unaltered activation of the mitogen-activated protein kinases ERK 1 and ERK 2. |
| 1846 | 9032279 | Expression of IRS-1 in IRS-1-deficient cells by retroviral gene transduction restores IGF-1-stimulated mitogenesis, PI 3-kinase activation, and c-fos and egr-1 induction in proportion to the level of reconstitution. |
| 1847 | 9032279 | Increasing the level of IRS-2 in these cells by using a retrovirus reconstitutes IGF-1 activation of PI 3-kinase and immediate-early gene expression to the same degree as expression of IRS-1; however, IRS-2 overexpression has only a minor effect on IGF-1 stimulation of cell cycle progression. |
| 1848 | 9032279 | These results indicate that IRS-1 is not necessary for activation of ERK 1 and ERK 2 and that activation of ERK 1 and ERK 2 is not sufficient for IGF-1-stimulated activation of c-fos and egr-1. |
| 1849 | 9032279 | These data also provide evidence that IRS-1 and IRS-2 are not functionally interchangeable signaling intermediates for stimulation of mitogenesis despite their highly conserved structure and many common functions such as activating PI 3-kinase and early gene expression. |
| 1850 | 9032279 | Differential signaling by insulin receptor substrate 1 (IRS-1) and IRS-2 in IRS-1-deficient cells. |
| 1851 | 9032279 | Mice made insulin receptor substrate 1 (IRS-1) deficient by targeted gene knockout exhibit growth retardation and abnormal glucose metabolism due to resistance to the actions of insulin-like growth factor 1 (IGF-1) and insulin (E. |
| 1852 | 9032279 | Embryonic fibroblasts and 3T3 cell lines derived from IRS-1-deficient embryos exhibit no IGF-1-stimulated IRS-1 phosphorylation or IRS-1-associated phosphatidylinositol 3-kinase (PI 3-kinase) activity but exhibit normal phosphorylation of IRS-2 and Shc and normal IRS-2-associated PI 3-kinase activity. |
| 1853 | 9032279 | IRS-1 deficiency results in a 70 to 80% reduction in IGF-1-stimulated cell growth and parallel decreases in IGF-1-stimulated S-phase entry, PI 3-kinase activity, and induction of the immediate-early genes c-fos and egr-1 but unaltered activation of the mitogen-activated protein kinases ERK 1 and ERK 2. |
| 1854 | 9032279 | Expression of IRS-1 in IRS-1-deficient cells by retroviral gene transduction restores IGF-1-stimulated mitogenesis, PI 3-kinase activation, and c-fos and egr-1 induction in proportion to the level of reconstitution. |
| 1855 | 9032279 | Increasing the level of IRS-2 in these cells by using a retrovirus reconstitutes IGF-1 activation of PI 3-kinase and immediate-early gene expression to the same degree as expression of IRS-1; however, IRS-2 overexpression has only a minor effect on IGF-1 stimulation of cell cycle progression. |
| 1856 | 9032279 | These results indicate that IRS-1 is not necessary for activation of ERK 1 and ERK 2 and that activation of ERK 1 and ERK 2 is not sufficient for IGF-1-stimulated activation of c-fos and egr-1. |
| 1857 | 9032279 | These data also provide evidence that IRS-1 and IRS-2 are not functionally interchangeable signaling intermediates for stimulation of mitogenesis despite their highly conserved structure and many common functions such as activating PI 3-kinase and early gene expression. |
| 1858 | 9032279 | Differential signaling by insulin receptor substrate 1 (IRS-1) and IRS-2 in IRS-1-deficient cells. |
| 1859 | 9032279 | Mice made insulin receptor substrate 1 (IRS-1) deficient by targeted gene knockout exhibit growth retardation and abnormal glucose metabolism due to resistance to the actions of insulin-like growth factor 1 (IGF-1) and insulin (E. |
| 1860 | 9032279 | Embryonic fibroblasts and 3T3 cell lines derived from IRS-1-deficient embryos exhibit no IGF-1-stimulated IRS-1 phosphorylation or IRS-1-associated phosphatidylinositol 3-kinase (PI 3-kinase) activity but exhibit normal phosphorylation of IRS-2 and Shc and normal IRS-2-associated PI 3-kinase activity. |
| 1861 | 9032279 | IRS-1 deficiency results in a 70 to 80% reduction in IGF-1-stimulated cell growth and parallel decreases in IGF-1-stimulated S-phase entry, PI 3-kinase activity, and induction of the immediate-early genes c-fos and egr-1 but unaltered activation of the mitogen-activated protein kinases ERK 1 and ERK 2. |
| 1862 | 9032279 | Expression of IRS-1 in IRS-1-deficient cells by retroviral gene transduction restores IGF-1-stimulated mitogenesis, PI 3-kinase activation, and c-fos and egr-1 induction in proportion to the level of reconstitution. |
| 1863 | 9032279 | Increasing the level of IRS-2 in these cells by using a retrovirus reconstitutes IGF-1 activation of PI 3-kinase and immediate-early gene expression to the same degree as expression of IRS-1; however, IRS-2 overexpression has only a minor effect on IGF-1 stimulation of cell cycle progression. |
| 1864 | 9032279 | These results indicate that IRS-1 is not necessary for activation of ERK 1 and ERK 2 and that activation of ERK 1 and ERK 2 is not sufficient for IGF-1-stimulated activation of c-fos and egr-1. |
| 1865 | 9032279 | These data also provide evidence that IRS-1 and IRS-2 are not functionally interchangeable signaling intermediates for stimulation of mitogenesis despite their highly conserved structure and many common functions such as activating PI 3-kinase and early gene expression. |
| 1866 | 9032279 | Differential signaling by insulin receptor substrate 1 (IRS-1) and IRS-2 in IRS-1-deficient cells. |
| 1867 | 9032279 | Mice made insulin receptor substrate 1 (IRS-1) deficient by targeted gene knockout exhibit growth retardation and abnormal glucose metabolism due to resistance to the actions of insulin-like growth factor 1 (IGF-1) and insulin (E. |
| 1868 | 9032279 | Embryonic fibroblasts and 3T3 cell lines derived from IRS-1-deficient embryos exhibit no IGF-1-stimulated IRS-1 phosphorylation or IRS-1-associated phosphatidylinositol 3-kinase (PI 3-kinase) activity but exhibit normal phosphorylation of IRS-2 and Shc and normal IRS-2-associated PI 3-kinase activity. |
| 1869 | 9032279 | IRS-1 deficiency results in a 70 to 80% reduction in IGF-1-stimulated cell growth and parallel decreases in IGF-1-stimulated S-phase entry, PI 3-kinase activity, and induction of the immediate-early genes c-fos and egr-1 but unaltered activation of the mitogen-activated protein kinases ERK 1 and ERK 2. |
| 1870 | 9032279 | Expression of IRS-1 in IRS-1-deficient cells by retroviral gene transduction restores IGF-1-stimulated mitogenesis, PI 3-kinase activation, and c-fos and egr-1 induction in proportion to the level of reconstitution. |
| 1871 | 9032279 | Increasing the level of IRS-2 in these cells by using a retrovirus reconstitutes IGF-1 activation of PI 3-kinase and immediate-early gene expression to the same degree as expression of IRS-1; however, IRS-2 overexpression has only a minor effect on IGF-1 stimulation of cell cycle progression. |
| 1872 | 9032279 | These results indicate that IRS-1 is not necessary for activation of ERK 1 and ERK 2 and that activation of ERK 1 and ERK 2 is not sufficient for IGF-1-stimulated activation of c-fos and egr-1. |
| 1873 | 9032279 | These data also provide evidence that IRS-1 and IRS-2 are not functionally interchangeable signaling intermediates for stimulation of mitogenesis despite their highly conserved structure and many common functions such as activating PI 3-kinase and early gene expression. |
| 1874 | 9032279 | Differential signaling by insulin receptor substrate 1 (IRS-1) and IRS-2 in IRS-1-deficient cells. |
| 1875 | 9032279 | Mice made insulin receptor substrate 1 (IRS-1) deficient by targeted gene knockout exhibit growth retardation and abnormal glucose metabolism due to resistance to the actions of insulin-like growth factor 1 (IGF-1) and insulin (E. |
| 1876 | 9032279 | Embryonic fibroblasts and 3T3 cell lines derived from IRS-1-deficient embryos exhibit no IGF-1-stimulated IRS-1 phosphorylation or IRS-1-associated phosphatidylinositol 3-kinase (PI 3-kinase) activity but exhibit normal phosphorylation of IRS-2 and Shc and normal IRS-2-associated PI 3-kinase activity. |
| 1877 | 9032279 | IRS-1 deficiency results in a 70 to 80% reduction in IGF-1-stimulated cell growth and parallel decreases in IGF-1-stimulated S-phase entry, PI 3-kinase activity, and induction of the immediate-early genes c-fos and egr-1 but unaltered activation of the mitogen-activated protein kinases ERK 1 and ERK 2. |
| 1878 | 9032279 | Expression of IRS-1 in IRS-1-deficient cells by retroviral gene transduction restores IGF-1-stimulated mitogenesis, PI 3-kinase activation, and c-fos and egr-1 induction in proportion to the level of reconstitution. |
| 1879 | 9032279 | Increasing the level of IRS-2 in these cells by using a retrovirus reconstitutes IGF-1 activation of PI 3-kinase and immediate-early gene expression to the same degree as expression of IRS-1; however, IRS-2 overexpression has only a minor effect on IGF-1 stimulation of cell cycle progression. |
| 1880 | 9032279 | These results indicate that IRS-1 is not necessary for activation of ERK 1 and ERK 2 and that activation of ERK 1 and ERK 2 is not sufficient for IGF-1-stimulated activation of c-fos and egr-1. |
| 1881 | 9032279 | These data also provide evidence that IRS-1 and IRS-2 are not functionally interchangeable signaling intermediates for stimulation of mitogenesis despite their highly conserved structure and many common functions such as activating PI 3-kinase and early gene expression. |
| 1882 | 9032279 | Differential signaling by insulin receptor substrate 1 (IRS-1) and IRS-2 in IRS-1-deficient cells. |
| 1883 | 9032279 | Mice made insulin receptor substrate 1 (IRS-1) deficient by targeted gene knockout exhibit growth retardation and abnormal glucose metabolism due to resistance to the actions of insulin-like growth factor 1 (IGF-1) and insulin (E. |
| 1884 | 9032279 | Embryonic fibroblasts and 3T3 cell lines derived from IRS-1-deficient embryos exhibit no IGF-1-stimulated IRS-1 phosphorylation or IRS-1-associated phosphatidylinositol 3-kinase (PI 3-kinase) activity but exhibit normal phosphorylation of IRS-2 and Shc and normal IRS-2-associated PI 3-kinase activity. |
| 1885 | 9032279 | IRS-1 deficiency results in a 70 to 80% reduction in IGF-1-stimulated cell growth and parallel decreases in IGF-1-stimulated S-phase entry, PI 3-kinase activity, and induction of the immediate-early genes c-fos and egr-1 but unaltered activation of the mitogen-activated protein kinases ERK 1 and ERK 2. |
| 1886 | 9032279 | Expression of IRS-1 in IRS-1-deficient cells by retroviral gene transduction restores IGF-1-stimulated mitogenesis, PI 3-kinase activation, and c-fos and egr-1 induction in proportion to the level of reconstitution. |
| 1887 | 9032279 | Increasing the level of IRS-2 in these cells by using a retrovirus reconstitutes IGF-1 activation of PI 3-kinase and immediate-early gene expression to the same degree as expression of IRS-1; however, IRS-2 overexpression has only a minor effect on IGF-1 stimulation of cell cycle progression. |
| 1888 | 9032279 | These results indicate that IRS-1 is not necessary for activation of ERK 1 and ERK 2 and that activation of ERK 1 and ERK 2 is not sufficient for IGF-1-stimulated activation of c-fos and egr-1. |
| 1889 | 9032279 | These data also provide evidence that IRS-1 and IRS-2 are not functionally interchangeable signaling intermediates for stimulation of mitogenesis despite their highly conserved structure and many common functions such as activating PI 3-kinase and early gene expression. |
| 1890 | 9038347 | Mice double heterozygous for null alleles in the insulin receptor and insulin receptor substrate-1 genes exhibit the expected approximately 50% reduction in expression of these two proteins, but a synergism at a level of insulin resistance with 5- to 50-fold elevated plasma insulin levels and comparable levels of beta cell hyperplasia. |
| 1891 | 9054447 | Specific increase in p85alpha expression in response to dexamethasone is associated with inhibition of insulin-like growth factor-I stimulated phosphatidylinositol 3-kinase activity in cultured muscle cells. |
| 1892 | 9054447 | The stimulation of phosphatidylinositol (PI) 3-kinase by insulin-like growth factor I (IGF-I) in L6 cultured skeletal muscle cells is inhibited by the glucocorticoid dexamethasone. |
| 1893 | 9054447 | The objective of this study was to investigate the mechanism of dexamethasone action by determining its effects on the expression of the p85alpha and p85beta regulatory subunit isoforms of PI 3-kinase, their coupling with the p110 catalytic subunit, and their association with insulin receptor substrate 1 (IRS-1) in response to IGF-I stimulation. |
| 1894 | 9054447 | Dexamethasone induced a 300% increase in p85alpha protein content in the L6 cultured myoblast cell line, whereas it increased p110 content by only 38% and had no effect on p85beta. |
| 1895 | 9054447 | Stimulation with IGF-I induced the association of p85alpha and p85beta with IRS-1, and this was accompanied by increased amounts of the p110 catalytic subunit and markedly increased PI 3-kinase activity in IRS-1 immunoprecipitates. |
| 1896 | 9054447 | In cells treated with dexamethasone, greater amounts of p85alpha and lower amounts of p85beta, respectively, were found in IRS-1 immunoprecipitates, such that the alpha/beta ratio was markedly higher than in control cells. |
| 1897 | 9054447 | In spite of the increase in both total and IRS-1-associated p85alpha following dexamethasone treatment, IRS-1-associated p110 catalytic subunit and PI 3-kinase activity were decreased by approximately 50%. |
| 1898 | 9054447 | Thus, dexamethasone induces a specific increase in expression of the p85alpha regulatory subunit that is not associated with a coordinate increase in the p110 catalytic subunit of PI 3-kinase. |
| 1899 | 9054447 | As a consequence, in dexamethasone-treated cells, p85alpha that is not coupled with p110 competes with both p85alpha.p110 and p85beta.p110 complexes for association with IRS-1, leading to increased p85alpha but decreased p85beta, p110, and PI 3-kinase activity in IRS-1 immunoprecipitates. |
| 1900 | 9054447 | Specific increase in p85alpha expression in response to dexamethasone is associated with inhibition of insulin-like growth factor-I stimulated phosphatidylinositol 3-kinase activity in cultured muscle cells. |
| 1901 | 9054447 | The stimulation of phosphatidylinositol (PI) 3-kinase by insulin-like growth factor I (IGF-I) in L6 cultured skeletal muscle cells is inhibited by the glucocorticoid dexamethasone. |
| 1902 | 9054447 | The objective of this study was to investigate the mechanism of dexamethasone action by determining its effects on the expression of the p85alpha and p85beta regulatory subunit isoforms of PI 3-kinase, their coupling with the p110 catalytic subunit, and their association with insulin receptor substrate 1 (IRS-1) in response to IGF-I stimulation. |
| 1903 | 9054447 | Dexamethasone induced a 300% increase in p85alpha protein content in the L6 cultured myoblast cell line, whereas it increased p110 content by only 38% and had no effect on p85beta. |
| 1904 | 9054447 | Stimulation with IGF-I induced the association of p85alpha and p85beta with IRS-1, and this was accompanied by increased amounts of the p110 catalytic subunit and markedly increased PI 3-kinase activity in IRS-1 immunoprecipitates. |
| 1905 | 9054447 | In cells treated with dexamethasone, greater amounts of p85alpha and lower amounts of p85beta, respectively, were found in IRS-1 immunoprecipitates, such that the alpha/beta ratio was markedly higher than in control cells. |
| 1906 | 9054447 | In spite of the increase in both total and IRS-1-associated p85alpha following dexamethasone treatment, IRS-1-associated p110 catalytic subunit and PI 3-kinase activity were decreased by approximately 50%. |
| 1907 | 9054447 | Thus, dexamethasone induces a specific increase in expression of the p85alpha regulatory subunit that is not associated with a coordinate increase in the p110 catalytic subunit of PI 3-kinase. |
| 1908 | 9054447 | As a consequence, in dexamethasone-treated cells, p85alpha that is not coupled with p110 competes with both p85alpha.p110 and p85beta.p110 complexes for association with IRS-1, leading to increased p85alpha but decreased p85beta, p110, and PI 3-kinase activity in IRS-1 immunoprecipitates. |
| 1909 | 9054447 | Specific increase in p85alpha expression in response to dexamethasone is associated with inhibition of insulin-like growth factor-I stimulated phosphatidylinositol 3-kinase activity in cultured muscle cells. |
| 1910 | 9054447 | The stimulation of phosphatidylinositol (PI) 3-kinase by insulin-like growth factor I (IGF-I) in L6 cultured skeletal muscle cells is inhibited by the glucocorticoid dexamethasone. |
| 1911 | 9054447 | The objective of this study was to investigate the mechanism of dexamethasone action by determining its effects on the expression of the p85alpha and p85beta regulatory subunit isoforms of PI 3-kinase, their coupling with the p110 catalytic subunit, and their association with insulin receptor substrate 1 (IRS-1) in response to IGF-I stimulation. |
| 1912 | 9054447 | Dexamethasone induced a 300% increase in p85alpha protein content in the L6 cultured myoblast cell line, whereas it increased p110 content by only 38% and had no effect on p85beta. |
| 1913 | 9054447 | Stimulation with IGF-I induced the association of p85alpha and p85beta with IRS-1, and this was accompanied by increased amounts of the p110 catalytic subunit and markedly increased PI 3-kinase activity in IRS-1 immunoprecipitates. |
| 1914 | 9054447 | In cells treated with dexamethasone, greater amounts of p85alpha and lower amounts of p85beta, respectively, were found in IRS-1 immunoprecipitates, such that the alpha/beta ratio was markedly higher than in control cells. |
| 1915 | 9054447 | In spite of the increase in both total and IRS-1-associated p85alpha following dexamethasone treatment, IRS-1-associated p110 catalytic subunit and PI 3-kinase activity were decreased by approximately 50%. |
| 1916 | 9054447 | Thus, dexamethasone induces a specific increase in expression of the p85alpha regulatory subunit that is not associated with a coordinate increase in the p110 catalytic subunit of PI 3-kinase. |
| 1917 | 9054447 | As a consequence, in dexamethasone-treated cells, p85alpha that is not coupled with p110 competes with both p85alpha.p110 and p85beta.p110 complexes for association with IRS-1, leading to increased p85alpha but decreased p85beta, p110, and PI 3-kinase activity in IRS-1 immunoprecipitates. |
| 1918 | 9054447 | Specific increase in p85alpha expression in response to dexamethasone is associated with inhibition of insulin-like growth factor-I stimulated phosphatidylinositol 3-kinase activity in cultured muscle cells. |
| 1919 | 9054447 | The stimulation of phosphatidylinositol (PI) 3-kinase by insulin-like growth factor I (IGF-I) in L6 cultured skeletal muscle cells is inhibited by the glucocorticoid dexamethasone. |
| 1920 | 9054447 | The objective of this study was to investigate the mechanism of dexamethasone action by determining its effects on the expression of the p85alpha and p85beta regulatory subunit isoforms of PI 3-kinase, their coupling with the p110 catalytic subunit, and their association with insulin receptor substrate 1 (IRS-1) in response to IGF-I stimulation. |
| 1921 | 9054447 | Dexamethasone induced a 300% increase in p85alpha protein content in the L6 cultured myoblast cell line, whereas it increased p110 content by only 38% and had no effect on p85beta. |
| 1922 | 9054447 | Stimulation with IGF-I induced the association of p85alpha and p85beta with IRS-1, and this was accompanied by increased amounts of the p110 catalytic subunit and markedly increased PI 3-kinase activity in IRS-1 immunoprecipitates. |
| 1923 | 9054447 | In cells treated with dexamethasone, greater amounts of p85alpha and lower amounts of p85beta, respectively, were found in IRS-1 immunoprecipitates, such that the alpha/beta ratio was markedly higher than in control cells. |
| 1924 | 9054447 | In spite of the increase in both total and IRS-1-associated p85alpha following dexamethasone treatment, IRS-1-associated p110 catalytic subunit and PI 3-kinase activity were decreased by approximately 50%. |
| 1925 | 9054447 | Thus, dexamethasone induces a specific increase in expression of the p85alpha regulatory subunit that is not associated with a coordinate increase in the p110 catalytic subunit of PI 3-kinase. |
| 1926 | 9054447 | As a consequence, in dexamethasone-treated cells, p85alpha that is not coupled with p110 competes with both p85alpha.p110 and p85beta.p110 complexes for association with IRS-1, leading to increased p85alpha but decreased p85beta, p110, and PI 3-kinase activity in IRS-1 immunoprecipitates. |
| 1927 | 9059762 | Studies of genes involved in insulin secretion or insulin action have been successful to a certain extent by showing the implication of the IRS-1 gene, the Rad gene, the glucagon receptor gene, or the sulfonylurea receptor (SUR) gene (among others) in a low percentage of cases of NIDDM in particular populations. |
| 1928 | 9062343 | Development of non-insulin-dependent diabetes mellitus in the double knockout mice with disruption of insulin receptor substrate-1 and beta cell glucokinase genes. |
| 1929 | 9062343 | Heterozygous mice with beta cell glucokinase (GK) gene knockout showed impaired glucose tolerance due to decreased insulin secretion to glucose. |
| 1930 | 9062343 | To elucidate the interplay between insulin resistance and insulin secretory defect for the development of NIDDM, we generated double knockout mice with disruption of IRS-1 and beta cell GK genes by crossing the mice with each of the single gene knockout. |
| 1931 | 9062343 | The double knockout mice showed fasting hyperinsulinemia and selective hyperplasia of the beta cells as the IRS-1 knockout mice (fasting insulin levels: 0.38 +/- 0.30 [double knockout], 0.35 +/- 0.27 [IRS-1 knockout] versus 0.25 +/- 0.12 [wild type] ng/ml) (proportion of areas of insulin-positive cells to the pancreas: 1.18 +/- 0.68%; P < 0.01 [double knockout], 1.20 +/- 0.93%; P < 0.05 [IRS-1 knockout] versus 0.54 +/- 0.26% [wild type]), but impaired insulin secretion to glucose (the ratio of increment of insulin to that of glucose during the first 30 min after load: 31 [double knockout] versus 163 [wild type] or 183 [IRS-1 knockout] ng insulin/mg glucose x 10(3)). |
| 1932 | 9062343 | Development of non-insulin-dependent diabetes mellitus in the double knockout mice with disruption of insulin receptor substrate-1 and beta cell glucokinase genes. |
| 1933 | 9062343 | Heterozygous mice with beta cell glucokinase (GK) gene knockout showed impaired glucose tolerance due to decreased insulin secretion to glucose. |
| 1934 | 9062343 | To elucidate the interplay between insulin resistance and insulin secretory defect for the development of NIDDM, we generated double knockout mice with disruption of IRS-1 and beta cell GK genes by crossing the mice with each of the single gene knockout. |
| 1935 | 9062343 | The double knockout mice showed fasting hyperinsulinemia and selective hyperplasia of the beta cells as the IRS-1 knockout mice (fasting insulin levels: 0.38 +/- 0.30 [double knockout], 0.35 +/- 0.27 [IRS-1 knockout] versus 0.25 +/- 0.12 [wild type] ng/ml) (proportion of areas of insulin-positive cells to the pancreas: 1.18 +/- 0.68%; P < 0.01 [double knockout], 1.20 +/- 0.93%; P < 0.05 [IRS-1 knockout] versus 0.54 +/- 0.26% [wild type]), but impaired insulin secretion to glucose (the ratio of increment of insulin to that of glucose during the first 30 min after load: 31 [double knockout] versus 163 [wild type] or 183 [IRS-1 knockout] ng insulin/mg glucose x 10(3)). |
| 1936 | 9062343 | Development of non-insulin-dependent diabetes mellitus in the double knockout mice with disruption of insulin receptor substrate-1 and beta cell glucokinase genes. |
| 1937 | 9062343 | Heterozygous mice with beta cell glucokinase (GK) gene knockout showed impaired glucose tolerance due to decreased insulin secretion to glucose. |
| 1938 | 9062343 | To elucidate the interplay between insulin resistance and insulin secretory defect for the development of NIDDM, we generated double knockout mice with disruption of IRS-1 and beta cell GK genes by crossing the mice with each of the single gene knockout. |
| 1939 | 9062343 | The double knockout mice showed fasting hyperinsulinemia and selective hyperplasia of the beta cells as the IRS-1 knockout mice (fasting insulin levels: 0.38 +/- 0.30 [double knockout], 0.35 +/- 0.27 [IRS-1 knockout] versus 0.25 +/- 0.12 [wild type] ng/ml) (proportion of areas of insulin-positive cells to the pancreas: 1.18 +/- 0.68%; P < 0.01 [double knockout], 1.20 +/- 0.93%; P < 0.05 [IRS-1 knockout] versus 0.54 +/- 0.26% [wild type]), but impaired insulin secretion to glucose (the ratio of increment of insulin to that of glucose during the first 30 min after load: 31 [double knockout] versus 163 [wild type] or 183 [IRS-1 knockout] ng insulin/mg glucose x 10(3)). |
| 1940 | 9082023 | Glucose-induced insulin secretion is impaired and insulin-induced phosphorylation of the insulin receptor and insulin receptor substrate-1 are increased in protein-deficient rats. |
| 1941 | 9082023 | Immunoblotting and immunoprecipitation were used to study the phosphorylation of the insulin receptor and the insulin receptor substrate-1 as well as the insulin receptor substrate-1-p85 subunit of phosphatidylinositol 3-kinase association in response to insulin. |
| 1942 | 9082023 | Therefore, we conclude that a decreased glucose-induced insulin secretion in pancreatic islets from protein-malnourished rats is responsible, at least in part, for an increased phosphorylation of the insulin receptor, insulin receptor substrate-1 and its association with phosphatidylinositol 3-kinase. |
| 1943 | 9082023 | Glucose-induced insulin secretion is impaired and insulin-induced phosphorylation of the insulin receptor and insulin receptor substrate-1 are increased in protein-deficient rats. |
| 1944 | 9082023 | Immunoblotting and immunoprecipitation were used to study the phosphorylation of the insulin receptor and the insulin receptor substrate-1 as well as the insulin receptor substrate-1-p85 subunit of phosphatidylinositol 3-kinase association in response to insulin. |
| 1945 | 9082023 | Therefore, we conclude that a decreased glucose-induced insulin secretion in pancreatic islets from protein-malnourished rats is responsible, at least in part, for an increased phosphorylation of the insulin receptor, insulin receptor substrate-1 and its association with phosphatidylinositol 3-kinase. |
| 1946 | 9082023 | Glucose-induced insulin secretion is impaired and insulin-induced phosphorylation of the insulin receptor and insulin receptor substrate-1 are increased in protein-deficient rats. |
| 1947 | 9082023 | Immunoblotting and immunoprecipitation were used to study the phosphorylation of the insulin receptor and the insulin receptor substrate-1 as well as the insulin receptor substrate-1-p85 subunit of phosphatidylinositol 3-kinase association in response to insulin. |
| 1948 | 9082023 | Therefore, we conclude that a decreased glucose-induced insulin secretion in pancreatic islets from protein-malnourished rats is responsible, at least in part, for an increased phosphorylation of the insulin receptor, insulin receptor substrate-1 and its association with phosphatidylinositol 3-kinase. |
| 1949 | 9108124 | Insulin receptor substrate (IRS) 1 is reduced and IRS-2 is the main docking protein for phosphatidylinositol 3-kinase in adipocytes from subjects with non-insulin-dependent diabetes mellitus. |
| 1950 | 9108124 | The large docking protein IRS-1 is a major substrate for the insulin receptor and other tyrosine kinases. |
| 1951 | 9108124 | Gene disruption of IRS-1 in mice is associated with an impaired insulin-stimulated glucose disposal in vivo and glucose transport in vitro, but the survival of the animals and residual insulin sensitivity is dependent on the presence of the alternative docking protein IRS-2. |
| 1952 | 9108124 | We examined the expression and function of IRS-1 and IRS-2 in adipocytes from healthy and diabetic individuals. |
| 1953 | 9108124 | Cells from subjects with non-insulin-dependent diabetes mellitus (NIDDM), but not with insulin-dependent diabetes mellitus, had an impaired insulin effect and a marked reduction (70 +/- 6%) in the expression of IRS-1 protein, whereas IRS-2 was unchanged. |
| 1954 | 9108124 | In normal cells, IRS-1 was the main docking protein for the binding and activation of insulin-stimulated PI 3-kinase; IRS-2 was also functional but required a higher insulin concentration for a similar binding and activation of PI 3-kinase. |
| 1955 | 9108124 | In contrast in NIDDM cells with a low IRS-1 content, IRS-2 became the main docking protein. |
| 1956 | 9108124 | Insulin receptor substrate (IRS) 1 is reduced and IRS-2 is the main docking protein for phosphatidylinositol 3-kinase in adipocytes from subjects with non-insulin-dependent diabetes mellitus. |
| 1957 | 9108124 | The large docking protein IRS-1 is a major substrate for the insulin receptor and other tyrosine kinases. |
| 1958 | 9108124 | Gene disruption of IRS-1 in mice is associated with an impaired insulin-stimulated glucose disposal in vivo and glucose transport in vitro, but the survival of the animals and residual insulin sensitivity is dependent on the presence of the alternative docking protein IRS-2. |
| 1959 | 9108124 | We examined the expression and function of IRS-1 and IRS-2 in adipocytes from healthy and diabetic individuals. |
| 1960 | 9108124 | Cells from subjects with non-insulin-dependent diabetes mellitus (NIDDM), but not with insulin-dependent diabetes mellitus, had an impaired insulin effect and a marked reduction (70 +/- 6%) in the expression of IRS-1 protein, whereas IRS-2 was unchanged. |
| 1961 | 9108124 | In normal cells, IRS-1 was the main docking protein for the binding and activation of insulin-stimulated PI 3-kinase; IRS-2 was also functional but required a higher insulin concentration for a similar binding and activation of PI 3-kinase. |
| 1962 | 9108124 | In contrast in NIDDM cells with a low IRS-1 content, IRS-2 became the main docking protein. |
| 1963 | 9108124 | Insulin receptor substrate (IRS) 1 is reduced and IRS-2 is the main docking protein for phosphatidylinositol 3-kinase in adipocytes from subjects with non-insulin-dependent diabetes mellitus. |
| 1964 | 9108124 | The large docking protein IRS-1 is a major substrate for the insulin receptor and other tyrosine kinases. |
| 1965 | 9108124 | Gene disruption of IRS-1 in mice is associated with an impaired insulin-stimulated glucose disposal in vivo and glucose transport in vitro, but the survival of the animals and residual insulin sensitivity is dependent on the presence of the alternative docking protein IRS-2. |
| 1966 | 9108124 | We examined the expression and function of IRS-1 and IRS-2 in adipocytes from healthy and diabetic individuals. |
| 1967 | 9108124 | Cells from subjects with non-insulin-dependent diabetes mellitus (NIDDM), but not with insulin-dependent diabetes mellitus, had an impaired insulin effect and a marked reduction (70 +/- 6%) in the expression of IRS-1 protein, whereas IRS-2 was unchanged. |
| 1968 | 9108124 | In normal cells, IRS-1 was the main docking protein for the binding and activation of insulin-stimulated PI 3-kinase; IRS-2 was also functional but required a higher insulin concentration for a similar binding and activation of PI 3-kinase. |
| 1969 | 9108124 | In contrast in NIDDM cells with a low IRS-1 content, IRS-2 became the main docking protein. |
| 1970 | 9108124 | Insulin receptor substrate (IRS) 1 is reduced and IRS-2 is the main docking protein for phosphatidylinositol 3-kinase in adipocytes from subjects with non-insulin-dependent diabetes mellitus. |
| 1971 | 9108124 | The large docking protein IRS-1 is a major substrate for the insulin receptor and other tyrosine kinases. |
| 1972 | 9108124 | Gene disruption of IRS-1 in mice is associated with an impaired insulin-stimulated glucose disposal in vivo and glucose transport in vitro, but the survival of the animals and residual insulin sensitivity is dependent on the presence of the alternative docking protein IRS-2. |
| 1973 | 9108124 | We examined the expression and function of IRS-1 and IRS-2 in adipocytes from healthy and diabetic individuals. |
| 1974 | 9108124 | Cells from subjects with non-insulin-dependent diabetes mellitus (NIDDM), but not with insulin-dependent diabetes mellitus, had an impaired insulin effect and a marked reduction (70 +/- 6%) in the expression of IRS-1 protein, whereas IRS-2 was unchanged. |
| 1975 | 9108124 | In normal cells, IRS-1 was the main docking protein for the binding and activation of insulin-stimulated PI 3-kinase; IRS-2 was also functional but required a higher insulin concentration for a similar binding and activation of PI 3-kinase. |
| 1976 | 9108124 | In contrast in NIDDM cells with a low IRS-1 content, IRS-2 became the main docking protein. |
| 1977 | 9108124 | Insulin receptor substrate (IRS) 1 is reduced and IRS-2 is the main docking protein for phosphatidylinositol 3-kinase in adipocytes from subjects with non-insulin-dependent diabetes mellitus. |
| 1978 | 9108124 | The large docking protein IRS-1 is a major substrate for the insulin receptor and other tyrosine kinases. |
| 1979 | 9108124 | Gene disruption of IRS-1 in mice is associated with an impaired insulin-stimulated glucose disposal in vivo and glucose transport in vitro, but the survival of the animals and residual insulin sensitivity is dependent on the presence of the alternative docking protein IRS-2. |
| 1980 | 9108124 | We examined the expression and function of IRS-1 and IRS-2 in adipocytes from healthy and diabetic individuals. |
| 1981 | 9108124 | Cells from subjects with non-insulin-dependent diabetes mellitus (NIDDM), but not with insulin-dependent diabetes mellitus, had an impaired insulin effect and a marked reduction (70 +/- 6%) in the expression of IRS-1 protein, whereas IRS-2 was unchanged. |
| 1982 | 9108124 | In normal cells, IRS-1 was the main docking protein for the binding and activation of insulin-stimulated PI 3-kinase; IRS-2 was also functional but required a higher insulin concentration for a similar binding and activation of PI 3-kinase. |
| 1983 | 9108124 | In contrast in NIDDM cells with a low IRS-1 content, IRS-2 became the main docking protein. |
| 1984 | 9108124 | Insulin receptor substrate (IRS) 1 is reduced and IRS-2 is the main docking protein for phosphatidylinositol 3-kinase in adipocytes from subjects with non-insulin-dependent diabetes mellitus. |
| 1985 | 9108124 | The large docking protein IRS-1 is a major substrate for the insulin receptor and other tyrosine kinases. |
| 1986 | 9108124 | Gene disruption of IRS-1 in mice is associated with an impaired insulin-stimulated glucose disposal in vivo and glucose transport in vitro, but the survival of the animals and residual insulin sensitivity is dependent on the presence of the alternative docking protein IRS-2. |
| 1987 | 9108124 | We examined the expression and function of IRS-1 and IRS-2 in adipocytes from healthy and diabetic individuals. |
| 1988 | 9108124 | Cells from subjects with non-insulin-dependent diabetes mellitus (NIDDM), but not with insulin-dependent diabetes mellitus, had an impaired insulin effect and a marked reduction (70 +/- 6%) in the expression of IRS-1 protein, whereas IRS-2 was unchanged. |
| 1989 | 9108124 | In normal cells, IRS-1 was the main docking protein for the binding and activation of insulin-stimulated PI 3-kinase; IRS-2 was also functional but required a higher insulin concentration for a similar binding and activation of PI 3-kinase. |
| 1990 | 9108124 | In contrast in NIDDM cells with a low IRS-1 content, IRS-2 became the main docking protein. |
| 1991 | 9162610 | Two mutations of the IRS-1 gene (Gly(972)Arg and Ala(513)Pro) have been described, although their roles in the development of insulin resistance and non-insulin-dependent diabetes mellitus (NIDDM) remain controversial. |
| 1992 | 9166661 | Impact of natural IRS-1 mutations on insulin signals: mutations of IRS-1 in the PTB domain and near SH2 protein binding sites result in impaired function at different steps of IRS-1 signaling. |
| 1993 | 9166661 | In this study, we have examined the impact of three natural IRS-1 mutations identified in NIDDM patients (G971R, P170R, and M209T) on insulin signaling. |
| 1994 | 9166661 | G971R is located near src homology 2 protein binding sites, and P170R and M209T are located in the phosphotyrosine binding domain of IRS-1. 32D-IR cells, stably overexpressing human insulin receptor, were transfected with wild-type human IRS-1 cDNA (WT) or three mutant IRS-1 cDNAs and analyzed. |
| 1995 | 9166661 | Upon insulin stimulation, cells expressing G971R showed a 39% decrease (P < 0.005) in phosphatidylinositol 3-kinase (PI 3-kinase) activity, a 43% decrease (P < 0.01) in binding of the 85-kDa regulatory subunit of PI 3-kinase, and a 22% decrease (P < 0.05) in mitogen-activated protein kinase activity compared with those expressing WT. |
| 1996 | 9166661 | After insulin stimulation, cells expressing P170R and M209T showed significant decreases in IRS-1 phosphorylation (37 and 42%, respectively; both P < 0.05) and in IRS-1 binding to the insulin receptor (48 and 53%, respectively; P < 0.01) compared with WT. |
| 1997 | 9166661 | G971R showed no changes in IRS-1 phosphorylation and in IRS-1 binding to the insulin receptor compared with WT. |
| 1998 | 9166661 | These data suggest that the impaired mitogenic response of P170R and M209T was mainly due to reduced binding to the insulin receptor, whereas the impaired response of G971R was mainly due to reduced association with PI 3-kinase p85. |
| 1999 | 9166661 | Impact of natural IRS-1 mutations on insulin signals: mutations of IRS-1 in the PTB domain and near SH2 protein binding sites result in impaired function at different steps of IRS-1 signaling. |
| 2000 | 9166661 | In this study, we have examined the impact of three natural IRS-1 mutations identified in NIDDM patients (G971R, P170R, and M209T) on insulin signaling. |
| 2001 | 9166661 | G971R is located near src homology 2 protein binding sites, and P170R and M209T are located in the phosphotyrosine binding domain of IRS-1. 32D-IR cells, stably overexpressing human insulin receptor, were transfected with wild-type human IRS-1 cDNA (WT) or three mutant IRS-1 cDNAs and analyzed. |
| 2002 | 9166661 | Upon insulin stimulation, cells expressing G971R showed a 39% decrease (P < 0.005) in phosphatidylinositol 3-kinase (PI 3-kinase) activity, a 43% decrease (P < 0.01) in binding of the 85-kDa regulatory subunit of PI 3-kinase, and a 22% decrease (P < 0.05) in mitogen-activated protein kinase activity compared with those expressing WT. |
| 2003 | 9166661 | After insulin stimulation, cells expressing P170R and M209T showed significant decreases in IRS-1 phosphorylation (37 and 42%, respectively; both P < 0.05) and in IRS-1 binding to the insulin receptor (48 and 53%, respectively; P < 0.01) compared with WT. |
| 2004 | 9166661 | G971R showed no changes in IRS-1 phosphorylation and in IRS-1 binding to the insulin receptor compared with WT. |
| 2005 | 9166661 | These data suggest that the impaired mitogenic response of P170R and M209T was mainly due to reduced binding to the insulin receptor, whereas the impaired response of G971R was mainly due to reduced association with PI 3-kinase p85. |
| 2006 | 9166661 | Impact of natural IRS-1 mutations on insulin signals: mutations of IRS-1 in the PTB domain and near SH2 protein binding sites result in impaired function at different steps of IRS-1 signaling. |
| 2007 | 9166661 | In this study, we have examined the impact of three natural IRS-1 mutations identified in NIDDM patients (G971R, P170R, and M209T) on insulin signaling. |
| 2008 | 9166661 | G971R is located near src homology 2 protein binding sites, and P170R and M209T are located in the phosphotyrosine binding domain of IRS-1. 32D-IR cells, stably overexpressing human insulin receptor, were transfected with wild-type human IRS-1 cDNA (WT) or three mutant IRS-1 cDNAs and analyzed. |
| 2009 | 9166661 | Upon insulin stimulation, cells expressing G971R showed a 39% decrease (P < 0.005) in phosphatidylinositol 3-kinase (PI 3-kinase) activity, a 43% decrease (P < 0.01) in binding of the 85-kDa regulatory subunit of PI 3-kinase, and a 22% decrease (P < 0.05) in mitogen-activated protein kinase activity compared with those expressing WT. |
| 2010 | 9166661 | After insulin stimulation, cells expressing P170R and M209T showed significant decreases in IRS-1 phosphorylation (37 and 42%, respectively; both P < 0.05) and in IRS-1 binding to the insulin receptor (48 and 53%, respectively; P < 0.01) compared with WT. |
| 2011 | 9166661 | G971R showed no changes in IRS-1 phosphorylation and in IRS-1 binding to the insulin receptor compared with WT. |
| 2012 | 9166661 | These data suggest that the impaired mitogenic response of P170R and M209T was mainly due to reduced binding to the insulin receptor, whereas the impaired response of G971R was mainly due to reduced association with PI 3-kinase p85. |
| 2013 | 9166661 | Impact of natural IRS-1 mutations on insulin signals: mutations of IRS-1 in the PTB domain and near SH2 protein binding sites result in impaired function at different steps of IRS-1 signaling. |
| 2014 | 9166661 | In this study, we have examined the impact of three natural IRS-1 mutations identified in NIDDM patients (G971R, P170R, and M209T) on insulin signaling. |
| 2015 | 9166661 | G971R is located near src homology 2 protein binding sites, and P170R and M209T are located in the phosphotyrosine binding domain of IRS-1. 32D-IR cells, stably overexpressing human insulin receptor, were transfected with wild-type human IRS-1 cDNA (WT) or three mutant IRS-1 cDNAs and analyzed. |
| 2016 | 9166661 | Upon insulin stimulation, cells expressing G971R showed a 39% decrease (P < 0.005) in phosphatidylinositol 3-kinase (PI 3-kinase) activity, a 43% decrease (P < 0.01) in binding of the 85-kDa regulatory subunit of PI 3-kinase, and a 22% decrease (P < 0.05) in mitogen-activated protein kinase activity compared with those expressing WT. |
| 2017 | 9166661 | After insulin stimulation, cells expressing P170R and M209T showed significant decreases in IRS-1 phosphorylation (37 and 42%, respectively; both P < 0.05) and in IRS-1 binding to the insulin receptor (48 and 53%, respectively; P < 0.01) compared with WT. |
| 2018 | 9166661 | G971R showed no changes in IRS-1 phosphorylation and in IRS-1 binding to the insulin receptor compared with WT. |
| 2019 | 9166661 | These data suggest that the impaired mitogenic response of P170R and M209T was mainly due to reduced binding to the insulin receptor, whereas the impaired response of G971R was mainly due to reduced association with PI 3-kinase p85. |
| 2020 | 9166661 | Impact of natural IRS-1 mutations on insulin signals: mutations of IRS-1 in the PTB domain and near SH2 protein binding sites result in impaired function at different steps of IRS-1 signaling. |
| 2021 | 9166661 | In this study, we have examined the impact of three natural IRS-1 mutations identified in NIDDM patients (G971R, P170R, and M209T) on insulin signaling. |
| 2022 | 9166661 | G971R is located near src homology 2 protein binding sites, and P170R and M209T are located in the phosphotyrosine binding domain of IRS-1. 32D-IR cells, stably overexpressing human insulin receptor, were transfected with wild-type human IRS-1 cDNA (WT) or three mutant IRS-1 cDNAs and analyzed. |
| 2023 | 9166661 | Upon insulin stimulation, cells expressing G971R showed a 39% decrease (P < 0.005) in phosphatidylinositol 3-kinase (PI 3-kinase) activity, a 43% decrease (P < 0.01) in binding of the 85-kDa regulatory subunit of PI 3-kinase, and a 22% decrease (P < 0.05) in mitogen-activated protein kinase activity compared with those expressing WT. |
| 2024 | 9166661 | After insulin stimulation, cells expressing P170R and M209T showed significant decreases in IRS-1 phosphorylation (37 and 42%, respectively; both P < 0.05) and in IRS-1 binding to the insulin receptor (48 and 53%, respectively; P < 0.01) compared with WT. |
| 2025 | 9166661 | G971R showed no changes in IRS-1 phosphorylation and in IRS-1 binding to the insulin receptor compared with WT. |
| 2026 | 9166661 | These data suggest that the impaired mitogenic response of P170R and M209T was mainly due to reduced binding to the insulin receptor, whereas the impaired response of G971R was mainly due to reduced association with PI 3-kinase p85. |
| 2027 | 9202243 | Tyrosine residues in the C-terminal domain of the insulin-like growth factor-I receptor mediate mitogenic and tumorigenic signals. |
| 2028 | 9202243 | We investigated cellular proliferation, the transforming activity, and activation of known signal transduction pathways in NIH-3T3 cells stably expressing insulin-like growth factor-I receptors (IGF-IRs) with amino acid substitutions in the carboxy(C)-terminal domain. |
| 2029 | 9202243 | The IsY clones lost the transforming ability of the wild type IGF-IR, whereas DBY clones formed colonies. |
| 2030 | 9202243 | IGF-I-stimulated autophosphorylation of the IGF-IR and tyrosine phosphorylation of IRS-1 and SHC, known substrates in the IGF-IR signal transduction pathway, were studied. |
| 2031 | 9202243 | Furthermore, the mutated IGF-IRs did not alter Grb2 association with phosphorylated IRS-1 and SHC. |
| 2032 | 9202243 | IGF-I stimulation of Crk-II phosphorylation, a novel substrate of the IGF-IR, was similar in cells expressing mutated and wild-type IGF-IRs. |
| 2033 | 9202243 | Tyrosine residues in the C-terminal domain of the insulin-like growth factor-I receptor mediate mitogenic and tumorigenic signals. |
| 2034 | 9202243 | We investigated cellular proliferation, the transforming activity, and activation of known signal transduction pathways in NIH-3T3 cells stably expressing insulin-like growth factor-I receptors (IGF-IRs) with amino acid substitutions in the carboxy(C)-terminal domain. |
| 2035 | 9202243 | The IsY clones lost the transforming ability of the wild type IGF-IR, whereas DBY clones formed colonies. |
| 2036 | 9202243 | IGF-I-stimulated autophosphorylation of the IGF-IR and tyrosine phosphorylation of IRS-1 and SHC, known substrates in the IGF-IR signal transduction pathway, were studied. |
| 2037 | 9202243 | Furthermore, the mutated IGF-IRs did not alter Grb2 association with phosphorylated IRS-1 and SHC. |
| 2038 | 9202243 | IGF-I stimulation of Crk-II phosphorylation, a novel substrate of the IGF-IR, was similar in cells expressing mutated and wild-type IGF-IRs. |
| 2039 | 9204766 | The discovery of the first intracellular substrate for insulin, IRS-1, redirected the field of diabetes research and has led to many important advances in our understanding of insulin action. |
| 2040 | 9204766 | Recent work has also identified other structurally similar molecules, including IRS-2, the Drosophila protein, DOS, and the Grb2-binding protein, Gab1, suggesting that this intracellular signalling strategy is conserved evolutionarily and is utilized by an expanding number of receptor systems. |
| 2041 | 9204876 | During insulin stimulation, p85 associated with pp60(IRS3) more rapidly than with IRS-1 or IRS-2. |
| 2042 | 9204876 | In mice lacking IRS-1, p85 associated more strongly with pp60(IRS3) than with IRS-2, suggesting that pp60(IRS3) provides an alternate pathway in these cells. |
| 2043 | 9204876 | Synthetic peptides containing two phosphorylated YMPM motifs displace pp60(IRS3) and IRS-1 from alphap85 immune complexes, suggesting that pp60(IRS3), like IRS-1, engages both SH2 domains in p85. |
| 2044 | 9204876 | During insulin stimulation, p85 associated with pp60(IRS3) more rapidly than with IRS-1 or IRS-2. |
| 2045 | 9204876 | In mice lacking IRS-1, p85 associated more strongly with pp60(IRS3) than with IRS-2, suggesting that pp60(IRS3) provides an alternate pathway in these cells. |
| 2046 | 9204876 | Synthetic peptides containing two phosphorylated YMPM motifs displace pp60(IRS3) and IRS-1 from alphap85 immune complexes, suggesting that pp60(IRS3), like IRS-1, engages both SH2 domains in p85. |
| 2047 | 9204876 | During insulin stimulation, p85 associated with pp60(IRS3) more rapidly than with IRS-1 or IRS-2. |
| 2048 | 9204876 | In mice lacking IRS-1, p85 associated more strongly with pp60(IRS3) than with IRS-2, suggesting that pp60(IRS3) provides an alternate pathway in these cells. |
| 2049 | 9204876 | Synthetic peptides containing two phosphorylated YMPM motifs displace pp60(IRS3) and IRS-1 from alphap85 immune complexes, suggesting that pp60(IRS3), like IRS-1, engages both SH2 domains in p85. |
| 2050 | 9227454 | Growth hormone-induced insulin resistance: role of the insulin receptor, IRS-1, GLUT-1, and GLUT-4. |
| 2051 | 9227454 | Similarly, insulin-stimulated phosphorylation of insulin receptor substrate-1 (IRS-1) was decreased 25% by GH, but the abundance of IRS-1 was not affected. |
| 2052 | 9227454 | GH decreased basal GLUT-1 abundance in the low-density microsome and plasma membrane fractions of epididymal adipocytes by 50 and 42%, respectively, but decreased basal GLUT-4 abundance only in the low-density microsome fraction by 24%. |
| 2053 | 9227454 | Growth hormone-induced insulin resistance: role of the insulin receptor, IRS-1, GLUT-1, and GLUT-4. |
| 2054 | 9227454 | Similarly, insulin-stimulated phosphorylation of insulin receptor substrate-1 (IRS-1) was decreased 25% by GH, but the abundance of IRS-1 was not affected. |
| 2055 | 9227454 | GH decreased basal GLUT-1 abundance in the low-density microsome and plasma membrane fractions of epididymal adipocytes by 50 and 42%, respectively, but decreased basal GLUT-4 abundance only in the low-density microsome fraction by 24%. |
| 2056 | 9248696 | By utilizing the insulin receptor substrate (IRS)-proteins (IRS-1 and IRS-2), the insulin signal can be amplified or attenuated independently of insulin binding and tyrosine kinase activity, providing an extensible mechanism for signal transmission in multiple cellular backgrounds. |
| 2057 | 9252480 | Isolated ventricular cardiomyocytes obtained from lean and genetically (fa/fa) obese Zucker rats were used to correlate alterations of insulin-induced glucose transport activation and GLUT-4 translocation to possible defects of the insulin signaling cascade. |
| 2058 | 9252480 | Maximal stimulation with insulin was found to produce an unaltered translocation of GLUT-4 to the plasma membrane (4.2- and 3.7-fold increase for lean and obese rats, respectively). |
| 2059 | 9252480 | The reduced sensitivity of glucose transport at 8 x 10(-11) M insulin was then found to correlate to a completely blunted response of IRS-1-associated phosphatidylinositol 3-kinase activity in cardiomyocytes from obese rats. |
| 2060 | 9252480 | Those data show that cardiac insulin resistance of obesity involves defective insulin signaling at low concentrations of the hormone, whereas GLUT-4 translocation is fully operative in the isolated cell. |
| 2061 | 9252480 | It is suggested that hyperphosphorylation of IRS-1 may significantly contribute to the pathogenesis of insulin resistance in the heart. |
| 2062 | 9293959 | Isolated adult rat ventricular cardiomyocytes were used to investigate the effects of contractile activity on 3-O-methylglucose transport on the translocation of the insulin-responsive glucose transporter GLUT4, and the possible activation of intermediates of the insulin signaling cascade. |
| 2063 | 9293959 | Subcellular fractionation and immunoblotting analysis of GLUT4 distribution indicated that both contraction and insulin induced an identical increase (8-9-fold) of GLUT4 in the plasma membrane with a concomitant decrease (one third) in the microsomal fraction. |
| 2064 | 9293959 | However, immunoprecipitation of insulin receptor substrate-1 (IRS-1) showed that the p85 regulatory subunit of phosphatidylinositol-3 kinase did not associate with IRS-1 upon contraction but with a marked stimulated association in response to insulin. |
| 2065 | 9293959 | These data suggest the existence of identical insulin- and contraction-recruitable GLUT4 pool. |
| 2066 | 9293959 | Contraction-induced signaling may use a limited part of the insulin-signaling cascade, possibly involving IRS-2. |
| 2067 | 9293959 | We further suggest that insulin resistance at the level of IRS-1 will not affect contraction-regulated glucose uptake by the heart. |
| 2068 | 9293959 | Isolated adult rat ventricular cardiomyocytes were used to investigate the effects of contractile activity on 3-O-methylglucose transport on the translocation of the insulin-responsive glucose transporter GLUT4, and the possible activation of intermediates of the insulin signaling cascade. |
| 2069 | 9293959 | Subcellular fractionation and immunoblotting analysis of GLUT4 distribution indicated that both contraction and insulin induced an identical increase (8-9-fold) of GLUT4 in the plasma membrane with a concomitant decrease (one third) in the microsomal fraction. |
| 2070 | 9293959 | However, immunoprecipitation of insulin receptor substrate-1 (IRS-1) showed that the p85 regulatory subunit of phosphatidylinositol-3 kinase did not associate with IRS-1 upon contraction but with a marked stimulated association in response to insulin. |
| 2071 | 9293959 | These data suggest the existence of identical insulin- and contraction-recruitable GLUT4 pool. |
| 2072 | 9293959 | Contraction-induced signaling may use a limited part of the insulin-signaling cascade, possibly involving IRS-2. |
| 2073 | 9293959 | We further suggest that insulin resistance at the level of IRS-1 will not affect contraction-regulated glucose uptake by the heart. |
| 2074 | 9295312 | Following phosphorylation by the insulin receptor kinase, the insulin receptor substrates (IRS)-1 and IRS-2 bind to and activate several Src homology 2 (SH2) domain proteins. |
| 2075 | 9295312 | Western blot analysis of extracts of rat muscle demonstrated co-immunoprecipitation of both IRS-1 and IRS-2 with the skeletal muscle Ca2+-ATPase (SERCA1) and the cardiac muscle isoform (SERCA2). |
| 2076 | 9295312 | In primary cultures of aortic smooth muscle cells and C2C12 cells, the insulin-stimulated interaction between IRS proteins and SERCA1 and -2 was dose-dependent with a maximum induction at 100 nM insulin. |
| 2077 | 9295312 | This interaction was confirmed in a "pull down" experiment using a glutathione S-transferase fusion protein containing the C terminus of the human SERCA isoform and phosphorylated IRS-1 in vitro and could be blocked by a FLVRES-like domain peptide present in the human SERCA sequence. |
| 2078 | 9295312 | Affinity chromatography of phosphopeptide libraries using the glutathione S-transferase fusion protein of the C terminus of SERCA1 indicated a consensus sequence for binding of XpYGSS; this is identical to potential tyrosine phosphorylation sites at position 431 of human IRS-1 and at position 500 of human IRS-2. |
| 2079 | 9295312 | In streptozotocin diabetic rats the interaction between IRS proteins and SERCA1 in skeletal muscle and SERCA2 in cardiac muscle was significantly reduced. |
| 2080 | 9295312 | Following phosphorylation by the insulin receptor kinase, the insulin receptor substrates (IRS)-1 and IRS-2 bind to and activate several Src homology 2 (SH2) domain proteins. |
| 2081 | 9295312 | Western blot analysis of extracts of rat muscle demonstrated co-immunoprecipitation of both IRS-1 and IRS-2 with the skeletal muscle Ca2+-ATPase (SERCA1) and the cardiac muscle isoform (SERCA2). |
| 2082 | 9295312 | In primary cultures of aortic smooth muscle cells and C2C12 cells, the insulin-stimulated interaction between IRS proteins and SERCA1 and -2 was dose-dependent with a maximum induction at 100 nM insulin. |
| 2083 | 9295312 | This interaction was confirmed in a "pull down" experiment using a glutathione S-transferase fusion protein containing the C terminus of the human SERCA isoform and phosphorylated IRS-1 in vitro and could be blocked by a FLVRES-like domain peptide present in the human SERCA sequence. |
| 2084 | 9295312 | Affinity chromatography of phosphopeptide libraries using the glutathione S-transferase fusion protein of the C terminus of SERCA1 indicated a consensus sequence for binding of XpYGSS; this is identical to potential tyrosine phosphorylation sites at position 431 of human IRS-1 and at position 500 of human IRS-2. |
| 2085 | 9295312 | In streptozotocin diabetic rats the interaction between IRS proteins and SERCA1 in skeletal muscle and SERCA2 in cardiac muscle was significantly reduced. |
| 2086 | 9295312 | Following phosphorylation by the insulin receptor kinase, the insulin receptor substrates (IRS)-1 and IRS-2 bind to and activate several Src homology 2 (SH2) domain proteins. |
| 2087 | 9295312 | Western blot analysis of extracts of rat muscle demonstrated co-immunoprecipitation of both IRS-1 and IRS-2 with the skeletal muscle Ca2+-ATPase (SERCA1) and the cardiac muscle isoform (SERCA2). |
| 2088 | 9295312 | In primary cultures of aortic smooth muscle cells and C2C12 cells, the insulin-stimulated interaction between IRS proteins and SERCA1 and -2 was dose-dependent with a maximum induction at 100 nM insulin. |
| 2089 | 9295312 | This interaction was confirmed in a "pull down" experiment using a glutathione S-transferase fusion protein containing the C terminus of the human SERCA isoform and phosphorylated IRS-1 in vitro and could be blocked by a FLVRES-like domain peptide present in the human SERCA sequence. |
| 2090 | 9295312 | Affinity chromatography of phosphopeptide libraries using the glutathione S-transferase fusion protein of the C terminus of SERCA1 indicated a consensus sequence for binding of XpYGSS; this is identical to potential tyrosine phosphorylation sites at position 431 of human IRS-1 and at position 500 of human IRS-2. |
| 2091 | 9295312 | In streptozotocin diabetic rats the interaction between IRS proteins and SERCA1 in skeletal muscle and SERCA2 in cardiac muscle was significantly reduced. |
| 2092 | 9312188 | Thiazolidinediones block tumor necrosis factor-alpha-induced inhibition of insulin signaling. |
| 2093 | 9312188 | TNF-alpha has been shown to be an important mediator of insulin resistance linked to obesity. |
| 2094 | 9312188 | Here we show that TZDs have powerful effects on the ability of TNF-alpha to alter the most proximal steps of insulin signaling, including tyrosine phosphorylation of the insulin receptor and its major substrate, IRS-1, and activation of PI3-kinase. |
| 2095 | 9312188 | Troglitazone or pioglitazone essentially eliminate the reduction in tyrosine phosphorylation of IR and IRS-1 caused by TNF-alpha in fat cells, even at relatively high doses (25 ng/ml). |
| 2096 | 9312188 | The TZDs do not inhibit all TNF-alpha signaling in that the transcription factor NF-kB is still induced well. |
| 2097 | 9312188 | These data indicate that TZDs can specifically block certain actions of TNF-alpha related to insulin resistance, suggesting that this block may contribute to their antidiabetic actions. |
| 2098 | 9312188 | Thiazolidinediones block tumor necrosis factor-alpha-induced inhibition of insulin signaling. |
| 2099 | 9312188 | TNF-alpha has been shown to be an important mediator of insulin resistance linked to obesity. |
| 2100 | 9312188 | Here we show that TZDs have powerful effects on the ability of TNF-alpha to alter the most proximal steps of insulin signaling, including tyrosine phosphorylation of the insulin receptor and its major substrate, IRS-1, and activation of PI3-kinase. |
| 2101 | 9312188 | Troglitazone or pioglitazone essentially eliminate the reduction in tyrosine phosphorylation of IR and IRS-1 caused by TNF-alpha in fat cells, even at relatively high doses (25 ng/ml). |
| 2102 | 9312188 | The TZDs do not inhibit all TNF-alpha signaling in that the transcription factor NF-kB is still induced well. |
| 2103 | 9312188 | These data indicate that TZDs can specifically block certain actions of TNF-alpha related to insulin resistance, suggesting that this block may contribute to their antidiabetic actions. |
| 2104 | 9329383 | To identify molecular defects responsible for this disease, we tested the implication of 14 candidate genes coding for proteins involved either in insulin action, i.e. insulin receptor, insulin receptor substrate 1, insulin-like growth factor I receptor, diabetes-associated ras-like protein (Rad), and glycogen synthase, or in lipid metabolism, i.e. lipoprotein lipase; apolipoproteins CII, AII, and CIII; hepatic lipase; hormone-sensitive lipase; the beta 3-adrenergic receptor; leptin; and fatty acid-binding protein 2. |
| 2105 | 9346913 | Heterologous pleckstrin homology domains do not couple IRS-1 to the insulin receptor. |
| 2106 | 9346913 | Based on the hypothesis that PH domains may have a common function such as membrane targeting we tested the ability of PH domains from other signaling molecules to link IRS-1 to the insulin receptor. |
| 2107 | 9346913 | Chimeric IRS-1 proteins containing a homologous PH domain derived from other IRS proteins (IRS-2 or Gab-1) were tyrosine phosphorylated normally in response to insulin. |
| 2108 | 9346913 | In contrast, heterologous PH domains from the beta-adrenergic receptor kinase, phospholipase Cgamma, or spectrin failed to mediate tyrosine phosphorylation of chimeric IRS-1 proteins, even in cells expressing high levels of insulin receptor. |
| 2109 | 9346913 | Moreover, IRS-1 proteins containing heterologous PH domains did not bind phosphorylated NPEY motifs derived from the insulin receptor, suggesting that the presence of these structures interfered with the function of the adjacent PTB binding domain. |
| 2110 | 9346913 | Thus, tyrosine phosphorylation of IRS-1 by the insulin receptor specifically requires a PH domain derived from IRS proteins. |
| 2111 | 9346913 | Heterologous pleckstrin homology domains do not couple IRS-1 to the insulin receptor. |
| 2112 | 9346913 | Based on the hypothesis that PH domains may have a common function such as membrane targeting we tested the ability of PH domains from other signaling molecules to link IRS-1 to the insulin receptor. |
| 2113 | 9346913 | Chimeric IRS-1 proteins containing a homologous PH domain derived from other IRS proteins (IRS-2 or Gab-1) were tyrosine phosphorylated normally in response to insulin. |
| 2114 | 9346913 | In contrast, heterologous PH domains from the beta-adrenergic receptor kinase, phospholipase Cgamma, or spectrin failed to mediate tyrosine phosphorylation of chimeric IRS-1 proteins, even in cells expressing high levels of insulin receptor. |
| 2115 | 9346913 | Moreover, IRS-1 proteins containing heterologous PH domains did not bind phosphorylated NPEY motifs derived from the insulin receptor, suggesting that the presence of these structures interfered with the function of the adjacent PTB binding domain. |
| 2116 | 9346913 | Thus, tyrosine phosphorylation of IRS-1 by the insulin receptor specifically requires a PH domain derived from IRS proteins. |
| 2117 | 9346913 | Heterologous pleckstrin homology domains do not couple IRS-1 to the insulin receptor. |
| 2118 | 9346913 | Based on the hypothesis that PH domains may have a common function such as membrane targeting we tested the ability of PH domains from other signaling molecules to link IRS-1 to the insulin receptor. |
| 2119 | 9346913 | Chimeric IRS-1 proteins containing a homologous PH domain derived from other IRS proteins (IRS-2 or Gab-1) were tyrosine phosphorylated normally in response to insulin. |
| 2120 | 9346913 | In contrast, heterologous PH domains from the beta-adrenergic receptor kinase, phospholipase Cgamma, or spectrin failed to mediate tyrosine phosphorylation of chimeric IRS-1 proteins, even in cells expressing high levels of insulin receptor. |
| 2121 | 9346913 | Moreover, IRS-1 proteins containing heterologous PH domains did not bind phosphorylated NPEY motifs derived from the insulin receptor, suggesting that the presence of these structures interfered with the function of the adjacent PTB binding domain. |
| 2122 | 9346913 | Thus, tyrosine phosphorylation of IRS-1 by the insulin receptor specifically requires a PH domain derived from IRS proteins. |
| 2123 | 9346913 | Heterologous pleckstrin homology domains do not couple IRS-1 to the insulin receptor. |
| 2124 | 9346913 | Based on the hypothesis that PH domains may have a common function such as membrane targeting we tested the ability of PH domains from other signaling molecules to link IRS-1 to the insulin receptor. |
| 2125 | 9346913 | Chimeric IRS-1 proteins containing a homologous PH domain derived from other IRS proteins (IRS-2 or Gab-1) were tyrosine phosphorylated normally in response to insulin. |
| 2126 | 9346913 | In contrast, heterologous PH domains from the beta-adrenergic receptor kinase, phospholipase Cgamma, or spectrin failed to mediate tyrosine phosphorylation of chimeric IRS-1 proteins, even in cells expressing high levels of insulin receptor. |
| 2127 | 9346913 | Moreover, IRS-1 proteins containing heterologous PH domains did not bind phosphorylated NPEY motifs derived from the insulin receptor, suggesting that the presence of these structures interfered with the function of the adjacent PTB binding domain. |
| 2128 | 9346913 | Thus, tyrosine phosphorylation of IRS-1 by the insulin receptor specifically requires a PH domain derived from IRS proteins. |
| 2129 | 9346913 | Heterologous pleckstrin homology domains do not couple IRS-1 to the insulin receptor. |
| 2130 | 9346913 | Based on the hypothesis that PH domains may have a common function such as membrane targeting we tested the ability of PH domains from other signaling molecules to link IRS-1 to the insulin receptor. |
| 2131 | 9346913 | Chimeric IRS-1 proteins containing a homologous PH domain derived from other IRS proteins (IRS-2 or Gab-1) were tyrosine phosphorylated normally in response to insulin. |
| 2132 | 9346913 | In contrast, heterologous PH domains from the beta-adrenergic receptor kinase, phospholipase Cgamma, or spectrin failed to mediate tyrosine phosphorylation of chimeric IRS-1 proteins, even in cells expressing high levels of insulin receptor. |
| 2133 | 9346913 | Moreover, IRS-1 proteins containing heterologous PH domains did not bind phosphorylated NPEY motifs derived from the insulin receptor, suggesting that the presence of these structures interfered with the function of the adjacent PTB binding domain. |
| 2134 | 9346913 | Thus, tyrosine phosphorylation of IRS-1 by the insulin receptor specifically requires a PH domain derived from IRS proteins. |
| 2135 | 9346913 | Heterologous pleckstrin homology domains do not couple IRS-1 to the insulin receptor. |
| 2136 | 9346913 | Based on the hypothesis that PH domains may have a common function such as membrane targeting we tested the ability of PH domains from other signaling molecules to link IRS-1 to the insulin receptor. |
| 2137 | 9346913 | Chimeric IRS-1 proteins containing a homologous PH domain derived from other IRS proteins (IRS-2 or Gab-1) were tyrosine phosphorylated normally in response to insulin. |
| 2138 | 9346913 | In contrast, heterologous PH domains from the beta-adrenergic receptor kinase, phospholipase Cgamma, or spectrin failed to mediate tyrosine phosphorylation of chimeric IRS-1 proteins, even in cells expressing high levels of insulin receptor. |
| 2139 | 9346913 | Moreover, IRS-1 proteins containing heterologous PH domains did not bind phosphorylated NPEY motifs derived from the insulin receptor, suggesting that the presence of these structures interfered with the function of the adjacent PTB binding domain. |
| 2140 | 9346913 | Thus, tyrosine phosphorylation of IRS-1 by the insulin receptor specifically requires a PH domain derived from IRS proteins. |
| 2141 | 9348224 | Two members of this family (IRS-1 and IRS-2) have been identified previously. |
| 2142 | 9348224 | Unlike the genes encoding IRS-1 and IRS-2, the IRS-3 gene contains an intron (344 bp in length) in the region between the pleckstrin homology and the phosphotyrosine-binding domains. |
| 2143 | 9348224 | Two members of this family (IRS-1 and IRS-2) have been identified previously. |
| 2144 | 9348224 | Unlike the genes encoding IRS-1 and IRS-2, the IRS-3 gene contains an intron (344 bp in length) in the region between the pleckstrin homology and the phosphotyrosine-binding domains. |
| 2145 | 9349593 | A 973 valine to methionine mutation of the human insulin receptor: interaction with insulin-receptor substrate-1 and Shc in HEK 293 cells. |
| 2146 | 9349593 | A population-based study in the Netherlands has recently demonstrated that a mutation of the human insulin receptor (HIR-973 valine to methionine) is associated with hyperglycaemia and an increased prevalence of non-insulin-dependent diabetes mellitus (NIDDM). |
| 2147 | 9349593 | This mutant was transiently overexpressed in HEK 293 cells either alone or together with insulin-receptor substrate-1 (IRS-1) or Shc. |
| 2148 | 9349593 | Insulin stimulated autophosphorylation, phosphorylation of the substrates IRS-1 and Shc as well as activation of phosphatidylinositol-3 (PI3)-kinase were studied. |
| 2149 | 9349593 | Human insulin receptor with a juxtamembrane deletion HIR-deltaJM which is known to impair HIR/IRS-1 interaction was used as control. |
| 2150 | 9349593 | When PI3-kinase activity was measured in IRS-1 precipitates similar activity was found for HIR-wt and HIR-973 whereas PI3-kinase stimulation was reduced with HIR-deltaJM. |
| 2151 | 9349593 | The close vicinity of this mutation to insulin receptor domains which are involved in IRS-1 and Shc binding may, however, alter the interaction of the insulin receptor with these substrates. |
| 2152 | 9349593 | A 973 valine to methionine mutation of the human insulin receptor: interaction with insulin-receptor substrate-1 and Shc in HEK 293 cells. |
| 2153 | 9349593 | A population-based study in the Netherlands has recently demonstrated that a mutation of the human insulin receptor (HIR-973 valine to methionine) is associated with hyperglycaemia and an increased prevalence of non-insulin-dependent diabetes mellitus (NIDDM). |
| 2154 | 9349593 | This mutant was transiently overexpressed in HEK 293 cells either alone or together with insulin-receptor substrate-1 (IRS-1) or Shc. |
| 2155 | 9349593 | Insulin stimulated autophosphorylation, phosphorylation of the substrates IRS-1 and Shc as well as activation of phosphatidylinositol-3 (PI3)-kinase were studied. |
| 2156 | 9349593 | Human insulin receptor with a juxtamembrane deletion HIR-deltaJM which is known to impair HIR/IRS-1 interaction was used as control. |
| 2157 | 9349593 | When PI3-kinase activity was measured in IRS-1 precipitates similar activity was found for HIR-wt and HIR-973 whereas PI3-kinase stimulation was reduced with HIR-deltaJM. |
| 2158 | 9349593 | The close vicinity of this mutation to insulin receptor domains which are involved in IRS-1 and Shc binding may, however, alter the interaction of the insulin receptor with these substrates. |
| 2159 | 9349593 | A 973 valine to methionine mutation of the human insulin receptor: interaction with insulin-receptor substrate-1 and Shc in HEK 293 cells. |
| 2160 | 9349593 | A population-based study in the Netherlands has recently demonstrated that a mutation of the human insulin receptor (HIR-973 valine to methionine) is associated with hyperglycaemia and an increased prevalence of non-insulin-dependent diabetes mellitus (NIDDM). |
| 2161 | 9349593 | This mutant was transiently overexpressed in HEK 293 cells either alone or together with insulin-receptor substrate-1 (IRS-1) or Shc. |
| 2162 | 9349593 | Insulin stimulated autophosphorylation, phosphorylation of the substrates IRS-1 and Shc as well as activation of phosphatidylinositol-3 (PI3)-kinase were studied. |
| 2163 | 9349593 | Human insulin receptor with a juxtamembrane deletion HIR-deltaJM which is known to impair HIR/IRS-1 interaction was used as control. |
| 2164 | 9349593 | When PI3-kinase activity was measured in IRS-1 precipitates similar activity was found for HIR-wt and HIR-973 whereas PI3-kinase stimulation was reduced with HIR-deltaJM. |
| 2165 | 9349593 | The close vicinity of this mutation to insulin receptor domains which are involved in IRS-1 and Shc binding may, however, alter the interaction of the insulin receptor with these substrates. |
| 2166 | 9349593 | A 973 valine to methionine mutation of the human insulin receptor: interaction with insulin-receptor substrate-1 and Shc in HEK 293 cells. |
| 2167 | 9349593 | A population-based study in the Netherlands has recently demonstrated that a mutation of the human insulin receptor (HIR-973 valine to methionine) is associated with hyperglycaemia and an increased prevalence of non-insulin-dependent diabetes mellitus (NIDDM). |
| 2168 | 9349593 | This mutant was transiently overexpressed in HEK 293 cells either alone or together with insulin-receptor substrate-1 (IRS-1) or Shc. |
| 2169 | 9349593 | Insulin stimulated autophosphorylation, phosphorylation of the substrates IRS-1 and Shc as well as activation of phosphatidylinositol-3 (PI3)-kinase were studied. |
| 2170 | 9349593 | Human insulin receptor with a juxtamembrane deletion HIR-deltaJM which is known to impair HIR/IRS-1 interaction was used as control. |
| 2171 | 9349593 | When PI3-kinase activity was measured in IRS-1 precipitates similar activity was found for HIR-wt and HIR-973 whereas PI3-kinase stimulation was reduced with HIR-deltaJM. |
| 2172 | 9349593 | The close vicinity of this mutation to insulin receptor domains which are involved in IRS-1 and Shc binding may, however, alter the interaction of the insulin receptor with these substrates. |
| 2173 | 9349593 | A 973 valine to methionine mutation of the human insulin receptor: interaction with insulin-receptor substrate-1 and Shc in HEK 293 cells. |
| 2174 | 9349593 | A population-based study in the Netherlands has recently demonstrated that a mutation of the human insulin receptor (HIR-973 valine to methionine) is associated with hyperglycaemia and an increased prevalence of non-insulin-dependent diabetes mellitus (NIDDM). |
| 2175 | 9349593 | This mutant was transiently overexpressed in HEK 293 cells either alone or together with insulin-receptor substrate-1 (IRS-1) or Shc. |
| 2176 | 9349593 | Insulin stimulated autophosphorylation, phosphorylation of the substrates IRS-1 and Shc as well as activation of phosphatidylinositol-3 (PI3)-kinase were studied. |
| 2177 | 9349593 | Human insulin receptor with a juxtamembrane deletion HIR-deltaJM which is known to impair HIR/IRS-1 interaction was used as control. |
| 2178 | 9349593 | When PI3-kinase activity was measured in IRS-1 precipitates similar activity was found for HIR-wt and HIR-973 whereas PI3-kinase stimulation was reduced with HIR-deltaJM. |
| 2179 | 9349593 | The close vicinity of this mutation to insulin receptor domains which are involved in IRS-1 and Shc binding may, however, alter the interaction of the insulin receptor with these substrates. |
| 2180 | 9349593 | A 973 valine to methionine mutation of the human insulin receptor: interaction with insulin-receptor substrate-1 and Shc in HEK 293 cells. |
| 2181 | 9349593 | A population-based study in the Netherlands has recently demonstrated that a mutation of the human insulin receptor (HIR-973 valine to methionine) is associated with hyperglycaemia and an increased prevalence of non-insulin-dependent diabetes mellitus (NIDDM). |
| 2182 | 9349593 | This mutant was transiently overexpressed in HEK 293 cells either alone or together with insulin-receptor substrate-1 (IRS-1) or Shc. |
| 2183 | 9349593 | Insulin stimulated autophosphorylation, phosphorylation of the substrates IRS-1 and Shc as well as activation of phosphatidylinositol-3 (PI3)-kinase were studied. |
| 2184 | 9349593 | Human insulin receptor with a juxtamembrane deletion HIR-deltaJM which is known to impair HIR/IRS-1 interaction was used as control. |
| 2185 | 9349593 | When PI3-kinase activity was measured in IRS-1 precipitates similar activity was found for HIR-wt and HIR-973 whereas PI3-kinase stimulation was reduced with HIR-deltaJM. |
| 2186 | 9349593 | The close vicinity of this mutation to insulin receptor domains which are involved in IRS-1 and Shc binding may, however, alter the interaction of the insulin receptor with these substrates. |
| 2187 | 9356013 | The insulin-like effects of vanadate are independent of the insulin receptor and insulin receptor substrate 1 (IRS-1) phosphorylation. |
| 2188 | 9356025 | Concomitant insulin stimulation (three- to six-fold [P < 0.05]) of thigh glucose clearance, muscle insulin receptor tyrosine kinase (IRTK), insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation, and IRS-1-associated phosphatidylinositol 3-kinase (PI 3-kinase) was observed in the rested leg. |
| 2189 | 9356025 | A twofold higher insulin-stimulated glucose clearance in the exercised compared with the rested thigh was accompanied by unaltered maximal IRTK activation and IRS-1 tyrosine phosphorylation, and by a decreased (approximately 50%, P < 0.05) maximal IRS-1 associated PI 3-kinase activation. |
| 2190 | 9356025 | Prior exercise caused significantly faster insulin-stimulated tyrosine phosphorylation of IRS-1, PI 3-kinase activity, and glucose clearance compared with those in the rested thigh. |
| 2191 | 9356025 | Concomitant insulin stimulation (three- to six-fold [P < 0.05]) of thigh glucose clearance, muscle insulin receptor tyrosine kinase (IRTK), insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation, and IRS-1-associated phosphatidylinositol 3-kinase (PI 3-kinase) was observed in the rested leg. |
| 2192 | 9356025 | A twofold higher insulin-stimulated glucose clearance in the exercised compared with the rested thigh was accompanied by unaltered maximal IRTK activation and IRS-1 tyrosine phosphorylation, and by a decreased (approximately 50%, P < 0.05) maximal IRS-1 associated PI 3-kinase activation. |
| 2193 | 9356025 | Prior exercise caused significantly faster insulin-stimulated tyrosine phosphorylation of IRS-1, PI 3-kinase activity, and glucose clearance compared with those in the rested thigh. |
| 2194 | 9356025 | Concomitant insulin stimulation (three- to six-fold [P < 0.05]) of thigh glucose clearance, muscle insulin receptor tyrosine kinase (IRTK), insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation, and IRS-1-associated phosphatidylinositol 3-kinase (PI 3-kinase) was observed in the rested leg. |
| 2195 | 9356025 | A twofold higher insulin-stimulated glucose clearance in the exercised compared with the rested thigh was accompanied by unaltered maximal IRTK activation and IRS-1 tyrosine phosphorylation, and by a decreased (approximately 50%, P < 0.05) maximal IRS-1 associated PI 3-kinase activation. |
| 2196 | 9356025 | Prior exercise caused significantly faster insulin-stimulated tyrosine phosphorylation of IRS-1, PI 3-kinase activity, and glucose clearance compared with those in the rested thigh. |
| 2197 | 9368055 | Insulin receptor substrate-2 (IRS-2) can mediate the action of insulin to stimulate translocation of GLUT4 to the cell surface in rat adipose cells. |
| 2198 | 9368055 | Insulin receptor substrates-1 and -2 (IRS-1 and -2) are important substrates of the insulin receptor tyrosine kinase. |
| 2199 | 9368055 | In the present study, we demonstrate that IRS-2 can mediate translocation of the insulin responsive glucose transporter GLUT4 in a physiologically relevant target cell for insulin action. |
| 2200 | 9368055 | Co-immunoprecipitation experiments performed on cell lysates derived from freshly isolated rat adipose cells incubated in the presence or absence of insulin indicated that twice as much phosphatidylinositol 3-kinase was associated with endogenous IRS-1 as with IRS-2 after insulin stimulation. |
| 2201 | 9368055 | When rat adipose cells in primary culture were transfected with expression vectors for IRS-1 or IRS-2, we observed 40-fold overexpression of human IRS-1 or murine IRS-2. |
| 2202 | 9368055 | To examine the role of IRS-2 in insulin-stimulated translocation of GLUT4, we studied the effects of overexpression of IRS-1 and -2 on translocation of a co-transfected epitope-tagged GLUT4 (GLUT4-HA). |
| 2203 | 9368055 | Overexpression of IRS-1 or IRS-2 in adipose cells resulted in a significant increase in the basal level of cell surface GLUT4 (in the absence of insulin). |
| 2204 | 9368055 | Interestingly, at maximally effective concentrations of insulin (60 nM), the level of cell surface GLUT4 in cells overexpressing IRS-1 or -2 significantly exceeded the maximal recruitment observed in the control cells (160 and 135% of control, respectively; p < 0.003). |
| 2205 | 9368055 | Our data directly demonstrate that IRS-2, like IRS-1, is capable of participating in insulin signal transduction pathways leading to the recruitment of GLUT4. |
| 2206 | 9368055 | Insulin receptor substrate-2 (IRS-2) can mediate the action of insulin to stimulate translocation of GLUT4 to the cell surface in rat adipose cells. |
| 2207 | 9368055 | Insulin receptor substrates-1 and -2 (IRS-1 and -2) are important substrates of the insulin receptor tyrosine kinase. |
| 2208 | 9368055 | In the present study, we demonstrate that IRS-2 can mediate translocation of the insulin responsive glucose transporter GLUT4 in a physiologically relevant target cell for insulin action. |
| 2209 | 9368055 | Co-immunoprecipitation experiments performed on cell lysates derived from freshly isolated rat adipose cells incubated in the presence or absence of insulin indicated that twice as much phosphatidylinositol 3-kinase was associated with endogenous IRS-1 as with IRS-2 after insulin stimulation. |
| 2210 | 9368055 | When rat adipose cells in primary culture were transfected with expression vectors for IRS-1 or IRS-2, we observed 40-fold overexpression of human IRS-1 or murine IRS-2. |
| 2211 | 9368055 | To examine the role of IRS-2 in insulin-stimulated translocation of GLUT4, we studied the effects of overexpression of IRS-1 and -2 on translocation of a co-transfected epitope-tagged GLUT4 (GLUT4-HA). |
| 2212 | 9368055 | Overexpression of IRS-1 or IRS-2 in adipose cells resulted in a significant increase in the basal level of cell surface GLUT4 (in the absence of insulin). |
| 2213 | 9368055 | Interestingly, at maximally effective concentrations of insulin (60 nM), the level of cell surface GLUT4 in cells overexpressing IRS-1 or -2 significantly exceeded the maximal recruitment observed in the control cells (160 and 135% of control, respectively; p < 0.003). |
| 2214 | 9368055 | Our data directly demonstrate that IRS-2, like IRS-1, is capable of participating in insulin signal transduction pathways leading to the recruitment of GLUT4. |
| 2215 | 9368055 | Insulin receptor substrate-2 (IRS-2) can mediate the action of insulin to stimulate translocation of GLUT4 to the cell surface in rat adipose cells. |
| 2216 | 9368055 | Insulin receptor substrates-1 and -2 (IRS-1 and -2) are important substrates of the insulin receptor tyrosine kinase. |
| 2217 | 9368055 | In the present study, we demonstrate that IRS-2 can mediate translocation of the insulin responsive glucose transporter GLUT4 in a physiologically relevant target cell for insulin action. |
| 2218 | 9368055 | Co-immunoprecipitation experiments performed on cell lysates derived from freshly isolated rat adipose cells incubated in the presence or absence of insulin indicated that twice as much phosphatidylinositol 3-kinase was associated with endogenous IRS-1 as with IRS-2 after insulin stimulation. |
| 2219 | 9368055 | When rat adipose cells in primary culture were transfected with expression vectors for IRS-1 or IRS-2, we observed 40-fold overexpression of human IRS-1 or murine IRS-2. |
| 2220 | 9368055 | To examine the role of IRS-2 in insulin-stimulated translocation of GLUT4, we studied the effects of overexpression of IRS-1 and -2 on translocation of a co-transfected epitope-tagged GLUT4 (GLUT4-HA). |
| 2221 | 9368055 | Overexpression of IRS-1 or IRS-2 in adipose cells resulted in a significant increase in the basal level of cell surface GLUT4 (in the absence of insulin). |
| 2222 | 9368055 | Interestingly, at maximally effective concentrations of insulin (60 nM), the level of cell surface GLUT4 in cells overexpressing IRS-1 or -2 significantly exceeded the maximal recruitment observed in the control cells (160 and 135% of control, respectively; p < 0.003). |
| 2223 | 9368055 | Our data directly demonstrate that IRS-2, like IRS-1, is capable of participating in insulin signal transduction pathways leading to the recruitment of GLUT4. |
| 2224 | 9368055 | Insulin receptor substrate-2 (IRS-2) can mediate the action of insulin to stimulate translocation of GLUT4 to the cell surface in rat adipose cells. |
| 2225 | 9368055 | Insulin receptor substrates-1 and -2 (IRS-1 and -2) are important substrates of the insulin receptor tyrosine kinase. |
| 2226 | 9368055 | In the present study, we demonstrate that IRS-2 can mediate translocation of the insulin responsive glucose transporter GLUT4 in a physiologically relevant target cell for insulin action. |
| 2227 | 9368055 | Co-immunoprecipitation experiments performed on cell lysates derived from freshly isolated rat adipose cells incubated in the presence or absence of insulin indicated that twice as much phosphatidylinositol 3-kinase was associated with endogenous IRS-1 as with IRS-2 after insulin stimulation. |
| 2228 | 9368055 | When rat adipose cells in primary culture were transfected with expression vectors for IRS-1 or IRS-2, we observed 40-fold overexpression of human IRS-1 or murine IRS-2. |
| 2229 | 9368055 | To examine the role of IRS-2 in insulin-stimulated translocation of GLUT4, we studied the effects of overexpression of IRS-1 and -2 on translocation of a co-transfected epitope-tagged GLUT4 (GLUT4-HA). |
| 2230 | 9368055 | Overexpression of IRS-1 or IRS-2 in adipose cells resulted in a significant increase in the basal level of cell surface GLUT4 (in the absence of insulin). |
| 2231 | 9368055 | Interestingly, at maximally effective concentrations of insulin (60 nM), the level of cell surface GLUT4 in cells overexpressing IRS-1 or -2 significantly exceeded the maximal recruitment observed in the control cells (160 and 135% of control, respectively; p < 0.003). |
| 2232 | 9368055 | Our data directly demonstrate that IRS-2, like IRS-1, is capable of participating in insulin signal transduction pathways leading to the recruitment of GLUT4. |
| 2233 | 9368055 | Insulin receptor substrate-2 (IRS-2) can mediate the action of insulin to stimulate translocation of GLUT4 to the cell surface in rat adipose cells. |
| 2234 | 9368055 | Insulin receptor substrates-1 and -2 (IRS-1 and -2) are important substrates of the insulin receptor tyrosine kinase. |
| 2235 | 9368055 | In the present study, we demonstrate that IRS-2 can mediate translocation of the insulin responsive glucose transporter GLUT4 in a physiologically relevant target cell for insulin action. |
| 2236 | 9368055 | Co-immunoprecipitation experiments performed on cell lysates derived from freshly isolated rat adipose cells incubated in the presence or absence of insulin indicated that twice as much phosphatidylinositol 3-kinase was associated with endogenous IRS-1 as with IRS-2 after insulin stimulation. |
| 2237 | 9368055 | When rat adipose cells in primary culture were transfected with expression vectors for IRS-1 or IRS-2, we observed 40-fold overexpression of human IRS-1 or murine IRS-2. |
| 2238 | 9368055 | To examine the role of IRS-2 in insulin-stimulated translocation of GLUT4, we studied the effects of overexpression of IRS-1 and -2 on translocation of a co-transfected epitope-tagged GLUT4 (GLUT4-HA). |
| 2239 | 9368055 | Overexpression of IRS-1 or IRS-2 in adipose cells resulted in a significant increase in the basal level of cell surface GLUT4 (in the absence of insulin). |
| 2240 | 9368055 | Interestingly, at maximally effective concentrations of insulin (60 nM), the level of cell surface GLUT4 in cells overexpressing IRS-1 or -2 significantly exceeded the maximal recruitment observed in the control cells (160 and 135% of control, respectively; p < 0.003). |
| 2241 | 9368055 | Our data directly demonstrate that IRS-2, like IRS-1, is capable of participating in insulin signal transduction pathways leading to the recruitment of GLUT4. |
| 2242 | 9368055 | Insulin receptor substrate-2 (IRS-2) can mediate the action of insulin to stimulate translocation of GLUT4 to the cell surface in rat adipose cells. |
| 2243 | 9368055 | Insulin receptor substrates-1 and -2 (IRS-1 and -2) are important substrates of the insulin receptor tyrosine kinase. |
| 2244 | 9368055 | In the present study, we demonstrate that IRS-2 can mediate translocation of the insulin responsive glucose transporter GLUT4 in a physiologically relevant target cell for insulin action. |
| 2245 | 9368055 | Co-immunoprecipitation experiments performed on cell lysates derived from freshly isolated rat adipose cells incubated in the presence or absence of insulin indicated that twice as much phosphatidylinositol 3-kinase was associated with endogenous IRS-1 as with IRS-2 after insulin stimulation. |
| 2246 | 9368055 | When rat adipose cells in primary culture were transfected with expression vectors for IRS-1 or IRS-2, we observed 40-fold overexpression of human IRS-1 or murine IRS-2. |
| 2247 | 9368055 | To examine the role of IRS-2 in insulin-stimulated translocation of GLUT4, we studied the effects of overexpression of IRS-1 and -2 on translocation of a co-transfected epitope-tagged GLUT4 (GLUT4-HA). |
| 2248 | 9368055 | Overexpression of IRS-1 or IRS-2 in adipose cells resulted in a significant increase in the basal level of cell surface GLUT4 (in the absence of insulin). |
| 2249 | 9368055 | Interestingly, at maximally effective concentrations of insulin (60 nM), the level of cell surface GLUT4 in cells overexpressing IRS-1 or -2 significantly exceeded the maximal recruitment observed in the control cells (160 and 135% of control, respectively; p < 0.003). |
| 2250 | 9368055 | Our data directly demonstrate that IRS-2, like IRS-1, is capable of participating in insulin signal transduction pathways leading to the recruitment of GLUT4. |
| 2251 | 9368055 | Insulin receptor substrate-2 (IRS-2) can mediate the action of insulin to stimulate translocation of GLUT4 to the cell surface in rat adipose cells. |
| 2252 | 9368055 | Insulin receptor substrates-1 and -2 (IRS-1 and -2) are important substrates of the insulin receptor tyrosine kinase. |
| 2253 | 9368055 | In the present study, we demonstrate that IRS-2 can mediate translocation of the insulin responsive glucose transporter GLUT4 in a physiologically relevant target cell for insulin action. |
| 2254 | 9368055 | Co-immunoprecipitation experiments performed on cell lysates derived from freshly isolated rat adipose cells incubated in the presence or absence of insulin indicated that twice as much phosphatidylinositol 3-kinase was associated with endogenous IRS-1 as with IRS-2 after insulin stimulation. |
| 2255 | 9368055 | When rat adipose cells in primary culture were transfected with expression vectors for IRS-1 or IRS-2, we observed 40-fold overexpression of human IRS-1 or murine IRS-2. |
| 2256 | 9368055 | To examine the role of IRS-2 in insulin-stimulated translocation of GLUT4, we studied the effects of overexpression of IRS-1 and -2 on translocation of a co-transfected epitope-tagged GLUT4 (GLUT4-HA). |
| 2257 | 9368055 | Overexpression of IRS-1 or IRS-2 in adipose cells resulted in a significant increase in the basal level of cell surface GLUT4 (in the absence of insulin). |
| 2258 | 9368055 | Interestingly, at maximally effective concentrations of insulin (60 nM), the level of cell surface GLUT4 in cells overexpressing IRS-1 or -2 significantly exceeded the maximal recruitment observed in the control cells (160 and 135% of control, respectively; p < 0.003). |
| 2259 | 9368055 | Our data directly demonstrate that IRS-2, like IRS-1, is capable of participating in insulin signal transduction pathways leading to the recruitment of GLUT4. |
| 2260 | 9388210 | Inhibition of insulin receptor activation by insulin-like growth factor binding proteins. |
| 2261 | 9388210 | The insulin-like growth factors (IGFs) are transported by a family of high-affinity binding proteins (IGFBPs) that protect IGFs from degradation, limit their binding to IGF receptors, and modulate IGF actions. |
| 2262 | 9388210 | We now demonstrate that IGFBP-7/mac25, a newly identified member of the IGFBP superfamily that binds IGFs specifically with low affinity is a high-affinity insulin binding protein. |
| 2263 | 9388210 | IGFBP-7 blocks insulin binding to the insulin receptor and thereby inhibiting the earliest steps in insulin action, such as autophosphorylation of the insulin receptor beta subunit and phosphorylation of IRS-1, indicating that IGFBP-7 is a functional insulin-binding protein. |
| 2264 | 9388210 | Like IGFBP-7, an NH2-terminal fragment of IGFBP-3 (IGFBP-3((1-87))), also binds insulin with high affinity and blocks insulin action. |
| 2265 | 9392479 | The clinical use of ACE inhibitors has been associated with increased insulin sensitivity. |
| 2266 | 9392479 | In the present study, we examined the phosphorylation status of the insulin receptor and IRS-1, as well as the association between IRS-1 and PI 3-kinase in the liver and muscle of 20-month-old rats treated acutely with captopril, using immunoprecipitation with antipeptide antibodies to the insulin receptor and IRS-1, and immunoblotting with antiphosphotyrosine and anti-PI 3-kinase antibodies. |
| 2267 | 9392479 | Insulin stimulation increased receptor autophosphorylation to 462 +/- 253% (P < 0.05) in the liver and 697 +/- 78% (P < 0.001) in the muscle of ACE inhibitor-treated rats. |
| 2268 | 9392479 | There were also increases to 250 +/- 17% (P < 0.001) and 280 +/- 50% (P < 0.05) in the insulin-stimulated IRS-1 phosphorylation levels in the liver and muscle, respectively, of animals treated with captopril. |
| 2269 | 9392479 | The insulin-stimulated IRS-1 association with PI 3-kinase rose to 305 +/- 20% (P < 0.001) in liver and 267 +/- 48% (P < 0.05) in muscle. |
| 2270 | 9392479 | Losartan, an ANG receptor blocker, had no significant effect on insulin-stimulated IRS-1 phosphorylation in both tissues. |
| 2271 | 9392479 | The acute administration of bradykinin increased insulin-stimulated tyrosine phosphorylation of the insulin receptor and IRS-1 in the liver and muscle. |
| 2272 | 9392479 | These data demonstrate that ACE inhibitors modulate the early steps of insulin signaling, and that this effect may be simulated by the administration of bradykinin. |
| 2273 | 9392479 | The clinical use of ACE inhibitors has been associated with increased insulin sensitivity. |
| 2274 | 9392479 | In the present study, we examined the phosphorylation status of the insulin receptor and IRS-1, as well as the association between IRS-1 and PI 3-kinase in the liver and muscle of 20-month-old rats treated acutely with captopril, using immunoprecipitation with antipeptide antibodies to the insulin receptor and IRS-1, and immunoblotting with antiphosphotyrosine and anti-PI 3-kinase antibodies. |
| 2275 | 9392479 | Insulin stimulation increased receptor autophosphorylation to 462 +/- 253% (P < 0.05) in the liver and 697 +/- 78% (P < 0.001) in the muscle of ACE inhibitor-treated rats. |
| 2276 | 9392479 | There were also increases to 250 +/- 17% (P < 0.001) and 280 +/- 50% (P < 0.05) in the insulin-stimulated IRS-1 phosphorylation levels in the liver and muscle, respectively, of animals treated with captopril. |
| 2277 | 9392479 | The insulin-stimulated IRS-1 association with PI 3-kinase rose to 305 +/- 20% (P < 0.001) in liver and 267 +/- 48% (P < 0.05) in muscle. |
| 2278 | 9392479 | Losartan, an ANG receptor blocker, had no significant effect on insulin-stimulated IRS-1 phosphorylation in both tissues. |
| 2279 | 9392479 | The acute administration of bradykinin increased insulin-stimulated tyrosine phosphorylation of the insulin receptor and IRS-1 in the liver and muscle. |
| 2280 | 9392479 | These data demonstrate that ACE inhibitors modulate the early steps of insulin signaling, and that this effect may be simulated by the administration of bradykinin. |
| 2281 | 9392479 | The clinical use of ACE inhibitors has been associated with increased insulin sensitivity. |
| 2282 | 9392479 | In the present study, we examined the phosphorylation status of the insulin receptor and IRS-1, as well as the association between IRS-1 and PI 3-kinase in the liver and muscle of 20-month-old rats treated acutely with captopril, using immunoprecipitation with antipeptide antibodies to the insulin receptor and IRS-1, and immunoblotting with antiphosphotyrosine and anti-PI 3-kinase antibodies. |
| 2283 | 9392479 | Insulin stimulation increased receptor autophosphorylation to 462 +/- 253% (P < 0.05) in the liver and 697 +/- 78% (P < 0.001) in the muscle of ACE inhibitor-treated rats. |
| 2284 | 9392479 | There were also increases to 250 +/- 17% (P < 0.001) and 280 +/- 50% (P < 0.05) in the insulin-stimulated IRS-1 phosphorylation levels in the liver and muscle, respectively, of animals treated with captopril. |
| 2285 | 9392479 | The insulin-stimulated IRS-1 association with PI 3-kinase rose to 305 +/- 20% (P < 0.001) in liver and 267 +/- 48% (P < 0.05) in muscle. |
| 2286 | 9392479 | Losartan, an ANG receptor blocker, had no significant effect on insulin-stimulated IRS-1 phosphorylation in both tissues. |
| 2287 | 9392479 | The acute administration of bradykinin increased insulin-stimulated tyrosine phosphorylation of the insulin receptor and IRS-1 in the liver and muscle. |
| 2288 | 9392479 | These data demonstrate that ACE inhibitors modulate the early steps of insulin signaling, and that this effect may be simulated by the administration of bradykinin. |
| 2289 | 9392479 | The clinical use of ACE inhibitors has been associated with increased insulin sensitivity. |
| 2290 | 9392479 | In the present study, we examined the phosphorylation status of the insulin receptor and IRS-1, as well as the association between IRS-1 and PI 3-kinase in the liver and muscle of 20-month-old rats treated acutely with captopril, using immunoprecipitation with antipeptide antibodies to the insulin receptor and IRS-1, and immunoblotting with antiphosphotyrosine and anti-PI 3-kinase antibodies. |
| 2291 | 9392479 | Insulin stimulation increased receptor autophosphorylation to 462 +/- 253% (P < 0.05) in the liver and 697 +/- 78% (P < 0.001) in the muscle of ACE inhibitor-treated rats. |
| 2292 | 9392479 | There were also increases to 250 +/- 17% (P < 0.001) and 280 +/- 50% (P < 0.05) in the insulin-stimulated IRS-1 phosphorylation levels in the liver and muscle, respectively, of animals treated with captopril. |
| 2293 | 9392479 | The insulin-stimulated IRS-1 association with PI 3-kinase rose to 305 +/- 20% (P < 0.001) in liver and 267 +/- 48% (P < 0.05) in muscle. |
| 2294 | 9392479 | Losartan, an ANG receptor blocker, had no significant effect on insulin-stimulated IRS-1 phosphorylation in both tissues. |
| 2295 | 9392479 | The acute administration of bradykinin increased insulin-stimulated tyrosine phosphorylation of the insulin receptor and IRS-1 in the liver and muscle. |
| 2296 | 9392479 | These data demonstrate that ACE inhibitors modulate the early steps of insulin signaling, and that this effect may be simulated by the administration of bradykinin. |
| 2297 | 9392479 | The clinical use of ACE inhibitors has been associated with increased insulin sensitivity. |
| 2298 | 9392479 | In the present study, we examined the phosphorylation status of the insulin receptor and IRS-1, as well as the association between IRS-1 and PI 3-kinase in the liver and muscle of 20-month-old rats treated acutely with captopril, using immunoprecipitation with antipeptide antibodies to the insulin receptor and IRS-1, and immunoblotting with antiphosphotyrosine and anti-PI 3-kinase antibodies. |
| 2299 | 9392479 | Insulin stimulation increased receptor autophosphorylation to 462 +/- 253% (P < 0.05) in the liver and 697 +/- 78% (P < 0.001) in the muscle of ACE inhibitor-treated rats. |
| 2300 | 9392479 | There were also increases to 250 +/- 17% (P < 0.001) and 280 +/- 50% (P < 0.05) in the insulin-stimulated IRS-1 phosphorylation levels in the liver and muscle, respectively, of animals treated with captopril. |
| 2301 | 9392479 | The insulin-stimulated IRS-1 association with PI 3-kinase rose to 305 +/- 20% (P < 0.001) in liver and 267 +/- 48% (P < 0.05) in muscle. |
| 2302 | 9392479 | Losartan, an ANG receptor blocker, had no significant effect on insulin-stimulated IRS-1 phosphorylation in both tissues. |
| 2303 | 9392479 | The acute administration of bradykinin increased insulin-stimulated tyrosine phosphorylation of the insulin receptor and IRS-1 in the liver and muscle. |
| 2304 | 9392479 | These data demonstrate that ACE inhibitors modulate the early steps of insulin signaling, and that this effect may be simulated by the administration of bradykinin. |
| 2305 | 9398740 | This observation led to the hypothesis that these amino acid substitutions may impair the function of IRS-1, thereby causing the insulin resistance seen in patients with NIDDM. |
| 2306 | 9398740 | We constructed four IRS-1 expression vectors for transfection in COS-7 cells: wild-type, single mutant (Gly819-->Arg), double mutant (Gly819-->Arg; Gly972-->Arg), and triple mutant (Gly819-->Arg; Gly972-->Arg; Arg1221-->Cys) IRS-1. |
| 2307 | 9398740 | The mutations did not alter the level of expression or the extent of insulin receptor-mediated tyrosine phosphorylation of recombinant IRS-1. |
| 2308 | 9398740 | Moreover, the mutations did not lead to a detectable impairment in the association of recombinant IRS-1 with important downstream effectors, including the p85 subunit of phosphatidylinositol 3-kinase and growth factor receptor-binding protein-2. |
| 2309 | 9398740 | This observation led to the hypothesis that these amino acid substitutions may impair the function of IRS-1, thereby causing the insulin resistance seen in patients with NIDDM. |
| 2310 | 9398740 | We constructed four IRS-1 expression vectors for transfection in COS-7 cells: wild-type, single mutant (Gly819-->Arg), double mutant (Gly819-->Arg; Gly972-->Arg), and triple mutant (Gly819-->Arg; Gly972-->Arg; Arg1221-->Cys) IRS-1. |
| 2311 | 9398740 | The mutations did not alter the level of expression or the extent of insulin receptor-mediated tyrosine phosphorylation of recombinant IRS-1. |
| 2312 | 9398740 | Moreover, the mutations did not lead to a detectable impairment in the association of recombinant IRS-1 with important downstream effectors, including the p85 subunit of phosphatidylinositol 3-kinase and growth factor receptor-binding protein-2. |
| 2313 | 9398740 | This observation led to the hypothesis that these amino acid substitutions may impair the function of IRS-1, thereby causing the insulin resistance seen in patients with NIDDM. |
| 2314 | 9398740 | We constructed four IRS-1 expression vectors for transfection in COS-7 cells: wild-type, single mutant (Gly819-->Arg), double mutant (Gly819-->Arg; Gly972-->Arg), and triple mutant (Gly819-->Arg; Gly972-->Arg; Arg1221-->Cys) IRS-1. |
| 2315 | 9398740 | The mutations did not alter the level of expression or the extent of insulin receptor-mediated tyrosine phosphorylation of recombinant IRS-1. |
| 2316 | 9398740 | Moreover, the mutations did not lead to a detectable impairment in the association of recombinant IRS-1 with important downstream effectors, including the p85 subunit of phosphatidylinositol 3-kinase and growth factor receptor-binding protein-2. |
| 2317 | 9398740 | This observation led to the hypothesis that these amino acid substitutions may impair the function of IRS-1, thereby causing the insulin resistance seen in patients with NIDDM. |
| 2318 | 9398740 | We constructed four IRS-1 expression vectors for transfection in COS-7 cells: wild-type, single mutant (Gly819-->Arg), double mutant (Gly819-->Arg; Gly972-->Arg), and triple mutant (Gly819-->Arg; Gly972-->Arg; Arg1221-->Cys) IRS-1. |
| 2319 | 9398740 | The mutations did not alter the level of expression or the extent of insulin receptor-mediated tyrosine phosphorylation of recombinant IRS-1. |
| 2320 | 9398740 | Moreover, the mutations did not lead to a detectable impairment in the association of recombinant IRS-1 with important downstream effectors, including the p85 subunit of phosphatidylinositol 3-kinase and growth factor receptor-binding protein-2. |
| 2321 | 9399964 | Differential regulation of insulin receptor substrates-1 and -2 (IRS-1 and IRS-2) and phosphatidylinositol 3-kinase isoforms in liver and muscle of the obese diabetic (ob/ob) mouse. |
| 2322 | 9399964 | In this study, we have evaluated the roles of IRS-1 and IRS-2 in signaling to the phosphatidylinositol (PI) 3-kinase pathway in the ob/ob mouse, a model of the insulin resistance of obesity and non-insulin-dependent diabetes mellitus. |
| 2323 | 9399964 | We find that the levels of expression of both IRS-1 and IRS-2 are decreased approximately 50% in muscle, whereas in liver the decrease is significantly greater for IRS-2 (72%) than for IRS-1 (29%). |
| 2324 | 9399964 | This results in differential decreases in IRS-1 and IRS-2 phosphorylation, docking of the p85alpha regulatory subunit of PI 3-kinase, and activation of this enzyme in these two insulin target tissues. |
| 2325 | 9399964 | This resulted in a 45% decrease in the p85alpha form of PI 3-kinase, a ninefold increase in the AS53/p55alpha, and a twofold increase in p50alpha isoforms. |
| 2326 | 9399964 | Thus, there are multiple alterations in the early steps of insulin signaling in the ob/ob mouse, with differential regulation of IRS-1 and IRS-2, various PI 3-kinase regulatory isoforms, and a lack of compensation for the decrease in insulin signaling by any of the known alternative pathways at these levels. |
| 2327 | 9399964 | Differential regulation of insulin receptor substrates-1 and -2 (IRS-1 and IRS-2) and phosphatidylinositol 3-kinase isoforms in liver and muscle of the obese diabetic (ob/ob) mouse. |
| 2328 | 9399964 | In this study, we have evaluated the roles of IRS-1 and IRS-2 in signaling to the phosphatidylinositol (PI) 3-kinase pathway in the ob/ob mouse, a model of the insulin resistance of obesity and non-insulin-dependent diabetes mellitus. |
| 2329 | 9399964 | We find that the levels of expression of both IRS-1 and IRS-2 are decreased approximately 50% in muscle, whereas in liver the decrease is significantly greater for IRS-2 (72%) than for IRS-1 (29%). |
| 2330 | 9399964 | This results in differential decreases in IRS-1 and IRS-2 phosphorylation, docking of the p85alpha regulatory subunit of PI 3-kinase, and activation of this enzyme in these two insulin target tissues. |
| 2331 | 9399964 | This resulted in a 45% decrease in the p85alpha form of PI 3-kinase, a ninefold increase in the AS53/p55alpha, and a twofold increase in p50alpha isoforms. |
| 2332 | 9399964 | Thus, there are multiple alterations in the early steps of insulin signaling in the ob/ob mouse, with differential regulation of IRS-1 and IRS-2, various PI 3-kinase regulatory isoforms, and a lack of compensation for the decrease in insulin signaling by any of the known alternative pathways at these levels. |
| 2333 | 9399964 | Differential regulation of insulin receptor substrates-1 and -2 (IRS-1 and IRS-2) and phosphatidylinositol 3-kinase isoforms in liver and muscle of the obese diabetic (ob/ob) mouse. |
| 2334 | 9399964 | In this study, we have evaluated the roles of IRS-1 and IRS-2 in signaling to the phosphatidylinositol (PI) 3-kinase pathway in the ob/ob mouse, a model of the insulin resistance of obesity and non-insulin-dependent diabetes mellitus. |
| 2335 | 9399964 | We find that the levels of expression of both IRS-1 and IRS-2 are decreased approximately 50% in muscle, whereas in liver the decrease is significantly greater for IRS-2 (72%) than for IRS-1 (29%). |
| 2336 | 9399964 | This results in differential decreases in IRS-1 and IRS-2 phosphorylation, docking of the p85alpha regulatory subunit of PI 3-kinase, and activation of this enzyme in these two insulin target tissues. |
| 2337 | 9399964 | This resulted in a 45% decrease in the p85alpha form of PI 3-kinase, a ninefold increase in the AS53/p55alpha, and a twofold increase in p50alpha isoforms. |
| 2338 | 9399964 | Thus, there are multiple alterations in the early steps of insulin signaling in the ob/ob mouse, with differential regulation of IRS-1 and IRS-2, various PI 3-kinase regulatory isoforms, and a lack of compensation for the decrease in insulin signaling by any of the known alternative pathways at these levels. |
| 2339 | 9399964 | Differential regulation of insulin receptor substrates-1 and -2 (IRS-1 and IRS-2) and phosphatidylinositol 3-kinase isoforms in liver and muscle of the obese diabetic (ob/ob) mouse. |
| 2340 | 9399964 | In this study, we have evaluated the roles of IRS-1 and IRS-2 in signaling to the phosphatidylinositol (PI) 3-kinase pathway in the ob/ob mouse, a model of the insulin resistance of obesity and non-insulin-dependent diabetes mellitus. |
| 2341 | 9399964 | We find that the levels of expression of both IRS-1 and IRS-2 are decreased approximately 50% in muscle, whereas in liver the decrease is significantly greater for IRS-2 (72%) than for IRS-1 (29%). |
| 2342 | 9399964 | This results in differential decreases in IRS-1 and IRS-2 phosphorylation, docking of the p85alpha regulatory subunit of PI 3-kinase, and activation of this enzyme in these two insulin target tissues. |
| 2343 | 9399964 | This resulted in a 45% decrease in the p85alpha form of PI 3-kinase, a ninefold increase in the AS53/p55alpha, and a twofold increase in p50alpha isoforms. |
| 2344 | 9399964 | Thus, there are multiple alterations in the early steps of insulin signaling in the ob/ob mouse, with differential regulation of IRS-1 and IRS-2, various PI 3-kinase regulatory isoforms, and a lack of compensation for the decrease in insulin signaling by any of the known alternative pathways at these levels. |
| 2345 | 9399964 | Differential regulation of insulin receptor substrates-1 and -2 (IRS-1 and IRS-2) and phosphatidylinositol 3-kinase isoforms in liver and muscle of the obese diabetic (ob/ob) mouse. |
| 2346 | 9399964 | In this study, we have evaluated the roles of IRS-1 and IRS-2 in signaling to the phosphatidylinositol (PI) 3-kinase pathway in the ob/ob mouse, a model of the insulin resistance of obesity and non-insulin-dependent diabetes mellitus. |
| 2347 | 9399964 | We find that the levels of expression of both IRS-1 and IRS-2 are decreased approximately 50% in muscle, whereas in liver the decrease is significantly greater for IRS-2 (72%) than for IRS-1 (29%). |
| 2348 | 9399964 | This results in differential decreases in IRS-1 and IRS-2 phosphorylation, docking of the p85alpha regulatory subunit of PI 3-kinase, and activation of this enzyme in these two insulin target tissues. |
| 2349 | 9399964 | This resulted in a 45% decrease in the p85alpha form of PI 3-kinase, a ninefold increase in the AS53/p55alpha, and a twofold increase in p50alpha isoforms. |
| 2350 | 9399964 | Thus, there are multiple alterations in the early steps of insulin signaling in the ob/ob mouse, with differential regulation of IRS-1 and IRS-2, various PI 3-kinase regulatory isoforms, and a lack of compensation for the decrease in insulin signaling by any of the known alternative pathways at these levels. |
| 2351 | 9421370 | Effects of cell-permeable ceramides and tumor necrosis factor-alpha on insulin signaling and glucose uptake in 3T3-L1 adipocytes. |
| 2352 | 9421370 | Long-term increases in PI 3-kinase activity associated with insulin receptor substrate 1 (IRS-1) increased GLUT1 and GLUT4 concentrations in plasma membranes. |
| 2353 | 9421370 | This together with increased GLUT1 (but not GLUT4) synthesis explains the increase in non-insulin-dependent glucose uptake. |
| 2354 | 9421370 | C2-ceramide inhibited insulin-stimulated glucose uptake after 2 h by decreasing insulin-induced translocation of GLUT1 and GLUT4 to plasma membranes. |
| 2355 | 9421370 | Incubation for 24 h with tumor necrosis factor-alpha (TNF-alpha) but not C2-ceramide decreased the concentration and insulin-induced tyrosine phosphorylation of IRS-1 in this experimental system. |
| 2356 | 9421370 | Our work provides further mechanisms for the effects of TNF-alpha and ceramides in increasing non-insulin-dependent glucose uptake and decreasing insulin-stimulated uptake in vivo. |
| 2357 | 9421370 | Effects of cell-permeable ceramides and tumor necrosis factor-alpha on insulin signaling and glucose uptake in 3T3-L1 adipocytes. |
| 2358 | 9421370 | Long-term increases in PI 3-kinase activity associated with insulin receptor substrate 1 (IRS-1) increased GLUT1 and GLUT4 concentrations in plasma membranes. |
| 2359 | 9421370 | This together with increased GLUT1 (but not GLUT4) synthesis explains the increase in non-insulin-dependent glucose uptake. |
| 2360 | 9421370 | C2-ceramide inhibited insulin-stimulated glucose uptake after 2 h by decreasing insulin-induced translocation of GLUT1 and GLUT4 to plasma membranes. |
| 2361 | 9421370 | Incubation for 24 h with tumor necrosis factor-alpha (TNF-alpha) but not C2-ceramide decreased the concentration and insulin-induced tyrosine phosphorylation of IRS-1 in this experimental system. |
| 2362 | 9421370 | Our work provides further mechanisms for the effects of TNF-alpha and ceramides in increasing non-insulin-dependent glucose uptake and decreasing insulin-stimulated uptake in vivo. |
| 2363 | 9421369 | Altered expression levels and impaired steps in the pathway to phosphatidylinositol 3-kinase activation via insulin receptor substrates 1 and 2 in Zucker fatty rats. |
| 2364 | 9421369 | To elucidate the mechanism of obesity-related insulin resistance, we investigated the impaired steps in the processes of phosphatidylinositol (PI) 3-kinase activation through binding with insulin receptor substrates 1 and 2 (IRS-1 and IRS-2) in liver and muscle of Zucker fatty rats. |
| 2365 | 9421369 | The expressions of IRS-1 and IRS-2 were shown to be downregulated in both liver and muscle in fatty rats (hepatic IRS-1, 83%; hepatic IRS-2, 45%; muscle IRS-1, 60%; muscle IRS-2, 78%), resulting in decreased tyrosine phosphorylation in response to insulin stimulation. |
| 2366 | 9421369 | Despite the decrease in the tyrosine phosphorylation levels of hepatic IRS-1 and IRS-2 being mild to moderate, associated PI 3-kinase activities were dramatically decreased in fatty rats (IRS-1, 14%; IRS-2, 10%), which may suggest alteration in the sites of phosphorylated tyrosine residues of hepatic IRS-1 and IRS-2. |
| 2367 | 9421369 | In addition, we demonstrated that the expressions of p85alpha and p55alpha regulatory subunits of PI 3-kinase were reduced (p85alpha, 67%; p55alpha, 54%), and that the p50alpha regulatory subunit was markedly upregulated (176%) in the livers of fatty rats without apparent alterations in expressions of the catalytic subunits p110alpha and p110beta. |
| 2368 | 9421369 | Altered expression levels and impaired steps in the pathway to phosphatidylinositol 3-kinase activation via insulin receptor substrates 1 and 2 in Zucker fatty rats. |
| 2369 | 9421369 | To elucidate the mechanism of obesity-related insulin resistance, we investigated the impaired steps in the processes of phosphatidylinositol (PI) 3-kinase activation through binding with insulin receptor substrates 1 and 2 (IRS-1 and IRS-2) in liver and muscle of Zucker fatty rats. |
| 2370 | 9421369 | The expressions of IRS-1 and IRS-2 were shown to be downregulated in both liver and muscle in fatty rats (hepatic IRS-1, 83%; hepatic IRS-2, 45%; muscle IRS-1, 60%; muscle IRS-2, 78%), resulting in decreased tyrosine phosphorylation in response to insulin stimulation. |
| 2371 | 9421369 | Despite the decrease in the tyrosine phosphorylation levels of hepatic IRS-1 and IRS-2 being mild to moderate, associated PI 3-kinase activities were dramatically decreased in fatty rats (IRS-1, 14%; IRS-2, 10%), which may suggest alteration in the sites of phosphorylated tyrosine residues of hepatic IRS-1 and IRS-2. |
| 2372 | 9421369 | In addition, we demonstrated that the expressions of p85alpha and p55alpha regulatory subunits of PI 3-kinase were reduced (p85alpha, 67%; p55alpha, 54%), and that the p50alpha regulatory subunit was markedly upregulated (176%) in the livers of fatty rats without apparent alterations in expressions of the catalytic subunits p110alpha and p110beta. |
| 2373 | 9421369 | Altered expression levels and impaired steps in the pathway to phosphatidylinositol 3-kinase activation via insulin receptor substrates 1 and 2 in Zucker fatty rats. |
| 2374 | 9421369 | To elucidate the mechanism of obesity-related insulin resistance, we investigated the impaired steps in the processes of phosphatidylinositol (PI) 3-kinase activation through binding with insulin receptor substrates 1 and 2 (IRS-1 and IRS-2) in liver and muscle of Zucker fatty rats. |
| 2375 | 9421369 | The expressions of IRS-1 and IRS-2 were shown to be downregulated in both liver and muscle in fatty rats (hepatic IRS-1, 83%; hepatic IRS-2, 45%; muscle IRS-1, 60%; muscle IRS-2, 78%), resulting in decreased tyrosine phosphorylation in response to insulin stimulation. |
| 2376 | 9421369 | Despite the decrease in the tyrosine phosphorylation levels of hepatic IRS-1 and IRS-2 being mild to moderate, associated PI 3-kinase activities were dramatically decreased in fatty rats (IRS-1, 14%; IRS-2, 10%), which may suggest alteration in the sites of phosphorylated tyrosine residues of hepatic IRS-1 and IRS-2. |
| 2377 | 9421369 | In addition, we demonstrated that the expressions of p85alpha and p55alpha regulatory subunits of PI 3-kinase were reduced (p85alpha, 67%; p55alpha, 54%), and that the p50alpha regulatory subunit was markedly upregulated (176%) in the livers of fatty rats without apparent alterations in expressions of the catalytic subunits p110alpha and p110beta. |
| 2378 | 9421381 | No difference in mRNA expression between omental and subcutaneous adipose tissue was observed for hormone sensitive lipase, lipoprotein lipase, 6-phosphofructo-1-kinase, insulin receptor substrate 1, p85alpha regulatory subunit of phosphatidylinositol-3-kinase, and Rad. |
| 2379 | 9421381 | Perhaps consistent with a less efficient insulin signaling, a twofold reduction in GLUT4, glycogen synthase, and leptin mRNA expression was observed in omental adipose tissue. |
| 2380 | 9422724 | To test this, binding studies were conducted with tandem domains from the five signaling enzymes: phosphatidylinositol 3-kinase p85, ZAP-70, Syk, SHP-2, and phospholipase C-gamma1. |
| 2381 | 9422724 | Bisphosphorylated TAMs (tyrosine-based activation motifs) were derived from biologically relevant sites in platelet-derived growth factor, T cell, B cell, and high affinity IgE receptors and the receptor substrates IRS-1 (insulin receptor substrate-1) and SHPS-1/SIRP. |
| 2382 | 9422753 | 14-3-3beta protein associates with insulin receptor substrate 1 and decreases insulin-stimulated phosphatidylinositol 3'-kinase activity in 3T3L1 adipocytes. |
| 2383 | 9422753 | An in vitro binding study revealed that glutathione S-transferase-14-3-3beta fusion protein directly associates with recombinant IRS-1. |
| 2384 | 9422753 | Pretreatment of recombinant IRS-1 with alkaline phosphatase clearly decreased this association. |
| 2385 | 9422753 | When the cells are treated with insulin, phosphatidylinositol 3'-kinase (PI3K) is supposed to complex either 14-3-3beta-IRS-1 or IRS-1. |
| 2386 | 9422753 | The specific activity of the PI3K in the former was approximately half of that in the latter, suggesting that 14-3-3beta protein bound to IRS-1 inhibits insulin-stimulated lipid kinase activity of PI3K in 3T3L1 adipocytes. |
| 2387 | 9422753 | 14-3-3beta protein associates with insulin receptor substrate 1 and decreases insulin-stimulated phosphatidylinositol 3'-kinase activity in 3T3L1 adipocytes. |
| 2388 | 9422753 | An in vitro binding study revealed that glutathione S-transferase-14-3-3beta fusion protein directly associates with recombinant IRS-1. |
| 2389 | 9422753 | Pretreatment of recombinant IRS-1 with alkaline phosphatase clearly decreased this association. |
| 2390 | 9422753 | When the cells are treated with insulin, phosphatidylinositol 3'-kinase (PI3K) is supposed to complex either 14-3-3beta-IRS-1 or IRS-1. |
| 2391 | 9422753 | The specific activity of the PI3K in the former was approximately half of that in the latter, suggesting that 14-3-3beta protein bound to IRS-1 inhibits insulin-stimulated lipid kinase activity of PI3K in 3T3L1 adipocytes. |
| 2392 | 9422753 | 14-3-3beta protein associates with insulin receptor substrate 1 and decreases insulin-stimulated phosphatidylinositol 3'-kinase activity in 3T3L1 adipocytes. |
| 2393 | 9422753 | An in vitro binding study revealed that glutathione S-transferase-14-3-3beta fusion protein directly associates with recombinant IRS-1. |
| 2394 | 9422753 | Pretreatment of recombinant IRS-1 with alkaline phosphatase clearly decreased this association. |
| 2395 | 9422753 | When the cells are treated with insulin, phosphatidylinositol 3'-kinase (PI3K) is supposed to complex either 14-3-3beta-IRS-1 or IRS-1. |
| 2396 | 9422753 | The specific activity of the PI3K in the former was approximately half of that in the latter, suggesting that 14-3-3beta protein bound to IRS-1 inhibits insulin-stimulated lipid kinase activity of PI3K in 3T3L1 adipocytes. |
| 2397 | 9422753 | 14-3-3beta protein associates with insulin receptor substrate 1 and decreases insulin-stimulated phosphatidylinositol 3'-kinase activity in 3T3L1 adipocytes. |
| 2398 | 9422753 | An in vitro binding study revealed that glutathione S-transferase-14-3-3beta fusion protein directly associates with recombinant IRS-1. |
| 2399 | 9422753 | Pretreatment of recombinant IRS-1 with alkaline phosphatase clearly decreased this association. |
| 2400 | 9422753 | When the cells are treated with insulin, phosphatidylinositol 3'-kinase (PI3K) is supposed to complex either 14-3-3beta-IRS-1 or IRS-1. |
| 2401 | 9422753 | The specific activity of the PI3K in the former was approximately half of that in the latter, suggesting that 14-3-3beta protein bound to IRS-1 inhibits insulin-stimulated lipid kinase activity of PI3K in 3T3L1 adipocytes. |
| 2402 | 9422753 | 14-3-3beta protein associates with insulin receptor substrate 1 and decreases insulin-stimulated phosphatidylinositol 3'-kinase activity in 3T3L1 adipocytes. |
| 2403 | 9422753 | An in vitro binding study revealed that glutathione S-transferase-14-3-3beta fusion protein directly associates with recombinant IRS-1. |
| 2404 | 9422753 | Pretreatment of recombinant IRS-1 with alkaline phosphatase clearly decreased this association. |
| 2405 | 9422753 | When the cells are treated with insulin, phosphatidylinositol 3'-kinase (PI3K) is supposed to complex either 14-3-3beta-IRS-1 or IRS-1. |
| 2406 | 9422753 | The specific activity of the PI3K in the former was approximately half of that in the latter, suggesting that 14-3-3beta protein bound to IRS-1 inhibits insulin-stimulated lipid kinase activity of PI3K in 3T3L1 adipocytes. |
| 2407 | 9440478 | In adipocytes isolated from control rats, insulin (5 nmol/L) stimulated particulate serine/threonine protein phosphatase-1 (PP-1) activity (56% increase over the basal value after 5 minutes). |
| 2408 | 9440478 | In contrast, adipocytes from diabetic GK rats exhibited a 32% decrease in basal (P < .05) and a 65% decrease in insulin-stimulated PP-1 activity compared with values in control Wistar rats. |
| 2409 | 9440478 | Insulin treatment resulted in a 50% to 60% inhibition in PP-2A activity in control rats, but failed to inhibit PP-2A activity in diabetic GK rat adipocytes. |
| 2410 | 9440478 | The defects in PP-1/PP-2A activation/inactivation were accompanied by inhibition of insulin's effect on mitogen-activated protein kinase (MAPK) activation. |
| 2411 | 9440478 | In addition, insulin-stimulated tyrosine phosphorylation of insulin receptor (IR) substrate-1 (IRS-1) was decreased more than 90% compared with control values, while a twofold increase in basal IRS-1 phosphorylation status was observed in diabetic GK rats. |
| 2412 | 9440478 | The abnormalities in IRS-1 phosphorylation were accompanied by a severe impairment of insulin-mediated targeting of the Grb2/Sos complex to the plasma membrane. |
| 2413 | 9440478 | We conclude that (1) a rapid activation of PP-1 along with concomitant inhibition of cytosolic PP-2A may be important in the mechanism of insulin action in a normal cell, and (2) the resistance to insulin in terms of glucose uptake and glycogen synthesis observed in diabetic GK rats is partly due to defective regulation of PP-1, PP-2A, and MAPK caused by multiple defects in the upstream insulin signaling components (IRS-1/phosphatidylinositol-3-kinase [PI3-kinase] and Grb2/Sos) that participate in insulin-mediated activation of PP-1 and inactivation of PP-2A. |
| 2414 | 9440478 | In adipocytes isolated from control rats, insulin (5 nmol/L) stimulated particulate serine/threonine protein phosphatase-1 (PP-1) activity (56% increase over the basal value after 5 minutes). |
| 2415 | 9440478 | In contrast, adipocytes from diabetic GK rats exhibited a 32% decrease in basal (P < .05) and a 65% decrease in insulin-stimulated PP-1 activity compared with values in control Wistar rats. |
| 2416 | 9440478 | Insulin treatment resulted in a 50% to 60% inhibition in PP-2A activity in control rats, but failed to inhibit PP-2A activity in diabetic GK rat adipocytes. |
| 2417 | 9440478 | The defects in PP-1/PP-2A activation/inactivation were accompanied by inhibition of insulin's effect on mitogen-activated protein kinase (MAPK) activation. |
| 2418 | 9440478 | In addition, insulin-stimulated tyrosine phosphorylation of insulin receptor (IR) substrate-1 (IRS-1) was decreased more than 90% compared with control values, while a twofold increase in basal IRS-1 phosphorylation status was observed in diabetic GK rats. |
| 2419 | 9440478 | The abnormalities in IRS-1 phosphorylation were accompanied by a severe impairment of insulin-mediated targeting of the Grb2/Sos complex to the plasma membrane. |
| 2420 | 9440478 | We conclude that (1) a rapid activation of PP-1 along with concomitant inhibition of cytosolic PP-2A may be important in the mechanism of insulin action in a normal cell, and (2) the resistance to insulin in terms of glucose uptake and glycogen synthesis observed in diabetic GK rats is partly due to defective regulation of PP-1, PP-2A, and MAPK caused by multiple defects in the upstream insulin signaling components (IRS-1/phosphatidylinositol-3-kinase [PI3-kinase] and Grb2/Sos) that participate in insulin-mediated activation of PP-1 and inactivation of PP-2A. |
| 2421 | 9440478 | In adipocytes isolated from control rats, insulin (5 nmol/L) stimulated particulate serine/threonine protein phosphatase-1 (PP-1) activity (56% increase over the basal value after 5 minutes). |
| 2422 | 9440478 | In contrast, adipocytes from diabetic GK rats exhibited a 32% decrease in basal (P < .05) and a 65% decrease in insulin-stimulated PP-1 activity compared with values in control Wistar rats. |
| 2423 | 9440478 | Insulin treatment resulted in a 50% to 60% inhibition in PP-2A activity in control rats, but failed to inhibit PP-2A activity in diabetic GK rat adipocytes. |
| 2424 | 9440478 | The defects in PP-1/PP-2A activation/inactivation were accompanied by inhibition of insulin's effect on mitogen-activated protein kinase (MAPK) activation. |
| 2425 | 9440478 | In addition, insulin-stimulated tyrosine phosphorylation of insulin receptor (IR) substrate-1 (IRS-1) was decreased more than 90% compared with control values, while a twofold increase in basal IRS-1 phosphorylation status was observed in diabetic GK rats. |
| 2426 | 9440478 | The abnormalities in IRS-1 phosphorylation were accompanied by a severe impairment of insulin-mediated targeting of the Grb2/Sos complex to the plasma membrane. |
| 2427 | 9440478 | We conclude that (1) a rapid activation of PP-1 along with concomitant inhibition of cytosolic PP-2A may be important in the mechanism of insulin action in a normal cell, and (2) the resistance to insulin in terms of glucose uptake and glycogen synthesis observed in diabetic GK rats is partly due to defective regulation of PP-1, PP-2A, and MAPK caused by multiple defects in the upstream insulin signaling components (IRS-1/phosphatidylinositol-3-kinase [PI3-kinase] and Grb2/Sos) that participate in insulin-mediated activation of PP-1 and inactivation of PP-2A. |
| 2428 | 9461521 | A novel phosphoinositolglycan-peptide (PIG-P) from the yeast Saccharomyces cerevisiae potently mimicks insulin action on glucose transport and metabolism in rat muscle and adipose tissue. |
| 2429 | 9461521 | Rapid onset and reversibility of PIG-P action on glucose transport were observed in isolated adipocytes with a half-time of transport stimulation of 6-8 min (insulin less than 5 min). |
| 2430 | 9461521 | Combined treatment with PIG-P and insulin indicated additive stimulation of glucose transport at submaximal concentrations and non-additive action of both agents at maximal doses. |
| 2431 | 9461521 | The tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) was markedly increased in response to PIG-P in rat cardiomyocytes without any effect on the tyrosine phosphorylation of the insulin receptor beta-subunit. |
| 2432 | 9461521 | Downstream signalling of IRS-1 was then analysed by monitoring IRS-1-associated phosphatidylinositol 3-kinase (PI 3-kinase) activity in cardiomyocytes. |
| 2433 | 9461521 | A stable (2 and 15 min incubation with PIG-P) 7-fold stimulation corresponding to about 50% of insulin action could be detected. |
| 2434 | 9461521 | Increased tyrosine phosphorylation of IRS-1 and enhanced PI 3-kinase activity in response to PIG-P independent of the insulin receptor was also observed in isolated adipocytes. |
| 2435 | 9461521 | These data suggest divergent upstream signalling by insulin and PIG-P involving phosphoproteins not affected by insulin. |
| 2436 | 9461521 | However, PIG-P and insulin action converge at the level of IRS-1 inducing insulin-independent PI 3-kinase-mediated signalling to glucose transport. |
| 2437 | 9461521 | A novel phosphoinositolglycan-peptide (PIG-P) from the yeast Saccharomyces cerevisiae potently mimicks insulin action on glucose transport and metabolism in rat muscle and adipose tissue. |
| 2438 | 9461521 | Rapid onset and reversibility of PIG-P action on glucose transport were observed in isolated adipocytes with a half-time of transport stimulation of 6-8 min (insulin less than 5 min). |
| 2439 | 9461521 | Combined treatment with PIG-P and insulin indicated additive stimulation of glucose transport at submaximal concentrations and non-additive action of both agents at maximal doses. |
| 2440 | 9461521 | The tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) was markedly increased in response to PIG-P in rat cardiomyocytes without any effect on the tyrosine phosphorylation of the insulin receptor beta-subunit. |
| 2441 | 9461521 | Downstream signalling of IRS-1 was then analysed by monitoring IRS-1-associated phosphatidylinositol 3-kinase (PI 3-kinase) activity in cardiomyocytes. |
| 2442 | 9461521 | A stable (2 and 15 min incubation with PIG-P) 7-fold stimulation corresponding to about 50% of insulin action could be detected. |
| 2443 | 9461521 | Increased tyrosine phosphorylation of IRS-1 and enhanced PI 3-kinase activity in response to PIG-P independent of the insulin receptor was also observed in isolated adipocytes. |
| 2444 | 9461521 | These data suggest divergent upstream signalling by insulin and PIG-P involving phosphoproteins not affected by insulin. |
| 2445 | 9461521 | However, PIG-P and insulin action converge at the level of IRS-1 inducing insulin-independent PI 3-kinase-mediated signalling to glucose transport. |
| 2446 | 9461521 | A novel phosphoinositolglycan-peptide (PIG-P) from the yeast Saccharomyces cerevisiae potently mimicks insulin action on glucose transport and metabolism in rat muscle and adipose tissue. |
| 2447 | 9461521 | Rapid onset and reversibility of PIG-P action on glucose transport were observed in isolated adipocytes with a half-time of transport stimulation of 6-8 min (insulin less than 5 min). |
| 2448 | 9461521 | Combined treatment with PIG-P and insulin indicated additive stimulation of glucose transport at submaximal concentrations and non-additive action of both agents at maximal doses. |
| 2449 | 9461521 | The tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) was markedly increased in response to PIG-P in rat cardiomyocytes without any effect on the tyrosine phosphorylation of the insulin receptor beta-subunit. |
| 2450 | 9461521 | Downstream signalling of IRS-1 was then analysed by monitoring IRS-1-associated phosphatidylinositol 3-kinase (PI 3-kinase) activity in cardiomyocytes. |
| 2451 | 9461521 | A stable (2 and 15 min incubation with PIG-P) 7-fold stimulation corresponding to about 50% of insulin action could be detected. |
| 2452 | 9461521 | Increased tyrosine phosphorylation of IRS-1 and enhanced PI 3-kinase activity in response to PIG-P independent of the insulin receptor was also observed in isolated adipocytes. |
| 2453 | 9461521 | These data suggest divergent upstream signalling by insulin and PIG-P involving phosphoproteins not affected by insulin. |
| 2454 | 9461521 | However, PIG-P and insulin action converge at the level of IRS-1 inducing insulin-independent PI 3-kinase-mediated signalling to glucose transport. |
| 2455 | 9461521 | A novel phosphoinositolglycan-peptide (PIG-P) from the yeast Saccharomyces cerevisiae potently mimicks insulin action on glucose transport and metabolism in rat muscle and adipose tissue. |
| 2456 | 9461521 | Rapid onset and reversibility of PIG-P action on glucose transport were observed in isolated adipocytes with a half-time of transport stimulation of 6-8 min (insulin less than 5 min). |
| 2457 | 9461521 | Combined treatment with PIG-P and insulin indicated additive stimulation of glucose transport at submaximal concentrations and non-additive action of both agents at maximal doses. |
| 2458 | 9461521 | The tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) was markedly increased in response to PIG-P in rat cardiomyocytes without any effect on the tyrosine phosphorylation of the insulin receptor beta-subunit. |
| 2459 | 9461521 | Downstream signalling of IRS-1 was then analysed by monitoring IRS-1-associated phosphatidylinositol 3-kinase (PI 3-kinase) activity in cardiomyocytes. |
| 2460 | 9461521 | A stable (2 and 15 min incubation with PIG-P) 7-fold stimulation corresponding to about 50% of insulin action could be detected. |
| 2461 | 9461521 | Increased tyrosine phosphorylation of IRS-1 and enhanced PI 3-kinase activity in response to PIG-P independent of the insulin receptor was also observed in isolated adipocytes. |
| 2462 | 9461521 | These data suggest divergent upstream signalling by insulin and PIG-P involving phosphoproteins not affected by insulin. |
| 2463 | 9461521 | However, PIG-P and insulin action converge at the level of IRS-1 inducing insulin-independent PI 3-kinase-mediated signalling to glucose transport. |
| 2464 | 9468528 | Insulin-like growth factor-I receptor internalization regulates signaling via the Shc/mitogen-activated protein kinase pathway, but not the insulin receptor substrate-1 pathway. |
| 2465 | 9468528 | Insulin-like growth factor-I (IGF-I) receptors activate divergent signaling pathways by phosphorylating multiple cellular proteins, including insulin receptor substrate-1 (IRS-1) and the Shc proteins. |
| 2466 | 9468528 | This study investigates the relationship between IGF-I receptor internalization and signaling via IRS-1 and Shc. |
| 2467 | 9468528 | A mutation in the C terminus of the IGF-I receptor decreased both the rate of receptor internalization and IGF-I-stimulated Shc phosphorylation by more than 50%, but did not affect IRS-1 phosphorylation. |
| 2468 | 9468528 | Low temperature (15 degrees C) decreased IGF-I receptor internalization and completely inhibited Shc phosphorylation. |
| 2469 | 9468528 | Dansylcadaverine decreased receptor internalization and Shc phosphorylation, but did not change receptor or IRS-1 phosphorylation. |
| 2470 | 9468528 | Consistent with these findings, dansylcadaverine inhibited IGF-I-stimulated Shc-Grb2 association, mitogen-activated protein kinase phosphorylation, and p90 ribosomal S6 kinase activation, but did not affect the association of phosphatidylinositide 3-kinase with IRS-1 or activation of p70 S6 kinase. |
| 2471 | 9468528 | These data support the concept that Shc/mitogen-activated protein kinase pathway activation requires IGF-I receptor internalization, whereas the IRS-1 pathway is activated by both cell surface and endosomal receptors. |
| 2472 | 9468528 | Insulin-like growth factor-I receptor internalization regulates signaling via the Shc/mitogen-activated protein kinase pathway, but not the insulin receptor substrate-1 pathway. |
| 2473 | 9468528 | Insulin-like growth factor-I (IGF-I) receptors activate divergent signaling pathways by phosphorylating multiple cellular proteins, including insulin receptor substrate-1 (IRS-1) and the Shc proteins. |
| 2474 | 9468528 | This study investigates the relationship between IGF-I receptor internalization and signaling via IRS-1 and Shc. |
| 2475 | 9468528 | A mutation in the C terminus of the IGF-I receptor decreased both the rate of receptor internalization and IGF-I-stimulated Shc phosphorylation by more than 50%, but did not affect IRS-1 phosphorylation. |
| 2476 | 9468528 | Low temperature (15 degrees C) decreased IGF-I receptor internalization and completely inhibited Shc phosphorylation. |
| 2477 | 9468528 | Dansylcadaverine decreased receptor internalization and Shc phosphorylation, but did not change receptor or IRS-1 phosphorylation. |
| 2478 | 9468528 | Consistent with these findings, dansylcadaverine inhibited IGF-I-stimulated Shc-Grb2 association, mitogen-activated protein kinase phosphorylation, and p90 ribosomal S6 kinase activation, but did not affect the association of phosphatidylinositide 3-kinase with IRS-1 or activation of p70 S6 kinase. |
| 2479 | 9468528 | These data support the concept that Shc/mitogen-activated protein kinase pathway activation requires IGF-I receptor internalization, whereas the IRS-1 pathway is activated by both cell surface and endosomal receptors. |
| 2480 | 9468528 | Insulin-like growth factor-I receptor internalization regulates signaling via the Shc/mitogen-activated protein kinase pathway, but not the insulin receptor substrate-1 pathway. |
| 2481 | 9468528 | Insulin-like growth factor-I (IGF-I) receptors activate divergent signaling pathways by phosphorylating multiple cellular proteins, including insulin receptor substrate-1 (IRS-1) and the Shc proteins. |
| 2482 | 9468528 | This study investigates the relationship between IGF-I receptor internalization and signaling via IRS-1 and Shc. |
| 2483 | 9468528 | A mutation in the C terminus of the IGF-I receptor decreased both the rate of receptor internalization and IGF-I-stimulated Shc phosphorylation by more than 50%, but did not affect IRS-1 phosphorylation. |
| 2484 | 9468528 | Low temperature (15 degrees C) decreased IGF-I receptor internalization and completely inhibited Shc phosphorylation. |
| 2485 | 9468528 | Dansylcadaverine decreased receptor internalization and Shc phosphorylation, but did not change receptor or IRS-1 phosphorylation. |
| 2486 | 9468528 | Consistent with these findings, dansylcadaverine inhibited IGF-I-stimulated Shc-Grb2 association, mitogen-activated protein kinase phosphorylation, and p90 ribosomal S6 kinase activation, but did not affect the association of phosphatidylinositide 3-kinase with IRS-1 or activation of p70 S6 kinase. |
| 2487 | 9468528 | These data support the concept that Shc/mitogen-activated protein kinase pathway activation requires IGF-I receptor internalization, whereas the IRS-1 pathway is activated by both cell surface and endosomal receptors. |
| 2488 | 9468528 | Insulin-like growth factor-I receptor internalization regulates signaling via the Shc/mitogen-activated protein kinase pathway, but not the insulin receptor substrate-1 pathway. |
| 2489 | 9468528 | Insulin-like growth factor-I (IGF-I) receptors activate divergent signaling pathways by phosphorylating multiple cellular proteins, including insulin receptor substrate-1 (IRS-1) and the Shc proteins. |
| 2490 | 9468528 | This study investigates the relationship between IGF-I receptor internalization and signaling via IRS-1 and Shc. |
| 2491 | 9468528 | A mutation in the C terminus of the IGF-I receptor decreased both the rate of receptor internalization and IGF-I-stimulated Shc phosphorylation by more than 50%, but did not affect IRS-1 phosphorylation. |
| 2492 | 9468528 | Low temperature (15 degrees C) decreased IGF-I receptor internalization and completely inhibited Shc phosphorylation. |
| 2493 | 9468528 | Dansylcadaverine decreased receptor internalization and Shc phosphorylation, but did not change receptor or IRS-1 phosphorylation. |
| 2494 | 9468528 | Consistent with these findings, dansylcadaverine inhibited IGF-I-stimulated Shc-Grb2 association, mitogen-activated protein kinase phosphorylation, and p90 ribosomal S6 kinase activation, but did not affect the association of phosphatidylinositide 3-kinase with IRS-1 or activation of p70 S6 kinase. |
| 2495 | 9468528 | These data support the concept that Shc/mitogen-activated protein kinase pathway activation requires IGF-I receptor internalization, whereas the IRS-1 pathway is activated by both cell surface and endosomal receptors. |
| 2496 | 9468528 | Insulin-like growth factor-I receptor internalization regulates signaling via the Shc/mitogen-activated protein kinase pathway, but not the insulin receptor substrate-1 pathway. |
| 2497 | 9468528 | Insulin-like growth factor-I (IGF-I) receptors activate divergent signaling pathways by phosphorylating multiple cellular proteins, including insulin receptor substrate-1 (IRS-1) and the Shc proteins. |
| 2498 | 9468528 | This study investigates the relationship between IGF-I receptor internalization and signaling via IRS-1 and Shc. |
| 2499 | 9468528 | A mutation in the C terminus of the IGF-I receptor decreased both the rate of receptor internalization and IGF-I-stimulated Shc phosphorylation by more than 50%, but did not affect IRS-1 phosphorylation. |
| 2500 | 9468528 | Low temperature (15 degrees C) decreased IGF-I receptor internalization and completely inhibited Shc phosphorylation. |
| 2501 | 9468528 | Dansylcadaverine decreased receptor internalization and Shc phosphorylation, but did not change receptor or IRS-1 phosphorylation. |
| 2502 | 9468528 | Consistent with these findings, dansylcadaverine inhibited IGF-I-stimulated Shc-Grb2 association, mitogen-activated protein kinase phosphorylation, and p90 ribosomal S6 kinase activation, but did not affect the association of phosphatidylinositide 3-kinase with IRS-1 or activation of p70 S6 kinase. |
| 2503 | 9468528 | These data support the concept that Shc/mitogen-activated protein kinase pathway activation requires IGF-I receptor internalization, whereas the IRS-1 pathway is activated by both cell surface and endosomal receptors. |
| 2504 | 9468528 | Insulin-like growth factor-I receptor internalization regulates signaling via the Shc/mitogen-activated protein kinase pathway, but not the insulin receptor substrate-1 pathway. |
| 2505 | 9468528 | Insulin-like growth factor-I (IGF-I) receptors activate divergent signaling pathways by phosphorylating multiple cellular proteins, including insulin receptor substrate-1 (IRS-1) and the Shc proteins. |
| 2506 | 9468528 | This study investigates the relationship between IGF-I receptor internalization and signaling via IRS-1 and Shc. |
| 2507 | 9468528 | A mutation in the C terminus of the IGF-I receptor decreased both the rate of receptor internalization and IGF-I-stimulated Shc phosphorylation by more than 50%, but did not affect IRS-1 phosphorylation. |
| 2508 | 9468528 | Low temperature (15 degrees C) decreased IGF-I receptor internalization and completely inhibited Shc phosphorylation. |
| 2509 | 9468528 | Dansylcadaverine decreased receptor internalization and Shc phosphorylation, but did not change receptor or IRS-1 phosphorylation. |
| 2510 | 9468528 | Consistent with these findings, dansylcadaverine inhibited IGF-I-stimulated Shc-Grb2 association, mitogen-activated protein kinase phosphorylation, and p90 ribosomal S6 kinase activation, but did not affect the association of phosphatidylinositide 3-kinase with IRS-1 or activation of p70 S6 kinase. |
| 2511 | 9468528 | These data support the concept that Shc/mitogen-activated protein kinase pathway activation requires IGF-I receptor internalization, whereas the IRS-1 pathway is activated by both cell surface and endosomal receptors. |
| 2512 | 9468528 | Insulin-like growth factor-I receptor internalization regulates signaling via the Shc/mitogen-activated protein kinase pathway, but not the insulin receptor substrate-1 pathway. |
| 2513 | 9468528 | Insulin-like growth factor-I (IGF-I) receptors activate divergent signaling pathways by phosphorylating multiple cellular proteins, including insulin receptor substrate-1 (IRS-1) and the Shc proteins. |
| 2514 | 9468528 | This study investigates the relationship between IGF-I receptor internalization and signaling via IRS-1 and Shc. |
| 2515 | 9468528 | A mutation in the C terminus of the IGF-I receptor decreased both the rate of receptor internalization and IGF-I-stimulated Shc phosphorylation by more than 50%, but did not affect IRS-1 phosphorylation. |
| 2516 | 9468528 | Low temperature (15 degrees C) decreased IGF-I receptor internalization and completely inhibited Shc phosphorylation. |
| 2517 | 9468528 | Dansylcadaverine decreased receptor internalization and Shc phosphorylation, but did not change receptor or IRS-1 phosphorylation. |
| 2518 | 9468528 | Consistent with these findings, dansylcadaverine inhibited IGF-I-stimulated Shc-Grb2 association, mitogen-activated protein kinase phosphorylation, and p90 ribosomal S6 kinase activation, but did not affect the association of phosphatidylinositide 3-kinase with IRS-1 or activation of p70 S6 kinase. |
| 2519 | 9468528 | These data support the concept that Shc/mitogen-activated protein kinase pathway activation requires IGF-I receptor internalization, whereas the IRS-1 pathway is activated by both cell surface and endosomal receptors. |
| 2520 | 9492043 | p53 regulates insulin-like growth factor-I (IGF-I) receptor expression and IGF-I-induced tyrosine phosphorylation in an osteosarcoma cell line: interaction between p53 and Sp1. |
| 2521 | 9492043 | The insulin-like growth factor-I receptor (IGF-IR) is involved in tumorigenesis. |
| 2522 | 9492043 | The aim of the present study was to investigate whether the IGF-IR is a physiological target for p53 in osteosarcoma cells. |
| 2523 | 9492043 | The p53-induced regulation of IGF-IR levels was studied in a tetracycline-regulated expression system. |
| 2524 | 9492043 | When expressed in Saos-2, osteosarcoma cells that lack p53, wild-type p53 decreased, whereas mutated p53 increased IGF-IR expression, and IGF-I-induced tyrosine phosphorylation of the IGF-IR. |
| 2525 | 9492043 | Similarly, wild-type p53 decreased IGF-I-induced tyrosine phosphorylation of IRS-1. |
| 2526 | 9492043 | A functional and physical interaction between p53 and Sp1, in the regulation of the IGF-R, was studied in osteosarcoma cells. |
| 2527 | 9492043 | Expression of p53 decreased IGF-IR promoter activity, whereas no effect on promoter activity was seen by Sp1 expressed alone. |
| 2528 | 9492043 | However, Sp1 counteracted the inhibitory effect of p53 on IGF-IR promoter activity in a dose-dependent manner. |
| 2529 | 9492043 | Furthermore, wild-type and mutated p53 were coimmunoprecipitated with Sp1, indicating a physical interaction between p53 and Sp1. |
| 2530 | 9492043 | In conclusion, p53 regulates IGF-IR expression, as reflected by a reduction in IGF-IR protein and a parallel reduction in IGF-I-induced tyrosine phosphorylation of the IGF-IR and IRS-1 in an osteosarcoma cell line. |
| 2531 | 9492043 | These data indicate that the IGF-I receptor is a physiological target for p53 in osteosarcoma cells. |
| 2532 | 9492043 | Furthermore, data supporting an interaction between p53 and Sp1 in the regulation of the promoter activity of IGF-IR are presented. |
| 2533 | 9492043 | p53 regulates insulin-like growth factor-I (IGF-I) receptor expression and IGF-I-induced tyrosine phosphorylation in an osteosarcoma cell line: interaction between p53 and Sp1. |
| 2534 | 9492043 | The insulin-like growth factor-I receptor (IGF-IR) is involved in tumorigenesis. |
| 2535 | 9492043 | The aim of the present study was to investigate whether the IGF-IR is a physiological target for p53 in osteosarcoma cells. |
| 2536 | 9492043 | The p53-induced regulation of IGF-IR levels was studied in a tetracycline-regulated expression system. |
| 2537 | 9492043 | When expressed in Saos-2, osteosarcoma cells that lack p53, wild-type p53 decreased, whereas mutated p53 increased IGF-IR expression, and IGF-I-induced tyrosine phosphorylation of the IGF-IR. |
| 2538 | 9492043 | Similarly, wild-type p53 decreased IGF-I-induced tyrosine phosphorylation of IRS-1. |
| 2539 | 9492043 | A functional and physical interaction between p53 and Sp1, in the regulation of the IGF-R, was studied in osteosarcoma cells. |
| 2540 | 9492043 | Expression of p53 decreased IGF-IR promoter activity, whereas no effect on promoter activity was seen by Sp1 expressed alone. |
| 2541 | 9492043 | However, Sp1 counteracted the inhibitory effect of p53 on IGF-IR promoter activity in a dose-dependent manner. |
| 2542 | 9492043 | Furthermore, wild-type and mutated p53 were coimmunoprecipitated with Sp1, indicating a physical interaction between p53 and Sp1. |
| 2543 | 9492043 | In conclusion, p53 regulates IGF-IR expression, as reflected by a reduction in IGF-IR protein and a parallel reduction in IGF-I-induced tyrosine phosphorylation of the IGF-IR and IRS-1 in an osteosarcoma cell line. |
| 2544 | 9492043 | These data indicate that the IGF-I receptor is a physiological target for p53 in osteosarcoma cells. |
| 2545 | 9492043 | Furthermore, data supporting an interaction between p53 and Sp1 in the regulation of the promoter activity of IGF-IR are presented. |
| 2546 | 9495343 | Disruption of IRS-1 in mice retards growth, but diabetes does not develop because insulin secretion increases to compensate for the mild resistance to insulin. |
| 2547 | 9495343 | Here we show that disruption of IRS-2 impairs both peripheral insulin signalling and pancreatic beta-cell function. |
| 2548 | 9518262 | Overexpression of membrane glycoprotein PC-1 can influence insulin action at a post-receptor site. |
| 2549 | 9518262 | An elevated content of membrane glycoprotein PC-1 has been observed in cells and tissues of insulin resistant patients. |
| 2550 | 9518262 | In addition, in vitro overexpression of PC-1 in cultured cells induces insulin resistance associated with diminished insulin receptor tyrosine kinase activity. |
| 2551 | 9518262 | We now find that PC-1 overexpression also influences insulin receptor signaling at a step downstream of insulin receptor tyrosine kinase, independent of insulin receptor tyrosine kinase. |
| 2552 | 9518262 | In the present studies, we employed Chinese hamster ovary cells that overexpress the human insulin receptor (CHO IR cells; approximately 10(6) receptors per cell), and transfected them with human PC-1 c-DNA (CHO IR PC-1). |
| 2553 | 9518262 | In CHO IR PC-1 cells, insulin receptor tyrosine kinase activity was unchanged, following insulin treatment of cells. |
| 2554 | 9518262 | In CHO IR PC-1 cells, insulin stimulation of mitogen-activated protein (MAP) kinase activity was normal, suggesting that PC-1 overexpression did not affect insulin receptor activation of Ras, which is upstream of MAP kinase. |
| 2555 | 9518262 | Also, insulin-stimulated phosphatidylinositol (PI)-3-kinase activity was normal, suggesting that PC-1 overexpression did not interfere with the activation of this enzyme by insulin receptor substrate-1. |
| 2556 | 9518262 | In these cells, however, insulin stimulation of p70 ribosomal S6 kinase activity was diminished. |
| 2557 | 9518262 | These studies suggest, therefore, that, in addition to blocking insulin receptor tyrosine kinase activation, PC-1 can also block insulin receptor signaling at a post-receptor site. |
| 2558 | 9519710 | Possibility of distinct insulin-signaling pathways beyond phosphatidylinositol 3-kinase-mediating glucose transport and lipogenesis. |
| 2559 | 9519710 | Tyrosine phosphorylation of the insulin receptor (IR), insulin receptor substrates 1 and 2 (IRS-1 and IRS-2), and pp60, and phosphatidylinositol (PI) 3-kinase activity (using PI as substrate) and mitogen-activated protein kinase (MAPK) activity were assayed in cell lysates. |
| 2560 | 9519710 | Englitazone did not increase IR, IRS-1/IRS-2, pp60, or MAPK phosphorylation, nor did it enhance insulin's stimulation of these parameters. |
| 2561 | 9519710 | Significant (63%) inhibition of insulin-stimulated lipogenesis occurred at a concentration of englitazone (30 micromol/l) that did not affect MAPK activation, which suggests that the drug's inhibitory effect on lipogenesis is not mediated by this pathway. |
| 2562 | 9519710 | Possibility of distinct insulin-signaling pathways beyond phosphatidylinositol 3-kinase-mediating glucose transport and lipogenesis. |
| 2563 | 9519710 | Tyrosine phosphorylation of the insulin receptor (IR), insulin receptor substrates 1 and 2 (IRS-1 and IRS-2), and pp60, and phosphatidylinositol (PI) 3-kinase activity (using PI as substrate) and mitogen-activated protein kinase (MAPK) activity were assayed in cell lysates. |
| 2564 | 9519710 | Englitazone did not increase IR, IRS-1/IRS-2, pp60, or MAPK phosphorylation, nor did it enhance insulin's stimulation of these parameters. |
| 2565 | 9519710 | Significant (63%) inhibition of insulin-stimulated lipogenesis occurred at a concentration of englitazone (30 micromol/l) that did not affect MAPK activation, which suggests that the drug's inhibitory effect on lipogenesis is not mediated by this pathway. |
| 2566 | 9525995 | Exposure of cells to high physiologic concentrations of amino acids activates intermediates important in the initiation of protein synthesis, including p70 S6 kinase and PHAS-I, in synergy with insulin. |
| 2567 | 9525995 | Concurrently, amino acids inhibit early steps in insulin action critical for glucose transport and inhibition of gluconeogenesis, including decreased insulin-stimulated tyrosine phosphorylation of IRS-1 and IRS-2, decreased binding of grb 2 and the p85 subunit of phosphatidylinositol 3-kinase to IRS-1 and IRS-2, and a marked inhibition of insulin-stimulated phosphatidylinositol 3-kinase. |
| 2568 | 9565570 | Differential compartmentalization and trafficking of insulin receptor substrate (IRS)-1 and IRS-2. |
| 2569 | 9565570 | We find that insulin receptor substrate (IRS)-1 is 2-fold more concentrated in the intracellular membrane (IM) compartment than in cytosol, whereas IRS-2 is 2-fold more concentrated in cytosol than in IM. |
| 2570 | 9565570 | Insulin stimulation induces rapid tyrosine phosphorylation of both IRS-1 and IRS-2. |
| 2571 | 9565570 | Furthermore, after insulin stimulation, both IRS-1 and IRS-2 translocate from IM to cytosol with a t1/2 of 3.5 min. |
| 2572 | 9565570 | By comparison, within 1 min after insulin stimulation, 40% of the total pool of the 85-kDa subunit of phosphatidylinositol 3-kinase (p85) is recruited from cytosol to IM, the greater part of which can be accounted for by binding to IRS-1 present in the IM. |
| 2573 | 9565570 | The p85 binding and phosphatidylinositol 3-kinase activity associated with IRS-2 rapidly decrease in both IM and cytosol, whereas those associated with IRS-1 stay at a relatively high level in IM and increase with time in cytosol despite a return of p85 to the cytosol and decreasing tyrosine phosphorylation of cytosolic IRS-1. |
| 2574 | 9565570 | These data indicate that IRS-1 and IRS-2 are differentially distributed in the cell and move from IM to cytosol following insulin stimulation. |
| 2575 | 9565570 | Insulin-stimulated IRS-1 and IRS-2 signaling occurs mainly in the IM and shows different kinetics; IRS-1-mediated signaling is more stable, whereas IRS-2-mediated signaling is more transient. |
| 2576 | 9565570 | Differential compartmentalization and trafficking of insulin receptor substrate (IRS)-1 and IRS-2. |
| 2577 | 9565570 | We find that insulin receptor substrate (IRS)-1 is 2-fold more concentrated in the intracellular membrane (IM) compartment than in cytosol, whereas IRS-2 is 2-fold more concentrated in cytosol than in IM. |
| 2578 | 9565570 | Insulin stimulation induces rapid tyrosine phosphorylation of both IRS-1 and IRS-2. |
| 2579 | 9565570 | Furthermore, after insulin stimulation, both IRS-1 and IRS-2 translocate from IM to cytosol with a t1/2 of 3.5 min. |
| 2580 | 9565570 | By comparison, within 1 min after insulin stimulation, 40% of the total pool of the 85-kDa subunit of phosphatidylinositol 3-kinase (p85) is recruited from cytosol to IM, the greater part of which can be accounted for by binding to IRS-1 present in the IM. |
| 2581 | 9565570 | The p85 binding and phosphatidylinositol 3-kinase activity associated with IRS-2 rapidly decrease in both IM and cytosol, whereas those associated with IRS-1 stay at a relatively high level in IM and increase with time in cytosol despite a return of p85 to the cytosol and decreasing tyrosine phosphorylation of cytosolic IRS-1. |
| 2582 | 9565570 | These data indicate that IRS-1 and IRS-2 are differentially distributed in the cell and move from IM to cytosol following insulin stimulation. |
| 2583 | 9565570 | Insulin-stimulated IRS-1 and IRS-2 signaling occurs mainly in the IM and shows different kinetics; IRS-1-mediated signaling is more stable, whereas IRS-2-mediated signaling is more transient. |
| 2584 | 9565570 | Differential compartmentalization and trafficking of insulin receptor substrate (IRS)-1 and IRS-2. |
| 2585 | 9565570 | We find that insulin receptor substrate (IRS)-1 is 2-fold more concentrated in the intracellular membrane (IM) compartment than in cytosol, whereas IRS-2 is 2-fold more concentrated in cytosol than in IM. |
| 2586 | 9565570 | Insulin stimulation induces rapid tyrosine phosphorylation of both IRS-1 and IRS-2. |
| 2587 | 9565570 | Furthermore, after insulin stimulation, both IRS-1 and IRS-2 translocate from IM to cytosol with a t1/2 of 3.5 min. |
| 2588 | 9565570 | By comparison, within 1 min after insulin stimulation, 40% of the total pool of the 85-kDa subunit of phosphatidylinositol 3-kinase (p85) is recruited from cytosol to IM, the greater part of which can be accounted for by binding to IRS-1 present in the IM. |
| 2589 | 9565570 | The p85 binding and phosphatidylinositol 3-kinase activity associated with IRS-2 rapidly decrease in both IM and cytosol, whereas those associated with IRS-1 stay at a relatively high level in IM and increase with time in cytosol despite a return of p85 to the cytosol and decreasing tyrosine phosphorylation of cytosolic IRS-1. |
| 2590 | 9565570 | These data indicate that IRS-1 and IRS-2 are differentially distributed in the cell and move from IM to cytosol following insulin stimulation. |
| 2591 | 9565570 | Insulin-stimulated IRS-1 and IRS-2 signaling occurs mainly in the IM and shows different kinetics; IRS-1-mediated signaling is more stable, whereas IRS-2-mediated signaling is more transient. |
| 2592 | 9565570 | Differential compartmentalization and trafficking of insulin receptor substrate (IRS)-1 and IRS-2. |
| 2593 | 9565570 | We find that insulin receptor substrate (IRS)-1 is 2-fold more concentrated in the intracellular membrane (IM) compartment than in cytosol, whereas IRS-2 is 2-fold more concentrated in cytosol than in IM. |
| 2594 | 9565570 | Insulin stimulation induces rapid tyrosine phosphorylation of both IRS-1 and IRS-2. |
| 2595 | 9565570 | Furthermore, after insulin stimulation, both IRS-1 and IRS-2 translocate from IM to cytosol with a t1/2 of 3.5 min. |
| 2596 | 9565570 | By comparison, within 1 min after insulin stimulation, 40% of the total pool of the 85-kDa subunit of phosphatidylinositol 3-kinase (p85) is recruited from cytosol to IM, the greater part of which can be accounted for by binding to IRS-1 present in the IM. |
| 2597 | 9565570 | The p85 binding and phosphatidylinositol 3-kinase activity associated with IRS-2 rapidly decrease in both IM and cytosol, whereas those associated with IRS-1 stay at a relatively high level in IM and increase with time in cytosol despite a return of p85 to the cytosol and decreasing tyrosine phosphorylation of cytosolic IRS-1. |
| 2598 | 9565570 | These data indicate that IRS-1 and IRS-2 are differentially distributed in the cell and move from IM to cytosol following insulin stimulation. |
| 2599 | 9565570 | Insulin-stimulated IRS-1 and IRS-2 signaling occurs mainly in the IM and shows different kinetics; IRS-1-mediated signaling is more stable, whereas IRS-2-mediated signaling is more transient. |
| 2600 | 9565570 | Differential compartmentalization and trafficking of insulin receptor substrate (IRS)-1 and IRS-2. |
| 2601 | 9565570 | We find that insulin receptor substrate (IRS)-1 is 2-fold more concentrated in the intracellular membrane (IM) compartment than in cytosol, whereas IRS-2 is 2-fold more concentrated in cytosol than in IM. |
| 2602 | 9565570 | Insulin stimulation induces rapid tyrosine phosphorylation of both IRS-1 and IRS-2. |
| 2603 | 9565570 | Furthermore, after insulin stimulation, both IRS-1 and IRS-2 translocate from IM to cytosol with a t1/2 of 3.5 min. |
| 2604 | 9565570 | By comparison, within 1 min after insulin stimulation, 40% of the total pool of the 85-kDa subunit of phosphatidylinositol 3-kinase (p85) is recruited from cytosol to IM, the greater part of which can be accounted for by binding to IRS-1 present in the IM. |
| 2605 | 9565570 | The p85 binding and phosphatidylinositol 3-kinase activity associated with IRS-2 rapidly decrease in both IM and cytosol, whereas those associated with IRS-1 stay at a relatively high level in IM and increase with time in cytosol despite a return of p85 to the cytosol and decreasing tyrosine phosphorylation of cytosolic IRS-1. |
| 2606 | 9565570 | These data indicate that IRS-1 and IRS-2 are differentially distributed in the cell and move from IM to cytosol following insulin stimulation. |
| 2607 | 9565570 | Insulin-stimulated IRS-1 and IRS-2 signaling occurs mainly in the IM and shows different kinetics; IRS-1-mediated signaling is more stable, whereas IRS-2-mediated signaling is more transient. |
| 2608 | 9565570 | Differential compartmentalization and trafficking of insulin receptor substrate (IRS)-1 and IRS-2. |
| 2609 | 9565570 | We find that insulin receptor substrate (IRS)-1 is 2-fold more concentrated in the intracellular membrane (IM) compartment than in cytosol, whereas IRS-2 is 2-fold more concentrated in cytosol than in IM. |
| 2610 | 9565570 | Insulin stimulation induces rapid tyrosine phosphorylation of both IRS-1 and IRS-2. |
| 2611 | 9565570 | Furthermore, after insulin stimulation, both IRS-1 and IRS-2 translocate from IM to cytosol with a t1/2 of 3.5 min. |
| 2612 | 9565570 | By comparison, within 1 min after insulin stimulation, 40% of the total pool of the 85-kDa subunit of phosphatidylinositol 3-kinase (p85) is recruited from cytosol to IM, the greater part of which can be accounted for by binding to IRS-1 present in the IM. |
| 2613 | 9565570 | The p85 binding and phosphatidylinositol 3-kinase activity associated with IRS-2 rapidly decrease in both IM and cytosol, whereas those associated with IRS-1 stay at a relatively high level in IM and increase with time in cytosol despite a return of p85 to the cytosol and decreasing tyrosine phosphorylation of cytosolic IRS-1. |
| 2614 | 9565570 | These data indicate that IRS-1 and IRS-2 are differentially distributed in the cell and move from IM to cytosol following insulin stimulation. |
| 2615 | 9565570 | Insulin-stimulated IRS-1 and IRS-2 signaling occurs mainly in the IM and shows different kinetics; IRS-1-mediated signaling is more stable, whereas IRS-2-mediated signaling is more transient. |
| 2616 | 9568681 | Tumor necrosis factor-alpha acutely inhibits insulin signaling in human adipocytes: implication of the p80 tumor necrosis factor receptor. |
| 2617 | 9568681 | Tumor necrosis factor (TNF)-alpha is postulated to play a major role in the pathogenesis of obesity-linked insulin resistance, probably resulting from an interaction with insulin signaling pathways. |
| 2618 | 9568681 | This cross talk has now been investigated in human adipocytes at the level of phosphatidylinositol (PI) 3-kinase, and the TNF receptors (TNFRs) mediating these processes have been identified. |
| 2619 | 9568681 | Interaction of TNF-alpha with insulin signaling was determined by quantification of insulin receptor substrate (IRS)-1-associated PI 3-kinase activity. |
| 2620 | 9568681 | Preincubation of adipocytes with 5 nmol/l TNF-alpha for 15 min resulted in a 60-70% reduction of insulin action, reaching a stable inhibition (40%) after longer incubation with the cytokine. |
| 2621 | 9568681 | The inhibitory action of TNF-alpha was dose-dependent, already detectable at 10 pmol/l, and was correlated to inhibition of tyrosine phosphorylation of IRS-1 with an unaltered autophosphorylation of the insulin receptor beta-subunit. |
| 2622 | 9568681 | The modulation of insulin signaling by TNF-alpha was found to be paralleled by a comparable inhibition of insulin-stimulated glucose transport. |
| 2623 | 9568681 | An agonistic TNFR1 antibody completely mimicked the inhibitory action of TNF-alpha on insulin signaling, whereas at 100 pmol/l TNF-alpha, a nonagonistic p80 TNFR antibody, was shown to ameliorate the inhibitory action of the cytokine. |
| 2624 | 9568681 | These findings indicate that in human adipocytes, low concentrations of TNF-alpha induce a rapid inhibition of insulin signaling at the level of PI 3-kinase. |
| 2625 | 9568681 | We suggest that under these conditions, the p80 TNFR is essential for initiating the intracellular cross talk that involves signaling by the p60 TNFR. |
| 2626 | 9578588 | Vanadyl sulfate-stimulated glycogen synthesis is associated with activation of phosphatidylinositol 3-kinase and is independent of insulin receptor tyrosine phosphorylation. |
| 2627 | 9578588 | We have shown earlier that different vanadium salts stimulate the MAP kinase pathway and ribosomal-S-6-kinase (p70s6k) in chinese hamster ovary cells overexpressing human insulin receptor (CHO-HIR cells) [Pandey, S. |
| 2628 | 9578588 | In the present studies, we have investigated if similar to insulin, VS also activates phosphatidylinositol 3-kinase (PI3-k) activity, and whether VS-induced activation of the PI3-k, MAP kinase, and p70s6k pathways contributes to glycogen synthesis. |
| 2629 | 9578588 | On the other hand, PD98059 and rapamycin, specific inhibitors of the MAP kinase pathway and p70s6k, respectively, were unable to inhibit VS-stimulated glycogen synthesis. |
| 2630 | 9578588 | Moreover, VS-stimulated glycogen synthesis and PI3-k were observed without any change in the tyrosine phosphorylation of insulin receptor (IR) beta-subunit but were associated with increased tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1). |
| 2631 | 9578588 | In addition, PI3-k activation was detected in IRS-1 immunoprecipitates from VS-stimulated cells, indicating that tyrosine-phosphorylated IRS-1 was able to interact and thereby activate PI3-k in response to VS. |
| 2632 | 9578588 | Taken together, these results provide evidence that tyrosine phosphorylation of IRS-1 and activation of PI3-k play a key role in mediating the insulinomimetic effect of VS on glycogen synthesis independent of IR-tyrosine phosphorylation. |
| 2633 | 9578588 | Vanadyl sulfate-stimulated glycogen synthesis is associated with activation of phosphatidylinositol 3-kinase and is independent of insulin receptor tyrosine phosphorylation. |
| 2634 | 9578588 | We have shown earlier that different vanadium salts stimulate the MAP kinase pathway and ribosomal-S-6-kinase (p70s6k) in chinese hamster ovary cells overexpressing human insulin receptor (CHO-HIR cells) [Pandey, S. |
| 2635 | 9578588 | In the present studies, we have investigated if similar to insulin, VS also activates phosphatidylinositol 3-kinase (PI3-k) activity, and whether VS-induced activation of the PI3-k, MAP kinase, and p70s6k pathways contributes to glycogen synthesis. |
| 2636 | 9578588 | On the other hand, PD98059 and rapamycin, specific inhibitors of the MAP kinase pathway and p70s6k, respectively, were unable to inhibit VS-stimulated glycogen synthesis. |
| 2637 | 9578588 | Moreover, VS-stimulated glycogen synthesis and PI3-k were observed without any change in the tyrosine phosphorylation of insulin receptor (IR) beta-subunit but were associated with increased tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1). |
| 2638 | 9578588 | In addition, PI3-k activation was detected in IRS-1 immunoprecipitates from VS-stimulated cells, indicating that tyrosine-phosphorylated IRS-1 was able to interact and thereby activate PI3-k in response to VS. |
| 2639 | 9578588 | Taken together, these results provide evidence that tyrosine phosphorylation of IRS-1 and activation of PI3-k play a key role in mediating the insulinomimetic effect of VS on glycogen synthesis independent of IR-tyrosine phosphorylation. |
| 2640 | 9578588 | Vanadyl sulfate-stimulated glycogen synthesis is associated with activation of phosphatidylinositol 3-kinase and is independent of insulin receptor tyrosine phosphorylation. |
| 2641 | 9578588 | We have shown earlier that different vanadium salts stimulate the MAP kinase pathway and ribosomal-S-6-kinase (p70s6k) in chinese hamster ovary cells overexpressing human insulin receptor (CHO-HIR cells) [Pandey, S. |
| 2642 | 9578588 | In the present studies, we have investigated if similar to insulin, VS also activates phosphatidylinositol 3-kinase (PI3-k) activity, and whether VS-induced activation of the PI3-k, MAP kinase, and p70s6k pathways contributes to glycogen synthesis. |
| 2643 | 9578588 | On the other hand, PD98059 and rapamycin, specific inhibitors of the MAP kinase pathway and p70s6k, respectively, were unable to inhibit VS-stimulated glycogen synthesis. |
| 2644 | 9578588 | Moreover, VS-stimulated glycogen synthesis and PI3-k were observed without any change in the tyrosine phosphorylation of insulin receptor (IR) beta-subunit but were associated with increased tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1). |
| 2645 | 9578588 | In addition, PI3-k activation was detected in IRS-1 immunoprecipitates from VS-stimulated cells, indicating that tyrosine-phosphorylated IRS-1 was able to interact and thereby activate PI3-k in response to VS. |
| 2646 | 9578588 | Taken together, these results provide evidence that tyrosine phosphorylation of IRS-1 and activation of PI3-k play a key role in mediating the insulinomimetic effect of VS on glycogen synthesis independent of IR-tyrosine phosphorylation. |
| 2647 | 9582514 | Insulin-like growth factor-I-induced DNA synthesis in insulin-secreting cell line RINm5F is associated with phosphorylation of the insulin-like growth factor-I receptor and the insulin receptor substrate-2. |
| 2648 | 9582514 | A proliferative effect of insulin-like growth factor-I (IGF-I) was previously shown in pancreatic islets. |
| 2649 | 9582514 | However, the mechanism under which IGF-I actions are exerted in insulin-secreting cells is not clear. |
| 2650 | 9582514 | Under basal conditions, IGF-I did not induce insulin release or changes in cytosolic free Ca2+ concentration. |
| 2651 | 9582514 | Immunoprecipitation of proteins from RINm5F cells, using phosphotyrosine antibodies, followed by western blotting using antibody against IRS-1 revealed no distinct band of phosphorylated insulin receptor substrate (IRS)-1. |
| 2652 | 9582514 | Instead, tyrosine-phosphorylated IRS-2 was detected and stimulated by IGF-I when western blotting was performed using antibody against IRS-2. |
| 2653 | 9582514 | These results indicate that IRS-1 is not likely to be involved in IGF-I signalling in RINm5F cells. |
| 2654 | 9582514 | Hence, IGF-I stimulated DNA synthesis in RINm5F cells was associated with phosphorylation of IGF-I receptors and IRS-2. |
| 2655 | 9582514 | Insulin-like growth factor-I-induced DNA synthesis in insulin-secreting cell line RINm5F is associated with phosphorylation of the insulin-like growth factor-I receptor and the insulin receptor substrate-2. |
| 2656 | 9582514 | A proliferative effect of insulin-like growth factor-I (IGF-I) was previously shown in pancreatic islets. |
| 2657 | 9582514 | However, the mechanism under which IGF-I actions are exerted in insulin-secreting cells is not clear. |
| 2658 | 9582514 | Under basal conditions, IGF-I did not induce insulin release or changes in cytosolic free Ca2+ concentration. |
| 2659 | 9582514 | Immunoprecipitation of proteins from RINm5F cells, using phosphotyrosine antibodies, followed by western blotting using antibody against IRS-1 revealed no distinct band of phosphorylated insulin receptor substrate (IRS)-1. |
| 2660 | 9582514 | Instead, tyrosine-phosphorylated IRS-2 was detected and stimulated by IGF-I when western blotting was performed using antibody against IRS-2. |
| 2661 | 9582514 | These results indicate that IRS-1 is not likely to be involved in IGF-I signalling in RINm5F cells. |
| 2662 | 9582514 | Hence, IGF-I stimulated DNA synthesis in RINm5F cells was associated with phosphorylation of IGF-I receptors and IRS-2. |
| 2663 | 9588442 | Short-term exposure to tumor necrosis factor-alpha does not affect insulin-stimulated glucose uptake in skeletal muscle. |
| 2664 | 9588442 | It has been hypothesized that increased production of tumor necrosis factor-alpha (TNF-alpha) plays a role in causing the insulin resistance associated with obesity. |
| 2665 | 9588442 | Obesity with insulin resistance is associated with increased production of TNF-alpha by fat cells. |
| 2666 | 9588442 | Exposure of 3T3-L1 adipocytes to TNF-alpha for 3-4 days makes them insulin resistant. |
| 2667 | 9588442 | TNF-alpha has also been reported to rapidly (15-60 min) cause insulin resistance, with a decrease in insulin-stimulated tyrosine phosphorylation, in a number of cultured cell lines. |
| 2668 | 9588442 | Because skeletal muscle is the major tissue responsible for insulin-stimulated glucose disposal, we performed the present study to determine if acute exposure to TNF-alpha causes insulin resistance in muscle. |
| 2669 | 9588442 | We found that exposure of soleus muscles to 6 nmol/l TNF-alpha for 45 min in vitro had no inhibitory effect on insulin-stimulated tyrosine phosphorylation of the insulin receptor or insulin receptor substrate 1 (IRS-1) or on phosphatidylinositol 3-kinase association with IRS-1. |
| 2670 | 9588442 | Incubation of epitrochlearis and soleus muscles with 6 nmol/l TNF-alpha for 45 min or 4 h had no effect on insulin-stimulated 2-deoxyglucose (2-DG) uptake. |
| 2671 | 9588442 | Treatment of epitrochlearis muscles with 2 nmol/l TNF-alpha for 8 h also had no effect on insulin-stimulated 2-DG uptake. |
| 2672 | 9588442 | We conclude that in contrast to Fao hepatoma cells and 3T3-L1 fibroblasts, skeletal muscle does not become insulin resistant in response to short-term exposure to TNF-alpha. |
| 2673 | 9609124 | In addition, we have shown that physiological levels of insulin induce a 1.6-2.0 fold increase in GLUT4 content in skeletal muscle plasma membranes from control subjects, whereas no significant increase was noted in NIDDM skeletal muscle. |
| 2674 | 9609124 | Impaired insulin-stimulated GLUT4 translocation and glucose transport in NIDDM skeletal muscle is associated with reduced insulin-stimulated IRS-1 tyrosine phosphorylation and PI3-kinase activity. |
| 2675 | 9648831 | A gene candidate approach revealed that mRNA levels of the oncogenes c-fos and c-jun were equivalently expressed in insulinoma and islet cells, as was the mRNA for the mitogenic signal transduction molecule insulin receptor substrate (IRS)-1. |
| 2676 | 9648831 | However, in contrast to that of IRS-1, IRS-2 gene expression was 60- to 70-fold higher in the insulinoma tissue compared with islets, which was reflected at the protein as well as the mRNA level. |
| 2677 | 9648831 | This serum-stimulated DNA synthesis was prevented by inhibitors of tyrosine protein kinase and phosphatidylinositol (PI) 3-kinase activities, as well as the activation of mitogen-activated protein (MAP) kinase and p70S6K. |
| 2678 | 9648831 | Moreover, serum also activated MAP-kinase (erk-1 and erk-2 isoforms) and 70 kD S6 kinase. |
| 2679 | 9660809 | Replacement of tyrosine 1251 in the carboxyl terminus of the insulin-like growth factor-I receptor disrupts the actin cytoskeleton and inhibits proliferation and anchorage-independent growth. |
| 2680 | 9660809 | Insulin-like growth factor (IGF)-I signaling through the IGF-I receptor modulates cellular adhesion and proliferation and the transforming ability of cells overexpressing the IGF-I receptor. |
| 2681 | 9660809 | Tyrosine residues 1250 and 1251 are not essential for tyrosine phosphorylation of two known substrates; insulin receptor substrate-1 and SHC, nor association of known downstream adaptor proteins to these substrates. |
| 2682 | 9660809 | In addition, these mutant IGF-I receptors do not affect IGF-I-stimulated p42/p44 mitogen-activated protein kinase activation or phosphatidylinositol (PI) 3'-kinase activity. |
| 2683 | 9690058 | Forty-nine families with at least two affected patients in the sibship (567 individuals) were selected and tested by PCR-RFLP techniques for reported mutations in 10 diabetes or obesity candidate genes: glucagon receptor, insulin receptor substrate 1, insulin receptor, human beta 3 adrenergic receptor, fatty acid binding protein 2, mitochondrial tRNA(Leu(UUR)), sulphonylurea receptor, human uncoupling protein and the glycogen-associated regulatory subunit of protein phosphatase-1. |
| 2684 | 9690058 | No mutations were found in glucokinase, glucagon receptor and mitochondrial genes in any of the 49 probands. |
| 2685 | 9690058 | Frequencies of polymorphisms at other loci were similar to those reported in Caucasian populations, except for 4 of the loci at which a higher frequency of variants was observed: human beta 3 adrenergic receptor, human uncoupling type 1 protein, fatty acid binding protein 2 and the glycogen-associated regulatory subunit of protein phosphatase-1. |
| 2686 | 9726601 | IRS-1 and IRS-2 have been shown to have key roles in cellular transmission of the action of insulin, insulin-like growth factor-1 and various cytokines. |
| 2687 | 9726601 | We have previously identified amino acid polymorphisms in the human IRS-1 and IRS-2 proteins. |
| 2688 | 9726601 | Given the documented importance of IRS-1 and -2 in insulin signalling and the implications of distribution of these genes for the pathogenesis of insulin resistance and diabetes, we decided that the most recently identified member of the IRS family, IRS-4, was a relevant candidate to examine for genetic variability which might be associated with subsets of diabetes or insulin resistance. |
| 2689 | 9726601 | The gene encoding IRS-4 was analysed by the single strand conformation polymorphism technique in 83 Danish Caucasians with Type II (non-insulin-dependent) diabetes mellitus. |
| 2690 | 9726601 | The insulin sensitivity index as estimated by Bergman's minimal model of the young healthy subjects carrying either polymorphism was indistinguishable from the carriers of wild-type IRS-4. |
| 2691 | 9726601 | In conclusion, amino acid polymorphisms in human IRS-4 are common in Caucasians but are not associated with Type II diabetes or with insulin resistance in young healthy subjects. |
| 2692 | 9726601 | IRS-1 and IRS-2 have been shown to have key roles in cellular transmission of the action of insulin, insulin-like growth factor-1 and various cytokines. |
| 2693 | 9726601 | We have previously identified amino acid polymorphisms in the human IRS-1 and IRS-2 proteins. |
| 2694 | 9726601 | Given the documented importance of IRS-1 and -2 in insulin signalling and the implications of distribution of these genes for the pathogenesis of insulin resistance and diabetes, we decided that the most recently identified member of the IRS family, IRS-4, was a relevant candidate to examine for genetic variability which might be associated with subsets of diabetes or insulin resistance. |
| 2695 | 9726601 | The gene encoding IRS-4 was analysed by the single strand conformation polymorphism technique in 83 Danish Caucasians with Type II (non-insulin-dependent) diabetes mellitus. |
| 2696 | 9726601 | The insulin sensitivity index as estimated by Bergman's minimal model of the young healthy subjects carrying either polymorphism was indistinguishable from the carriers of wild-type IRS-4. |
| 2697 | 9726601 | In conclusion, amino acid polymorphisms in human IRS-4 are common in Caucasians but are not associated with Type II diabetes or with insulin resistance in young healthy subjects. |
| 2698 | 9726601 | IRS-1 and IRS-2 have been shown to have key roles in cellular transmission of the action of insulin, insulin-like growth factor-1 and various cytokines. |
| 2699 | 9726601 | We have previously identified amino acid polymorphisms in the human IRS-1 and IRS-2 proteins. |
| 2700 | 9726601 | Given the documented importance of IRS-1 and -2 in insulin signalling and the implications of distribution of these genes for the pathogenesis of insulin resistance and diabetes, we decided that the most recently identified member of the IRS family, IRS-4, was a relevant candidate to examine for genetic variability which might be associated with subsets of diabetes or insulin resistance. |
| 2701 | 9726601 | The gene encoding IRS-4 was analysed by the single strand conformation polymorphism technique in 83 Danish Caucasians with Type II (non-insulin-dependent) diabetes mellitus. |
| 2702 | 9726601 | The insulin sensitivity index as estimated by Bergman's minimal model of the young healthy subjects carrying either polymorphism was indistinguishable from the carriers of wild-type IRS-4. |
| 2703 | 9726601 | In conclusion, amino acid polymorphisms in human IRS-4 are common in Caucasians but are not associated with Type II diabetes or with insulin resistance in young healthy subjects. |
| 2704 | 9753293 | Prolonged oxidative stress impairs insulin-induced GLUT4 translocation in 3T3-L1 adipocytes. |
| 2705 | 9753293 | Although insulin induced a 2.5-fold increase in plasma membrane GLUT4 content and a 50% reduction in its abundance in the low-density microsomal (LDM) fraction in control cells, oxidation completely prevented these responses. |
| 2706 | 9753293 | The net effect of insulin on 2-deoxyglucose uptake activity was reduced in oxidized cells and could be attributed to GLUT1 translocation. |
| 2707 | 9753293 | Insulin stimulation of insulin receptor substrate (IRS) 1 tyrosine phosphorylation and the association of IRS-1 with phosphatidylinositol (PI) 3-kinase were not impaired by oxidative stress. |
| 2708 | 9753293 | However, a 1.9-fold increase in the LDM content of the p85 subunit of PI 3-kinase after insulin stimulation was observed in control, but not in oxidized, cells. |
| 2709 | 9753293 | These findings suggest that prolonged low-grade oxidative stress impairs insulin-stimulated GLUT4 translocation, potentially by interfering with compartment-specific activation of PI 3-kinase. |
| 2710 | 9756938 | The COOH-terminal tyrosine phosphorylation sites on IRS-1 bind SHP-2 and negatively regulate insulin signaling. |
| 2711 | 9756938 | Tyrosine-phosphorylated motifs on the IRS proteins bind to the SH2 domains in proteins that mediate downstream signals, including phosphatidylinositol 3'-kinase, GRB-2, and SHP-2. |
| 2712 | 9756938 | We investigated the function of the two SHP-2 binding COOH-terminal tyrosines of IRS-1 by replacing them with phenylalanine (IRS-1(FCT)). |
| 2713 | 9756938 | IRS-1(FCT) failed to bind SHP-2 or mediate its tyrosine phosphorylation during insulin stimulation. |
| 2714 | 9756938 | Although several reports suggest a critical role for SHP-2 in insulin stimulated mitogen-activated protein kinase activation and cell proliferation, IRS-1(FCT) mediated these effects normally in 32D cells. |
| 2715 | 9756938 | These results suggest that SHP-2 attentuates the phosphorylation and downstream signal transmission of IRS-1 and that the interaction of IRS-1 and SHP-2 is an important regulatory event which attenuates insulin metabolic responses. |
| 2716 | 9756938 | The COOH-terminal tyrosine phosphorylation sites on IRS-1 bind SHP-2 and negatively regulate insulin signaling. |
| 2717 | 9756938 | Tyrosine-phosphorylated motifs on the IRS proteins bind to the SH2 domains in proteins that mediate downstream signals, including phosphatidylinositol 3'-kinase, GRB-2, and SHP-2. |
| 2718 | 9756938 | We investigated the function of the two SHP-2 binding COOH-terminal tyrosines of IRS-1 by replacing them with phenylalanine (IRS-1(FCT)). |
| 2719 | 9756938 | IRS-1(FCT) failed to bind SHP-2 or mediate its tyrosine phosphorylation during insulin stimulation. |
| 2720 | 9756938 | Although several reports suggest a critical role for SHP-2 in insulin stimulated mitogen-activated protein kinase activation and cell proliferation, IRS-1(FCT) mediated these effects normally in 32D cells. |
| 2721 | 9756938 | These results suggest that SHP-2 attentuates the phosphorylation and downstream signal transmission of IRS-1 and that the interaction of IRS-1 and SHP-2 is an important regulatory event which attenuates insulin metabolic responses. |
| 2722 | 9756938 | The COOH-terminal tyrosine phosphorylation sites on IRS-1 bind SHP-2 and negatively regulate insulin signaling. |
| 2723 | 9756938 | Tyrosine-phosphorylated motifs on the IRS proteins bind to the SH2 domains in proteins that mediate downstream signals, including phosphatidylinositol 3'-kinase, GRB-2, and SHP-2. |
| 2724 | 9756938 | We investigated the function of the two SHP-2 binding COOH-terminal tyrosines of IRS-1 by replacing them with phenylalanine (IRS-1(FCT)). |
| 2725 | 9756938 | IRS-1(FCT) failed to bind SHP-2 or mediate its tyrosine phosphorylation during insulin stimulation. |
| 2726 | 9756938 | Although several reports suggest a critical role for SHP-2 in insulin stimulated mitogen-activated protein kinase activation and cell proliferation, IRS-1(FCT) mediated these effects normally in 32D cells. |
| 2727 | 9756938 | These results suggest that SHP-2 attentuates the phosphorylation and downstream signal transmission of IRS-1 and that the interaction of IRS-1 and SHP-2 is an important regulatory event which attenuates insulin metabolic responses. |
| 2728 | 9756938 | The COOH-terminal tyrosine phosphorylation sites on IRS-1 bind SHP-2 and negatively regulate insulin signaling. |
| 2729 | 9756938 | Tyrosine-phosphorylated motifs on the IRS proteins bind to the SH2 domains in proteins that mediate downstream signals, including phosphatidylinositol 3'-kinase, GRB-2, and SHP-2. |
| 2730 | 9756938 | We investigated the function of the two SHP-2 binding COOH-terminal tyrosines of IRS-1 by replacing them with phenylalanine (IRS-1(FCT)). |
| 2731 | 9756938 | IRS-1(FCT) failed to bind SHP-2 or mediate its tyrosine phosphorylation during insulin stimulation. |
| 2732 | 9756938 | Although several reports suggest a critical role for SHP-2 in insulin stimulated mitogen-activated protein kinase activation and cell proliferation, IRS-1(FCT) mediated these effects normally in 32D cells. |
| 2733 | 9756938 | These results suggest that SHP-2 attentuates the phosphorylation and downstream signal transmission of IRS-1 and that the interaction of IRS-1 and SHP-2 is an important regulatory event which attenuates insulin metabolic responses. |
| 2734 | 9756938 | The COOH-terminal tyrosine phosphorylation sites on IRS-1 bind SHP-2 and negatively regulate insulin signaling. |
| 2735 | 9756938 | Tyrosine-phosphorylated motifs on the IRS proteins bind to the SH2 domains in proteins that mediate downstream signals, including phosphatidylinositol 3'-kinase, GRB-2, and SHP-2. |
| 2736 | 9756938 | We investigated the function of the two SHP-2 binding COOH-terminal tyrosines of IRS-1 by replacing them with phenylalanine (IRS-1(FCT)). |
| 2737 | 9756938 | IRS-1(FCT) failed to bind SHP-2 or mediate its tyrosine phosphorylation during insulin stimulation. |
| 2738 | 9756938 | Although several reports suggest a critical role for SHP-2 in insulin stimulated mitogen-activated protein kinase activation and cell proliferation, IRS-1(FCT) mediated these effects normally in 32D cells. |
| 2739 | 9756938 | These results suggest that SHP-2 attentuates the phosphorylation and downstream signal transmission of IRS-1 and that the interaction of IRS-1 and SHP-2 is an important regulatory event which attenuates insulin metabolic responses. |
| 2740 | 9761714 | The expression of a number of genes encoding key players in insulin signalling and action, including insulin, insulin receptor (IR), downstream signalling molecules such as insulin receptor substrate-1 (IRS-1) and IRS-2, glucose transporters (GLUT4, GLUT2) and important metabolic enzymes such as glucokinase, has now been altered in transgenic or knockout mice. |
| 2741 | 9761714 | Genes encoding insulin-like growth factors (IGF-I and IGF-II) and their type I receptor (IGF-IR) have also been disrupted. |
| 2742 | 9761714 | However, IR could replace IGF-IR if efficiently activated by IGF-II. |
| 2743 | 9761714 | Concerning the issues of specificity and redundancy, studies with cell lines derived from IRS-1-deficient mice showed that IRS-1 and IRS-2 are also not completely interchangeable. |
| 2744 | 9761714 | The expression of a number of genes encoding key players in insulin signalling and action, including insulin, insulin receptor (IR), downstream signalling molecules such as insulin receptor substrate-1 (IRS-1) and IRS-2, glucose transporters (GLUT4, GLUT2) and important metabolic enzymes such as glucokinase, has now been altered in transgenic or knockout mice. |
| 2745 | 9761714 | Genes encoding insulin-like growth factors (IGF-I and IGF-II) and their type I receptor (IGF-IR) have also been disrupted. |
| 2746 | 9761714 | However, IR could replace IGF-IR if efficiently activated by IGF-II. |
| 2747 | 9761714 | Concerning the issues of specificity and redundancy, studies with cell lines derived from IRS-1-deficient mice showed that IRS-1 and IRS-2 are also not completely interchangeable. |
| 2748 | 9774692 | Insulin and insulin-like growth factor 1 (IGF-1) evoke diverse biological effects through receptor-mediated tyrosine phosphorylation of insulin receptor substrate (IRS) proteins. |
| 2749 | 9774692 | We investigated the elements of IRS-1 signaling that inhibit apoptosis of interleukin 3 (IL-3)-deprived 32D myeloid progenitor cells. 32D cells have few insulin receptors and no IRS proteins; therefore, insulin failed to inhibit apoptosis during IL-3 withdrawal. |
| 2750 | 9774692 | By contrast, insulin stimulated the PI 3-kinase cascade, inhibited apoptosis, and promoted replication of 32DIR cells expressing IRS-1. |
| 2751 | 9774692 | As expected, insulin did not stimulate PI 3-kinase in 32DIR cells, which expressed a truncated IRS-1 protein lacking the tail of tyrosine phosphorylation sites. |
| 2752 | 9774692 | However, this truncated IRS-1 protein, which retained the NH2-terminal pleckstrin homology (PH) and phosphotyrosine binding (PTB) domains, mediated phosphorylation of PKB/akt, inhibition of apoptosis, and replication of 32DIR cells during insulin stimulation. |
| 2753 | 9774692 | Without IRS-1, a chimeric insulin receptor containing a tail of tyrosine phosphorylation sites derived from IRS-1 activated the PI 3-kinase cascade but failed to inhibit apoptosis. |
| 2754 | 9774692 | Thus, phosphotyrosine-independent IRS-1-linked pathways may be critical for survival and growth of IL-3-deprived 32D cells during insulin stimulation. |
| 2755 | 9774692 | Insulin and insulin-like growth factor 1 (IGF-1) evoke diverse biological effects through receptor-mediated tyrosine phosphorylation of insulin receptor substrate (IRS) proteins. |
| 2756 | 9774692 | We investigated the elements of IRS-1 signaling that inhibit apoptosis of interleukin 3 (IL-3)-deprived 32D myeloid progenitor cells. 32D cells have few insulin receptors and no IRS proteins; therefore, insulin failed to inhibit apoptosis during IL-3 withdrawal. |
| 2757 | 9774692 | By contrast, insulin stimulated the PI 3-kinase cascade, inhibited apoptosis, and promoted replication of 32DIR cells expressing IRS-1. |
| 2758 | 9774692 | As expected, insulin did not stimulate PI 3-kinase in 32DIR cells, which expressed a truncated IRS-1 protein lacking the tail of tyrosine phosphorylation sites. |
| 2759 | 9774692 | However, this truncated IRS-1 protein, which retained the NH2-terminal pleckstrin homology (PH) and phosphotyrosine binding (PTB) domains, mediated phosphorylation of PKB/akt, inhibition of apoptosis, and replication of 32DIR cells during insulin stimulation. |
| 2760 | 9774692 | Without IRS-1, a chimeric insulin receptor containing a tail of tyrosine phosphorylation sites derived from IRS-1 activated the PI 3-kinase cascade but failed to inhibit apoptosis. |
| 2761 | 9774692 | Thus, phosphotyrosine-independent IRS-1-linked pathways may be critical for survival and growth of IL-3-deprived 32D cells during insulin stimulation. |
| 2762 | 9774692 | Insulin and insulin-like growth factor 1 (IGF-1) evoke diverse biological effects through receptor-mediated tyrosine phosphorylation of insulin receptor substrate (IRS) proteins. |
| 2763 | 9774692 | We investigated the elements of IRS-1 signaling that inhibit apoptosis of interleukin 3 (IL-3)-deprived 32D myeloid progenitor cells. 32D cells have few insulin receptors and no IRS proteins; therefore, insulin failed to inhibit apoptosis during IL-3 withdrawal. |
| 2764 | 9774692 | By contrast, insulin stimulated the PI 3-kinase cascade, inhibited apoptosis, and promoted replication of 32DIR cells expressing IRS-1. |
| 2765 | 9774692 | As expected, insulin did not stimulate PI 3-kinase in 32DIR cells, which expressed a truncated IRS-1 protein lacking the tail of tyrosine phosphorylation sites. |
| 2766 | 9774692 | However, this truncated IRS-1 protein, which retained the NH2-terminal pleckstrin homology (PH) and phosphotyrosine binding (PTB) domains, mediated phosphorylation of PKB/akt, inhibition of apoptosis, and replication of 32DIR cells during insulin stimulation. |
| 2767 | 9774692 | Without IRS-1, a chimeric insulin receptor containing a tail of tyrosine phosphorylation sites derived from IRS-1 activated the PI 3-kinase cascade but failed to inhibit apoptosis. |
| 2768 | 9774692 | Thus, phosphotyrosine-independent IRS-1-linked pathways may be critical for survival and growth of IL-3-deprived 32D cells during insulin stimulation. |
| 2769 | 9774692 | Insulin and insulin-like growth factor 1 (IGF-1) evoke diverse biological effects through receptor-mediated tyrosine phosphorylation of insulin receptor substrate (IRS) proteins. |
| 2770 | 9774692 | We investigated the elements of IRS-1 signaling that inhibit apoptosis of interleukin 3 (IL-3)-deprived 32D myeloid progenitor cells. 32D cells have few insulin receptors and no IRS proteins; therefore, insulin failed to inhibit apoptosis during IL-3 withdrawal. |
| 2771 | 9774692 | By contrast, insulin stimulated the PI 3-kinase cascade, inhibited apoptosis, and promoted replication of 32DIR cells expressing IRS-1. |
| 2772 | 9774692 | As expected, insulin did not stimulate PI 3-kinase in 32DIR cells, which expressed a truncated IRS-1 protein lacking the tail of tyrosine phosphorylation sites. |
| 2773 | 9774692 | However, this truncated IRS-1 protein, which retained the NH2-terminal pleckstrin homology (PH) and phosphotyrosine binding (PTB) domains, mediated phosphorylation of PKB/akt, inhibition of apoptosis, and replication of 32DIR cells during insulin stimulation. |
| 2774 | 9774692 | Without IRS-1, a chimeric insulin receptor containing a tail of tyrosine phosphorylation sites derived from IRS-1 activated the PI 3-kinase cascade but failed to inhibit apoptosis. |
| 2775 | 9774692 | Thus, phosphotyrosine-independent IRS-1-linked pathways may be critical for survival and growth of IL-3-deprived 32D cells during insulin stimulation. |
| 2776 | 9774692 | Insulin and insulin-like growth factor 1 (IGF-1) evoke diverse biological effects through receptor-mediated tyrosine phosphorylation of insulin receptor substrate (IRS) proteins. |
| 2777 | 9774692 | We investigated the elements of IRS-1 signaling that inhibit apoptosis of interleukin 3 (IL-3)-deprived 32D myeloid progenitor cells. 32D cells have few insulin receptors and no IRS proteins; therefore, insulin failed to inhibit apoptosis during IL-3 withdrawal. |
| 2778 | 9774692 | By contrast, insulin stimulated the PI 3-kinase cascade, inhibited apoptosis, and promoted replication of 32DIR cells expressing IRS-1. |
| 2779 | 9774692 | As expected, insulin did not stimulate PI 3-kinase in 32DIR cells, which expressed a truncated IRS-1 protein lacking the tail of tyrosine phosphorylation sites. |
| 2780 | 9774692 | However, this truncated IRS-1 protein, which retained the NH2-terminal pleckstrin homology (PH) and phosphotyrosine binding (PTB) domains, mediated phosphorylation of PKB/akt, inhibition of apoptosis, and replication of 32DIR cells during insulin stimulation. |
| 2781 | 9774692 | Without IRS-1, a chimeric insulin receptor containing a tail of tyrosine phosphorylation sites derived from IRS-1 activated the PI 3-kinase cascade but failed to inhibit apoptosis. |
| 2782 | 9774692 | Thus, phosphotyrosine-independent IRS-1-linked pathways may be critical for survival and growth of IL-3-deprived 32D cells during insulin stimulation. |
| 2783 | 9781315 | Intense interest is now focused on whether reduced insulin-mediated glucose transport in muscle from NIDDM patients results from alterations in the insulin signal transduction pathway or from alterations in traffic and/or translocation of GLUT4 to the plasma membrane. |
| 2784 | 9781315 | Recently, potential targets for impaired traffic/translocation of GLUT4 have been reported to include defective phosphorylation of IRS-1 and reduced PI-3 kinase activity. |
| 2785 | 9781315 | In addition to insulin signaling defects, impaired glucose transport may result from a defect(s) in the activation or functional capacity of GLUT4. |
| 2786 | 9781315 | Overexpression of GLUT4 in muscle results in increased glucose uptake and metabolism, and protects against the development of insulin resistance in transgenic mice. |
| 2787 | 9781315 | Genetic ablation of GLUT4 results in impaired insulin tolerance and defects in glucose metabolism in skeletal muscle. |
| 2788 | 9794462 | Association of the p85 adapter subunit of PI 3-kinase to IRS-1 was not modified by the drug. |
| 2789 | 9813005 | Using a yeast two-hybrid system, we identified several proteins that interact with the PH domains in IRS-1 and IRS-2, including Lon protease, myeloblast protein, and nucleolin. |
| 2790 | 9813005 | Although the roles of these molecules in insulin action are not yet known, each protein contained an acidic motif that interacted with the PH domain of IRS-2. |
| 2791 | 9813005 | However, only the acidic motif in nucleolin bound to IRS-1, suggesting that the PH domain in IRS-1 and IRS-2 are not identical. |
| 2792 | 9813005 | Moreover, synthetic peptides based on the acidic motif in Lon protease and myeloblast protein inhibited the binding of nucleolin to the PH domain of IRS-2 but not to the PH domain of IRS-1, confirming the selectivity of these PH domains. |
| 2793 | 9813005 | In 32D cells, nucleolin bound to both IRS-1 and IRS-2, and expression of the acidic motif of nucleolin inhibited insulin-stimulated tyrosine phosphorylation of IRS-1 and IRS-2. |
| 2794 | 9813005 | These results suggest that the binding of acidic motifs to the PH domain of IRS-1 and IRS-2 disrupts coupling to the activated insulin receptor. |
| 2795 | 9813005 | Using a yeast two-hybrid system, we identified several proteins that interact with the PH domains in IRS-1 and IRS-2, including Lon protease, myeloblast protein, and nucleolin. |
| 2796 | 9813005 | Although the roles of these molecules in insulin action are not yet known, each protein contained an acidic motif that interacted with the PH domain of IRS-2. |
| 2797 | 9813005 | However, only the acidic motif in nucleolin bound to IRS-1, suggesting that the PH domain in IRS-1 and IRS-2 are not identical. |
| 2798 | 9813005 | Moreover, synthetic peptides based on the acidic motif in Lon protease and myeloblast protein inhibited the binding of nucleolin to the PH domain of IRS-2 but not to the PH domain of IRS-1, confirming the selectivity of these PH domains. |
| 2799 | 9813005 | In 32D cells, nucleolin bound to both IRS-1 and IRS-2, and expression of the acidic motif of nucleolin inhibited insulin-stimulated tyrosine phosphorylation of IRS-1 and IRS-2. |
| 2800 | 9813005 | These results suggest that the binding of acidic motifs to the PH domain of IRS-1 and IRS-2 disrupts coupling to the activated insulin receptor. |
| 2801 | 9813005 | Using a yeast two-hybrid system, we identified several proteins that interact with the PH domains in IRS-1 and IRS-2, including Lon protease, myeloblast protein, and nucleolin. |
| 2802 | 9813005 | Although the roles of these molecules in insulin action are not yet known, each protein contained an acidic motif that interacted with the PH domain of IRS-2. |
| 2803 | 9813005 | However, only the acidic motif in nucleolin bound to IRS-1, suggesting that the PH domain in IRS-1 and IRS-2 are not identical. |
| 2804 | 9813005 | Moreover, synthetic peptides based on the acidic motif in Lon protease and myeloblast protein inhibited the binding of nucleolin to the PH domain of IRS-2 but not to the PH domain of IRS-1, confirming the selectivity of these PH domains. |
| 2805 | 9813005 | In 32D cells, nucleolin bound to both IRS-1 and IRS-2, and expression of the acidic motif of nucleolin inhibited insulin-stimulated tyrosine phosphorylation of IRS-1 and IRS-2. |
| 2806 | 9813005 | These results suggest that the binding of acidic motifs to the PH domain of IRS-1 and IRS-2 disrupts coupling to the activated insulin receptor. |
| 2807 | 9813005 | Using a yeast two-hybrid system, we identified several proteins that interact with the PH domains in IRS-1 and IRS-2, including Lon protease, myeloblast protein, and nucleolin. |
| 2808 | 9813005 | Although the roles of these molecules in insulin action are not yet known, each protein contained an acidic motif that interacted with the PH domain of IRS-2. |
| 2809 | 9813005 | However, only the acidic motif in nucleolin bound to IRS-1, suggesting that the PH domain in IRS-1 and IRS-2 are not identical. |
| 2810 | 9813005 | Moreover, synthetic peptides based on the acidic motif in Lon protease and myeloblast protein inhibited the binding of nucleolin to the PH domain of IRS-2 but not to the PH domain of IRS-1, confirming the selectivity of these PH domains. |
| 2811 | 9813005 | In 32D cells, nucleolin bound to both IRS-1 and IRS-2, and expression of the acidic motif of nucleolin inhibited insulin-stimulated tyrosine phosphorylation of IRS-1 and IRS-2. |
| 2812 | 9813005 | These results suggest that the binding of acidic motifs to the PH domain of IRS-1 and IRS-2 disrupts coupling to the activated insulin receptor. |
| 2813 | 9813005 | Using a yeast two-hybrid system, we identified several proteins that interact with the PH domains in IRS-1 and IRS-2, including Lon protease, myeloblast protein, and nucleolin. |
| 2814 | 9813005 | Although the roles of these molecules in insulin action are not yet known, each protein contained an acidic motif that interacted with the PH domain of IRS-2. |
| 2815 | 9813005 | However, only the acidic motif in nucleolin bound to IRS-1, suggesting that the PH domain in IRS-1 and IRS-2 are not identical. |
| 2816 | 9813005 | Moreover, synthetic peptides based on the acidic motif in Lon protease and myeloblast protein inhibited the binding of nucleolin to the PH domain of IRS-2 but not to the PH domain of IRS-1, confirming the selectivity of these PH domains. |
| 2817 | 9813005 | In 32D cells, nucleolin bound to both IRS-1 and IRS-2, and expression of the acidic motif of nucleolin inhibited insulin-stimulated tyrosine phosphorylation of IRS-1 and IRS-2. |
| 2818 | 9813005 | These results suggest that the binding of acidic motifs to the PH domain of IRS-1 and IRS-2 disrupts coupling to the activated insulin receptor. |
| 2819 | 9841495 | Elevated glucose increases mesangial cell sensitivity to insulin-like growth factor I. |
| 2820 | 9841495 | To determine the effects of glucose on insulin-like growth factor I (IGF-I)-induced mesangial cell (MC) proliferation, we have examined the relationships between IGF binding protein 2 (IGFBP-2) secretion and proliferation in murine MCs (MMCs). |
| 2821 | 9841495 | IGFBP-2 secretion was stimulated by IGF-I in NG but was unaltered in HG. |
| 2822 | 9841495 | Insulin treatment yielded similar results at 10-fold higher doses, indicating that this response is IGF-I receptor dependent. |
| 2823 | 9841495 | MMCs in HG displayed increased IGF-I-stimulated insulin receptor substrate-1/2 phosphorylation and activator protein-1 transcriptional activity compared with NG controls. |
| 2824 | 9841495 | Accordingly, although IGF-I was not proliferative in NG, it increased [3H]thymidine incorporation and cell number in HG to an extent proportional to the decrease in IGFBP-2. |
| 2825 | 9841495 | Thus hyperglycemia, as seen in diabetes, may increase MC IGF-I sensitivity by reducing IGFBP-2 expression, in turn increasing its proliferative and secretory responses and contributing to the development of diabetic glomerulosclerosis. |
| 2826 | 9844354 | Insulin action starts with binding to a membrane receptor (insulin receptor-tyrosine kinase) and with activating an insulin receptor substrate 1 (IRS-1) and substrate 2 (IRS-2). |
| 2827 | 9844354 | Insulin receptors interact at least with three cascade reactions, phosphorylating G proteins and IRS-1, that activate PLC "ras" and PI-3-K. |
| 2828 | 9844354 | The obese skeletal muscle shows a reduction of insulin receptor and IRS-1 phosphorylation and of PI-3-K activation; the scarce expression of these proteins would determine the muscular IR. |
| 2829 | 9844354 | Insulin action starts with binding to a membrane receptor (insulin receptor-tyrosine kinase) and with activating an insulin receptor substrate 1 (IRS-1) and substrate 2 (IRS-2). |
| 2830 | 9844354 | Insulin receptors interact at least with three cascade reactions, phosphorylating G proteins and IRS-1, that activate PLC "ras" and PI-3-K. |
| 2831 | 9844354 | The obese skeletal muscle shows a reduction of insulin receptor and IRS-1 phosphorylation and of PI-3-K activation; the scarce expression of these proteins would determine the muscular IR. |
| 2832 | 9844354 | Insulin action starts with binding to a membrane receptor (insulin receptor-tyrosine kinase) and with activating an insulin receptor substrate 1 (IRS-1) and substrate 2 (IRS-2). |
| 2833 | 9844354 | Insulin receptors interact at least with three cascade reactions, phosphorylating G proteins and IRS-1, that activate PLC "ras" and PI-3-K. |
| 2834 | 9844354 | The obese skeletal muscle shows a reduction of insulin receptor and IRS-1 phosphorylation and of PI-3-K activation; the scarce expression of these proteins would determine the muscular IR. |
| 2835 | 9892238 | Enhanced insulin-stimulated activation of phosphatidylinositol 3-kinase in the liver of high-fat-fed rats. |
| 2836 | 9892238 | Insulin receptor substrate (IRS)-1 and IRS-2, which mediate phosphatidylinositol (PI) 3-kinase activation, play essential roles in insulin-induced translocation of GLUT4 and in glycogen synthesis. |
| 2837 | 9892238 | In this study, we investigated the process of PI 3-kinase activation via binding with IRS-1 and -2 in liver, muscle, and fat of high-fat-fed rats, a model of insulin-resistant diabetes. |
| 2838 | 9892238 | In the liver of high-fat-fed rats, insulin increased the PI 3-kinase regulatory subunit p85alpha and the PI 3-kinase activities associated with IRS-1 3.6- and 2.4-fold, and with IRS-2, 4.7- and 3.0-fold, respectively, compared with those in control rats. |
| 2839 | 9892238 | The tyrosine phosphorylation levels of IRS-1 and IRS-2 were not significantly altered, however. |
| 2840 | 9892238 | Taking into consideration that hepatic PI 3-kinase activation is severely impaired in obese diabetic models such as Zucker fatty rats, it is possible that the mechanism by which a high-fat diet causes insulin resistance is quite different from that associated with obesity and overeating due to abnormality in the leptin system. |
| 2841 | 9892238 | Enhanced insulin-stimulated activation of phosphatidylinositol 3-kinase in the liver of high-fat-fed rats. |
| 2842 | 9892238 | Insulin receptor substrate (IRS)-1 and IRS-2, which mediate phosphatidylinositol (PI) 3-kinase activation, play essential roles in insulin-induced translocation of GLUT4 and in glycogen synthesis. |
| 2843 | 9892238 | In this study, we investigated the process of PI 3-kinase activation via binding with IRS-1 and -2 in liver, muscle, and fat of high-fat-fed rats, a model of insulin-resistant diabetes. |
| 2844 | 9892238 | In the liver of high-fat-fed rats, insulin increased the PI 3-kinase regulatory subunit p85alpha and the PI 3-kinase activities associated with IRS-1 3.6- and 2.4-fold, and with IRS-2, 4.7- and 3.0-fold, respectively, compared with those in control rats. |
| 2845 | 9892238 | The tyrosine phosphorylation levels of IRS-1 and IRS-2 were not significantly altered, however. |
| 2846 | 9892238 | Taking into consideration that hepatic PI 3-kinase activation is severely impaired in obese diabetic models such as Zucker fatty rats, it is possible that the mechanism by which a high-fat diet causes insulin resistance is quite different from that associated with obesity and overeating due to abnormality in the leptin system. |
| 2847 | 9892238 | Enhanced insulin-stimulated activation of phosphatidylinositol 3-kinase in the liver of high-fat-fed rats. |
| 2848 | 9892238 | Insulin receptor substrate (IRS)-1 and IRS-2, which mediate phosphatidylinositol (PI) 3-kinase activation, play essential roles in insulin-induced translocation of GLUT4 and in glycogen synthesis. |
| 2849 | 9892238 | In this study, we investigated the process of PI 3-kinase activation via binding with IRS-1 and -2 in liver, muscle, and fat of high-fat-fed rats, a model of insulin-resistant diabetes. |
| 2850 | 9892238 | In the liver of high-fat-fed rats, insulin increased the PI 3-kinase regulatory subunit p85alpha and the PI 3-kinase activities associated with IRS-1 3.6- and 2.4-fold, and with IRS-2, 4.7- and 3.0-fold, respectively, compared with those in control rats. |
| 2851 | 9892238 | The tyrosine phosphorylation levels of IRS-1 and IRS-2 were not significantly altered, however. |
| 2852 | 9892238 | Taking into consideration that hepatic PI 3-kinase activation is severely impaired in obese diabetic models such as Zucker fatty rats, it is possible that the mechanism by which a high-fat diet causes insulin resistance is quite different from that associated with obesity and overeating due to abnormality in the leptin system. |
| 2853 | 9932214 | The binding of insulin to its receptor induces autophosphorylation of the receptor on tyrosine residues and thereby stimulates its tyrosine kinase activity towards intracellular substrates such as Shc or IRS1. |
| 2854 | 9932214 | Tyrosine phosphorylation of IRSs and Shc by the insulin receptor permits the activation of two major signalling pathways, the MAP kinase pathway and the Pl 3-kinase pathway. |
| 2855 | 9932214 | The MAP kinase pathway does not appear to play a significant role in the transmission of the metabolic effects of insulin. |
| 2856 | 10067837 | In vivo insulin signaling in the myocardium of streptozotocin-diabetic rats: opposite effects of diabetes on insulin stimulation of glycogen synthase and c-Fos. |
| 2857 | 10067837 | Insulin rapidly stimulated tyrosine phosphorylation of the insulin receptor, insulin receptor substrate-1 (IRS-1) and, to a lesser extent, IRS-2 in normal and diabetic myocardium. |
| 2858 | 10067837 | In diabetic rats, there was 2-fold higher insulin receptor content and insulin-stimulated receptor tyrosine phosphorylation in comparison with control rats. |
| 2859 | 10067837 | Under the same experimental conditions, there was a marked increase in insulin stimulation of myocardial c-fos messenger RNA content in diabetic animals in comparison with controls. |
| 2860 | 10077007 | Action of insulin receptor substrate-3 (IRS-3) and IRS-4 to stimulate translocation of GLUT4 in rat adipose cells. |
| 2861 | 10077007 | Previously, we have demonstrated that insulin receptor substrates (IRS)-1 and -2 can mediate insulin's action to promote translocation of GLUT4 glucose transporters to the cell surface in rat adipose cells. |
| 2862 | 10077007 | Nevertheless, as demonstrated in this study, both IRS-3 and IRS-4 can also stimulate translocation of GLUT4. |
| 2863 | 10077007 | Rat adipose cells were cotransfected with expression vectors for hemagglutinin (HA) epitope-tagged GLUT4 (GLUT4-HA) and human IRS-1, murine IRS-3, or human IRS-4. |
| 2864 | 10077007 | Overexpression of IRS-1 led to a 2-fold increase in cell surface GLUT4-HA in cells incubated in the absence of insulin; overexpression of either IRS-3 or IRS-4 elicited a larger increase in cell surface GLUT4-HA. |
| 2865 | 10077007 | Because phosphatidylinositol (PI) 3-kinase is essential for insulin-stimulated translocation of GLUT4, we also studied a mutant IRS-3 molecule (IRS-3-F4) in which Phe was substituted for Tyr in all four YXXM motifs (the phosphorylation sites predicted to bind to and activate PI 3-kinase). |
| 2866 | 10077007 | Our data suggest that IRS-3 and IRS-4 are capable of mediating PI 3-kinase-dependent metabolic actions of insulin in adipose cells, and that IRS proteins play a physiological role in mediating translocation of GLUT4. |
| 2867 | 10077007 | Action of insulin receptor substrate-3 (IRS-3) and IRS-4 to stimulate translocation of GLUT4 in rat adipose cells. |
| 2868 | 10077007 | Previously, we have demonstrated that insulin receptor substrates (IRS)-1 and -2 can mediate insulin's action to promote translocation of GLUT4 glucose transporters to the cell surface in rat adipose cells. |
| 2869 | 10077007 | Nevertheless, as demonstrated in this study, both IRS-3 and IRS-4 can also stimulate translocation of GLUT4. |
| 2870 | 10077007 | Rat adipose cells were cotransfected with expression vectors for hemagglutinin (HA) epitope-tagged GLUT4 (GLUT4-HA) and human IRS-1, murine IRS-3, or human IRS-4. |
| 2871 | 10077007 | Overexpression of IRS-1 led to a 2-fold increase in cell surface GLUT4-HA in cells incubated in the absence of insulin; overexpression of either IRS-3 or IRS-4 elicited a larger increase in cell surface GLUT4-HA. |
| 2872 | 10077007 | Because phosphatidylinositol (PI) 3-kinase is essential for insulin-stimulated translocation of GLUT4, we also studied a mutant IRS-3 molecule (IRS-3-F4) in which Phe was substituted for Tyr in all four YXXM motifs (the phosphorylation sites predicted to bind to and activate PI 3-kinase). |
| 2873 | 10077007 | Our data suggest that IRS-3 and IRS-4 are capable of mediating PI 3-kinase-dependent metabolic actions of insulin in adipose cells, and that IRS proteins play a physiological role in mediating translocation of GLUT4. |
| 2874 | 10078575 | In soleus muscle from GK rats, submaximal and maximal insulin-stimulated insulin receptor substrate (IRS)-1 tyrosine phosphorylation and IRS-1-associated phosphatidylinositol (PI) 3-kinase activity were markedly reduced, compared with that of Wistar rats, but only submaximal insulin-stimulated PI 3-kinase was restored after phlorizin treatment. |
| 2875 | 10078575 | In EDL muscle, insulin-stimulated IRS-1 tyrosine phosphorylation and IRS-1-associated PI-3 kinase were not altered between GK and Wistar rats. |
| 2876 | 10078575 | Maximal insulin-stimulated Akt (protein kinase B) kinase activity is decreased in soleus muscle from GK rats and restored upon normalization of glycemia (Krook et al., Diabetes 46:2100-2114, 1997). |
| 2877 | 10078575 | Here, we show that in EDL muscle from GK rats, maximal insulin-stimulated Akt kinase activity is also impaired and restored to Wistar rat levels after phlorizin treatment. |
| 2878 | 10084586 | We have analyzed the association of variants in the genes for amylin, insulin receptor, insulin receptor substrate-1 (IRS-1), and coagulation factor V with type 2 diabetes mellitus. |
| 2879 | 10084586 | No association was found for variants in the genes for amylin, IRS-1, and coagulation factor V, nor was there any evidence for epistatic interactions between these gene variants. |
| 2880 | 10084586 | We have analyzed the association of variants in the genes for amylin, insulin receptor, insulin receptor substrate-1 (IRS-1), and coagulation factor V with type 2 diabetes mellitus. |
| 2881 | 10084586 | No association was found for variants in the genes for amylin, IRS-1, and coagulation factor V, nor was there any evidence for epistatic interactions between these gene variants. |
| 2882 | 10096790 | Defective regulation of phosphatidylinositol-3-kinase gene expression in skeletal muscle and adipose tissue of non-insulin-dependent diabetes mellitus patients. |
| 2883 | 10096790 | We investigated the regulation of the mRNA expression of the insulin receptor, insulin receptor substrate-1 (IRS-1) and p85alpha-phosphatidylinositol-3-kinase (PI-3K), three major actors of insulin action, in skeletal muscle from 10 healthy lean volunteers, 13 obese patients with Type II (non-insulin-dependent) diabetes mellitus and 7 non-diabetic obese subjects. |
| 2884 | 10096790 | In contrast, insulin increased p85alpha-phosphatidylinositol-3-kinase mRNA expression in muscle from non-diabetic subjects (+98+/-22% in lean and +127+/-16% in obese, p<0.02) but this effect was totally impaired in Type II diabetic patients (+5+/-12%, NS). |
| 2885 | 10096790 | A similar defect in insulin action on p85alpha-phosphatidylinositol-3-kinase mRNA expression was observed in abdominal subcutaneous adipose tissue (+138+/-25%, p<0.01 in lean and +46+/-14%, p<0.02 in obese and +29+/-11%, NS in Type II diabetic patients). |
| 2886 | 10096790 | The lack of action of insulin on p85alpha-phosphatidylinositol-3-kinase mRNA in diabetic subjects was probably not due to a deleterious effect of hyperglycaemia since improvement of the glycaemic control for 10 days did not restore the response in muscle or in adipose tissue. |
| 2887 | 10096790 | This study provides evidence for a defect in the regulation by insulin of PI-3K gene expression in Type II diabetic patients, thus reinforcing the concept that alterations at the gene expression might be involved in the pathogeny of Type II diabetes. |
| 2888 | 10102697 | Islet transplantation restores normal levels of insulin receptor and substrate tyrosine phosphorylation and phosphatidylinositol 3-kinase activity in skeletal muscle and myocardium of streptozocin-induced diabetic rats. |
| 2889 | 10102697 | Compared with controls, diabetic rats were characterized by multiple insulin signaling abnormalities in skeletal muscle, which included 1) increased insulin-stimulated tyrosine phosphorylation of the insulin receptor beta-subunit and insulin receptor substrates IRS-1 and IRS-2, 2) increased substrate tyrosine phosphorylation in the basal state, 3) a decreased amount of IRS-1 protein, 4) markedly elevated basal and insulin-stimulated phosphatidylinositol (PI) 3-kinase activity in anti-IRS-1 immunoprecipitates from total tissue extracts, and 5) increased PI 3-kinase activity in low-density microsomes. |
| 2890 | 10102697 | In addition, STZ-diabetes resulted in decreased IRS-1 and increased IRS-2 protein levels in myocardium. |
| 2891 | 10102697 | Islet transplantation fully corrected the diabetes-induced changes in protein tyrosine phosphorylation and PI 3-kinase activity and normalized IRS-1 and IRS-2 protein content in both skeletal muscle and myocardium. |
| 2892 | 10102697 | Islet transplantation restores normal levels of insulin receptor and substrate tyrosine phosphorylation and phosphatidylinositol 3-kinase activity in skeletal muscle and myocardium of streptozocin-induced diabetic rats. |
| 2893 | 10102697 | Compared with controls, diabetic rats were characterized by multiple insulin signaling abnormalities in skeletal muscle, which included 1) increased insulin-stimulated tyrosine phosphorylation of the insulin receptor beta-subunit and insulin receptor substrates IRS-1 and IRS-2, 2) increased substrate tyrosine phosphorylation in the basal state, 3) a decreased amount of IRS-1 protein, 4) markedly elevated basal and insulin-stimulated phosphatidylinositol (PI) 3-kinase activity in anti-IRS-1 immunoprecipitates from total tissue extracts, and 5) increased PI 3-kinase activity in low-density microsomes. |
| 2894 | 10102697 | In addition, STZ-diabetes resulted in decreased IRS-1 and increased IRS-2 protein levels in myocardium. |
| 2895 | 10102697 | Islet transplantation fully corrected the diabetes-induced changes in protein tyrosine phosphorylation and PI 3-kinase activity and normalized IRS-1 and IRS-2 protein content in both skeletal muscle and myocardium. |
| 2896 | 10102697 | Islet transplantation restores normal levels of insulin receptor and substrate tyrosine phosphorylation and phosphatidylinositol 3-kinase activity in skeletal muscle and myocardium of streptozocin-induced diabetic rats. |
| 2897 | 10102697 | Compared with controls, diabetic rats were characterized by multiple insulin signaling abnormalities in skeletal muscle, which included 1) increased insulin-stimulated tyrosine phosphorylation of the insulin receptor beta-subunit and insulin receptor substrates IRS-1 and IRS-2, 2) increased substrate tyrosine phosphorylation in the basal state, 3) a decreased amount of IRS-1 protein, 4) markedly elevated basal and insulin-stimulated phosphatidylinositol (PI) 3-kinase activity in anti-IRS-1 immunoprecipitates from total tissue extracts, and 5) increased PI 3-kinase activity in low-density microsomes. |
| 2898 | 10102697 | In addition, STZ-diabetes resulted in decreased IRS-1 and increased IRS-2 protein levels in myocardium. |
| 2899 | 10102697 | Islet transplantation fully corrected the diabetes-induced changes in protein tyrosine phosphorylation and PI 3-kinase activity and normalized IRS-1 and IRS-2 protein content in both skeletal muscle and myocardium. |
| 2900 | 10187855 | Oxidative stress disrupts insulin-induced cellular redistribution of insulin receptor substrate-1 and phosphatidylinositol 3-kinase in 3T3-L1 adipocytes. |
| 2901 | 10187855 | A putative cellular mechanism for impaired protein kinase B activation and GLUT4 translocation. |
| 2902 | 10187855 | In a recent study we have demonstrated that 3T3-L1 adipocytes exposed to low micromolar H2O2 concentrations display impaired insulin stimulated GLUT4 translocation from internal membrane pools to the plasma membrane (Rudich, A., Tirosh, A., Potashnik, R., Hemi, R., Kannety, H., and Bashan, N. (1998) Diabetes 47, 1562-1569). |
| 2903 | 10187855 | This was associated with reduced insulin-stimulated IRS-1 and p85-associated PI 3-kinase activities in the LDM (84 and 96% inhibition, respectively). |
| 2904 | 10187855 | The effect of this finding on the downstream insulin signal was demonstrated by a 90% reduction in insulin stimulated protein kinase B (PKB) serine 473 phosphorylation and impaired activation of PKBalpha and PKBgamma. |
| 2905 | 10187855 | These data suggest that activation of PKB and GLUT4 translocation are insulin signaling events dependent upon a normal insulin induced cellular compartmentalization of PI 3-kinase and IRS-1, which is oxidative stress-sensitive. |
| 2906 | 10187855 | Oxidative stress disrupts insulin-induced cellular redistribution of insulin receptor substrate-1 and phosphatidylinositol 3-kinase in 3T3-L1 adipocytes. |
| 2907 | 10187855 | A putative cellular mechanism for impaired protein kinase B activation and GLUT4 translocation. |
| 2908 | 10187855 | In a recent study we have demonstrated that 3T3-L1 adipocytes exposed to low micromolar H2O2 concentrations display impaired insulin stimulated GLUT4 translocation from internal membrane pools to the plasma membrane (Rudich, A., Tirosh, A., Potashnik, R., Hemi, R., Kannety, H., and Bashan, N. (1998) Diabetes 47, 1562-1569). |
| 2909 | 10187855 | This was associated with reduced insulin-stimulated IRS-1 and p85-associated PI 3-kinase activities in the LDM (84 and 96% inhibition, respectively). |
| 2910 | 10187855 | The effect of this finding on the downstream insulin signal was demonstrated by a 90% reduction in insulin stimulated protein kinase B (PKB) serine 473 phosphorylation and impaired activation of PKBalpha and PKBgamma. |
| 2911 | 10187855 | These data suggest that activation of PKB and GLUT4 translocation are insulin signaling events dependent upon a normal insulin induced cellular compartmentalization of PI 3-kinase and IRS-1, which is oxidative stress-sensitive. |
| 2912 | 10187855 | Oxidative stress disrupts insulin-induced cellular redistribution of insulin receptor substrate-1 and phosphatidylinositol 3-kinase in 3T3-L1 adipocytes. |
| 2913 | 10187855 | A putative cellular mechanism for impaired protein kinase B activation and GLUT4 translocation. |
| 2914 | 10187855 | In a recent study we have demonstrated that 3T3-L1 adipocytes exposed to low micromolar H2O2 concentrations display impaired insulin stimulated GLUT4 translocation from internal membrane pools to the plasma membrane (Rudich, A., Tirosh, A., Potashnik, R., Hemi, R., Kannety, H., and Bashan, N. (1998) Diabetes 47, 1562-1569). |
| 2915 | 10187855 | This was associated with reduced insulin-stimulated IRS-1 and p85-associated PI 3-kinase activities in the LDM (84 and 96% inhibition, respectively). |
| 2916 | 10187855 | The effect of this finding on the downstream insulin signal was demonstrated by a 90% reduction in insulin stimulated protein kinase B (PKB) serine 473 phosphorylation and impaired activation of PKBalpha and PKBgamma. |
| 2917 | 10187855 | These data suggest that activation of PKB and GLUT4 translocation are insulin signaling events dependent upon a normal insulin induced cellular compartmentalization of PI 3-kinase and IRS-1, which is oxidative stress-sensitive. |
| 2918 | 10212838 | The insulin-signalling cascade from the insulin receptor to PI-3-K was also found to be abnormal, resulting in a severely reduced phosphorylation degree of the IRS-1 (IRS-2?) |
| 2919 | 10318852 | Membrane-targeted phosphatidylinositol 3-kinase mimics insulin actions and induces a state of cellular insulin resistance. |
| 2920 | 10318852 | Even at this submaximal PI 3-kinase activity, p110(CAAX) fully stimulated p70 S6 kinase, Akt, 2-deoxyglucose uptake, and Ras, whereas, p110(WT) had little or no effect on these downstream effects. |
| 2921 | 10318852 | Interestingly p110(CAAX) did not activate MAP kinase, despite its stimulation of p21(ras). |
| 2922 | 10318852 | Surprisingly, p110(CAAX) did not increase basal glycogen synthase activity, and inhibited insulin stimulated activity, indicative of cellular resistance to this action of insulin. p110(CAAX) also inhibited insulin stimulated, but not platelet-derived growth factor-stimulated mitogen-activated protein kinase phosphorylation, demonstrating that the p110(CAAX) induced inhibition of mitogen-activated protein kinase and insulin signaling is specific, and not due to some toxic or nonspecific effect on the cells. |
| 2923 | 10318852 | Moreover, p110(CAAX) stimulated IRS-1 Ser/Thr phosphorylation, and inhibited IRS-1 associated PI 3-kinase activity, without affecting insulin receptor tyrosine phosphorylation, suggesting that it may play an important role as a negative regulator for insulin signaling. |
| 2924 | 10320051 | Expression of this variant in 32-D cells is associated with a significant (20-30%) impairment of insulin-stimulated PI3-kinase activity, as well as reduced binding of IRS-1 to the p85 regulatory subunit of PI3-kinase. |
| 2925 | 10320051 | Mutational analysis has also shown that homozygous carriers of a codon Met 326 Ile mutation in the p85 subunit of phosphatidylinositol-3 (PI3)-kinase (about 2% of the Caucasian population) have lower glucose tolerance, glucose effectiveness. |
| 2926 | 10320051 | A further Asp to Tyr polymorphism has been identified at codon 905 of the gene encoding the regulatory subunit of glycogen-associated protein phosphatase-1 (PP1G). |
| 2927 | 10320052 | Mechanisms of TNF-alpha-induced insulin resistance. |
| 2928 | 10320052 | There is now substantial evidence linking TNF-alpha to the presentation of insulin resistance in humans, animals and in vitro systems. |
| 2929 | 10320052 | We explored the relationship between TNF-alpha and insulin resistance using knockout mice deficient for either TNF-alpha or one or both of its receptors, p55 and p75. |
| 2930 | 10320052 | In studies of TNF-alpha-deficient knockout mice with diet-induced obesity, obese TNF-alpha knockouts responded to an exogenous dose of insulin or glucose much more efficiently than TNF-alpha wild-type animals. |
| 2931 | 10320052 | This finding suggests that deletion of TNF-alpha leads to increased insulin sensitivity, ie decreased insulin resistance. |
| 2932 | 10320052 | Since the improvement in sensitivity was slightly greater with double mutants, p55 alone cannot be responsible for TNF-alpha's promotion of insulin resistance in obese mice, despite the likelihood that it is more important than p75. |
| 2933 | 10320052 | How TNF-alpha-related insulin resistance is mediated is not fully clear, although phosphorylation of serine residues on IRS-1 has previously been shown to be important. |
| 2934 | 10320052 | When we monitored Glut 4 expression in obese TNF-alpha wild-type and knockout mice, we found no convincing evidence that TNF-alpha mediation of the down-regulation of Glut 4 mRNA expression is responsible for insulin resistance. |
| 2935 | 10320052 | However, we found an approximately 2-fold increase in insulin-stimulated tyrosine phosphorylation of the insulin receptor in the muscle and adipose tissue of TNF-alpha knockout mice, suggesting that insulin receptor signalling is an important target for TNF-alpha. |
| 2936 | 10320052 | Other possible mediators of TNF-alpha-induced insulin resistance include circulating free fatty acids (FFAs) and leptin. |
| 2937 | 10320053 | It has been known for some time that down-regulation and reduced kinase activity of the insulin receptor play a role in insulin resistance; however, it has recently emerged that defects in the intracellular responses to insulin are also very important. |
| 2938 | 10320053 | We found that the insulin-stimulated activation of MAP kinase was defective in obese, insulin-resistant mice. |
| 2939 | 10320053 | Similarly, we investigated insulin-stimulated PI3-kinase activation in the isolated soleus muscle of lean and obese mice, and found a marked reduction in the PI3-kinase activation of obese animals. |
| 2940 | 10320053 | The magnitude of the effect was greater than the reduction in insulin receptor activation, suggesting that impairment of PI3-kinase activation is a very important element in the development of insulin resistance in obese mice. |
| 2941 | 10320053 | In keeping with this, we found that the defect in PI3-kinase activation developed in young obese mice before the emergence of overt insulin resistance. |
| 2942 | 10320053 | In adipocytes from young obese mice in which insulin resistance had not yet developed, we found that there were already marked defects in IRS-1 tyrosine phosphorylation. |
| 2943 | 10320053 | Such a process could contribute to the defective IRS-1 tyrosine phosphorylation in insulin-resistant animals. |
| 2944 | 10320053 | We found that brief exposure of 3T3-L1 adipocytes to platelet-derived growth factor led to IRS-1 serine/threonine phosphorylation through a PI3-kinase-dependent pathway, and that this prevented phosphorylation of the tyrosine residues of IRS-1. |
| 2945 | 10320053 | Such a mechanism, induced by growth factors, TNF-alpha or some other agent, may play an important role in the development of insulin resistance in obese mice. |
| 2946 | 10320053 | It has been known for some time that down-regulation and reduced kinase activity of the insulin receptor play a role in insulin resistance; however, it has recently emerged that defects in the intracellular responses to insulin are also very important. |
| 2947 | 10320053 | We found that the insulin-stimulated activation of MAP kinase was defective in obese, insulin-resistant mice. |
| 2948 | 10320053 | Similarly, we investigated insulin-stimulated PI3-kinase activation in the isolated soleus muscle of lean and obese mice, and found a marked reduction in the PI3-kinase activation of obese animals. |
| 2949 | 10320053 | The magnitude of the effect was greater than the reduction in insulin receptor activation, suggesting that impairment of PI3-kinase activation is a very important element in the development of insulin resistance in obese mice. |
| 2950 | 10320053 | In keeping with this, we found that the defect in PI3-kinase activation developed in young obese mice before the emergence of overt insulin resistance. |
| 2951 | 10320053 | In adipocytes from young obese mice in which insulin resistance had not yet developed, we found that there were already marked defects in IRS-1 tyrosine phosphorylation. |
| 2952 | 10320053 | Such a process could contribute to the defective IRS-1 tyrosine phosphorylation in insulin-resistant animals. |
| 2953 | 10320053 | We found that brief exposure of 3T3-L1 adipocytes to platelet-derived growth factor led to IRS-1 serine/threonine phosphorylation through a PI3-kinase-dependent pathway, and that this prevented phosphorylation of the tyrosine residues of IRS-1. |
| 2954 | 10320053 | Such a mechanism, induced by growth factors, TNF-alpha or some other agent, may play an important role in the development of insulin resistance in obese mice. |
| 2955 | 10320053 | It has been known for some time that down-regulation and reduced kinase activity of the insulin receptor play a role in insulin resistance; however, it has recently emerged that defects in the intracellular responses to insulin are also very important. |
| 2956 | 10320053 | We found that the insulin-stimulated activation of MAP kinase was defective in obese, insulin-resistant mice. |
| 2957 | 10320053 | Similarly, we investigated insulin-stimulated PI3-kinase activation in the isolated soleus muscle of lean and obese mice, and found a marked reduction in the PI3-kinase activation of obese animals. |
| 2958 | 10320053 | The magnitude of the effect was greater than the reduction in insulin receptor activation, suggesting that impairment of PI3-kinase activation is a very important element in the development of insulin resistance in obese mice. |
| 2959 | 10320053 | In keeping with this, we found that the defect in PI3-kinase activation developed in young obese mice before the emergence of overt insulin resistance. |
| 2960 | 10320053 | In adipocytes from young obese mice in which insulin resistance had not yet developed, we found that there were already marked defects in IRS-1 tyrosine phosphorylation. |
| 2961 | 10320053 | Such a process could contribute to the defective IRS-1 tyrosine phosphorylation in insulin-resistant animals. |
| 2962 | 10320053 | We found that brief exposure of 3T3-L1 adipocytes to platelet-derived growth factor led to IRS-1 serine/threonine phosphorylation through a PI3-kinase-dependent pathway, and that this prevented phosphorylation of the tyrosine residues of IRS-1. |
| 2963 | 10320053 | Such a mechanism, induced by growth factors, TNF-alpha or some other agent, may play an important role in the development of insulin resistance in obese mice. |
| 2964 | 10320054 | Crosstalk between insulin and angiotensin II signalling systems. |
| 2965 | 10320054 | Pharmacological inhibition of the renin-angiotensin system has been found to reduce not only hypertension, but also insulin resistance. |
| 2966 | 10320054 | This raises the possibility that the renin-angiotensin system may interact with insulin signalling. |
| 2967 | 10320054 | We have investigated the relationship between insulin and angiotensin II (AII) intracellular signalling in vivo using an intact rat heart model, and in vitro using rat aorta smooth muscle cells (RASMC). |
| 2968 | 10320054 | Results generated in the in vivo studies indicate that, like insulin, AII stimulates tyrosine phosphorylation of the insulin receptor substrates IRS-1 and IRS-2. |
| 2969 | 10320054 | This leads to binding of IRS-1 and IRS-2 to PI3-kinase. |
| 2970 | 10320054 | Moreover, AII inhibits insulin-stimulated IRS-1/IRS-2-associated PI3-kinase activity. |
| 2971 | 10320054 | The results of the in vitro studies indicate that AII inhibits insulin-stimulated, IRS-1-associated PI3-kinase activity by interfering with the docking of IRS-1 with the p85 regulatory subunit of PI3-kinase. |
| 2972 | 10320054 | It appears that AII achieves this effect by stimulating serine phosphorylation of the insulin receptor beta-subunit IRS-1, and the p85 regulatory subunit of PI3-kinase. |
| 2973 | 10320054 | Overactivity of the renin-angiotensin system is likely to impair insulin signalling and contribute to insulin resistance observed in essential hypertension. |
| 2974 | 10320054 | Crosstalk between insulin and angiotensin II signalling systems. |
| 2975 | 10320054 | Pharmacological inhibition of the renin-angiotensin system has been found to reduce not only hypertension, but also insulin resistance. |
| 2976 | 10320054 | This raises the possibility that the renin-angiotensin system may interact with insulin signalling. |
| 2977 | 10320054 | We have investigated the relationship between insulin and angiotensin II (AII) intracellular signalling in vivo using an intact rat heart model, and in vitro using rat aorta smooth muscle cells (RASMC). |
| 2978 | 10320054 | Results generated in the in vivo studies indicate that, like insulin, AII stimulates tyrosine phosphorylation of the insulin receptor substrates IRS-1 and IRS-2. |
| 2979 | 10320054 | This leads to binding of IRS-1 and IRS-2 to PI3-kinase. |
| 2980 | 10320054 | Moreover, AII inhibits insulin-stimulated IRS-1/IRS-2-associated PI3-kinase activity. |
| 2981 | 10320054 | The results of the in vitro studies indicate that AII inhibits insulin-stimulated, IRS-1-associated PI3-kinase activity by interfering with the docking of IRS-1 with the p85 regulatory subunit of PI3-kinase. |
| 2982 | 10320054 | It appears that AII achieves this effect by stimulating serine phosphorylation of the insulin receptor beta-subunit IRS-1, and the p85 regulatory subunit of PI3-kinase. |
| 2983 | 10320054 | Overactivity of the renin-angiotensin system is likely to impair insulin signalling and contribute to insulin resistance observed in essential hypertension. |
| 2984 | 10320054 | Crosstalk between insulin and angiotensin II signalling systems. |
| 2985 | 10320054 | Pharmacological inhibition of the renin-angiotensin system has been found to reduce not only hypertension, but also insulin resistance. |
| 2986 | 10320054 | This raises the possibility that the renin-angiotensin system may interact with insulin signalling. |
| 2987 | 10320054 | We have investigated the relationship between insulin and angiotensin II (AII) intracellular signalling in vivo using an intact rat heart model, and in vitro using rat aorta smooth muscle cells (RASMC). |
| 2988 | 10320054 | Results generated in the in vivo studies indicate that, like insulin, AII stimulates tyrosine phosphorylation of the insulin receptor substrates IRS-1 and IRS-2. |
| 2989 | 10320054 | This leads to binding of IRS-1 and IRS-2 to PI3-kinase. |
| 2990 | 10320054 | Moreover, AII inhibits insulin-stimulated IRS-1/IRS-2-associated PI3-kinase activity. |
| 2991 | 10320054 | The results of the in vitro studies indicate that AII inhibits insulin-stimulated, IRS-1-associated PI3-kinase activity by interfering with the docking of IRS-1 with the p85 regulatory subunit of PI3-kinase. |
| 2992 | 10320054 | It appears that AII achieves this effect by stimulating serine phosphorylation of the insulin receptor beta-subunit IRS-1, and the p85 regulatory subunit of PI3-kinase. |
| 2993 | 10320054 | Overactivity of the renin-angiotensin system is likely to impair insulin signalling and contribute to insulin resistance observed in essential hypertension. |
| 2994 | 10320054 | Crosstalk between insulin and angiotensin II signalling systems. |
| 2995 | 10320054 | Pharmacological inhibition of the renin-angiotensin system has been found to reduce not only hypertension, but also insulin resistance. |
| 2996 | 10320054 | This raises the possibility that the renin-angiotensin system may interact with insulin signalling. |
| 2997 | 10320054 | We have investigated the relationship between insulin and angiotensin II (AII) intracellular signalling in vivo using an intact rat heart model, and in vitro using rat aorta smooth muscle cells (RASMC). |
| 2998 | 10320054 | Results generated in the in vivo studies indicate that, like insulin, AII stimulates tyrosine phosphorylation of the insulin receptor substrates IRS-1 and IRS-2. |
| 2999 | 10320054 | This leads to binding of IRS-1 and IRS-2 to PI3-kinase. |
| 3000 | 10320054 | Moreover, AII inhibits insulin-stimulated IRS-1/IRS-2-associated PI3-kinase activity. |
| 3001 | 10320054 | The results of the in vitro studies indicate that AII inhibits insulin-stimulated, IRS-1-associated PI3-kinase activity by interfering with the docking of IRS-1 with the p85 regulatory subunit of PI3-kinase. |
| 3002 | 10320054 | It appears that AII achieves this effect by stimulating serine phosphorylation of the insulin receptor beta-subunit IRS-1, and the p85 regulatory subunit of PI3-kinase. |
| 3003 | 10320054 | Overactivity of the renin-angiotensin system is likely to impair insulin signalling and contribute to insulin resistance observed in essential hypertension. |
| 3004 | 10320054 | Crosstalk between insulin and angiotensin II signalling systems. |
| 3005 | 10320054 | Pharmacological inhibition of the renin-angiotensin system has been found to reduce not only hypertension, but also insulin resistance. |
| 3006 | 10320054 | This raises the possibility that the renin-angiotensin system may interact with insulin signalling. |
| 3007 | 10320054 | We have investigated the relationship between insulin and angiotensin II (AII) intracellular signalling in vivo using an intact rat heart model, and in vitro using rat aorta smooth muscle cells (RASMC). |
| 3008 | 10320054 | Results generated in the in vivo studies indicate that, like insulin, AII stimulates tyrosine phosphorylation of the insulin receptor substrates IRS-1 and IRS-2. |
| 3009 | 10320054 | This leads to binding of IRS-1 and IRS-2 to PI3-kinase. |
| 3010 | 10320054 | Moreover, AII inhibits insulin-stimulated IRS-1/IRS-2-associated PI3-kinase activity. |
| 3011 | 10320054 | The results of the in vitro studies indicate that AII inhibits insulin-stimulated, IRS-1-associated PI3-kinase activity by interfering with the docking of IRS-1 with the p85 regulatory subunit of PI3-kinase. |
| 3012 | 10320054 | It appears that AII achieves this effect by stimulating serine phosphorylation of the insulin receptor beta-subunit IRS-1, and the p85 regulatory subunit of PI3-kinase. |
| 3013 | 10320054 | Overactivity of the renin-angiotensin system is likely to impair insulin signalling and contribute to insulin resistance observed in essential hypertension. |
| 3014 | 10320056 | Insulin-mediated pseudoacromegaly in a patient with severe insulin resistance: association of defective insulin-stimulated glucose transport with impaired phosphatidylinositol 3-kinase activity in fibroblasts. |
| 3015 | 10320056 | In cultured fibroblasts derived from the patient, (i) insulin-stimulated glucose transport, (ii) the subcellular distribution of GLUT1 glucose transporters, (iii) insulin-stimulated IRS-1-immunoprecipitable phosphatidylinositol (PI) 3-kinase activity, as well as (iv) protein expression of the small GTP-binding protein Rab4 was determined. |
| 3016 | 10320056 | The results indicate, that insulin's ability to stimulate glucose transport is defective in the patients fibroblasts although the GLUT1 content in the plasma membrane was increased by 34% when compared to control cells. |
| 3017 | 10320056 | Furthermore, the IRS-1 dependent activation of PI 3-kinase was reduced by 39.6% after incubation with 10 nM insulin for 5 min. |
| 3018 | 10329736 | Interaction of insulin receptor substrate 3 with insulin receptor, insulin receptor-related receptor, insulin-like growth factor-1 receptor, and downstream signaling proteins. |
| 3019 | 10329736 | IRS3 is considerably shorter than IRS1, IRS2, and IRS4, and is predicted to interact with a distinct group of downstream signaling molecules. |
| 3020 | 10329736 | As determined in a modified yeast two-hybrid system, mIRS3 bound strongly to the p85 subunit of phosphatidylinositol 3-kinase. |
| 3021 | 10329736 | Although high affinity interaction required the presence of at least two of the four YXXM motifs in mIRS3, there was not a requirement for specific YXXM motifs. mIRS3 also bound to SHP2, Grb2, Nck, and Shc, but less strongly than to p85. |
| 3022 | 10329736 | Insulin stimulation promoted the association of mIRS3 with p85, SHP2, Nck, and Shc. |
| 3023 | 10329736 | Despite weak association between mIRS3 and Grb2, this interaction was not increased by insulin, and may not be mediated by the SH2 domain of Grb2. |
| 3024 | 10329736 | Thus, in contrast to other IRS proteins, mIRS3 appears to have greater specificity for activation of the phosphatidylinositol 3-kinase pathway rather than the Grb2/Ras pathway. |
| 3025 | 10329981 | Differential regulation of MAP kinase, p70(S6K), and Akt by contraction and insulin in rat skeletal muscle. |
| 3026 | 10329981 | To study the effects of contractile activity on mitogen-activated protein kinase (MAP kinase), p70 S6 kinase (p70(S6K)), and Akt kinase signaling in rat skeletal muscle, hindlimb muscles were contracted by electrical stimulation of the sciatic nerve for periods of 15 s to 60 min. |
| 3027 | 10329981 | Contraction resulted in a rapid and transient activation of Raf-1 and MAP kinase kinase 1, a rapid and more sustained activation of MAP kinase and the 90-kDa ribosomal S6 kinase 2, and a dramatic increase in c-fos mRNA expression. |
| 3028 | 10329981 | Contraction also resulted in an apparent increase in the association of Raf-1 with p21Ras, although stimulation of MAP kinase signaling occurred independent of Shc, IRS1, and IRS2 tyrosine phosphorylation or the formation of Shc/Grb2 or IRS1/Grb2 complexes. |
| 3029 | 10329981 | Insulin was considerably less effective than contraction in stimulating the MAP kinase pathway. |
| 3030 | 10329981 | However, insulin, but not contraction, increased p70(S6K) and Akt activities in the muscle. |
| 3031 | 10329981 | These results demonstrate that contraction-induced activation of the MAP kinase pathway is independent of proximal steps in insulin and/or growth factor-mediated signaling, and that contraction and insulin have discordant effects with respect to the activation of the MAP kinase pathway vs. p70(S6K) and Akt. |
| 3032 | 10329981 | Of the numerous stimulators of MAP kinase in skeletal muscle, contractile activity emerges as a potent and physiologically relevant activator of MAP kinase signaling, and thus activation of this pathway is likely to be an important molecular mechanism by which skeletal muscle cells transduce mechanical and/or biochemical signals into downstream biological responses. |
| 3033 | 10331411 | Effects of overexpression of human GLUT4 gene on maternal diabetes and fetal growth in spontaneous gestational diabetic C57BLKS/J Lepr(db/+) mice. |
| 3034 | 10331411 | To investigate the effects of the leptin receptor mutation on maternal metabolism and fetal growth during pregnancy, we studied +/+, db/+, and db/+ transgenic mice that overexpress the human GLUT4 gene two- to three-fold (db/+TG6). |
| 3035 | 10331411 | In skeletal muscle, insulin-stimulated tyrosine phosphorylation was decreased in pregnant +/+ mice, and even more so in db/+ mice: insulin receptor beta (IR-beta), +/+ 34%, db/+ 57% decrease, P<0.05; insulin receptor substrate 1 (IRS-1), +/+ 44%, db/+ 61% decrease, P<0.05; and phosphoinositol (PI) 3-kinase (p85alpha), +/+ 33%, db/+ 65% decrease, P<0.05. |
| 3036 | 10331411 | Overexpression of GLUT4 in db/+TG6 mice markedly improved glucose-stimulated insulin secretion, by 250%, and increased IRbeta, IRS-1, and p85alpha phosphorylation twofold, despite no change in concentration of these proteins. |
| 3037 | 10331411 | GLUT4 overexpression markedly improves insulin-signaling in GDM, resulting in increased insulin secretion and improved glycemic control. |
| 3038 | 10331411 | Effects of overexpression of human GLUT4 gene on maternal diabetes and fetal growth in spontaneous gestational diabetic C57BLKS/J Lepr(db/+) mice. |
| 3039 | 10331411 | To investigate the effects of the leptin receptor mutation on maternal metabolism and fetal growth during pregnancy, we studied +/+, db/+, and db/+ transgenic mice that overexpress the human GLUT4 gene two- to three-fold (db/+TG6). |
| 3040 | 10331411 | In skeletal muscle, insulin-stimulated tyrosine phosphorylation was decreased in pregnant +/+ mice, and even more so in db/+ mice: insulin receptor beta (IR-beta), +/+ 34%, db/+ 57% decrease, P<0.05; insulin receptor substrate 1 (IRS-1), +/+ 44%, db/+ 61% decrease, P<0.05; and phosphoinositol (PI) 3-kinase (p85alpha), +/+ 33%, db/+ 65% decrease, P<0.05. |
| 3041 | 10331411 | Overexpression of GLUT4 in db/+TG6 mice markedly improved glucose-stimulated insulin secretion, by 250%, and increased IRbeta, IRS-1, and p85alpha phosphorylation twofold, despite no change in concentration of these proteins. |
| 3042 | 10331411 | GLUT4 overexpression markedly improves insulin-signaling in GDM, resulting in increased insulin secretion and improved glycemic control. |
| 3043 | 10334307 | Glucosamine infusion in rats rapidly impairs insulin stimulation of phosphoinositide 3-kinase but does not alter activation of Akt/protein kinase B in skeletal muscle. |
| 3044 | 10334307 | Glucosamine, a metabolite of glucose via the hexosamine biosynthetic pathway, potently induces insulin resistance in skeletal muscle by impairing insulin-induced GLUT4 translocation to the plasma membrane. |
| 3045 | 10334307 | Activation of phosphoinositide (PI) 3-kinase is necessary for insulin-stimulated GLUT4 translocation, and the serine/threonine kinase Akt/protein kinase B (PKB) is a downstream mediator of some actions of PI 3-kinase. |
| 3046 | 10334307 | To determine whether glucosamine-induced insulin resistance could be due to impaired signaling, we measured insulin receptor substrate (IRS)-1 and insulin receptor tyrosine phosphorylation; PI 3-kinase activity associated with IRS-1, IRS-2, and phosphotyrosine; and Akt activity and phosphorylation in skeletal muscle of rats infused for 2 h with glucosamine (6.0 mg x kg(-1) x min(-1)) or saline. |
| 3047 | 10334307 | After 1 min of insulin stimulation, phosphorylation of IRS-1 and insulin receptor increased 6- to 8-fold in saline-infused rats and 7- to 10-fold in glucosamine-infused rats. |
| 3048 | 10334307 | In saline-infused rats, 1 min of insulin stimulation increased PI 3-kinase activity associated with IRS-1, IRS-2, or phosphotyrosine 7.6-, 6.4-, and 10-fold, respectively. |
| 3049 | 10334307 | In glucosamine-infused rats treated for 1 min with insulin, PI 3-kinase activity associated with IRS-1 was reduced 28% (P < 0.01) and that associated with phosphotyrosine was reduced 43% (P < 0.01). |
| 3050 | 10334307 | Insulin for 1 min stimulated Akt/PKB activity approximately 5-fold in both saline- and glucosamine-infused rats; insulin-induced hyperphosphorylation of Akt/PKB was not different between groups. |
| 3051 | 10334307 | Glucosamine infusion alone had no effect on tyrosine phosphorylation of the insulin receptor or IRS-1 or on stimulation of PI 3-kinase or Akt/PKB activity. |
| 3052 | 10334307 | However, 2 h of insulin clamp reduced PI 3-kinase activity associated with IRS-1, IRS-2, or phosphotyrosine to <30% of that seen with 1 min of insulin. |
| 3053 | 10334307 | Our data show that 1) glucosamine infusion in rats is associated with an impairment in the early activation of PI 3-kinase by insulin in skeletal muscle, 2) this insulin-resistant state does not involve alterations in the activation of Akt/PKB, and 3) prolonged insulin infusion under clamp conditions results in a blunting of the PI 3-kinase response to insulin. |
| 3054 | 10334307 | Glucosamine infusion in rats rapidly impairs insulin stimulation of phosphoinositide 3-kinase but does not alter activation of Akt/protein kinase B in skeletal muscle. |
| 3055 | 10334307 | Glucosamine, a metabolite of glucose via the hexosamine biosynthetic pathway, potently induces insulin resistance in skeletal muscle by impairing insulin-induced GLUT4 translocation to the plasma membrane. |
| 3056 | 10334307 | Activation of phosphoinositide (PI) 3-kinase is necessary for insulin-stimulated GLUT4 translocation, and the serine/threonine kinase Akt/protein kinase B (PKB) is a downstream mediator of some actions of PI 3-kinase. |
| 3057 | 10334307 | To determine whether glucosamine-induced insulin resistance could be due to impaired signaling, we measured insulin receptor substrate (IRS)-1 and insulin receptor tyrosine phosphorylation; PI 3-kinase activity associated with IRS-1, IRS-2, and phosphotyrosine; and Akt activity and phosphorylation in skeletal muscle of rats infused for 2 h with glucosamine (6.0 mg x kg(-1) x min(-1)) or saline. |
| 3058 | 10334307 | After 1 min of insulin stimulation, phosphorylation of IRS-1 and insulin receptor increased 6- to 8-fold in saline-infused rats and 7- to 10-fold in glucosamine-infused rats. |
| 3059 | 10334307 | In saline-infused rats, 1 min of insulin stimulation increased PI 3-kinase activity associated with IRS-1, IRS-2, or phosphotyrosine 7.6-, 6.4-, and 10-fold, respectively. |
| 3060 | 10334307 | In glucosamine-infused rats treated for 1 min with insulin, PI 3-kinase activity associated with IRS-1 was reduced 28% (P < 0.01) and that associated with phosphotyrosine was reduced 43% (P < 0.01). |
| 3061 | 10334307 | Insulin for 1 min stimulated Akt/PKB activity approximately 5-fold in both saline- and glucosamine-infused rats; insulin-induced hyperphosphorylation of Akt/PKB was not different between groups. |
| 3062 | 10334307 | Glucosamine infusion alone had no effect on tyrosine phosphorylation of the insulin receptor or IRS-1 or on stimulation of PI 3-kinase or Akt/PKB activity. |
| 3063 | 10334307 | However, 2 h of insulin clamp reduced PI 3-kinase activity associated with IRS-1, IRS-2, or phosphotyrosine to <30% of that seen with 1 min of insulin. |
| 3064 | 10334307 | Our data show that 1) glucosamine infusion in rats is associated with an impairment in the early activation of PI 3-kinase by insulin in skeletal muscle, 2) this insulin-resistant state does not involve alterations in the activation of Akt/PKB, and 3) prolonged insulin infusion under clamp conditions results in a blunting of the PI 3-kinase response to insulin. |
| 3065 | 10334307 | Glucosamine infusion in rats rapidly impairs insulin stimulation of phosphoinositide 3-kinase but does not alter activation of Akt/protein kinase B in skeletal muscle. |
| 3066 | 10334307 | Glucosamine, a metabolite of glucose via the hexosamine biosynthetic pathway, potently induces insulin resistance in skeletal muscle by impairing insulin-induced GLUT4 translocation to the plasma membrane. |
| 3067 | 10334307 | Activation of phosphoinositide (PI) 3-kinase is necessary for insulin-stimulated GLUT4 translocation, and the serine/threonine kinase Akt/protein kinase B (PKB) is a downstream mediator of some actions of PI 3-kinase. |
| 3068 | 10334307 | To determine whether glucosamine-induced insulin resistance could be due to impaired signaling, we measured insulin receptor substrate (IRS)-1 and insulin receptor tyrosine phosphorylation; PI 3-kinase activity associated with IRS-1, IRS-2, and phosphotyrosine; and Akt activity and phosphorylation in skeletal muscle of rats infused for 2 h with glucosamine (6.0 mg x kg(-1) x min(-1)) or saline. |
| 3069 | 10334307 | After 1 min of insulin stimulation, phosphorylation of IRS-1 and insulin receptor increased 6- to 8-fold in saline-infused rats and 7- to 10-fold in glucosamine-infused rats. |
| 3070 | 10334307 | In saline-infused rats, 1 min of insulin stimulation increased PI 3-kinase activity associated with IRS-1, IRS-2, or phosphotyrosine 7.6-, 6.4-, and 10-fold, respectively. |
| 3071 | 10334307 | In glucosamine-infused rats treated for 1 min with insulin, PI 3-kinase activity associated with IRS-1 was reduced 28% (P < 0.01) and that associated with phosphotyrosine was reduced 43% (P < 0.01). |
| 3072 | 10334307 | Insulin for 1 min stimulated Akt/PKB activity approximately 5-fold in both saline- and glucosamine-infused rats; insulin-induced hyperphosphorylation of Akt/PKB was not different between groups. |
| 3073 | 10334307 | Glucosamine infusion alone had no effect on tyrosine phosphorylation of the insulin receptor or IRS-1 or on stimulation of PI 3-kinase or Akt/PKB activity. |
| 3074 | 10334307 | However, 2 h of insulin clamp reduced PI 3-kinase activity associated with IRS-1, IRS-2, or phosphotyrosine to <30% of that seen with 1 min of insulin. |
| 3075 | 10334307 | Our data show that 1) glucosamine infusion in rats is associated with an impairment in the early activation of PI 3-kinase by insulin in skeletal muscle, 2) this insulin-resistant state does not involve alterations in the activation of Akt/PKB, and 3) prolonged insulin infusion under clamp conditions results in a blunting of the PI 3-kinase response to insulin. |
| 3076 | 10334307 | Glucosamine infusion in rats rapidly impairs insulin stimulation of phosphoinositide 3-kinase but does not alter activation of Akt/protein kinase B in skeletal muscle. |
| 3077 | 10334307 | Glucosamine, a metabolite of glucose via the hexosamine biosynthetic pathway, potently induces insulin resistance in skeletal muscle by impairing insulin-induced GLUT4 translocation to the plasma membrane. |
| 3078 | 10334307 | Activation of phosphoinositide (PI) 3-kinase is necessary for insulin-stimulated GLUT4 translocation, and the serine/threonine kinase Akt/protein kinase B (PKB) is a downstream mediator of some actions of PI 3-kinase. |
| 3079 | 10334307 | To determine whether glucosamine-induced insulin resistance could be due to impaired signaling, we measured insulin receptor substrate (IRS)-1 and insulin receptor tyrosine phosphorylation; PI 3-kinase activity associated with IRS-1, IRS-2, and phosphotyrosine; and Akt activity and phosphorylation in skeletal muscle of rats infused for 2 h with glucosamine (6.0 mg x kg(-1) x min(-1)) or saline. |
| 3080 | 10334307 | After 1 min of insulin stimulation, phosphorylation of IRS-1 and insulin receptor increased 6- to 8-fold in saline-infused rats and 7- to 10-fold in glucosamine-infused rats. |
| 3081 | 10334307 | In saline-infused rats, 1 min of insulin stimulation increased PI 3-kinase activity associated with IRS-1, IRS-2, or phosphotyrosine 7.6-, 6.4-, and 10-fold, respectively. |
| 3082 | 10334307 | In glucosamine-infused rats treated for 1 min with insulin, PI 3-kinase activity associated with IRS-1 was reduced 28% (P < 0.01) and that associated with phosphotyrosine was reduced 43% (P < 0.01). |
| 3083 | 10334307 | Insulin for 1 min stimulated Akt/PKB activity approximately 5-fold in both saline- and glucosamine-infused rats; insulin-induced hyperphosphorylation of Akt/PKB was not different between groups. |
| 3084 | 10334307 | Glucosamine infusion alone had no effect on tyrosine phosphorylation of the insulin receptor or IRS-1 or on stimulation of PI 3-kinase or Akt/PKB activity. |
| 3085 | 10334307 | However, 2 h of insulin clamp reduced PI 3-kinase activity associated with IRS-1, IRS-2, or phosphotyrosine to <30% of that seen with 1 min of insulin. |
| 3086 | 10334307 | Our data show that 1) glucosamine infusion in rats is associated with an impairment in the early activation of PI 3-kinase by insulin in skeletal muscle, 2) this insulin-resistant state does not involve alterations in the activation of Akt/PKB, and 3) prolonged insulin infusion under clamp conditions results in a blunting of the PI 3-kinase response to insulin. |
| 3087 | 10334307 | Glucosamine infusion in rats rapidly impairs insulin stimulation of phosphoinositide 3-kinase but does not alter activation of Akt/protein kinase B in skeletal muscle. |
| 3088 | 10334307 | Glucosamine, a metabolite of glucose via the hexosamine biosynthetic pathway, potently induces insulin resistance in skeletal muscle by impairing insulin-induced GLUT4 translocation to the plasma membrane. |
| 3089 | 10334307 | Activation of phosphoinositide (PI) 3-kinase is necessary for insulin-stimulated GLUT4 translocation, and the serine/threonine kinase Akt/protein kinase B (PKB) is a downstream mediator of some actions of PI 3-kinase. |
| 3090 | 10334307 | To determine whether glucosamine-induced insulin resistance could be due to impaired signaling, we measured insulin receptor substrate (IRS)-1 and insulin receptor tyrosine phosphorylation; PI 3-kinase activity associated with IRS-1, IRS-2, and phosphotyrosine; and Akt activity and phosphorylation in skeletal muscle of rats infused for 2 h with glucosamine (6.0 mg x kg(-1) x min(-1)) or saline. |
| 3091 | 10334307 | After 1 min of insulin stimulation, phosphorylation of IRS-1 and insulin receptor increased 6- to 8-fold in saline-infused rats and 7- to 10-fold in glucosamine-infused rats. |
| 3092 | 10334307 | In saline-infused rats, 1 min of insulin stimulation increased PI 3-kinase activity associated with IRS-1, IRS-2, or phosphotyrosine 7.6-, 6.4-, and 10-fold, respectively. |
| 3093 | 10334307 | In glucosamine-infused rats treated for 1 min with insulin, PI 3-kinase activity associated with IRS-1 was reduced 28% (P < 0.01) and that associated with phosphotyrosine was reduced 43% (P < 0.01). |
| 3094 | 10334307 | Insulin for 1 min stimulated Akt/PKB activity approximately 5-fold in both saline- and glucosamine-infused rats; insulin-induced hyperphosphorylation of Akt/PKB was not different between groups. |
| 3095 | 10334307 | Glucosamine infusion alone had no effect on tyrosine phosphorylation of the insulin receptor or IRS-1 or on stimulation of PI 3-kinase or Akt/PKB activity. |
| 3096 | 10334307 | However, 2 h of insulin clamp reduced PI 3-kinase activity associated with IRS-1, IRS-2, or phosphotyrosine to <30% of that seen with 1 min of insulin. |
| 3097 | 10334307 | Our data show that 1) glucosamine infusion in rats is associated with an impairment in the early activation of PI 3-kinase by insulin in skeletal muscle, 2) this insulin-resistant state does not involve alterations in the activation of Akt/PKB, and 3) prolonged insulin infusion under clamp conditions results in a blunting of the PI 3-kinase response to insulin. |
| 3098 | 10334307 | Glucosamine infusion in rats rapidly impairs insulin stimulation of phosphoinositide 3-kinase but does not alter activation of Akt/protein kinase B in skeletal muscle. |
| 3099 | 10334307 | Glucosamine, a metabolite of glucose via the hexosamine biosynthetic pathway, potently induces insulin resistance in skeletal muscle by impairing insulin-induced GLUT4 translocation to the plasma membrane. |
| 3100 | 10334307 | Activation of phosphoinositide (PI) 3-kinase is necessary for insulin-stimulated GLUT4 translocation, and the serine/threonine kinase Akt/protein kinase B (PKB) is a downstream mediator of some actions of PI 3-kinase. |
| 3101 | 10334307 | To determine whether glucosamine-induced insulin resistance could be due to impaired signaling, we measured insulin receptor substrate (IRS)-1 and insulin receptor tyrosine phosphorylation; PI 3-kinase activity associated with IRS-1, IRS-2, and phosphotyrosine; and Akt activity and phosphorylation in skeletal muscle of rats infused for 2 h with glucosamine (6.0 mg x kg(-1) x min(-1)) or saline. |
| 3102 | 10334307 | After 1 min of insulin stimulation, phosphorylation of IRS-1 and insulin receptor increased 6- to 8-fold in saline-infused rats and 7- to 10-fold in glucosamine-infused rats. |
| 3103 | 10334307 | In saline-infused rats, 1 min of insulin stimulation increased PI 3-kinase activity associated with IRS-1, IRS-2, or phosphotyrosine 7.6-, 6.4-, and 10-fold, respectively. |
| 3104 | 10334307 | In glucosamine-infused rats treated for 1 min with insulin, PI 3-kinase activity associated with IRS-1 was reduced 28% (P < 0.01) and that associated with phosphotyrosine was reduced 43% (P < 0.01). |
| 3105 | 10334307 | Insulin for 1 min stimulated Akt/PKB activity approximately 5-fold in both saline- and glucosamine-infused rats; insulin-induced hyperphosphorylation of Akt/PKB was not different between groups. |
| 3106 | 10334307 | Glucosamine infusion alone had no effect on tyrosine phosphorylation of the insulin receptor or IRS-1 or on stimulation of PI 3-kinase or Akt/PKB activity. |
| 3107 | 10334307 | However, 2 h of insulin clamp reduced PI 3-kinase activity associated with IRS-1, IRS-2, or phosphotyrosine to <30% of that seen with 1 min of insulin. |
| 3108 | 10334307 | Our data show that 1) glucosamine infusion in rats is associated with an impairment in the early activation of PI 3-kinase by insulin in skeletal muscle, 2) this insulin-resistant state does not involve alterations in the activation of Akt/PKB, and 3) prolonged insulin infusion under clamp conditions results in a blunting of the PI 3-kinase response to insulin. |
| 3109 | 10334320 | These included cholecystokinin A and B receptors (CCK-AR and CCK-BR), glucagon-like peptide 1 receptor (GLP-1R), the LIM/homeodomain islet-1 gene (Isl-1), the caudal-type homeodomain 3 (CDX-3), the uncoupling protein 1 (UCP-1), the beta3-adrenoceptor (beta3-AR), the fatty acid-binding protein 2 (FABP-2), the hormone-sensitive lipase (HSL), the lipoprotein lipase (LPL), the apoprotein-C2 (apo-C2), the insulin receptor substrate-1 (IRS-1), the peroxisome proliferator-activated receptor-gamma (PPAR-gamma), tumor necrosis factor-alpha (TNF-alpha), and the liver carnitine palmitoyltransferase-1 (CPT-1). |
| 3110 | 10334320 | Phenotypes related to obesity such as BMI, adult life body weight gain, fasting leptin, insulin, fasting glycerol, and free fatty acids were used for nonparametric sib-pair analyses. |
| 3111 | 10334320 | Moreover, a suggestive indication for linkage was found between the Isl-1 locus and BMI and leptin values (P = 0.001 and 0.0003, respectively) and leptin adjusted for BMI (P = 0.0001). |
| 3112 | 10334320 | Multipoint analyses for leptin trait with Isl-1 and two flanking markers (D5S418 and D5S407) showed that the logarithm of odds (LOD) score is 1.73, coinciding with the Isl-1 locus. |
| 3113 | 10334320 | Although marginally positive indications for linkage in subgroups of families were found with IRS-1, CPT-1, and HSL loci, our data suggested that these genes are not major contributors to obesity. |
| 3114 | 10334320 | These included cholecystokinin A and B receptors (CCK-AR and CCK-BR), glucagon-like peptide 1 receptor (GLP-1R), the LIM/homeodomain islet-1 gene (Isl-1), the caudal-type homeodomain 3 (CDX-3), the uncoupling protein 1 (UCP-1), the beta3-adrenoceptor (beta3-AR), the fatty acid-binding protein 2 (FABP-2), the hormone-sensitive lipase (HSL), the lipoprotein lipase (LPL), the apoprotein-C2 (apo-C2), the insulin receptor substrate-1 (IRS-1), the peroxisome proliferator-activated receptor-gamma (PPAR-gamma), tumor necrosis factor-alpha (TNF-alpha), and the liver carnitine palmitoyltransferase-1 (CPT-1). |
| 3115 | 10334320 | Phenotypes related to obesity such as BMI, adult life body weight gain, fasting leptin, insulin, fasting glycerol, and free fatty acids were used for nonparametric sib-pair analyses. |
| 3116 | 10334320 | Moreover, a suggestive indication for linkage was found between the Isl-1 locus and BMI and leptin values (P = 0.001 and 0.0003, respectively) and leptin adjusted for BMI (P = 0.0001). |
| 3117 | 10334320 | Multipoint analyses for leptin trait with Isl-1 and two flanking markers (D5S418 and D5S407) showed that the logarithm of odds (LOD) score is 1.73, coinciding with the Isl-1 locus. |
| 3118 | 10334320 | Although marginally positive indications for linkage in subgroups of families were found with IRS-1, CPT-1, and HSL loci, our data suggested that these genes are not major contributors to obesity. |
| 3119 | 10342810 | Insulin receptor-related receptor is expressed in pancreatic beta-cells and stimulates tyrosine phosphorylation of insulin receptor substrate-1 and -2. |
| 3120 | 10342810 | The analysis revealed that insulin receptor-related receptor (IRR) is highly expressed in the islets as well as in several highly differentiated beta-cell lines derived from transgenic mice. |
| 3121 | 10342810 | To examine the IRR signaling pathway, a chimeric receptor consisting of the extracellular domain of insulin receptor and the intracellular domain of IRR was expressed in Chinese hamster ovary cells. |
| 3122 | 10342810 | It also stimulates the tyrosine phosphorylation of insulin receptor substrate (IRS)-1 and IRS-2, indicating that both proteins serve as substrates of IRR-protein tyrosine kinase in intact cells. |
| 3123 | 10342810 | The phenotype of the IRS-2 knockout mouse recently reported suggests that an IRS-2-mediated signaling pathway controls the compensatory increase in pancreatic beta-cell mass in insulin-resistant states. |
| 3124 | 10342810 | From our findings of the specific expression of IRR and its ability of signaling to IRS-2, we speculate that this receptor might play a role in the regulation of beta-cell mass. |
| 3125 | 10342814 | The mouse ob gene encodes leptin, an adipocyte hormone that regulates body weight and energy expenditure. |
| 3126 | 10342814 | In lean mice, leptin acutely increases glucose metabolism in an insulin-independent manner, which could account, at least in part, for some of the antidiabetic effect of the hormone. |
| 3127 | 10342814 | To investigate further the acute effect of leptin on glucose metabolism in insulin-resistant obese diabetic mice, leptin (40 ng x g(-1) x h(-1)) was administered intravenously for 6 h in C57Bl/6J ob/ob mice. |
| 3128 | 10342814 | Plasma insulin concentration increased moderately but neither glucose, glucagon, thyroid hormones, growth hormone, nor IGF-1 levels were different from phosphate-buffered saline-infused C57Bl/6J ob/ob mice. |
| 3129 | 10342814 | In addition, leptin stimulated hepatic glucose production, which was associated with increased glucose-6-phosphatase activity. |
| 3130 | 10342814 | Interestingly, hepatic insulin receptor substrate (IRS)1-associated phosphatidylinositol 3-kinase activity was slightly elevated, but neither the content of glucose transporter GLUT2 nor the phosphorylation state of the insulin receptor and IRS-1 were changed by acute leptin treatment. |
| 3131 | 10342814 | Insulin resistance of skeletal muscle and WAT, while not affected by acute leptin treatment, could also be corrected in the long term and account for some of leptin's antidiabetic effects. |
| 3132 | 10342815 | Free fatty acid-induced insulin resistance is associated with activation of protein kinase C theta and alterations in the insulin signaling cascade. |
| 3133 | 10342815 | This lipid-induced decrease in insulin-stimulated muscle glucose metabolism was associated with 1) a approximately 50% reduction in insulin-stimulated insulin receptor substrate (IRS)-1-associated phosphatidylinositol (PI) 3-kinase activity (P < 0.05 vs. control), 2) a blunting in insulin-stimulated IRS-1 tyrosine phosphorylation (P < 0.05, lipid-infused versus glycerol-infused), and 3) a four-fold increase in membrane-bound, or active, protein kinase C (PKC) theta (P < 0.05 vs. control). |
| 3134 | 10382598 | Augmented growth response to IGF-1 via increased IRS-1 in Chinese hamster ovary cells expressing kinase-negative insulin receptors. |
| 3135 | 10389840 | Membrane glycoprotein plasma cell 1 (PC-1) has been shown to be increased in type 2 diabetes and involved in insulin resistance through inhibiting the insulin receptor tyrosine kinase, which was demonstrated using cultured breast cancer cells. |
| 3136 | 10389840 | Thus, we considered it necessary to investigate the effect of PC-1 using highly insulin-sensitive cells. |
| 3137 | 10389840 | Here, we used two of the following approaches: 1) investigating PC-1 expression levels in insulin-responsive tissues in rat models of diabetes and 2) overexpressing PC-1 in 3T3-L1 adipocytes. |
| 3138 | 10389840 | We found that PC-1 was highly expressed in insulin-responsive tissues, such as liver and adipose tissue, in normal rats. |
| 3139 | 10389840 | Thus, PC-1 expression levels were not associated with high-fat-diet-induced insulin resistance or hyperglycemia. |
| 3140 | 10389840 | However, insulin-induced tyrosine phosphorylation of the insulin receptor and insulin receptor substrate 1, activation of phosphatidylinositol 3-kinase, and glucose uptake were not affected by PC-1 overexpression. |
| 3141 | 10389840 | These results strongly suggest that increased PC-1 expression is not causally related to insulin resistance. |
| 3142 | 10389839 | Insulin-induced insulin receptor substrate-1 degradation is mediated by the proteasome degradation pathway. |
| 3143 | 10389839 | We report that chronic insulin treatment induces the degradation of IRS-1, but not IRS-2, protein in cultured cells. |
| 3144 | 10389839 | The insulin-induced degradation of IRS-1 can be prevented by pretreatment with lactacystin, a specific inhibitor for proteasome degradation. |
| 3145 | 10389839 | These data demonstrate, for the first time, that insulin-induced degradation of IRS-1 is mediated by the proteasome degradation pathway. |
| 3146 | 10389839 | IRS-2 can escape from the insulin-induced proteasome degradation, suggesting the existence of specific structural requirements for this degradation process. |
| 3147 | 10389839 | Insulin-induced insulin receptor substrate-1 degradation is mediated by the proteasome degradation pathway. |
| 3148 | 10389839 | We report that chronic insulin treatment induces the degradation of IRS-1, but not IRS-2, protein in cultured cells. |
| 3149 | 10389839 | The insulin-induced degradation of IRS-1 can be prevented by pretreatment with lactacystin, a specific inhibitor for proteasome degradation. |
| 3150 | 10389839 | These data demonstrate, for the first time, that insulin-induced degradation of IRS-1 is mediated by the proteasome degradation pathway. |
| 3151 | 10389839 | IRS-2 can escape from the insulin-induced proteasome degradation, suggesting the existence of specific structural requirements for this degradation process. |
| 3152 | 10389839 | Insulin-induced insulin receptor substrate-1 degradation is mediated by the proteasome degradation pathway. |
| 3153 | 10389839 | We report that chronic insulin treatment induces the degradation of IRS-1, but not IRS-2, protein in cultured cells. |
| 3154 | 10389839 | The insulin-induced degradation of IRS-1 can be prevented by pretreatment with lactacystin, a specific inhibitor for proteasome degradation. |
| 3155 | 10389839 | These data demonstrate, for the first time, that insulin-induced degradation of IRS-1 is mediated by the proteasome degradation pathway. |
| 3156 | 10389839 | IRS-2 can escape from the insulin-induced proteasome degradation, suggesting the existence of specific structural requirements for this degradation process. |
| 3157 | 10389839 | Insulin-induced insulin receptor substrate-1 degradation is mediated by the proteasome degradation pathway. |
| 3158 | 10389839 | We report that chronic insulin treatment induces the degradation of IRS-1, but not IRS-2, protein in cultured cells. |
| 3159 | 10389839 | The insulin-induced degradation of IRS-1 can be prevented by pretreatment with lactacystin, a specific inhibitor for proteasome degradation. |
| 3160 | 10389839 | These data demonstrate, for the first time, that insulin-induced degradation of IRS-1 is mediated by the proteasome degradation pathway. |
| 3161 | 10389839 | IRS-2 can escape from the insulin-induced proteasome degradation, suggesting the existence of specific structural requirements for this degradation process. |
| 3162 | 10414926 | Insulin inhibits glucagon secretion by the activation of PI3-kinase in In-R1-G9 cells. |
| 3163 | 10414926 | In this study, we confirmed that, in In-R1-G9 cells, a pancreatic alpha cell line, insulin stimulated phosphorylation of insulin receptor substrate-1 (IRS-1) and activated phosphatidylinositol 3-kinase (PI3-kinase). |
| 3164 | 10414926 | We further studied, using wortmannin, an inhibitor of PI3-kinase, whether the inhibitory effect of insulin on glucagon secretion was mediated through PI3-kinase pathway in these cells. |
| 3165 | 10414926 | Insulin increased the amount of 85 kDa subunit of PI3-kinase in plasma membrane fraction (PM), with a reciprocal decrease of the kinase in cytosol fraction (CY). |
| 3166 | 10414926 | Insulin also increased PI3-kinase activity in PM, but not in CY. |
| 3167 | 10414926 | Recruitment and activation of PI3-kinase in plasma membrane might be relevant at least in part to insulin-induced inhibition of glucagon release. |
| 3168 | 10417963 | Targeted gene mutations define the roles of insulin and IGF-I receptors in mouse embryonic development. |
| 3169 | 10417963 | Insulin-like growth factors (IGFs) and their receptors regulate embryonic and post-natal growth. |
| 3170 | 10417963 | Genetic evidence derived from targeted mouse mutants indicates that both the insulin receptor (IR) and IGF-I receptors (IGF-IRs) are required for mouse embryonic growth. |
| 3171 | 10417963 | However, the roles of IRs and IGF-IRs are functionally distinct, with IGF-IRs mediating both IGF-I and IGF-II actions, and IRs mediating IGF-II, rather than insulin, action. |
| 3172 | 10417963 | The combined interactions of IGF-IRs and IRs with IGF-I and IGF-II account for the entirety of the growth effects of these two ligands, and provide the molecular basis for IGFs-mediated intrauterine growth and differentiation. |
| 3173 | 10417963 | Genetic ablation experiments of insulin receptor substrate-1 (IRS-1) and -2 (IRS-2), two important molecules in the IR and IGF-IR signaling pathways, are also beginning to shed light onto the mechanisms accounting for the specificity of IR and IGF-IR signaling. |
| 3174 | 10418851 | Assessments of the response to hyperglycemic-hyperinsulinemic clamping have shown that abnormalities of muscle glycogen synthesis, apparently mediated by a defect in GLUT-4 transport and/or hexokinase activity, play a major role in causing insulin resistance in type 2 diabetes. |
| 3175 | 10418851 | Studies of the mechanisms by which free fatty acids (FFA) cause insulin resistance in humans indicate that increased FFA levels inhibit glucose transport, which may be a consequence of decreased insulin receptor substrate (IRS-1)-associated phosphatidylinositol 3-kinase activity. 13C NMR spectroscopy studies have documented that liver glycogen concentrations are reduced and the rate of hepatic gluconeogenesis is increased in subjects with type 2 diabetes; thus, the higher rate of glucose production in type 2 diabetes can be attributed entirely to increased rates of hepatic gluconeogenesis. |
| 3176 | 10421979 | The development of late onset non-insulin dependent diabetes mellitus (NIDDM) is due to a complicated interplay between genes and environment on one side, and the interaction between metabolic defects in various tissues including the pancreatic beta cell (decreased insulin secretion), skeletal muscle (insulin resistance), liver (increased gluconeogenesis), adipose tissue (increased lipolysis) and possibly gut incretin hormones (defective glucagon like peptide 1 (GLP1) secretion) on the other side. |
| 3177 | 10421979 | Evidence for a genetic component includes the finding of a variety of metabolic defects in various tissues in non-diabetic subjects with a genetic predisposition to NIDDM, higher concordance rates for abnormal glucose tolerance including NIDDM in monozygotic compared with dizygotic twins, and the more recent demonstration of different NIDDM susceptibility genes at the sites of Insulin Receptor Substrate 1 (IRS1), the beta-3 adrenergic receptor, and the sulfonylurea receptor. |
| 3178 | 10422520 | [Relation between cytokines (TNF-alpha, IL-1 and 6) and homocysteine in android obesity and the phenomenon of insulin resistance syndromes]. |
| 3179 | 10422520 | TNF-alpha (so-called cachectin), IL-1 and 6 are important regulating agents in the homeostasis of energy in the organism, as among others they control processes of apoptosis and thus also the volume of adipose and muscular tissues. |
| 3180 | 10422520 | By acting on phosphorylation of IRS-1 and PI-3 kinase TNF-alpha promotes significantly insulin resistance, causes deterioration of diabetes, as well as elevated body temperature, sleepiness and anorexia. |
| 3181 | 10422520 | In a group of 65 patients, mostly with android obesity, in hyperleptinaemic and insulin resistant probands with coronarographically confirmed microvascular angina pectoris (n = 22) or IHD, mostly after a myocardial infarction (n = 43) with one or more significant stenoses on the epicardial coronary arteries in half the patients positive or elevated TNF-alpha was found and in 28% also IL-6. |
| 3182 | 10426374 | At a cellular level, these metabolic effects were paralleled by inhibition of postreceptor insulin signaling critical for glucose transport and glycogen storage, including a 45% reduction in insulin-stimulated insulin receptor substrate (IRS)-1 tyrosine phosphorylation (P = 0.02), a 44% decrease in IRS-1 association with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase (P = 0.03), a 34% reduction in IRS-1-associated PI 3-kinase activity (P = 0.03), and a 51% reduction in insulin-stimulated glycogen synthase activity (P = 0.03). |
| 3183 | 10426374 | We also demonstrated that glucosamine infusion results in O-linked N-acetylglucosamine modification of IRS-1 and IRS-2. |
| 3184 | 10426374 | At a cellular level, these metabolic effects were paralleled by inhibition of postreceptor insulin signaling critical for glucose transport and glycogen storage, including a 45% reduction in insulin-stimulated insulin receptor substrate (IRS)-1 tyrosine phosphorylation (P = 0.02), a 44% decrease in IRS-1 association with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase (P = 0.03), a 34% reduction in IRS-1-associated PI 3-kinase activity (P = 0.03), and a 51% reduction in insulin-stimulated glycogen synthase activity (P = 0.03). |
| 3185 | 10426374 | We also demonstrated that glucosamine infusion results in O-linked N-acetylglucosamine modification of IRS-1 and IRS-2. |
| 3186 | 10430617 | The Gly972-->Arg amino acid polymorphism in IRS-1 impairs insulin secretion in pancreatic beta cells. |
| 3187 | 10430617 | Carriers of the Arg(972) substitution are characterized by lower fasting insulin and C-peptide levels compared with non-carriers, suggesting that the Arg(972) IRS-1 variant may contribute to impairment of insulin secretion. |
| 3188 | 10430617 | In this study, we stably overexpressed both wild-type IRS-1 (RIN-WT) and Arg(972) IRS-1 variant (RIN-Arg(972)) in RIN beta cells to investigate directly whether the polymorphism in codon 972 of IRS-1 impairs insulin secretion. |
| 3189 | 10430617 | The Arg(972) IRS-1 variant did not affect expression or function of endogenous IRS-2. |
| 3190 | 10430617 | RIN-WT showed a marked increase in both glucose- and insulin-stimulated tyrosine phosphorylation of IRS-1 compared with control RIN cells. |
| 3191 | 10430617 | The Arg(972) IRS-1 variant did not alter the extent of either glucose- or insulin-stimulated tyrosine phosphorylation of recombinant IRS-1. |
| 3192 | 10430617 | However, RIN-Arg(972) showed a significant decrease in binding of the p85 subunit of phosphatidylinositol-3-kinase (PI 3-kinase) with IRS-1, compared with RIN-WT. |
| 3193 | 10430617 | By contrast, RIN cells expressing Arg(972) IRS-1 exhibited a marked decrease in both glucose- and sulfonylurea-stimulated insulin secretion compared with RIN-WT. |
| 3194 | 10430617 | These data suggest that the insulin signaling pathway involving the IRS-1/PI 3-kinase may play an important role in the insulin secretory process in pancreatic beta cells. |
| 3195 | 10430617 | More importantly, the results suggest that the common Arg(972) IRS-1 polymorphism may impair glucose-stimulated insulin secretion, thus contributing to the relative insulin deficiency observed in carriers of this variant. |
| 3196 | 10430617 | The Gly972-->Arg amino acid polymorphism in IRS-1 impairs insulin secretion in pancreatic beta cells. |
| 3197 | 10430617 | Carriers of the Arg(972) substitution are characterized by lower fasting insulin and C-peptide levels compared with non-carriers, suggesting that the Arg(972) IRS-1 variant may contribute to impairment of insulin secretion. |
| 3198 | 10430617 | In this study, we stably overexpressed both wild-type IRS-1 (RIN-WT) and Arg(972) IRS-1 variant (RIN-Arg(972)) in RIN beta cells to investigate directly whether the polymorphism in codon 972 of IRS-1 impairs insulin secretion. |
| 3199 | 10430617 | The Arg(972) IRS-1 variant did not affect expression or function of endogenous IRS-2. |
| 3200 | 10430617 | RIN-WT showed a marked increase in both glucose- and insulin-stimulated tyrosine phosphorylation of IRS-1 compared with control RIN cells. |
| 3201 | 10430617 | The Arg(972) IRS-1 variant did not alter the extent of either glucose- or insulin-stimulated tyrosine phosphorylation of recombinant IRS-1. |
| 3202 | 10430617 | However, RIN-Arg(972) showed a significant decrease in binding of the p85 subunit of phosphatidylinositol-3-kinase (PI 3-kinase) with IRS-1, compared with RIN-WT. |
| 3203 | 10430617 | By contrast, RIN cells expressing Arg(972) IRS-1 exhibited a marked decrease in both glucose- and sulfonylurea-stimulated insulin secretion compared with RIN-WT. |
| 3204 | 10430617 | These data suggest that the insulin signaling pathway involving the IRS-1/PI 3-kinase may play an important role in the insulin secretory process in pancreatic beta cells. |
| 3205 | 10430617 | More importantly, the results suggest that the common Arg(972) IRS-1 polymorphism may impair glucose-stimulated insulin secretion, thus contributing to the relative insulin deficiency observed in carriers of this variant. |
| 3206 | 10430617 | The Gly972-->Arg amino acid polymorphism in IRS-1 impairs insulin secretion in pancreatic beta cells. |
| 3207 | 10430617 | Carriers of the Arg(972) substitution are characterized by lower fasting insulin and C-peptide levels compared with non-carriers, suggesting that the Arg(972) IRS-1 variant may contribute to impairment of insulin secretion. |
| 3208 | 10430617 | In this study, we stably overexpressed both wild-type IRS-1 (RIN-WT) and Arg(972) IRS-1 variant (RIN-Arg(972)) in RIN beta cells to investigate directly whether the polymorphism in codon 972 of IRS-1 impairs insulin secretion. |
| 3209 | 10430617 | The Arg(972) IRS-1 variant did not affect expression or function of endogenous IRS-2. |
| 3210 | 10430617 | RIN-WT showed a marked increase in both glucose- and insulin-stimulated tyrosine phosphorylation of IRS-1 compared with control RIN cells. |
| 3211 | 10430617 | The Arg(972) IRS-1 variant did not alter the extent of either glucose- or insulin-stimulated tyrosine phosphorylation of recombinant IRS-1. |
| 3212 | 10430617 | However, RIN-Arg(972) showed a significant decrease in binding of the p85 subunit of phosphatidylinositol-3-kinase (PI 3-kinase) with IRS-1, compared with RIN-WT. |
| 3213 | 10430617 | By contrast, RIN cells expressing Arg(972) IRS-1 exhibited a marked decrease in both glucose- and sulfonylurea-stimulated insulin secretion compared with RIN-WT. |
| 3214 | 10430617 | These data suggest that the insulin signaling pathway involving the IRS-1/PI 3-kinase may play an important role in the insulin secretory process in pancreatic beta cells. |
| 3215 | 10430617 | More importantly, the results suggest that the common Arg(972) IRS-1 polymorphism may impair glucose-stimulated insulin secretion, thus contributing to the relative insulin deficiency observed in carriers of this variant. |
| 3216 | 10430617 | The Gly972-->Arg amino acid polymorphism in IRS-1 impairs insulin secretion in pancreatic beta cells. |
| 3217 | 10430617 | Carriers of the Arg(972) substitution are characterized by lower fasting insulin and C-peptide levels compared with non-carriers, suggesting that the Arg(972) IRS-1 variant may contribute to impairment of insulin secretion. |
| 3218 | 10430617 | In this study, we stably overexpressed both wild-type IRS-1 (RIN-WT) and Arg(972) IRS-1 variant (RIN-Arg(972)) in RIN beta cells to investigate directly whether the polymorphism in codon 972 of IRS-1 impairs insulin secretion. |
| 3219 | 10430617 | The Arg(972) IRS-1 variant did not affect expression or function of endogenous IRS-2. |
| 3220 | 10430617 | RIN-WT showed a marked increase in both glucose- and insulin-stimulated tyrosine phosphorylation of IRS-1 compared with control RIN cells. |
| 3221 | 10430617 | The Arg(972) IRS-1 variant did not alter the extent of either glucose- or insulin-stimulated tyrosine phosphorylation of recombinant IRS-1. |
| 3222 | 10430617 | However, RIN-Arg(972) showed a significant decrease in binding of the p85 subunit of phosphatidylinositol-3-kinase (PI 3-kinase) with IRS-1, compared with RIN-WT. |
| 3223 | 10430617 | By contrast, RIN cells expressing Arg(972) IRS-1 exhibited a marked decrease in both glucose- and sulfonylurea-stimulated insulin secretion compared with RIN-WT. |
| 3224 | 10430617 | These data suggest that the insulin signaling pathway involving the IRS-1/PI 3-kinase may play an important role in the insulin secretory process in pancreatic beta cells. |
| 3225 | 10430617 | More importantly, the results suggest that the common Arg(972) IRS-1 polymorphism may impair glucose-stimulated insulin secretion, thus contributing to the relative insulin deficiency observed in carriers of this variant. |
| 3226 | 10430617 | The Gly972-->Arg amino acid polymorphism in IRS-1 impairs insulin secretion in pancreatic beta cells. |
| 3227 | 10430617 | Carriers of the Arg(972) substitution are characterized by lower fasting insulin and C-peptide levels compared with non-carriers, suggesting that the Arg(972) IRS-1 variant may contribute to impairment of insulin secretion. |
| 3228 | 10430617 | In this study, we stably overexpressed both wild-type IRS-1 (RIN-WT) and Arg(972) IRS-1 variant (RIN-Arg(972)) in RIN beta cells to investigate directly whether the polymorphism in codon 972 of IRS-1 impairs insulin secretion. |
| 3229 | 10430617 | The Arg(972) IRS-1 variant did not affect expression or function of endogenous IRS-2. |
| 3230 | 10430617 | RIN-WT showed a marked increase in both glucose- and insulin-stimulated tyrosine phosphorylation of IRS-1 compared with control RIN cells. |
| 3231 | 10430617 | The Arg(972) IRS-1 variant did not alter the extent of either glucose- or insulin-stimulated tyrosine phosphorylation of recombinant IRS-1. |
| 3232 | 10430617 | However, RIN-Arg(972) showed a significant decrease in binding of the p85 subunit of phosphatidylinositol-3-kinase (PI 3-kinase) with IRS-1, compared with RIN-WT. |
| 3233 | 10430617 | By contrast, RIN cells expressing Arg(972) IRS-1 exhibited a marked decrease in both glucose- and sulfonylurea-stimulated insulin secretion compared with RIN-WT. |
| 3234 | 10430617 | These data suggest that the insulin signaling pathway involving the IRS-1/PI 3-kinase may play an important role in the insulin secretory process in pancreatic beta cells. |
| 3235 | 10430617 | More importantly, the results suggest that the common Arg(972) IRS-1 polymorphism may impair glucose-stimulated insulin secretion, thus contributing to the relative insulin deficiency observed in carriers of this variant. |
| 3236 | 10430617 | The Gly972-->Arg amino acid polymorphism in IRS-1 impairs insulin secretion in pancreatic beta cells. |
| 3237 | 10430617 | Carriers of the Arg(972) substitution are characterized by lower fasting insulin and C-peptide levels compared with non-carriers, suggesting that the Arg(972) IRS-1 variant may contribute to impairment of insulin secretion. |
| 3238 | 10430617 | In this study, we stably overexpressed both wild-type IRS-1 (RIN-WT) and Arg(972) IRS-1 variant (RIN-Arg(972)) in RIN beta cells to investigate directly whether the polymorphism in codon 972 of IRS-1 impairs insulin secretion. |
| 3239 | 10430617 | The Arg(972) IRS-1 variant did not affect expression or function of endogenous IRS-2. |
| 3240 | 10430617 | RIN-WT showed a marked increase in both glucose- and insulin-stimulated tyrosine phosphorylation of IRS-1 compared with control RIN cells. |
| 3241 | 10430617 | The Arg(972) IRS-1 variant did not alter the extent of either glucose- or insulin-stimulated tyrosine phosphorylation of recombinant IRS-1. |
| 3242 | 10430617 | However, RIN-Arg(972) showed a significant decrease in binding of the p85 subunit of phosphatidylinositol-3-kinase (PI 3-kinase) with IRS-1, compared with RIN-WT. |
| 3243 | 10430617 | By contrast, RIN cells expressing Arg(972) IRS-1 exhibited a marked decrease in both glucose- and sulfonylurea-stimulated insulin secretion compared with RIN-WT. |
| 3244 | 10430617 | These data suggest that the insulin signaling pathway involving the IRS-1/PI 3-kinase may play an important role in the insulin secretory process in pancreatic beta cells. |
| 3245 | 10430617 | More importantly, the results suggest that the common Arg(972) IRS-1 polymorphism may impair glucose-stimulated insulin secretion, thus contributing to the relative insulin deficiency observed in carriers of this variant. |
| 3246 | 10430617 | The Gly972-->Arg amino acid polymorphism in IRS-1 impairs insulin secretion in pancreatic beta cells. |
| 3247 | 10430617 | Carriers of the Arg(972) substitution are characterized by lower fasting insulin and C-peptide levels compared with non-carriers, suggesting that the Arg(972) IRS-1 variant may contribute to impairment of insulin secretion. |
| 3248 | 10430617 | In this study, we stably overexpressed both wild-type IRS-1 (RIN-WT) and Arg(972) IRS-1 variant (RIN-Arg(972)) in RIN beta cells to investigate directly whether the polymorphism in codon 972 of IRS-1 impairs insulin secretion. |
| 3249 | 10430617 | The Arg(972) IRS-1 variant did not affect expression or function of endogenous IRS-2. |
| 3250 | 10430617 | RIN-WT showed a marked increase in both glucose- and insulin-stimulated tyrosine phosphorylation of IRS-1 compared with control RIN cells. |
| 3251 | 10430617 | The Arg(972) IRS-1 variant did not alter the extent of either glucose- or insulin-stimulated tyrosine phosphorylation of recombinant IRS-1. |
| 3252 | 10430617 | However, RIN-Arg(972) showed a significant decrease in binding of the p85 subunit of phosphatidylinositol-3-kinase (PI 3-kinase) with IRS-1, compared with RIN-WT. |
| 3253 | 10430617 | By contrast, RIN cells expressing Arg(972) IRS-1 exhibited a marked decrease in both glucose- and sulfonylurea-stimulated insulin secretion compared with RIN-WT. |
| 3254 | 10430617 | These data suggest that the insulin signaling pathway involving the IRS-1/PI 3-kinase may play an important role in the insulin secretory process in pancreatic beta cells. |
| 3255 | 10430617 | More importantly, the results suggest that the common Arg(972) IRS-1 polymorphism may impair glucose-stimulated insulin secretion, thus contributing to the relative insulin deficiency observed in carriers of this variant. |
| 3256 | 10430617 | The Gly972-->Arg amino acid polymorphism in IRS-1 impairs insulin secretion in pancreatic beta cells. |
| 3257 | 10430617 | Carriers of the Arg(972) substitution are characterized by lower fasting insulin and C-peptide levels compared with non-carriers, suggesting that the Arg(972) IRS-1 variant may contribute to impairment of insulin secretion. |
| 3258 | 10430617 | In this study, we stably overexpressed both wild-type IRS-1 (RIN-WT) and Arg(972) IRS-1 variant (RIN-Arg(972)) in RIN beta cells to investigate directly whether the polymorphism in codon 972 of IRS-1 impairs insulin secretion. |
| 3259 | 10430617 | The Arg(972) IRS-1 variant did not affect expression or function of endogenous IRS-2. |
| 3260 | 10430617 | RIN-WT showed a marked increase in both glucose- and insulin-stimulated tyrosine phosphorylation of IRS-1 compared with control RIN cells. |
| 3261 | 10430617 | The Arg(972) IRS-1 variant did not alter the extent of either glucose- or insulin-stimulated tyrosine phosphorylation of recombinant IRS-1. |
| 3262 | 10430617 | However, RIN-Arg(972) showed a significant decrease in binding of the p85 subunit of phosphatidylinositol-3-kinase (PI 3-kinase) with IRS-1, compared with RIN-WT. |
| 3263 | 10430617 | By contrast, RIN cells expressing Arg(972) IRS-1 exhibited a marked decrease in both glucose- and sulfonylurea-stimulated insulin secretion compared with RIN-WT. |
| 3264 | 10430617 | These data suggest that the insulin signaling pathway involving the IRS-1/PI 3-kinase may play an important role in the insulin secretory process in pancreatic beta cells. |
| 3265 | 10430617 | More importantly, the results suggest that the common Arg(972) IRS-1 polymorphism may impair glucose-stimulated insulin secretion, thus contributing to the relative insulin deficiency observed in carriers of this variant. |
| 3266 | 10430617 | The Gly972-->Arg amino acid polymorphism in IRS-1 impairs insulin secretion in pancreatic beta cells. |
| 3267 | 10430617 | Carriers of the Arg(972) substitution are characterized by lower fasting insulin and C-peptide levels compared with non-carriers, suggesting that the Arg(972) IRS-1 variant may contribute to impairment of insulin secretion. |
| 3268 | 10430617 | In this study, we stably overexpressed both wild-type IRS-1 (RIN-WT) and Arg(972) IRS-1 variant (RIN-Arg(972)) in RIN beta cells to investigate directly whether the polymorphism in codon 972 of IRS-1 impairs insulin secretion. |
| 3269 | 10430617 | The Arg(972) IRS-1 variant did not affect expression or function of endogenous IRS-2. |
| 3270 | 10430617 | RIN-WT showed a marked increase in both glucose- and insulin-stimulated tyrosine phosphorylation of IRS-1 compared with control RIN cells. |
| 3271 | 10430617 | The Arg(972) IRS-1 variant did not alter the extent of either glucose- or insulin-stimulated tyrosine phosphorylation of recombinant IRS-1. |
| 3272 | 10430617 | However, RIN-Arg(972) showed a significant decrease in binding of the p85 subunit of phosphatidylinositol-3-kinase (PI 3-kinase) with IRS-1, compared with RIN-WT. |
| 3273 | 10430617 | By contrast, RIN cells expressing Arg(972) IRS-1 exhibited a marked decrease in both glucose- and sulfonylurea-stimulated insulin secretion compared with RIN-WT. |
| 3274 | 10430617 | These data suggest that the insulin signaling pathway involving the IRS-1/PI 3-kinase may play an important role in the insulin secretory process in pancreatic beta cells. |
| 3275 | 10430617 | More importantly, the results suggest that the common Arg(972) IRS-1 polymorphism may impair glucose-stimulated insulin secretion, thus contributing to the relative insulin deficiency observed in carriers of this variant. |
| 3276 | 10430617 | The Gly972-->Arg amino acid polymorphism in IRS-1 impairs insulin secretion in pancreatic beta cells. |
| 3277 | 10430617 | Carriers of the Arg(972) substitution are characterized by lower fasting insulin and C-peptide levels compared with non-carriers, suggesting that the Arg(972) IRS-1 variant may contribute to impairment of insulin secretion. |
| 3278 | 10430617 | In this study, we stably overexpressed both wild-type IRS-1 (RIN-WT) and Arg(972) IRS-1 variant (RIN-Arg(972)) in RIN beta cells to investigate directly whether the polymorphism in codon 972 of IRS-1 impairs insulin secretion. |
| 3279 | 10430617 | The Arg(972) IRS-1 variant did not affect expression or function of endogenous IRS-2. |
| 3280 | 10430617 | RIN-WT showed a marked increase in both glucose- and insulin-stimulated tyrosine phosphorylation of IRS-1 compared with control RIN cells. |
| 3281 | 10430617 | The Arg(972) IRS-1 variant did not alter the extent of either glucose- or insulin-stimulated tyrosine phosphorylation of recombinant IRS-1. |
| 3282 | 10430617 | However, RIN-Arg(972) showed a significant decrease in binding of the p85 subunit of phosphatidylinositol-3-kinase (PI 3-kinase) with IRS-1, compared with RIN-WT. |
| 3283 | 10430617 | By contrast, RIN cells expressing Arg(972) IRS-1 exhibited a marked decrease in both glucose- and sulfonylurea-stimulated insulin secretion compared with RIN-WT. |
| 3284 | 10430617 | These data suggest that the insulin signaling pathway involving the IRS-1/PI 3-kinase may play an important role in the insulin secretory process in pancreatic beta cells. |
| 3285 | 10430617 | More importantly, the results suggest that the common Arg(972) IRS-1 polymorphism may impair glucose-stimulated insulin secretion, thus contributing to the relative insulin deficiency observed in carriers of this variant. |
| 3286 | 10449437 | In this report, insulin signaling on the phosphatidylinositol 3-kinase (PI 3-kinase) and mitogen-activated protein (MAP) kinase pathways were compared in vascular tissues of lean and obese Zucker (fa/fa) rats in both ex vivo and in vivo studies. |
| 3287 | 10449437 | Ex vivo, insulin-stimulated tyrosine phosphorylation of insulin receptor beta subunits (IRbeta) in the aorta and microvessels of obese rats was significantly decreased compared with lean rats, although the protein levels of IRbeta in the 2 groups were not different. |
| 3288 | 10449437 | Insulin-induced tyrosine phosphorylation of insulin receptor substrates 1 and 2 (IRS-1 and IRS-2) and their protein levels were decreased in the aorta of obese rats compared with lean rats. |
| 3289 | 10449437 | The association of p85 subunit to the IRS proteins and the IRS-associated PI 3-kinase activities stimulated by insulin in the aorta of obese rats were significantly decreased compared with the lean rats. |
| 3290 | 10449437 | In addition, insulin-stimulated serine phosphorylation of Akt, a downstream kinase of PI 3-kinase pathway, was also reduced significantly in isolated microvessels from obese rats compared with the lean rats. |
| 3291 | 10449437 | In contrast, insulin stimulated tyrosine phosphorylation of MAP kinase (ERK-1/2) equally in isolated microvessels of lean and obese rats, although basal tyrosine phosphorylation of ERK-1/2 was higher in the obese rats. |
| 3292 | 10449437 | To our knowledge, these data provided the first direct measurements of insulin signaling in the vascular tissues, and documented a selective resistance to PI 3-kinase (but not to MAP kinase pathway) in the vascular tissues of obese Zucker rats. |
| 3293 | 10471495 | Irs-2 coordinates Igf-1 receptor-mediated beta-cell development and peripheral insulin signalling. |
| 3294 | 10471495 | Insulin receptor substrates (Irs proteins) mediate the pleiotropic effects of insulin and Igf-1 (insulin-like growth factor-1), including regulation of glucose homeostasis and cell growth and survival. |
| 3295 | 10471495 | Our experiments revealed that Irs-1 and Irs-2 are critical for embryonic and post-natal growth, with Irs-1 having the predominant role. |
| 3296 | 10471495 | By contrast, both Irs-1 and Irs-2 function in peripheral carbohydrate metabolism, but Irs-2 has the major role in beta-cell development and compensation for peripheral insulin resistance. |
| 3297 | 10471495 | To establish a role for the Igf-1 receptor in beta-cells, we intercrossed mice heterozygous for null alleles of Igf1r and Irs2. |
| 3298 | 10471495 | Our results reveal that Igf-1 receptors promote beta-cell development and survival through the Irs-2 signalling pathway. |
| 3299 | 10471495 | Thus, Irs-2 integrates the effects of insulin in peripheral target tissues with Igf-1 in pancreatic beta-cells to maintain glucose homeostasis. |
| 3300 | 10471495 | Irs-2 coordinates Igf-1 receptor-mediated beta-cell development and peripheral insulin signalling. |
| 3301 | 10471495 | Insulin receptor substrates (Irs proteins) mediate the pleiotropic effects of insulin and Igf-1 (insulin-like growth factor-1), including regulation of glucose homeostasis and cell growth and survival. |
| 3302 | 10471495 | Our experiments revealed that Irs-1 and Irs-2 are critical for embryonic and post-natal growth, with Irs-1 having the predominant role. |
| 3303 | 10471495 | By contrast, both Irs-1 and Irs-2 function in peripheral carbohydrate metabolism, but Irs-2 has the major role in beta-cell development and compensation for peripheral insulin resistance. |
| 3304 | 10471495 | To establish a role for the Igf-1 receptor in beta-cells, we intercrossed mice heterozygous for null alleles of Igf1r and Irs2. |
| 3305 | 10471495 | Our results reveal that Igf-1 receptors promote beta-cell development and survival through the Irs-2 signalling pathway. |
| 3306 | 10471495 | Thus, Irs-2 integrates the effects of insulin in peripheral target tissues with Igf-1 in pancreatic beta-cells to maintain glucose homeostasis. |
| 3307 | 10480612 | Compared with nonpregnant control subjects, maximal insulin-stimulated IRS-1 tyrosine phosphorylation was significantly lower by 59 +/- 24% (mean +/- SD) (P < 0.05) and 62 +/- 28% (P < 0.05) in pregnant control and GDM subjects, respectively. |
| 3308 | 10480612 | Both pregnant control and GDM subjects exhibited a 1.5- to 2-fold increase in the levels of IRS-2 (P < 0.01) and p85alpha regulatory subunit of phosphatidylinositol (PI) 3-kinase (P < 0.05), despite reduced glucose transport activity. |
| 3309 | 10480612 | These data indicate that insulin resistance to glucose transport during pregnancy is uniquely associated with a decrease in IRS-1 tyrosine phosphorylation, primarily due to decreased expression of IRS-1 protein. |
| 3310 | 10480612 | Compared with nonpregnant control subjects, maximal insulin-stimulated IRS-1 tyrosine phosphorylation was significantly lower by 59 +/- 24% (mean +/- SD) (P < 0.05) and 62 +/- 28% (P < 0.05) in pregnant control and GDM subjects, respectively. |
| 3311 | 10480612 | Both pregnant control and GDM subjects exhibited a 1.5- to 2-fold increase in the levels of IRS-2 (P < 0.01) and p85alpha regulatory subunit of phosphatidylinositol (PI) 3-kinase (P < 0.05), despite reduced glucose transport activity. |
| 3312 | 10480612 | These data indicate that insulin resistance to glucose transport during pregnancy is uniquely associated with a decrease in IRS-1 tyrosine phosphorylation, primarily due to decreased expression of IRS-1 protein. |
| 3313 | 10480621 | Variants of the insulin receptor substrate-1 and fatty acid binding protein 2 genes and the risk of type 2 diabetes, obesity, and hyperinsulinemia in African-Americans: the Atherosclerosis Risk in Communities Study. |
| 3314 | 10480621 | The allele frequencies of the Gly972Arg variant of the insulin receptor substrate-1 (IRS-1) gene and the Ala54Thr variant of the fatty acid binding protein 2 (FABP2) gene were compared in 992 normal control subjects and three patient groups: 1) 321 type 2 diabetic individuals, 2) 260 severely obese individuals, and 3) 258 markedly hyperinsulinemic individuals without diabetes. |
| 3315 | 10480621 | Allele frequencies of Gly972Arg IRS-1 and Ala54Thr FABP2 were 0.07 and 0.22, respectively; there were no differences in allele or genotype frequencies between patients and control subjects for either gene variant. |
| 3316 | 10480621 | In addition, individuals with at least one IRS-1 Arg972 allele and two FABP2 Thr54 alleles had a BMI of 33.3 (7.9) kg/m2, compared with 30.0 (6.3) kg/m2 for those with neither allele (P = 0.05). |
| 3317 | 10480621 | These results suggest that in African-Americans, these variants in the IRS-1 and FABP2 genes are not associated with the risk of type 2 diabetes, severe obesity, or marked hyperinsulinemia, but that their independent and joint effects may be associated with small increases in BMI. |
| 3318 | 10480621 | Variants of the insulin receptor substrate-1 and fatty acid binding protein 2 genes and the risk of type 2 diabetes, obesity, and hyperinsulinemia in African-Americans: the Atherosclerosis Risk in Communities Study. |
| 3319 | 10480621 | The allele frequencies of the Gly972Arg variant of the insulin receptor substrate-1 (IRS-1) gene and the Ala54Thr variant of the fatty acid binding protein 2 (FABP2) gene were compared in 992 normal control subjects and three patient groups: 1) 321 type 2 diabetic individuals, 2) 260 severely obese individuals, and 3) 258 markedly hyperinsulinemic individuals without diabetes. |
| 3320 | 10480621 | Allele frequencies of Gly972Arg IRS-1 and Ala54Thr FABP2 were 0.07 and 0.22, respectively; there were no differences in allele or genotype frequencies between patients and control subjects for either gene variant. |
| 3321 | 10480621 | In addition, individuals with at least one IRS-1 Arg972 allele and two FABP2 Thr54 alleles had a BMI of 33.3 (7.9) kg/m2, compared with 30.0 (6.3) kg/m2 for those with neither allele (P = 0.05). |
| 3322 | 10480621 | These results suggest that in African-Americans, these variants in the IRS-1 and FABP2 genes are not associated with the risk of type 2 diabetes, severe obesity, or marked hyperinsulinemia, but that their independent and joint effects may be associated with small increases in BMI. |
| 3323 | 10480621 | Variants of the insulin receptor substrate-1 and fatty acid binding protein 2 genes and the risk of type 2 diabetes, obesity, and hyperinsulinemia in African-Americans: the Atherosclerosis Risk in Communities Study. |
| 3324 | 10480621 | The allele frequencies of the Gly972Arg variant of the insulin receptor substrate-1 (IRS-1) gene and the Ala54Thr variant of the fatty acid binding protein 2 (FABP2) gene were compared in 992 normal control subjects and three patient groups: 1) 321 type 2 diabetic individuals, 2) 260 severely obese individuals, and 3) 258 markedly hyperinsulinemic individuals without diabetes. |
| 3325 | 10480621 | Allele frequencies of Gly972Arg IRS-1 and Ala54Thr FABP2 were 0.07 and 0.22, respectively; there were no differences in allele or genotype frequencies between patients and control subjects for either gene variant. |
| 3326 | 10480621 | In addition, individuals with at least one IRS-1 Arg972 allele and two FABP2 Thr54 alleles had a BMI of 33.3 (7.9) kg/m2, compared with 30.0 (6.3) kg/m2 for those with neither allele (P = 0.05). |
| 3327 | 10480621 | These results suggest that in African-Americans, these variants in the IRS-1 and FABP2 genes are not associated with the risk of type 2 diabetes, severe obesity, or marked hyperinsulinemia, but that their independent and joint effects may be associated with small increases in BMI. |
| 3328 | 10480621 | Variants of the insulin receptor substrate-1 and fatty acid binding protein 2 genes and the risk of type 2 diabetes, obesity, and hyperinsulinemia in African-Americans: the Atherosclerosis Risk in Communities Study. |
| 3329 | 10480621 | The allele frequencies of the Gly972Arg variant of the insulin receptor substrate-1 (IRS-1) gene and the Ala54Thr variant of the fatty acid binding protein 2 (FABP2) gene were compared in 992 normal control subjects and three patient groups: 1) 321 type 2 diabetic individuals, 2) 260 severely obese individuals, and 3) 258 markedly hyperinsulinemic individuals without diabetes. |
| 3330 | 10480621 | Allele frequencies of Gly972Arg IRS-1 and Ala54Thr FABP2 were 0.07 and 0.22, respectively; there were no differences in allele or genotype frequencies between patients and control subjects for either gene variant. |
| 3331 | 10480621 | In addition, individuals with at least one IRS-1 Arg972 allele and two FABP2 Thr54 alleles had a BMI of 33.3 (7.9) kg/m2, compared with 30.0 (6.3) kg/m2 for those with neither allele (P = 0.05). |
| 3332 | 10480621 | These results suggest that in African-Americans, these variants in the IRS-1 and FABP2 genes are not associated with the risk of type 2 diabetes, severe obesity, or marked hyperinsulinemia, but that their independent and joint effects may be associated with small increases in BMI. |
| 3333 | 10480621 | Variants of the insulin receptor substrate-1 and fatty acid binding protein 2 genes and the risk of type 2 diabetes, obesity, and hyperinsulinemia in African-Americans: the Atherosclerosis Risk in Communities Study. |
| 3334 | 10480621 | The allele frequencies of the Gly972Arg variant of the insulin receptor substrate-1 (IRS-1) gene and the Ala54Thr variant of the fatty acid binding protein 2 (FABP2) gene were compared in 992 normal control subjects and three patient groups: 1) 321 type 2 diabetic individuals, 2) 260 severely obese individuals, and 3) 258 markedly hyperinsulinemic individuals without diabetes. |
| 3335 | 10480621 | Allele frequencies of Gly972Arg IRS-1 and Ala54Thr FABP2 were 0.07 and 0.22, respectively; there were no differences in allele or genotype frequencies between patients and control subjects for either gene variant. |
| 3336 | 10480621 | In addition, individuals with at least one IRS-1 Arg972 allele and two FABP2 Thr54 alleles had a BMI of 33.3 (7.9) kg/m2, compared with 30.0 (6.3) kg/m2 for those with neither allele (P = 0.05). |
| 3337 | 10480621 | These results suggest that in African-Americans, these variants in the IRS-1 and FABP2 genes are not associated with the risk of type 2 diabetes, severe obesity, or marked hyperinsulinemia, but that their independent and joint effects may be associated with small increases in BMI. |
| 3338 | 10482045 | Amino acid polymorphism Gly 972 Arg in IRS-1 is not associated to lower clamp-derived insulin sensitivity in young healthy first degree relatives of patients with type 2 diabetes. |
| 3339 | 10512356 | Calorie restriction increases insulin-stimulated glucose transport in skeletal muscle from IRS-1 knockout mice. |
| 3340 | 10512356 | To determine whether insulin receptor substrate (IRS)-1 is essential for the insulin-sensitizing effect of CR, we measured in vitro 2-deoxyglucose (2DG) uptake in the presence and absence of insulin by skeletal muscle isolated from wild-type (WT) mice and transgenic mice lacking IRS-1 (knockout [KO]) after either ad libitum (AL) feeding or 20 days of CR (60% of ad libitum intake). |
| 3341 | 10512356 | Genotype also did not alter the CR-induced decrease in plasma constituents (glucose, insulin, and leptin) or body composition (body weight, fat pad/body weight ratio). |
| 3342 | 10512356 | Consistent with previous studies in rats, IRS-1 protein expression in muscle was reduced in WT-CR compared with WT-AL mice, and muscle IRS-2 abundance was unchanged by diet. |
| 3343 | 10512356 | These data demonstrate that IRS-1 is not essential for the CR-induced increase in insulin-stimulated glucose transport in skeletal muscle, and the absence of IRS-1 does not modify any of the characteristic adaptations of CR that were evaluated. |
| 3344 | 10512356 | Calorie restriction increases insulin-stimulated glucose transport in skeletal muscle from IRS-1 knockout mice. |
| 3345 | 10512356 | To determine whether insulin receptor substrate (IRS)-1 is essential for the insulin-sensitizing effect of CR, we measured in vitro 2-deoxyglucose (2DG) uptake in the presence and absence of insulin by skeletal muscle isolated from wild-type (WT) mice and transgenic mice lacking IRS-1 (knockout [KO]) after either ad libitum (AL) feeding or 20 days of CR (60% of ad libitum intake). |
| 3346 | 10512356 | Genotype also did not alter the CR-induced decrease in plasma constituents (glucose, insulin, and leptin) or body composition (body weight, fat pad/body weight ratio). |
| 3347 | 10512356 | Consistent with previous studies in rats, IRS-1 protein expression in muscle was reduced in WT-CR compared with WT-AL mice, and muscle IRS-2 abundance was unchanged by diet. |
| 3348 | 10512356 | These data demonstrate that IRS-1 is not essential for the CR-induced increase in insulin-stimulated glucose transport in skeletal muscle, and the absence of IRS-1 does not modify any of the characteristic adaptations of CR that were evaluated. |
| 3349 | 10512356 | Calorie restriction increases insulin-stimulated glucose transport in skeletal muscle from IRS-1 knockout mice. |
| 3350 | 10512356 | To determine whether insulin receptor substrate (IRS)-1 is essential for the insulin-sensitizing effect of CR, we measured in vitro 2-deoxyglucose (2DG) uptake in the presence and absence of insulin by skeletal muscle isolated from wild-type (WT) mice and transgenic mice lacking IRS-1 (knockout [KO]) after either ad libitum (AL) feeding or 20 days of CR (60% of ad libitum intake). |
| 3351 | 10512356 | Genotype also did not alter the CR-induced decrease in plasma constituents (glucose, insulin, and leptin) or body composition (body weight, fat pad/body weight ratio). |
| 3352 | 10512356 | Consistent with previous studies in rats, IRS-1 protein expression in muscle was reduced in WT-CR compared with WT-AL mice, and muscle IRS-2 abundance was unchanged by diet. |
| 3353 | 10512356 | These data demonstrate that IRS-1 is not essential for the CR-induced increase in insulin-stimulated glucose transport in skeletal muscle, and the absence of IRS-1 does not modify any of the characteristic adaptations of CR that were evaluated. |
| 3354 | 10512356 | Calorie restriction increases insulin-stimulated glucose transport in skeletal muscle from IRS-1 knockout mice. |
| 3355 | 10512356 | To determine whether insulin receptor substrate (IRS)-1 is essential for the insulin-sensitizing effect of CR, we measured in vitro 2-deoxyglucose (2DG) uptake in the presence and absence of insulin by skeletal muscle isolated from wild-type (WT) mice and transgenic mice lacking IRS-1 (knockout [KO]) after either ad libitum (AL) feeding or 20 days of CR (60% of ad libitum intake). |
| 3356 | 10512356 | Genotype also did not alter the CR-induced decrease in plasma constituents (glucose, insulin, and leptin) or body composition (body weight, fat pad/body weight ratio). |
| 3357 | 10512356 | Consistent with previous studies in rats, IRS-1 protein expression in muscle was reduced in WT-CR compared with WT-AL mice, and muscle IRS-2 abundance was unchanged by diet. |
| 3358 | 10512356 | These data demonstrate that IRS-1 is not essential for the CR-induced increase in insulin-stimulated glucose transport in skeletal muscle, and the absence of IRS-1 does not modify any of the characteristic adaptations of CR that were evaluated. |
| 3359 | 10542046 | Cross-talk mechanisms in the development of insulin resistance of skeletal muscle cells palmitate rather than tumour necrosis factor inhibits insulin-dependent protein kinase B (PKB)/Akt stimulation and glucose uptake. |
| 3360 | 10542046 | Tumour necrosis factor (TNF) and nonesterified fatty acids have been proposed to be crucial factors in the development of the insulin-resistant state. |
| 3361 | 10542046 | We here show that, although TNF downregulated insulin-induced insulin receptor (IR) and IR substrate (IRS)-1 phosphorylation as well as phosphoinositide 3-kinase (PI3-kinase) activity in pmi28 myotubes, this was, unlike in adipocytes, not sufficient to affect insulin-induced glucose transport. |
| 3362 | 10542046 | Rather, TNF increased membrane expression of GLUT1 and glucose transport in these muscle cells. |
| 3363 | 10542046 | In contrast, the nonesterified fatty acid palmitate inhibited insulin-induced signalling cascades not only at the level of IR and IRS-1 phosphorylation, but also at the level protein kinase B (PKB/Akt), which is thought to be directly involved in the insulin-induced translocation of GLUT4, and inhibited insulin-induced glucose uptake. |
| 3364 | 10542046 | Palmitate also abrogated TNF-dependent enhancement of basal glucose uptake, suggesting that palmitate has the capacity to render muscle cells resistant not only to insulin but also to TNF with respect to glucose transport by GLUT4 and GLUT1, respectively. |
| 3365 | 10542046 | Our data illustrate the complexity of the mechanisms governing insulin resistance of skeletal muscle, questioning the role of TNF as a direct inhibitor of glucose homoeostasis in this tissue and shedding new light on an as yet unrecognized multifunctional role for the predominant nonesterified fatty acid palmitate in this process. |
| 3366 | 10574950 | Insulin-induced tyrosine phosphorylation of the insulin receptor, insulin receptor substrate 1 (IRS-1), and IRS-2 was reduced by prestimulation of beta(3)-adrenergic receptors (CL316243). |
| 3367 | 10574950 | Similarly, insulin-induced IRS-1-associated and phosphotyrosine-associated phosphatidylinositol 3-kinase (PI 3-kinase) activity, but not IRS-2-associated PI 3-kinase activity, was reduced by beta(3)-adrenergic prestimulation. |
| 3368 | 10574950 | Furthermore, insulin-stimulated activation of Akt, but not mitogen-activated protein kinase, was diminished. |
| 3369 | 10574950 | Furthermore inhibition of protein kinase C restored the beta(3)-receptor-mediated reductions in insulin-induced IRS-1 tyrosine phosphorylation and IRS-1-associated PI 3-kinase activity. |
| 3370 | 10574950 | This interaction is protein kinase A-dependent and, at least in part, protein kinase C-dependent, and could play an important role in the pathogenesis of insulin resistance associated with sympathetic overactivity and regulation of brown fat metabolism. |
| 3371 | 10574950 | Insulin-induced tyrosine phosphorylation of the insulin receptor, insulin receptor substrate 1 (IRS-1), and IRS-2 was reduced by prestimulation of beta(3)-adrenergic receptors (CL316243). |
| 3372 | 10574950 | Similarly, insulin-induced IRS-1-associated and phosphotyrosine-associated phosphatidylinositol 3-kinase (PI 3-kinase) activity, but not IRS-2-associated PI 3-kinase activity, was reduced by beta(3)-adrenergic prestimulation. |
| 3373 | 10574950 | Furthermore, insulin-stimulated activation of Akt, but not mitogen-activated protein kinase, was diminished. |
| 3374 | 10574950 | Furthermore inhibition of protein kinase C restored the beta(3)-receptor-mediated reductions in insulin-induced IRS-1 tyrosine phosphorylation and IRS-1-associated PI 3-kinase activity. |
| 3375 | 10574950 | This interaction is protein kinase A-dependent and, at least in part, protein kinase C-dependent, and could play an important role in the pathogenesis of insulin resistance associated with sympathetic overactivity and regulation of brown fat metabolism. |
| 3376 | 10591678 | A common mutation (G972R) of the IRS-1 gene has been shown to impair IRS-1 function, and it has been associated with reduced insulin sensitivity and lipid abnormalities. |
| 3377 | 10594015 | IRS-4 mediates protein kinase B signaling during insulin stimulation without promoting antiapoptosis. |
| 3378 | 10594015 | Insulin receptor substrate (IRS) proteins are tyrosine phosphorylated and mediate multiple signals during activation of the receptors for insulin, insulin-like growth factor 1 (IGF-1), and various cytokines. |
| 3379 | 10594015 | In order to distinguish common and unique functions of IRS-1, IRS-2, and IRS-4, we expressed them individually in 32D myeloid progenitor cells containing the human insulin receptor (32D(IR)). |
| 3380 | 10594015 | Insulin promoted the association of Grb-2 with IRS-1 and IRS-4, whereas IRS-2 weakly bound Grb-2; consequently, IRS-1 and IRS-4 enhanced insulin-stimulated mitogen-activated protein kinase activity. |
| 3381 | 10594015 | During insulin stimulation, IRS-1 and IRS-2 strongly bound p85alpha/beta, which activated phosphatidylinositol (PI) 3-kinase, protein kinase B (PKB)/Akt, and p70(s6k), and promoted the phosphorylation of BAD. |
| 3382 | 10594015 | IRS-4 also promoted the activation of PKB/Akt and BAD phosphorylation during insulin stimulation; however, it weakly bound or activated p85-associated PI 3-kinase and failed to mediate the activation of p70(s6k). |
| 3383 | 10594015 | Insulin strongly inhibited apoptosis of interleukin-3 (IL-3)-deprived 32D(IR) cells expressing IRS-1 or IRS-2 but failed to inhibit apoptosis of cells expressing IRS-4. |
| 3384 | 10594015 | Consequently, 32D(IR) cells expressing IRS-4 proliferated slowly during insulin stimulation. |
| 3385 | 10594015 | Thus, the activation of PKB/Akt and BAD phosphorylation might not be sufficient to inhibit the apoptosis of IL-3-deprived 32D(IR) cells unless p85-associated PI 3-kinase or p70(s6k) are strongly activated. |
| 3386 | 10594015 | IRS-4 mediates protein kinase B signaling during insulin stimulation without promoting antiapoptosis. |
| 3387 | 10594015 | Insulin receptor substrate (IRS) proteins are tyrosine phosphorylated and mediate multiple signals during activation of the receptors for insulin, insulin-like growth factor 1 (IGF-1), and various cytokines. |
| 3388 | 10594015 | In order to distinguish common and unique functions of IRS-1, IRS-2, and IRS-4, we expressed them individually in 32D myeloid progenitor cells containing the human insulin receptor (32D(IR)). |
| 3389 | 10594015 | Insulin promoted the association of Grb-2 with IRS-1 and IRS-4, whereas IRS-2 weakly bound Grb-2; consequently, IRS-1 and IRS-4 enhanced insulin-stimulated mitogen-activated protein kinase activity. |
| 3390 | 10594015 | During insulin stimulation, IRS-1 and IRS-2 strongly bound p85alpha/beta, which activated phosphatidylinositol (PI) 3-kinase, protein kinase B (PKB)/Akt, and p70(s6k), and promoted the phosphorylation of BAD. |
| 3391 | 10594015 | IRS-4 also promoted the activation of PKB/Akt and BAD phosphorylation during insulin stimulation; however, it weakly bound or activated p85-associated PI 3-kinase and failed to mediate the activation of p70(s6k). |
| 3392 | 10594015 | Insulin strongly inhibited apoptosis of interleukin-3 (IL-3)-deprived 32D(IR) cells expressing IRS-1 or IRS-2 but failed to inhibit apoptosis of cells expressing IRS-4. |
| 3393 | 10594015 | Consequently, 32D(IR) cells expressing IRS-4 proliferated slowly during insulin stimulation. |
| 3394 | 10594015 | Thus, the activation of PKB/Akt and BAD phosphorylation might not be sufficient to inhibit the apoptosis of IL-3-deprived 32D(IR) cells unless p85-associated PI 3-kinase or p70(s6k) are strongly activated. |
| 3395 | 10594015 | IRS-4 mediates protein kinase B signaling during insulin stimulation without promoting antiapoptosis. |
| 3396 | 10594015 | Insulin receptor substrate (IRS) proteins are tyrosine phosphorylated and mediate multiple signals during activation of the receptors for insulin, insulin-like growth factor 1 (IGF-1), and various cytokines. |
| 3397 | 10594015 | In order to distinguish common and unique functions of IRS-1, IRS-2, and IRS-4, we expressed them individually in 32D myeloid progenitor cells containing the human insulin receptor (32D(IR)). |
| 3398 | 10594015 | Insulin promoted the association of Grb-2 with IRS-1 and IRS-4, whereas IRS-2 weakly bound Grb-2; consequently, IRS-1 and IRS-4 enhanced insulin-stimulated mitogen-activated protein kinase activity. |
| 3399 | 10594015 | During insulin stimulation, IRS-1 and IRS-2 strongly bound p85alpha/beta, which activated phosphatidylinositol (PI) 3-kinase, protein kinase B (PKB)/Akt, and p70(s6k), and promoted the phosphorylation of BAD. |
| 3400 | 10594015 | IRS-4 also promoted the activation of PKB/Akt and BAD phosphorylation during insulin stimulation; however, it weakly bound or activated p85-associated PI 3-kinase and failed to mediate the activation of p70(s6k). |
| 3401 | 10594015 | Insulin strongly inhibited apoptosis of interleukin-3 (IL-3)-deprived 32D(IR) cells expressing IRS-1 or IRS-2 but failed to inhibit apoptosis of cells expressing IRS-4. |
| 3402 | 10594015 | Consequently, 32D(IR) cells expressing IRS-4 proliferated slowly during insulin stimulation. |
| 3403 | 10594015 | Thus, the activation of PKB/Akt and BAD phosphorylation might not be sufficient to inhibit the apoptosis of IL-3-deprived 32D(IR) cells unless p85-associated PI 3-kinase or p70(s6k) are strongly activated. |
| 3404 | 10594015 | IRS-4 mediates protein kinase B signaling during insulin stimulation without promoting antiapoptosis. |
| 3405 | 10594015 | Insulin receptor substrate (IRS) proteins are tyrosine phosphorylated and mediate multiple signals during activation of the receptors for insulin, insulin-like growth factor 1 (IGF-1), and various cytokines. |
| 3406 | 10594015 | In order to distinguish common and unique functions of IRS-1, IRS-2, and IRS-4, we expressed them individually in 32D myeloid progenitor cells containing the human insulin receptor (32D(IR)). |
| 3407 | 10594015 | Insulin promoted the association of Grb-2 with IRS-1 and IRS-4, whereas IRS-2 weakly bound Grb-2; consequently, IRS-1 and IRS-4 enhanced insulin-stimulated mitogen-activated protein kinase activity. |
| 3408 | 10594015 | During insulin stimulation, IRS-1 and IRS-2 strongly bound p85alpha/beta, which activated phosphatidylinositol (PI) 3-kinase, protein kinase B (PKB)/Akt, and p70(s6k), and promoted the phosphorylation of BAD. |
| 3409 | 10594015 | IRS-4 also promoted the activation of PKB/Akt and BAD phosphorylation during insulin stimulation; however, it weakly bound or activated p85-associated PI 3-kinase and failed to mediate the activation of p70(s6k). |
| 3410 | 10594015 | Insulin strongly inhibited apoptosis of interleukin-3 (IL-3)-deprived 32D(IR) cells expressing IRS-1 or IRS-2 but failed to inhibit apoptosis of cells expressing IRS-4. |
| 3411 | 10594015 | Consequently, 32D(IR) cells expressing IRS-4 proliferated slowly during insulin stimulation. |
| 3412 | 10594015 | Thus, the activation of PKB/Akt and BAD phosphorylation might not be sufficient to inhibit the apoptosis of IL-3-deprived 32D(IR) cells unless p85-associated PI 3-kinase or p70(s6k) are strongly activated. |
| 3413 | 10606633 | Freshly isolated islets from IRS-1 knockout mice and SV40-transformed IRS-1-deficient beta-cell lines exhibit marked insulin secretory defects in response to glucose and arginine. |
| 3414 | 10606633 | Furthermore, insulin expression is reduced by about 2-fold in the IRS-1-null islets and beta-cell lines, and this defect can be partially restored by transfecting the cells with IRS-1. |
| 3415 | 10606633 | These data provide evidence for an important role of IRS-1 in islet function and provide a novel functional link between the insulin signaling and insulin secretion pathways. |
| 3416 | 10606633 | Freshly isolated islets from IRS-1 knockout mice and SV40-transformed IRS-1-deficient beta-cell lines exhibit marked insulin secretory defects in response to glucose and arginine. |
| 3417 | 10606633 | Furthermore, insulin expression is reduced by about 2-fold in the IRS-1-null islets and beta-cell lines, and this defect can be partially restored by transfecting the cells with IRS-1. |
| 3418 | 10606633 | These data provide evidence for an important role of IRS-1 in islet function and provide a novel functional link between the insulin signaling and insulin secretion pathways. |
| 3419 | 10606633 | Freshly isolated islets from IRS-1 knockout mice and SV40-transformed IRS-1-deficient beta-cell lines exhibit marked insulin secretory defects in response to glucose and arginine. |
| 3420 | 10606633 | Furthermore, insulin expression is reduced by about 2-fold in the IRS-1-null islets and beta-cell lines, and this defect can be partially restored by transfecting the cells with IRS-1. |
| 3421 | 10606633 | These data provide evidence for an important role of IRS-1 in islet function and provide a novel functional link between the insulin signaling and insulin secretion pathways. |
| 3422 | 10642598 | Tissue-specific insulin resistance in mice with mutations in the insulin receptor, IRS-1, and IRS-2. |
| 3423 | 10642598 | To analyze the role of the insulin signaling pathway in these processes, we have generated mice with combined heterozygous null mutations in insulin receptor (ir), insulin receptor substrate (irs-1), and/or irs-2. |
| 3424 | 10642598 | Diabetes developed in 40% of ir/irs-1/irs-2(+/-), 20% of ir/irs-1(+/-), 17% of ir/irs-2(+/-), and 5% of ir(+/-) mice. |
| 3425 | 10642598 | Although combined heterozygosity for ir/irs-1(+/-) and ir/irs-2(+/-) results in a similar number of diabetic mice, there are significant differences in the underlying metabolic abnormalities. ir/irs-1(+/-) mice develop severe insulin resistance in skeletal muscle and liver, with compensatory beta-cell hyperplasia. |
| 3426 | 10642598 | In contrast, ir/irs-2(+/-) mice develop severe insulin resistance in liver, mild insulin resistance in skeletal muscle, and modest beta-cell hyperplasia. |
| 3427 | 10642598 | These data indicate tissue-specific differences in the roles of IRSs to mediate insulin action, with irs-1 playing a prominent role in skeletal muscle and irs-2 in liver. |
| 3428 | 10642598 | Tissue-specific insulin resistance in mice with mutations in the insulin receptor, IRS-1, and IRS-2. |
| 3429 | 10642598 | To analyze the role of the insulin signaling pathway in these processes, we have generated mice with combined heterozygous null mutations in insulin receptor (ir), insulin receptor substrate (irs-1), and/or irs-2. |
| 3430 | 10642598 | Diabetes developed in 40% of ir/irs-1/irs-2(+/-), 20% of ir/irs-1(+/-), 17% of ir/irs-2(+/-), and 5% of ir(+/-) mice. |
| 3431 | 10642598 | Although combined heterozygosity for ir/irs-1(+/-) and ir/irs-2(+/-) results in a similar number of diabetic mice, there are significant differences in the underlying metabolic abnormalities. ir/irs-1(+/-) mice develop severe insulin resistance in skeletal muscle and liver, with compensatory beta-cell hyperplasia. |
| 3432 | 10642598 | In contrast, ir/irs-2(+/-) mice develop severe insulin resistance in liver, mild insulin resistance in skeletal muscle, and modest beta-cell hyperplasia. |
| 3433 | 10642598 | These data indicate tissue-specific differences in the roles of IRSs to mediate insulin action, with irs-1 playing a prominent role in skeletal muscle and irs-2 in liver. |
| 3434 | 10642598 | Tissue-specific insulin resistance in mice with mutations in the insulin receptor, IRS-1, and IRS-2. |
| 3435 | 10642598 | To analyze the role of the insulin signaling pathway in these processes, we have generated mice with combined heterozygous null mutations in insulin receptor (ir), insulin receptor substrate (irs-1), and/or irs-2. |
| 3436 | 10642598 | Diabetes developed in 40% of ir/irs-1/irs-2(+/-), 20% of ir/irs-1(+/-), 17% of ir/irs-2(+/-), and 5% of ir(+/-) mice. |
| 3437 | 10642598 | Although combined heterozygosity for ir/irs-1(+/-) and ir/irs-2(+/-) results in a similar number of diabetic mice, there are significant differences in the underlying metabolic abnormalities. ir/irs-1(+/-) mice develop severe insulin resistance in skeletal muscle and liver, with compensatory beta-cell hyperplasia. |
| 3438 | 10642598 | In contrast, ir/irs-2(+/-) mice develop severe insulin resistance in liver, mild insulin resistance in skeletal muscle, and modest beta-cell hyperplasia. |
| 3439 | 10642598 | These data indicate tissue-specific differences in the roles of IRSs to mediate insulin action, with irs-1 playing a prominent role in skeletal muscle and irs-2 in liver. |
| 3440 | 10642598 | Tissue-specific insulin resistance in mice with mutations in the insulin receptor, IRS-1, and IRS-2. |
| 3441 | 10642598 | To analyze the role of the insulin signaling pathway in these processes, we have generated mice with combined heterozygous null mutations in insulin receptor (ir), insulin receptor substrate (irs-1), and/or irs-2. |
| 3442 | 10642598 | Diabetes developed in 40% of ir/irs-1/irs-2(+/-), 20% of ir/irs-1(+/-), 17% of ir/irs-2(+/-), and 5% of ir(+/-) mice. |
| 3443 | 10642598 | Although combined heterozygosity for ir/irs-1(+/-) and ir/irs-2(+/-) results in a similar number of diabetic mice, there are significant differences in the underlying metabolic abnormalities. ir/irs-1(+/-) mice develop severe insulin resistance in skeletal muscle and liver, with compensatory beta-cell hyperplasia. |
| 3444 | 10642598 | In contrast, ir/irs-2(+/-) mice develop severe insulin resistance in liver, mild insulin resistance in skeletal muscle, and modest beta-cell hyperplasia. |
| 3445 | 10642598 | These data indicate tissue-specific differences in the roles of IRSs to mediate insulin action, with irs-1 playing a prominent role in skeletal muscle and irs-2 in liver. |
| 3446 | 10642598 | Tissue-specific insulin resistance in mice with mutations in the insulin receptor, IRS-1, and IRS-2. |
| 3447 | 10642598 | To analyze the role of the insulin signaling pathway in these processes, we have generated mice with combined heterozygous null mutations in insulin receptor (ir), insulin receptor substrate (irs-1), and/or irs-2. |
| 3448 | 10642598 | Diabetes developed in 40% of ir/irs-1/irs-2(+/-), 20% of ir/irs-1(+/-), 17% of ir/irs-2(+/-), and 5% of ir(+/-) mice. |
| 3449 | 10642598 | Although combined heterozygosity for ir/irs-1(+/-) and ir/irs-2(+/-) results in a similar number of diabetic mice, there are significant differences in the underlying metabolic abnormalities. ir/irs-1(+/-) mice develop severe insulin resistance in skeletal muscle and liver, with compensatory beta-cell hyperplasia. |
| 3450 | 10642598 | In contrast, ir/irs-2(+/-) mice develop severe insulin resistance in liver, mild insulin resistance in skeletal muscle, and modest beta-cell hyperplasia. |
| 3451 | 10642598 | These data indicate tissue-specific differences in the roles of IRSs to mediate insulin action, with irs-1 playing a prominent role in skeletal muscle and irs-2 in liver. |
| 3452 | 10660596 | Tyrosine dephosphorylation and deactivation of insulin receptor substrate-1 by protein-tyrosine phosphatase 1B. |
| 3453 | 10660596 | The specific activity of four candidate protein-tyrosine phosphatases (protein-tyrosine phosphatase 1B (PTP1B), SH2 domain-containing PTPase-2 (SHP-2), leukocyte common antigen-related (LAR), and leukocyte antigen-related phosphatase) (LRP) toward IRS-1 dephosphorylation was studied using recombinant proteins in vitro. |
| 3454 | 10660596 | When evaluated as a ratio of activity versus IRS-1 to that versus p-nitrophenyl phosphate, PTP1B remained significantly more active by 3.1-293-fold, respectively. |
| 3455 | 10660596 | Overlay blots with recombinant Src homology 2 domains of IRS-1 adaptor proteins showed that the loss of IRS-1 binding of Crk, GRB2, SHP-2, and the p85 subunit of phosphatidylinositol 3'-kinase paralleled the rate of overall IRS-1 dephosphorylation. |
| 3456 | 10660596 | Further studies revealed that the adaptor protein GRB2 strongly promoted the formation of a stable protein complex between tyrosine-phosphorylated IRS-1 and catalytically inactive PTP1B, increasing their co-immunoprecipitation from an equimolar solution by 13.5 +/- 3.3-fold (n = 7; p < 0.01). |
| 3457 | 10660596 | Inclusion of GRB2 in a reaction mixture of IRS-1 and active PTP1B also increased the overall rate of IRS-1 tyrosine dephosphorylation by 2.7-3.9-fold (p < 0.01). |
| 3458 | 10660596 | These results provide new insight into novel molecular interactions involving PTP1B and GRB2 that may influence the steady-state capacity of IRS-1 to function as a phosphotyrosine scaffold and possibly affect the balance of postreceptor insulin signaling. |
| 3459 | 10660596 | Tyrosine dephosphorylation and deactivation of insulin receptor substrate-1 by protein-tyrosine phosphatase 1B. |
| 3460 | 10660596 | The specific activity of four candidate protein-tyrosine phosphatases (protein-tyrosine phosphatase 1B (PTP1B), SH2 domain-containing PTPase-2 (SHP-2), leukocyte common antigen-related (LAR), and leukocyte antigen-related phosphatase) (LRP) toward IRS-1 dephosphorylation was studied using recombinant proteins in vitro. |
| 3461 | 10660596 | When evaluated as a ratio of activity versus IRS-1 to that versus p-nitrophenyl phosphate, PTP1B remained significantly more active by 3.1-293-fold, respectively. |
| 3462 | 10660596 | Overlay blots with recombinant Src homology 2 domains of IRS-1 adaptor proteins showed that the loss of IRS-1 binding of Crk, GRB2, SHP-2, and the p85 subunit of phosphatidylinositol 3'-kinase paralleled the rate of overall IRS-1 dephosphorylation. |
| 3463 | 10660596 | Further studies revealed that the adaptor protein GRB2 strongly promoted the formation of a stable protein complex between tyrosine-phosphorylated IRS-1 and catalytically inactive PTP1B, increasing their co-immunoprecipitation from an equimolar solution by 13.5 +/- 3.3-fold (n = 7; p < 0.01). |
| 3464 | 10660596 | Inclusion of GRB2 in a reaction mixture of IRS-1 and active PTP1B also increased the overall rate of IRS-1 tyrosine dephosphorylation by 2.7-3.9-fold (p < 0.01). |
| 3465 | 10660596 | These results provide new insight into novel molecular interactions involving PTP1B and GRB2 that may influence the steady-state capacity of IRS-1 to function as a phosphotyrosine scaffold and possibly affect the balance of postreceptor insulin signaling. |
| 3466 | 10660596 | Tyrosine dephosphorylation and deactivation of insulin receptor substrate-1 by protein-tyrosine phosphatase 1B. |
| 3467 | 10660596 | The specific activity of four candidate protein-tyrosine phosphatases (protein-tyrosine phosphatase 1B (PTP1B), SH2 domain-containing PTPase-2 (SHP-2), leukocyte common antigen-related (LAR), and leukocyte antigen-related phosphatase) (LRP) toward IRS-1 dephosphorylation was studied using recombinant proteins in vitro. |
| 3468 | 10660596 | When evaluated as a ratio of activity versus IRS-1 to that versus p-nitrophenyl phosphate, PTP1B remained significantly more active by 3.1-293-fold, respectively. |
| 3469 | 10660596 | Overlay blots with recombinant Src homology 2 domains of IRS-1 adaptor proteins showed that the loss of IRS-1 binding of Crk, GRB2, SHP-2, and the p85 subunit of phosphatidylinositol 3'-kinase paralleled the rate of overall IRS-1 dephosphorylation. |
| 3470 | 10660596 | Further studies revealed that the adaptor protein GRB2 strongly promoted the formation of a stable protein complex between tyrosine-phosphorylated IRS-1 and catalytically inactive PTP1B, increasing their co-immunoprecipitation from an equimolar solution by 13.5 +/- 3.3-fold (n = 7; p < 0.01). |
| 3471 | 10660596 | Inclusion of GRB2 in a reaction mixture of IRS-1 and active PTP1B also increased the overall rate of IRS-1 tyrosine dephosphorylation by 2.7-3.9-fold (p < 0.01). |
| 3472 | 10660596 | These results provide new insight into novel molecular interactions involving PTP1B and GRB2 that may influence the steady-state capacity of IRS-1 to function as a phosphotyrosine scaffold and possibly affect the balance of postreceptor insulin signaling. |
| 3473 | 10660596 | Tyrosine dephosphorylation and deactivation of insulin receptor substrate-1 by protein-tyrosine phosphatase 1B. |
| 3474 | 10660596 | The specific activity of four candidate protein-tyrosine phosphatases (protein-tyrosine phosphatase 1B (PTP1B), SH2 domain-containing PTPase-2 (SHP-2), leukocyte common antigen-related (LAR), and leukocyte antigen-related phosphatase) (LRP) toward IRS-1 dephosphorylation was studied using recombinant proteins in vitro. |
| 3475 | 10660596 | When evaluated as a ratio of activity versus IRS-1 to that versus p-nitrophenyl phosphate, PTP1B remained significantly more active by 3.1-293-fold, respectively. |
| 3476 | 10660596 | Overlay blots with recombinant Src homology 2 domains of IRS-1 adaptor proteins showed that the loss of IRS-1 binding of Crk, GRB2, SHP-2, and the p85 subunit of phosphatidylinositol 3'-kinase paralleled the rate of overall IRS-1 dephosphorylation. |
| 3477 | 10660596 | Further studies revealed that the adaptor protein GRB2 strongly promoted the formation of a stable protein complex between tyrosine-phosphorylated IRS-1 and catalytically inactive PTP1B, increasing their co-immunoprecipitation from an equimolar solution by 13.5 +/- 3.3-fold (n = 7; p < 0.01). |
| 3478 | 10660596 | Inclusion of GRB2 in a reaction mixture of IRS-1 and active PTP1B also increased the overall rate of IRS-1 tyrosine dephosphorylation by 2.7-3.9-fold (p < 0.01). |
| 3479 | 10660596 | These results provide new insight into novel molecular interactions involving PTP1B and GRB2 that may influence the steady-state capacity of IRS-1 to function as a phosphotyrosine scaffold and possibly affect the balance of postreceptor insulin signaling. |
| 3480 | 10660596 | Tyrosine dephosphorylation and deactivation of insulin receptor substrate-1 by protein-tyrosine phosphatase 1B. |
| 3481 | 10660596 | The specific activity of four candidate protein-tyrosine phosphatases (protein-tyrosine phosphatase 1B (PTP1B), SH2 domain-containing PTPase-2 (SHP-2), leukocyte common antigen-related (LAR), and leukocyte antigen-related phosphatase) (LRP) toward IRS-1 dephosphorylation was studied using recombinant proteins in vitro. |
| 3482 | 10660596 | When evaluated as a ratio of activity versus IRS-1 to that versus p-nitrophenyl phosphate, PTP1B remained significantly more active by 3.1-293-fold, respectively. |
| 3483 | 10660596 | Overlay blots with recombinant Src homology 2 domains of IRS-1 adaptor proteins showed that the loss of IRS-1 binding of Crk, GRB2, SHP-2, and the p85 subunit of phosphatidylinositol 3'-kinase paralleled the rate of overall IRS-1 dephosphorylation. |
| 3484 | 10660596 | Further studies revealed that the adaptor protein GRB2 strongly promoted the formation of a stable protein complex between tyrosine-phosphorylated IRS-1 and catalytically inactive PTP1B, increasing their co-immunoprecipitation from an equimolar solution by 13.5 +/- 3.3-fold (n = 7; p < 0.01). |
| 3485 | 10660596 | Inclusion of GRB2 in a reaction mixture of IRS-1 and active PTP1B also increased the overall rate of IRS-1 tyrosine dephosphorylation by 2.7-3.9-fold (p < 0.01). |
| 3486 | 10660596 | These results provide new insight into novel molecular interactions involving PTP1B and GRB2 that may influence the steady-state capacity of IRS-1 to function as a phosphotyrosine scaffold and possibly affect the balance of postreceptor insulin signaling. |
| 3487 | 10660596 | Tyrosine dephosphorylation and deactivation of insulin receptor substrate-1 by protein-tyrosine phosphatase 1B. |
| 3488 | 10660596 | The specific activity of four candidate protein-tyrosine phosphatases (protein-tyrosine phosphatase 1B (PTP1B), SH2 domain-containing PTPase-2 (SHP-2), leukocyte common antigen-related (LAR), and leukocyte antigen-related phosphatase) (LRP) toward IRS-1 dephosphorylation was studied using recombinant proteins in vitro. |
| 3489 | 10660596 | When evaluated as a ratio of activity versus IRS-1 to that versus p-nitrophenyl phosphate, PTP1B remained significantly more active by 3.1-293-fold, respectively. |
| 3490 | 10660596 | Overlay blots with recombinant Src homology 2 domains of IRS-1 adaptor proteins showed that the loss of IRS-1 binding of Crk, GRB2, SHP-2, and the p85 subunit of phosphatidylinositol 3'-kinase paralleled the rate of overall IRS-1 dephosphorylation. |
| 3491 | 10660596 | Further studies revealed that the adaptor protein GRB2 strongly promoted the formation of a stable protein complex between tyrosine-phosphorylated IRS-1 and catalytically inactive PTP1B, increasing their co-immunoprecipitation from an equimolar solution by 13.5 +/- 3.3-fold (n = 7; p < 0.01). |
| 3492 | 10660596 | Inclusion of GRB2 in a reaction mixture of IRS-1 and active PTP1B also increased the overall rate of IRS-1 tyrosine dephosphorylation by 2.7-3.9-fold (p < 0.01). |
| 3493 | 10660596 | These results provide new insight into novel molecular interactions involving PTP1B and GRB2 that may influence the steady-state capacity of IRS-1 to function as a phosphotyrosine scaffold and possibly affect the balance of postreceptor insulin signaling. |
| 3494 | 10660596 | Tyrosine dephosphorylation and deactivation of insulin receptor substrate-1 by protein-tyrosine phosphatase 1B. |
| 3495 | 10660596 | The specific activity of four candidate protein-tyrosine phosphatases (protein-tyrosine phosphatase 1B (PTP1B), SH2 domain-containing PTPase-2 (SHP-2), leukocyte common antigen-related (LAR), and leukocyte antigen-related phosphatase) (LRP) toward IRS-1 dephosphorylation was studied using recombinant proteins in vitro. |
| 3496 | 10660596 | When evaluated as a ratio of activity versus IRS-1 to that versus p-nitrophenyl phosphate, PTP1B remained significantly more active by 3.1-293-fold, respectively. |
| 3497 | 10660596 | Overlay blots with recombinant Src homology 2 domains of IRS-1 adaptor proteins showed that the loss of IRS-1 binding of Crk, GRB2, SHP-2, and the p85 subunit of phosphatidylinositol 3'-kinase paralleled the rate of overall IRS-1 dephosphorylation. |
| 3498 | 10660596 | Further studies revealed that the adaptor protein GRB2 strongly promoted the formation of a stable protein complex between tyrosine-phosphorylated IRS-1 and catalytically inactive PTP1B, increasing their co-immunoprecipitation from an equimolar solution by 13.5 +/- 3.3-fold (n = 7; p < 0.01). |
| 3499 | 10660596 | Inclusion of GRB2 in a reaction mixture of IRS-1 and active PTP1B also increased the overall rate of IRS-1 tyrosine dephosphorylation by 2.7-3.9-fold (p < 0.01). |
| 3500 | 10660596 | These results provide new insight into novel molecular interactions involving PTP1B and GRB2 that may influence the steady-state capacity of IRS-1 to function as a phosphotyrosine scaffold and possibly affect the balance of postreceptor insulin signaling. |
| 3501 | 10675357 | Insulin resistance differentially affects the PI 3-kinase- and MAP kinase-mediated signaling in human muscle. |
| 3502 | 10675357 | Insulin stimulation of the phosphatidylinositol 3-kinase (PI 3-kinase) pathway, as measured by phosphorylation of the insulin receptor and IRS-1 and by IRS protein association with p85 and with PI 3-kinase, was dramatically reduced in obese nondiabetics and virtually absent in type 2 diabetic patients. |
| 3503 | 10675357 | Insulin stimulation of the MAP kinase pathway was normal in obese and diabetic subjects. |
| 3504 | 10675357 | Insulin stimulation of glucose-disposal correlated with association of p85 with IRS-1. |
| 3505 | 10675357 | Exercise 24 hours before the euglycemic clamp increased phosphorylation of insulin receptor and IRS-1 in obese and diabetic subjects but did not increase glucose uptake or PI 3-kinase association with IRS-1 upon insulin stimulation. |
| 3506 | 10675357 | Thus, insulin resistance differentially affects the PI 3-kinase and MAP kinase signaling pathways, and insulin-stimulated IRS-1-association with PI 3-kinase defines a key step in insulin resistance. |
| 3507 | 10675357 | Insulin resistance differentially affects the PI 3-kinase- and MAP kinase-mediated signaling in human muscle. |
| 3508 | 10675357 | Insulin stimulation of the phosphatidylinositol 3-kinase (PI 3-kinase) pathway, as measured by phosphorylation of the insulin receptor and IRS-1 and by IRS protein association with p85 and with PI 3-kinase, was dramatically reduced in obese nondiabetics and virtually absent in type 2 diabetic patients. |
| 3509 | 10675357 | Insulin stimulation of the MAP kinase pathway was normal in obese and diabetic subjects. |
| 3510 | 10675357 | Insulin stimulation of glucose-disposal correlated with association of p85 with IRS-1. |
| 3511 | 10675357 | Exercise 24 hours before the euglycemic clamp increased phosphorylation of insulin receptor and IRS-1 in obese and diabetic subjects but did not increase glucose uptake or PI 3-kinase association with IRS-1 upon insulin stimulation. |
| 3512 | 10675357 | Thus, insulin resistance differentially affects the PI 3-kinase and MAP kinase signaling pathways, and insulin-stimulated IRS-1-association with PI 3-kinase defines a key step in insulin resistance. |
| 3513 | 10675357 | Insulin resistance differentially affects the PI 3-kinase- and MAP kinase-mediated signaling in human muscle. |
| 3514 | 10675357 | Insulin stimulation of the phosphatidylinositol 3-kinase (PI 3-kinase) pathway, as measured by phosphorylation of the insulin receptor and IRS-1 and by IRS protein association with p85 and with PI 3-kinase, was dramatically reduced in obese nondiabetics and virtually absent in type 2 diabetic patients. |
| 3515 | 10675357 | Insulin stimulation of the MAP kinase pathway was normal in obese and diabetic subjects. |
| 3516 | 10675357 | Insulin stimulation of glucose-disposal correlated with association of p85 with IRS-1. |
| 3517 | 10675357 | Exercise 24 hours before the euglycemic clamp increased phosphorylation of insulin receptor and IRS-1 in obese and diabetic subjects but did not increase glucose uptake or PI 3-kinase association with IRS-1 upon insulin stimulation. |
| 3518 | 10675357 | Thus, insulin resistance differentially affects the PI 3-kinase and MAP kinase signaling pathways, and insulin-stimulated IRS-1-association with PI 3-kinase defines a key step in insulin resistance. |
| 3519 | 10688912 | Selective interaction between leptin and insulin signaling pathways in a hepatic cell line. |
| 3520 | 10688912 | Leptin is a 16-kDa hormone secreted by adipocytes and plays an important role in control of feeding behavior and energy expenditure. |
| 3521 | 10688912 | In obesity, circulating levels of leptin and insulin are high because of the presence of increased body fat mass and insulin resistance. |
| 3522 | 10688912 | Recent reports have suggested that leptin can act through some of the components of the insulin signaling cascade, such as insulin receptor substrates (IRS-1 and IRS-2), phosphatidylinositol 3-kinase (PI 3-kinase), and mitogen-activated protein kinase, and can modify insulin-induced changes in gene expression in vitro and in vivo. |
| 3523 | 10688912 | Well differentiated hepatoma cells (Fao) possess both the long and short forms of the leptin receptor and respond to leptin with a stimulation of c-fos gene expression. |
| 3524 | 10688912 | In Fao cells, leptin alone had no effects on the insulin signaling pathway, but leptin pretreatment transiently enhanced insulin-induced tyrosine phosphorylation and PI 3-kinase binding to IRS-1, while producing an inhibition of tyrosine phosphorylation and PI 3-kinase binding to IRS-2. |
| 3525 | 10688912 | Leptin alone also induced serine phosphorylation of Akt and glycogen synthase kinase 3 but to a lesser extent than insulin, and the combination of these hormones was not additive. |
| 3526 | 10688912 | These results suggest complex interactions between the leptin and insulin signaling pathways that can potentially lead to differential modification of the metabolic and mitotic effects of insulin exerted through IRS-1 and IRS-2 and the downstream kinases that they activate. |
| 3527 | 10688912 | Selective interaction between leptin and insulin signaling pathways in a hepatic cell line. |
| 3528 | 10688912 | Leptin is a 16-kDa hormone secreted by adipocytes and plays an important role in control of feeding behavior and energy expenditure. |
| 3529 | 10688912 | In obesity, circulating levels of leptin and insulin are high because of the presence of increased body fat mass and insulin resistance. |
| 3530 | 10688912 | Recent reports have suggested that leptin can act through some of the components of the insulin signaling cascade, such as insulin receptor substrates (IRS-1 and IRS-2), phosphatidylinositol 3-kinase (PI 3-kinase), and mitogen-activated protein kinase, and can modify insulin-induced changes in gene expression in vitro and in vivo. |
| 3531 | 10688912 | Well differentiated hepatoma cells (Fao) possess both the long and short forms of the leptin receptor and respond to leptin with a stimulation of c-fos gene expression. |
| 3532 | 10688912 | In Fao cells, leptin alone had no effects on the insulin signaling pathway, but leptin pretreatment transiently enhanced insulin-induced tyrosine phosphorylation and PI 3-kinase binding to IRS-1, while producing an inhibition of tyrosine phosphorylation and PI 3-kinase binding to IRS-2. |
| 3533 | 10688912 | Leptin alone also induced serine phosphorylation of Akt and glycogen synthase kinase 3 but to a lesser extent than insulin, and the combination of these hormones was not additive. |
| 3534 | 10688912 | These results suggest complex interactions between the leptin and insulin signaling pathways that can potentially lead to differential modification of the metabolic and mitotic effects of insulin exerted through IRS-1 and IRS-2 and the downstream kinases that they activate. |
| 3535 | 10688912 | Selective interaction between leptin and insulin signaling pathways in a hepatic cell line. |
| 3536 | 10688912 | Leptin is a 16-kDa hormone secreted by adipocytes and plays an important role in control of feeding behavior and energy expenditure. |
| 3537 | 10688912 | In obesity, circulating levels of leptin and insulin are high because of the presence of increased body fat mass and insulin resistance. |
| 3538 | 10688912 | Recent reports have suggested that leptin can act through some of the components of the insulin signaling cascade, such as insulin receptor substrates (IRS-1 and IRS-2), phosphatidylinositol 3-kinase (PI 3-kinase), and mitogen-activated protein kinase, and can modify insulin-induced changes in gene expression in vitro and in vivo. |
| 3539 | 10688912 | Well differentiated hepatoma cells (Fao) possess both the long and short forms of the leptin receptor and respond to leptin with a stimulation of c-fos gene expression. |
| 3540 | 10688912 | In Fao cells, leptin alone had no effects on the insulin signaling pathway, but leptin pretreatment transiently enhanced insulin-induced tyrosine phosphorylation and PI 3-kinase binding to IRS-1, while producing an inhibition of tyrosine phosphorylation and PI 3-kinase binding to IRS-2. |
| 3541 | 10688912 | Leptin alone also induced serine phosphorylation of Akt and glycogen synthase kinase 3 but to a lesser extent than insulin, and the combination of these hormones was not additive. |
| 3542 | 10688912 | These results suggest complex interactions between the leptin and insulin signaling pathways that can potentially lead to differential modification of the metabolic and mitotic effects of insulin exerted through IRS-1 and IRS-2 and the downstream kinases that they activate. |
| 3543 | 10694991 | Recent progress suggests that postreceptor mechanisms that contribute to insulin resistance of pregnancy appear to be multifactorial, but are exerted at the beta-subunit of the insulin receptor and at the level of IRS-1. |
| 3544 | 10694991 | Results also suggest that increased insulin receptor serine/threonine phosphorylation and PC-1 could underlie the insulin resistance of pregnancy and pathogenesis of GDM. |
| 3545 | 10698715 | Initial signalling events of insulin action, including receptor kinase activation, the tyrosine phosphorylation of insulin receptor substrate (IRS)-1 and IRS-2 and the recruitment of PI-3K to IRS-1 and IRS-2, were found not to be involved in contraction-mediated signalling. |
| 3546 | 10707549 | Since the molecular mechanism of insulin resistance is still unknown, insulin receptor dysfunction including abnormal IRS-1 phosphorylation is considered to be responsible for insulin resistance in some pathological states. |
| 3547 | 10707549 | Regarding the mechanism of insulin resistance related obesity, the increased expression of Tumor necrosis factor alpha and abnormality in PTPase in skeletal muscle are postulated. |
| 3548 | 10707551 | Genetic factors affecting the insulin sensitivities have been described, including the mutations of genes of insulin receptor, insulin receptor substrate-1, glycogen synthase, uncoupling proteins, beta3-adrenergic receptor, and peroxisome proliferator-activated receptor gamma. |
| 3549 | 10722680 | Both of these abnormalities were associated with defects in insulin activation of insulin receptor substrate-1 and -2-associated phosphatidylinositol 3-kinase activity and a 2-fold increase in muscle and liver triglyceride content. |
| 3550 | 10722680 | In conclusion, these results suggest that the development of insulin resistance in type 2 diabetes may be due to alterations in the partitioning of fat between the adipocyte and muscle/liver leading to accumulation of triglyceride in the latter tissues with subsequent impairment of insulin signaling and action. |
| 3551 | 10722755 | The c-Jun NH(2)-terminal kinase promotes insulin resistance during association with insulin receptor substrate-1 and phosphorylation of Ser(307). |
| 3552 | 10722755 | Tumor necrosis factor alpha (TNFalpha) inhibits insulin action, in part, through serine phosphorylation of IRS proteins; however, the phosphorylation sites that mediate the inhibition are unknown. |
| 3553 | 10722755 | TNFalpha promotes multipotential signal transduction cascades, including the activation of the Jun NH(2)-terminal kinase (JNK). |
| 3554 | 10722755 | Endogenous JNK associates with IRS-1 in Chinese hamster ovary cells. |
| 3555 | 10722755 | Anisomycin, a strong activator of JNK in these cells, stimulates the activity of JNK bound to IRS-1 and inhibits the insulin-stimulated tyrosine phosphorylation of IRS-1. |
| 3556 | 10722755 | Serine 307 is a major site of JNK phosphorylation in IRS-1. |
| 3557 | 10722755 | Mutation of serine 307 to alanine eliminates phosphorylation of IRS-1 by JNK and abrogates the inhibitory effect of TNFalpha on insulin-stimulated tyrosine phosphorylation of IRS-1. |
| 3558 | 10722755 | These results suggest that phosphorylation of serine 307 might mediate, at least partially, the inhibitory effect of proinflammatory cytokines like TNFalpha on IRS-1 function. |
| 3559 | 10722755 | The c-Jun NH(2)-terminal kinase promotes insulin resistance during association with insulin receptor substrate-1 and phosphorylation of Ser(307). |
| 3560 | 10722755 | Tumor necrosis factor alpha (TNFalpha) inhibits insulin action, in part, through serine phosphorylation of IRS proteins; however, the phosphorylation sites that mediate the inhibition are unknown. |
| 3561 | 10722755 | TNFalpha promotes multipotential signal transduction cascades, including the activation of the Jun NH(2)-terminal kinase (JNK). |
| 3562 | 10722755 | Endogenous JNK associates with IRS-1 in Chinese hamster ovary cells. |
| 3563 | 10722755 | Anisomycin, a strong activator of JNK in these cells, stimulates the activity of JNK bound to IRS-1 and inhibits the insulin-stimulated tyrosine phosphorylation of IRS-1. |
| 3564 | 10722755 | Serine 307 is a major site of JNK phosphorylation in IRS-1. |
| 3565 | 10722755 | Mutation of serine 307 to alanine eliminates phosphorylation of IRS-1 by JNK and abrogates the inhibitory effect of TNFalpha on insulin-stimulated tyrosine phosphorylation of IRS-1. |
| 3566 | 10722755 | These results suggest that phosphorylation of serine 307 might mediate, at least partially, the inhibitory effect of proinflammatory cytokines like TNFalpha on IRS-1 function. |
| 3567 | 10722755 | The c-Jun NH(2)-terminal kinase promotes insulin resistance during association with insulin receptor substrate-1 and phosphorylation of Ser(307). |
| 3568 | 10722755 | Tumor necrosis factor alpha (TNFalpha) inhibits insulin action, in part, through serine phosphorylation of IRS proteins; however, the phosphorylation sites that mediate the inhibition are unknown. |
| 3569 | 10722755 | TNFalpha promotes multipotential signal transduction cascades, including the activation of the Jun NH(2)-terminal kinase (JNK). |
| 3570 | 10722755 | Endogenous JNK associates with IRS-1 in Chinese hamster ovary cells. |
| 3571 | 10722755 | Anisomycin, a strong activator of JNK in these cells, stimulates the activity of JNK bound to IRS-1 and inhibits the insulin-stimulated tyrosine phosphorylation of IRS-1. |
| 3572 | 10722755 | Serine 307 is a major site of JNK phosphorylation in IRS-1. |
| 3573 | 10722755 | Mutation of serine 307 to alanine eliminates phosphorylation of IRS-1 by JNK and abrogates the inhibitory effect of TNFalpha on insulin-stimulated tyrosine phosphorylation of IRS-1. |
| 3574 | 10722755 | These results suggest that phosphorylation of serine 307 might mediate, at least partially, the inhibitory effect of proinflammatory cytokines like TNFalpha on IRS-1 function. |
| 3575 | 10722755 | The c-Jun NH(2)-terminal kinase promotes insulin resistance during association with insulin receptor substrate-1 and phosphorylation of Ser(307). |
| 3576 | 10722755 | Tumor necrosis factor alpha (TNFalpha) inhibits insulin action, in part, through serine phosphorylation of IRS proteins; however, the phosphorylation sites that mediate the inhibition are unknown. |
| 3577 | 10722755 | TNFalpha promotes multipotential signal transduction cascades, including the activation of the Jun NH(2)-terminal kinase (JNK). |
| 3578 | 10722755 | Endogenous JNK associates with IRS-1 in Chinese hamster ovary cells. |
| 3579 | 10722755 | Anisomycin, a strong activator of JNK in these cells, stimulates the activity of JNK bound to IRS-1 and inhibits the insulin-stimulated tyrosine phosphorylation of IRS-1. |
| 3580 | 10722755 | Serine 307 is a major site of JNK phosphorylation in IRS-1. |
| 3581 | 10722755 | Mutation of serine 307 to alanine eliminates phosphorylation of IRS-1 by JNK and abrogates the inhibitory effect of TNFalpha on insulin-stimulated tyrosine phosphorylation of IRS-1. |
| 3582 | 10722755 | These results suggest that phosphorylation of serine 307 might mediate, at least partially, the inhibitory effect of proinflammatory cytokines like TNFalpha on IRS-1 function. |
| 3583 | 10722755 | The c-Jun NH(2)-terminal kinase promotes insulin resistance during association with insulin receptor substrate-1 and phosphorylation of Ser(307). |
| 3584 | 10722755 | Tumor necrosis factor alpha (TNFalpha) inhibits insulin action, in part, through serine phosphorylation of IRS proteins; however, the phosphorylation sites that mediate the inhibition are unknown. |
| 3585 | 10722755 | TNFalpha promotes multipotential signal transduction cascades, including the activation of the Jun NH(2)-terminal kinase (JNK). |
| 3586 | 10722755 | Endogenous JNK associates with IRS-1 in Chinese hamster ovary cells. |
| 3587 | 10722755 | Anisomycin, a strong activator of JNK in these cells, stimulates the activity of JNK bound to IRS-1 and inhibits the insulin-stimulated tyrosine phosphorylation of IRS-1. |
| 3588 | 10722755 | Serine 307 is a major site of JNK phosphorylation in IRS-1. |
| 3589 | 10722755 | Mutation of serine 307 to alanine eliminates phosphorylation of IRS-1 by JNK and abrogates the inhibitory effect of TNFalpha on insulin-stimulated tyrosine phosphorylation of IRS-1. |
| 3590 | 10722755 | These results suggest that phosphorylation of serine 307 might mediate, at least partially, the inhibitory effect of proinflammatory cytokines like TNFalpha on IRS-1 function. |
| 3591 | 10722755 | The c-Jun NH(2)-terminal kinase promotes insulin resistance during association with insulin receptor substrate-1 and phosphorylation of Ser(307). |
| 3592 | 10722755 | Tumor necrosis factor alpha (TNFalpha) inhibits insulin action, in part, through serine phosphorylation of IRS proteins; however, the phosphorylation sites that mediate the inhibition are unknown. |
| 3593 | 10722755 | TNFalpha promotes multipotential signal transduction cascades, including the activation of the Jun NH(2)-terminal kinase (JNK). |
| 3594 | 10722755 | Endogenous JNK associates with IRS-1 in Chinese hamster ovary cells. |
| 3595 | 10722755 | Anisomycin, a strong activator of JNK in these cells, stimulates the activity of JNK bound to IRS-1 and inhibits the insulin-stimulated tyrosine phosphorylation of IRS-1. |
| 3596 | 10722755 | Serine 307 is a major site of JNK phosphorylation in IRS-1. |
| 3597 | 10722755 | Mutation of serine 307 to alanine eliminates phosphorylation of IRS-1 by JNK and abrogates the inhibitory effect of TNFalpha on insulin-stimulated tyrosine phosphorylation of IRS-1. |
| 3598 | 10722755 | These results suggest that phosphorylation of serine 307 might mediate, at least partially, the inhibitory effect of proinflammatory cytokines like TNFalpha on IRS-1 function. |
| 3599 | 10726921 | In muscle obtained during clamp studies prior to vanadium therapy, insulin stimulated the tyrosine phosphorylation of the insulin receptor, insulin receptor substrate-1 (IRS-1), and Shc proteins by 2- to 3-fold, while phosphatidylinositol 3-kinase (PI 3-kinase) activity associated with IRS-1 increased 4.7-fold during insulin stimulation (P = .02). |
| 3600 | 10726921 | Following vanadium, there was a consistent trend for increased basal levels of insulin receptor, Shc, and IRS-1 protein tyrosine phosphorylation and IRS-1-associated PI 3-kinase, but no further increase with insulin. |
| 3601 | 10726921 | Vanadyl modifies proteins in human skeletal muscle involved in early insulin signaling, including basal insulin receptor and substrate tyrosine phosphorylation and activation of PI 3-kinase, and is not additive or synergistic with insulin at these steps. |
| 3602 | 10726921 | In muscle obtained during clamp studies prior to vanadium therapy, insulin stimulated the tyrosine phosphorylation of the insulin receptor, insulin receptor substrate-1 (IRS-1), and Shc proteins by 2- to 3-fold, while phosphatidylinositol 3-kinase (PI 3-kinase) activity associated with IRS-1 increased 4.7-fold during insulin stimulation (P = .02). |
| 3603 | 10726921 | Following vanadium, there was a consistent trend for increased basal levels of insulin receptor, Shc, and IRS-1 protein tyrosine phosphorylation and IRS-1-associated PI 3-kinase, but no further increase with insulin. |
| 3604 | 10726921 | Vanadyl modifies proteins in human skeletal muscle involved in early insulin signaling, including basal insulin receptor and substrate tyrosine phosphorylation and activation of PI 3-kinase, and is not additive or synergistic with insulin at these steps. |
| 3605 | 10744689 | Phosphorylation of PDE3B by phosphatidylinositol 3-kinase associated with the insulin receptor. |
| 3606 | 10744689 | Phosphatidylinositol 3-kinase mediates several actions of insulin including its antilipolytic effect. |
| 3607 | 10744689 | This effect is elicited by the insulin-stimulated serine phosphorylation and activation of cGMP-inhibited phosphodiesterase (PDE3B). |
| 3608 | 10744689 | In human adipocytes, we found that insulin differentially stimulated phosphatidylinositol 3-kinase activity; the lipid kinase activity was associated with IRS-1, whereas the serine kinase activity was associated with the insulin receptor and phosphorylated a number of proteins including p85, p110, and a 135-kDa protein identified as PDE3B. |
| 3609 | 10744748 | The insulin receptor substrate (IRS) family of proteins mediate a variety of intracellular signaling events by serving as signaling platforms downstream of several receptor tyrosine kinases including the insulin and insulin-like growth factor-1 (IGF-1) receptors. |
| 3610 | 10744748 | Recently, several new members of this family have been identified including IRS-3, IRS-4, and growth factor receptor-binding protein 2-associated binder-1 (Gab-1). 3T3 cell lines derived from IRS-1-deficient embryos exhibit a 70-80% reduction in IGF-1-stimulated S-phase entry and a parallel decrease in the induction of the immediate-early genes c-fos and egr-1 but unaltered activation of the mitogen-activated protein kinases extracellular signal-regulated kinase-1 and extracellular signal-regulated kinase-2. |
| 3611 | 10744748 | Overexpression of Gab-1 in IRS-1-deficient fibroblasts also results in the restoration of egr-1 induction to levels similar to those achieved by IRS-1 reconstitution and markedly increases IGF-1-stimulated S-phase progression. |
| 3612 | 10744748 | Gab-1 is capable of regulating these biological end points despite the absence of IGF-1 stimulated tyrosine phosphorylation. |
| 3613 | 10744748 | These data provide evidence that Gab-1 may serve as a unique signaling intermediate in insulin/IGF-1 signaling for induction of early gene expression and stimulation of mitogenesis without direct tyrosine phosphorylation. |
| 3614 | 10751417 | Overexpression of protein-tyrosine phosphatase-1B in adipocytes inhibits insulin-stimulated phosphoinositide 3-kinase activity without altering glucose transport or Akt/Protein kinase B activation. |
| 3615 | 10751417 | Previous studies suggested that protein-tyrosine phosphatase 1B (PTP1B) antagonizes insulin action by catalyzing dephosphorylation of the insulin receptor (IR) and/or other key proteins in the insulin signaling pathway. |
| 3616 | 10751417 | In adipose tissue and muscle of obese humans and rodents, PTP1B expression is increased, which led to the hypothesis that PTP1B plays a role in the pathogenesis of insulin resistance. |
| 3617 | 10751417 | Consistent with this, mice in which the PTP1B gene was disrupted exhibit increased insulin sensitivity. |
| 3618 | 10751417 | To test whether increased expression of PTP1B in an insulin-sensitive cell type could contribute to insulin resistance, we overexpressed wild-type PTP1B in 3T3L1 adipocytes using adenovirus-mediated gene delivery. |
| 3619 | 10751417 | Compared with control cells, cells expressing high levels of PTP1B showed a 50-60% decrease in maximally insulin-stimulated tyrosyl phosphorylation of IR and insulin receptor substrate-1 (IRS-1) and phosphoinositide 3-kinase (PI3K) activity associated with IRS-1 or with phosphotyrosine. |
| 3620 | 10751417 | Phosphorylation of p42 and p44 MAP kinase (MAPK) was reduced approximately 32%. |
| 3621 | 10751417 | Overexpression of PTP1B had no effect on basal, submaximally or maximally (100 nm) insulin-stimulated glucose transport or on the EC(50) for transport. |
| 3622 | 10751417 | Our results suggest that: 1) insulin stimulation of glucose transport in adipocytes requires </=45% of maximal tyrosyl phosphorylation of IR or IRS-1 and <50% of maximal activation of PI3K, 2) a novel PI3K-independent pathway may play a role in insulin-induced glucose transport in adipocytes, and 3) overexpression of PTP1B alone in adipocytes does not impair glucose transport. |
| 3623 | 10751417 | Overexpression of protein-tyrosine phosphatase-1B in adipocytes inhibits insulin-stimulated phosphoinositide 3-kinase activity without altering glucose transport or Akt/Protein kinase B activation. |
| 3624 | 10751417 | Previous studies suggested that protein-tyrosine phosphatase 1B (PTP1B) antagonizes insulin action by catalyzing dephosphorylation of the insulin receptor (IR) and/or other key proteins in the insulin signaling pathway. |
| 3625 | 10751417 | In adipose tissue and muscle of obese humans and rodents, PTP1B expression is increased, which led to the hypothesis that PTP1B plays a role in the pathogenesis of insulin resistance. |
| 3626 | 10751417 | Consistent with this, mice in which the PTP1B gene was disrupted exhibit increased insulin sensitivity. |
| 3627 | 10751417 | To test whether increased expression of PTP1B in an insulin-sensitive cell type could contribute to insulin resistance, we overexpressed wild-type PTP1B in 3T3L1 adipocytes using adenovirus-mediated gene delivery. |
| 3628 | 10751417 | Compared with control cells, cells expressing high levels of PTP1B showed a 50-60% decrease in maximally insulin-stimulated tyrosyl phosphorylation of IR and insulin receptor substrate-1 (IRS-1) and phosphoinositide 3-kinase (PI3K) activity associated with IRS-1 or with phosphotyrosine. |
| 3629 | 10751417 | Phosphorylation of p42 and p44 MAP kinase (MAPK) was reduced approximately 32%. |
| 3630 | 10751417 | Overexpression of PTP1B had no effect on basal, submaximally or maximally (100 nm) insulin-stimulated glucose transport or on the EC(50) for transport. |
| 3631 | 10751417 | Our results suggest that: 1) insulin stimulation of glucose transport in adipocytes requires </=45% of maximal tyrosyl phosphorylation of IR or IRS-1 and <50% of maximal activation of PI3K, 2) a novel PI3K-independent pathway may play a role in insulin-induced glucose transport in adipocytes, and 3) overexpression of PTP1B alone in adipocytes does not impair glucose transport. |
| 3632 | 10802154 | We have previously shown that bradykinin potentiated insulin-induced glucose uptake through GLUT4 translocation in canine adipocytes and skeletal muscles. |
| 3633 | 10802154 | For this purpose, 32D cells, which express a limited number of insulin receptors and lack endogenous bradykinin B2 receptor (BK2R) or insulin receptor substrate (IRS)-1 were transfected with BK2R cDNA and/or insulin receptor cDNA and/or IRS-1 cDNA, and analyzed. |
| 3634 | 10802154 | In 32D cells that expressed BK2R and insulin receptor (32D-BKR/IR), bradykinin alone had no effect on the phosphorylation of the insulin receptor, but it enhanced insulin-stimulated tyrosine phosphorylation of the insulin receptor. |
| 3635 | 10802154 | In 32D cells that expressed BK2R, insulin receptor and IRS-1 (32D-BKR/IR/IRS1), bradykinin also enhanced insulin-stimulated tyrosine phosphorylation of the insulin receptor and IRS-1. |
| 3636 | 10802154 | An increase in insulin-stimulated phosphorylation of IRS-1 by treatment with bradykinin in 32D-BKR/IR/IRS1 cell was associated with increased binding of 85 kD subunit of phosphatidylinositol 3 (PI 3)-kinase and increased IRS-1 associated PI 3-kinase activity. |
| 3637 | 10802154 | These effects of bradykinin were not observed in 32D cells which lack the expression of BK2R (32D-IR/IRS1) or insulin receptor (32D-BKR/IRS1). |
| 3638 | 10802154 | Our results clearly demonstrated that bradykinin enhanced insulin-stimulated tyrosine kinase activity of the insulin receptor and downstream insulin signal cascade through the BK2R mediated signal pathway. |
| 3639 | 10802154 | We have previously shown that bradykinin potentiated insulin-induced glucose uptake through GLUT4 translocation in canine adipocytes and skeletal muscles. |
| 3640 | 10802154 | For this purpose, 32D cells, which express a limited number of insulin receptors and lack endogenous bradykinin B2 receptor (BK2R) or insulin receptor substrate (IRS)-1 were transfected with BK2R cDNA and/or insulin receptor cDNA and/or IRS-1 cDNA, and analyzed. |
| 3641 | 10802154 | In 32D cells that expressed BK2R and insulin receptor (32D-BKR/IR), bradykinin alone had no effect on the phosphorylation of the insulin receptor, but it enhanced insulin-stimulated tyrosine phosphorylation of the insulin receptor. |
| 3642 | 10802154 | In 32D cells that expressed BK2R, insulin receptor and IRS-1 (32D-BKR/IR/IRS1), bradykinin also enhanced insulin-stimulated tyrosine phosphorylation of the insulin receptor and IRS-1. |
| 3643 | 10802154 | An increase in insulin-stimulated phosphorylation of IRS-1 by treatment with bradykinin in 32D-BKR/IR/IRS1 cell was associated with increased binding of 85 kD subunit of phosphatidylinositol 3 (PI 3)-kinase and increased IRS-1 associated PI 3-kinase activity. |
| 3644 | 10802154 | These effects of bradykinin were not observed in 32D cells which lack the expression of BK2R (32D-IR/IRS1) or insulin receptor (32D-BKR/IRS1). |
| 3645 | 10802154 | Our results clearly demonstrated that bradykinin enhanced insulin-stimulated tyrosine kinase activity of the insulin receptor and downstream insulin signal cascade through the BK2R mediated signal pathway. |
| 3646 | 10802154 | We have previously shown that bradykinin potentiated insulin-induced glucose uptake through GLUT4 translocation in canine adipocytes and skeletal muscles. |
| 3647 | 10802154 | For this purpose, 32D cells, which express a limited number of insulin receptors and lack endogenous bradykinin B2 receptor (BK2R) or insulin receptor substrate (IRS)-1 were transfected with BK2R cDNA and/or insulin receptor cDNA and/or IRS-1 cDNA, and analyzed. |
| 3648 | 10802154 | In 32D cells that expressed BK2R and insulin receptor (32D-BKR/IR), bradykinin alone had no effect on the phosphorylation of the insulin receptor, but it enhanced insulin-stimulated tyrosine phosphorylation of the insulin receptor. |
| 3649 | 10802154 | In 32D cells that expressed BK2R, insulin receptor and IRS-1 (32D-BKR/IR/IRS1), bradykinin also enhanced insulin-stimulated tyrosine phosphorylation of the insulin receptor and IRS-1. |
| 3650 | 10802154 | An increase in insulin-stimulated phosphorylation of IRS-1 by treatment with bradykinin in 32D-BKR/IR/IRS1 cell was associated with increased binding of 85 kD subunit of phosphatidylinositol 3 (PI 3)-kinase and increased IRS-1 associated PI 3-kinase activity. |
| 3651 | 10802154 | These effects of bradykinin were not observed in 32D cells which lack the expression of BK2R (32D-IR/IRS1) or insulin receptor (32D-BKR/IRS1). |
| 3652 | 10802154 | Our results clearly demonstrated that bradykinin enhanced insulin-stimulated tyrosine kinase activity of the insulin receptor and downstream insulin signal cascade through the BK2R mediated signal pathway. |
| 3653 | 10802154 | We have previously shown that bradykinin potentiated insulin-induced glucose uptake through GLUT4 translocation in canine adipocytes and skeletal muscles. |
| 3654 | 10802154 | For this purpose, 32D cells, which express a limited number of insulin receptors and lack endogenous bradykinin B2 receptor (BK2R) or insulin receptor substrate (IRS)-1 were transfected with BK2R cDNA and/or insulin receptor cDNA and/or IRS-1 cDNA, and analyzed. |
| 3655 | 10802154 | In 32D cells that expressed BK2R and insulin receptor (32D-BKR/IR), bradykinin alone had no effect on the phosphorylation of the insulin receptor, but it enhanced insulin-stimulated tyrosine phosphorylation of the insulin receptor. |
| 3656 | 10802154 | In 32D cells that expressed BK2R, insulin receptor and IRS-1 (32D-BKR/IR/IRS1), bradykinin also enhanced insulin-stimulated tyrosine phosphorylation of the insulin receptor and IRS-1. |
| 3657 | 10802154 | An increase in insulin-stimulated phosphorylation of IRS-1 by treatment with bradykinin in 32D-BKR/IR/IRS1 cell was associated with increased binding of 85 kD subunit of phosphatidylinositol 3 (PI 3)-kinase and increased IRS-1 associated PI 3-kinase activity. |
| 3658 | 10802154 | These effects of bradykinin were not observed in 32D cells which lack the expression of BK2R (32D-IR/IRS1) or insulin receptor (32D-BKR/IRS1). |
| 3659 | 10802154 | Our results clearly demonstrated that bradykinin enhanced insulin-stimulated tyrosine kinase activity of the insulin receptor and downstream insulin signal cascade through the BK2R mediated signal pathway. |
| 3660 | 10811851 | Expression of an IRS-1 mutant (IRS-1Deltap85) lacking the binding site for the p85 subunit of phosphatidylinositol 3-kinase (PI3K) also restored insulin sensitivity, although PI3K is known to play a crucial role in insulin's metabolic responses. |
| 3661 | 10811851 | Protein kinase B (PKB) activity in liver was decreased in null mice compared with the wild-type and the null mice expressing IRS-1 or IRS-1Deltap85. |
| 3662 | 10811851 | In primary hepatocytes isolated from null mice, expression of IRS-1 enhanced both PI3K and PKB activities, but expression of IRS-1Deltap85 enhanced only PKB. |
| 3663 | 10811851 | These data suggest that PKB in liver plays a pivotal role in systemic glucose homeostasis and that PKB activation might be sufficient for reducing insulin resistance even without full activation of PI3K. |
| 3664 | 10811851 | Expression of an IRS-1 mutant (IRS-1Deltap85) lacking the binding site for the p85 subunit of phosphatidylinositol 3-kinase (PI3K) also restored insulin sensitivity, although PI3K is known to play a crucial role in insulin's metabolic responses. |
| 3665 | 10811851 | Protein kinase B (PKB) activity in liver was decreased in null mice compared with the wild-type and the null mice expressing IRS-1 or IRS-1Deltap85. |
| 3666 | 10811851 | In primary hepatocytes isolated from null mice, expression of IRS-1 enhanced both PI3K and PKB activities, but expression of IRS-1Deltap85 enhanced only PKB. |
| 3667 | 10811851 | These data suggest that PKB in liver plays a pivotal role in systemic glucose homeostasis and that PKB activation might be sufficient for reducing insulin resistance even without full activation of PI3K. |
| 3668 | 10811851 | Expression of an IRS-1 mutant (IRS-1Deltap85) lacking the binding site for the p85 subunit of phosphatidylinositol 3-kinase (PI3K) also restored insulin sensitivity, although PI3K is known to play a crucial role in insulin's metabolic responses. |
| 3669 | 10811851 | Protein kinase B (PKB) activity in liver was decreased in null mice compared with the wild-type and the null mice expressing IRS-1 or IRS-1Deltap85. |
| 3670 | 10811851 | In primary hepatocytes isolated from null mice, expression of IRS-1 enhanced both PI3K and PKB activities, but expression of IRS-1Deltap85 enhanced only PKB. |
| 3671 | 10811851 | These data suggest that PKB in liver plays a pivotal role in systemic glucose homeostasis and that PKB activation might be sufficient for reducing insulin resistance even without full activation of PI3K. |
| 3672 | 10813377 | In vascular smooth muscle cells (VSMCs), insulin transduces a mitogenic signal that is dependent on the ERK1/2 MAP kinases. |
| 3673 | 10813377 | TRO at I and 10 microM had no significant effect on insulin-stimulated ERK1/2 activity. |
| 3674 | 10813377 | At 20 microM, however, TRO modestly enhanced insulin-stimulated ERK1/2 activity by 1.5-fold. |
| 3675 | 10813377 | TRO at 1-20 microM potently inhibited insulin-stimulated, ERK1/2-dependent Elk-1 transcription factor activity. |
| 3676 | 10813377 | Neither early steps in insulin signaling nor the phosphatidylinositol 3-kinase (PI3K) branch of this pathway were affected by TRO, because it had no effect on IRS-1 phosphorylation, PI3K/IRS-1 association, or Akt phosphorylation. |
| 3677 | 10813377 | In summary, these data show that TRO inhibits mitogenic signaling by insulin at a point distal of ERK1/2 activation, potentially by a PPARgamma-mediated inhibition of ERK-dependent phosphorylation and activation of nuclear transcription factors that regulate cell growth. |
| 3678 | 10826514 | A study on the genetics of obesity: influence of polymorphisms of the beta-3-adrenergic receptor and insulin receptor substrate 1 in relation to weight loss, waist to hip ratio and frequencies of common cardiovascular risk factors. |
| 3679 | 10826514 | Beta-3-adrenergic receptor (beta-3-AR) and insulin receptor substrate 1 (IRS-1) have been implicated in the pathogenesis of obesity and in obesity related increase in insulin resistance which is associated with, among other diseases, dyslipidemia and type 2 diabetes mellitus. |
| 3680 | 10826514 | We examined the association between mutations of the IRS-1 gene at codon 972, mutations of the beta-3-AR gene at codon 64, and the combination of both mutations with the degree of weight loss, waist to hip ratio and the prevalence of hypertension, dyslipidemia and type 2 diabetes mellitus. |
| 3681 | 10826514 | Twenty-four women (11.4%) were polymorph only for the beta-3-AR mutation, 23 women (10.9%) only for the IRS-1 mutation, and 6 subjects (2.9%) were polymorph for both alleles. |
| 3682 | 10826514 | Our findings suggest there is a synergy between the polymorphisms of Trp64Arg beta-3-AR and Gly972Arg IRS-1 in Caucasian German obese women leading to a decreased weight loss. |
| 3683 | 10826514 | A study on the genetics of obesity: influence of polymorphisms of the beta-3-adrenergic receptor and insulin receptor substrate 1 in relation to weight loss, waist to hip ratio and frequencies of common cardiovascular risk factors. |
| 3684 | 10826514 | Beta-3-adrenergic receptor (beta-3-AR) and insulin receptor substrate 1 (IRS-1) have been implicated in the pathogenesis of obesity and in obesity related increase in insulin resistance which is associated with, among other diseases, dyslipidemia and type 2 diabetes mellitus. |
| 3685 | 10826514 | We examined the association between mutations of the IRS-1 gene at codon 972, mutations of the beta-3-AR gene at codon 64, and the combination of both mutations with the degree of weight loss, waist to hip ratio and the prevalence of hypertension, dyslipidemia and type 2 diabetes mellitus. |
| 3686 | 10826514 | Twenty-four women (11.4%) were polymorph only for the beta-3-AR mutation, 23 women (10.9%) only for the IRS-1 mutation, and 6 subjects (2.9%) were polymorph for both alleles. |
| 3687 | 10826514 | Our findings suggest there is a synergy between the polymorphisms of Trp64Arg beta-3-AR and Gly972Arg IRS-1 in Caucasian German obese women leading to a decreased weight loss. |
| 3688 | 10826514 | A study on the genetics of obesity: influence of polymorphisms of the beta-3-adrenergic receptor and insulin receptor substrate 1 in relation to weight loss, waist to hip ratio and frequencies of common cardiovascular risk factors. |
| 3689 | 10826514 | Beta-3-adrenergic receptor (beta-3-AR) and insulin receptor substrate 1 (IRS-1) have been implicated in the pathogenesis of obesity and in obesity related increase in insulin resistance which is associated with, among other diseases, dyslipidemia and type 2 diabetes mellitus. |
| 3690 | 10826514 | We examined the association between mutations of the IRS-1 gene at codon 972, mutations of the beta-3-AR gene at codon 64, and the combination of both mutations with the degree of weight loss, waist to hip ratio and the prevalence of hypertension, dyslipidemia and type 2 diabetes mellitus. |
| 3691 | 10826514 | Twenty-four women (11.4%) were polymorph only for the beta-3-AR mutation, 23 women (10.9%) only for the IRS-1 mutation, and 6 subjects (2.9%) were polymorph for both alleles. |
| 3692 | 10826514 | Our findings suggest there is a synergy between the polymorphisms of Trp64Arg beta-3-AR and Gly972Arg IRS-1 in Caucasian German obese women leading to a decreased weight loss. |
| 3693 | 10826514 | A study on the genetics of obesity: influence of polymorphisms of the beta-3-adrenergic receptor and insulin receptor substrate 1 in relation to weight loss, waist to hip ratio and frequencies of common cardiovascular risk factors. |
| 3694 | 10826514 | Beta-3-adrenergic receptor (beta-3-AR) and insulin receptor substrate 1 (IRS-1) have been implicated in the pathogenesis of obesity and in obesity related increase in insulin resistance which is associated with, among other diseases, dyslipidemia and type 2 diabetes mellitus. |
| 3695 | 10826514 | We examined the association between mutations of the IRS-1 gene at codon 972, mutations of the beta-3-AR gene at codon 64, and the combination of both mutations with the degree of weight loss, waist to hip ratio and the prevalence of hypertension, dyslipidemia and type 2 diabetes mellitus. |
| 3696 | 10826514 | Twenty-four women (11.4%) were polymorph only for the beta-3-AR mutation, 23 women (10.9%) only for the IRS-1 mutation, and 6 subjects (2.9%) were polymorph for both alleles. |
| 3697 | 10826514 | Our findings suggest there is a synergy between the polymorphisms of Trp64Arg beta-3-AR and Gly972Arg IRS-1 in Caucasian German obese women leading to a decreased weight loss. |
| 3698 | 10826514 | A study on the genetics of obesity: influence of polymorphisms of the beta-3-adrenergic receptor and insulin receptor substrate 1 in relation to weight loss, waist to hip ratio and frequencies of common cardiovascular risk factors. |
| 3699 | 10826514 | Beta-3-adrenergic receptor (beta-3-AR) and insulin receptor substrate 1 (IRS-1) have been implicated in the pathogenesis of obesity and in obesity related increase in insulin resistance which is associated with, among other diseases, dyslipidemia and type 2 diabetes mellitus. |
| 3700 | 10826514 | We examined the association between mutations of the IRS-1 gene at codon 972, mutations of the beta-3-AR gene at codon 64, and the combination of both mutations with the degree of weight loss, waist to hip ratio and the prevalence of hypertension, dyslipidemia and type 2 diabetes mellitus. |
| 3701 | 10826514 | Twenty-four women (11.4%) were polymorph only for the beta-3-AR mutation, 23 women (10.9%) only for the IRS-1 mutation, and 6 subjects (2.9%) were polymorph for both alleles. |
| 3702 | 10826514 | Our findings suggest there is a synergy between the polymorphisms of Trp64Arg beta-3-AR and Gly972Arg IRS-1 in Caucasian German obese women leading to a decreased weight loss. |
| 3703 | 10829031 | Essential role of insulin receptor substrate-2 in insulin stimulation of Glut4 translocation and glucose uptake in brown adipocytes. |
| 3704 | 10829031 | Insulin and insulin-like growth factor I signals are mediated via phosphorylation of a family of insulin receptor substrate (IRS) proteins, which may serve both complementary and overlapping functions in the cell. |
| 3705 | 10829031 | To study the metabolic effects of these proteins in more detail, we established brown adipocyte cell lines from wild type and various IRS knockout (KO) animals and characterized insulin action in these cells in vitro. |
| 3706 | 10829031 | In differentiated IRS-2 KO adipocytes, insulin-induced glucose uptake was decreased by 50% compared with their wild type counterparts. |
| 3707 | 10829031 | This was the result of a decrease in insulin-stimulated Glut4 translocation to the plasma membrane. |
| 3708 | 10829031 | This decrease in insulin-induced glucose uptake could be partially reconstituted in these cells by retrovirus-mediated re-expression of IRS-2, but not overexpression of IRS-1. |
| 3709 | 10829031 | The phosphorylation and activity of Akt, a major downstream effector of PI 3-kinase, as well as Akt-dependent phosphorylation of glycogen synthase kinase-3 and p70S6 kinase were not affected by the lack of IRS-2; however, there was a decrease in insulin stimulation of Akt associated with the plasma membrane. |
| 3710 | 10829031 | These results provide evidence for a critical role of IRS-2 as a mediator of insulin-stimulated Glut4 translocation and glucose uptake in adipocytes. |
| 3711 | 10834933 | Reduced glucose uptake precedes insulin signaling defects in adipocytes from heterozygous GLUT4 knockout mice. |
| 3712 | 10834933 | Decreased GLUT4 expression, impaired insulin receptor (IR), IRS-1, and pp60/IRS-3 tyrosine phosphorylation are characteristics of adipocytes from insulin-resistant animal models and obese NIDDM humans. |
| 3713 | 10834933 | However, the sequence of events leading to the development of insulin signaling defects and the significance of decreased GLUT4 expression in causing adipocyte insulin resistance are unknown. |
| 3714 | 10834933 | The present study used male heterozygous GLUT4 knockout mice (GLUT4(+/-)) as a novel model of diabetes to study the development of insulin signaling defects in adipocytes with the progression of whole body insulin resistance and diabetes. |
| 3715 | 10834933 | The expression of GLUT4 protein and the maximal insulin-stimulated glucose transport was 50% decreased in adipocytes from all three groups. |
| 3716 | 10834933 | From 35 to 70% reductions in insulin-stimulated tyrosine phosphorylation of IR, IRS-1, and pp60/IRS-3 were noted with no changes in the cellular content of IR, IRS-1, and p85 in N/H adipocytes. |
| 3717 | 10834933 | Insulin-stimulated protein tyrosine phosphorylation was further decreased to 12-23% in H/H adipose cells accompanied by 42% decreased IR and 80% increased p85 expression. |
| 3718 | 10834933 | Insulin-stimulated, IRS-1-associated PI3 kinase activity was decreased by 20% in N/H and 68% reduced in H/H GLUT4(+/-) adipocytes. |
| 3719 | 10834933 | However, total insulin-stimulated PI3 kinase activity was normal in H/H GLUT4(+/-) adipocytes. |
| 3720 | 10834933 | Furthermore, the data indicate that the cellular content of GLUT4 is the rate-limiting factor in mediating maximal insulin-stimulated glucose uptake in GLUT4(+/-) adipocytes. |
| 3721 | 10834933 | Reduced glucose uptake precedes insulin signaling defects in adipocytes from heterozygous GLUT4 knockout mice. |
| 3722 | 10834933 | Decreased GLUT4 expression, impaired insulin receptor (IR), IRS-1, and pp60/IRS-3 tyrosine phosphorylation are characteristics of adipocytes from insulin-resistant animal models and obese NIDDM humans. |
| 3723 | 10834933 | However, the sequence of events leading to the development of insulin signaling defects and the significance of decreased GLUT4 expression in causing adipocyte insulin resistance are unknown. |
| 3724 | 10834933 | The present study used male heterozygous GLUT4 knockout mice (GLUT4(+/-)) as a novel model of diabetes to study the development of insulin signaling defects in adipocytes with the progression of whole body insulin resistance and diabetes. |
| 3725 | 10834933 | The expression of GLUT4 protein and the maximal insulin-stimulated glucose transport was 50% decreased in adipocytes from all three groups. |
| 3726 | 10834933 | From 35 to 70% reductions in insulin-stimulated tyrosine phosphorylation of IR, IRS-1, and pp60/IRS-3 were noted with no changes in the cellular content of IR, IRS-1, and p85 in N/H adipocytes. |
| 3727 | 10834933 | Insulin-stimulated protein tyrosine phosphorylation was further decreased to 12-23% in H/H adipose cells accompanied by 42% decreased IR and 80% increased p85 expression. |
| 3728 | 10834933 | Insulin-stimulated, IRS-1-associated PI3 kinase activity was decreased by 20% in N/H and 68% reduced in H/H GLUT4(+/-) adipocytes. |
| 3729 | 10834933 | However, total insulin-stimulated PI3 kinase activity was normal in H/H GLUT4(+/-) adipocytes. |
| 3730 | 10834933 | Furthermore, the data indicate that the cellular content of GLUT4 is the rate-limiting factor in mediating maximal insulin-stimulated glucose uptake in GLUT4(+/-) adipocytes. |
| 3731 | 10842657 | However, the fat cells may still play an important role in insulin resistance and Syndrome X through, for instance, its endocrine functions (production of leptin, TNF alpha, PAI-1, etc.) and involvement in lipid metabolism (FFA release and hydrolysis of triglycerides). |
| 3732 | 10842657 | Examinations of the intracellular signaling mechanisms for insulin in fat cells from individuals with Type 2 diabetes revealed markedly lower insulin-stimulated PI3-kinase activity. |
| 3733 | 10842657 | Downstream activation and serine phosphorylation of PKB/Akt by insulin were also markedly reduced in Type 2 diabetes. |
| 3734 | 10842657 | Thus, these data show that both PI3-kinase and PKB activation by insulin are markedly reduced in Type 2 diabetes. |
| 3735 | 10842657 | We also examined whether an attenuated activation of PI3-kinase by insulin can be seen in non-diabetic insulin-resistant states. |
| 3736 | 10842657 | Thus, impaired IRS-1 expression and downstream signaling events in fat cells in response to insulin are associated with insulin resistance and Syndrome X. |
| 3737 | 10842668 | The faK mutation is a premature stop codon in the extracellular domain of the leptin receptor, resulting in a natural receptor knockout. |
| 3738 | 10842668 | Insulin-stimulated phosphorylation of tyrosine residues on the insulin receptor and on the associated docking protein IRS-1 are reduced in skeletal muscle and liver compared to SHR, due mainly to diminished expression of insulin receptor and IRS-1 proteins. |
| 3739 | 10842668 | Moxonidine enhanced expression and insulin-stimulated phosphorylation of IRS-1 in skeletal muscle by 74 and 27%, respectively. |
| 3740 | 10842668 | The faK mutation is a premature stop codon in the extracellular domain of the leptin receptor, resulting in a natural receptor knockout. |
| 3741 | 10842668 | Insulin-stimulated phosphorylation of tyrosine residues on the insulin receptor and on the associated docking protein IRS-1 are reduced in skeletal muscle and liver compared to SHR, due mainly to diminished expression of insulin receptor and IRS-1 proteins. |
| 3742 | 10842668 | Moxonidine enhanced expression and insulin-stimulated phosphorylation of IRS-1 in skeletal muscle by 74 and 27%, respectively. |
| 3743 | 10844412 | Insulin sensitivity is not affected by mutation of codon 972 of the human IRS-1 gene. |
| 3744 | 10852716 | Finally, no covalent association between IR beta-subunit and IRS-1, the protein tyrosine phosphatase LAR or SHP-2 was observed in BMH-treated cells expressing the wild-type human IR. |
| 3745 | 10866039 | We studied the impact of 16 serine residues in HIR by mutation to alanine and co-overexpression in human embryonic kidney (HEK) 293 cells together with the docking proteins insulin receptor substrate (IRS)-1, IRS-2, or (SHC) Src homologous and collagen-like. |
| 3746 | 10866039 | Coexpression of HIR with IRS-1, IRS-2, and SHC strongly enhanced tyrosine phosphorylation of these proteins. |
| 3747 | 10866039 | A similar increase in tyrosine phosphorylation was observed in cells overexpressing IRS-1, IRS-2, or SHC together with all HIR mutants except HIR delta JM and a mutant carrying exchanges of serines 1177, 1178, and 1182 to alanine (HIR1177/78/82), although this mutant showed normal autophosphorylation. |
| 3748 | 10866039 | We studied the impact of 16 serine residues in HIR by mutation to alanine and co-overexpression in human embryonic kidney (HEK) 293 cells together with the docking proteins insulin receptor substrate (IRS)-1, IRS-2, or (SHC) Src homologous and collagen-like. |
| 3749 | 10866039 | Coexpression of HIR with IRS-1, IRS-2, and SHC strongly enhanced tyrosine phosphorylation of these proteins. |
| 3750 | 10866039 | A similar increase in tyrosine phosphorylation was observed in cells overexpressing IRS-1, IRS-2, or SHC together with all HIR mutants except HIR delta JM and a mutant carrying exchanges of serines 1177, 1178, and 1182 to alanine (HIR1177/78/82), although this mutant showed normal autophosphorylation. |
| 3751 | 10866052 | In these cells, insulin stimulation of glucose uptake, glycogen synthesis, insulin receptor (IR) kinase activity, and insulin receptor substrate 1-associated phosphatidylinositol 3-kinase (PI 3-kinase) activity were measured. |
| 3752 | 10866052 | Furthermore, insulin activation of protein kinase B (PKB) was compared with immunoblotting of serine residues at position 473. |
| 3753 | 10866052 | Insulin stimulation (1 nmol/l) of IR kinase and PI 3-kinase were maximal within 5 min (approximately 8- and 5-fold over basal, respectively), and insulin activation of PKB was maximal within 15 min (approximately 3.5-fold over basal). |
| 3754 | 10868945 | Insulin-stimulated (0.6-60 nmol/l) tyrosine phosphorylation of the insulin receptor beta-subunit, mitogen-activated protein (MAP) kinase phosphorylation, and glycogen synthase activity were not altered in type 2 diabetic subjects. |
| 3755 | 10868945 | In contrast, insulin-stimulated tyrosine phosphorylation of IRS-1 and anti-phosphotyrosine-associated PI 3-kinase activity were reduced 40-55% in type 2 diabetic subjects at high insulin concentrations (2.4 and 60 nmol/l, respectively). |
| 3756 | 10868945 | Aberrant protein expression cannot account for these insulin-signaling defects because expression of insulin receptor, IRS-1, IRS-2, MAP kinase, or glycogen synthase was similar between type 2 diabetic and control subjects. |
| 3757 | 10868945 | In skeletal muscle from type 2 diabetic subjects, IRS-1 phosphorylation, PI 3-kinase activity, and glucose transport activity were impaired, whereas insulin receptor tyrosine phosphorylation, MAP kinase phosphorylation, and glycogen synthase activity were normal. |
| 3758 | 10868945 | Insulin-stimulated (0.6-60 nmol/l) tyrosine phosphorylation of the insulin receptor beta-subunit, mitogen-activated protein (MAP) kinase phosphorylation, and glycogen synthase activity were not altered in type 2 diabetic subjects. |
| 3759 | 10868945 | In contrast, insulin-stimulated tyrosine phosphorylation of IRS-1 and anti-phosphotyrosine-associated PI 3-kinase activity were reduced 40-55% in type 2 diabetic subjects at high insulin concentrations (2.4 and 60 nmol/l, respectively). |
| 3760 | 10868945 | Aberrant protein expression cannot account for these insulin-signaling defects because expression of insulin receptor, IRS-1, IRS-2, MAP kinase, or glycogen synthase was similar between type 2 diabetic and control subjects. |
| 3761 | 10868945 | In skeletal muscle from type 2 diabetic subjects, IRS-1 phosphorylation, PI 3-kinase activity, and glucose transport activity were impaired, whereas insulin receptor tyrosine phosphorylation, MAP kinase phosphorylation, and glycogen synthase activity were normal. |
| 3762 | 10868945 | Insulin-stimulated (0.6-60 nmol/l) tyrosine phosphorylation of the insulin receptor beta-subunit, mitogen-activated protein (MAP) kinase phosphorylation, and glycogen synthase activity were not altered in type 2 diabetic subjects. |
| 3763 | 10868945 | In contrast, insulin-stimulated tyrosine phosphorylation of IRS-1 and anti-phosphotyrosine-associated PI 3-kinase activity were reduced 40-55% in type 2 diabetic subjects at high insulin concentrations (2.4 and 60 nmol/l, respectively). |
| 3764 | 10868945 | Aberrant protein expression cannot account for these insulin-signaling defects because expression of insulin receptor, IRS-1, IRS-2, MAP kinase, or glycogen synthase was similar between type 2 diabetic and control subjects. |
| 3765 | 10868945 | In skeletal muscle from type 2 diabetic subjects, IRS-1 phosphorylation, PI 3-kinase activity, and glucose transport activity were impaired, whereas insulin receptor tyrosine phosphorylation, MAP kinase phosphorylation, and glycogen synthase activity were normal. |
| 3766 | 10868952 | However, prior exercise did not result in a greater or more rapid increase in insulin-induced receptor tyrosine kinase (IRTK) activity (t1/2 = 50 min), serine phosphorylation of Akt (t1/2 = 1-2 min), or serine phosphorylation of glycogen synthase kinase-3 (GSK-3) (t1/2 = 1-2 min) or in a larger or more rapid decrease in GSK-3 activity (t1/2 = 3-8 min). |
| 3767 | 10868952 | We conclude the following: 1) physiological hyperinsulinemia induces sustained activation of insulin-signaling molecules in human skeletal muscle; 2) the more distal insulin-signaling components (Akt, GSK-3) are activated much more rapidly than the proximal signaling molecules (IRTK as well as insulin receptor substrate 1 and phosphatidylinositol 3-kinase [Wojtaszewski et al., Diabetes 46:1775-1781, 1997]); and 3) prior exercise increases insulin stimulation of both glucose uptake and glycogen synthase activity in the absence of an upregulation of signaling events in human skeletal muscle. |
| 3768 | 10889791 | Among these, the genes for beta 3-adrenergic receptor, hormone-sensitive lipase, lipoprotein lipase, IRS-1, PC-1, skeletal muscle glycogen synthase, etc. appear to increase the risk of the metabolic syndrome. |
| 3769 | 10905496 | Divergent regulation of Akt1 and Akt2 isoforms in insulin target tissues of obese Zucker rats. |
| 3770 | 10905496 | To determine whether impaired Akt (protein kinase B or rac) activation contributes to insulin resistance in vivo, we examined the expression, phosphorylation, and kinase activities of Akt1 and Akt2 isoforms in insulin target tissues of insulin-resistant obese Zucker rats. |
| 3771 | 10905496 | In lean rats, insulin (10 U/kg i.v. x 2.5 min) stimulated Akt1 activity 6.2-, 8.8-, and 4.4-fold and Akt2 activity 5.4-, 9.3-, and 1.8-fold in muscle, liver, and adipose tissue, respectively. |
| 3772 | 10905496 | In obese rats, insulin-stimulated Akt1 activity decreased 30% in muscle and 21% in adipose tissue but increased 37% in liver compared with lean littermates. |
| 3773 | 10905496 | Insulin-stimulated Akt2 activity decreased 29% in muscle and 37% in liver but increased 24% in adipose tissue. |
| 3774 | 10905496 | Akt2 protein levels were reduced 56% in muscle and 35% in liver of obese rats, but Akt1 expression was unaltered. |
| 3775 | 10905496 | Phosphoinositide 3-kinase (PI3K) activity associated with insulin receptor substrate (IRS)-1 or phosphotyrosine was reduced 67-86% in tissues of obese rats because of lower IRS-1 protein levels and reduced insulin receptor and IRS-1 phosphorylation. |
| 3776 | 10905496 | In adipose tissue of obese rats, in spite of an 86% reduction in insulin-stimulated PI3K activity, activation of Akt2 was increased. |
| 3777 | 10905496 | Maximal insulin-stimulated (100 nmol/l) glucose transport was reduced 70% in isolated adipocytes, with a rightward shift in the insulin dose response for transport and for Akt1 stimulation but normal sensitivity for Akt2. |
| 3778 | 10905496 | These findings suggest that PI3K-dependent effects on glucose transport in adipocytes are not mediated primarily by Akt2. |
| 3779 | 10905496 | Akt1 and Akt2 activations by insulin have a similar time course and are maximal by 2.5 min in adipocytes of both lean and obese rats. |
| 3780 | 10905496 | We conclude that 1) activation of Akt1 and Akt2 in vivo is much less impaired than activation of PI3K in this insulin-resistant state, and 2) the mechanisms for divergent alterations in insulin action on Akt1 and Akt2 activities in tissues of insulin-resistant obese rats involve tissue- and isoform-specific changes in both expression and activation. |
| 3781 | 10909975 | Expression of insulin receptor substrate 1, phosphatidylinositol 3-kinase, protein kinase B, and glycogen synthase was normal in the relative cultures with impaired insulin responsiveness. |
| 3782 | 10909978 | IRS-1 phosphorylation was normally stimulated by insulin in both intact Hep(MUT) and L6 skeletal muscle cells expressing the IR1152 mutant (L6(MUT)). |
| 3783 | 10909978 | At variance, IRS-2 phosphorylation exhibited high basal levels with no further insulin-dependent increase in L6(MUT) but almost normal phosphorylation, both basal and insulin-stimulated, in the Hep(MUT) cells. |
| 3784 | 10909978 | In vitro, IR1152 mutant preparations from both the L6(MUT) and the Hep(MUT) cells exhibited increased basal and no insulin-stimulated phosphorylation of IRS-2 immobilized from either muscle or liver cells. |
| 3785 | 10909978 | Block of receptor internalization (wild-type and mutant) in the liver and muscle cells also inhibited IRS-2, but not IRS-1, phosphorylation. |
| 3786 | 10909978 | In both cell types, receptor internalization seems necessary for IRS-2 but not IRS-1 phosphorylation. |
| 3787 | 10909978 | IRS-1 phosphorylation was normally stimulated by insulin in both intact Hep(MUT) and L6 skeletal muscle cells expressing the IR1152 mutant (L6(MUT)). |
| 3788 | 10909978 | At variance, IRS-2 phosphorylation exhibited high basal levels with no further insulin-dependent increase in L6(MUT) but almost normal phosphorylation, both basal and insulin-stimulated, in the Hep(MUT) cells. |
| 3789 | 10909978 | In vitro, IR1152 mutant preparations from both the L6(MUT) and the Hep(MUT) cells exhibited increased basal and no insulin-stimulated phosphorylation of IRS-2 immobilized from either muscle or liver cells. |
| 3790 | 10909978 | Block of receptor internalization (wild-type and mutant) in the liver and muscle cells also inhibited IRS-2, but not IRS-1, phosphorylation. |
| 3791 | 10909978 | In both cell types, receptor internalization seems necessary for IRS-2 but not IRS-1 phosphorylation. |
| 3792 | 10909978 | IRS-1 phosphorylation was normally stimulated by insulin in both intact Hep(MUT) and L6 skeletal muscle cells expressing the IR1152 mutant (L6(MUT)). |
| 3793 | 10909978 | At variance, IRS-2 phosphorylation exhibited high basal levels with no further insulin-dependent increase in L6(MUT) but almost normal phosphorylation, both basal and insulin-stimulated, in the Hep(MUT) cells. |
| 3794 | 10909978 | In vitro, IR1152 mutant preparations from both the L6(MUT) and the Hep(MUT) cells exhibited increased basal and no insulin-stimulated phosphorylation of IRS-2 immobilized from either muscle or liver cells. |
| 3795 | 10909978 | Block of receptor internalization (wild-type and mutant) in the liver and muscle cells also inhibited IRS-2, but not IRS-1, phosphorylation. |
| 3796 | 10909978 | In both cell types, receptor internalization seems necessary for IRS-2 but not IRS-1 phosphorylation. |
| 3797 | 10924321 | Elevated expression and activity of protein-tyrosine phosphatase 1B in skeletal muscle of insulin-resistant type II diabetic Goto-Kakizaki rats. |
| 3798 | 10924321 | Relative to non-diabetic control rats (WKY), insulin-stimulated insulin receptor (IR) autophosphorylation and insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation were significantly inhibited in GK skeletal muscles. |
| 3799 | 10946909 | Variability of the insulin receptor substrate-1, hepatocyte nuclear factor-1alpha (HNF-1alpha), HNF-4alpha, and HNF-6 genes and size at birth in a population-based sample of young Danish subjects. |
| 3800 | 10946909 | The Gly/Arg972 of insulin receptor substrate-1 (IRS-1), the Thr/Ile130 of the hepatocyte nuclear factor-4alpha (HNF-4alpha), the Pro/Ala75 of HNF-6, and the Ile/Leu27, Ala/Val93, and Ser/Asn4s7 polymorphisms of the HNF-lalpha gene were examined for association with birth weight and length and the ponderal index. |
| 3801 | 10946909 | In conclusion, common variability in the genes encoding the IRS-1, HNF-lalpha, HNF-4alpha, and HNF-6 proteins can be excluded as major factors influencing size at birth among Danish Caucasian subjects. |
| 3802 | 10946909 | Variability of the insulin receptor substrate-1, hepatocyte nuclear factor-1alpha (HNF-1alpha), HNF-4alpha, and HNF-6 genes and size at birth in a population-based sample of young Danish subjects. |
| 3803 | 10946909 | The Gly/Arg972 of insulin receptor substrate-1 (IRS-1), the Thr/Ile130 of the hepatocyte nuclear factor-4alpha (HNF-4alpha), the Pro/Ala75 of HNF-6, and the Ile/Leu27, Ala/Val93, and Ser/Asn4s7 polymorphisms of the HNF-lalpha gene were examined for association with birth weight and length and the ponderal index. |
| 3804 | 10946909 | In conclusion, common variability in the genes encoding the IRS-1, HNF-lalpha, HNF-4alpha, and HNF-6 proteins can be excluded as major factors influencing size at birth among Danish Caucasian subjects. |
| 3805 | 10946909 | Variability of the insulin receptor substrate-1, hepatocyte nuclear factor-1alpha (HNF-1alpha), HNF-4alpha, and HNF-6 genes and size at birth in a population-based sample of young Danish subjects. |
| 3806 | 10946909 | The Gly/Arg972 of insulin receptor substrate-1 (IRS-1), the Thr/Ile130 of the hepatocyte nuclear factor-4alpha (HNF-4alpha), the Pro/Ala75 of HNF-6, and the Ile/Leu27, Ala/Val93, and Ser/Asn4s7 polymorphisms of the HNF-lalpha gene were examined for association with birth weight and length and the ponderal index. |
| 3807 | 10946909 | In conclusion, common variability in the genes encoding the IRS-1, HNF-lalpha, HNF-4alpha, and HNF-6 proteins can be excluded as major factors influencing size at birth among Danish Caucasian subjects. |
| 3808 | 10958681 | Cellular compartmentalization in insulin action: altered signaling by a lipid-modified IRS-1. |
| 3809 | 10958681 | To determine the importance of this distribution to IRS-1-mediated signaling, we constructed a prenylated, constitutively membrane-bound IRS-1 by adding the COOH-terminal 9 amino acids from p21(ras), including the CAAX motif, to IRS-1 (IRS-CAAX) and analyzed its function in 32D cells expressing the insulin receptor. |
| 3810 | 10958681 | Insulin-stimulated tyrosyl phosphorylation of IRS-CAAX was slightly decreased, while IRS-CAAX-mediated phosphatidylinositol 3'-kinase (PI3'-kinase) binding and activation were decreased by approximately 75% compared to those for wild-type IRS-1. |
| 3811 | 10958681 | Similarly, expression of IRS-CAAX desensitized insulin-stimulated [(3)H]thymidine incorporation into DNA by about an order of magnitude compared to IRS-1. |
| 3812 | 10958681 | By contrast, IRS-CAAX-expressing cells demonstrated increased signaling by mitogen-activated protein kinase, Akt, and p70(S6) kinase in response to insulin. |
| 3813 | 10958681 | Hence, tight association with the membrane increased IRS-1 serine phosphorylation and reduced coupling between the insulin receptor, PI3'-kinase, and proliferative signaling while enhancing other signaling pathways. |
| 3814 | 10958681 | Thus, the correct distribution of IRS-1 between the cytoplasm and membrane compartments is critical to the normal balance in the network of insulin signaling. |
| 3815 | 10958681 | Cellular compartmentalization in insulin action: altered signaling by a lipid-modified IRS-1. |
| 3816 | 10958681 | To determine the importance of this distribution to IRS-1-mediated signaling, we constructed a prenylated, constitutively membrane-bound IRS-1 by adding the COOH-terminal 9 amino acids from p21(ras), including the CAAX motif, to IRS-1 (IRS-CAAX) and analyzed its function in 32D cells expressing the insulin receptor. |
| 3817 | 10958681 | Insulin-stimulated tyrosyl phosphorylation of IRS-CAAX was slightly decreased, while IRS-CAAX-mediated phosphatidylinositol 3'-kinase (PI3'-kinase) binding and activation were decreased by approximately 75% compared to those for wild-type IRS-1. |
| 3818 | 10958681 | Similarly, expression of IRS-CAAX desensitized insulin-stimulated [(3)H]thymidine incorporation into DNA by about an order of magnitude compared to IRS-1. |
| 3819 | 10958681 | By contrast, IRS-CAAX-expressing cells demonstrated increased signaling by mitogen-activated protein kinase, Akt, and p70(S6) kinase in response to insulin. |
| 3820 | 10958681 | Hence, tight association with the membrane increased IRS-1 serine phosphorylation and reduced coupling between the insulin receptor, PI3'-kinase, and proliferative signaling while enhancing other signaling pathways. |
| 3821 | 10958681 | Thus, the correct distribution of IRS-1 between the cytoplasm and membrane compartments is critical to the normal balance in the network of insulin signaling. |
| 3822 | 10958681 | Cellular compartmentalization in insulin action: altered signaling by a lipid-modified IRS-1. |
| 3823 | 10958681 | To determine the importance of this distribution to IRS-1-mediated signaling, we constructed a prenylated, constitutively membrane-bound IRS-1 by adding the COOH-terminal 9 amino acids from p21(ras), including the CAAX motif, to IRS-1 (IRS-CAAX) and analyzed its function in 32D cells expressing the insulin receptor. |
| 3824 | 10958681 | Insulin-stimulated tyrosyl phosphorylation of IRS-CAAX was slightly decreased, while IRS-CAAX-mediated phosphatidylinositol 3'-kinase (PI3'-kinase) binding and activation were decreased by approximately 75% compared to those for wild-type IRS-1. |
| 3825 | 10958681 | Similarly, expression of IRS-CAAX desensitized insulin-stimulated [(3)H]thymidine incorporation into DNA by about an order of magnitude compared to IRS-1. |
| 3826 | 10958681 | By contrast, IRS-CAAX-expressing cells demonstrated increased signaling by mitogen-activated protein kinase, Akt, and p70(S6) kinase in response to insulin. |
| 3827 | 10958681 | Hence, tight association with the membrane increased IRS-1 serine phosphorylation and reduced coupling between the insulin receptor, PI3'-kinase, and proliferative signaling while enhancing other signaling pathways. |
| 3828 | 10958681 | Thus, the correct distribution of IRS-1 between the cytoplasm and membrane compartments is critical to the normal balance in the network of insulin signaling. |
| 3829 | 10958681 | Cellular compartmentalization in insulin action: altered signaling by a lipid-modified IRS-1. |
| 3830 | 10958681 | To determine the importance of this distribution to IRS-1-mediated signaling, we constructed a prenylated, constitutively membrane-bound IRS-1 by adding the COOH-terminal 9 amino acids from p21(ras), including the CAAX motif, to IRS-1 (IRS-CAAX) and analyzed its function in 32D cells expressing the insulin receptor. |
| 3831 | 10958681 | Insulin-stimulated tyrosyl phosphorylation of IRS-CAAX was slightly decreased, while IRS-CAAX-mediated phosphatidylinositol 3'-kinase (PI3'-kinase) binding and activation were decreased by approximately 75% compared to those for wild-type IRS-1. |
| 3832 | 10958681 | Similarly, expression of IRS-CAAX desensitized insulin-stimulated [(3)H]thymidine incorporation into DNA by about an order of magnitude compared to IRS-1. |
| 3833 | 10958681 | By contrast, IRS-CAAX-expressing cells demonstrated increased signaling by mitogen-activated protein kinase, Akt, and p70(S6) kinase in response to insulin. |
| 3834 | 10958681 | Hence, tight association with the membrane increased IRS-1 serine phosphorylation and reduced coupling between the insulin receptor, PI3'-kinase, and proliferative signaling while enhancing other signaling pathways. |
| 3835 | 10958681 | Thus, the correct distribution of IRS-1 between the cytoplasm and membrane compartments is critical to the normal balance in the network of insulin signaling. |
| 3836 | 10958681 | Cellular compartmentalization in insulin action: altered signaling by a lipid-modified IRS-1. |
| 3837 | 10958681 | To determine the importance of this distribution to IRS-1-mediated signaling, we constructed a prenylated, constitutively membrane-bound IRS-1 by adding the COOH-terminal 9 amino acids from p21(ras), including the CAAX motif, to IRS-1 (IRS-CAAX) and analyzed its function in 32D cells expressing the insulin receptor. |
| 3838 | 10958681 | Insulin-stimulated tyrosyl phosphorylation of IRS-CAAX was slightly decreased, while IRS-CAAX-mediated phosphatidylinositol 3'-kinase (PI3'-kinase) binding and activation were decreased by approximately 75% compared to those for wild-type IRS-1. |
| 3839 | 10958681 | Similarly, expression of IRS-CAAX desensitized insulin-stimulated [(3)H]thymidine incorporation into DNA by about an order of magnitude compared to IRS-1. |
| 3840 | 10958681 | By contrast, IRS-CAAX-expressing cells demonstrated increased signaling by mitogen-activated protein kinase, Akt, and p70(S6) kinase in response to insulin. |
| 3841 | 10958681 | Hence, tight association with the membrane increased IRS-1 serine phosphorylation and reduced coupling between the insulin receptor, PI3'-kinase, and proliferative signaling while enhancing other signaling pathways. |
| 3842 | 10958681 | Thus, the correct distribution of IRS-1 between the cytoplasm and membrane compartments is critical to the normal balance in the network of insulin signaling. |
| 3843 | 10958681 | Cellular compartmentalization in insulin action: altered signaling by a lipid-modified IRS-1. |
| 3844 | 10958681 | To determine the importance of this distribution to IRS-1-mediated signaling, we constructed a prenylated, constitutively membrane-bound IRS-1 by adding the COOH-terminal 9 amino acids from p21(ras), including the CAAX motif, to IRS-1 (IRS-CAAX) and analyzed its function in 32D cells expressing the insulin receptor. |
| 3845 | 10958681 | Insulin-stimulated tyrosyl phosphorylation of IRS-CAAX was slightly decreased, while IRS-CAAX-mediated phosphatidylinositol 3'-kinase (PI3'-kinase) binding and activation were decreased by approximately 75% compared to those for wild-type IRS-1. |
| 3846 | 10958681 | Similarly, expression of IRS-CAAX desensitized insulin-stimulated [(3)H]thymidine incorporation into DNA by about an order of magnitude compared to IRS-1. |
| 3847 | 10958681 | By contrast, IRS-CAAX-expressing cells demonstrated increased signaling by mitogen-activated protein kinase, Akt, and p70(S6) kinase in response to insulin. |
| 3848 | 10958681 | Hence, tight association with the membrane increased IRS-1 serine phosphorylation and reduced coupling between the insulin receptor, PI3'-kinase, and proliferative signaling while enhancing other signaling pathways. |
| 3849 | 10958681 | Thus, the correct distribution of IRS-1 between the cytoplasm and membrane compartments is critical to the normal balance in the network of insulin signaling. |
| 3850 | 10973656 | Expression of insulin-receptor substrate-1 and -2 in ovaries from women with insulin resistance and from controls. |
| 3851 | 10987057 | Exploration of variability in candidate genes by direct sequencing in some genetic syndromes of severe insulin resistance and acanthosis nigricans (mainly the Type A syndrome) revealed mutations of the insulin receptor gene associated with major defects in insulin binding or kinase activity. |
| 3852 | 10987057 | Genotype-phenotype correlations in first degree relatives of an index case caring the Type A syndrome, suggested that association of allelic variants of IRS-1 and IRS-2 with insulin receptor mutations contribute, by synergistic effects, to phenotypic expression of defects in signal transduction. |
| 3853 | 11006100 | In the present study we have examined the proteins involved in the insulin signaling cascade during and after differentiation of human adipocyte precursor cells and their correlation with glucose uptake. |
| 3854 | 11006100 | The differentiation of human adipocytes was characterized by a two- to threefold stimulation of glucose transport in response to insulin and a marked increase protein expression for the insulin receptor, IRS-1, GLUT-4, PI 3-kinase, and PKB, with respect to undifferentiated cells. |
| 3855 | 11006100 | In contrast, there were small changes in the protein expression of IRS-2, and no changes in PKC zeta and MAP kinases, although basal MAP kinase activity and GLUT-1 protein were reduced during differentiation. |
| 3856 | 11006100 | In conclusion, there are quantitative differences in the regulation of IRS-1 and other proteins during differentiation which may contribute to more efficient insulin signaling leading to glucose uptake in mature fat cells. |
| 3857 | 11006100 | In the present study we have examined the proteins involved in the insulin signaling cascade during and after differentiation of human adipocyte precursor cells and their correlation with glucose uptake. |
| 3858 | 11006100 | The differentiation of human adipocytes was characterized by a two- to threefold stimulation of glucose transport in response to insulin and a marked increase protein expression for the insulin receptor, IRS-1, GLUT-4, PI 3-kinase, and PKB, with respect to undifferentiated cells. |
| 3859 | 11006100 | In contrast, there were small changes in the protein expression of IRS-2, and no changes in PKC zeta and MAP kinases, although basal MAP kinase activity and GLUT-1 protein were reduced during differentiation. |
| 3860 | 11006100 | In conclusion, there are quantitative differences in the regulation of IRS-1 and other proteins during differentiation which may contribute to more efficient insulin signaling leading to glucose uptake in mature fat cells. |
| 3861 | 11007772 | Expression of constitutively active phosphatidylinositol 3-kinase inhibits activation of caspase 3 and apoptosis of cardiac muscle cells. |
| 3862 | 11007772 | Recent studies showed that insulin-like growth factor I (IGF-I) inhibits apoptosis of cardiac muscle cells and improves myocardial function in experimental heart failure. |
| 3863 | 11007772 | This study was carried out to elucidate the role of phosphatidylinositol 3-kinase (PI 3-kinase) in the anti-apoptotic actions of IGF-I in cardiomyocytes and to explore whether expression of constitutively active PI 3-kinase can inhibit apoptosis in cardiomyocytes. |
| 3864 | 11007772 | Transduction of cardiomyocytes with constitutively active PI 3-kinase specifically lead to serine phosphorylation of Akt, whereas phosphorylation of IGF-I receptor, IRS1/2 and p44/42 mitogen-activated protein kinase were not increased. |
| 3865 | 11007772 | These findings indicate the existence of an IGF-I receptor-PI 3-kinase-caspase 3 pathway in cardiomyocytes that plays an important role in the anti-apoptotic actions of IGF-I in heart. |
| 3866 | 11016454 | On the other hand, dexamethasone treatment did not alter the amount of GLUT4 protein in total cell lysates but decreased the insulin-stimulated GLUT4 translocation to the plasma membrane, which possibly caused decreased insulin-stimulated glucose uptake. |
| 3867 | 11016454 | To investigate whether the reduced IRS-1 content is involved in insulin resistance, IRS-1 was overexpressed in dexamethasone-treated 3T3-L1 adipocytes using an adenovirus transfection system. |
| 3868 | 11016454 | Despite protein expression and phosphorylation levels of IRS-1 being normalized, insulin-induced 2-deoxy-D-[3H]glucose uptake impaired by dexamethasone showed no significant improvement. |
| 3869 | 11016454 | Subsequently, we examined the effect of dexamethasone on the glucose uptake increase induced by overexpression of GLUT2-tagged p110alpha, constitutively active Akt (myristoylated Akt), oxidative stress (30 mU glucose oxidase for 2 h), 2 mmol/l 5-aminoimidazole-4-carboxamide ribonucleoside for 30 min, and osmotic shock (600 mmol/l sorbitol for 30 min). |
| 3870 | 11016454 | Thus, in conclusion, the GLUT1 decrease may be involved in the dexamethasone-induced decrease in basal glucose transport activity, and the mechanism of dexamethasone-induced insulin resistance in glucose transport activity (rather than the inhibition of phosphatidylinositol 3-kinase activation resulting from a decreased IRS-1 content) is likely to underlie impaired glucose transporter regulation. |
| 3871 | 11016454 | On the other hand, dexamethasone treatment did not alter the amount of GLUT4 protein in total cell lysates but decreased the insulin-stimulated GLUT4 translocation to the plasma membrane, which possibly caused decreased insulin-stimulated glucose uptake. |
| 3872 | 11016454 | To investigate whether the reduced IRS-1 content is involved in insulin resistance, IRS-1 was overexpressed in dexamethasone-treated 3T3-L1 adipocytes using an adenovirus transfection system. |
| 3873 | 11016454 | Despite protein expression and phosphorylation levels of IRS-1 being normalized, insulin-induced 2-deoxy-D-[3H]glucose uptake impaired by dexamethasone showed no significant improvement. |
| 3874 | 11016454 | Subsequently, we examined the effect of dexamethasone on the glucose uptake increase induced by overexpression of GLUT2-tagged p110alpha, constitutively active Akt (myristoylated Akt), oxidative stress (30 mU glucose oxidase for 2 h), 2 mmol/l 5-aminoimidazole-4-carboxamide ribonucleoside for 30 min, and osmotic shock (600 mmol/l sorbitol for 30 min). |
| 3875 | 11016454 | Thus, in conclusion, the GLUT1 decrease may be involved in the dexamethasone-induced decrease in basal glucose transport activity, and the mechanism of dexamethasone-induced insulin resistance in glucose transport activity (rather than the inhibition of phosphatidylinositol 3-kinase activation resulting from a decreased IRS-1 content) is likely to underlie impaired glucose transporter regulation. |
| 3876 | 11016454 | On the other hand, dexamethasone treatment did not alter the amount of GLUT4 protein in total cell lysates but decreased the insulin-stimulated GLUT4 translocation to the plasma membrane, which possibly caused decreased insulin-stimulated glucose uptake. |
| 3877 | 11016454 | To investigate whether the reduced IRS-1 content is involved in insulin resistance, IRS-1 was overexpressed in dexamethasone-treated 3T3-L1 adipocytes using an adenovirus transfection system. |
| 3878 | 11016454 | Despite protein expression and phosphorylation levels of IRS-1 being normalized, insulin-induced 2-deoxy-D-[3H]glucose uptake impaired by dexamethasone showed no significant improvement. |
| 3879 | 11016454 | Subsequently, we examined the effect of dexamethasone on the glucose uptake increase induced by overexpression of GLUT2-tagged p110alpha, constitutively active Akt (myristoylated Akt), oxidative stress (30 mU glucose oxidase for 2 h), 2 mmol/l 5-aminoimidazole-4-carboxamide ribonucleoside for 30 min, and osmotic shock (600 mmol/l sorbitol for 30 min). |
| 3880 | 11016454 | Thus, in conclusion, the GLUT1 decrease may be involved in the dexamethasone-induced decrease in basal glucose transport activity, and the mechanism of dexamethasone-induced insulin resistance in glucose transport activity (rather than the inhibition of phosphatidylinositol 3-kinase activation resulting from a decreased IRS-1 content) is likely to underlie impaired glucose transporter regulation. |
| 3881 | 11043572 | Tumor necrosis factor alpha-mediated insulin resistance, but not dedifferentiation, is abrogated by MEK1/2 inhibitors in 3T3-L1 adipocytes. |
| 3882 | 11043572 | Tumor necrosis factor-alpha (TNFalpha) has been implicated as a contributing mediator of insulin resistance observed in pathophysiological conditions such as obesity, cancer-induced cachexia, and bacterial infections. |
| 3883 | 11043572 | Previous studies have demonstrated that TNFalpha confers insulin resistance by promoting phosphorylation of serine residues on insulin receptor substrate 1 (IRS-1), thereby diminishing subsequent insulin-induced tyrosine phosphorylation of IRS-1. |
| 3884 | 11043572 | However, little is known about which signaling molecules are involved in this process in adipocytes and about the temporal sequence of events that ultimately leads to TNFalpha-stimulated IRS-1 serine phosphorylation. |
| 3885 | 11043572 | In this study, we demonstrate that specific inhibitors of the MAP kinase kinase (MEK)1/2-p42/44 mitogen-activated protein (MAP) kinase pathway restore insulin signaling to normal levels despite the presence of TNFalpha. |
| 3886 | 11043572 | Additional experiments show that MEK1/2 activity is required for TNFalpha-induced IRS-1 serine phosphorylation, thereby suggesting a mechanism by which these inhibitors restore insulin signaling. |
| 3887 | 11043572 | We observe that TNFalpha requires 2.5-4 h to markedly reduce insulin-triggered tyrosine phosphorylation of IRS-1 in 3T3-L1 adipocytes. |
| 3888 | 11043572 | Although TNFalpha activates p42/44 MAP kinase, maximal stimulation is observed within 10-30 min. |
| 3889 | 11043572 | To our surprise, p42/44 activity returns to basal levels well before IRS-1 serine phosphorylation and insulin resistance are observed. |
| 3890 | 11043572 | These activation kinetics suggest a mechanism of p42/44 action more complicated than a direct phosphorylation of IRS-1 triggered by the early spike of TNFalpha-induced p42/44 activity. |
| 3891 | 11043572 | Chronic TNFalpha treatment (>> 72 h) causes adipocyte dedifferentiation, as evidenced by the loss of triglycerides and down-regulation of adipocyte-specific markers. |
| 3892 | 11043572 | We observe that this longer term TNFalpha-mediated dedifferentiation effect utilizes alternative, p42/44 MAP kinase-independent intracellular pathways. |
| 3893 | 11043572 | This study suggests that TNFalpha-mediated insulin resistance, but not adipocyte dedifferentiation, is mediated by the MEK1/2-p42/44 MAP kinase pathway. |
| 3894 | 11043572 | Tumor necrosis factor alpha-mediated insulin resistance, but not dedifferentiation, is abrogated by MEK1/2 inhibitors in 3T3-L1 adipocytes. |
| 3895 | 11043572 | Tumor necrosis factor-alpha (TNFalpha) has been implicated as a contributing mediator of insulin resistance observed in pathophysiological conditions such as obesity, cancer-induced cachexia, and bacterial infections. |
| 3896 | 11043572 | Previous studies have demonstrated that TNFalpha confers insulin resistance by promoting phosphorylation of serine residues on insulin receptor substrate 1 (IRS-1), thereby diminishing subsequent insulin-induced tyrosine phosphorylation of IRS-1. |
| 3897 | 11043572 | However, little is known about which signaling molecules are involved in this process in adipocytes and about the temporal sequence of events that ultimately leads to TNFalpha-stimulated IRS-1 serine phosphorylation. |
| 3898 | 11043572 | In this study, we demonstrate that specific inhibitors of the MAP kinase kinase (MEK)1/2-p42/44 mitogen-activated protein (MAP) kinase pathway restore insulin signaling to normal levels despite the presence of TNFalpha. |
| 3899 | 11043572 | Additional experiments show that MEK1/2 activity is required for TNFalpha-induced IRS-1 serine phosphorylation, thereby suggesting a mechanism by which these inhibitors restore insulin signaling. |
| 3900 | 11043572 | We observe that TNFalpha requires 2.5-4 h to markedly reduce insulin-triggered tyrosine phosphorylation of IRS-1 in 3T3-L1 adipocytes. |
| 3901 | 11043572 | Although TNFalpha activates p42/44 MAP kinase, maximal stimulation is observed within 10-30 min. |
| 3902 | 11043572 | To our surprise, p42/44 activity returns to basal levels well before IRS-1 serine phosphorylation and insulin resistance are observed. |
| 3903 | 11043572 | These activation kinetics suggest a mechanism of p42/44 action more complicated than a direct phosphorylation of IRS-1 triggered by the early spike of TNFalpha-induced p42/44 activity. |
| 3904 | 11043572 | Chronic TNFalpha treatment (>> 72 h) causes adipocyte dedifferentiation, as evidenced by the loss of triglycerides and down-regulation of adipocyte-specific markers. |
| 3905 | 11043572 | We observe that this longer term TNFalpha-mediated dedifferentiation effect utilizes alternative, p42/44 MAP kinase-independent intracellular pathways. |
| 3906 | 11043572 | This study suggests that TNFalpha-mediated insulin resistance, but not adipocyte dedifferentiation, is mediated by the MEK1/2-p42/44 MAP kinase pathway. |
| 3907 | 11043572 | Tumor necrosis factor alpha-mediated insulin resistance, but not dedifferentiation, is abrogated by MEK1/2 inhibitors in 3T3-L1 adipocytes. |
| 3908 | 11043572 | Tumor necrosis factor-alpha (TNFalpha) has been implicated as a contributing mediator of insulin resistance observed in pathophysiological conditions such as obesity, cancer-induced cachexia, and bacterial infections. |
| 3909 | 11043572 | Previous studies have demonstrated that TNFalpha confers insulin resistance by promoting phosphorylation of serine residues on insulin receptor substrate 1 (IRS-1), thereby diminishing subsequent insulin-induced tyrosine phosphorylation of IRS-1. |
| 3910 | 11043572 | However, little is known about which signaling molecules are involved in this process in adipocytes and about the temporal sequence of events that ultimately leads to TNFalpha-stimulated IRS-1 serine phosphorylation. |
| 3911 | 11043572 | In this study, we demonstrate that specific inhibitors of the MAP kinase kinase (MEK)1/2-p42/44 mitogen-activated protein (MAP) kinase pathway restore insulin signaling to normal levels despite the presence of TNFalpha. |
| 3912 | 11043572 | Additional experiments show that MEK1/2 activity is required for TNFalpha-induced IRS-1 serine phosphorylation, thereby suggesting a mechanism by which these inhibitors restore insulin signaling. |
| 3913 | 11043572 | We observe that TNFalpha requires 2.5-4 h to markedly reduce insulin-triggered tyrosine phosphorylation of IRS-1 in 3T3-L1 adipocytes. |
| 3914 | 11043572 | Although TNFalpha activates p42/44 MAP kinase, maximal stimulation is observed within 10-30 min. |
| 3915 | 11043572 | To our surprise, p42/44 activity returns to basal levels well before IRS-1 serine phosphorylation and insulin resistance are observed. |
| 3916 | 11043572 | These activation kinetics suggest a mechanism of p42/44 action more complicated than a direct phosphorylation of IRS-1 triggered by the early spike of TNFalpha-induced p42/44 activity. |
| 3917 | 11043572 | Chronic TNFalpha treatment (>> 72 h) causes adipocyte dedifferentiation, as evidenced by the loss of triglycerides and down-regulation of adipocyte-specific markers. |
| 3918 | 11043572 | We observe that this longer term TNFalpha-mediated dedifferentiation effect utilizes alternative, p42/44 MAP kinase-independent intracellular pathways. |
| 3919 | 11043572 | This study suggests that TNFalpha-mediated insulin resistance, but not adipocyte dedifferentiation, is mediated by the MEK1/2-p42/44 MAP kinase pathway. |
| 3920 | 11043572 | Tumor necrosis factor alpha-mediated insulin resistance, but not dedifferentiation, is abrogated by MEK1/2 inhibitors in 3T3-L1 adipocytes. |
| 3921 | 11043572 | Tumor necrosis factor-alpha (TNFalpha) has been implicated as a contributing mediator of insulin resistance observed in pathophysiological conditions such as obesity, cancer-induced cachexia, and bacterial infections. |
| 3922 | 11043572 | Previous studies have demonstrated that TNFalpha confers insulin resistance by promoting phosphorylation of serine residues on insulin receptor substrate 1 (IRS-1), thereby diminishing subsequent insulin-induced tyrosine phosphorylation of IRS-1. |
| 3923 | 11043572 | However, little is known about which signaling molecules are involved in this process in adipocytes and about the temporal sequence of events that ultimately leads to TNFalpha-stimulated IRS-1 serine phosphorylation. |
| 3924 | 11043572 | In this study, we demonstrate that specific inhibitors of the MAP kinase kinase (MEK)1/2-p42/44 mitogen-activated protein (MAP) kinase pathway restore insulin signaling to normal levels despite the presence of TNFalpha. |
| 3925 | 11043572 | Additional experiments show that MEK1/2 activity is required for TNFalpha-induced IRS-1 serine phosphorylation, thereby suggesting a mechanism by which these inhibitors restore insulin signaling. |
| 3926 | 11043572 | We observe that TNFalpha requires 2.5-4 h to markedly reduce insulin-triggered tyrosine phosphorylation of IRS-1 in 3T3-L1 adipocytes. |
| 3927 | 11043572 | Although TNFalpha activates p42/44 MAP kinase, maximal stimulation is observed within 10-30 min. |
| 3928 | 11043572 | To our surprise, p42/44 activity returns to basal levels well before IRS-1 serine phosphorylation and insulin resistance are observed. |
| 3929 | 11043572 | These activation kinetics suggest a mechanism of p42/44 action more complicated than a direct phosphorylation of IRS-1 triggered by the early spike of TNFalpha-induced p42/44 activity. |
| 3930 | 11043572 | Chronic TNFalpha treatment (>> 72 h) causes adipocyte dedifferentiation, as evidenced by the loss of triglycerides and down-regulation of adipocyte-specific markers. |
| 3931 | 11043572 | We observe that this longer term TNFalpha-mediated dedifferentiation effect utilizes alternative, p42/44 MAP kinase-independent intracellular pathways. |
| 3932 | 11043572 | This study suggests that TNFalpha-mediated insulin resistance, but not adipocyte dedifferentiation, is mediated by the MEK1/2-p42/44 MAP kinase pathway. |
| 3933 | 11043572 | Tumor necrosis factor alpha-mediated insulin resistance, but not dedifferentiation, is abrogated by MEK1/2 inhibitors in 3T3-L1 adipocytes. |
| 3934 | 11043572 | Tumor necrosis factor-alpha (TNFalpha) has been implicated as a contributing mediator of insulin resistance observed in pathophysiological conditions such as obesity, cancer-induced cachexia, and bacterial infections. |
| 3935 | 11043572 | Previous studies have demonstrated that TNFalpha confers insulin resistance by promoting phosphorylation of serine residues on insulin receptor substrate 1 (IRS-1), thereby diminishing subsequent insulin-induced tyrosine phosphorylation of IRS-1. |
| 3936 | 11043572 | However, little is known about which signaling molecules are involved in this process in adipocytes and about the temporal sequence of events that ultimately leads to TNFalpha-stimulated IRS-1 serine phosphorylation. |
| 3937 | 11043572 | In this study, we demonstrate that specific inhibitors of the MAP kinase kinase (MEK)1/2-p42/44 mitogen-activated protein (MAP) kinase pathway restore insulin signaling to normal levels despite the presence of TNFalpha. |
| 3938 | 11043572 | Additional experiments show that MEK1/2 activity is required for TNFalpha-induced IRS-1 serine phosphorylation, thereby suggesting a mechanism by which these inhibitors restore insulin signaling. |
| 3939 | 11043572 | We observe that TNFalpha requires 2.5-4 h to markedly reduce insulin-triggered tyrosine phosphorylation of IRS-1 in 3T3-L1 adipocytes. |
| 3940 | 11043572 | Although TNFalpha activates p42/44 MAP kinase, maximal stimulation is observed within 10-30 min. |
| 3941 | 11043572 | To our surprise, p42/44 activity returns to basal levels well before IRS-1 serine phosphorylation and insulin resistance are observed. |
| 3942 | 11043572 | These activation kinetics suggest a mechanism of p42/44 action more complicated than a direct phosphorylation of IRS-1 triggered by the early spike of TNFalpha-induced p42/44 activity. |
| 3943 | 11043572 | Chronic TNFalpha treatment (>> 72 h) causes adipocyte dedifferentiation, as evidenced by the loss of triglycerides and down-regulation of adipocyte-specific markers. |
| 3944 | 11043572 | We observe that this longer term TNFalpha-mediated dedifferentiation effect utilizes alternative, p42/44 MAP kinase-independent intracellular pathways. |
| 3945 | 11043572 | This study suggests that TNFalpha-mediated insulin resistance, but not adipocyte dedifferentiation, is mediated by the MEK1/2-p42/44 MAP kinase pathway. |
| 3946 | 11043572 | Tumor necrosis factor alpha-mediated insulin resistance, but not dedifferentiation, is abrogated by MEK1/2 inhibitors in 3T3-L1 adipocytes. |
| 3947 | 11043572 | Tumor necrosis factor-alpha (TNFalpha) has been implicated as a contributing mediator of insulin resistance observed in pathophysiological conditions such as obesity, cancer-induced cachexia, and bacterial infections. |
| 3948 | 11043572 | Previous studies have demonstrated that TNFalpha confers insulin resistance by promoting phosphorylation of serine residues on insulin receptor substrate 1 (IRS-1), thereby diminishing subsequent insulin-induced tyrosine phosphorylation of IRS-1. |
| 3949 | 11043572 | However, little is known about which signaling molecules are involved in this process in adipocytes and about the temporal sequence of events that ultimately leads to TNFalpha-stimulated IRS-1 serine phosphorylation. |
| 3950 | 11043572 | In this study, we demonstrate that specific inhibitors of the MAP kinase kinase (MEK)1/2-p42/44 mitogen-activated protein (MAP) kinase pathway restore insulin signaling to normal levels despite the presence of TNFalpha. |
| 3951 | 11043572 | Additional experiments show that MEK1/2 activity is required for TNFalpha-induced IRS-1 serine phosphorylation, thereby suggesting a mechanism by which these inhibitors restore insulin signaling. |
| 3952 | 11043572 | We observe that TNFalpha requires 2.5-4 h to markedly reduce insulin-triggered tyrosine phosphorylation of IRS-1 in 3T3-L1 adipocytes. |
| 3953 | 11043572 | Although TNFalpha activates p42/44 MAP kinase, maximal stimulation is observed within 10-30 min. |
| 3954 | 11043572 | To our surprise, p42/44 activity returns to basal levels well before IRS-1 serine phosphorylation and insulin resistance are observed. |
| 3955 | 11043572 | These activation kinetics suggest a mechanism of p42/44 action more complicated than a direct phosphorylation of IRS-1 triggered by the early spike of TNFalpha-induced p42/44 activity. |
| 3956 | 11043572 | Chronic TNFalpha treatment (>> 72 h) causes adipocyte dedifferentiation, as evidenced by the loss of triglycerides and down-regulation of adipocyte-specific markers. |
| 3957 | 11043572 | We observe that this longer term TNFalpha-mediated dedifferentiation effect utilizes alternative, p42/44 MAP kinase-independent intracellular pathways. |
| 3958 | 11043572 | This study suggests that TNFalpha-mediated insulin resistance, but not adipocyte dedifferentiation, is mediated by the MEK1/2-p42/44 MAP kinase pathway. |
| 3959 | 11078443 | Sustained activation of insulin receptors internalized in GLUT4 vesicles of insulin-stimulated skeletal muscle. |
| 3960 | 11078443 | We report herein that, in skeletal muscle, in vivo stimulation with insulin induced a rapid internalization of the IR to an insulin-sensitive GLUT4-enriched intracellular membrane fraction. |
| 3961 | 11078443 | In marked contrast with hepatic endosomes or adipocyte low-density microsomes, no IR tyrosine dephosphorylation activity was observed in GLUT4-enriched vesicles isolated from skeletal muscle. |
| 3962 | 11078443 | The activated IR was recovered in immunopurified GLUT4 vesicles after insulin stimulation. |
| 3963 | 11078443 | Insulin also increased tyrosine-phosphorylated insulin receptor substrate 1 and phosphatidylinositol 3-kinase adapter (p85) subunit contents in the intracellular membrane fraction, but these signaling molecules were not directly associated with GLUT4 vesicles. |
| 3964 | 11078443 | We propose that compartmentalization of activated IRs to GLUT4 vesicles may play a role in sustaining insulin signaling at this locus in skeletal muscle. |
| 3965 | 11078455 | These results suggest that IRS-1 and IRS-2 may play different roles in the regulation of beta-cell mass and the function of individual beta-cells. |
| 3966 | 11080610 | Thus, studies of insulin resistance in Type 2 diabetes, obesity, fat-fed animals and lipid-treated cells have identified defects both at the level of insulin receptor-mediated tyrosine phosphorylation and at downstream sites such as protein kinase B (PKB) activation. |
| 3967 | 11080610 | The mechanisms giving rise to decreased insulin signalling include serine/threonine phosphorylation of insulin receptor substrate-1, but also direct inhibition of components such as PKB. |
| 3968 | 11113178 | Insulin receptor substrate 3 (IRS-3) and IRS-4 impair IRS-1- and IRS-2-mediated signaling. |
| 3969 | 11113178 | To investigate the roles of insulin receptor substrate 3 (IRS-3) and IRS-4 in the insulin-like growth factor 1 (IGF-1) signaling cascade, we introduced these proteins into 3T3 embryonic fibroblast cell lines prepared from wild-type (WT) and IRS-1 knockout (KO) mice by using a retroviral system. |
| 3970 | 11113178 | Following transduction of IRS-3 or IRS-4, the cells showed a significant decrease in IRS-2 mRNA and protein levels without any change in the IRS-1 protein level. |
| 3971 | 11113178 | However, IRS-3- or IRS-4-expressing cells also showed a marked decrease in IRS-1 and IRS-2 phosphorylation compared to the host cells. |
| 3972 | 11113178 | This decrease was accounted for in part by a decrease in the level of IRS-2 protein but occurred with no significant change in the IRS-1 protein level. |
| 3973 | 11113178 | IRS-3- or IRS-4-overexpressing cells showed an increase in basal phosphatidylinositol 3-kinase activity and basal Akt phosphorylation, while the IGF-1-stimulated levels correlated well with total tyrosine phosphorylation level of all IRS proteins in each cell line. |
| 3974 | 11113178 | In the IRS-1 KO cells, the impaired mitogenic response to IGF-1 was reconstituted with IRS-1 to supranormal levels and was returned to almost normal by IRS-2 or IRS-3 but was not improved by overexpression of IRS-4. |
| 3975 | 11113178 | These data suggest that IRS-3 and IRS-4 may act as negative regulators of the IGF-1 signaling pathway by suppressing the function of other IRS proteins at several steps. |
| 3976 | 11113178 | Insulin receptor substrate 3 (IRS-3) and IRS-4 impair IRS-1- and IRS-2-mediated signaling. |
| 3977 | 11113178 | To investigate the roles of insulin receptor substrate 3 (IRS-3) and IRS-4 in the insulin-like growth factor 1 (IGF-1) signaling cascade, we introduced these proteins into 3T3 embryonic fibroblast cell lines prepared from wild-type (WT) and IRS-1 knockout (KO) mice by using a retroviral system. |
| 3978 | 11113178 | Following transduction of IRS-3 or IRS-4, the cells showed a significant decrease in IRS-2 mRNA and protein levels without any change in the IRS-1 protein level. |
| 3979 | 11113178 | However, IRS-3- or IRS-4-expressing cells also showed a marked decrease in IRS-1 and IRS-2 phosphorylation compared to the host cells. |
| 3980 | 11113178 | This decrease was accounted for in part by a decrease in the level of IRS-2 protein but occurred with no significant change in the IRS-1 protein level. |
| 3981 | 11113178 | IRS-3- or IRS-4-overexpressing cells showed an increase in basal phosphatidylinositol 3-kinase activity and basal Akt phosphorylation, while the IGF-1-stimulated levels correlated well with total tyrosine phosphorylation level of all IRS proteins in each cell line. |
| 3982 | 11113178 | In the IRS-1 KO cells, the impaired mitogenic response to IGF-1 was reconstituted with IRS-1 to supranormal levels and was returned to almost normal by IRS-2 or IRS-3 but was not improved by overexpression of IRS-4. |
| 3983 | 11113178 | These data suggest that IRS-3 and IRS-4 may act as negative regulators of the IGF-1 signaling pathway by suppressing the function of other IRS proteins at several steps. |
| 3984 | 11113178 | Insulin receptor substrate 3 (IRS-3) and IRS-4 impair IRS-1- and IRS-2-mediated signaling. |
| 3985 | 11113178 | To investigate the roles of insulin receptor substrate 3 (IRS-3) and IRS-4 in the insulin-like growth factor 1 (IGF-1) signaling cascade, we introduced these proteins into 3T3 embryonic fibroblast cell lines prepared from wild-type (WT) and IRS-1 knockout (KO) mice by using a retroviral system. |
| 3986 | 11113178 | Following transduction of IRS-3 or IRS-4, the cells showed a significant decrease in IRS-2 mRNA and protein levels without any change in the IRS-1 protein level. |
| 3987 | 11113178 | However, IRS-3- or IRS-4-expressing cells also showed a marked decrease in IRS-1 and IRS-2 phosphorylation compared to the host cells. |
| 3988 | 11113178 | This decrease was accounted for in part by a decrease in the level of IRS-2 protein but occurred with no significant change in the IRS-1 protein level. |
| 3989 | 11113178 | IRS-3- or IRS-4-overexpressing cells showed an increase in basal phosphatidylinositol 3-kinase activity and basal Akt phosphorylation, while the IGF-1-stimulated levels correlated well with total tyrosine phosphorylation level of all IRS proteins in each cell line. |
| 3990 | 11113178 | In the IRS-1 KO cells, the impaired mitogenic response to IGF-1 was reconstituted with IRS-1 to supranormal levels and was returned to almost normal by IRS-2 or IRS-3 but was not improved by overexpression of IRS-4. |
| 3991 | 11113178 | These data suggest that IRS-3 and IRS-4 may act as negative regulators of the IGF-1 signaling pathway by suppressing the function of other IRS proteins at several steps. |
| 3992 | 11113178 | Insulin receptor substrate 3 (IRS-3) and IRS-4 impair IRS-1- and IRS-2-mediated signaling. |
| 3993 | 11113178 | To investigate the roles of insulin receptor substrate 3 (IRS-3) and IRS-4 in the insulin-like growth factor 1 (IGF-1) signaling cascade, we introduced these proteins into 3T3 embryonic fibroblast cell lines prepared from wild-type (WT) and IRS-1 knockout (KO) mice by using a retroviral system. |
| 3994 | 11113178 | Following transduction of IRS-3 or IRS-4, the cells showed a significant decrease in IRS-2 mRNA and protein levels without any change in the IRS-1 protein level. |
| 3995 | 11113178 | However, IRS-3- or IRS-4-expressing cells also showed a marked decrease in IRS-1 and IRS-2 phosphorylation compared to the host cells. |
| 3996 | 11113178 | This decrease was accounted for in part by a decrease in the level of IRS-2 protein but occurred with no significant change in the IRS-1 protein level. |
| 3997 | 11113178 | IRS-3- or IRS-4-overexpressing cells showed an increase in basal phosphatidylinositol 3-kinase activity and basal Akt phosphorylation, while the IGF-1-stimulated levels correlated well with total tyrosine phosphorylation level of all IRS proteins in each cell line. |
| 3998 | 11113178 | In the IRS-1 KO cells, the impaired mitogenic response to IGF-1 was reconstituted with IRS-1 to supranormal levels and was returned to almost normal by IRS-2 or IRS-3 but was not improved by overexpression of IRS-4. |
| 3999 | 11113178 | These data suggest that IRS-3 and IRS-4 may act as negative regulators of the IGF-1 signaling pathway by suppressing the function of other IRS proteins at several steps. |
| 4000 | 11113178 | Insulin receptor substrate 3 (IRS-3) and IRS-4 impair IRS-1- and IRS-2-mediated signaling. |
| 4001 | 11113178 | To investigate the roles of insulin receptor substrate 3 (IRS-3) and IRS-4 in the insulin-like growth factor 1 (IGF-1) signaling cascade, we introduced these proteins into 3T3 embryonic fibroblast cell lines prepared from wild-type (WT) and IRS-1 knockout (KO) mice by using a retroviral system. |
| 4002 | 11113178 | Following transduction of IRS-3 or IRS-4, the cells showed a significant decrease in IRS-2 mRNA and protein levels without any change in the IRS-1 protein level. |
| 4003 | 11113178 | However, IRS-3- or IRS-4-expressing cells also showed a marked decrease in IRS-1 and IRS-2 phosphorylation compared to the host cells. |
| 4004 | 11113178 | This decrease was accounted for in part by a decrease in the level of IRS-2 protein but occurred with no significant change in the IRS-1 protein level. |
| 4005 | 11113178 | IRS-3- or IRS-4-overexpressing cells showed an increase in basal phosphatidylinositol 3-kinase activity and basal Akt phosphorylation, while the IGF-1-stimulated levels correlated well with total tyrosine phosphorylation level of all IRS proteins in each cell line. |
| 4006 | 11113178 | In the IRS-1 KO cells, the impaired mitogenic response to IGF-1 was reconstituted with IRS-1 to supranormal levels and was returned to almost normal by IRS-2 or IRS-3 but was not improved by overexpression of IRS-4. |
| 4007 | 11113178 | These data suggest that IRS-3 and IRS-4 may act as negative regulators of the IGF-1 signaling pathway by suppressing the function of other IRS proteins at several steps. |
| 4008 | 11113183 | The p90 ribosomal S6 kinase (RSK), a cytosolic substrate for the extracellular signal-regulated kinase (ERK), is involved in transcriptional regulation, and one isoform (RSK2) has been implicated in the activation of glycogen synthase by insulin. |
| 4009 | 11113183 | To determine RSK2 function in vivo, mice lacking a functional rsk2 gene were generated and studied in response to insulin and exercise, two potent stimulators of the ERK cascade in skeletal muscle. |
| 4010 | 11113183 | While insulin and exercise significantly increased ERK phosphorylation in skeletal muscle from both WT and KO mice, the increases were twofold greater in the KO animals. |
| 4011 | 11113183 | The enhanced insulin-stimulated increases in ERK and glycogen synthase activities in KO mice were not associated with higher insulin receptor or with IRS1 tyrosine phosphorylation or with IRS1 binding to phosphatidylinositol 3-kinase. |
| 4012 | 11113183 | However, insulin-stimulated serine phosphorylation of Akt was significantly higher in the KO animals. c-fos mRNA was increased similarly in muscle from WT and KO mice in response to insulin (2. 5-fold) and exercise (15-fold). |
| 4013 | 11113183 | In conclusion, RSK2 likely plays a major role in feedback inhibition of the ERK pathway in skeletal muscle. |
| 4014 | 11113183 | Furthermore, RSK2 is not required for activation of muscle glycogen synthase by insulin but may indirectly modulate muscle glycogen synthase activity and/or glycogen content by other mechanisms, possibly through regulation of Akt. |
| 4015 | 11113183 | RSK2 knockout mice may be a good animal model for the study of Coffin-Lowry syndrome. |
| 4016 | 11113206 | The most widely distributed members of the family of insulin receptor substrate (IRS) proteins are IRS-1 and IRS-2. |
| 4017 | 11113206 | These proteins participate in insulin and insulin-like growth factor 1 signaling, as well as the actions of some cytokines, growth hormone, and prolactin. |
| 4018 | 11113206 | To more precisely define the specific role of IRS-1 in adipocyte biology, we established brown adipocyte cell lines from wild-type and IRS-1 knockout (KO) animals. |
| 4019 | 11113206 | Using differentiation protocols, both with and without insulin, preadipocyte cell lines derived from IRS-1 KO mice exhibited a marked decrease in differentiation and lipid accumulation (10 to 40%) compared to wild-type cells (90 to 100%). |
| 4020 | 11113206 | Furthermore, IRS-1 KO cells showed decreased expression of adipogenic marker proteins, such as peroxisome proliferator-activated receptor gamma (PPARgamma), CCAAT/enhancer-binding protein alpha (C/EBPalpha), fatty acid synthase, uncoupling protein-1, and glucose transporter 4. |
| 4021 | 11113206 | The differentiation deficit in the KO cells could be reversed almost completely by retrovirus-mediated reexpression of IRS-1, PPARgamma, or C/EBPalpha but not the thiazolidinedione troglitazone. |
| 4022 | 11113206 | Phosphatidylinositol 3-kinase (PI 3-kinase) assays performed at various stages of the differentiation process revealed a strong and transient activation in IRS-1, IRS-2, and phosphotyrosine-associated PI 3-kinase in the wild-type cells, whereas the IRS-1 KO cells showed impaired phosphotyrosine-associated PI 3-kinase activation, all of which was associated with IRS-2. |
| 4023 | 11113206 | Thus, IRS-1 appears to be an important mediator of brown adipocyte maturation. |
| 4024 | 11113206 | Furthermore, this signaling molecule appears to exert its unique role in the differentiation process via activation of PI 3-kinase and its downstream target, Akt, and is upstream of the effects of PPARgamma and C/EBPalpha. |
| 4025 | 11113206 | The most widely distributed members of the family of insulin receptor substrate (IRS) proteins are IRS-1 and IRS-2. |
| 4026 | 11113206 | These proteins participate in insulin and insulin-like growth factor 1 signaling, as well as the actions of some cytokines, growth hormone, and prolactin. |
| 4027 | 11113206 | To more precisely define the specific role of IRS-1 in adipocyte biology, we established brown adipocyte cell lines from wild-type and IRS-1 knockout (KO) animals. |
| 4028 | 11113206 | Using differentiation protocols, both with and without insulin, preadipocyte cell lines derived from IRS-1 KO mice exhibited a marked decrease in differentiation and lipid accumulation (10 to 40%) compared to wild-type cells (90 to 100%). |
| 4029 | 11113206 | Furthermore, IRS-1 KO cells showed decreased expression of adipogenic marker proteins, such as peroxisome proliferator-activated receptor gamma (PPARgamma), CCAAT/enhancer-binding protein alpha (C/EBPalpha), fatty acid synthase, uncoupling protein-1, and glucose transporter 4. |
| 4030 | 11113206 | The differentiation deficit in the KO cells could be reversed almost completely by retrovirus-mediated reexpression of IRS-1, PPARgamma, or C/EBPalpha but not the thiazolidinedione troglitazone. |
| 4031 | 11113206 | Phosphatidylinositol 3-kinase (PI 3-kinase) assays performed at various stages of the differentiation process revealed a strong and transient activation in IRS-1, IRS-2, and phosphotyrosine-associated PI 3-kinase in the wild-type cells, whereas the IRS-1 KO cells showed impaired phosphotyrosine-associated PI 3-kinase activation, all of which was associated with IRS-2. |
| 4032 | 11113206 | Thus, IRS-1 appears to be an important mediator of brown adipocyte maturation. |
| 4033 | 11113206 | Furthermore, this signaling molecule appears to exert its unique role in the differentiation process via activation of PI 3-kinase and its downstream target, Akt, and is upstream of the effects of PPARgamma and C/EBPalpha. |
| 4034 | 11113206 | The most widely distributed members of the family of insulin receptor substrate (IRS) proteins are IRS-1 and IRS-2. |
| 4035 | 11113206 | These proteins participate in insulin and insulin-like growth factor 1 signaling, as well as the actions of some cytokines, growth hormone, and prolactin. |
| 4036 | 11113206 | To more precisely define the specific role of IRS-1 in adipocyte biology, we established brown adipocyte cell lines from wild-type and IRS-1 knockout (KO) animals. |
| 4037 | 11113206 | Using differentiation protocols, both with and without insulin, preadipocyte cell lines derived from IRS-1 KO mice exhibited a marked decrease in differentiation and lipid accumulation (10 to 40%) compared to wild-type cells (90 to 100%). |
| 4038 | 11113206 | Furthermore, IRS-1 KO cells showed decreased expression of adipogenic marker proteins, such as peroxisome proliferator-activated receptor gamma (PPARgamma), CCAAT/enhancer-binding protein alpha (C/EBPalpha), fatty acid synthase, uncoupling protein-1, and glucose transporter 4. |
| 4039 | 11113206 | The differentiation deficit in the KO cells could be reversed almost completely by retrovirus-mediated reexpression of IRS-1, PPARgamma, or C/EBPalpha but not the thiazolidinedione troglitazone. |
| 4040 | 11113206 | Phosphatidylinositol 3-kinase (PI 3-kinase) assays performed at various stages of the differentiation process revealed a strong and transient activation in IRS-1, IRS-2, and phosphotyrosine-associated PI 3-kinase in the wild-type cells, whereas the IRS-1 KO cells showed impaired phosphotyrosine-associated PI 3-kinase activation, all of which was associated with IRS-2. |
| 4041 | 11113206 | Thus, IRS-1 appears to be an important mediator of brown adipocyte maturation. |
| 4042 | 11113206 | Furthermore, this signaling molecule appears to exert its unique role in the differentiation process via activation of PI 3-kinase and its downstream target, Akt, and is upstream of the effects of PPARgamma and C/EBPalpha. |
| 4043 | 11113206 | The most widely distributed members of the family of insulin receptor substrate (IRS) proteins are IRS-1 and IRS-2. |
| 4044 | 11113206 | These proteins participate in insulin and insulin-like growth factor 1 signaling, as well as the actions of some cytokines, growth hormone, and prolactin. |
| 4045 | 11113206 | To more precisely define the specific role of IRS-1 in adipocyte biology, we established brown adipocyte cell lines from wild-type and IRS-1 knockout (KO) animals. |
| 4046 | 11113206 | Using differentiation protocols, both with and without insulin, preadipocyte cell lines derived from IRS-1 KO mice exhibited a marked decrease in differentiation and lipid accumulation (10 to 40%) compared to wild-type cells (90 to 100%). |
| 4047 | 11113206 | Furthermore, IRS-1 KO cells showed decreased expression of adipogenic marker proteins, such as peroxisome proliferator-activated receptor gamma (PPARgamma), CCAAT/enhancer-binding protein alpha (C/EBPalpha), fatty acid synthase, uncoupling protein-1, and glucose transporter 4. |
| 4048 | 11113206 | The differentiation deficit in the KO cells could be reversed almost completely by retrovirus-mediated reexpression of IRS-1, PPARgamma, or C/EBPalpha but not the thiazolidinedione troglitazone. |
| 4049 | 11113206 | Phosphatidylinositol 3-kinase (PI 3-kinase) assays performed at various stages of the differentiation process revealed a strong and transient activation in IRS-1, IRS-2, and phosphotyrosine-associated PI 3-kinase in the wild-type cells, whereas the IRS-1 KO cells showed impaired phosphotyrosine-associated PI 3-kinase activation, all of which was associated with IRS-2. |
| 4050 | 11113206 | Thus, IRS-1 appears to be an important mediator of brown adipocyte maturation. |
| 4051 | 11113206 | Furthermore, this signaling molecule appears to exert its unique role in the differentiation process via activation of PI 3-kinase and its downstream target, Akt, and is upstream of the effects of PPARgamma and C/EBPalpha. |
| 4052 | 11113206 | The most widely distributed members of the family of insulin receptor substrate (IRS) proteins are IRS-1 and IRS-2. |
| 4053 | 11113206 | These proteins participate in insulin and insulin-like growth factor 1 signaling, as well as the actions of some cytokines, growth hormone, and prolactin. |
| 4054 | 11113206 | To more precisely define the specific role of IRS-1 in adipocyte biology, we established brown adipocyte cell lines from wild-type and IRS-1 knockout (KO) animals. |
| 4055 | 11113206 | Using differentiation protocols, both with and without insulin, preadipocyte cell lines derived from IRS-1 KO mice exhibited a marked decrease in differentiation and lipid accumulation (10 to 40%) compared to wild-type cells (90 to 100%). |
| 4056 | 11113206 | Furthermore, IRS-1 KO cells showed decreased expression of adipogenic marker proteins, such as peroxisome proliferator-activated receptor gamma (PPARgamma), CCAAT/enhancer-binding protein alpha (C/EBPalpha), fatty acid synthase, uncoupling protein-1, and glucose transporter 4. |
| 4057 | 11113206 | The differentiation deficit in the KO cells could be reversed almost completely by retrovirus-mediated reexpression of IRS-1, PPARgamma, or C/EBPalpha but not the thiazolidinedione troglitazone. |
| 4058 | 11113206 | Phosphatidylinositol 3-kinase (PI 3-kinase) assays performed at various stages of the differentiation process revealed a strong and transient activation in IRS-1, IRS-2, and phosphotyrosine-associated PI 3-kinase in the wild-type cells, whereas the IRS-1 KO cells showed impaired phosphotyrosine-associated PI 3-kinase activation, all of which was associated with IRS-2. |
| 4059 | 11113206 | Thus, IRS-1 appears to be an important mediator of brown adipocyte maturation. |
| 4060 | 11113206 | Furthermore, this signaling molecule appears to exert its unique role in the differentiation process via activation of PI 3-kinase and its downstream target, Akt, and is upstream of the effects of PPARgamma and C/EBPalpha. |
| 4061 | 11113206 | The most widely distributed members of the family of insulin receptor substrate (IRS) proteins are IRS-1 and IRS-2. |
| 4062 | 11113206 | These proteins participate in insulin and insulin-like growth factor 1 signaling, as well as the actions of some cytokines, growth hormone, and prolactin. |
| 4063 | 11113206 | To more precisely define the specific role of IRS-1 in adipocyte biology, we established brown adipocyte cell lines from wild-type and IRS-1 knockout (KO) animals. |
| 4064 | 11113206 | Using differentiation protocols, both with and without insulin, preadipocyte cell lines derived from IRS-1 KO mice exhibited a marked decrease in differentiation and lipid accumulation (10 to 40%) compared to wild-type cells (90 to 100%). |
| 4065 | 11113206 | Furthermore, IRS-1 KO cells showed decreased expression of adipogenic marker proteins, such as peroxisome proliferator-activated receptor gamma (PPARgamma), CCAAT/enhancer-binding protein alpha (C/EBPalpha), fatty acid synthase, uncoupling protein-1, and glucose transporter 4. |
| 4066 | 11113206 | The differentiation deficit in the KO cells could be reversed almost completely by retrovirus-mediated reexpression of IRS-1, PPARgamma, or C/EBPalpha but not the thiazolidinedione troglitazone. |
| 4067 | 11113206 | Phosphatidylinositol 3-kinase (PI 3-kinase) assays performed at various stages of the differentiation process revealed a strong and transient activation in IRS-1, IRS-2, and phosphotyrosine-associated PI 3-kinase in the wild-type cells, whereas the IRS-1 KO cells showed impaired phosphotyrosine-associated PI 3-kinase activation, all of which was associated with IRS-2. |
| 4068 | 11113206 | Thus, IRS-1 appears to be an important mediator of brown adipocyte maturation. |
| 4069 | 11113206 | Furthermore, this signaling molecule appears to exert its unique role in the differentiation process via activation of PI 3-kinase and its downstream target, Akt, and is upstream of the effects of PPARgamma and C/EBPalpha. |
| 4070 | 11113206 | The most widely distributed members of the family of insulin receptor substrate (IRS) proteins are IRS-1 and IRS-2. |
| 4071 | 11113206 | These proteins participate in insulin and insulin-like growth factor 1 signaling, as well as the actions of some cytokines, growth hormone, and prolactin. |
| 4072 | 11113206 | To more precisely define the specific role of IRS-1 in adipocyte biology, we established brown adipocyte cell lines from wild-type and IRS-1 knockout (KO) animals. |
| 4073 | 11113206 | Using differentiation protocols, both with and without insulin, preadipocyte cell lines derived from IRS-1 KO mice exhibited a marked decrease in differentiation and lipid accumulation (10 to 40%) compared to wild-type cells (90 to 100%). |
| 4074 | 11113206 | Furthermore, IRS-1 KO cells showed decreased expression of adipogenic marker proteins, such as peroxisome proliferator-activated receptor gamma (PPARgamma), CCAAT/enhancer-binding protein alpha (C/EBPalpha), fatty acid synthase, uncoupling protein-1, and glucose transporter 4. |
| 4075 | 11113206 | The differentiation deficit in the KO cells could be reversed almost completely by retrovirus-mediated reexpression of IRS-1, PPARgamma, or C/EBPalpha but not the thiazolidinedione troglitazone. |
| 4076 | 11113206 | Phosphatidylinositol 3-kinase (PI 3-kinase) assays performed at various stages of the differentiation process revealed a strong and transient activation in IRS-1, IRS-2, and phosphotyrosine-associated PI 3-kinase in the wild-type cells, whereas the IRS-1 KO cells showed impaired phosphotyrosine-associated PI 3-kinase activation, all of which was associated with IRS-2. |
| 4077 | 11113206 | Thus, IRS-1 appears to be an important mediator of brown adipocyte maturation. |
| 4078 | 11113206 | Furthermore, this signaling molecule appears to exert its unique role in the differentiation process via activation of PI 3-kinase and its downstream target, Akt, and is upstream of the effects of PPARgamma and C/EBPalpha. |
| 4079 | 11114102 | Four members (IRS-1, IRS-2, IRS-3, IRS-4) of this family have been identified which differ in their subcellular distribution and interaction with SH2 domain proteins. |
| 4080 | 11120660 | Diversification of cardiac insulin signaling involves the p85 alpha/beta subunits of phosphatidylinositol 3-kinase. |
| 4081 | 11120660 | Ventricular cardiomyocytes and cardiac tissue of lean and genetically obese (fa/fa) Zucker rats were used 1) to study the role of the p85 regulatory subunit isoforms p85 alpha and p85 beta for insulin signaling through the phosphatidylinositol (PI) 3-kinase pathway, and 2) to elucidate the implications of these mechanisms for cardiac insulin resistance. |
| 4082 | 11120660 | Western blot analysis of cardiomyocyte lysates revealed expression of p85 alpha and p85 beta but no detectable amounts of the splice variants of p85 alpha. |
| 4083 | 11120660 | Essentially no p85 alpha subunit of PI 3-kinase was found to be associated with insulin receptor substrate (IRS)-1 or IRS-2 in basal and insulin-stimulated (5 min) cardiomyocytes. |
| 4084 | 11120660 | Instead, insulin produced a twofold increase in p85 beta associated with IRS-1, leading to a three- to fourfold increase in p85 beta-associated PI 3-kinase activity. |
| 4085 | 11120660 | In GLUT-4-containing vesicles, an increased abundance (3.7 +/- 0.7-fold over basal) of p85 alpha was observed after insulin stimulation of lean animals, with no significant effect in the obese group. |
| 4086 | 11120660 | No p85 beta could be detected in GLUT-4-containing vesicles. |
| 4087 | 11120660 | We conclude that, in the heart, p85 alpha recruits PI 3-kinase activity to GLUT-4 vesicles, whereas p85 beta represents the main regulator of IRS-1- and IRS-2-mediated PI 3-kinase activation. |
| 4088 | 11120660 | Furthermore, multiple defects of PI 3-kinase activation, involving both the p85 alpha and the p85 beta adaptor subunits, may contribute to cardiac insulin resistance. |
| 4089 | 11145586 | Free fatty acid-induced inhibition of glucose and insulin-like growth factor I-induced deoxyribonucleic acid synthesis in the pancreatic beta-cell line INS-1. |
| 4090 | 11145586 | Pancreatic beta-cell mitogenesis is increased by insulin-like growth factor I (IGF-I) in a glucose-dependent manner. |
| 4091 | 11145586 | An examination of mitogenic signal transduction pathways in INS-1 cells revealed that glucose/IGF-I induction of early signaling elements in SH2-containing protein (Shc)- and insulin receptor substrate-1/2-mediated pathways leading to downstream mitogen-activated protein kinase and phosphoinositol 3'-kinase activation, were unaffected by FFA. |
| 4092 | 11145586 | However, glucose-/IGF-I-induced activation of protein kinase B (PKB) was significantly inhibited, and protein kinase Czeta was chronically activated by FFA. |
| 4093 | 11147790 | In this study, we have investigated the early events in the insulin pathway that trigger the degradation of IRS-1. |
| 4094 | 11147790 | Incubation of the adipocytes with insulin induced a fast electrophoretic mobility shift of IRS-1 and a subsequent degradation of the protein. |
| 4095 | 11147790 | Wortmannin and rapamycin blocked this mobility shift of IRS-1, maintained the insulin-induced tyrosine phosphorylation of IRS-1, and blocked its degradation. |
| 4096 | 11147790 | Incubation with okadaic acid increased the serine/threonine phosphorylation of IRS-1 and its degradation, mimicking insulin, and its effect was prevented by the proteasome inhibitor lactacystin, as well as by rapamycin. |
| 4097 | 11147790 | Treatment of the cells with the tyrosine phosphatase inhibitor orthovanadate in the presence of insulin or okadaic acid partially inhibited the degradation of IRS-1. |
| 4098 | 11147790 | Thus, regulation of serine/threonine versus tyrosine phosphorylation may modulate IRS-1 degradation, affecting insulin sensitivity. |
| 4099 | 11147790 | In this study, we have investigated the early events in the insulin pathway that trigger the degradation of IRS-1. |
| 4100 | 11147790 | Incubation of the adipocytes with insulin induced a fast electrophoretic mobility shift of IRS-1 and a subsequent degradation of the protein. |
| 4101 | 11147790 | Wortmannin and rapamycin blocked this mobility shift of IRS-1, maintained the insulin-induced tyrosine phosphorylation of IRS-1, and blocked its degradation. |
| 4102 | 11147790 | Incubation with okadaic acid increased the serine/threonine phosphorylation of IRS-1 and its degradation, mimicking insulin, and its effect was prevented by the proteasome inhibitor lactacystin, as well as by rapamycin. |
| 4103 | 11147790 | Treatment of the cells with the tyrosine phosphatase inhibitor orthovanadate in the presence of insulin or okadaic acid partially inhibited the degradation of IRS-1. |
| 4104 | 11147790 | Thus, regulation of serine/threonine versus tyrosine phosphorylation may modulate IRS-1 degradation, affecting insulin sensitivity. |
| 4105 | 11147790 | In this study, we have investigated the early events in the insulin pathway that trigger the degradation of IRS-1. |
| 4106 | 11147790 | Incubation of the adipocytes with insulin induced a fast electrophoretic mobility shift of IRS-1 and a subsequent degradation of the protein. |
| 4107 | 11147790 | Wortmannin and rapamycin blocked this mobility shift of IRS-1, maintained the insulin-induced tyrosine phosphorylation of IRS-1, and blocked its degradation. |
| 4108 | 11147790 | Incubation with okadaic acid increased the serine/threonine phosphorylation of IRS-1 and its degradation, mimicking insulin, and its effect was prevented by the proteasome inhibitor lactacystin, as well as by rapamycin. |
| 4109 | 11147790 | Treatment of the cells with the tyrosine phosphatase inhibitor orthovanadate in the presence of insulin or okadaic acid partially inhibited the degradation of IRS-1. |
| 4110 | 11147790 | Thus, regulation of serine/threonine versus tyrosine phosphorylation may modulate IRS-1 degradation, affecting insulin sensitivity. |
| 4111 | 11147790 | In this study, we have investigated the early events in the insulin pathway that trigger the degradation of IRS-1. |
| 4112 | 11147790 | Incubation of the adipocytes with insulin induced a fast electrophoretic mobility shift of IRS-1 and a subsequent degradation of the protein. |
| 4113 | 11147790 | Wortmannin and rapamycin blocked this mobility shift of IRS-1, maintained the insulin-induced tyrosine phosphorylation of IRS-1, and blocked its degradation. |
| 4114 | 11147790 | Incubation with okadaic acid increased the serine/threonine phosphorylation of IRS-1 and its degradation, mimicking insulin, and its effect was prevented by the proteasome inhibitor lactacystin, as well as by rapamycin. |
| 4115 | 11147790 | Treatment of the cells with the tyrosine phosphatase inhibitor orthovanadate in the presence of insulin or okadaic acid partially inhibited the degradation of IRS-1. |
| 4116 | 11147790 | Thus, regulation of serine/threonine versus tyrosine phosphorylation may modulate IRS-1 degradation, affecting insulin sensitivity. |
| 4117 | 11147790 | In this study, we have investigated the early events in the insulin pathway that trigger the degradation of IRS-1. |
| 4118 | 11147790 | Incubation of the adipocytes with insulin induced a fast electrophoretic mobility shift of IRS-1 and a subsequent degradation of the protein. |
| 4119 | 11147790 | Wortmannin and rapamycin blocked this mobility shift of IRS-1, maintained the insulin-induced tyrosine phosphorylation of IRS-1, and blocked its degradation. |
| 4120 | 11147790 | Incubation with okadaic acid increased the serine/threonine phosphorylation of IRS-1 and its degradation, mimicking insulin, and its effect was prevented by the proteasome inhibitor lactacystin, as well as by rapamycin. |
| 4121 | 11147790 | Treatment of the cells with the tyrosine phosphatase inhibitor orthovanadate in the presence of insulin or okadaic acid partially inhibited the degradation of IRS-1. |
| 4122 | 11147790 | Thus, regulation of serine/threonine versus tyrosine phosphorylation may modulate IRS-1 degradation, affecting insulin sensitivity. |
| 4123 | 11147790 | In this study, we have investigated the early events in the insulin pathway that trigger the degradation of IRS-1. |
| 4124 | 11147790 | Incubation of the adipocytes with insulin induced a fast electrophoretic mobility shift of IRS-1 and a subsequent degradation of the protein. |
| 4125 | 11147790 | Wortmannin and rapamycin blocked this mobility shift of IRS-1, maintained the insulin-induced tyrosine phosphorylation of IRS-1, and blocked its degradation. |
| 4126 | 11147790 | Incubation with okadaic acid increased the serine/threonine phosphorylation of IRS-1 and its degradation, mimicking insulin, and its effect was prevented by the proteasome inhibitor lactacystin, as well as by rapamycin. |
| 4127 | 11147790 | Treatment of the cells with the tyrosine phosphatase inhibitor orthovanadate in the presence of insulin or okadaic acid partially inhibited the degradation of IRS-1. |
| 4128 | 11147790 | Thus, regulation of serine/threonine versus tyrosine phosphorylation may modulate IRS-1 degradation, affecting insulin sensitivity. |
| 4129 | 11160134 | Insulin/IGF-1 and TNF-alpha stimulate phosphorylation of IRS-1 at inhibitory Ser307 via distinct pathways. |
| 4130 | 11160134 | Serine/threonine phosphorylation of IRS-1 might inhibit insulin signaling, but the relevant phosphorylation sites are difficult to identify in cultured cells and to validate in isolated tissues. |
| 4131 | 11160134 | Recently, we discovered that recombinant NH2-terminal Jun kinase phosphorylates IRS-1 at Ser307, which inhibits insulin-stimulated tyrosine phosphorylation of IRS-1. |
| 4132 | 11160134 | This antibody revealed that TNF-alpha, IGF-1, or insulin stimulated phosphorylation of IRS-1 at Ser307 in 3T3-L1 preadipocytes and adipocytes. |
| 4133 | 11160134 | Insulin injected into mice or rats also stimulated phosphorylation of Ser307 on IRS-1 immunoprecipitated from muscle; moreover, Ser307 was phosphorylated in human muscle during the hyperinsulinemic euglycemic clamp. |
| 4134 | 11160134 | Experiments in 3T3-L1 preadipocytes and adipocytes revealed that insulin-stimulated phosphorylation of Ser307 was inhibited by LY294002 or wortmannin, whereas TNF-alpha-stimulated phosphorylation was inhibited by PD98059. |
| 4135 | 11160134 | Thus, distinct kinase pathways might converge at Ser307 to mediate feedback or heterologous inhibition of IRS-1 signaling to counterregulate the insulin response. |
| 4136 | 11160134 | Insulin/IGF-1 and TNF-alpha stimulate phosphorylation of IRS-1 at inhibitory Ser307 via distinct pathways. |
| 4137 | 11160134 | Serine/threonine phosphorylation of IRS-1 might inhibit insulin signaling, but the relevant phosphorylation sites are difficult to identify in cultured cells and to validate in isolated tissues. |
| 4138 | 11160134 | Recently, we discovered that recombinant NH2-terminal Jun kinase phosphorylates IRS-1 at Ser307, which inhibits insulin-stimulated tyrosine phosphorylation of IRS-1. |
| 4139 | 11160134 | This antibody revealed that TNF-alpha, IGF-1, or insulin stimulated phosphorylation of IRS-1 at Ser307 in 3T3-L1 preadipocytes and adipocytes. |
| 4140 | 11160134 | Insulin injected into mice or rats also stimulated phosphorylation of Ser307 on IRS-1 immunoprecipitated from muscle; moreover, Ser307 was phosphorylated in human muscle during the hyperinsulinemic euglycemic clamp. |
| 4141 | 11160134 | Experiments in 3T3-L1 preadipocytes and adipocytes revealed that insulin-stimulated phosphorylation of Ser307 was inhibited by LY294002 or wortmannin, whereas TNF-alpha-stimulated phosphorylation was inhibited by PD98059. |
| 4142 | 11160134 | Thus, distinct kinase pathways might converge at Ser307 to mediate feedback or heterologous inhibition of IRS-1 signaling to counterregulate the insulin response. |
| 4143 | 11160134 | Insulin/IGF-1 and TNF-alpha stimulate phosphorylation of IRS-1 at inhibitory Ser307 via distinct pathways. |
| 4144 | 11160134 | Serine/threonine phosphorylation of IRS-1 might inhibit insulin signaling, but the relevant phosphorylation sites are difficult to identify in cultured cells and to validate in isolated tissues. |
| 4145 | 11160134 | Recently, we discovered that recombinant NH2-terminal Jun kinase phosphorylates IRS-1 at Ser307, which inhibits insulin-stimulated tyrosine phosphorylation of IRS-1. |
| 4146 | 11160134 | This antibody revealed that TNF-alpha, IGF-1, or insulin stimulated phosphorylation of IRS-1 at Ser307 in 3T3-L1 preadipocytes and adipocytes. |
| 4147 | 11160134 | Insulin injected into mice or rats also stimulated phosphorylation of Ser307 on IRS-1 immunoprecipitated from muscle; moreover, Ser307 was phosphorylated in human muscle during the hyperinsulinemic euglycemic clamp. |
| 4148 | 11160134 | Experiments in 3T3-L1 preadipocytes and adipocytes revealed that insulin-stimulated phosphorylation of Ser307 was inhibited by LY294002 or wortmannin, whereas TNF-alpha-stimulated phosphorylation was inhibited by PD98059. |
| 4149 | 11160134 | Thus, distinct kinase pathways might converge at Ser307 to mediate feedback or heterologous inhibition of IRS-1 signaling to counterregulate the insulin response. |
| 4150 | 11160134 | Insulin/IGF-1 and TNF-alpha stimulate phosphorylation of IRS-1 at inhibitory Ser307 via distinct pathways. |
| 4151 | 11160134 | Serine/threonine phosphorylation of IRS-1 might inhibit insulin signaling, but the relevant phosphorylation sites are difficult to identify in cultured cells and to validate in isolated tissues. |
| 4152 | 11160134 | Recently, we discovered that recombinant NH2-terminal Jun kinase phosphorylates IRS-1 at Ser307, which inhibits insulin-stimulated tyrosine phosphorylation of IRS-1. |
| 4153 | 11160134 | This antibody revealed that TNF-alpha, IGF-1, or insulin stimulated phosphorylation of IRS-1 at Ser307 in 3T3-L1 preadipocytes and adipocytes. |
| 4154 | 11160134 | Insulin injected into mice or rats also stimulated phosphorylation of Ser307 on IRS-1 immunoprecipitated from muscle; moreover, Ser307 was phosphorylated in human muscle during the hyperinsulinemic euglycemic clamp. |
| 4155 | 11160134 | Experiments in 3T3-L1 preadipocytes and adipocytes revealed that insulin-stimulated phosphorylation of Ser307 was inhibited by LY294002 or wortmannin, whereas TNF-alpha-stimulated phosphorylation was inhibited by PD98059. |
| 4156 | 11160134 | Thus, distinct kinase pathways might converge at Ser307 to mediate feedback or heterologous inhibition of IRS-1 signaling to counterregulate the insulin response. |
| 4157 | 11160134 | Insulin/IGF-1 and TNF-alpha stimulate phosphorylation of IRS-1 at inhibitory Ser307 via distinct pathways. |
| 4158 | 11160134 | Serine/threonine phosphorylation of IRS-1 might inhibit insulin signaling, but the relevant phosphorylation sites are difficult to identify in cultured cells and to validate in isolated tissues. |
| 4159 | 11160134 | Recently, we discovered that recombinant NH2-terminal Jun kinase phosphorylates IRS-1 at Ser307, which inhibits insulin-stimulated tyrosine phosphorylation of IRS-1. |
| 4160 | 11160134 | This antibody revealed that TNF-alpha, IGF-1, or insulin stimulated phosphorylation of IRS-1 at Ser307 in 3T3-L1 preadipocytes and adipocytes. |
| 4161 | 11160134 | Insulin injected into mice or rats also stimulated phosphorylation of Ser307 on IRS-1 immunoprecipitated from muscle; moreover, Ser307 was phosphorylated in human muscle during the hyperinsulinemic euglycemic clamp. |
| 4162 | 11160134 | Experiments in 3T3-L1 preadipocytes and adipocytes revealed that insulin-stimulated phosphorylation of Ser307 was inhibited by LY294002 or wortmannin, whereas TNF-alpha-stimulated phosphorylation was inhibited by PD98059. |
| 4163 | 11160134 | Thus, distinct kinase pathways might converge at Ser307 to mediate feedback or heterologous inhibition of IRS-1 signaling to counterregulate the insulin response. |
| 4164 | 11160134 | Insulin/IGF-1 and TNF-alpha stimulate phosphorylation of IRS-1 at inhibitory Ser307 via distinct pathways. |
| 4165 | 11160134 | Serine/threonine phosphorylation of IRS-1 might inhibit insulin signaling, but the relevant phosphorylation sites are difficult to identify in cultured cells and to validate in isolated tissues. |
| 4166 | 11160134 | Recently, we discovered that recombinant NH2-terminal Jun kinase phosphorylates IRS-1 at Ser307, which inhibits insulin-stimulated tyrosine phosphorylation of IRS-1. |
| 4167 | 11160134 | This antibody revealed that TNF-alpha, IGF-1, or insulin stimulated phosphorylation of IRS-1 at Ser307 in 3T3-L1 preadipocytes and adipocytes. |
| 4168 | 11160134 | Insulin injected into mice or rats also stimulated phosphorylation of Ser307 on IRS-1 immunoprecipitated from muscle; moreover, Ser307 was phosphorylated in human muscle during the hyperinsulinemic euglycemic clamp. |
| 4169 | 11160134 | Experiments in 3T3-L1 preadipocytes and adipocytes revealed that insulin-stimulated phosphorylation of Ser307 was inhibited by LY294002 or wortmannin, whereas TNF-alpha-stimulated phosphorylation was inhibited by PD98059. |
| 4170 | 11160134 | Thus, distinct kinase pathways might converge at Ser307 to mediate feedback or heterologous inhibition of IRS-1 signaling to counterregulate the insulin response. |
| 4171 | 11162649 | In addition, pV stimulated insulin secretion approximately 3-fold in depolarized cells at both low and high glucose. pV markedly increased the tyrosine phosphorylation of several proteins, including IRS-1 and -2, and also increased the phosphorylation of the downstream kinases PKB/Akt and MAPK. |
| 4172 | 11162649 | PKB/Akt, but not MAPK, was also phosphorylated in the absence of pV. |
| 4173 | 11162649 | Intracellular pV-stimulated tyrosine phosphorylation, including that of IRS-2, was generally increased by high glucose suggesting a further inhibition of PTP and/or enhanced tyrosine kinase activity. |
| 4174 | 11162649 | Thus, these data suggest that intracellular tyrosine and serine (PKB/Akt) phosphorylation are related to insulin secretion but they do not support a unique and direct link between IRS-2 tyrosine phosphorylation and glucose-stimulated insulin secretion. |
| 4175 | 11171554 | Defects in insulin signal transduction through the insulin-receptor substrate-1/phosphatidylinositol 3-kinase pathway is associated with reduced insulin-stimulated glucose transport activity in skeletal muscle from Type II diabetic patients. |
| 4176 | 11171554 | Glucose transport, the rate limiting step in glucose metabolism, is mediated by glucose transporter 4 (GLUT4) translocation and can be activated in skeletal muscle by two separate and distinct signaling pathways; one stimulated by insulin and the second by muscle contractions. |
| 4177 | 11193879 | PACAP-38 further increased insulin stimulated phosphatidylinositol (PI) 3-kinase activity, but has not effect on tyrosine phosphorylation of insulin receptor beta-subunit or IRS-1. |
| 4178 | 11237209 | It mediated insulin-like effects, including insulin receptor substrate-1 (IRS-1) phosphorylation and activation of phosphotidylinositide 3-kinase and Akt kinase. |
| 4179 | 11237209 | Furthermore, the compound was relatively selective for IR vs. insulin-like growth factor-I (IGF-I) receptor and other homologous receptor tyrosine kinases. |
| 4180 | 11250941 | Rosiglitazone, insulin treatment, and fasting correct defective activation of protein kinase C-zeta/lambda by insulin in vastus lateralis muscles and adipocytes of diabetic rats. |
| 4181 | 11250941 | Atypical protein kinases C (PKCs), zeta and lambda, and protein kinase B (PKB) are thought to function downstream of phosphatidylinositol 3-kinase (PI 3-kinase) and regulate glucose transport during insulin action in skeletal muscle and adipocytes. |
| 4182 | 11250941 | Presently, we evaluated the effects of these insulin-sensitizing modalities on the activation of insulin receptor substrate-1 (IRS-1)-dependent PI 3-kinase, PKC-zeta/lambda, and PKB in vastus lateralis skeletal muscles and adipocytes of nondiabetic and Goto-Kakizaki (GK) diabetic rats. |
| 4183 | 11250941 | Insulin provoked rapid increases in the activity of PI 3-kinase, PKC-zeta/lambda, and PKB in muscles and adipocytes of nondiabetic rats, but increases in IRS-1-dependent PI 3-kinase and PKC-zeta/lambda, but not PKB, activity were substantially diminished in GK muscles and adipocytes. |
| 4184 | 11250941 | Rosiglitazone treatment for 10-14 days, 10-day insulin treatment, and 60-h fasting reversed defects in PKC-zeta/lambda activation in GK muscles and adipocytes and increased glucose transport in GK adipocytes, without necessarily increasing IRS-1-dependent PI 3-kinase or PKB activation. |
| 4185 | 11250941 | Our findings suggest that insulin-sensitizing modalities, viz. thiazolidinediones, chronic insulin treatment, and short-term fasting, similarly improve defects in insulin-stimulated glucose transport at least partly by correcting defects in insulin-induced activation of PKC-zeta/lambda. |
| 4186 | 11256583 | Four members (IRS-1, IRS-2, IRS-3 and IRS-4) of this family have been identified that differ in tissue distribution, subcellular localisation, developmental expression, binding to the insulin receptor and interaction with SH2 domain-containing proteins. |
| 4187 | 11256583 | The available data are consistent with the notion that both IRS-1 and IRS-2 are important for insulin action and glucose homeostasis in vivo, whereas IRS-and IRS-4 appear to play a redundant role in the IRS signalling system. |
| 4188 | 11256583 | Considering their key role in both insulin action and insulin secretion, IRS-1 and IRS-2 molecules have been considered plausible candidate genes involved in the pathogenesis of Type 2 diabetes. |
| 4189 | 11256583 | Four members (IRS-1, IRS-2, IRS-3 and IRS-4) of this family have been identified that differ in tissue distribution, subcellular localisation, developmental expression, binding to the insulin receptor and interaction with SH2 domain-containing proteins. |
| 4190 | 11256583 | The available data are consistent with the notion that both IRS-1 and IRS-2 are important for insulin action and glucose homeostasis in vivo, whereas IRS-and IRS-4 appear to play a redundant role in the IRS signalling system. |
| 4191 | 11256583 | Considering their key role in both insulin action and insulin secretion, IRS-1 and IRS-2 molecules have been considered plausible candidate genes involved in the pathogenesis of Type 2 diabetes. |
| 4192 | 11256583 | Four members (IRS-1, IRS-2, IRS-3 and IRS-4) of this family have been identified that differ in tissue distribution, subcellular localisation, developmental expression, binding to the insulin receptor and interaction with SH2 domain-containing proteins. |
| 4193 | 11256583 | The available data are consistent with the notion that both IRS-1 and IRS-2 are important for insulin action and glucose homeostasis in vivo, whereas IRS-and IRS-4 appear to play a redundant role in the IRS signalling system. |
| 4194 | 11256583 | Considering their key role in both insulin action and insulin secretion, IRS-1 and IRS-2 molecules have been considered plausible candidate genes involved in the pathogenesis of Type 2 diabetes. |
| 4195 | 11274905 | Glucose-induced insulin resistance of phosphatidylinositol 3'-OH kinase and AKT/PKB is mediated by the hexosamine biosynthesis pathway. |
| 4196 | 11274905 | Overexpression of GFA in rat-1 fibroblasts results in insulin resistance for glycogen synthase (GS) activity, and renders these cells more sensitive to the effects of glucose. |
| 4197 | 11274905 | Insulin stimulated GS activity was found to occur via a PI-3 kinase (PI-3K)-dependent pathway as wortmannin, an inhibitor of PI-3K, blocked insulin's ability to stimulate GS activity. |
| 4198 | 11274905 | Subsequently, we examined the effects of hexosamines on PI-3K and Akt/PKB activity. |
| 4199 | 11274905 | After treatment with insulin (100 nM) for 5 min, cell extracts were assayed for IRS-1 associated and total PI-3K activity. |
| 4200 | 11274905 | At LG, insulin increased PI-3K activity by 43%. |
| 4201 | 11274905 | There was no insulin stimulation of PI-3K activity in cells cultured in HG or GlcN. |
| 4202 | 11274905 | At LG, insulin stimulated PKB activity. |
| 4203 | 11274905 | Again, both HG and GlcN significantly reduced insulin's ability to stimulate PKB activity. |
| 4204 | 11274905 | We conclude that the hexosamine-mediated insulin resistance of GS activity seen in rat-1 cells is mediated by hexosamine regulation of PI-3K and PKB. |
| 4205 | 11287365 | Inhibitory effect of hyperglycemia on insulin-induced Akt/protein kinase B activation in skeletal muscle. |
| 4206 | 11287365 | Similarly, insulin-induced phosphorylation and activation of Akt/protein kinase B (PKB) and GLUT-4 translocation were severely impaired. |
| 4207 | 11287365 | However, the upstream signal, including phosphorylation of the insulin receptor (IR) and insulin receptor substrate (IRS)-1 and -2 and activity of phosphatidylinositol (PI) 3-kinase associated with IRS-1/2, was enhanced. |
| 4208 | 11287365 | The amelioration of hyperglycemia by T-1095, a Na(+)-glucose transporter inhibitor, normalized the reduced insulin sensitivity in the soleus muscle and the impaired insulin-stimulated Akt/PKB phosphorylation and activity. |
| 4209 | 11287365 | In addition, the enhanced PI 3-kinase activation and phosphorylation of IR and IRS-1 and -2 were reduced to normal levels. |
| 4210 | 11287365 | These results suggest that sustained hyperglycemia impairs the insulin-signaling steps between PI 3-kinase and Akt/PKB, and that impaired Akt/PKB activity underlies hyperglycemia-induced insulin resistance in skeletal muscle. |
| 4211 | 11287365 | Inhibitory effect of hyperglycemia on insulin-induced Akt/protein kinase B activation in skeletal muscle. |
| 4212 | 11287365 | Similarly, insulin-induced phosphorylation and activation of Akt/protein kinase B (PKB) and GLUT-4 translocation were severely impaired. |
| 4213 | 11287365 | However, the upstream signal, including phosphorylation of the insulin receptor (IR) and insulin receptor substrate (IRS)-1 and -2 and activity of phosphatidylinositol (PI) 3-kinase associated with IRS-1/2, was enhanced. |
| 4214 | 11287365 | The amelioration of hyperglycemia by T-1095, a Na(+)-glucose transporter inhibitor, normalized the reduced insulin sensitivity in the soleus muscle and the impaired insulin-stimulated Akt/PKB phosphorylation and activity. |
| 4215 | 11287365 | In addition, the enhanced PI 3-kinase activation and phosphorylation of IR and IRS-1 and -2 were reduced to normal levels. |
| 4216 | 11287365 | These results suggest that sustained hyperglycemia impairs the insulin-signaling steps between PI 3-kinase and Akt/PKB, and that impaired Akt/PKB activity underlies hyperglycemia-induced insulin resistance in skeletal muscle. |
| 4217 | 11289048 | TLK16998 alone had no effect on IR signaling in mouse 3T3-L1 adipocytes but, at concentrations as low as 3.2 micromol/l, enhanced the effects of insulin on the phosphorylation of the IR beta-subunit and IR substrate 1, and on the amount of phosphatidylinositol 3-kinase that coimmunoprecipitated with IRS-1. |
| 4218 | 11289049 | The Q allele variant (GLN121) of membrane glycoprotein PC-1 interacts with the insulin receptor and inhibits insulin signaling more effectively than the common K allele variant (LYS121). |
| 4219 | 11289049 | When overexpressed, the membrane glycoprotein PC-1 may play a role in human insulin resistance through the inhibition of insulin receptor (IR) autophosphorylation. |
| 4220 | 11289049 | A PC-1 variant (K121Q, with lysine 121 replaced by glutamine) is also associated with whole-body insulin resistance when not overexpressed. |
| 4221 | 11289049 | In human MCF-7 cells, the Q allele was severalfold more effective (P < 0.05-0.01) than the K allele in reducing insulin stimulation of IR autophosphorylation, insulin receptor substrate-1 phosphorylation, phosphatidylinositol 3-kinase activity, glycogen synthesis, and cell proliferation. |
| 4222 | 11289049 | In transfected MCF-7 cells, 125I-labeled insulin binding and IR content were unchanged, and PC-1 overexpression did not influence IGF-1 stimulation of IGF-1 receptor autophosphorylation. |
| 4223 | 11289049 | This interaction was greater for the Q allele than for the K allele (P < 0.01), suggesting that direct PC-1-IR interactions are important for the PC-1 inhibitory effect on insulin signaling. |
| 4224 | 11289056 | Previously, transfection of IRS-1 with this polymorphism into insulin-secreting cells resulted in a marked reduction of glucose-stimulated insulin secretion compared with the wild-type transfected cells. |
| 4225 | 11289056 | In summary, our results suggest that the Gly972Arg polymorphism in IRS-1 is associated with decreased insulin secretion in response to glucose but not with insulin sensitivity. |
| 4226 | 11289056 | Previously, transfection of IRS-1 with this polymorphism into insulin-secreting cells resulted in a marked reduction of glucose-stimulated insulin secretion compared with the wild-type transfected cells. |
| 4227 | 11289056 | In summary, our results suggest that the Gly972Arg polymorphism in IRS-1 is associated with decreased insulin secretion in response to glucose but not with insulin sensitivity. |
| 4228 | 11292681 | Insulin resistance with low cellular IRS-1 expression is also associated with low GLUT4 expression and impaired insulin-stimulated glucose transport. |
| 4229 | 11334412 | Pioglitazone ameliorates tumor necrosis factor-alpha-induced insulin resistance by a mechanism independent of adipogenic activity of peroxisome proliferator--activated receptor-gamma. |
| 4230 | 11334412 | Tumor necrosis factor (TNF)-alpha is one of the candidate mediators of insulin resistance associated with obesity, a major risk factor for the development of type 2 diabetes. |
| 4231 | 11334412 | The insulin resistance induced by TNF-alpha is antagonized by thiazolidinediones (TZDs), a new class of insulin-sensitizing drugs. |
| 4232 | 11334412 | The aim of the current study was to dissect the mechanism whereby pioglitazone, one of the TZDs, ameliorates TNF-alpha-induced insulin resistance in 3T3-L1 adipocytes. |
| 4233 | 11334412 | Pioglitazone restored insulin-stimulated 2-deoxyglucose (DOG) uptake, which was reduced by TNF-alpha, with concomitant restorations in tyrosine phosphorylation and protein levels of insulin receptor (IR) and insulin receptor substrate (IRS)-1, as well as association of the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase with IRS-1 and PI 3-kinase activity. |
| 4234 | 11334412 | Adenovirus-mediated gene transfer of either wild-type human peroxisome proliferator-activated receptor (PPAR)-gamma2 or a mutant carrying a replacement at the consensus mitogen-activated protein kinase phosphorylation site (hPPAR-gamma2-S112A) promoted adipogenesis of 3T3-L1 fibroblasts and restored TNF-alpha-induced decrease of triglyceride in adipocytes as effectively as pioglitazone. |
| 4235 | 11334412 | Overexpression of the PPAR-gamma proteins in TNF-alpha-treated adipocytes restored protein levels of IR/IRS-1, but did not improve insulin-stimulated tyrosine phosphorylation of IR/IRS-1 or insulin-stimulated 2-DOG uptake. |
| 4236 | 11334412 | These results indicate that the ability of pioglitazone to restore insulin-stimulated tyrosine phosphorylation of IR/IRS-1, which is necessary for amelioration of TNF-alpha-induced insulin resistance, may be independent of the adipogenic activity of PPAR-gamma that regulates protein levels of IR/IRS-1. |
| 4237 | 11334412 | Pioglitazone ameliorates tumor necrosis factor-alpha-induced insulin resistance by a mechanism independent of adipogenic activity of peroxisome proliferator--activated receptor-gamma. |
| 4238 | 11334412 | Tumor necrosis factor (TNF)-alpha is one of the candidate mediators of insulin resistance associated with obesity, a major risk factor for the development of type 2 diabetes. |
| 4239 | 11334412 | The insulin resistance induced by TNF-alpha is antagonized by thiazolidinediones (TZDs), a new class of insulin-sensitizing drugs. |
| 4240 | 11334412 | The aim of the current study was to dissect the mechanism whereby pioglitazone, one of the TZDs, ameliorates TNF-alpha-induced insulin resistance in 3T3-L1 adipocytes. |
| 4241 | 11334412 | Pioglitazone restored insulin-stimulated 2-deoxyglucose (DOG) uptake, which was reduced by TNF-alpha, with concomitant restorations in tyrosine phosphorylation and protein levels of insulin receptor (IR) and insulin receptor substrate (IRS)-1, as well as association of the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase with IRS-1 and PI 3-kinase activity. |
| 4242 | 11334412 | Adenovirus-mediated gene transfer of either wild-type human peroxisome proliferator-activated receptor (PPAR)-gamma2 or a mutant carrying a replacement at the consensus mitogen-activated protein kinase phosphorylation site (hPPAR-gamma2-S112A) promoted adipogenesis of 3T3-L1 fibroblasts and restored TNF-alpha-induced decrease of triglyceride in adipocytes as effectively as pioglitazone. |
| 4243 | 11334412 | Overexpression of the PPAR-gamma proteins in TNF-alpha-treated adipocytes restored protein levels of IR/IRS-1, but did not improve insulin-stimulated tyrosine phosphorylation of IR/IRS-1 or insulin-stimulated 2-DOG uptake. |
| 4244 | 11334412 | These results indicate that the ability of pioglitazone to restore insulin-stimulated tyrosine phosphorylation of IR/IRS-1, which is necessary for amelioration of TNF-alpha-induced insulin resistance, may be independent of the adipogenic activity of PPAR-gamma that regulates protein levels of IR/IRS-1. |
| 4245 | 11334412 | Pioglitazone ameliorates tumor necrosis factor-alpha-induced insulin resistance by a mechanism independent of adipogenic activity of peroxisome proliferator--activated receptor-gamma. |
| 4246 | 11334412 | Tumor necrosis factor (TNF)-alpha is one of the candidate mediators of insulin resistance associated with obesity, a major risk factor for the development of type 2 diabetes. |
| 4247 | 11334412 | The insulin resistance induced by TNF-alpha is antagonized by thiazolidinediones (TZDs), a new class of insulin-sensitizing drugs. |
| 4248 | 11334412 | The aim of the current study was to dissect the mechanism whereby pioglitazone, one of the TZDs, ameliorates TNF-alpha-induced insulin resistance in 3T3-L1 adipocytes. |
| 4249 | 11334412 | Pioglitazone restored insulin-stimulated 2-deoxyglucose (DOG) uptake, which was reduced by TNF-alpha, with concomitant restorations in tyrosine phosphorylation and protein levels of insulin receptor (IR) and insulin receptor substrate (IRS)-1, as well as association of the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase with IRS-1 and PI 3-kinase activity. |
| 4250 | 11334412 | Adenovirus-mediated gene transfer of either wild-type human peroxisome proliferator-activated receptor (PPAR)-gamma2 or a mutant carrying a replacement at the consensus mitogen-activated protein kinase phosphorylation site (hPPAR-gamma2-S112A) promoted adipogenesis of 3T3-L1 fibroblasts and restored TNF-alpha-induced decrease of triglyceride in adipocytes as effectively as pioglitazone. |
| 4251 | 11334412 | Overexpression of the PPAR-gamma proteins in TNF-alpha-treated adipocytes restored protein levels of IR/IRS-1, but did not improve insulin-stimulated tyrosine phosphorylation of IR/IRS-1 or insulin-stimulated 2-DOG uptake. |
| 4252 | 11334412 | These results indicate that the ability of pioglitazone to restore insulin-stimulated tyrosine phosphorylation of IR/IRS-1, which is necessary for amelioration of TNF-alpha-induced insulin resistance, may be independent of the adipogenic activity of PPAR-gamma that regulates protein levels of IR/IRS-1. |
| 4253 | 11334415 | Liver-specific igf-1 gene deletion leads to muscle insulin insensitivity. |
| 4254 | 11334415 | Insulin and insulin-like growth factors (IGFs) mediate a variety of signals involved in mammalian development and metabolism. |
| 4255 | 11334415 | Insulin-induced autophosphorylation of the insulin receptor and tyrosine phosphorylation of insulin receptor substrate (IRS)-1 were absent in muscle, but were normal in liver and white adipose tissue of the LID mice. |
| 4256 | 11334415 | In contrast, IGF-I-induced autophosphorylation of its cognate receptor and phosphorylation of IRS-1 were normal in muscle of LID mice. |
| 4257 | 11334415 | Recombinant human IGF-I treatment of the LID mice caused a reduction in insulin levels and an increase in insulin sensitivity. |
| 4258 | 11334415 | These data provide evidence of the role of circulating IGF-I as an important component of overall insulin action in peripheral tissues. |
| 4259 | 11334418 | Basal mRNA levels (determined by reverse transcriptase-competitive polymerase chain reaction) of insulin receptor, insulin receptor substrate-1, p85alpha phosphatidylinositol 3-kinase (PI3K), p110alphaPI3K, p110betaPI3K, GLUT4, glycogen synthase, and sterol regulatory-element-binding protein-1c (SREBP-1c) were similar in muscle of control (n = 17), type 2 diabetic (n = 9), type 1 diabetic (n = 9), and nondiabetic obese (n = 9) subjects. |
| 4260 | 11342531 | Cytokines, such as tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-6, and hormones, such as growth hormone, are known to cause insulin resistance, but the mechanisms by which they inhibit the cellular response to insulin have not been elucidated. |
| 4261 | 11342531 | SOCS proteins are therefore attractive candidates as mediators of cytokine-induced insulin resistance. |
| 4262 | 11342531 | We have found that SOCS-1 and SOCS-6 interact with the IR when expressed in human hepatoma cells (HepG2) or in rat hepatoma cells overexpressing the human IR. |
| 4263 | 11342531 | In SOCS-1-expressing cells, insulin treatment increases the extent of interaction with the IR, whereas in SOCS-6-expressing cells the association with the IR appears to require insulin treatment. |
| 4264 | 11342531 | SOCS-1 and SOCS-6 do not inhibit insulin-dependent IR autophosphorylation, but both proteins inhibit insulin-dependent activation of ERK1/2 and protein kinase B in vivo and IR-directed phosphorylation of IRS-1 in vitro. |
| 4265 | 11342531 | These results suggest that SOCS proteins may be inhibitors of IR signaling and could mediate cytokine-induced insulin resistance and contribute to the pathogenesis of type II diabetes. |
| 4266 | 11375348 | Subcellular localization of insulin receptor substrate family proteins associated with phosphatidylinositol 3-kinase activity and alterations in lipolysis in primary mouse adipocytes from IRS-1 null mice. |
| 4267 | 11375348 | To clarify the roles of insulin receptor substrate (IRS) family proteins in phosphatidylinositol (PI) 3-kinase activation and insulin actions in adipocytes, we investigated the intracellular localization of IRS family proteins and PI 3-kinase activation in response to insulin by fractionation of mouse adipocytes from wild-type and IRS-1 null mice. |
| 4268 | 11375348 | In adipocytes from wild-type mice, tyrosine-phosphorylated IRS-1 and IRS-2, which were found to associate with PI 3-kinase in response to insulin, were detected in the plasma membrane (PM) and low-density microsome (LDM) fractions. |
| 4269 | 11375348 | In adipocytes from IRS-1-null mice, insulin-stimulated PI 3-kinase activity in anti-phosphotyrosine (alphaPY) immunoprecipitates in the LDM fraction was almost exclusively mediated via IRS-2 and was reduced to 25%; however, insulin-stimulated PI 3-kinase activity in the PM fraction was primarily mediated via IRS-3 and was reduced to 60%. |
| 4270 | 11375348 | To determine the potential functional impact of the distinct subcellular localization of IRSs and associating PI 3-kinase activity on adipocyte-specific metabolic actions, we examined lipolysis in IRS-1 null mice. |
| 4271 | 11375348 | The antilipolytic effect of insulin in IRS-1 null adipocytes, however, was comparable to that in wild-type mice. |
| 4272 | 11375348 | Thus, discordance between these two insulin actions as well as the transcriptional and translational effect (HSL mRNA and protein regulation) and the PM effect (antilipolysis) of insulin may be explained by distinct roles of both PI 3-kinase activity associated with IRS-1/IRS-2 and PI 3-kinase activity associated with IRS-3 in insulin actions related to their subcellular localization. |
| 4273 | 11375348 | Subcellular localization of insulin receptor substrate family proteins associated with phosphatidylinositol 3-kinase activity and alterations in lipolysis in primary mouse adipocytes from IRS-1 null mice. |
| 4274 | 11375348 | To clarify the roles of insulin receptor substrate (IRS) family proteins in phosphatidylinositol (PI) 3-kinase activation and insulin actions in adipocytes, we investigated the intracellular localization of IRS family proteins and PI 3-kinase activation in response to insulin by fractionation of mouse adipocytes from wild-type and IRS-1 null mice. |
| 4275 | 11375348 | In adipocytes from wild-type mice, tyrosine-phosphorylated IRS-1 and IRS-2, which were found to associate with PI 3-kinase in response to insulin, were detected in the plasma membrane (PM) and low-density microsome (LDM) fractions. |
| 4276 | 11375348 | In adipocytes from IRS-1-null mice, insulin-stimulated PI 3-kinase activity in anti-phosphotyrosine (alphaPY) immunoprecipitates in the LDM fraction was almost exclusively mediated via IRS-2 and was reduced to 25%; however, insulin-stimulated PI 3-kinase activity in the PM fraction was primarily mediated via IRS-3 and was reduced to 60%. |
| 4277 | 11375348 | To determine the potential functional impact of the distinct subcellular localization of IRSs and associating PI 3-kinase activity on adipocyte-specific metabolic actions, we examined lipolysis in IRS-1 null mice. |
| 4278 | 11375348 | The antilipolytic effect of insulin in IRS-1 null adipocytes, however, was comparable to that in wild-type mice. |
| 4279 | 11375348 | Thus, discordance between these two insulin actions as well as the transcriptional and translational effect (HSL mRNA and protein regulation) and the PM effect (antilipolysis) of insulin may be explained by distinct roles of both PI 3-kinase activity associated with IRS-1/IRS-2 and PI 3-kinase activity associated with IRS-3 in insulin actions related to their subcellular localization. |
| 4280 | 11375348 | Subcellular localization of insulin receptor substrate family proteins associated with phosphatidylinositol 3-kinase activity and alterations in lipolysis in primary mouse adipocytes from IRS-1 null mice. |
| 4281 | 11375348 | To clarify the roles of insulin receptor substrate (IRS) family proteins in phosphatidylinositol (PI) 3-kinase activation and insulin actions in adipocytes, we investigated the intracellular localization of IRS family proteins and PI 3-kinase activation in response to insulin by fractionation of mouse adipocytes from wild-type and IRS-1 null mice. |
| 4282 | 11375348 | In adipocytes from wild-type mice, tyrosine-phosphorylated IRS-1 and IRS-2, which were found to associate with PI 3-kinase in response to insulin, were detected in the plasma membrane (PM) and low-density microsome (LDM) fractions. |
| 4283 | 11375348 | In adipocytes from IRS-1-null mice, insulin-stimulated PI 3-kinase activity in anti-phosphotyrosine (alphaPY) immunoprecipitates in the LDM fraction was almost exclusively mediated via IRS-2 and was reduced to 25%; however, insulin-stimulated PI 3-kinase activity in the PM fraction was primarily mediated via IRS-3 and was reduced to 60%. |
| 4284 | 11375348 | To determine the potential functional impact of the distinct subcellular localization of IRSs and associating PI 3-kinase activity on adipocyte-specific metabolic actions, we examined lipolysis in IRS-1 null mice. |
| 4285 | 11375348 | The antilipolytic effect of insulin in IRS-1 null adipocytes, however, was comparable to that in wild-type mice. |
| 4286 | 11375348 | Thus, discordance between these two insulin actions as well as the transcriptional and translational effect (HSL mRNA and protein regulation) and the PM effect (antilipolysis) of insulin may be explained by distinct roles of both PI 3-kinase activity associated with IRS-1/IRS-2 and PI 3-kinase activity associated with IRS-3 in insulin actions related to their subcellular localization. |
| 4287 | 11375348 | Subcellular localization of insulin receptor substrate family proteins associated with phosphatidylinositol 3-kinase activity and alterations in lipolysis in primary mouse adipocytes from IRS-1 null mice. |
| 4288 | 11375348 | To clarify the roles of insulin receptor substrate (IRS) family proteins in phosphatidylinositol (PI) 3-kinase activation and insulin actions in adipocytes, we investigated the intracellular localization of IRS family proteins and PI 3-kinase activation in response to insulin by fractionation of mouse adipocytes from wild-type and IRS-1 null mice. |
| 4289 | 11375348 | In adipocytes from wild-type mice, tyrosine-phosphorylated IRS-1 and IRS-2, which were found to associate with PI 3-kinase in response to insulin, were detected in the plasma membrane (PM) and low-density microsome (LDM) fractions. |
| 4290 | 11375348 | In adipocytes from IRS-1-null mice, insulin-stimulated PI 3-kinase activity in anti-phosphotyrosine (alphaPY) immunoprecipitates in the LDM fraction was almost exclusively mediated via IRS-2 and was reduced to 25%; however, insulin-stimulated PI 3-kinase activity in the PM fraction was primarily mediated via IRS-3 and was reduced to 60%. |
| 4291 | 11375348 | To determine the potential functional impact of the distinct subcellular localization of IRSs and associating PI 3-kinase activity on adipocyte-specific metabolic actions, we examined lipolysis in IRS-1 null mice. |
| 4292 | 11375348 | The antilipolytic effect of insulin in IRS-1 null adipocytes, however, was comparable to that in wild-type mice. |
| 4293 | 11375348 | Thus, discordance between these two insulin actions as well as the transcriptional and translational effect (HSL mRNA and protein regulation) and the PM effect (antilipolysis) of insulin may be explained by distinct roles of both PI 3-kinase activity associated with IRS-1/IRS-2 and PI 3-kinase activity associated with IRS-3 in insulin actions related to their subcellular localization. |
| 4294 | 11375348 | Subcellular localization of insulin receptor substrate family proteins associated with phosphatidylinositol 3-kinase activity and alterations in lipolysis in primary mouse adipocytes from IRS-1 null mice. |
| 4295 | 11375348 | To clarify the roles of insulin receptor substrate (IRS) family proteins in phosphatidylinositol (PI) 3-kinase activation and insulin actions in adipocytes, we investigated the intracellular localization of IRS family proteins and PI 3-kinase activation in response to insulin by fractionation of mouse adipocytes from wild-type and IRS-1 null mice. |
| 4296 | 11375348 | In adipocytes from wild-type mice, tyrosine-phosphorylated IRS-1 and IRS-2, which were found to associate with PI 3-kinase in response to insulin, were detected in the plasma membrane (PM) and low-density microsome (LDM) fractions. |
| 4297 | 11375348 | In adipocytes from IRS-1-null mice, insulin-stimulated PI 3-kinase activity in anti-phosphotyrosine (alphaPY) immunoprecipitates in the LDM fraction was almost exclusively mediated via IRS-2 and was reduced to 25%; however, insulin-stimulated PI 3-kinase activity in the PM fraction was primarily mediated via IRS-3 and was reduced to 60%. |
| 4298 | 11375348 | To determine the potential functional impact of the distinct subcellular localization of IRSs and associating PI 3-kinase activity on adipocyte-specific metabolic actions, we examined lipolysis in IRS-1 null mice. |
| 4299 | 11375348 | The antilipolytic effect of insulin in IRS-1 null adipocytes, however, was comparable to that in wild-type mice. |
| 4300 | 11375348 | Thus, discordance between these two insulin actions as well as the transcriptional and translational effect (HSL mRNA and protein regulation) and the PM effect (antilipolysis) of insulin may be explained by distinct roles of both PI 3-kinase activity associated with IRS-1/IRS-2 and PI 3-kinase activity associated with IRS-3 in insulin actions related to their subcellular localization. |
| 4301 | 11375348 | Subcellular localization of insulin receptor substrate family proteins associated with phosphatidylinositol 3-kinase activity and alterations in lipolysis in primary mouse adipocytes from IRS-1 null mice. |
| 4302 | 11375348 | To clarify the roles of insulin receptor substrate (IRS) family proteins in phosphatidylinositol (PI) 3-kinase activation and insulin actions in adipocytes, we investigated the intracellular localization of IRS family proteins and PI 3-kinase activation in response to insulin by fractionation of mouse adipocytes from wild-type and IRS-1 null mice. |
| 4303 | 11375348 | In adipocytes from wild-type mice, tyrosine-phosphorylated IRS-1 and IRS-2, which were found to associate with PI 3-kinase in response to insulin, were detected in the plasma membrane (PM) and low-density microsome (LDM) fractions. |
| 4304 | 11375348 | In adipocytes from IRS-1-null mice, insulin-stimulated PI 3-kinase activity in anti-phosphotyrosine (alphaPY) immunoprecipitates in the LDM fraction was almost exclusively mediated via IRS-2 and was reduced to 25%; however, insulin-stimulated PI 3-kinase activity in the PM fraction was primarily mediated via IRS-3 and was reduced to 60%. |
| 4305 | 11375348 | To determine the potential functional impact of the distinct subcellular localization of IRSs and associating PI 3-kinase activity on adipocyte-specific metabolic actions, we examined lipolysis in IRS-1 null mice. |
| 4306 | 11375348 | The antilipolytic effect of insulin in IRS-1 null adipocytes, however, was comparable to that in wild-type mice. |
| 4307 | 11375348 | Thus, discordance between these two insulin actions as well as the transcriptional and translational effect (HSL mRNA and protein regulation) and the PM effect (antilipolysis) of insulin may be explained by distinct roles of both PI 3-kinase activity associated with IRS-1/IRS-2 and PI 3-kinase activity associated with IRS-3 in insulin actions related to their subcellular localization. |
| 4308 | 11388693 | In a set of in vivo experiments, the levels of alpha subunit of the insulin receptor, the insulin receptor substrate 1 (IRS-1) and the phosphatidylinositol 3-kinase (PI3K) were determined. [3H]-thymidine incorporation into DNA 24 or 48 h after surgery was assessed in all the experimental groups. |
| 4309 | 11388693 | IRS-1 and PI3K showed similar increases. |
| 4310 | 11388693 | In conclusion, increased expression of IR and IRS-1 leads to increased association of PI3K in vivo in diabetic regenerating rats. |
| 4311 | 11388693 | In a set of in vivo experiments, the levels of alpha subunit of the insulin receptor, the insulin receptor substrate 1 (IRS-1) and the phosphatidylinositol 3-kinase (PI3K) were determined. [3H]-thymidine incorporation into DNA 24 or 48 h after surgery was assessed in all the experimental groups. |
| 4312 | 11388693 | IRS-1 and PI3K showed similar increases. |
| 4313 | 11388693 | In conclusion, increased expression of IR and IRS-1 leads to increased association of PI3K in vivo in diabetic regenerating rats. |
| 4314 | 11388693 | In a set of in vivo experiments, the levels of alpha subunit of the insulin receptor, the insulin receptor substrate 1 (IRS-1) and the phosphatidylinositol 3-kinase (PI3K) were determined. [3H]-thymidine incorporation into DNA 24 or 48 h after surgery was assessed in all the experimental groups. |
| 4315 | 11388693 | IRS-1 and PI3K showed similar increases. |
| 4316 | 11388693 | In conclusion, increased expression of IR and IRS-1 leads to increased association of PI3K in vivo in diabetic regenerating rats. |
| 4317 | 11390966 | Tissue-specific overexpression of lipoprotein lipase causes tissue-specific insulin resistance. |
| 4318 | 11390966 | Transgenic mice with muscle- and liver-specific overexpression of lipoprotein lipase were studied during a 2-h hyperinsulinemic-euglycemic clamp to determine the effect of tissue-specific increase in fat on insulin action and signaling. |
| 4319 | 11390966 | Muscle-lipoprotein lipase mice had a 3-fold increase in muscle triglyceride content and were insulin resistant because of decreases in insulin-stimulated glucose uptake in skeletal muscle and insulin activation of insulin receptor substrate-1-associated phosphatidylinositol 3-kinase activity. |
| 4320 | 11390966 | In contrast, liver-lipoprotein lipase mice had a 2-fold increase in liver triglyceride content and were insulin resistant because of impaired ability of insulin to suppress endogenous glucose production associated with defects in insulin activation of insulin receptor substrate-2-associated phosphatidylinositol 3-kinase activity. |
| 4321 | 11410238 | Tumor necrosis factor-alpha (TNF-alpha) is a key component of obesity-diabetes link, we therefore examined the attenuating effect of VO(opt)(2) on impaired insulin signal transduction induced by TNF-alpha. |
| 4322 | 11410238 | Incubation of 3T3-L1, mouse adipocytes, with TNF-alpha reduced the phosphorylation of insulin receptor substrate-1 (IRS-1), whereas VO(opt)(2) treatment resulted in an enhancement of IRS-1 phosphorylation, irrespective of the presence or absence of TNF-alpha. |
| 4323 | 11410238 | Overall, the present study demonstrates that VO(opt)(2) exerts an anti-diabetic effect in ob/ob mice by ameliorating impaired glucose tolerance, and furthermore, attenuates the TNF-alpha-induced decrease in IRS-1 phosphorylation in adipocytes. |
| 4324 | 11410238 | These results suggest that the anti-diabetic action of VO(opt)(2) is derived from an attenuation of a TNF-alpha induced impaired insulin signal transduction via inhibition of protein tyrosine phosphatase, providing a potential clinical utility for VO(opt)(2) in the treatment of NIDDM. |
| 4325 | 11410238 | Tumor necrosis factor-alpha (TNF-alpha) is a key component of obesity-diabetes link, we therefore examined the attenuating effect of VO(opt)(2) on impaired insulin signal transduction induced by TNF-alpha. |
| 4326 | 11410238 | Incubation of 3T3-L1, mouse adipocytes, with TNF-alpha reduced the phosphorylation of insulin receptor substrate-1 (IRS-1), whereas VO(opt)(2) treatment resulted in an enhancement of IRS-1 phosphorylation, irrespective of the presence or absence of TNF-alpha. |
| 4327 | 11410238 | Overall, the present study demonstrates that VO(opt)(2) exerts an anti-diabetic effect in ob/ob mice by ameliorating impaired glucose tolerance, and furthermore, attenuates the TNF-alpha-induced decrease in IRS-1 phosphorylation in adipocytes. |
| 4328 | 11410238 | These results suggest that the anti-diabetic action of VO(opt)(2) is derived from an attenuation of a TNF-alpha induced impaired insulin signal transduction via inhibition of protein tyrosine phosphatase, providing a potential clinical utility for VO(opt)(2) in the treatment of NIDDM. |
| 4329 | 11412137 | Glucose transport, the rate limiting step in glucose metabolism, is mediated by glucose transporter 4 (GLUT4) and can be activated in skeletal muscle by two separate and distinct signalling pathways; one stimulated by insulin and the second by muscle contractions. |
| 4330 | 11412137 | Defects in insulin signal transduction through the insulin-receptor substrate-1/phosphatidylinositol 3-kinase pathway are associated with reduced insulin-stimulated glucose transporter 4 translocation and glucose transport activity in skeletal muscle from type II diabetic patients. |
| 4331 | 11440917 | Insulin receptor substrate (IRS)-1-associated phosphatidylinositol 3-kinase (PI 3K) activity was significantly decreased in PCOS (n = 12) compared with control skeletal muscle (n = 8; P < 0.05). |
| 4332 | 11440917 | There was no significant difference in the abundance of IR, IRS-1, or the p85 regulatory subunit of PI 3K in PCOS (n = 14) compared with control (n = 12) muscle. |
| 4333 | 11459778 | After IGF-I stimulation, insulin receptor substrate-1 and -2 phosphorylation and PI3K activity were restored to levels similar to or greater than those seen in wild-type cells. |
| 4334 | 11473053 | Growth hormone induces cellular insulin resistance by uncoupling phosphatidylinositol 3-kinase and its downstream signals in 3T3-L1 adipocytes. |
| 4335 | 11473053 | In this study, we demonstrated that chronic GH treatment of differentiated 3T3-L1 adipocytes reduces insulin-stimulated 2-deoxyglucose (DOG) uptake and activation of Akt (also known as protein kinase B), both of which are downstream effects of phosphatidylinositol (PI) 3-kinase, despite enhanced tyrosine phosphorylation of insulin receptor substrate (IRS)-1, association of IRS-1 with the p85 subunit of PI 3-kinase, and IRS-1-associated PI 3-kinase activity. |
| 4336 | 11473053 | In contrast, chronic GH treatment did not affect 2-DOG uptake and Akt activation induced by overexpression of a membrane-targeted form of the p110 subunit of PI 3-kinase (p110(CAAX)) or Akt activation stimulated by platelet-derived growth factor. |
| 4337 | 11473053 | Fractionation studies indicated that chronic GH treatment reduces insulin-stimulated translocation of Akt from the cytosol to the plasma membrane. |
| 4338 | 11473053 | Interestingly, chronic GH treatment increased insulin-stimulated association of IRS-1 with p85 and IRS-1-associated PI 3-kinase activity preferentially in the cytosol. |
| 4339 | 11473053 | Growth hormone induces cellular insulin resistance by uncoupling phosphatidylinositol 3-kinase and its downstream signals in 3T3-L1 adipocytes. |
| 4340 | 11473053 | In this study, we demonstrated that chronic GH treatment of differentiated 3T3-L1 adipocytes reduces insulin-stimulated 2-deoxyglucose (DOG) uptake and activation of Akt (also known as protein kinase B), both of which are downstream effects of phosphatidylinositol (PI) 3-kinase, despite enhanced tyrosine phosphorylation of insulin receptor substrate (IRS)-1, association of IRS-1 with the p85 subunit of PI 3-kinase, and IRS-1-associated PI 3-kinase activity. |
| 4341 | 11473053 | In contrast, chronic GH treatment did not affect 2-DOG uptake and Akt activation induced by overexpression of a membrane-targeted form of the p110 subunit of PI 3-kinase (p110(CAAX)) or Akt activation stimulated by platelet-derived growth factor. |
| 4342 | 11473053 | Fractionation studies indicated that chronic GH treatment reduces insulin-stimulated translocation of Akt from the cytosol to the plasma membrane. |
| 4343 | 11473053 | Interestingly, chronic GH treatment increased insulin-stimulated association of IRS-1 with p85 and IRS-1-associated PI 3-kinase activity preferentially in the cytosol. |
| 4344 | 11498021 | A family of insulin receptor substrate (IRS) proteins mediates the pleiotropic effects of insulin and insulin-like growth factor 1 (IGF-1) on cellular function by recruiting several intracellular signalling networks. |
| 4345 | 11498021 | Deletion of Irs1 produces a mild metabolic phenotype with compensated insulin resistance but also causes marked growth retardation. |
| 4346 | 11498021 | In contrast, mice lacking IRS-2 display nearly normal growth but develop diabetes owing to a combination of peripheral insulin resistance and beta-cell failure. |
| 4347 | 11498021 | As well as the classical metabolic events regulated by insulin signalling pathways, studies in lower organisms have implicated insulin/IGF-1 signalling pathways in the control of food intake and reproductive function. |
| 4348 | 11498021 | Additionally, IRS-2(-/-) females display increased food intake and develop obesity, despite elevated leptin levels, suggesting abnormalities in hypothalamic function. |
| 4349 | 11522686 | Role of allelic variants Gly972Arg of IRS-1 and Gly1057Asp of IRS-2 in moderate-to-severe insulin resistance of women with polycystic ovary syndrome. |
| 4350 | 11522686 | To assess the role of insulin receptor, insulin receptor substrate (IRS)-1, and IRS-2 genes in insulin resistance, we explored the genomic DNA in women with polycystic ovary syndrome (PCOS) and a variable degree (mean +/- SE) of insulin resistance (homeostasis model assessment index for insulin resistance [HOMA(IR)] 3.2 +/- 0.6, n = 53; control subjects 1.56 +/- 0.34, n = 102) using direct sequencing. |
| 4351 | 11522686 | Whereas no novel mutations were found in these genes, gene-dosage effects were found on fasting insulin for the Gly972Arg IRS-1 variant and on 2-h plasma glucose for the Gly1057Asp IRS-2 variant. |
| 4352 | 11522686 | The Gly972Arg IRS-1 variant was more prevalent in insulin-resistant patients compared with non-insulin-resistant individuals or control subjects (39.3 vs. 4.0 and 16.6%, P < 0.0031, respectively). |
| 4353 | 11522686 | A multivariate model that included BMI as a variable revealed significant effects of the Gly1057Asp IRS-2 variant on insulin resistance (P < 0.016, odds ratio [OR] 7.2, 95% CI 1.29-43.3). |
| 4354 | 11522686 | We conclude that polymorphic alleles of both IRS-1 and IRS-2, alone or in combination, may have a functional impact on the insulin-resistant component of PCOS. |
| 4355 | 11522686 | Role of allelic variants Gly972Arg of IRS-1 and Gly1057Asp of IRS-2 in moderate-to-severe insulin resistance of women with polycystic ovary syndrome. |
| 4356 | 11522686 | To assess the role of insulin receptor, insulin receptor substrate (IRS)-1, and IRS-2 genes in insulin resistance, we explored the genomic DNA in women with polycystic ovary syndrome (PCOS) and a variable degree (mean +/- SE) of insulin resistance (homeostasis model assessment index for insulin resistance [HOMA(IR)] 3.2 +/- 0.6, n = 53; control subjects 1.56 +/- 0.34, n = 102) using direct sequencing. |
| 4357 | 11522686 | Whereas no novel mutations were found in these genes, gene-dosage effects were found on fasting insulin for the Gly972Arg IRS-1 variant and on 2-h plasma glucose for the Gly1057Asp IRS-2 variant. |
| 4358 | 11522686 | The Gly972Arg IRS-1 variant was more prevalent in insulin-resistant patients compared with non-insulin-resistant individuals or control subjects (39.3 vs. 4.0 and 16.6%, P < 0.0031, respectively). |
| 4359 | 11522686 | A multivariate model that included BMI as a variable revealed significant effects of the Gly1057Asp IRS-2 variant on insulin resistance (P < 0.016, odds ratio [OR] 7.2, 95% CI 1.29-43.3). |
| 4360 | 11522686 | We conclude that polymorphic alleles of both IRS-1 and IRS-2, alone or in combination, may have a functional impact on the insulin-resistant component of PCOS. |
| 4361 | 11522686 | Role of allelic variants Gly972Arg of IRS-1 and Gly1057Asp of IRS-2 in moderate-to-severe insulin resistance of women with polycystic ovary syndrome. |
| 4362 | 11522686 | To assess the role of insulin receptor, insulin receptor substrate (IRS)-1, and IRS-2 genes in insulin resistance, we explored the genomic DNA in women with polycystic ovary syndrome (PCOS) and a variable degree (mean +/- SE) of insulin resistance (homeostasis model assessment index for insulin resistance [HOMA(IR)] 3.2 +/- 0.6, n = 53; control subjects 1.56 +/- 0.34, n = 102) using direct sequencing. |
| 4363 | 11522686 | Whereas no novel mutations were found in these genes, gene-dosage effects were found on fasting insulin for the Gly972Arg IRS-1 variant and on 2-h plasma glucose for the Gly1057Asp IRS-2 variant. |
| 4364 | 11522686 | The Gly972Arg IRS-1 variant was more prevalent in insulin-resistant patients compared with non-insulin-resistant individuals or control subjects (39.3 vs. 4.0 and 16.6%, P < 0.0031, respectively). |
| 4365 | 11522686 | A multivariate model that included BMI as a variable revealed significant effects of the Gly1057Asp IRS-2 variant on insulin resistance (P < 0.016, odds ratio [OR] 7.2, 95% CI 1.29-43.3). |
| 4366 | 11522686 | We conclude that polymorphic alleles of both IRS-1 and IRS-2, alone or in combination, may have a functional impact on the insulin-resistant component of PCOS. |
| 4367 | 11522686 | Role of allelic variants Gly972Arg of IRS-1 and Gly1057Asp of IRS-2 in moderate-to-severe insulin resistance of women with polycystic ovary syndrome. |
| 4368 | 11522686 | To assess the role of insulin receptor, insulin receptor substrate (IRS)-1, and IRS-2 genes in insulin resistance, we explored the genomic DNA in women with polycystic ovary syndrome (PCOS) and a variable degree (mean +/- SE) of insulin resistance (homeostasis model assessment index for insulin resistance [HOMA(IR)] 3.2 +/- 0.6, n = 53; control subjects 1.56 +/- 0.34, n = 102) using direct sequencing. |
| 4369 | 11522686 | Whereas no novel mutations were found in these genes, gene-dosage effects were found on fasting insulin for the Gly972Arg IRS-1 variant and on 2-h plasma glucose for the Gly1057Asp IRS-2 variant. |
| 4370 | 11522686 | The Gly972Arg IRS-1 variant was more prevalent in insulin-resistant patients compared with non-insulin-resistant individuals or control subjects (39.3 vs. 4.0 and 16.6%, P < 0.0031, respectively). |
| 4371 | 11522686 | A multivariate model that included BMI as a variable revealed significant effects of the Gly1057Asp IRS-2 variant on insulin resistance (P < 0.016, odds ratio [OR] 7.2, 95% CI 1.29-43.3). |
| 4372 | 11522686 | We conclude that polymorphic alleles of both IRS-1 and IRS-2, alone or in combination, may have a functional impact on the insulin-resistant component of PCOS. |
| 4373 | 11526109 | The localization of insulin receptor substrate (IRS) molecules may be responsible for the differential biological activities of insulin and other peptides such as platelet-derived growth factor. |
| 4374 | 11526109 | In response to insulin, recombinant IRS-1 translocated to the plasma membrane. |
| 4375 | 11526109 | Mutations of phosphoinositide-binding sites in both the pleckstrin homology and phosphotyrosine-binding domains significantly reduced the ability of Myc-tagged IRS-1 to translocate to the plasma membrane following insulin stimulation. |
| 4376 | 11526109 | The localization of insulin receptor substrate (IRS) molecules may be responsible for the differential biological activities of insulin and other peptides such as platelet-derived growth factor. |
| 4377 | 11526109 | In response to insulin, recombinant IRS-1 translocated to the plasma membrane. |
| 4378 | 11526109 | Mutations of phosphoinositide-binding sites in both the pleckstrin homology and phosphotyrosine-binding domains significantly reduced the ability of Myc-tagged IRS-1 to translocate to the plasma membrane following insulin stimulation. |
| 4379 | 11546773 | Regulation of insulin/insulin-like growth factor-1 signaling by proteasome-mediated degradation of insulin receptor substrate-2. |
| 4380 | 11546773 | Insulin and insulin-like growth factor-1 (IGF-1) regulate metabolism and body growth through homologous receptor tyrosine kinases that phosphorylate the insulin receptor substrate (IRS) proteins. |
| 4381 | 11546773 | IRS-2 is an important IRS protein, as it mediates peripheral insulin action and beta-cell survival. |
| 4382 | 11546773 | In this study, we show that insulin, IGF-1, or osmotic stress promoted ubiquitin/proteasome-mediated degradation of IRS-2 in 3T3-L1 cells, Fao hepatoma, cells and mouse embryo fibroblasts; however, insulin/IGF-1 did not promote degradation of IRS-1 in 3T3-L1 preadipocytes or mouse embryo fibroblasts. |
| 4383 | 11546773 | MG132 or lactacystin, specific inhibitors of 26S proteasome, blocked insulin/IGF-1-induced degradation of IRS-2 and enhanced the detection of ubiquitinated IRS-2. |
| 4384 | 11546773 | Insulin/IGF1-induced ubiquitination and degradation of IRS-2 was blocked by inhibitors of phosphatidylinositol 3-kinase (wortmannin or LY294002) or mTOR (rapamycin). |
| 4385 | 11546773 | Chronic insulin or IGF-1 treatment of IRS-1-deficient mouse embryo fibroblasts inhibited IRS-2-mediated activation of Akt and ERK1/2, which was reversed by lactacystin pretreatment. |
| 4386 | 11546773 | By contrast, IRS-1 activation of Akt and ERK1/2 was not inhibited by chronic insulin/IGF-1 stimulation in IRS-2-deficient mouse embryo fibroblasts. |
| 4387 | 11546773 | Thus, we identified a novel negative feedback mechanism by which the ubiquitin/proteasome-mediated degradation of IRS-2 limits the magnitude and duration of the response to insulin or IGF-1. |
| 4388 | 11546773 | Regulation of insulin/insulin-like growth factor-1 signaling by proteasome-mediated degradation of insulin receptor substrate-2. |
| 4389 | 11546773 | Insulin and insulin-like growth factor-1 (IGF-1) regulate metabolism and body growth through homologous receptor tyrosine kinases that phosphorylate the insulin receptor substrate (IRS) proteins. |
| 4390 | 11546773 | IRS-2 is an important IRS protein, as it mediates peripheral insulin action and beta-cell survival. |
| 4391 | 11546773 | In this study, we show that insulin, IGF-1, or osmotic stress promoted ubiquitin/proteasome-mediated degradation of IRS-2 in 3T3-L1 cells, Fao hepatoma, cells and mouse embryo fibroblasts; however, insulin/IGF-1 did not promote degradation of IRS-1 in 3T3-L1 preadipocytes or mouse embryo fibroblasts. |
| 4392 | 11546773 | MG132 or lactacystin, specific inhibitors of 26S proteasome, blocked insulin/IGF-1-induced degradation of IRS-2 and enhanced the detection of ubiquitinated IRS-2. |
| 4393 | 11546773 | Insulin/IGF1-induced ubiquitination and degradation of IRS-2 was blocked by inhibitors of phosphatidylinositol 3-kinase (wortmannin or LY294002) or mTOR (rapamycin). |
| 4394 | 11546773 | Chronic insulin or IGF-1 treatment of IRS-1-deficient mouse embryo fibroblasts inhibited IRS-2-mediated activation of Akt and ERK1/2, which was reversed by lactacystin pretreatment. |
| 4395 | 11546773 | By contrast, IRS-1 activation of Akt and ERK1/2 was not inhibited by chronic insulin/IGF-1 stimulation in IRS-2-deficient mouse embryo fibroblasts. |
| 4396 | 11546773 | Thus, we identified a novel negative feedback mechanism by which the ubiquitin/proteasome-mediated degradation of IRS-2 limits the magnitude and duration of the response to insulin or IGF-1. |
| 4397 | 11549666 | Insulin stimulation of glycogen synthase activity as well as phosphorylation of MAPK, p70 S6 kinase, and protein kinase B (Akt) were blocked by the phosphatidylinositol 3-kinase inhibitors wortmannin (50 nM) and LY294002 (10 microM). |
| 4398 | 11549666 | This increased sensitivity of diabetic muscle to impairment of insulin-stimulated glycogen synthase activity occurs together with diminished insulin-stimulation (by 40%) of IRS-1-associated phosphatidylinositol 3-kinase activity in the same cells. |
| 4399 | 11549666 | Protein expression of IRS-1, p85, p110, Akt, p70 S6 kinase, and MAPK were normal in diabetic cells, as was insulin-stimulated phosphorylation of Akt, p70 S6 kinase, and MAPK. |
| 4400 | 11549666 | These studies indicate that, despite prolonged growth and differentiation of diabetic muscle under normal metabolic culture conditions, defects of insulin-stimulated phosphatidylinositol 3-kinase and glycogen synthase activity in diabetic muscle persist, consistent with intrinsic (rather than acquired) defects of insulin action. |
| 4401 | 11563968 | Intact actin microfilaments are required for insulin-regulated glucose transporter isoform 4 (GLUT4) translocation to the plasma membrane. |
| 4402 | 11563968 | In the present investigation, ventricular cardiomyocytes were used to study the effects of two structurally different LO inhibitors (esculetin and nordihydroguaiaretic acid) on insulin signalling events, glucose uptake, GLUT4 translocation and the actin network organization. |
| 4403 | 11563968 | This was paralleled by a slight reduction in the insulin-induced tyrosine phosphorylation of insulin receptor substrate (IRS)-1 and IRS-2. |
| 4404 | 11563968 | However, inhibition of 12-LO did not affect the association of phosphatidylinositol 3-kinase with IRS-1 and the phosphorylation of Akt/protein kinase B in response to insulin. |
| 4405 | 11563968 | Insulin stimulation increased cell surface GLUT4 2-fold in control cells, whereas LO inhibition abrogated the insulin-stimulated GLUT4 translocation. |
| 4406 | 11563968 | LO inhibition blocks GLUT4 translocation without affecting downstream insulin signalling. |
| 4407 | 11574414 | In conclusion, acutely elevated FFA levels 1) induced a significant reduction in tracer-determined GDR paralleled by impaired tyrosine phosphorylation of IRS-1 and reduced IRS-1-associated PI 3-kinase activity and 2) induced a significant reduction in FAT/CD36 total protein. |
| 4408 | 11574414 | TZD pretreatment prevented FFA-induced decrements in insulin action and prevented the reduction in FAT/CD36 protein. |
| 4409 | 11587538 | Inhibition of ceramide production reverses TNF-induced insulin resistance. |
| 4410 | 11587538 | Ceramide has been implicated as a mediator of insulin resistance induced by tumor necrosis factor-alpha (TNF) in adipocytes. |
| 4411 | 11587538 | Neither exogenous short-chain ceramide analogs nor pharmacologic increases in endogenous caveolar pools of ceramide inhibited insulin-induced tyrosine phosphorylation of the IR and IRS-1. |
| 4412 | 11587538 | These results suggest that TNF-independent increases in caveolar pools of ceramide are not sufficient to inhibit insulin signaling but that in conjunction with other TNF-dependent signals, caveolar pools of ceramide are a critical component for insulin resistance by TNF. |
| 4413 | 11598104 | 5'-AMP-activated protein kinase phosphorylates IRS-1 on Ser-789 in mouse C2C12 myotubes in response to 5-aminoimidazole-4-carboxamide riboside. |
| 4414 | 11598104 | Activation of 5'-AMP-activated protein kinase (AMPK) by 5-aminoimidazole-4-carboxamide riboside (AICAR), exercise, or electrically stimulated contraction leads to increased glucose transport in skeletal muscle. |
| 4415 | 11598104 | Here we report the first evidence of a direct interaction between AMPK and the most upstream component of the insulin-signaling cascade, insulin receptor substrate-1 (IRS-1). |
| 4416 | 11598104 | We find that AMPK rapidly phosphorylates IRS-1 on Ser-789 in cell-free assays as well as in mouse C2C12 myotubes incubated with AICAR. |
| 4417 | 11598104 | In the C2C12 myotubes activation of AMPK by AICAR matched the phosphorylation of IRS-1 on Ser-789. |
| 4418 | 11598104 | This phosphorylation correlates with a 65% increase in insulin-stimulated IRS-1-associated phosphatidylinositol 3-kinase activity in C2C12 myotubes preincubated with AICAR. |
| 4419 | 11598104 | The binding of phosphatidylinositol 3-kinase to IRS-1 was not affected by AICAR. |
| 4420 | 11598104 | These results demonstrate the existence of an interaction between AMPK and early insulin signaling that could be of importance to our understanding of the potentiating effects of exercise on insulin signaling. |
| 4421 | 11598104 | 5'-AMP-activated protein kinase phosphorylates IRS-1 on Ser-789 in mouse C2C12 myotubes in response to 5-aminoimidazole-4-carboxamide riboside. |
| 4422 | 11598104 | Activation of 5'-AMP-activated protein kinase (AMPK) by 5-aminoimidazole-4-carboxamide riboside (AICAR), exercise, or electrically stimulated contraction leads to increased glucose transport in skeletal muscle. |
| 4423 | 11598104 | Here we report the first evidence of a direct interaction between AMPK and the most upstream component of the insulin-signaling cascade, insulin receptor substrate-1 (IRS-1). |
| 4424 | 11598104 | We find that AMPK rapidly phosphorylates IRS-1 on Ser-789 in cell-free assays as well as in mouse C2C12 myotubes incubated with AICAR. |
| 4425 | 11598104 | In the C2C12 myotubes activation of AMPK by AICAR matched the phosphorylation of IRS-1 on Ser-789. |
| 4426 | 11598104 | This phosphorylation correlates with a 65% increase in insulin-stimulated IRS-1-associated phosphatidylinositol 3-kinase activity in C2C12 myotubes preincubated with AICAR. |
| 4427 | 11598104 | The binding of phosphatidylinositol 3-kinase to IRS-1 was not affected by AICAR. |
| 4428 | 11598104 | These results demonstrate the existence of an interaction between AMPK and early insulin signaling that could be of importance to our understanding of the potentiating effects of exercise on insulin signaling. |
| 4429 | 11598104 | 5'-AMP-activated protein kinase phosphorylates IRS-1 on Ser-789 in mouse C2C12 myotubes in response to 5-aminoimidazole-4-carboxamide riboside. |
| 4430 | 11598104 | Activation of 5'-AMP-activated protein kinase (AMPK) by 5-aminoimidazole-4-carboxamide riboside (AICAR), exercise, or electrically stimulated contraction leads to increased glucose transport in skeletal muscle. |
| 4431 | 11598104 | Here we report the first evidence of a direct interaction between AMPK and the most upstream component of the insulin-signaling cascade, insulin receptor substrate-1 (IRS-1). |
| 4432 | 11598104 | We find that AMPK rapidly phosphorylates IRS-1 on Ser-789 in cell-free assays as well as in mouse C2C12 myotubes incubated with AICAR. |
| 4433 | 11598104 | In the C2C12 myotubes activation of AMPK by AICAR matched the phosphorylation of IRS-1 on Ser-789. |
| 4434 | 11598104 | This phosphorylation correlates with a 65% increase in insulin-stimulated IRS-1-associated phosphatidylinositol 3-kinase activity in C2C12 myotubes preincubated with AICAR. |
| 4435 | 11598104 | The binding of phosphatidylinositol 3-kinase to IRS-1 was not affected by AICAR. |
| 4436 | 11598104 | These results demonstrate the existence of an interaction between AMPK and early insulin signaling that could be of importance to our understanding of the potentiating effects of exercise on insulin signaling. |
| 4437 | 11598104 | 5'-AMP-activated protein kinase phosphorylates IRS-1 on Ser-789 in mouse C2C12 myotubes in response to 5-aminoimidazole-4-carboxamide riboside. |
| 4438 | 11598104 | Activation of 5'-AMP-activated protein kinase (AMPK) by 5-aminoimidazole-4-carboxamide riboside (AICAR), exercise, or electrically stimulated contraction leads to increased glucose transport in skeletal muscle. |
| 4439 | 11598104 | Here we report the first evidence of a direct interaction between AMPK and the most upstream component of the insulin-signaling cascade, insulin receptor substrate-1 (IRS-1). |
| 4440 | 11598104 | We find that AMPK rapidly phosphorylates IRS-1 on Ser-789 in cell-free assays as well as in mouse C2C12 myotubes incubated with AICAR. |
| 4441 | 11598104 | In the C2C12 myotubes activation of AMPK by AICAR matched the phosphorylation of IRS-1 on Ser-789. |
| 4442 | 11598104 | This phosphorylation correlates with a 65% increase in insulin-stimulated IRS-1-associated phosphatidylinositol 3-kinase activity in C2C12 myotubes preincubated with AICAR. |
| 4443 | 11598104 | The binding of phosphatidylinositol 3-kinase to IRS-1 was not affected by AICAR. |
| 4444 | 11598104 | These results demonstrate the existence of an interaction between AMPK and early insulin signaling that could be of importance to our understanding of the potentiating effects of exercise on insulin signaling. |
| 4445 | 11598104 | 5'-AMP-activated protein kinase phosphorylates IRS-1 on Ser-789 in mouse C2C12 myotubes in response to 5-aminoimidazole-4-carboxamide riboside. |
| 4446 | 11598104 | Activation of 5'-AMP-activated protein kinase (AMPK) by 5-aminoimidazole-4-carboxamide riboside (AICAR), exercise, or electrically stimulated contraction leads to increased glucose transport in skeletal muscle. |
| 4447 | 11598104 | Here we report the first evidence of a direct interaction between AMPK and the most upstream component of the insulin-signaling cascade, insulin receptor substrate-1 (IRS-1). |
| 4448 | 11598104 | We find that AMPK rapidly phosphorylates IRS-1 on Ser-789 in cell-free assays as well as in mouse C2C12 myotubes incubated with AICAR. |
| 4449 | 11598104 | In the C2C12 myotubes activation of AMPK by AICAR matched the phosphorylation of IRS-1 on Ser-789. |
| 4450 | 11598104 | This phosphorylation correlates with a 65% increase in insulin-stimulated IRS-1-associated phosphatidylinositol 3-kinase activity in C2C12 myotubes preincubated with AICAR. |
| 4451 | 11598104 | The binding of phosphatidylinositol 3-kinase to IRS-1 was not affected by AICAR. |
| 4452 | 11598104 | These results demonstrate the existence of an interaction between AMPK and early insulin signaling that could be of importance to our understanding of the potentiating effects of exercise on insulin signaling. |
| 4453 | 11604226 | In this study we investigated IRS-1 and IRS-2 tyrosine phosphorylation, their association with PI3-kinase and the phosphorylation of Akt, a serine-threonine kinase situated downstream to PI 3-kinase, in liver and muscle of two animal models of insulin resistance: 72 h of fasting and STZ-diabetic rats. |
| 4454 | 11604226 | There was an upregulation in insulin-induced IRS-1 and IRS-2 tyrosine phosphorylation and association with PI3-kinase in liver and muscle of both animal models of insulin resistance. |
| 4455 | 11604226 | Since an important difference between these two animal models of insulin resistance is the plasma glucose levels, we can suggest that in STZ diabetic rats, the reduction in Akt phosphorylation is probably related to hyperglycemia and may certainly contribute to the molecular mechanism of insulin resistance observed in these animals. |
| 4456 | 11604226 | In this study we investigated IRS-1 and IRS-2 tyrosine phosphorylation, their association with PI3-kinase and the phosphorylation of Akt, a serine-threonine kinase situated downstream to PI 3-kinase, in liver and muscle of two animal models of insulin resistance: 72 h of fasting and STZ-diabetic rats. |
| 4457 | 11604226 | There was an upregulation in insulin-induced IRS-1 and IRS-2 tyrosine phosphorylation and association with PI3-kinase in liver and muscle of both animal models of insulin resistance. |
| 4458 | 11604226 | Since an important difference between these two animal models of insulin resistance is the plasma glucose levels, we can suggest that in STZ diabetic rats, the reduction in Akt phosphorylation is probably related to hyperglycemia and may certainly contribute to the molecular mechanism of insulin resistance observed in these animals. |
| 4459 | 11606564 | One serine residue located near the phosphotyrosine-binding (PTB) domain in IRS-1 (Ser(307) in rat IRS-1 or Ser(312) in human IRS-1) is phosphorylated via several mechanisms, including insulin-stimulated kinases or stress-activated kinases like JNK1. |
| 4460 | 11606564 | During a yeast tri-hybrid assay, phosphorylation of Ser(307) by JNK1 disrupted the interaction between the catalytic domain of the insulin receptor and the PTB domain of IRS-1. |
| 4461 | 11606564 | In 32D myeloid progenitor cells, phosphorylation of Ser(307) inhibited insulin stimulation of the phosphatidylinositol 3-kinase and MAPK cascades. |
| 4462 | 11606564 | These results suggest that inhibition of PTB domain function in IRS-1 by phosphorylation of Ser(307) (Ser(312) in human IRS-1) might be a general mechanism to regulate insulin signaling. |
| 4463 | 11606564 | One serine residue located near the phosphotyrosine-binding (PTB) domain in IRS-1 (Ser(307) in rat IRS-1 or Ser(312) in human IRS-1) is phosphorylated via several mechanisms, including insulin-stimulated kinases or stress-activated kinases like JNK1. |
| 4464 | 11606564 | During a yeast tri-hybrid assay, phosphorylation of Ser(307) by JNK1 disrupted the interaction between the catalytic domain of the insulin receptor and the PTB domain of IRS-1. |
| 4465 | 11606564 | In 32D myeloid progenitor cells, phosphorylation of Ser(307) inhibited insulin stimulation of the phosphatidylinositol 3-kinase and MAPK cascades. |
| 4466 | 11606564 | These results suggest that inhibition of PTB domain function in IRS-1 by phosphorylation of Ser(307) (Ser(312) in human IRS-1) might be a general mechanism to regulate insulin signaling. |
| 4467 | 11606564 | One serine residue located near the phosphotyrosine-binding (PTB) domain in IRS-1 (Ser(307) in rat IRS-1 or Ser(312) in human IRS-1) is phosphorylated via several mechanisms, including insulin-stimulated kinases or stress-activated kinases like JNK1. |
| 4468 | 11606564 | During a yeast tri-hybrid assay, phosphorylation of Ser(307) by JNK1 disrupted the interaction between the catalytic domain of the insulin receptor and the PTB domain of IRS-1. |
| 4469 | 11606564 | In 32D myeloid progenitor cells, phosphorylation of Ser(307) inhibited insulin stimulation of the phosphatidylinositol 3-kinase and MAPK cascades. |
| 4470 | 11606564 | These results suggest that inhibition of PTB domain function in IRS-1 by phosphorylation of Ser(307) (Ser(312) in human IRS-1) might be a general mechanism to regulate insulin signaling. |
| 4471 | 11641236 | Four members (IRS-1, IRS-2, IRS-3, IRS-4) of this family have been identified that differ as to tissue distribution, subcellular localization, developmental expression, binding to the insulin receptor, and interaction with SH2 domain-containing proteins. |
| 4472 | 11641236 | The available data are consistent with the notion that IRS-1 and IRS-2 are not functionally interchangeable in tissues that are responsible for glucose production (liver), glucose uptake (skeletal muscle and adipose tissue), and insulin production (pancreatic beta cells). |
| 4473 | 11641236 | In fact, IRS-1 appears to have its major role in skeletal muscle whereas IRS-2 appears to regulate hepatic insulin action as well as pancreatic beta cell development and survival. |
| 4474 | 11641236 | Defects in muscle IRS-1 expression and function have been reported in insulin-resistant states such as obesity and type 2 diabetes. |
| 4475 | 11641236 | Four members (IRS-1, IRS-2, IRS-3, IRS-4) of this family have been identified that differ as to tissue distribution, subcellular localization, developmental expression, binding to the insulin receptor, and interaction with SH2 domain-containing proteins. |
| 4476 | 11641236 | The available data are consistent with the notion that IRS-1 and IRS-2 are not functionally interchangeable in tissues that are responsible for glucose production (liver), glucose uptake (skeletal muscle and adipose tissue), and insulin production (pancreatic beta cells). |
| 4477 | 11641236 | In fact, IRS-1 appears to have its major role in skeletal muscle whereas IRS-2 appears to regulate hepatic insulin action as well as pancreatic beta cell development and survival. |
| 4478 | 11641236 | Defects in muscle IRS-1 expression and function have been reported in insulin-resistant states such as obesity and type 2 diabetes. |
| 4479 | 11641236 | Four members (IRS-1, IRS-2, IRS-3, IRS-4) of this family have been identified that differ as to tissue distribution, subcellular localization, developmental expression, binding to the insulin receptor, and interaction with SH2 domain-containing proteins. |
| 4480 | 11641236 | The available data are consistent with the notion that IRS-1 and IRS-2 are not functionally interchangeable in tissues that are responsible for glucose production (liver), glucose uptake (skeletal muscle and adipose tissue), and insulin production (pancreatic beta cells). |
| 4481 | 11641236 | In fact, IRS-1 appears to have its major role in skeletal muscle whereas IRS-2 appears to regulate hepatic insulin action as well as pancreatic beta cell development and survival. |
| 4482 | 11641236 | Defects in muscle IRS-1 expression and function have been reported in insulin-resistant states such as obesity and type 2 diabetes. |
| 4483 | 11641236 | Four members (IRS-1, IRS-2, IRS-3, IRS-4) of this family have been identified that differ as to tissue distribution, subcellular localization, developmental expression, binding to the insulin receptor, and interaction with SH2 domain-containing proteins. |
| 4484 | 11641236 | The available data are consistent with the notion that IRS-1 and IRS-2 are not functionally interchangeable in tissues that are responsible for glucose production (liver), glucose uptake (skeletal muscle and adipose tissue), and insulin production (pancreatic beta cells). |
| 4485 | 11641236 | In fact, IRS-1 appears to have its major role in skeletal muscle whereas IRS-2 appears to regulate hepatic insulin action as well as pancreatic beta cell development and survival. |
| 4486 | 11641236 | Defects in muscle IRS-1 expression and function have been reported in insulin-resistant states such as obesity and type 2 diabetes. |
| 4487 | 11679436 | Skeletal muscle insulin resistance in normoglycemic subjects with a strong family history of type 2 diabetes is associated with decreased insulin-stimulated insulin receptor substrate-1 tyrosine phosphorylation. |
| 4488 | 11679436 | In contrast, the FH(+) group had decreased insulin stimulation of insulin receptor substrate (IRS)-1 tyrosine phosphorylation (0.522 +/- 0.077 vs. 1.328 +/- 0.115 density units; P < 0.01) and association of PI 3-kinase activity with IRS-1 (0.299 +/- 0.053 vs. 0.466 +/- 0.098 activity units; P < 0.05). |
| 4489 | 11679436 | Skeletal muscle insulin resistance in normoglycemic subjects with a strong family history of type 2 diabetes is associated with decreased insulin-stimulated insulin receptor substrate-1 tyrosine phosphorylation. |
| 4490 | 11679436 | In contrast, the FH(+) group had decreased insulin stimulation of insulin receptor substrate (IRS)-1 tyrosine phosphorylation (0.522 +/- 0.077 vs. 1.328 +/- 0.115 density units; P < 0.01) and association of PI 3-kinase activity with IRS-1 (0.299 +/- 0.053 vs. 0.466 +/- 0.098 activity units; P < 0.05). |
| 4491 | 11701440 | Normal Akt/PKB with reduced PI3K activation in insulin-resistant mice. |
| 4492 | 11701440 | Similarly, adipocytes from insulin-resistant mice have diminished insulin-stimulated IRS-1 phosphorylation and phosphatidylinositol 3-kinase (PI3K) activation. |
| 4493 | 11701440 | However, normal activation of protein kinase B (Akt/PKB) by insulin is observed. |
| 4494 | 11701440 | Thus BtB6 mice demonstrate the dissociation of insulin-stimulated PI3K activity and Akt/PKB activation and represent a useful model to investigate the causes of insulin resistance in humans. |
| 4495 | 11707432 | We have found that insulin resistance induced by tumor necrosis factor-alpha (TNF-alpha) in 3T3-L1 adipocytes was accompanied by increased GM3 ganglioside expression caused by elevating GM3 synthase activity and its mRNA. |
| 4496 | 11707432 | We also demonstrated that TNF-alpha simultaneously produced insulin resistance by uncoupling insulin receptor activity toward insulin receptor substrate-1 (IRS-1) and suppressing insulin-sensitive glucose transport. |
| 4497 | 11707432 | Pharmacological depletion of GM3 in adipocytes by an inhibitor of glucosylceramide synthase prevented the TNF-alpha-induced defect in insulin-dependent tyrosine phosphorylation of IRS-1 and also counteracted the TNF-alpha-induced serine phosphorylation of IRS-1. |
| 4498 | 11707432 | Moreover, when the adipocytes were incubated with exogenous GM3, suppression of tyrosine phosphorylation of insulin receptor and IRS-1 and glucose uptake in response to insulin stimulation was observed, demonstrating that GM3 itself is able to mimic the effects of TNF on insulin signaling. |
| 4499 | 11707432 | We used the obese Zucker fa/fa rat and ob/ob mouse, which are known to overproduce TNF-alpha mRNA in adipose tissues, as typical models of insulin resistance. |
| 4500 | 11707432 | Taken together, the increased synthesis of cellular GM3 by TNF may participate in the pathological conditions of insulin resistance in type 2 diabetes. |
| 4501 | 11707432 | We have found that insulin resistance induced by tumor necrosis factor-alpha (TNF-alpha) in 3T3-L1 adipocytes was accompanied by increased GM3 ganglioside expression caused by elevating GM3 synthase activity and its mRNA. |
| 4502 | 11707432 | We also demonstrated that TNF-alpha simultaneously produced insulin resistance by uncoupling insulin receptor activity toward insulin receptor substrate-1 (IRS-1) and suppressing insulin-sensitive glucose transport. |
| 4503 | 11707432 | Pharmacological depletion of GM3 in adipocytes by an inhibitor of glucosylceramide synthase prevented the TNF-alpha-induced defect in insulin-dependent tyrosine phosphorylation of IRS-1 and also counteracted the TNF-alpha-induced serine phosphorylation of IRS-1. |
| 4504 | 11707432 | Moreover, when the adipocytes were incubated with exogenous GM3, suppression of tyrosine phosphorylation of insulin receptor and IRS-1 and glucose uptake in response to insulin stimulation was observed, demonstrating that GM3 itself is able to mimic the effects of TNF on insulin signaling. |
| 4505 | 11707432 | We used the obese Zucker fa/fa rat and ob/ob mouse, which are known to overproduce TNF-alpha mRNA in adipose tissues, as typical models of insulin resistance. |
| 4506 | 11707432 | Taken together, the increased synthesis of cellular GM3 by TNF may participate in the pathological conditions of insulin resistance in type 2 diabetes. |
| 4507 | 11707432 | We have found that insulin resistance induced by tumor necrosis factor-alpha (TNF-alpha) in 3T3-L1 adipocytes was accompanied by increased GM3 ganglioside expression caused by elevating GM3 synthase activity and its mRNA. |
| 4508 | 11707432 | We also demonstrated that TNF-alpha simultaneously produced insulin resistance by uncoupling insulin receptor activity toward insulin receptor substrate-1 (IRS-1) and suppressing insulin-sensitive glucose transport. |
| 4509 | 11707432 | Pharmacological depletion of GM3 in adipocytes by an inhibitor of glucosylceramide synthase prevented the TNF-alpha-induced defect in insulin-dependent tyrosine phosphorylation of IRS-1 and also counteracted the TNF-alpha-induced serine phosphorylation of IRS-1. |
| 4510 | 11707432 | Moreover, when the adipocytes were incubated with exogenous GM3, suppression of tyrosine phosphorylation of insulin receptor and IRS-1 and glucose uptake in response to insulin stimulation was observed, demonstrating that GM3 itself is able to mimic the effects of TNF on insulin signaling. |
| 4511 | 11707432 | We used the obese Zucker fa/fa rat and ob/ob mouse, which are known to overproduce TNF-alpha mRNA in adipose tissues, as typical models of insulin resistance. |
| 4512 | 11707432 | Taken together, the increased synthesis of cellular GM3 by TNF may participate in the pathological conditions of insulin resistance in type 2 diabetes. |
| 4513 | 11723053 | The levels of insulin-stimulated tyrosine phosphorylation of the insulin receptor beta-subunit, insulin receptor substrate (IRS)-2, and p52(Shc) were increased in diabetic compared with control heart, whereas tyrosine phosphorylation of IRS-1 was unchanged. |
| 4514 | 11723053 | The amount of the p85 subunit of phosphatidylinositol 3-kinase (PI 3-kinase) and the level of PI 3-kinase activity associated with IRS-2 were also elevated in diabetes, whereas no changes in IRS-1-associated PI 3-kinase were observed. |
| 4515 | 11723053 | Insulin-induced phosphorylation of Akt on Thr-308 was increased fivefold in diabetic heart, whereas Akt phosphorylation on Ser-473 was normal. |
| 4516 | 11723053 | In contrast with Akt phosphorylation, insulin-induced phosphorylation of glycogen synthase kinase (GSK)-3, a major cellular substrate of Akt, was markedly reduced in diabetes. |
| 4517 | 11723053 | In islet-transplanted rats, the majority of the alterations in insulin-signaling proteins found in diabetic rats were normalized, but insulin stimulation of IRS-2 tyrosine phosphorylation and association with PI 3-kinase was blunted. |
| 4518 | 11723053 | In conclusion, in the diabetic heart, 1) IRS-1, IRS-2, and p52(Shc) are differently altered, 2) the levels of Akt phosphorylation on Ser-473 and Thr-308, respectively, are not coordinately regulated, and 3) the increased activity of proximal-signaling proteins (i.e., IRS-2 and PI 3-kinase) is not propagated distally to GSK-3. |
| 4519 | 11723053 | The levels of insulin-stimulated tyrosine phosphorylation of the insulin receptor beta-subunit, insulin receptor substrate (IRS)-2, and p52(Shc) were increased in diabetic compared with control heart, whereas tyrosine phosphorylation of IRS-1 was unchanged. |
| 4520 | 11723053 | The amount of the p85 subunit of phosphatidylinositol 3-kinase (PI 3-kinase) and the level of PI 3-kinase activity associated with IRS-2 were also elevated in diabetes, whereas no changes in IRS-1-associated PI 3-kinase were observed. |
| 4521 | 11723053 | Insulin-induced phosphorylation of Akt on Thr-308 was increased fivefold in diabetic heart, whereas Akt phosphorylation on Ser-473 was normal. |
| 4522 | 11723053 | In contrast with Akt phosphorylation, insulin-induced phosphorylation of glycogen synthase kinase (GSK)-3, a major cellular substrate of Akt, was markedly reduced in diabetes. |
| 4523 | 11723053 | In islet-transplanted rats, the majority of the alterations in insulin-signaling proteins found in diabetic rats were normalized, but insulin stimulation of IRS-2 tyrosine phosphorylation and association with PI 3-kinase was blunted. |
| 4524 | 11723053 | In conclusion, in the diabetic heart, 1) IRS-1, IRS-2, and p52(Shc) are differently altered, 2) the levels of Akt phosphorylation on Ser-473 and Thr-308, respectively, are not coordinately regulated, and 3) the increased activity of proximal-signaling proteins (i.e., IRS-2 and PI 3-kinase) is not propagated distally to GSK-3. |
| 4525 | 11723060 | The incremental increase in insulin action on IRS-1 tyrosine phosphorylation was lower in IGT relatives versus control subjects (P < 0.05). |
| 4526 | 11723060 | The incremental defects in signal transduction noted for IRS-1 and PI 3-kinase may be attributed to elevated basal phosphorylation/activity of these parameters, because absolute phosphorylation/activity under insulin-stimulated conditions was similar between IGT relatives and control subjects. |
| 4527 | 11723060 | Insulin increased Akt serine phosphorylation in control subjects and IGT relatives, with a tendency for reduced phosphorylation in IGT relatives (P = 0.12). |
| 4528 | 11723060 | In conclusion, aberrant phosphorylation/activity of IRS-1, PI 3-kinase, and Akt is observed in skeletal muscle from relatives of patients with type 2 diabetes with IGT. |
| 4529 | 11723060 | The incremental increase in insulin action on IRS-1 tyrosine phosphorylation was lower in IGT relatives versus control subjects (P < 0.05). |
| 4530 | 11723060 | The incremental defects in signal transduction noted for IRS-1 and PI 3-kinase may be attributed to elevated basal phosphorylation/activity of these parameters, because absolute phosphorylation/activity under insulin-stimulated conditions was similar between IGT relatives and control subjects. |
| 4531 | 11723060 | Insulin increased Akt serine phosphorylation in control subjects and IGT relatives, with a tendency for reduced phosphorylation in IGT relatives (P = 0.12). |
| 4532 | 11723060 | In conclusion, aberrant phosphorylation/activity of IRS-1, PI 3-kinase, and Akt is observed in skeletal muscle from relatives of patients with type 2 diabetes with IGT. |
| 4533 | 11723060 | The incremental increase in insulin action on IRS-1 tyrosine phosphorylation was lower in IGT relatives versus control subjects (P < 0.05). |
| 4534 | 11723060 | The incremental defects in signal transduction noted for IRS-1 and PI 3-kinase may be attributed to elevated basal phosphorylation/activity of these parameters, because absolute phosphorylation/activity under insulin-stimulated conditions was similar between IGT relatives and control subjects. |
| 4535 | 11723060 | Insulin increased Akt serine phosphorylation in control subjects and IGT relatives, with a tendency for reduced phosphorylation in IGT relatives (P = 0.12). |
| 4536 | 11723060 | In conclusion, aberrant phosphorylation/activity of IRS-1, PI 3-kinase, and Akt is observed in skeletal muscle from relatives of patients with type 2 diabetes with IGT. |
| 4537 | 11739098 | Western blot analysis revealed no significant differences in the amount of insulin receptor (IR), insulin receptor substrates-1 and -2 (IRS-1, IRS-2), and the p85 subunit of phosphatidylinositol (PI) 3-kinase. |
| 4538 | 11739098 | After saline injection, tyrosine phosphorylation (pY) of IR, IRS-1, and IRS-2 was not significantly different between groups. |
| 4539 | 11739098 | After insulin injection, pY of the IR was not different between groups, whereas pY of IRS-1 and IRS-2 was reduced (P < 0.05) in HSD vs. |
| 4540 | 11739098 | In addition, association of IRS-1 and IRS-2 with p85 was significantly reduced in HSD vs. |
| 4541 | 11739098 | These data demonstrate that an HSD impairs insulin-stimulated early postreceptor signaling (pY of IRS proteins, IRS interaction with p85). |
| 4542 | 11739098 | Western blot analysis revealed no significant differences in the amount of insulin receptor (IR), insulin receptor substrates-1 and -2 (IRS-1, IRS-2), and the p85 subunit of phosphatidylinositol (PI) 3-kinase. |
| 4543 | 11739098 | After saline injection, tyrosine phosphorylation (pY) of IR, IRS-1, and IRS-2 was not significantly different between groups. |
| 4544 | 11739098 | After insulin injection, pY of the IR was not different between groups, whereas pY of IRS-1 and IRS-2 was reduced (P < 0.05) in HSD vs. |
| 4545 | 11739098 | In addition, association of IRS-1 and IRS-2 with p85 was significantly reduced in HSD vs. |
| 4546 | 11739098 | These data demonstrate that an HSD impairs insulin-stimulated early postreceptor signaling (pY of IRS proteins, IRS interaction with p85). |
| 4547 | 11739098 | Western blot analysis revealed no significant differences in the amount of insulin receptor (IR), insulin receptor substrates-1 and -2 (IRS-1, IRS-2), and the p85 subunit of phosphatidylinositol (PI) 3-kinase. |
| 4548 | 11739098 | After saline injection, tyrosine phosphorylation (pY) of IR, IRS-1, and IRS-2 was not significantly different between groups. |
| 4549 | 11739098 | After insulin injection, pY of the IR was not different between groups, whereas pY of IRS-1 and IRS-2 was reduced (P < 0.05) in HSD vs. |
| 4550 | 11739098 | In addition, association of IRS-1 and IRS-2 with p85 was significantly reduced in HSD vs. |
| 4551 | 11739098 | These data demonstrate that an HSD impairs insulin-stimulated early postreceptor signaling (pY of IRS proteins, IRS interaction with p85). |
| 4552 | 11739098 | Western blot analysis revealed no significant differences in the amount of insulin receptor (IR), insulin receptor substrates-1 and -2 (IRS-1, IRS-2), and the p85 subunit of phosphatidylinositol (PI) 3-kinase. |
| 4553 | 11739098 | After saline injection, tyrosine phosphorylation (pY) of IR, IRS-1, and IRS-2 was not significantly different between groups. |
| 4554 | 11739098 | After insulin injection, pY of the IR was not different between groups, whereas pY of IRS-1 and IRS-2 was reduced (P < 0.05) in HSD vs. |
| 4555 | 11739098 | In addition, association of IRS-1 and IRS-2 with p85 was significantly reduced in HSD vs. |
| 4556 | 11739098 | These data demonstrate that an HSD impairs insulin-stimulated early postreceptor signaling (pY of IRS proteins, IRS interaction with p85). |
| 4557 | 11739394 | Active Rho kinase (ROK-alpha ) associates with insulin receptor substrate-1 and inhibits insulin signaling in vascular smooth muscle cells. |
| 4558 | 11739394 | Recent studies from our laboratory have shown that insulin stimulates myosin-bound phosphatase (MBP) in vascular smooth muscle cells (VSMCs) by decreasing site-specific phosphorylation of the myosin-bound subunit (MBS) of MBP via nitric oxide/cGMP-mediated Rho/Rho kinase inactivation. |
| 4559 | 11739394 | Here we tested potential interactions between Rho kinase and insulin signaling pathways. |
| 4560 | 11739394 | In control VSMCs, insulin inactivates ROK-alpha, the major Rho kinase isoform in VSMCs, and inhibits thrombin-induced increase in ROK-alpha association with the insulin receptor substrate-1 (IRS-1). |
| 4561 | 11739394 | Hypertension (in spontaneous hypertensive rats) or expression of an active RhoA(V14) up-regulates Rho kinase activity and increases ROK-alpha/IRS-1 association resulting in IRS-1 serine phosphorylation that leads to inhibition of both insulin-induced IRS-1 tyrosine phosphorylation and phosphatidylinositol 3-kinase (PI3-kinase) activation. |
| 4562 | 11739394 | In contrast, expression of dominant negative RhoA or cGMP-dependent protein kinase type I alpha inactivates Rho kinase, abolishes ROK-alpha/IRS-1 association, and potentiates insulin-induced tyrosine phosphorylation and PI3-kinase activation leading to decreased MBS(T695) phosphorylation and decreased MBP inhibition. |
| 4563 | 11739394 | Collectively, these results suggest a novel function for ROK-alpha in insulin signal transduction at the level of IRS-1 and potential cross-talk between cGMP-dependent protein kinase type I alpha, Rho/Rho kinase signaling, and insulin signaling at the level of IRS-1/PI3-kinase. |
| 4564 | 11739394 | Active Rho kinase (ROK-alpha ) associates with insulin receptor substrate-1 and inhibits insulin signaling in vascular smooth muscle cells. |
| 4565 | 11739394 | Recent studies from our laboratory have shown that insulin stimulates myosin-bound phosphatase (MBP) in vascular smooth muscle cells (VSMCs) by decreasing site-specific phosphorylation of the myosin-bound subunit (MBS) of MBP via nitric oxide/cGMP-mediated Rho/Rho kinase inactivation. |
| 4566 | 11739394 | Here we tested potential interactions between Rho kinase and insulin signaling pathways. |
| 4567 | 11739394 | In control VSMCs, insulin inactivates ROK-alpha, the major Rho kinase isoform in VSMCs, and inhibits thrombin-induced increase in ROK-alpha association with the insulin receptor substrate-1 (IRS-1). |
| 4568 | 11739394 | Hypertension (in spontaneous hypertensive rats) or expression of an active RhoA(V14) up-regulates Rho kinase activity and increases ROK-alpha/IRS-1 association resulting in IRS-1 serine phosphorylation that leads to inhibition of both insulin-induced IRS-1 tyrosine phosphorylation and phosphatidylinositol 3-kinase (PI3-kinase) activation. |
| 4569 | 11739394 | In contrast, expression of dominant negative RhoA or cGMP-dependent protein kinase type I alpha inactivates Rho kinase, abolishes ROK-alpha/IRS-1 association, and potentiates insulin-induced tyrosine phosphorylation and PI3-kinase activation leading to decreased MBS(T695) phosphorylation and decreased MBP inhibition. |
| 4570 | 11739394 | Collectively, these results suggest a novel function for ROK-alpha in insulin signal transduction at the level of IRS-1 and potential cross-talk between cGMP-dependent protein kinase type I alpha, Rho/Rho kinase signaling, and insulin signaling at the level of IRS-1/PI3-kinase. |
| 4571 | 11739394 | Active Rho kinase (ROK-alpha ) associates with insulin receptor substrate-1 and inhibits insulin signaling in vascular smooth muscle cells. |
| 4572 | 11739394 | Recent studies from our laboratory have shown that insulin stimulates myosin-bound phosphatase (MBP) in vascular smooth muscle cells (VSMCs) by decreasing site-specific phosphorylation of the myosin-bound subunit (MBS) of MBP via nitric oxide/cGMP-mediated Rho/Rho kinase inactivation. |
| 4573 | 11739394 | Here we tested potential interactions between Rho kinase and insulin signaling pathways. |
| 4574 | 11739394 | In control VSMCs, insulin inactivates ROK-alpha, the major Rho kinase isoform in VSMCs, and inhibits thrombin-induced increase in ROK-alpha association with the insulin receptor substrate-1 (IRS-1). |
| 4575 | 11739394 | Hypertension (in spontaneous hypertensive rats) or expression of an active RhoA(V14) up-regulates Rho kinase activity and increases ROK-alpha/IRS-1 association resulting in IRS-1 serine phosphorylation that leads to inhibition of both insulin-induced IRS-1 tyrosine phosphorylation and phosphatidylinositol 3-kinase (PI3-kinase) activation. |
| 4576 | 11739394 | In contrast, expression of dominant negative RhoA or cGMP-dependent protein kinase type I alpha inactivates Rho kinase, abolishes ROK-alpha/IRS-1 association, and potentiates insulin-induced tyrosine phosphorylation and PI3-kinase activation leading to decreased MBS(T695) phosphorylation and decreased MBP inhibition. |
| 4577 | 11739394 | Collectively, these results suggest a novel function for ROK-alpha in insulin signal transduction at the level of IRS-1 and potential cross-talk between cGMP-dependent protein kinase type I alpha, Rho/Rho kinase signaling, and insulin signaling at the level of IRS-1/PI3-kinase. |
| 4578 | 11739394 | Active Rho kinase (ROK-alpha ) associates with insulin receptor substrate-1 and inhibits insulin signaling in vascular smooth muscle cells. |
| 4579 | 11739394 | Recent studies from our laboratory have shown that insulin stimulates myosin-bound phosphatase (MBP) in vascular smooth muscle cells (VSMCs) by decreasing site-specific phosphorylation of the myosin-bound subunit (MBS) of MBP via nitric oxide/cGMP-mediated Rho/Rho kinase inactivation. |
| 4580 | 11739394 | Here we tested potential interactions between Rho kinase and insulin signaling pathways. |
| 4581 | 11739394 | In control VSMCs, insulin inactivates ROK-alpha, the major Rho kinase isoform in VSMCs, and inhibits thrombin-induced increase in ROK-alpha association with the insulin receptor substrate-1 (IRS-1). |
| 4582 | 11739394 | Hypertension (in spontaneous hypertensive rats) or expression of an active RhoA(V14) up-regulates Rho kinase activity and increases ROK-alpha/IRS-1 association resulting in IRS-1 serine phosphorylation that leads to inhibition of both insulin-induced IRS-1 tyrosine phosphorylation and phosphatidylinositol 3-kinase (PI3-kinase) activation. |
| 4583 | 11739394 | In contrast, expression of dominant negative RhoA or cGMP-dependent protein kinase type I alpha inactivates Rho kinase, abolishes ROK-alpha/IRS-1 association, and potentiates insulin-induced tyrosine phosphorylation and PI3-kinase activation leading to decreased MBS(T695) phosphorylation and decreased MBP inhibition. |
| 4584 | 11739394 | Collectively, these results suggest a novel function for ROK-alpha in insulin signal transduction at the level of IRS-1 and potential cross-talk between cGMP-dependent protein kinase type I alpha, Rho/Rho kinase signaling, and insulin signaling at the level of IRS-1/PI3-kinase. |
| 4585 | 11739394 | Active Rho kinase (ROK-alpha ) associates with insulin receptor substrate-1 and inhibits insulin signaling in vascular smooth muscle cells. |
| 4586 | 11739394 | Recent studies from our laboratory have shown that insulin stimulates myosin-bound phosphatase (MBP) in vascular smooth muscle cells (VSMCs) by decreasing site-specific phosphorylation of the myosin-bound subunit (MBS) of MBP via nitric oxide/cGMP-mediated Rho/Rho kinase inactivation. |
| 4587 | 11739394 | Here we tested potential interactions between Rho kinase and insulin signaling pathways. |
| 4588 | 11739394 | In control VSMCs, insulin inactivates ROK-alpha, the major Rho kinase isoform in VSMCs, and inhibits thrombin-induced increase in ROK-alpha association with the insulin receptor substrate-1 (IRS-1). |
| 4589 | 11739394 | Hypertension (in spontaneous hypertensive rats) or expression of an active RhoA(V14) up-regulates Rho kinase activity and increases ROK-alpha/IRS-1 association resulting in IRS-1 serine phosphorylation that leads to inhibition of both insulin-induced IRS-1 tyrosine phosphorylation and phosphatidylinositol 3-kinase (PI3-kinase) activation. |
| 4590 | 11739394 | In contrast, expression of dominant negative RhoA or cGMP-dependent protein kinase type I alpha inactivates Rho kinase, abolishes ROK-alpha/IRS-1 association, and potentiates insulin-induced tyrosine phosphorylation and PI3-kinase activation leading to decreased MBS(T695) phosphorylation and decreased MBP inhibition. |
| 4591 | 11739394 | Collectively, these results suggest a novel function for ROK-alpha in insulin signal transduction at the level of IRS-1 and potential cross-talk between cGMP-dependent protein kinase type I alpha, Rho/Rho kinase signaling, and insulin signaling at the level of IRS-1/PI3-kinase. |
| 4592 | 11756318 | Phosphatidylinositol 3-kinase redistribution is associated with skeletal muscle insulin resistance in gestational diabetes mellitus. |
| 4593 | 11756318 | In conjunction with the redistribution of PI 3-kinase to the insulin receptor, there is a selective increase in activation of downstream serine kinases Akt and p70S6. |
| 4594 | 11756318 | Furthermore, we show that redistribution of PI 3-kinase to the insulin receptor increases insulin-stimulated IRS-1 serine phosphorylation, impairs IRS-1 expression and its tyrosine phosphorylation, and decreases the ability of IRS-1 to bind and activate PI 3-kinase in response to insulin. |
| 4595 | 11756318 | Thus, the pool of IRS-1-associated PI 3-kinase activity is reduced, resulting in the inability of insulin to stimulate GLUT4 translocation to the plasma membrane. |
| 4596 | 11756339 | They had phosphorylation of the IGF-I receptor beta-subunit, phosphorylation of insulin receptor substrate (IRS)-1, and association of the p85 subunit (phosphatidylinositol 3-kinase [PI3K]) with the IGF-I receptor and IRS-1 in D-NOD cells in the basal state. |
| 4597 | 11756339 | Inhibiting autocrine IGF-I from binding to its receptor using an IGF-I-neutralizing antibody or inhibiting IGF-I signaling pathways using a specific PI3K inhibitor or a specific mitogen-activated protein kinase/extracellular response kinase kinase inhibitor decreased phosphorylated ERKs in D-NOD cells. |
| 4598 | 11781359 | Reduced expression of the murine p85alpha subunit of phosphoinositide 3-kinase improves insulin signaling and ameliorates diabetes. |
| 4599 | 11781359 | Heterozygous disruption of Pik3r1 improves insulin signaling and glucose homeostasis in normal mice and mice made insulin-resistant by heterozygous deletion of the Insulin receptor and/or insulin receptor substrate-1 (IRS1) genes. |
| 4600 | 11781359 | Reduced expression of p85 modulates the molecular balance between this protein, the p110 catalytic subunit of PI 3-kinase, and the IRS proteins. |
| 4601 | 11781359 | Thus, despite the decrease in p85alpha, PI 3-kinase activation is normal, insulin-stimulated Akt activity is increased, and glucose tolerance and insulin sensitivity are improved. |
| 4602 | 11781359 | Furthermore, Pik3r1 heterozygosity protects mice with genetic insulin resistance from developing diabetes. |
| 4603 | 11782469 | Insulin stimulates phosphorylation of the beta 2-adrenergic receptor by the insulin receptor, creating a potent feedback inhibitor of its tyrosine kinase. |
| 4604 | 11782469 | Herein we observe that expression of increased levels of beta(2)-adrenergic receptor increasingly inhibits insulin-stimulated phosphorylation of its primary downstream substrates (IRS-1,2). |
| 4605 | 11782469 | A Y364A mutant form of the beta(2)-adrenergic, in contrast, loses it ability to inhibit insulin-stimulated phosphorylation of IRS-1,2. |
| 4606 | 11782469 | Upon phosphorylation, the C-terminal cytoplasmic domain of the beta(2)-adrenergic receptor demonstrates a potent inhibitory feedback action that can block both insulin-stimulated autophosphorylation of the insulin receptor and phosphorylation of IRS-1,2 in NIH mouse 3T3-L1 adipocyte membranes. |
| 4607 | 11782469 | Studies in vitro with purified insulin receptor and the C-terminal cytoplasmic domain of the beta(2)-adrenergic receptor demonstrate that the tyrosine-phosphorylated beta-receptor domain is a potent counterregulatory inhibitor of the insulin receptor tyrosine kinase. |
| 4608 | 11782469 | Insulin stimulates phosphorylation of the beta 2-adrenergic receptor by the insulin receptor, creating a potent feedback inhibitor of its tyrosine kinase. |
| 4609 | 11782469 | Herein we observe that expression of increased levels of beta(2)-adrenergic receptor increasingly inhibits insulin-stimulated phosphorylation of its primary downstream substrates (IRS-1,2). |
| 4610 | 11782469 | A Y364A mutant form of the beta(2)-adrenergic, in contrast, loses it ability to inhibit insulin-stimulated phosphorylation of IRS-1,2. |
| 4611 | 11782469 | Upon phosphorylation, the C-terminal cytoplasmic domain of the beta(2)-adrenergic receptor demonstrates a potent inhibitory feedback action that can block both insulin-stimulated autophosphorylation of the insulin receptor and phosphorylation of IRS-1,2 in NIH mouse 3T3-L1 adipocyte membranes. |
| 4612 | 11782469 | Studies in vitro with purified insulin receptor and the C-terminal cytoplasmic domain of the beta(2)-adrenergic receptor demonstrate that the tyrosine-phosphorylated beta-receptor domain is a potent counterregulatory inhibitor of the insulin receptor tyrosine kinase. |
| 4613 | 11782469 | Insulin stimulates phosphorylation of the beta 2-adrenergic receptor by the insulin receptor, creating a potent feedback inhibitor of its tyrosine kinase. |
| 4614 | 11782469 | Herein we observe that expression of increased levels of beta(2)-adrenergic receptor increasingly inhibits insulin-stimulated phosphorylation of its primary downstream substrates (IRS-1,2). |
| 4615 | 11782469 | A Y364A mutant form of the beta(2)-adrenergic, in contrast, loses it ability to inhibit insulin-stimulated phosphorylation of IRS-1,2. |
| 4616 | 11782469 | Upon phosphorylation, the C-terminal cytoplasmic domain of the beta(2)-adrenergic receptor demonstrates a potent inhibitory feedback action that can block both insulin-stimulated autophosphorylation of the insulin receptor and phosphorylation of IRS-1,2 in NIH mouse 3T3-L1 adipocyte membranes. |
| 4617 | 11782469 | Studies in vitro with purified insulin receptor and the C-terminal cytoplasmic domain of the beta(2)-adrenergic receptor demonstrate that the tyrosine-phosphorylated beta-receptor domain is a potent counterregulatory inhibitor of the insulin receptor tyrosine kinase. |
| 4618 | 11785657 | Protein kinase C inhibits insulin-induced Akt activation in vascular smooth muscle cells. |
| 4619 | 11785657 | We hypothesized that the negative regulation of Akt in the vasculature by PKC could contribute to insulin resistant states and, may therefore play a role in the pathogenesis of cardiovascular disease. |
| 4620 | 11785657 | In this study, we specifically looked at the ability of PKC to inhibit Akt activation induced by insulin in cultured rat aortic vascular smooth muscle cells (VSMCs). |
| 4621 | 11785657 | A PKC activator, phorbol 12-myristate 13-acetate (PMA), inhibited insulin-dependent Akt phosphorylation. |
| 4622 | 11785657 | However, PMA did not inhibit platelet-derived growth factor (PDGF)-induced activation of Akt. |
| 4623 | 11785657 | In addition, we demonstrated that PMA inhibited the insulin-induced tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1). |
| 4624 | 11788369 | No differences were found in tyrosine phosphorylation of the insulin receptor, insulin receptor substrate-1, and phosphatidylinositol 3-kinase among the groups. |
| 4625 | 11788655 | Down-regulation of insulin receptor substrates (IRS)-1 and IRS-2 and Src homologous and collagen-like protein Shc gene expression by insulin in skeletal muscle is not associated with insulin resistance or type 2 diabetes. |
| 4626 | 11788655 | To examine whether altered gene expression of insulin receptor substrates (IRS)-1 and IRS-2 and Src homologous and collagen-like protein Shc is an inherited trait and is associated with muscle insulin resistance or type 2 diabetes, we measured mRNA levels of these genes by a relative quantitative RT-PCR method in muscle biopsies taken before and after an insulin clamp from 12 monozygotic twin pairs discordant for type 2 diabetes and 12 control subjects. |
| 4627 | 11788655 | Basal mRNA levels of IRS-1, IRS-2, and Shc were similar in the diabetic and nondiabetic twins as well as in the control subjects. |
| 4628 | 11788655 | Insulin decreased mRNA expression of IRS-1 by 72% (from 0.75 +/- 0.06 to 0.21 +/- 0.04 relative units; P < 0.001), IRS-2 by 71% (from 0.55 +/- 0.10 to 0.16 +/- 0.08 relative units; P < 0.03), and Shc by 25% (from 0.95 +/- 0.04 to 0.71 +/- 0.04 relative units; P < 0.01) vs. baseline as demonstrated in the control subjects. |
| 4629 | 11788655 | The postclamp Shc mRNA level was slightly higher in the diabetic twins (P = 0.05) but similar in the nondiabetic twins, as compared with the control subjects, whereas postclamp IRS-1 and IRS-2 mRNA levels were similar between the study groups. |
| 4630 | 11788655 | However, the decrease in Shc gene expression by insulin was not significantly different between the study groups. |
| 4631 | 11788655 | In conclusion, because insulin down-regulates IRS-1, IRS-2, and Shc gene expression in skeletal muscle in diabetic and nondiabetic monozygotic twins and control subjects to the same extent, it is unlikely that expression of these genes is an inherited trait or contributes to skeletal muscle insulin resistance. |
| 4632 | 11788655 | Down-regulation of insulin receptor substrates (IRS)-1 and IRS-2 and Src homologous and collagen-like protein Shc gene expression by insulin in skeletal muscle is not associated with insulin resistance or type 2 diabetes. |
| 4633 | 11788655 | To examine whether altered gene expression of insulin receptor substrates (IRS)-1 and IRS-2 and Src homologous and collagen-like protein Shc is an inherited trait and is associated with muscle insulin resistance or type 2 diabetes, we measured mRNA levels of these genes by a relative quantitative RT-PCR method in muscle biopsies taken before and after an insulin clamp from 12 monozygotic twin pairs discordant for type 2 diabetes and 12 control subjects. |
| 4634 | 11788655 | Basal mRNA levels of IRS-1, IRS-2, and Shc were similar in the diabetic and nondiabetic twins as well as in the control subjects. |
| 4635 | 11788655 | Insulin decreased mRNA expression of IRS-1 by 72% (from 0.75 +/- 0.06 to 0.21 +/- 0.04 relative units; P < 0.001), IRS-2 by 71% (from 0.55 +/- 0.10 to 0.16 +/- 0.08 relative units; P < 0.03), and Shc by 25% (from 0.95 +/- 0.04 to 0.71 +/- 0.04 relative units; P < 0.01) vs. baseline as demonstrated in the control subjects. |
| 4636 | 11788655 | The postclamp Shc mRNA level was slightly higher in the diabetic twins (P = 0.05) but similar in the nondiabetic twins, as compared with the control subjects, whereas postclamp IRS-1 and IRS-2 mRNA levels were similar between the study groups. |
| 4637 | 11788655 | However, the decrease in Shc gene expression by insulin was not significantly different between the study groups. |
| 4638 | 11788655 | In conclusion, because insulin down-regulates IRS-1, IRS-2, and Shc gene expression in skeletal muscle in diabetic and nondiabetic monozygotic twins and control subjects to the same extent, it is unlikely that expression of these genes is an inherited trait or contributes to skeletal muscle insulin resistance. |
| 4639 | 11788655 | Down-regulation of insulin receptor substrates (IRS)-1 and IRS-2 and Src homologous and collagen-like protein Shc gene expression by insulin in skeletal muscle is not associated with insulin resistance or type 2 diabetes. |
| 4640 | 11788655 | To examine whether altered gene expression of insulin receptor substrates (IRS)-1 and IRS-2 and Src homologous and collagen-like protein Shc is an inherited trait and is associated with muscle insulin resistance or type 2 diabetes, we measured mRNA levels of these genes by a relative quantitative RT-PCR method in muscle biopsies taken before and after an insulin clamp from 12 monozygotic twin pairs discordant for type 2 diabetes and 12 control subjects. |
| 4641 | 11788655 | Basal mRNA levels of IRS-1, IRS-2, and Shc were similar in the diabetic and nondiabetic twins as well as in the control subjects. |
| 4642 | 11788655 | Insulin decreased mRNA expression of IRS-1 by 72% (from 0.75 +/- 0.06 to 0.21 +/- 0.04 relative units; P < 0.001), IRS-2 by 71% (from 0.55 +/- 0.10 to 0.16 +/- 0.08 relative units; P < 0.03), and Shc by 25% (from 0.95 +/- 0.04 to 0.71 +/- 0.04 relative units; P < 0.01) vs. baseline as demonstrated in the control subjects. |
| 4643 | 11788655 | The postclamp Shc mRNA level was slightly higher in the diabetic twins (P = 0.05) but similar in the nondiabetic twins, as compared with the control subjects, whereas postclamp IRS-1 and IRS-2 mRNA levels were similar between the study groups. |
| 4644 | 11788655 | However, the decrease in Shc gene expression by insulin was not significantly different between the study groups. |
| 4645 | 11788655 | In conclusion, because insulin down-regulates IRS-1, IRS-2, and Shc gene expression in skeletal muscle in diabetic and nondiabetic monozygotic twins and control subjects to the same extent, it is unlikely that expression of these genes is an inherited trait or contributes to skeletal muscle insulin resistance. |
| 4646 | 11788655 | Down-regulation of insulin receptor substrates (IRS)-1 and IRS-2 and Src homologous and collagen-like protein Shc gene expression by insulin in skeletal muscle is not associated with insulin resistance or type 2 diabetes. |
| 4647 | 11788655 | To examine whether altered gene expression of insulin receptor substrates (IRS)-1 and IRS-2 and Src homologous and collagen-like protein Shc is an inherited trait and is associated with muscle insulin resistance or type 2 diabetes, we measured mRNA levels of these genes by a relative quantitative RT-PCR method in muscle biopsies taken before and after an insulin clamp from 12 monozygotic twin pairs discordant for type 2 diabetes and 12 control subjects. |
| 4648 | 11788655 | Basal mRNA levels of IRS-1, IRS-2, and Shc were similar in the diabetic and nondiabetic twins as well as in the control subjects. |
| 4649 | 11788655 | Insulin decreased mRNA expression of IRS-1 by 72% (from 0.75 +/- 0.06 to 0.21 +/- 0.04 relative units; P < 0.001), IRS-2 by 71% (from 0.55 +/- 0.10 to 0.16 +/- 0.08 relative units; P < 0.03), and Shc by 25% (from 0.95 +/- 0.04 to 0.71 +/- 0.04 relative units; P < 0.01) vs. baseline as demonstrated in the control subjects. |
| 4650 | 11788655 | The postclamp Shc mRNA level was slightly higher in the diabetic twins (P = 0.05) but similar in the nondiabetic twins, as compared with the control subjects, whereas postclamp IRS-1 and IRS-2 mRNA levels were similar between the study groups. |
| 4651 | 11788655 | However, the decrease in Shc gene expression by insulin was not significantly different between the study groups. |
| 4652 | 11788655 | In conclusion, because insulin down-regulates IRS-1, IRS-2, and Shc gene expression in skeletal muscle in diabetic and nondiabetic monozygotic twins and control subjects to the same extent, it is unlikely that expression of these genes is an inherited trait or contributes to skeletal muscle insulin resistance. |
| 4653 | 11812753 | Troglitazone but not metformin restores insulin-stimulated phosphoinositide 3-kinase activity and increases p110beta protein levels in skeletal muscle of type 2 diabetic subjects. |
| 4654 | 11812753 | Insulin-stimulated Akt activity also increased after troglitazone treatment (from 32 +/- 8 to 107 +/- 32% stimulation, P < 0.05) but was unchanged after metformin therapy. |
| 4655 | 11812753 | Protein expression of other key insulin signaling molecules (IRS-1, the p85 subunit of PI 3-kinase, and Akt) was unaltered after either treatment. |
| 4656 | 11815470 | We also showed that normal glucose-tolerant carriers of the Gly972Arg polymorphism in the insulin receptor substrate 1 have significantly reduced insulin secretion in response to glucose and arginine but not to GLP-1. |
| 4657 | 11832353 | Downregulated IRS-1 and PPARgamma in obese women with gestational diabetes: relationship to FFA during pregnancy. |
| 4658 | 11832353 | Adipose tissue insulin receptor substrate (IRS)-1 protein levels were 43% lower (P = 0.02) and p85alpha subunit of phosphatidylinositol 3-kinase was twofold higher (P = 0.03) in GDM compared with Preg-Con subjects. |
| 4659 | 11832353 | Lipoprotein lipase and fatty acid-binding protein-2 mRNA levels were 73 and 52% lower in GDM compared with Preg-Con subjects (P < 0.002). |
| 4660 | 11832353 | Thus GDM women have decreased IRS-1, which may contribute to reduced insulin suppression of lipolysis with advancing gestation. |
| 4661 | 11832353 | Downregulated IRS-1 and PPARgamma in obese women with gestational diabetes: relationship to FFA during pregnancy. |
| 4662 | 11832353 | Adipose tissue insulin receptor substrate (IRS)-1 protein levels were 43% lower (P = 0.02) and p85alpha subunit of phosphatidylinositol 3-kinase was twofold higher (P = 0.03) in GDM compared with Preg-Con subjects. |
| 4663 | 11832353 | Lipoprotein lipase and fatty acid-binding protein-2 mRNA levels were 73 and 52% lower in GDM compared with Preg-Con subjects (P < 0.002). |
| 4664 | 11832353 | Thus GDM women have decreased IRS-1, which may contribute to reduced insulin suppression of lipolysis with advancing gestation. |
| 4665 | 11856812 | Decreased IR, IRS-1, and IRS-2 tyrosyl phosphorylation in response to insulin was found in skeletal muscle, whereas a chronic activation of the IRS-PI 3-kinase pathway was found in liver. |
| 4666 | 11856812 | The induction of the expression of proteins that inhibit IR signaling such as suppressors of cytokine signaling (SOCS)-1 and -6 may also be involved in this alteration. |
| 4667 | 11862322 | The Pro12Ala polymorphism in the peroxisome proliferator-activated receptor (PPAR) gamma2 gene is associated with a reduced risk of type 2 diabetes. |
| 4668 | 11862322 | Interestingly, using the OGTT index, insulin sensitivity was significantly greater in X/Ala (PPARgamma2) + X/Arg (IRS-1) than in Pro/Pro (PPARgamma2) + X/Arg (IRS-1). |
| 4669 | 11862322 | On the other hand, insulin sensitivity was similar in the X/Ala (PPARgamma2) + Gly/Gly (IRS-1 972) and the Pro/Pro (PPARgamma2) + Gly/Gly (IRS-1). |
| 4670 | 11862322 | In conclusion, the Arg972 (IRS-1) background produced a marked difference in insulin sensitivity between X/Ala and Pro/Pro (PPARgamma) which was not present in the whole population or against the Gly972 (IRS-1) background. |
| 4671 | 11862322 | The Pro12Ala polymorphism in the peroxisome proliferator-activated receptor (PPAR) gamma2 gene is associated with a reduced risk of type 2 diabetes. |
| 4672 | 11862322 | Interestingly, using the OGTT index, insulin sensitivity was significantly greater in X/Ala (PPARgamma2) + X/Arg (IRS-1) than in Pro/Pro (PPARgamma2) + X/Arg (IRS-1). |
| 4673 | 11862322 | On the other hand, insulin sensitivity was similar in the X/Ala (PPARgamma2) + Gly/Gly (IRS-1 972) and the Pro/Pro (PPARgamma2) + Gly/Gly (IRS-1). |
| 4674 | 11862322 | In conclusion, the Arg972 (IRS-1) background produced a marked difference in insulin sensitivity between X/Ala and Pro/Pro (PPARgamma) which was not present in the whole population or against the Gly972 (IRS-1) background. |
| 4675 | 11862322 | The Pro12Ala polymorphism in the peroxisome proliferator-activated receptor (PPAR) gamma2 gene is associated with a reduced risk of type 2 diabetes. |
| 4676 | 11862322 | Interestingly, using the OGTT index, insulin sensitivity was significantly greater in X/Ala (PPARgamma2) + X/Arg (IRS-1) than in Pro/Pro (PPARgamma2) + X/Arg (IRS-1). |
| 4677 | 11862322 | On the other hand, insulin sensitivity was similar in the X/Ala (PPARgamma2) + Gly/Gly (IRS-1 972) and the Pro/Pro (PPARgamma2) + Gly/Gly (IRS-1). |
| 4678 | 11862322 | In conclusion, the Arg972 (IRS-1) background produced a marked difference in insulin sensitivity between X/Ala and Pro/Pro (PPARgamma) which was not present in the whole population or against the Gly972 (IRS-1) background. |
| 4679 | 11872654 | Insulin increased insulin receptor tyrosine kinase (IRTK), insulin receptor substrate 1-associated phosphatidylinositol (PI) 3-kinase activities, and Ser(473) phosphorylation of protein kinase B (PKB)/Akt significantly but similarly in rested and exercised legs. |
| 4680 | 11872654 | Furthermore, insulin significantly decreased glycogen synthase kinase-3alpha (GSK-3alpha) activity equally in both legs. |
| 4681 | 11872654 | We conclude that 1) caffeine impairs insulin-stimulated glucose uptake and GS activity in rested and exercised human skeletal muscle; 2) caffeine-induced impairment of insulin-stimulated muscle glucose uptake and downregulation of GS activity are not accompanied by alterations in IRTK, PI 3-kinase, PKB/Akt, or GSK-3alpha but may be associated with increases in epinephrine and intramuscular cAMP concentrations; and 3) exercise reduces the detrimental effects of caffeine on insulin action in muscle. |
| 4682 | 11872675 | Increased insulin sensitivity in IGF-I receptor--deficient brown adipocytes. |
| 4683 | 11872675 | Immortalized brown adipocyte cell lines have been generated from fetuses of mice deficient in the insulin-like growth factor I receptor gene (IGF-IR(-/-)), as well as from fetuses of wild-type mice (IGF-IR(+/+)). |
| 4684 | 11872675 | IGF-IR(-/-) brown adipocytes lacked IGF-IR protein expression; insulin receptor (IR) expression remained unchanged as compared with wild-type cells. |
| 4685 | 11872675 | Upon insulin stimulation, tyrosine phosphorylation of (insulin receptor substrate-1) IRS-1 was much higher in IGF-IR(-/-) brown adipocytes, although IRS-1 protein content was reduced. |
| 4686 | 11872675 | Downstream, the association IRS-1/growth factor receptor binding protein-2 (Grb-2) was augmented in the IGF-IR(-/-) brown adipocyte cell line. |
| 4687 | 11872675 | However, SHC expression and SHC tyrosine phosphorylation and its association with Grb-2 were unaltered in response to insulin in IGF-IR--deficient brown adipocytes. |
| 4688 | 11872675 | These cells also showed an enhanced activation of mitogen-activated protein kinase (MAPK) kinase (MEK1/2) and p42/p44 mitogen-activated protein kinase (MAPK) upon insulin stimulation. |
| 4689 | 11872675 | In addition, the lack of IGF-IR in brown adipocytes resulted in a higher mitogenic response (DNA synthesis, cell number, and proliferating cell nuclear antigen expression) to insulin than wild-type cells. |
| 4690 | 11872675 | Finally, cells lacking IGF-IR showed a much lower association between IR or IRS-1 and phosphotyrosine phosphatase 1B (PTP1B) and also a decreased PTP1B activity upon insulin stimulation. |
| 4691 | 11872675 | However, PTP1B/Grb-2 association remained unchanged in both cell types, regardless of insulin stimulation. |
| 4692 | 11872675 | Data presented here provide strong evidence that IGF-IR--deficient brown adipocytes show an increased insulin sensitivity via IRS-1/Grb-2/MAPK, resulting in an increased mitogenesis in response to insulin. |
| 4693 | 11872675 | Increased insulin sensitivity in IGF-I receptor--deficient brown adipocytes. |
| 4694 | 11872675 | Immortalized brown adipocyte cell lines have been generated from fetuses of mice deficient in the insulin-like growth factor I receptor gene (IGF-IR(-/-)), as well as from fetuses of wild-type mice (IGF-IR(+/+)). |
| 4695 | 11872675 | IGF-IR(-/-) brown adipocytes lacked IGF-IR protein expression; insulin receptor (IR) expression remained unchanged as compared with wild-type cells. |
| 4696 | 11872675 | Upon insulin stimulation, tyrosine phosphorylation of (insulin receptor substrate-1) IRS-1 was much higher in IGF-IR(-/-) brown adipocytes, although IRS-1 protein content was reduced. |
| 4697 | 11872675 | Downstream, the association IRS-1/growth factor receptor binding protein-2 (Grb-2) was augmented in the IGF-IR(-/-) brown adipocyte cell line. |
| 4698 | 11872675 | However, SHC expression and SHC tyrosine phosphorylation and its association with Grb-2 were unaltered in response to insulin in IGF-IR--deficient brown adipocytes. |
| 4699 | 11872675 | These cells also showed an enhanced activation of mitogen-activated protein kinase (MAPK) kinase (MEK1/2) and p42/p44 mitogen-activated protein kinase (MAPK) upon insulin stimulation. |
| 4700 | 11872675 | In addition, the lack of IGF-IR in brown adipocytes resulted in a higher mitogenic response (DNA synthesis, cell number, and proliferating cell nuclear antigen expression) to insulin than wild-type cells. |
| 4701 | 11872675 | Finally, cells lacking IGF-IR showed a much lower association between IR or IRS-1 and phosphotyrosine phosphatase 1B (PTP1B) and also a decreased PTP1B activity upon insulin stimulation. |
| 4702 | 11872675 | However, PTP1B/Grb-2 association remained unchanged in both cell types, regardless of insulin stimulation. |
| 4703 | 11872675 | Data presented here provide strong evidence that IGF-IR--deficient brown adipocytes show an increased insulin sensitivity via IRS-1/Grb-2/MAPK, resulting in an increased mitogenesis in response to insulin. |
| 4704 | 11872675 | Increased insulin sensitivity in IGF-I receptor--deficient brown adipocytes. |
| 4705 | 11872675 | Immortalized brown adipocyte cell lines have been generated from fetuses of mice deficient in the insulin-like growth factor I receptor gene (IGF-IR(-/-)), as well as from fetuses of wild-type mice (IGF-IR(+/+)). |
| 4706 | 11872675 | IGF-IR(-/-) brown adipocytes lacked IGF-IR protein expression; insulin receptor (IR) expression remained unchanged as compared with wild-type cells. |
| 4707 | 11872675 | Upon insulin stimulation, tyrosine phosphorylation of (insulin receptor substrate-1) IRS-1 was much higher in IGF-IR(-/-) brown adipocytes, although IRS-1 protein content was reduced. |
| 4708 | 11872675 | Downstream, the association IRS-1/growth factor receptor binding protein-2 (Grb-2) was augmented in the IGF-IR(-/-) brown adipocyte cell line. |
| 4709 | 11872675 | However, SHC expression and SHC tyrosine phosphorylation and its association with Grb-2 were unaltered in response to insulin in IGF-IR--deficient brown adipocytes. |
| 4710 | 11872675 | These cells also showed an enhanced activation of mitogen-activated protein kinase (MAPK) kinase (MEK1/2) and p42/p44 mitogen-activated protein kinase (MAPK) upon insulin stimulation. |
| 4711 | 11872675 | In addition, the lack of IGF-IR in brown adipocytes resulted in a higher mitogenic response (DNA synthesis, cell number, and proliferating cell nuclear antigen expression) to insulin than wild-type cells. |
| 4712 | 11872675 | Finally, cells lacking IGF-IR showed a much lower association between IR or IRS-1 and phosphotyrosine phosphatase 1B (PTP1B) and also a decreased PTP1B activity upon insulin stimulation. |
| 4713 | 11872675 | However, PTP1B/Grb-2 association remained unchanged in both cell types, regardless of insulin stimulation. |
| 4714 | 11872675 | Data presented here provide strong evidence that IGF-IR--deficient brown adipocytes show an increased insulin sensitivity via IRS-1/Grb-2/MAPK, resulting in an increased mitogenesis in response to insulin. |
| 4715 | 11872675 | Increased insulin sensitivity in IGF-I receptor--deficient brown adipocytes. |
| 4716 | 11872675 | Immortalized brown adipocyte cell lines have been generated from fetuses of mice deficient in the insulin-like growth factor I receptor gene (IGF-IR(-/-)), as well as from fetuses of wild-type mice (IGF-IR(+/+)). |
| 4717 | 11872675 | IGF-IR(-/-) brown adipocytes lacked IGF-IR protein expression; insulin receptor (IR) expression remained unchanged as compared with wild-type cells. |
| 4718 | 11872675 | Upon insulin stimulation, tyrosine phosphorylation of (insulin receptor substrate-1) IRS-1 was much higher in IGF-IR(-/-) brown adipocytes, although IRS-1 protein content was reduced. |
| 4719 | 11872675 | Downstream, the association IRS-1/growth factor receptor binding protein-2 (Grb-2) was augmented in the IGF-IR(-/-) brown adipocyte cell line. |
| 4720 | 11872675 | However, SHC expression and SHC tyrosine phosphorylation and its association with Grb-2 were unaltered in response to insulin in IGF-IR--deficient brown adipocytes. |
| 4721 | 11872675 | These cells also showed an enhanced activation of mitogen-activated protein kinase (MAPK) kinase (MEK1/2) and p42/p44 mitogen-activated protein kinase (MAPK) upon insulin stimulation. |
| 4722 | 11872675 | In addition, the lack of IGF-IR in brown adipocytes resulted in a higher mitogenic response (DNA synthesis, cell number, and proliferating cell nuclear antigen expression) to insulin than wild-type cells. |
| 4723 | 11872675 | Finally, cells lacking IGF-IR showed a much lower association between IR or IRS-1 and phosphotyrosine phosphatase 1B (PTP1B) and also a decreased PTP1B activity upon insulin stimulation. |
| 4724 | 11872675 | However, PTP1B/Grb-2 association remained unchanged in both cell types, regardless of insulin stimulation. |
| 4725 | 11872675 | Data presented here provide strong evidence that IGF-IR--deficient brown adipocytes show an increased insulin sensitivity via IRS-1/Grb-2/MAPK, resulting in an increased mitogenesis in response to insulin. |
| 4726 | 11872698 | Variations in insulin secretion in carriers of gene variants in IRS-1 and -2. |
| 4727 | 11872698 | Recently, it has been reported that the Gly(972)Arg variant in IRS-1 was associated with reduced insulin secretion during hyperglycemic clamps in German subjects with normal glucose tolerance. |
| 4728 | 11872698 | We have examined glucose-stimulated insulin secretion in relation to gene variants in the IRS-1 (Gly(972)Arg) and IRS-2 (Gly(1057)Asp) genes in two Dutch cohorts. |
| 4729 | 11872698 | All subjects were genotyped for the IRS-1 and IRS-2 variants by PCR-RFLP--based methods. |
| 4730 | 11872698 | We conclude that the common gene variants in IRS-1 and IRS-2 are not associated with altered glucose-stimulated insulin secretion in two populations from the Netherlands. |
| 4731 | 11872698 | Variations in insulin secretion in carriers of gene variants in IRS-1 and -2. |
| 4732 | 11872698 | Recently, it has been reported that the Gly(972)Arg variant in IRS-1 was associated with reduced insulin secretion during hyperglycemic clamps in German subjects with normal glucose tolerance. |
| 4733 | 11872698 | We have examined glucose-stimulated insulin secretion in relation to gene variants in the IRS-1 (Gly(972)Arg) and IRS-2 (Gly(1057)Asp) genes in two Dutch cohorts. |
| 4734 | 11872698 | All subjects were genotyped for the IRS-1 and IRS-2 variants by PCR-RFLP--based methods. |
| 4735 | 11872698 | We conclude that the common gene variants in IRS-1 and IRS-2 are not associated with altered glucose-stimulated insulin secretion in two populations from the Netherlands. |
| 4736 | 11872698 | Variations in insulin secretion in carriers of gene variants in IRS-1 and -2. |
| 4737 | 11872698 | Recently, it has been reported that the Gly(972)Arg variant in IRS-1 was associated with reduced insulin secretion during hyperglycemic clamps in German subjects with normal glucose tolerance. |
| 4738 | 11872698 | We have examined glucose-stimulated insulin secretion in relation to gene variants in the IRS-1 (Gly(972)Arg) and IRS-2 (Gly(1057)Asp) genes in two Dutch cohorts. |
| 4739 | 11872698 | All subjects were genotyped for the IRS-1 and IRS-2 variants by PCR-RFLP--based methods. |
| 4740 | 11872698 | We conclude that the common gene variants in IRS-1 and IRS-2 are not associated with altered glucose-stimulated insulin secretion in two populations from the Netherlands. |
| 4741 | 11872698 | Variations in insulin secretion in carriers of gene variants in IRS-1 and -2. |
| 4742 | 11872698 | Recently, it has been reported that the Gly(972)Arg variant in IRS-1 was associated with reduced insulin secretion during hyperglycemic clamps in German subjects with normal glucose tolerance. |
| 4743 | 11872698 | We have examined glucose-stimulated insulin secretion in relation to gene variants in the IRS-1 (Gly(972)Arg) and IRS-2 (Gly(1057)Asp) genes in two Dutch cohorts. |
| 4744 | 11872698 | All subjects were genotyped for the IRS-1 and IRS-2 variants by PCR-RFLP--based methods. |
| 4745 | 11872698 | We conclude that the common gene variants in IRS-1 and IRS-2 are not associated with altered glucose-stimulated insulin secretion in two populations from the Netherlands. |
| 4746 | 11872698 | Variations in insulin secretion in carriers of gene variants in IRS-1 and -2. |
| 4747 | 11872698 | Recently, it has been reported that the Gly(972)Arg variant in IRS-1 was associated with reduced insulin secretion during hyperglycemic clamps in German subjects with normal glucose tolerance. |
| 4748 | 11872698 | We have examined glucose-stimulated insulin secretion in relation to gene variants in the IRS-1 (Gly(972)Arg) and IRS-2 (Gly(1057)Asp) genes in two Dutch cohorts. |
| 4749 | 11872698 | All subjects were genotyped for the IRS-1 and IRS-2 variants by PCR-RFLP--based methods. |
| 4750 | 11872698 | We conclude that the common gene variants in IRS-1 and IRS-2 are not associated with altered glucose-stimulated insulin secretion in two populations from the Netherlands. |
| 4751 | 11875115 | 14-3-3 facilitates insulin-stimulated intracellular trafficking of insulin receptor substrate 1. |
| 4752 | 11875115 | The appearance of a complex between tyrosine-phosphorylated insulin receptor substrate 1 (IRS-1) and PI3K in a high-speed pellet fraction (HSP) is thought to be a key event in insulin action. |
| 4753 | 11875115 | Conversely, the disappearance of the IRS-1/PI3K complex from this fraction has been linked to insulin desensitization. |
| 4754 | 11875115 | The present study examines the role of 14-3-3, a specific phospho-serine binding protein, in mediating the disappearance of IRS-1 from the HSP after insulin treatment. |
| 4755 | 11875115 | An in vitro pull-down assay using recombinant 14-3-3 revealed that insulin enhances the association of 14-3-3 with IRS-1 in cultured adipocytes and that this is completely inhibited by wortmannin. |
| 4756 | 11875115 | An association of IRS-1 and 14-3-3 was also observed and was maximal after stimulation by insulin, when endogenous proteins were immunoprecipitated. |
| 4757 | 11875115 | Epidermal growth factor (EGF), 12-O-tetradecanoylphorbol-13-acetate, and okadaic acid, other agents that cause serine/threonine phosphorylation of IRS-1, also stimulated IRS binding to 14-3-3. |
| 4758 | 11875115 | The enhancement of IRS-1 binding to 14-3-3 by insulin was accompanied by movement of IRS-1 and the p85 subunit of PI3K from the HSP to the cytosol. |
| 4759 | 11875115 | In keeping with a key role of 14-3-3 in mediating this redistribution of IRS-1, the complexes of IRS-1 and 14-3-3 were found in the cytosol but not in the HSP of insulin-treated cells. |
| 4760 | 11875115 | In addition, colocalization of IRS-1 and 14-3-3 was observed in the cytoplasm after insulin treatment by confocal microscopy. |
| 4761 | 11875115 | Finally, the addition of a phosphorylated 14-3-3 binding peptide to an adipocyte homogenate (to remove 14-3-3 from IRS-1) increased the abundance of IRS-1/PI3K complexes in the HSP and decreased their abundance in the cytosol. |
| 4762 | 11875115 | 14-3-3 facilitates insulin-stimulated intracellular trafficking of insulin receptor substrate 1. |
| 4763 | 11875115 | The appearance of a complex between tyrosine-phosphorylated insulin receptor substrate 1 (IRS-1) and PI3K in a high-speed pellet fraction (HSP) is thought to be a key event in insulin action. |
| 4764 | 11875115 | Conversely, the disappearance of the IRS-1/PI3K complex from this fraction has been linked to insulin desensitization. |
| 4765 | 11875115 | The present study examines the role of 14-3-3, a specific phospho-serine binding protein, in mediating the disappearance of IRS-1 from the HSP after insulin treatment. |
| 4766 | 11875115 | An in vitro pull-down assay using recombinant 14-3-3 revealed that insulin enhances the association of 14-3-3 with IRS-1 in cultured adipocytes and that this is completely inhibited by wortmannin. |
| 4767 | 11875115 | An association of IRS-1 and 14-3-3 was also observed and was maximal after stimulation by insulin, when endogenous proteins were immunoprecipitated. |
| 4768 | 11875115 | Epidermal growth factor (EGF), 12-O-tetradecanoylphorbol-13-acetate, and okadaic acid, other agents that cause serine/threonine phosphorylation of IRS-1, also stimulated IRS binding to 14-3-3. |
| 4769 | 11875115 | The enhancement of IRS-1 binding to 14-3-3 by insulin was accompanied by movement of IRS-1 and the p85 subunit of PI3K from the HSP to the cytosol. |
| 4770 | 11875115 | In keeping with a key role of 14-3-3 in mediating this redistribution of IRS-1, the complexes of IRS-1 and 14-3-3 were found in the cytosol but not in the HSP of insulin-treated cells. |
| 4771 | 11875115 | In addition, colocalization of IRS-1 and 14-3-3 was observed in the cytoplasm after insulin treatment by confocal microscopy. |
| 4772 | 11875115 | Finally, the addition of a phosphorylated 14-3-3 binding peptide to an adipocyte homogenate (to remove 14-3-3 from IRS-1) increased the abundance of IRS-1/PI3K complexes in the HSP and decreased their abundance in the cytosol. |
| 4773 | 11875115 | 14-3-3 facilitates insulin-stimulated intracellular trafficking of insulin receptor substrate 1. |
| 4774 | 11875115 | The appearance of a complex between tyrosine-phosphorylated insulin receptor substrate 1 (IRS-1) and PI3K in a high-speed pellet fraction (HSP) is thought to be a key event in insulin action. |
| 4775 | 11875115 | Conversely, the disappearance of the IRS-1/PI3K complex from this fraction has been linked to insulin desensitization. |
| 4776 | 11875115 | The present study examines the role of 14-3-3, a specific phospho-serine binding protein, in mediating the disappearance of IRS-1 from the HSP after insulin treatment. |
| 4777 | 11875115 | An in vitro pull-down assay using recombinant 14-3-3 revealed that insulin enhances the association of 14-3-3 with IRS-1 in cultured adipocytes and that this is completely inhibited by wortmannin. |
| 4778 | 11875115 | An association of IRS-1 and 14-3-3 was also observed and was maximal after stimulation by insulin, when endogenous proteins were immunoprecipitated. |
| 4779 | 11875115 | Epidermal growth factor (EGF), 12-O-tetradecanoylphorbol-13-acetate, and okadaic acid, other agents that cause serine/threonine phosphorylation of IRS-1, also stimulated IRS binding to 14-3-3. |
| 4780 | 11875115 | The enhancement of IRS-1 binding to 14-3-3 by insulin was accompanied by movement of IRS-1 and the p85 subunit of PI3K from the HSP to the cytosol. |
| 4781 | 11875115 | In keeping with a key role of 14-3-3 in mediating this redistribution of IRS-1, the complexes of IRS-1 and 14-3-3 were found in the cytosol but not in the HSP of insulin-treated cells. |
| 4782 | 11875115 | In addition, colocalization of IRS-1 and 14-3-3 was observed in the cytoplasm after insulin treatment by confocal microscopy. |
| 4783 | 11875115 | Finally, the addition of a phosphorylated 14-3-3 binding peptide to an adipocyte homogenate (to remove 14-3-3 from IRS-1) increased the abundance of IRS-1/PI3K complexes in the HSP and decreased their abundance in the cytosol. |
| 4784 | 11875115 | 14-3-3 facilitates insulin-stimulated intracellular trafficking of insulin receptor substrate 1. |
| 4785 | 11875115 | The appearance of a complex between tyrosine-phosphorylated insulin receptor substrate 1 (IRS-1) and PI3K in a high-speed pellet fraction (HSP) is thought to be a key event in insulin action. |
| 4786 | 11875115 | Conversely, the disappearance of the IRS-1/PI3K complex from this fraction has been linked to insulin desensitization. |
| 4787 | 11875115 | The present study examines the role of 14-3-3, a specific phospho-serine binding protein, in mediating the disappearance of IRS-1 from the HSP after insulin treatment. |
| 4788 | 11875115 | An in vitro pull-down assay using recombinant 14-3-3 revealed that insulin enhances the association of 14-3-3 with IRS-1 in cultured adipocytes and that this is completely inhibited by wortmannin. |
| 4789 | 11875115 | An association of IRS-1 and 14-3-3 was also observed and was maximal after stimulation by insulin, when endogenous proteins were immunoprecipitated. |
| 4790 | 11875115 | Epidermal growth factor (EGF), 12-O-tetradecanoylphorbol-13-acetate, and okadaic acid, other agents that cause serine/threonine phosphorylation of IRS-1, also stimulated IRS binding to 14-3-3. |
| 4791 | 11875115 | The enhancement of IRS-1 binding to 14-3-3 by insulin was accompanied by movement of IRS-1 and the p85 subunit of PI3K from the HSP to the cytosol. |
| 4792 | 11875115 | In keeping with a key role of 14-3-3 in mediating this redistribution of IRS-1, the complexes of IRS-1 and 14-3-3 were found in the cytosol but not in the HSP of insulin-treated cells. |
| 4793 | 11875115 | In addition, colocalization of IRS-1 and 14-3-3 was observed in the cytoplasm after insulin treatment by confocal microscopy. |
| 4794 | 11875115 | Finally, the addition of a phosphorylated 14-3-3 binding peptide to an adipocyte homogenate (to remove 14-3-3 from IRS-1) increased the abundance of IRS-1/PI3K complexes in the HSP and decreased their abundance in the cytosol. |
| 4795 | 11875115 | 14-3-3 facilitates insulin-stimulated intracellular trafficking of insulin receptor substrate 1. |
| 4796 | 11875115 | The appearance of a complex between tyrosine-phosphorylated insulin receptor substrate 1 (IRS-1) and PI3K in a high-speed pellet fraction (HSP) is thought to be a key event in insulin action. |
| 4797 | 11875115 | Conversely, the disappearance of the IRS-1/PI3K complex from this fraction has been linked to insulin desensitization. |
| 4798 | 11875115 | The present study examines the role of 14-3-3, a specific phospho-serine binding protein, in mediating the disappearance of IRS-1 from the HSP after insulin treatment. |
| 4799 | 11875115 | An in vitro pull-down assay using recombinant 14-3-3 revealed that insulin enhances the association of 14-3-3 with IRS-1 in cultured adipocytes and that this is completely inhibited by wortmannin. |
| 4800 | 11875115 | An association of IRS-1 and 14-3-3 was also observed and was maximal after stimulation by insulin, when endogenous proteins were immunoprecipitated. |
| 4801 | 11875115 | Epidermal growth factor (EGF), 12-O-tetradecanoylphorbol-13-acetate, and okadaic acid, other agents that cause serine/threonine phosphorylation of IRS-1, also stimulated IRS binding to 14-3-3. |
| 4802 | 11875115 | The enhancement of IRS-1 binding to 14-3-3 by insulin was accompanied by movement of IRS-1 and the p85 subunit of PI3K from the HSP to the cytosol. |
| 4803 | 11875115 | In keeping with a key role of 14-3-3 in mediating this redistribution of IRS-1, the complexes of IRS-1 and 14-3-3 were found in the cytosol but not in the HSP of insulin-treated cells. |
| 4804 | 11875115 | In addition, colocalization of IRS-1 and 14-3-3 was observed in the cytoplasm after insulin treatment by confocal microscopy. |
| 4805 | 11875115 | Finally, the addition of a phosphorylated 14-3-3 binding peptide to an adipocyte homogenate (to remove 14-3-3 from IRS-1) increased the abundance of IRS-1/PI3K complexes in the HSP and decreased their abundance in the cytosol. |
| 4806 | 11875115 | 14-3-3 facilitates insulin-stimulated intracellular trafficking of insulin receptor substrate 1. |
| 4807 | 11875115 | The appearance of a complex between tyrosine-phosphorylated insulin receptor substrate 1 (IRS-1) and PI3K in a high-speed pellet fraction (HSP) is thought to be a key event in insulin action. |
| 4808 | 11875115 | Conversely, the disappearance of the IRS-1/PI3K complex from this fraction has been linked to insulin desensitization. |
| 4809 | 11875115 | The present study examines the role of 14-3-3, a specific phospho-serine binding protein, in mediating the disappearance of IRS-1 from the HSP after insulin treatment. |
| 4810 | 11875115 | An in vitro pull-down assay using recombinant 14-3-3 revealed that insulin enhances the association of 14-3-3 with IRS-1 in cultured adipocytes and that this is completely inhibited by wortmannin. |
| 4811 | 11875115 | An association of IRS-1 and 14-3-3 was also observed and was maximal after stimulation by insulin, when endogenous proteins were immunoprecipitated. |
| 4812 | 11875115 | Epidermal growth factor (EGF), 12-O-tetradecanoylphorbol-13-acetate, and okadaic acid, other agents that cause serine/threonine phosphorylation of IRS-1, also stimulated IRS binding to 14-3-3. |
| 4813 | 11875115 | The enhancement of IRS-1 binding to 14-3-3 by insulin was accompanied by movement of IRS-1 and the p85 subunit of PI3K from the HSP to the cytosol. |
| 4814 | 11875115 | In keeping with a key role of 14-3-3 in mediating this redistribution of IRS-1, the complexes of IRS-1 and 14-3-3 were found in the cytosol but not in the HSP of insulin-treated cells. |
| 4815 | 11875115 | In addition, colocalization of IRS-1 and 14-3-3 was observed in the cytoplasm after insulin treatment by confocal microscopy. |
| 4816 | 11875115 | Finally, the addition of a phosphorylated 14-3-3 binding peptide to an adipocyte homogenate (to remove 14-3-3 from IRS-1) increased the abundance of IRS-1/PI3K complexes in the HSP and decreased their abundance in the cytosol. |
| 4817 | 11875115 | 14-3-3 facilitates insulin-stimulated intracellular trafficking of insulin receptor substrate 1. |
| 4818 | 11875115 | The appearance of a complex between tyrosine-phosphorylated insulin receptor substrate 1 (IRS-1) and PI3K in a high-speed pellet fraction (HSP) is thought to be a key event in insulin action. |
| 4819 | 11875115 | Conversely, the disappearance of the IRS-1/PI3K complex from this fraction has been linked to insulin desensitization. |
| 4820 | 11875115 | The present study examines the role of 14-3-3, a specific phospho-serine binding protein, in mediating the disappearance of IRS-1 from the HSP after insulin treatment. |
| 4821 | 11875115 | An in vitro pull-down assay using recombinant 14-3-3 revealed that insulin enhances the association of 14-3-3 with IRS-1 in cultured adipocytes and that this is completely inhibited by wortmannin. |
| 4822 | 11875115 | An association of IRS-1 and 14-3-3 was also observed and was maximal after stimulation by insulin, when endogenous proteins were immunoprecipitated. |
| 4823 | 11875115 | Epidermal growth factor (EGF), 12-O-tetradecanoylphorbol-13-acetate, and okadaic acid, other agents that cause serine/threonine phosphorylation of IRS-1, also stimulated IRS binding to 14-3-3. |
| 4824 | 11875115 | The enhancement of IRS-1 binding to 14-3-3 by insulin was accompanied by movement of IRS-1 and the p85 subunit of PI3K from the HSP to the cytosol. |
| 4825 | 11875115 | In keeping with a key role of 14-3-3 in mediating this redistribution of IRS-1, the complexes of IRS-1 and 14-3-3 were found in the cytosol but not in the HSP of insulin-treated cells. |
| 4826 | 11875115 | In addition, colocalization of IRS-1 and 14-3-3 was observed in the cytoplasm after insulin treatment by confocal microscopy. |
| 4827 | 11875115 | Finally, the addition of a phosphorylated 14-3-3 binding peptide to an adipocyte homogenate (to remove 14-3-3 from IRS-1) increased the abundance of IRS-1/PI3K complexes in the HSP and decreased their abundance in the cytosol. |
| 4828 | 11875115 | 14-3-3 facilitates insulin-stimulated intracellular trafficking of insulin receptor substrate 1. |
| 4829 | 11875115 | The appearance of a complex between tyrosine-phosphorylated insulin receptor substrate 1 (IRS-1) and PI3K in a high-speed pellet fraction (HSP) is thought to be a key event in insulin action. |
| 4830 | 11875115 | Conversely, the disappearance of the IRS-1/PI3K complex from this fraction has been linked to insulin desensitization. |
| 4831 | 11875115 | The present study examines the role of 14-3-3, a specific phospho-serine binding protein, in mediating the disappearance of IRS-1 from the HSP after insulin treatment. |
| 4832 | 11875115 | An in vitro pull-down assay using recombinant 14-3-3 revealed that insulin enhances the association of 14-3-3 with IRS-1 in cultured adipocytes and that this is completely inhibited by wortmannin. |
| 4833 | 11875115 | An association of IRS-1 and 14-3-3 was also observed and was maximal after stimulation by insulin, when endogenous proteins were immunoprecipitated. |
| 4834 | 11875115 | Epidermal growth factor (EGF), 12-O-tetradecanoylphorbol-13-acetate, and okadaic acid, other agents that cause serine/threonine phosphorylation of IRS-1, also stimulated IRS binding to 14-3-3. |
| 4835 | 11875115 | The enhancement of IRS-1 binding to 14-3-3 by insulin was accompanied by movement of IRS-1 and the p85 subunit of PI3K from the HSP to the cytosol. |
| 4836 | 11875115 | In keeping with a key role of 14-3-3 in mediating this redistribution of IRS-1, the complexes of IRS-1 and 14-3-3 were found in the cytosol but not in the HSP of insulin-treated cells. |
| 4837 | 11875115 | In addition, colocalization of IRS-1 and 14-3-3 was observed in the cytoplasm after insulin treatment by confocal microscopy. |
| 4838 | 11875115 | Finally, the addition of a phosphorylated 14-3-3 binding peptide to an adipocyte homogenate (to remove 14-3-3 from IRS-1) increased the abundance of IRS-1/PI3K complexes in the HSP and decreased their abundance in the cytosol. |
| 4839 | 11875115 | 14-3-3 facilitates insulin-stimulated intracellular trafficking of insulin receptor substrate 1. |
| 4840 | 11875115 | The appearance of a complex between tyrosine-phosphorylated insulin receptor substrate 1 (IRS-1) and PI3K in a high-speed pellet fraction (HSP) is thought to be a key event in insulin action. |
| 4841 | 11875115 | Conversely, the disappearance of the IRS-1/PI3K complex from this fraction has been linked to insulin desensitization. |
| 4842 | 11875115 | The present study examines the role of 14-3-3, a specific phospho-serine binding protein, in mediating the disappearance of IRS-1 from the HSP after insulin treatment. |
| 4843 | 11875115 | An in vitro pull-down assay using recombinant 14-3-3 revealed that insulin enhances the association of 14-3-3 with IRS-1 in cultured adipocytes and that this is completely inhibited by wortmannin. |
| 4844 | 11875115 | An association of IRS-1 and 14-3-3 was also observed and was maximal after stimulation by insulin, when endogenous proteins were immunoprecipitated. |
| 4845 | 11875115 | Epidermal growth factor (EGF), 12-O-tetradecanoylphorbol-13-acetate, and okadaic acid, other agents that cause serine/threonine phosphorylation of IRS-1, also stimulated IRS binding to 14-3-3. |
| 4846 | 11875115 | The enhancement of IRS-1 binding to 14-3-3 by insulin was accompanied by movement of IRS-1 and the p85 subunit of PI3K from the HSP to the cytosol. |
| 4847 | 11875115 | In keeping with a key role of 14-3-3 in mediating this redistribution of IRS-1, the complexes of IRS-1 and 14-3-3 were found in the cytosol but not in the HSP of insulin-treated cells. |
| 4848 | 11875115 | In addition, colocalization of IRS-1 and 14-3-3 was observed in the cytoplasm after insulin treatment by confocal microscopy. |
| 4849 | 11875115 | Finally, the addition of a phosphorylated 14-3-3 binding peptide to an adipocyte homogenate (to remove 14-3-3 from IRS-1) increased the abundance of IRS-1/PI3K complexes in the HSP and decreased their abundance in the cytosol. |
| 4850 | 11875115 | 14-3-3 facilitates insulin-stimulated intracellular trafficking of insulin receptor substrate 1. |
| 4851 | 11875115 | The appearance of a complex between tyrosine-phosphorylated insulin receptor substrate 1 (IRS-1) and PI3K in a high-speed pellet fraction (HSP) is thought to be a key event in insulin action. |
| 4852 | 11875115 | Conversely, the disappearance of the IRS-1/PI3K complex from this fraction has been linked to insulin desensitization. |
| 4853 | 11875115 | The present study examines the role of 14-3-3, a specific phospho-serine binding protein, in mediating the disappearance of IRS-1 from the HSP after insulin treatment. |
| 4854 | 11875115 | An in vitro pull-down assay using recombinant 14-3-3 revealed that insulin enhances the association of 14-3-3 with IRS-1 in cultured adipocytes and that this is completely inhibited by wortmannin. |
| 4855 | 11875115 | An association of IRS-1 and 14-3-3 was also observed and was maximal after stimulation by insulin, when endogenous proteins were immunoprecipitated. |
| 4856 | 11875115 | Epidermal growth factor (EGF), 12-O-tetradecanoylphorbol-13-acetate, and okadaic acid, other agents that cause serine/threonine phosphorylation of IRS-1, also stimulated IRS binding to 14-3-3. |
| 4857 | 11875115 | The enhancement of IRS-1 binding to 14-3-3 by insulin was accompanied by movement of IRS-1 and the p85 subunit of PI3K from the HSP to the cytosol. |
| 4858 | 11875115 | In keeping with a key role of 14-3-3 in mediating this redistribution of IRS-1, the complexes of IRS-1 and 14-3-3 were found in the cytosol but not in the HSP of insulin-treated cells. |
| 4859 | 11875115 | In addition, colocalization of IRS-1 and 14-3-3 was observed in the cytoplasm after insulin treatment by confocal microscopy. |
| 4860 | 11875115 | Finally, the addition of a phosphorylated 14-3-3 binding peptide to an adipocyte homogenate (to remove 14-3-3 from IRS-1) increased the abundance of IRS-1/PI3K complexes in the HSP and decreased their abundance in the cytosol. |
| 4861 | 11875115 | 14-3-3 facilitates insulin-stimulated intracellular trafficking of insulin receptor substrate 1. |
| 4862 | 11875115 | The appearance of a complex between tyrosine-phosphorylated insulin receptor substrate 1 (IRS-1) and PI3K in a high-speed pellet fraction (HSP) is thought to be a key event in insulin action. |
| 4863 | 11875115 | Conversely, the disappearance of the IRS-1/PI3K complex from this fraction has been linked to insulin desensitization. |
| 4864 | 11875115 | The present study examines the role of 14-3-3, a specific phospho-serine binding protein, in mediating the disappearance of IRS-1 from the HSP after insulin treatment. |
| 4865 | 11875115 | An in vitro pull-down assay using recombinant 14-3-3 revealed that insulin enhances the association of 14-3-3 with IRS-1 in cultured adipocytes and that this is completely inhibited by wortmannin. |
| 4866 | 11875115 | An association of IRS-1 and 14-3-3 was also observed and was maximal after stimulation by insulin, when endogenous proteins were immunoprecipitated. |
| 4867 | 11875115 | Epidermal growth factor (EGF), 12-O-tetradecanoylphorbol-13-acetate, and okadaic acid, other agents that cause serine/threonine phosphorylation of IRS-1, also stimulated IRS binding to 14-3-3. |
| 4868 | 11875115 | The enhancement of IRS-1 binding to 14-3-3 by insulin was accompanied by movement of IRS-1 and the p85 subunit of PI3K from the HSP to the cytosol. |
| 4869 | 11875115 | In keeping with a key role of 14-3-3 in mediating this redistribution of IRS-1, the complexes of IRS-1 and 14-3-3 were found in the cytosol but not in the HSP of insulin-treated cells. |
| 4870 | 11875115 | In addition, colocalization of IRS-1 and 14-3-3 was observed in the cytoplasm after insulin treatment by confocal microscopy. |
| 4871 | 11875115 | Finally, the addition of a phosphorylated 14-3-3 binding peptide to an adipocyte homogenate (to remove 14-3-3 from IRS-1) increased the abundance of IRS-1/PI3K complexes in the HSP and decreased their abundance in the cytosol. |
| 4872 | 11916914 | Activation of IRS-2-mediated signal transduction by IGF-1, but not TGF-alpha or EGF, augments pancreatic beta-cell proliferation. |
| 4873 | 11916914 | Transforming growth factor (TGF)-alpha- and epidermal growth factor (EGF)-induced signal transduction was directly compared with that of glucose and insulin-like growth factor-1 (IGF-1) in INS-1 cells. |
| 4874 | 11916914 | TGF-alpha/EGF transiently (<20 min) induced phosphorylation of extracellular-regulated kinase (Erk)-1/2 (>20-fold), glycogen synthase kinase (GSK)-3 (>10-fold), and protein kinase B (PKB) (Ser(473) and Thr(308)), but did not increase [(3)H]thymidine incorporation. |
| 4875 | 11916914 | In contrast, phosphorylation of Erk1/2, GSK-3, and PKB in response to glucose and IGF-1 was more prolonged (>24 h) and, though not as robust as TGF-alpha/EGF, did increase beta-cell proliferation. |
| 4876 | 11916914 | Phosphorylation of p70(S6K) was also increased by IGF-1/glucose, but not by TGF-alpha/EGF, despite upstream PKB activation. |
| 4877 | 11916914 | It was found that IGF-1 induced phosphatidylinositol 3-kinase (PI3K) association with insulin receptor substrate (IRS)-1 and -2 in a glucose-dependent manner, whereas TGF-alpha/EGF did not. |
| 4878 | 11916914 | The importance of specific IRS-2-mediated signaling events was emphasized in that adenoviral-mediated overexpression of IRS-2 further increased glucose/IGF-1-induced beta-cell proliferation (more than twofold; P < 0.05) compared with control or adenoviral-mediated IRS-1 overexpressing INS-1 cells. |
| 4879 | 11916914 | Neither IRS-1 nor IRS-2 overexpression induced a beta-cell proliferative response to TGF-alpha/EGF. |
| 4880 | 11916914 | Thus, a prolonged activation of Erk1/2 and PI3K signaling pathways is important in committing a beta-cell to a mitogenic event, and it is likely that this sustained activation is instigated by signal transduction occurring specifically through IRS-2. |
| 4881 | 11916914 | Activation of IRS-2-mediated signal transduction by IGF-1, but not TGF-alpha or EGF, augments pancreatic beta-cell proliferation. |
| 4882 | 11916914 | Transforming growth factor (TGF)-alpha- and epidermal growth factor (EGF)-induced signal transduction was directly compared with that of glucose and insulin-like growth factor-1 (IGF-1) in INS-1 cells. |
| 4883 | 11916914 | TGF-alpha/EGF transiently (<20 min) induced phosphorylation of extracellular-regulated kinase (Erk)-1/2 (>20-fold), glycogen synthase kinase (GSK)-3 (>10-fold), and protein kinase B (PKB) (Ser(473) and Thr(308)), but did not increase [(3)H]thymidine incorporation. |
| 4884 | 11916914 | In contrast, phosphorylation of Erk1/2, GSK-3, and PKB in response to glucose and IGF-1 was more prolonged (>24 h) and, though not as robust as TGF-alpha/EGF, did increase beta-cell proliferation. |
| 4885 | 11916914 | Phosphorylation of p70(S6K) was also increased by IGF-1/glucose, but not by TGF-alpha/EGF, despite upstream PKB activation. |
| 4886 | 11916914 | It was found that IGF-1 induced phosphatidylinositol 3-kinase (PI3K) association with insulin receptor substrate (IRS)-1 and -2 in a glucose-dependent manner, whereas TGF-alpha/EGF did not. |
| 4887 | 11916914 | The importance of specific IRS-2-mediated signaling events was emphasized in that adenoviral-mediated overexpression of IRS-2 further increased glucose/IGF-1-induced beta-cell proliferation (more than twofold; P < 0.05) compared with control or adenoviral-mediated IRS-1 overexpressing INS-1 cells. |
| 4888 | 11916914 | Neither IRS-1 nor IRS-2 overexpression induced a beta-cell proliferative response to TGF-alpha/EGF. |
| 4889 | 11916914 | Thus, a prolonged activation of Erk1/2 and PI3K signaling pathways is important in committing a beta-cell to a mitogenic event, and it is likely that this sustained activation is instigated by signal transduction occurring specifically through IRS-2. |
| 4890 | 11916925 | Insulin resistance, defective insulin receptor substrate 2-associated phosphatidylinositol-3' kinase activation, and impaired atypical protein kinase C (zeta/lambda) activation in myotubes from obese patients with impaired glucose tolerance. |
| 4891 | 11916925 | This insulin resistance was associated with impaired insulin receptor substrate (IRS)-2-associated phosphatidylinositol 3' (PI3) kinase activation and IRS-2 tyrosine phosphorylation as well as significantly decreased protein kinase C (PKC)-zeta/lambda activation in response to insulin. |
| 4892 | 11916925 | IRS-1- associated PI3 kinase activation and insulin receptor autophosphorylation were comparable in the two groups. |
| 4893 | 11916925 | Protein expression levels for the insulin receptor, IRS-1, IRS-2, the p85 regulatory subunit of PI3 kinase, Akt, PKC-zeta/lambda, GLUT1, and GLUT4 were also similar in the two groups. |
| 4894 | 11916925 | This is associated with impaired IRS-2-associated PI3 kinase activation and PKC-zeta/lambda activation. |
| 4895 | 11959983 | Elevated nucleocytoplasmic glycosylation by O-GlcNAc results in insulin resistance associated with defects in Akt activation in 3T3-L1 adipocytes. |
| 4896 | 11959983 | Cycling of the O-GlcNAc posttranslational modification was blocked by pharmacological inhibition of O-GlcNAcase, the enzyme that catalyzes O-GlcNAc removal from proteins, with O-(2-acetamido-2-deoxy-d-glucopyranosylidene)amino-N-phenylcarbamate (PUGNAc). |
| 4897 | 11959983 | PUGNAc treatment increased levels of O-GlcNAc and caused insulin resistance in 3T3-L1 adipocytes. |
| 4898 | 11959983 | Insulin resistance induced through the HSP by glucosamine and chronic insulin treatment correlated with increased O-GlcNAc levels on nucleocytoplasmic proteins. |
| 4899 | 11959983 | Whereas insulin receptor autophosphorylation and insulin receptor substrate 2 tyrosine phosphorylation were not affected by PUGNAc inhibition of O-GlcNAcase, downstream phosphorylation of Akt at Thr-308 and glycogen synthase kinase 3 beta at Ser-9 was inhibited. |
| 4900 | 11959983 | PUGNAc-induced insulin resistance was associated with increased O-GlcNAc modification of several proteins including insulin receptor substrate 1 and beta-catenin, two important effectors of insulin signaling. |
| 4901 | 11959983 | These results suggest that elevation of O-GlcNAc levels attenuate insulin signaling and contribute to the mechanism by which increased flux through the HSP leads to insulin resistance in adipocytes. |
| 4902 | 11964395 | The steady-state levels of PEPCK and glucose-6-phosphatase mRNAs were elevated in livers of TG mice and were resistant to down-regulation by insulin. |
| 4903 | 11964395 | Conversely, GLUT2 and glucokinase mRNA levels were appropriately regulated by insulin, suggesting that insulin resistance is selective to gluconeogenic gene expression. |
| 4904 | 11964395 | Insulin-stimulated phosphorylation of the insulin receptor, insulin receptor substrate (IRS)-1, and associated phosphatidylinositol 3-kinase were normal in TG mice, whereas IRS-2 protein and phosphorylation were down-regulated compared with control mice. |
| 4905 | 11964395 | Furthermore, these results demonstrate that PEPCK overexpression results in a metabolic pattern that increases glucose-6-phosphatase mRNA and results in a selective decrease in IRS-2 protein, decreased phosphatidylinositol 3-kinase activity, and reduced ability of insulin to suppress gluconeogenic gene expression. |
| 4906 | 11964395 | However, acute suppression of HGP and glycolytic gene expression remained intact, suggesting that FFA and/or IRS-1 signaling, in addition to reduced IRS-2, plays an important role in downstream insulin signal transduction pathways involved in control of gluconeogenesis and progression to type II diabetes mellitus. |
| 4907 | 11965829 | Candidate genes for the metabolic syndrome include those for the beta 3-adrenergic receptor, lipoprotein lipase, hormone sensitive lipase, peroxisome proliferator-activated receptor-gamma, insulin receptor substrate-1 and glycogen synthase. |
| 4908 | 11978627 | Tumor necrosis factor-alpha suppresses adipocyte-specific genes and activates expression of preadipocyte genes in 3T3-L1 adipocytes: nuclear factor-kappaB activation by TNF-alpha is obligatory. |
| 4909 | 11978627 | Tumor necrosis factor-alpha (TNF-alpha) is a contributing cause of the insulin resistance seen in obesity and obesity-linked type 2 diabetes, but the mechanism(s) by which TNF-alpha induces insulin resistance is not understood. |
| 4910 | 11978627 | TNF-alpha-induced genes include transcription factors implicated in preadipocyte gene expression or NF-kappaB activation, cytokines and cytokine-induced proteins, growth factors, enzymes, and signaling molecules. |
| 4911 | 11978627 | Importantly, a number of adipocyte-abundant genes, including GLUT4, hormone sensitive lipase, long-chain fatty acyl-CoA synthase, adipocyte complement-related protein of 30 kDa, and transcription factors CCAAT/enhancer binding protein-alpha, receptor retinoid X receptor-alpha, and peroxisome profilerator-activated receptor gamma were significantly downregulated by TNF-alpha treatment. |
| 4912 | 11978627 | Correspondingly, 24-h exposure of 3T3-L1 adipocytes to TNF-alpha resulted in reduced protein levels of GLUT4 and several insulin signaling proteins, including the insulin receptor, insulin receptor substrate 1 (IRS-1), and protein kinase B (AKT). |
| 4913 | 11978627 | Nuclear factor-kappaB (NF-kappaB) was activated within 15 min of TNF-alpha addition. 3T3-L1 adipocytes expressing IkappaBalpha-DN, a nondegradable NF-kappaB inhibitor, exhibited normal morphology, global gene expression, and insulin responses. |
| 4914 | 11978627 | However, absence of NF-kappaB activation abolished suppression of >98% of the genes normally suppressed by TNF-alpha and induction of 60-70% of the genes normally induced by TNF-alpha. |
| 4915 | 11978627 | Moreover, extensive cell death occurred in IkappaBalpha-DN-expressing adipocytes after 2 h of TNF-alpha treatment. |
| 4916 | 11978627 | Thus the changes in adipocyte gene expression induced by TNF-alpha could lead to insulin resistance. |
| 4917 | 11978627 | Further, NF-kappaB is an obligatory mediator of most of these TNF-alpha responses. |
| 4918 | 11978638 | Insulin secretory function is impaired in isolated human islets carrying the Gly(972)-->Arg IRS-1 polymorphism. |
| 4919 | 11978638 | Recently, the common Gly(972)-->Arg amino acid polymorphism of insulin receptor substrate 1 (Arg(972) IRS-1) has been associated with human type 2 diabetes. |
| 4920 | 11978638 | In this study, we report on some functional and morphological properties of isolated human islets carrying the Arg(972) IRS-1 polymorphism. |
| 4921 | 11978638 | Stepwise glucose increase (1.7 to 16.7 mmol/l) significantly potentiated insulin secretion from control islets, but not Arg(972) IRS-1 islets, with the latter also showing a relatively lower response to glyburide and a significantly higher response to arginine. |
| 4922 | 11978638 | Proinsulin release mirrored insulin secretion, and the insulin-to-proinsulin ratio in response to arginine was significantly lower from Arg(972) IRS-1 islets than from control islets. |
| 4923 | 11978638 | Electron microscopy showed that Arg(972) IRS-1 beta-cells had a severalfold greater number of immature secretory granules and a lower number of mature granules than control beta-cells. |
| 4924 | 11978638 | In conclusion, Arg(972) IRS-1 islets have reduced insulin content, impaired insulin secretion, and a lower amount of mature secretory granules. |
| 4925 | 11978638 | Insulin secretory function is impaired in isolated human islets carrying the Gly(972)-->Arg IRS-1 polymorphism. |
| 4926 | 11978638 | Recently, the common Gly(972)-->Arg amino acid polymorphism of insulin receptor substrate 1 (Arg(972) IRS-1) has been associated with human type 2 diabetes. |
| 4927 | 11978638 | In this study, we report on some functional and morphological properties of isolated human islets carrying the Arg(972) IRS-1 polymorphism. |
| 4928 | 11978638 | Stepwise glucose increase (1.7 to 16.7 mmol/l) significantly potentiated insulin secretion from control islets, but not Arg(972) IRS-1 islets, with the latter also showing a relatively lower response to glyburide and a significantly higher response to arginine. |
| 4929 | 11978638 | Proinsulin release mirrored insulin secretion, and the insulin-to-proinsulin ratio in response to arginine was significantly lower from Arg(972) IRS-1 islets than from control islets. |
| 4930 | 11978638 | Electron microscopy showed that Arg(972) IRS-1 beta-cells had a severalfold greater number of immature secretory granules and a lower number of mature granules than control beta-cells. |
| 4931 | 11978638 | In conclusion, Arg(972) IRS-1 islets have reduced insulin content, impaired insulin secretion, and a lower amount of mature secretory granules. |
| 4932 | 11978638 | Insulin secretory function is impaired in isolated human islets carrying the Gly(972)-->Arg IRS-1 polymorphism. |
| 4933 | 11978638 | Recently, the common Gly(972)-->Arg amino acid polymorphism of insulin receptor substrate 1 (Arg(972) IRS-1) has been associated with human type 2 diabetes. |
| 4934 | 11978638 | In this study, we report on some functional and morphological properties of isolated human islets carrying the Arg(972) IRS-1 polymorphism. |
| 4935 | 11978638 | Stepwise glucose increase (1.7 to 16.7 mmol/l) significantly potentiated insulin secretion from control islets, but not Arg(972) IRS-1 islets, with the latter also showing a relatively lower response to glyburide and a significantly higher response to arginine. |
| 4936 | 11978638 | Proinsulin release mirrored insulin secretion, and the insulin-to-proinsulin ratio in response to arginine was significantly lower from Arg(972) IRS-1 islets than from control islets. |
| 4937 | 11978638 | Electron microscopy showed that Arg(972) IRS-1 beta-cells had a severalfold greater number of immature secretory granules and a lower number of mature granules than control beta-cells. |
| 4938 | 11978638 | In conclusion, Arg(972) IRS-1 islets have reduced insulin content, impaired insulin secretion, and a lower amount of mature secretory granules. |
| 4939 | 11978638 | Insulin secretory function is impaired in isolated human islets carrying the Gly(972)-->Arg IRS-1 polymorphism. |
| 4940 | 11978638 | Recently, the common Gly(972)-->Arg amino acid polymorphism of insulin receptor substrate 1 (Arg(972) IRS-1) has been associated with human type 2 diabetes. |
| 4941 | 11978638 | In this study, we report on some functional and morphological properties of isolated human islets carrying the Arg(972) IRS-1 polymorphism. |
| 4942 | 11978638 | Stepwise glucose increase (1.7 to 16.7 mmol/l) significantly potentiated insulin secretion from control islets, but not Arg(972) IRS-1 islets, with the latter also showing a relatively lower response to glyburide and a significantly higher response to arginine. |
| 4943 | 11978638 | Proinsulin release mirrored insulin secretion, and the insulin-to-proinsulin ratio in response to arginine was significantly lower from Arg(972) IRS-1 islets than from control islets. |
| 4944 | 11978638 | Electron microscopy showed that Arg(972) IRS-1 beta-cells had a severalfold greater number of immature secretory granules and a lower number of mature granules than control beta-cells. |
| 4945 | 11978638 | In conclusion, Arg(972) IRS-1 islets have reduced insulin content, impaired insulin secretion, and a lower amount of mature secretory granules. |
| 4946 | 11978638 | Insulin secretory function is impaired in isolated human islets carrying the Gly(972)-->Arg IRS-1 polymorphism. |
| 4947 | 11978638 | Recently, the common Gly(972)-->Arg amino acid polymorphism of insulin receptor substrate 1 (Arg(972) IRS-1) has been associated with human type 2 diabetes. |
| 4948 | 11978638 | In this study, we report on some functional and morphological properties of isolated human islets carrying the Arg(972) IRS-1 polymorphism. |
| 4949 | 11978638 | Stepwise glucose increase (1.7 to 16.7 mmol/l) significantly potentiated insulin secretion from control islets, but not Arg(972) IRS-1 islets, with the latter also showing a relatively lower response to glyburide and a significantly higher response to arginine. |
| 4950 | 11978638 | Proinsulin release mirrored insulin secretion, and the insulin-to-proinsulin ratio in response to arginine was significantly lower from Arg(972) IRS-1 islets than from control islets. |
| 4951 | 11978638 | Electron microscopy showed that Arg(972) IRS-1 beta-cells had a severalfold greater number of immature secretory granules and a lower number of mature granules than control beta-cells. |
| 4952 | 11978638 | In conclusion, Arg(972) IRS-1 islets have reduced insulin content, impaired insulin secretion, and a lower amount of mature secretory granules. |
| 4953 | 11978638 | Insulin secretory function is impaired in isolated human islets carrying the Gly(972)-->Arg IRS-1 polymorphism. |
| 4954 | 11978638 | Recently, the common Gly(972)-->Arg amino acid polymorphism of insulin receptor substrate 1 (Arg(972) IRS-1) has been associated with human type 2 diabetes. |
| 4955 | 11978638 | In this study, we report on some functional and morphological properties of isolated human islets carrying the Arg(972) IRS-1 polymorphism. |
| 4956 | 11978638 | Stepwise glucose increase (1.7 to 16.7 mmol/l) significantly potentiated insulin secretion from control islets, but not Arg(972) IRS-1 islets, with the latter also showing a relatively lower response to glyburide and a significantly higher response to arginine. |
| 4957 | 11978638 | Proinsulin release mirrored insulin secretion, and the insulin-to-proinsulin ratio in response to arginine was significantly lower from Arg(972) IRS-1 islets than from control islets. |
| 4958 | 11978638 | Electron microscopy showed that Arg(972) IRS-1 beta-cells had a severalfold greater number of immature secretory granules and a lower number of mature granules than control beta-cells. |
| 4959 | 11978638 | In conclusion, Arg(972) IRS-1 islets have reduced insulin content, impaired insulin secretion, and a lower amount of mature secretory granules. |
| 4960 | 11978638 | Insulin secretory function is impaired in isolated human islets carrying the Gly(972)-->Arg IRS-1 polymorphism. |
| 4961 | 11978638 | Recently, the common Gly(972)-->Arg amino acid polymorphism of insulin receptor substrate 1 (Arg(972) IRS-1) has been associated with human type 2 diabetes. |
| 4962 | 11978638 | In this study, we report on some functional and morphological properties of isolated human islets carrying the Arg(972) IRS-1 polymorphism. |
| 4963 | 11978638 | Stepwise glucose increase (1.7 to 16.7 mmol/l) significantly potentiated insulin secretion from control islets, but not Arg(972) IRS-1 islets, with the latter also showing a relatively lower response to glyburide and a significantly higher response to arginine. |
| 4964 | 11978638 | Proinsulin release mirrored insulin secretion, and the insulin-to-proinsulin ratio in response to arginine was significantly lower from Arg(972) IRS-1 islets than from control islets. |
| 4965 | 11978638 | Electron microscopy showed that Arg(972) IRS-1 beta-cells had a severalfold greater number of immature secretory granules and a lower number of mature granules than control beta-cells. |
| 4966 | 11978638 | In conclusion, Arg(972) IRS-1 islets have reduced insulin content, impaired insulin secretion, and a lower amount of mature secretory granules. |
| 4967 | 11994408 | Pdx1 restores beta cell function in Irs2 knockout mice. |
| 4968 | 11994408 | Mutations in Pdx1 or upstream hepatocyte nuclear factors cause autosomal forms of early-onset diabetes (maturity-onset diabetes of the young [MODY]). |
| 4969 | 11994408 | In mice, the Irs2 branch of the insulin/Igf signaling system mediates peripheral insulin action and pancreatic beta cell growth and function. |
| 4970 | 11994408 | To investigate whether beta cell failure in Irs2(-/-) mice might be related to dysfunction of MODY-related transcription factors, we measured the expression of Pdx1 in islets from young Irs2(-/-) mice. |
| 4971 | 11994408 | Before the onset of diabetes, Pdx1 was reduced in islets from Irs2(-/-) mice, whereas it was expressed normally in islets from wild-type or Irs1(-/-) mice, which do not develop diabetes. |
| 4972 | 11994408 | Whereas male Irs2(-/-)Pdx1(+/+) mice developed diabetes between 8 and 10 weeks of age, haploinsufficiency for Pdx1 caused diabetes in newborn Irs2(-/-) mice. |
| 4973 | 11994408 | By contrast, transgenic expression of Pdx1 restored beta cell mass and function in Irs2(-/-) mice and promoted glucose tolerance throughout life, as these mice survived for at least 20 months without diabetes. |
| 4974 | 11994408 | Our results suggest that dysregulation of Pdx1 might represent a common link between ordinary type 2 diabetes and MODY. |
| 4975 | 12006586 | The enhanced serine kinase specifically phosphorylates the conserved Ser(789) residue in IRS-1, which is in a sequence motif separate from the ones for MAPK, c-Jun N-terminal kinase, glycogen-synthase kinase 3 (GSK-3), Akt, phosphatidylinositol 3'-kinase, or casein kinase. |
| 4976 | 12006586 | It is similar to the phosphorylation motif for AMP-activated protein kinase, but the serine kinase in the insulin-resistant animals was shown not to be an AMP-activated protein kinase, suggesting a potential novel serine kinase. |
| 4977 | 12006586 | Using a specific antibody against Ser(P)(789) peptide of IRS-1, we then demonstrated for the first time a striking increase of Ser(789)-phosphorylated IRS-1 in livers of insulin-resistant rodent models, indicating enhanced serine kinase activity in vivo. |
| 4978 | 12006586 | Taken together, these data strongly suggest that unknown serine kinase activity and Ser(789) phosphorylation of IRS-1 may play an important role in attenuating insulin signaling in insulin-resistant animal models. |
| 4979 | 12006586 | The enhanced serine kinase specifically phosphorylates the conserved Ser(789) residue in IRS-1, which is in a sequence motif separate from the ones for MAPK, c-Jun N-terminal kinase, glycogen-synthase kinase 3 (GSK-3), Akt, phosphatidylinositol 3'-kinase, or casein kinase. |
| 4980 | 12006586 | It is similar to the phosphorylation motif for AMP-activated protein kinase, but the serine kinase in the insulin-resistant animals was shown not to be an AMP-activated protein kinase, suggesting a potential novel serine kinase. |
| 4981 | 12006586 | Using a specific antibody against Ser(P)(789) peptide of IRS-1, we then demonstrated for the first time a striking increase of Ser(789)-phosphorylated IRS-1 in livers of insulin-resistant rodent models, indicating enhanced serine kinase activity in vivo. |
| 4982 | 12006586 | Taken together, these data strongly suggest that unknown serine kinase activity and Ser(789) phosphorylation of IRS-1 may play an important role in attenuating insulin signaling in insulin-resistant animal models. |
| 4983 | 12006586 | The enhanced serine kinase specifically phosphorylates the conserved Ser(789) residue in IRS-1, which is in a sequence motif separate from the ones for MAPK, c-Jun N-terminal kinase, glycogen-synthase kinase 3 (GSK-3), Akt, phosphatidylinositol 3'-kinase, or casein kinase. |
| 4984 | 12006586 | It is similar to the phosphorylation motif for AMP-activated protein kinase, but the serine kinase in the insulin-resistant animals was shown not to be an AMP-activated protein kinase, suggesting a potential novel serine kinase. |
| 4985 | 12006586 | Using a specific antibody against Ser(P)(789) peptide of IRS-1, we then demonstrated for the first time a striking increase of Ser(789)-phosphorylated IRS-1 in livers of insulin-resistant rodent models, indicating enhanced serine kinase activity in vivo. |
| 4986 | 12006586 | Taken together, these data strongly suggest that unknown serine kinase activity and Ser(789) phosphorylation of IRS-1 may play an important role in attenuating insulin signaling in insulin-resistant animal models. |
| 4987 | 12023872 | Receptors for insulin and insulin-like growth factor-1 and insulin receptor substrate-1 mediate pathways that regulate islet function. |
| 4988 | 12023872 | Tissue-specific knockout of the insulin receptor (betaIRKO) or IGF-1 receptor (betaIGFRKO) in pancreatic beta-cells leads to altered glucose-sensing and glucose intolerance in adult mice, and betaIRKO mice show an age-dependent decrease in islet size and beta-cell mass. |
| 4989 | 12023872 | The IRS-1 knockouts also display islet hyperplasia, defects in insulin secretory responses to multiple stimuli both in vivo and in vitro, reduced islet insulin content and an increased number of autophagic vacuoles in the beta-cells. |
| 4990 | 12023872 | Re-expression of IRS-1 in cultured beta-cells is able to partially restore the insulin content indicating that IRS-1 is involved in the regulation of insulin synthesis. |
| 4991 | 12023872 | Taken together, these data provide evidence that insulin and IGF-1 receptors and IRS-1, and potentially other proteins in the insulin/IGF-1 signalling pathway, contribute to the regulation of islet hormone secretion and synthesis and therefore in the maintenance of glucose homeostasis. |
| 4992 | 12023872 | Receptors for insulin and insulin-like growth factor-1 and insulin receptor substrate-1 mediate pathways that regulate islet function. |
| 4993 | 12023872 | Tissue-specific knockout of the insulin receptor (betaIRKO) or IGF-1 receptor (betaIGFRKO) in pancreatic beta-cells leads to altered glucose-sensing and glucose intolerance in adult mice, and betaIRKO mice show an age-dependent decrease in islet size and beta-cell mass. |
| 4994 | 12023872 | The IRS-1 knockouts also display islet hyperplasia, defects in insulin secretory responses to multiple stimuli both in vivo and in vitro, reduced islet insulin content and an increased number of autophagic vacuoles in the beta-cells. |
| 4995 | 12023872 | Re-expression of IRS-1 in cultured beta-cells is able to partially restore the insulin content indicating that IRS-1 is involved in the regulation of insulin synthesis. |
| 4996 | 12023872 | Taken together, these data provide evidence that insulin and IGF-1 receptors and IRS-1, and potentially other proteins in the insulin/IGF-1 signalling pathway, contribute to the regulation of islet hormone secretion and synthesis and therefore in the maintenance of glucose homeostasis. |
| 4997 | 12023872 | Receptors for insulin and insulin-like growth factor-1 and insulin receptor substrate-1 mediate pathways that regulate islet function. |
| 4998 | 12023872 | Tissue-specific knockout of the insulin receptor (betaIRKO) or IGF-1 receptor (betaIGFRKO) in pancreatic beta-cells leads to altered glucose-sensing and glucose intolerance in adult mice, and betaIRKO mice show an age-dependent decrease in islet size and beta-cell mass. |
| 4999 | 12023872 | The IRS-1 knockouts also display islet hyperplasia, defects in insulin secretory responses to multiple stimuli both in vivo and in vitro, reduced islet insulin content and an increased number of autophagic vacuoles in the beta-cells. |
| 5000 | 12023872 | Re-expression of IRS-1 in cultured beta-cells is able to partially restore the insulin content indicating that IRS-1 is involved in the regulation of insulin synthesis. |
| 5001 | 12023872 | Taken together, these data provide evidence that insulin and IGF-1 receptors and IRS-1, and potentially other proteins in the insulin/IGF-1 signalling pathway, contribute to the regulation of islet hormone secretion and synthesis and therefore in the maintenance of glucose homeostasis. |
| 5002 | 12023872 | Receptors for insulin and insulin-like growth factor-1 and insulin receptor substrate-1 mediate pathways that regulate islet function. |
| 5003 | 12023872 | Tissue-specific knockout of the insulin receptor (betaIRKO) or IGF-1 receptor (betaIGFRKO) in pancreatic beta-cells leads to altered glucose-sensing and glucose intolerance in adult mice, and betaIRKO mice show an age-dependent decrease in islet size and beta-cell mass. |
| 5004 | 12023872 | The IRS-1 knockouts also display islet hyperplasia, defects in insulin secretory responses to multiple stimuli both in vivo and in vitro, reduced islet insulin content and an increased number of autophagic vacuoles in the beta-cells. |
| 5005 | 12023872 | Re-expression of IRS-1 in cultured beta-cells is able to partially restore the insulin content indicating that IRS-1 is involved in the regulation of insulin synthesis. |
| 5006 | 12023872 | Taken together, these data provide evidence that insulin and IGF-1 receptors and IRS-1, and potentially other proteins in the insulin/IGF-1 signalling pathway, contribute to the regulation of islet hormone secretion and synthesis and therefore in the maintenance of glucose homeostasis. |
| 5007 | 12031952 | Role of the insulin receptor substrate 1 and phosphatidylinositol 3-kinase signaling pathway in insulin-induced expression of sterol regulatory element binding protein 1c and glucokinase genes in rat hepatocytes. |
| 5008 | 12031952 | The mechanism by which insulin induces the expression of the sterol regulatory element binding protein 1c (SREBP-1c) and glucokinase genes was investigated in cultured rat hepatocytes. |
| 5009 | 12031952 | Overexpression of an NH(2)-terminal fragment of IRS-1 that contains the pleckstrin homology and phosphotyrosine binding domains (insulin receptor substrate-1 NH(2)-terminal fragment [IRS-1N]) inhibited insulin-induced tyrosine phosphorylation of IRS-1 as well as the association of IRS-1 with phosphatidylinositol (PI) 3-kinase activity, whereas the tyrosine phosphorylation of IRS-2 and its association with PI 3-kinase activity were slightly enhanced. |
| 5010 | 12031952 | The equivalent fragment of IRS-2 (IRS-2N) prevented insulin-induced tyrosine phosphorylation of both IRS-1 and IRS-2, although that of IRS-1 was inhibited more efficiently. |
| 5011 | 12031952 | The insulin-induced increases in the abundance of SREBP-1c and glucokinase mRNAs, both of which were sensitive to a dominant-negative mutant of PI 3-kinase, were blocked in cells in which the insulin-induced tyrosine phosphorylation of IRS-1 was inhibited by IRS-1N or IRS-2N. |
| 5012 | 12031952 | A dominant-negative mutant of Akt enhanced insulin-induced tyrosine phosphorylation of IRS-1 (but not that of IRS-2) and its association with PI 3-kinase activity, suggesting that Akt contributes to negative feedback regulation of IRS-1. |
| 5013 | 12031952 | The Akt mutant also promoted the effects of insulin on the accumulation of SREBP-1c and glucokinase mRNAs. |
| 5014 | 12031952 | These results suggest that the IRS-1-PI 3-kinase pathway is essential for insulin-induced expression of SREBP-1c and glucokinase genes. |
| 5015 | 12031952 | Role of the insulin receptor substrate 1 and phosphatidylinositol 3-kinase signaling pathway in insulin-induced expression of sterol regulatory element binding protein 1c and glucokinase genes in rat hepatocytes. |
| 5016 | 12031952 | The mechanism by which insulin induces the expression of the sterol regulatory element binding protein 1c (SREBP-1c) and glucokinase genes was investigated in cultured rat hepatocytes. |
| 5017 | 12031952 | Overexpression of an NH(2)-terminal fragment of IRS-1 that contains the pleckstrin homology and phosphotyrosine binding domains (insulin receptor substrate-1 NH(2)-terminal fragment [IRS-1N]) inhibited insulin-induced tyrosine phosphorylation of IRS-1 as well as the association of IRS-1 with phosphatidylinositol (PI) 3-kinase activity, whereas the tyrosine phosphorylation of IRS-2 and its association with PI 3-kinase activity were slightly enhanced. |
| 5018 | 12031952 | The equivalent fragment of IRS-2 (IRS-2N) prevented insulin-induced tyrosine phosphorylation of both IRS-1 and IRS-2, although that of IRS-1 was inhibited more efficiently. |
| 5019 | 12031952 | The insulin-induced increases in the abundance of SREBP-1c and glucokinase mRNAs, both of which were sensitive to a dominant-negative mutant of PI 3-kinase, were blocked in cells in which the insulin-induced tyrosine phosphorylation of IRS-1 was inhibited by IRS-1N or IRS-2N. |
| 5020 | 12031952 | A dominant-negative mutant of Akt enhanced insulin-induced tyrosine phosphorylation of IRS-1 (but not that of IRS-2) and its association with PI 3-kinase activity, suggesting that Akt contributes to negative feedback regulation of IRS-1. |
| 5021 | 12031952 | The Akt mutant also promoted the effects of insulin on the accumulation of SREBP-1c and glucokinase mRNAs. |
| 5022 | 12031952 | These results suggest that the IRS-1-PI 3-kinase pathway is essential for insulin-induced expression of SREBP-1c and glucokinase genes. |
| 5023 | 12031952 | Role of the insulin receptor substrate 1 and phosphatidylinositol 3-kinase signaling pathway in insulin-induced expression of sterol regulatory element binding protein 1c and glucokinase genes in rat hepatocytes. |
| 5024 | 12031952 | The mechanism by which insulin induces the expression of the sterol regulatory element binding protein 1c (SREBP-1c) and glucokinase genes was investigated in cultured rat hepatocytes. |
| 5025 | 12031952 | Overexpression of an NH(2)-terminal fragment of IRS-1 that contains the pleckstrin homology and phosphotyrosine binding domains (insulin receptor substrate-1 NH(2)-terminal fragment [IRS-1N]) inhibited insulin-induced tyrosine phosphorylation of IRS-1 as well as the association of IRS-1 with phosphatidylinositol (PI) 3-kinase activity, whereas the tyrosine phosphorylation of IRS-2 and its association with PI 3-kinase activity were slightly enhanced. |
| 5026 | 12031952 | The equivalent fragment of IRS-2 (IRS-2N) prevented insulin-induced tyrosine phosphorylation of both IRS-1 and IRS-2, although that of IRS-1 was inhibited more efficiently. |
| 5027 | 12031952 | The insulin-induced increases in the abundance of SREBP-1c and glucokinase mRNAs, both of which were sensitive to a dominant-negative mutant of PI 3-kinase, were blocked in cells in which the insulin-induced tyrosine phosphorylation of IRS-1 was inhibited by IRS-1N or IRS-2N. |
| 5028 | 12031952 | A dominant-negative mutant of Akt enhanced insulin-induced tyrosine phosphorylation of IRS-1 (but not that of IRS-2) and its association with PI 3-kinase activity, suggesting that Akt contributes to negative feedback regulation of IRS-1. |
| 5029 | 12031952 | The Akt mutant also promoted the effects of insulin on the accumulation of SREBP-1c and glucokinase mRNAs. |
| 5030 | 12031952 | These results suggest that the IRS-1-PI 3-kinase pathway is essential for insulin-induced expression of SREBP-1c and glucokinase genes. |
| 5031 | 12031952 | Role of the insulin receptor substrate 1 and phosphatidylinositol 3-kinase signaling pathway in insulin-induced expression of sterol regulatory element binding protein 1c and glucokinase genes in rat hepatocytes. |
| 5032 | 12031952 | The mechanism by which insulin induces the expression of the sterol regulatory element binding protein 1c (SREBP-1c) and glucokinase genes was investigated in cultured rat hepatocytes. |
| 5033 | 12031952 | Overexpression of an NH(2)-terminal fragment of IRS-1 that contains the pleckstrin homology and phosphotyrosine binding domains (insulin receptor substrate-1 NH(2)-terminal fragment [IRS-1N]) inhibited insulin-induced tyrosine phosphorylation of IRS-1 as well as the association of IRS-1 with phosphatidylinositol (PI) 3-kinase activity, whereas the tyrosine phosphorylation of IRS-2 and its association with PI 3-kinase activity were slightly enhanced. |
| 5034 | 12031952 | The equivalent fragment of IRS-2 (IRS-2N) prevented insulin-induced tyrosine phosphorylation of both IRS-1 and IRS-2, although that of IRS-1 was inhibited more efficiently. |
| 5035 | 12031952 | The insulin-induced increases in the abundance of SREBP-1c and glucokinase mRNAs, both of which were sensitive to a dominant-negative mutant of PI 3-kinase, were blocked in cells in which the insulin-induced tyrosine phosphorylation of IRS-1 was inhibited by IRS-1N or IRS-2N. |
| 5036 | 12031952 | A dominant-negative mutant of Akt enhanced insulin-induced tyrosine phosphorylation of IRS-1 (but not that of IRS-2) and its association with PI 3-kinase activity, suggesting that Akt contributes to negative feedback regulation of IRS-1. |
| 5037 | 12031952 | The Akt mutant also promoted the effects of insulin on the accumulation of SREBP-1c and glucokinase mRNAs. |
| 5038 | 12031952 | These results suggest that the IRS-1-PI 3-kinase pathway is essential for insulin-induced expression of SREBP-1c and glucokinase genes. |
| 5039 | 12031952 | Role of the insulin receptor substrate 1 and phosphatidylinositol 3-kinase signaling pathway in insulin-induced expression of sterol regulatory element binding protein 1c and glucokinase genes in rat hepatocytes. |
| 5040 | 12031952 | The mechanism by which insulin induces the expression of the sterol regulatory element binding protein 1c (SREBP-1c) and glucokinase genes was investigated in cultured rat hepatocytes. |
| 5041 | 12031952 | Overexpression of an NH(2)-terminal fragment of IRS-1 that contains the pleckstrin homology and phosphotyrosine binding domains (insulin receptor substrate-1 NH(2)-terminal fragment [IRS-1N]) inhibited insulin-induced tyrosine phosphorylation of IRS-1 as well as the association of IRS-1 with phosphatidylinositol (PI) 3-kinase activity, whereas the tyrosine phosphorylation of IRS-2 and its association with PI 3-kinase activity were slightly enhanced. |
| 5042 | 12031952 | The equivalent fragment of IRS-2 (IRS-2N) prevented insulin-induced tyrosine phosphorylation of both IRS-1 and IRS-2, although that of IRS-1 was inhibited more efficiently. |
| 5043 | 12031952 | The insulin-induced increases in the abundance of SREBP-1c and glucokinase mRNAs, both of which were sensitive to a dominant-negative mutant of PI 3-kinase, were blocked in cells in which the insulin-induced tyrosine phosphorylation of IRS-1 was inhibited by IRS-1N or IRS-2N. |
| 5044 | 12031952 | A dominant-negative mutant of Akt enhanced insulin-induced tyrosine phosphorylation of IRS-1 (but not that of IRS-2) and its association with PI 3-kinase activity, suggesting that Akt contributes to negative feedback regulation of IRS-1. |
| 5045 | 12031952 | The Akt mutant also promoted the effects of insulin on the accumulation of SREBP-1c and glucokinase mRNAs. |
| 5046 | 12031952 | These results suggest that the IRS-1-PI 3-kinase pathway is essential for insulin-induced expression of SREBP-1c and glucokinase genes. |
| 5047 | 12031980 | Recently, we have shown that intravenous lipid emulsion (liposyn) infusion during a 120-min euglycemic-hyperinsulinemic clamp led to significant reductions in insulin action and fatty acid translocase (FAT/CD36) skeletal muscle protein expression. |
| 5048 | 12031980 | Here, we report that a fourfold elevation in plasma FFA concentration induced a 40% reduction in the insulin-stimulated glucose disposal rate, a 30% decline in insulin-stimulated skeletal muscle insulin substrate receptor-1 (IRS-1) phosphorylation, a 48% decrease in IRS-1-associated phosphatidylinositol (PI) 3-kinase activity, and a 50% reduction in muscle FAT/CD36 protein expression in male rats. |
| 5049 | 12031980 | In striking contrast, we found no effect of FFA elevation to cause insulin resistance, changes in IRS-1/PI 3-kinase, or FAT/CD36 protein levels in female animals. |
| 5050 | 12031980 | Recently, we have shown that intravenous lipid emulsion (liposyn) infusion during a 120-min euglycemic-hyperinsulinemic clamp led to significant reductions in insulin action and fatty acid translocase (FAT/CD36) skeletal muscle protein expression. |
| 5051 | 12031980 | Here, we report that a fourfold elevation in plasma FFA concentration induced a 40% reduction in the insulin-stimulated glucose disposal rate, a 30% decline in insulin-stimulated skeletal muscle insulin substrate receptor-1 (IRS-1) phosphorylation, a 48% decrease in IRS-1-associated phosphatidylinositol (PI) 3-kinase activity, and a 50% reduction in muscle FAT/CD36 protein expression in male rats. |
| 5052 | 12031980 | In striking contrast, we found no effect of FFA elevation to cause insulin resistance, changes in IRS-1/PI 3-kinase, or FAT/CD36 protein levels in female animals. |
| 5053 | 12031982 | Differential effects of tumor necrosis factor-alpha on protein kinase C isoforms alpha and delta mediate inhibition of insulin receptor signaling. |
| 5054 | 12031982 | Tumor necrosis factor-alpha (TNF-alpha) is a multifunctional cytokine that interferes with insulin signaling, but the molecular mechanisms of this effect are unclear. |
| 5055 | 12031982 | Because certain protein kinase C (PKC) isoforms are activated by insulin, we examined the role of PKC in TNF-alpha inhibition of insulin signaling in primary cultures of mouse skeletal muscle. |
| 5056 | 12031982 | TNF-alpha, given 5 min before insulin, inhibited insulin-induced tyrosine phosphorylation of insulin receptor (IR), IR substrate (IRS)-1, insulin-induced association of IRS-1 with the p85 subunit of phosphatidylinositol 3-kinase (PI3-K), and insulin-induced glucose uptake. |
| 5057 | 12031982 | Insulin and TNF-alpha each caused tyrosine phosphorylation and activation of PKCs delta and alpha, but when TNF-alpha preceded insulin, the effects were less than that produced by each substance alone. |
| 5058 | 12031982 | Insulin induced PKCdelta specifically to coprecipitate with IR, an effect blocked by TNF-alpha. |
| 5059 | 12031982 | Both PKCalpha and -delta are constitutively associated with IRS-1. |
| 5060 | 12031982 | Whereas insulin decreased coprecipitation of IRS-1 with PKCalpha, it increased coprecipitation of IRS-1 with PKCdelta. |
| 5061 | 12031982 | TNF-alpha blocked the effects of insulin on association of both PKCs with IRS-1. |
| 5062 | 12031982 | To further investigate the involvement of PKCs in inhibitory actions of TNF-alpha on insulin signaling, we overexpressed specific PKC isoforms in mature myotubes. |
| 5063 | 12031982 | PKCalpha overexpression inhibited basal and insulin-induced IR autophosphorylation, whereas PKCdelta overexpression increased IR autophosphorylation and abrogated the inhibitory effect of TNF-alpha on IR autophosphorylation and signaling to PI3-K. |
| 5064 | 12031982 | Blockade of PKCalpha antagonized the inhibitory effects of TNF-alpha on both insulin-induced IR tyrosine phosphorylation and IR signaling to PI3-K. |
| 5065 | 12031982 | We suggest that the effects of TNF-alpha on IR tyrosine phosphorylation are mediated via alteration of insulin-induced activation and association of PKCdelta and -alpha with upstream signaling molecules. |
| 5066 | 12031982 | Differential effects of tumor necrosis factor-alpha on protein kinase C isoforms alpha and delta mediate inhibition of insulin receptor signaling. |
| 5067 | 12031982 | Tumor necrosis factor-alpha (TNF-alpha) is a multifunctional cytokine that interferes with insulin signaling, but the molecular mechanisms of this effect are unclear. |
| 5068 | 12031982 | Because certain protein kinase C (PKC) isoforms are activated by insulin, we examined the role of PKC in TNF-alpha inhibition of insulin signaling in primary cultures of mouse skeletal muscle. |
| 5069 | 12031982 | TNF-alpha, given 5 min before insulin, inhibited insulin-induced tyrosine phosphorylation of insulin receptor (IR), IR substrate (IRS)-1, insulin-induced association of IRS-1 with the p85 subunit of phosphatidylinositol 3-kinase (PI3-K), and insulin-induced glucose uptake. |
| 5070 | 12031982 | Insulin and TNF-alpha each caused tyrosine phosphorylation and activation of PKCs delta and alpha, but when TNF-alpha preceded insulin, the effects were less than that produced by each substance alone. |
| 5071 | 12031982 | Insulin induced PKCdelta specifically to coprecipitate with IR, an effect blocked by TNF-alpha. |
| 5072 | 12031982 | Both PKCalpha and -delta are constitutively associated with IRS-1. |
| 5073 | 12031982 | Whereas insulin decreased coprecipitation of IRS-1 with PKCalpha, it increased coprecipitation of IRS-1 with PKCdelta. |
| 5074 | 12031982 | TNF-alpha blocked the effects of insulin on association of both PKCs with IRS-1. |
| 5075 | 12031982 | To further investigate the involvement of PKCs in inhibitory actions of TNF-alpha on insulin signaling, we overexpressed specific PKC isoforms in mature myotubes. |
| 5076 | 12031982 | PKCalpha overexpression inhibited basal and insulin-induced IR autophosphorylation, whereas PKCdelta overexpression increased IR autophosphorylation and abrogated the inhibitory effect of TNF-alpha on IR autophosphorylation and signaling to PI3-K. |
| 5077 | 12031982 | Blockade of PKCalpha antagonized the inhibitory effects of TNF-alpha on both insulin-induced IR tyrosine phosphorylation and IR signaling to PI3-K. |
| 5078 | 12031982 | We suggest that the effects of TNF-alpha on IR tyrosine phosphorylation are mediated via alteration of insulin-induced activation and association of PKCdelta and -alpha with upstream signaling molecules. |
| 5079 | 12031982 | Differential effects of tumor necrosis factor-alpha on protein kinase C isoforms alpha and delta mediate inhibition of insulin receptor signaling. |
| 5080 | 12031982 | Tumor necrosis factor-alpha (TNF-alpha) is a multifunctional cytokine that interferes with insulin signaling, but the molecular mechanisms of this effect are unclear. |
| 5081 | 12031982 | Because certain protein kinase C (PKC) isoforms are activated by insulin, we examined the role of PKC in TNF-alpha inhibition of insulin signaling in primary cultures of mouse skeletal muscle. |
| 5082 | 12031982 | TNF-alpha, given 5 min before insulin, inhibited insulin-induced tyrosine phosphorylation of insulin receptor (IR), IR substrate (IRS)-1, insulin-induced association of IRS-1 with the p85 subunit of phosphatidylinositol 3-kinase (PI3-K), and insulin-induced glucose uptake. |
| 5083 | 12031982 | Insulin and TNF-alpha each caused tyrosine phosphorylation and activation of PKCs delta and alpha, but when TNF-alpha preceded insulin, the effects were less than that produced by each substance alone. |
| 5084 | 12031982 | Insulin induced PKCdelta specifically to coprecipitate with IR, an effect blocked by TNF-alpha. |
| 5085 | 12031982 | Both PKCalpha and -delta are constitutively associated with IRS-1. |
| 5086 | 12031982 | Whereas insulin decreased coprecipitation of IRS-1 with PKCalpha, it increased coprecipitation of IRS-1 with PKCdelta. |
| 5087 | 12031982 | TNF-alpha blocked the effects of insulin on association of both PKCs with IRS-1. |
| 5088 | 12031982 | To further investigate the involvement of PKCs in inhibitory actions of TNF-alpha on insulin signaling, we overexpressed specific PKC isoforms in mature myotubes. |
| 5089 | 12031982 | PKCalpha overexpression inhibited basal and insulin-induced IR autophosphorylation, whereas PKCdelta overexpression increased IR autophosphorylation and abrogated the inhibitory effect of TNF-alpha on IR autophosphorylation and signaling to PI3-K. |
| 5090 | 12031982 | Blockade of PKCalpha antagonized the inhibitory effects of TNF-alpha on both insulin-induced IR tyrosine phosphorylation and IR signaling to PI3-K. |
| 5091 | 12031982 | We suggest that the effects of TNF-alpha on IR tyrosine phosphorylation are mediated via alteration of insulin-induced activation and association of PKCdelta and -alpha with upstream signaling molecules. |
| 5092 | 12031982 | Differential effects of tumor necrosis factor-alpha on protein kinase C isoforms alpha and delta mediate inhibition of insulin receptor signaling. |
| 5093 | 12031982 | Tumor necrosis factor-alpha (TNF-alpha) is a multifunctional cytokine that interferes with insulin signaling, but the molecular mechanisms of this effect are unclear. |
| 5094 | 12031982 | Because certain protein kinase C (PKC) isoforms are activated by insulin, we examined the role of PKC in TNF-alpha inhibition of insulin signaling in primary cultures of mouse skeletal muscle. |
| 5095 | 12031982 | TNF-alpha, given 5 min before insulin, inhibited insulin-induced tyrosine phosphorylation of insulin receptor (IR), IR substrate (IRS)-1, insulin-induced association of IRS-1 with the p85 subunit of phosphatidylinositol 3-kinase (PI3-K), and insulin-induced glucose uptake. |
| 5096 | 12031982 | Insulin and TNF-alpha each caused tyrosine phosphorylation and activation of PKCs delta and alpha, but when TNF-alpha preceded insulin, the effects were less than that produced by each substance alone. |
| 5097 | 12031982 | Insulin induced PKCdelta specifically to coprecipitate with IR, an effect blocked by TNF-alpha. |
| 5098 | 12031982 | Both PKCalpha and -delta are constitutively associated with IRS-1. |
| 5099 | 12031982 | Whereas insulin decreased coprecipitation of IRS-1 with PKCalpha, it increased coprecipitation of IRS-1 with PKCdelta. |
| 5100 | 12031982 | TNF-alpha blocked the effects of insulin on association of both PKCs with IRS-1. |
| 5101 | 12031982 | To further investigate the involvement of PKCs in inhibitory actions of TNF-alpha on insulin signaling, we overexpressed specific PKC isoforms in mature myotubes. |
| 5102 | 12031982 | PKCalpha overexpression inhibited basal and insulin-induced IR autophosphorylation, whereas PKCdelta overexpression increased IR autophosphorylation and abrogated the inhibitory effect of TNF-alpha on IR autophosphorylation and signaling to PI3-K. |
| 5103 | 12031982 | Blockade of PKCalpha antagonized the inhibitory effects of TNF-alpha on both insulin-induced IR tyrosine phosphorylation and IR signaling to PI3-K. |
| 5104 | 12031982 | We suggest that the effects of TNF-alpha on IR tyrosine phosphorylation are mediated via alteration of insulin-induced activation and association of PKCdelta and -alpha with upstream signaling molecules. |
| 5105 | 12079844 | Protein kinase C and lipid-induced insulin resistance in skeletal muscle. |
| 5106 | 12079844 | Thus, increased diacylglycerol levels in muscle are associated with the activation of one or more isoforms of the protein kinase C family, which is known to attenuate insulin signaling, especially at the level of IRS-1. |
| 5107 | 12079844 | In addition, de novo synthesis of ceramide can inhibit more distal sites by the activation of protein phosphatase 2A and hence promote the dephosphorylation and inactivation of protein kinase B. |
| 5108 | 12080441 | Marked impairments in insulin's intracellular signaling cascade are present in fat cells from type 2 diabetic patients, including reduced IRS-1 gene and protein expression, impaired insulin-stimulated PI3-kinase and PKB/Akt activities. |
| 5109 | 12080441 | In contrast, upstream insulin signaling in skeletal muscle from diabetic subjects only shows modest impairments and PKB/Akt activation in vivo by insulin appears normal. |
| 5110 | 12080441 | Similar marked impairments in insulin signaling, including reduced IRS-1 expression, impaired insulin-stimulated PI3-kinase and PKB/Akt activities are also seen in some (approximately 30%) normoglycemic individuals with genetic predisposition for type 2 diabetes. |
| 5111 | 12080441 | The individuals with reduced cellular expression of IRS-1 and GLUT4 are also markedly insulin resistant and exhibit several characteristics of the Insulin Resistance Syndrome.Thus, a 'diabetic' pattern is seen in the fat cells also in normoglycemic subjects and this is associated with a marked insulin resistance in vivo. |
| 5112 | 12080441 | Marked impairments in insulin's intracellular signaling cascade are present in fat cells from type 2 diabetic patients, including reduced IRS-1 gene and protein expression, impaired insulin-stimulated PI3-kinase and PKB/Akt activities. |
| 5113 | 12080441 | In contrast, upstream insulin signaling in skeletal muscle from diabetic subjects only shows modest impairments and PKB/Akt activation in vivo by insulin appears normal. |
| 5114 | 12080441 | Similar marked impairments in insulin signaling, including reduced IRS-1 expression, impaired insulin-stimulated PI3-kinase and PKB/Akt activities are also seen in some (approximately 30%) normoglycemic individuals with genetic predisposition for type 2 diabetes. |
| 5115 | 12080441 | The individuals with reduced cellular expression of IRS-1 and GLUT4 are also markedly insulin resistant and exhibit several characteristics of the Insulin Resistance Syndrome.Thus, a 'diabetic' pattern is seen in the fat cells also in normoglycemic subjects and this is associated with a marked insulin resistance in vivo. |
| 5116 | 12080441 | Marked impairments in insulin's intracellular signaling cascade are present in fat cells from type 2 diabetic patients, including reduced IRS-1 gene and protein expression, impaired insulin-stimulated PI3-kinase and PKB/Akt activities. |
| 5117 | 12080441 | In contrast, upstream insulin signaling in skeletal muscle from diabetic subjects only shows modest impairments and PKB/Akt activation in vivo by insulin appears normal. |
| 5118 | 12080441 | Similar marked impairments in insulin signaling, including reduced IRS-1 expression, impaired insulin-stimulated PI3-kinase and PKB/Akt activities are also seen in some (approximately 30%) normoglycemic individuals with genetic predisposition for type 2 diabetes. |
| 5119 | 12080441 | The individuals with reduced cellular expression of IRS-1 and GLUT4 are also markedly insulin resistant and exhibit several characteristics of the Insulin Resistance Syndrome.Thus, a 'diabetic' pattern is seen in the fat cells also in normoglycemic subjects and this is associated with a marked insulin resistance in vivo. |
| 5120 | 12082100 | Differential roles of insulin receptor substrates in the anti-apoptotic function of insulin-like growth factor-1 and insulin. |
| 5121 | 12082100 | Insulin-like growth factor-1 (IGF-1) and insulin are known to prevent apoptosis. |
| 5122 | 12082100 | The signaling network of IGF-1 and insulin occurs via multiple pathways involving different insulin receptor substrates (IRSs). |
| 5123 | 12082100 | To define their roles in the anti-apoptotic function of IGF-1 and insulin, we established brown pre-adipocyte cell lines from wild-type and IRS knockout (KO) animals. |
| 5124 | 12082100 | In response to 16 h of serum deprivation, IRS-1-deficient cells showed a significant decrease in response to IGF-1 protection from apoptosis, whereas no changes were observed in the IRS-2, IRS-3, or IRS-4 KO cells. |
| 5125 | 12082100 | At this early time point, IGF-1 and insulin were able to protect both wild-type and IRS-1 KO cells from death by 85-90%. |
| 5126 | 12082100 | After a longer period of serum deprivation, the protective ability of insulin and IGF-1 was decreased, and this was especially reduced in the IRS-1 KO cells. |
| 5127 | 12082100 | Reconstitution of these cells with IRS-1, IRS-2, IRS-3, or IRS-1/IRS-2 chimeras restored the anti-apoptotic effects of IGF-1, whereas overexpression of IRS-4 had no effect at long time points and actually reduced the effect of IGF-1 at the short time point. |
| 5128 | 12082100 | Phosphorylation of the transcription factors cAMP response element-binding protein and FKHR by IGF-1 and insulin was markedly reduced in IRS-1 KO cells. |
| 5129 | 12082100 | In addition, both IGF-1 and insulin prevented caspase-3 cleavage in the wild-type cells, and this effect was greatly reduced in the IRS-1-deficient cells. |
| 5130 | 12082100 | These findings suggest that the IRS proteins may play differential roles in the anti-apoptotic effects of IGF-1 and insulin in brown pre-adipocytes, with IRS-1 being predominant, possibly acting through caspase-3-, CREB-, and FKHR-dependent mechanisms. |
| 5131 | 12082100 | Differential roles of insulin receptor substrates in the anti-apoptotic function of insulin-like growth factor-1 and insulin. |
| 5132 | 12082100 | Insulin-like growth factor-1 (IGF-1) and insulin are known to prevent apoptosis. |
| 5133 | 12082100 | The signaling network of IGF-1 and insulin occurs via multiple pathways involving different insulin receptor substrates (IRSs). |
| 5134 | 12082100 | To define their roles in the anti-apoptotic function of IGF-1 and insulin, we established brown pre-adipocyte cell lines from wild-type and IRS knockout (KO) animals. |
| 5135 | 12082100 | In response to 16 h of serum deprivation, IRS-1-deficient cells showed a significant decrease in response to IGF-1 protection from apoptosis, whereas no changes were observed in the IRS-2, IRS-3, or IRS-4 KO cells. |
| 5136 | 12082100 | At this early time point, IGF-1 and insulin were able to protect both wild-type and IRS-1 KO cells from death by 85-90%. |
| 5137 | 12082100 | After a longer period of serum deprivation, the protective ability of insulin and IGF-1 was decreased, and this was especially reduced in the IRS-1 KO cells. |
| 5138 | 12082100 | Reconstitution of these cells with IRS-1, IRS-2, IRS-3, or IRS-1/IRS-2 chimeras restored the anti-apoptotic effects of IGF-1, whereas overexpression of IRS-4 had no effect at long time points and actually reduced the effect of IGF-1 at the short time point. |
| 5139 | 12082100 | Phosphorylation of the transcription factors cAMP response element-binding protein and FKHR by IGF-1 and insulin was markedly reduced in IRS-1 KO cells. |
| 5140 | 12082100 | In addition, both IGF-1 and insulin prevented caspase-3 cleavage in the wild-type cells, and this effect was greatly reduced in the IRS-1-deficient cells. |
| 5141 | 12082100 | These findings suggest that the IRS proteins may play differential roles in the anti-apoptotic effects of IGF-1 and insulin in brown pre-adipocytes, with IRS-1 being predominant, possibly acting through caspase-3-, CREB-, and FKHR-dependent mechanisms. |
| 5142 | 12082100 | Differential roles of insulin receptor substrates in the anti-apoptotic function of insulin-like growth factor-1 and insulin. |
| 5143 | 12082100 | Insulin-like growth factor-1 (IGF-1) and insulin are known to prevent apoptosis. |
| 5144 | 12082100 | The signaling network of IGF-1 and insulin occurs via multiple pathways involving different insulin receptor substrates (IRSs). |
| 5145 | 12082100 | To define their roles in the anti-apoptotic function of IGF-1 and insulin, we established brown pre-adipocyte cell lines from wild-type and IRS knockout (KO) animals. |
| 5146 | 12082100 | In response to 16 h of serum deprivation, IRS-1-deficient cells showed a significant decrease in response to IGF-1 protection from apoptosis, whereas no changes were observed in the IRS-2, IRS-3, or IRS-4 KO cells. |
| 5147 | 12082100 | At this early time point, IGF-1 and insulin were able to protect both wild-type and IRS-1 KO cells from death by 85-90%. |
| 5148 | 12082100 | After a longer period of serum deprivation, the protective ability of insulin and IGF-1 was decreased, and this was especially reduced in the IRS-1 KO cells. |
| 5149 | 12082100 | Reconstitution of these cells with IRS-1, IRS-2, IRS-3, or IRS-1/IRS-2 chimeras restored the anti-apoptotic effects of IGF-1, whereas overexpression of IRS-4 had no effect at long time points and actually reduced the effect of IGF-1 at the short time point. |
| 5150 | 12082100 | Phosphorylation of the transcription factors cAMP response element-binding protein and FKHR by IGF-1 and insulin was markedly reduced in IRS-1 KO cells. |
| 5151 | 12082100 | In addition, both IGF-1 and insulin prevented caspase-3 cleavage in the wild-type cells, and this effect was greatly reduced in the IRS-1-deficient cells. |
| 5152 | 12082100 | These findings suggest that the IRS proteins may play differential roles in the anti-apoptotic effects of IGF-1 and insulin in brown pre-adipocytes, with IRS-1 being predominant, possibly acting through caspase-3-, CREB-, and FKHR-dependent mechanisms. |
| 5153 | 12082100 | Differential roles of insulin receptor substrates in the anti-apoptotic function of insulin-like growth factor-1 and insulin. |
| 5154 | 12082100 | Insulin-like growth factor-1 (IGF-1) and insulin are known to prevent apoptosis. |
| 5155 | 12082100 | The signaling network of IGF-1 and insulin occurs via multiple pathways involving different insulin receptor substrates (IRSs). |
| 5156 | 12082100 | To define their roles in the anti-apoptotic function of IGF-1 and insulin, we established brown pre-adipocyte cell lines from wild-type and IRS knockout (KO) animals. |
| 5157 | 12082100 | In response to 16 h of serum deprivation, IRS-1-deficient cells showed a significant decrease in response to IGF-1 protection from apoptosis, whereas no changes were observed in the IRS-2, IRS-3, or IRS-4 KO cells. |
| 5158 | 12082100 | At this early time point, IGF-1 and insulin were able to protect both wild-type and IRS-1 KO cells from death by 85-90%. |
| 5159 | 12082100 | After a longer period of serum deprivation, the protective ability of insulin and IGF-1 was decreased, and this was especially reduced in the IRS-1 KO cells. |
| 5160 | 12082100 | Reconstitution of these cells with IRS-1, IRS-2, IRS-3, or IRS-1/IRS-2 chimeras restored the anti-apoptotic effects of IGF-1, whereas overexpression of IRS-4 had no effect at long time points and actually reduced the effect of IGF-1 at the short time point. |
| 5161 | 12082100 | Phosphorylation of the transcription factors cAMP response element-binding protein and FKHR by IGF-1 and insulin was markedly reduced in IRS-1 KO cells. |
| 5162 | 12082100 | In addition, both IGF-1 and insulin prevented caspase-3 cleavage in the wild-type cells, and this effect was greatly reduced in the IRS-1-deficient cells. |
| 5163 | 12082100 | These findings suggest that the IRS proteins may play differential roles in the anti-apoptotic effects of IGF-1 and insulin in brown pre-adipocytes, with IRS-1 being predominant, possibly acting through caspase-3-, CREB-, and FKHR-dependent mechanisms. |
| 5164 | 12082100 | Differential roles of insulin receptor substrates in the anti-apoptotic function of insulin-like growth factor-1 and insulin. |
| 5165 | 12082100 | Insulin-like growth factor-1 (IGF-1) and insulin are known to prevent apoptosis. |
| 5166 | 12082100 | The signaling network of IGF-1 and insulin occurs via multiple pathways involving different insulin receptor substrates (IRSs). |
| 5167 | 12082100 | To define their roles in the anti-apoptotic function of IGF-1 and insulin, we established brown pre-adipocyte cell lines from wild-type and IRS knockout (KO) animals. |
| 5168 | 12082100 | In response to 16 h of serum deprivation, IRS-1-deficient cells showed a significant decrease in response to IGF-1 protection from apoptosis, whereas no changes were observed in the IRS-2, IRS-3, or IRS-4 KO cells. |
| 5169 | 12082100 | At this early time point, IGF-1 and insulin were able to protect both wild-type and IRS-1 KO cells from death by 85-90%. |
| 5170 | 12082100 | After a longer period of serum deprivation, the protective ability of insulin and IGF-1 was decreased, and this was especially reduced in the IRS-1 KO cells. |
| 5171 | 12082100 | Reconstitution of these cells with IRS-1, IRS-2, IRS-3, or IRS-1/IRS-2 chimeras restored the anti-apoptotic effects of IGF-1, whereas overexpression of IRS-4 had no effect at long time points and actually reduced the effect of IGF-1 at the short time point. |
| 5172 | 12082100 | Phosphorylation of the transcription factors cAMP response element-binding protein and FKHR by IGF-1 and insulin was markedly reduced in IRS-1 KO cells. |
| 5173 | 12082100 | In addition, both IGF-1 and insulin prevented caspase-3 cleavage in the wild-type cells, and this effect was greatly reduced in the IRS-1-deficient cells. |
| 5174 | 12082100 | These findings suggest that the IRS proteins may play differential roles in the anti-apoptotic effects of IGF-1 and insulin in brown pre-adipocytes, with IRS-1 being predominant, possibly acting through caspase-3-, CREB-, and FKHR-dependent mechanisms. |
| 5175 | 12086937 | Sustained exposure of L6 myotubes to high glucose and insulin decreases insulin-stimulated GLUT4 translocation but upregulates GLUT4 activity. |
| 5176 | 12086937 | In adipose cell cultures, high glucose and insulin cause insulin resistance of glucose uptake, but because of altered GLUT4 expression and contribution of GLUT1 to glucose uptake, the basis of insulin resistance could not be ascertained. |
| 5177 | 12086937 | Preincubation for 24 h with high glucose and insulin (high Glc/Ins) reduced insulin-stimulated GLUT4 translocation by 50%, without affecting GLUT4 expression. |
| 5178 | 12086937 | Insulin receptor and insulin receptor substrate-1 tyrosine phosphorylation, phosphatidylinositol 3-kinase activation, and Akt phosphorylation also diminished, as did insulin-mediated glucose uptake. |
| 5179 | 12086937 | High Glc/Ins elevated basal p38 mitogen-activated protein kinase (MAPK) phosphorylation and activity, and a short inhibition of p38 MAPK with SB202190 corrected the rise in basal glucose uptake, suggesting that p38 MAPK activity contributes to this rise. |
| 5180 | 12086937 | We propose that in a cellular model of skeletal muscle, chronic exposure to high Glc/Ins reduced the acute, insulin-elicited GLUT4 translocation. |
| 5181 | 12086949 | Upregulation of uptake activity occurred without any change in total cellular GLUT1 or GLUT4 protein content. |
| 5182 | 12086949 | Together with the INH-induced increase in insulin-stimulated glucose uptake, there was an approximately 3.5-fold increase (P < 0.05) in insulin receptor substrate (IRS)-1 protein abundance. |
| 5183 | 12086949 | Despite upregulation of IRS-1, maximal insulin stimulation of Akt phosphorylation was unaltered by INH treatment. |
| 5184 | 12086960 | Our results demonstrate that JAK2, insulin receptor substrate (IRS)-1, Shc, ERKs, and Akt are widely distributed in the kidney, and after GH treatment, there is a significant increase in phosphorylation of these proteins in STZ-induced diabetic rats compared with controls. |
| 5185 | 12086960 | Moreover, the GH-induced association of IRS-1/phosphatidylinositol 3-kinase, IRS-1/growth factor receptor bound 2 (Grb2), and Shc/Grb2 are increased in diabetic rats as well. |
| 5186 | 12107372 | Other possible mechanisms of insulin resistance in cytokine-treated cells include nitration of insulin receptor substrate-1 tyrosine residues by nitric oxide-derived reactive nitrogen species as well as direct interference with insulin signaling molecules further downstream such as protein kinase B/Akt. |
| 5187 | 12133893 | A single bout of prolonged aerobic exercise (30-60 min at approximately 60-70% of maximal oxygen consumption) can significantly lower plasma glucose levels, owing to normal contraction-induced stimulation of GLUT-4 glucose transporter translocation and glucose transport activity in insulin-resistant skeletal muscle. |
| 5188 | 12133893 | This training-induced enhancement of insulin action is associated with upregulation of specific components of the glucose transport system in insulin-resistant muscle and includes increased protein expression of GLUT-4 and insulin receptor substrate-1. |
| 5189 | 12138086 | Epidermal growth factor and transforming growth factor alpha mimic the effects of insulin in human fat cells and augment downstream signaling in insulin resistance. |
| 5190 | 12138086 | The ability of the growth factors epidermal growth factor (EGF), transforming growth factor alpha, and platelet-derived growth factor to exert insulin-like effects on glucose transport and lipolysis were examined in human and rat fat cells. |
| 5191 | 12138086 | No effects were found in rat fat cells, whereas EGF (EC(50) for glucose transport approximately 0.02 nm) and transforming growth factor alpha (EC(50) approximately 0.2 nm), but not platelet-derived growth factor, mimicked the effects of insulin (EC(50) approximately 0.2 nm) on both pathways. |
| 5192 | 12138086 | EGF increased the tyrosine phosphorylation of several proteins (the EGF receptor, insulin receptor substrate (IRS)-1, IRS-2, and Grb2-associated binder 1), whereas Shc and Gab2 were only weakly and inconsistently phosphorylated. p85, the regulatory subunit of phosphatidylinositol 3-kinase (PI 3-kinase), was also found to associate with all of these docking molecules, showing that EGF activated PI 3-kinase pools that were additional to those of insulin. |
| 5193 | 12138086 | EGF and/or insulin increased protein kinase B/Akt serine phosphorylation to a similar extent, whereas mitogen-activated protein kinase phosphorylation was more pronounced for EGF than for insulin. |
| 5194 | 12138086 | The impaired insulin-stimulated downstream signaling, measured as protein kinase B/Akt serine phosphorylation, in insulin-resistant cells (Type 2 diabetes) was improved by the addition of EGF. |
| 5195 | 12138086 | EGF mimics the effects of insulin on both the metabolic and mitogenic pathways but utilize in part different signaling pathways. |
| 5196 | 12138086 | Both insulin and EGF increase the tyrosine phosphorylation and activation of IRS-1 and IRS-2, whereas EGF is also capable of activating additional PI 3-kinase pools and, thus, can augment the downstream signaling of insulin in insulin-resistant states like Type 2 diabetes. |
| 5197 | 12145147 | Insulin-induced tyrosine phosphorylation of insulin receptor substrate (IRS)-1 was completely blocked, with unaltered expression of IRS-1. |
| 5198 | 12145147 | Troglitazone increased insulin action on IRS-1 phosphorylation, in both the absence and presence of co-culture. |
| 5199 | 12145147 | Insulin-regulated activation of Akt kinase in the myocytes was significantly reduced after co-culture, with troglitazone restoring insulin action. |
| 5200 | 12145147 | Addition of tumor necrosis factor (TNF)-alpha (2.5 nmol/l) to myocytes for 48 h reduced IRS-1 expression and inhibited IRS-1 and Akt phosphorylation comparable to the effect of co-culture. |
| 5201 | 12145147 | In conclusion, the release of fat cell factors induces insulin resistance in human skeletal muscle cells; however, TNF-alpha and resistin appear not to be involved in this process. |
| 5202 | 12145147 | Insulin-induced tyrosine phosphorylation of insulin receptor substrate (IRS)-1 was completely blocked, with unaltered expression of IRS-1. |
| 5203 | 12145147 | Troglitazone increased insulin action on IRS-1 phosphorylation, in both the absence and presence of co-culture. |
| 5204 | 12145147 | Insulin-regulated activation of Akt kinase in the myocytes was significantly reduced after co-culture, with troglitazone restoring insulin action. |
| 5205 | 12145147 | Addition of tumor necrosis factor (TNF)-alpha (2.5 nmol/l) to myocytes for 48 h reduced IRS-1 expression and inhibited IRS-1 and Akt phosphorylation comparable to the effect of co-culture. |
| 5206 | 12145147 | In conclusion, the release of fat cell factors induces insulin resistance in human skeletal muscle cells; however, TNF-alpha and resistin appear not to be involved in this process. |
| 5207 | 12145147 | Insulin-induced tyrosine phosphorylation of insulin receptor substrate (IRS)-1 was completely blocked, with unaltered expression of IRS-1. |
| 5208 | 12145147 | Troglitazone increased insulin action on IRS-1 phosphorylation, in both the absence and presence of co-culture. |
| 5209 | 12145147 | Insulin-regulated activation of Akt kinase in the myocytes was significantly reduced after co-culture, with troglitazone restoring insulin action. |
| 5210 | 12145147 | Addition of tumor necrosis factor (TNF)-alpha (2.5 nmol/l) to myocytes for 48 h reduced IRS-1 expression and inhibited IRS-1 and Akt phosphorylation comparable to the effect of co-culture. |
| 5211 | 12145147 | In conclusion, the release of fat cell factors induces insulin resistance in human skeletal muscle cells; however, TNF-alpha and resistin appear not to be involved in this process. |
| 5212 | 12145152 | Potentiation of insulin signaling in tissues of Zucker obese rats after acute and long-term treatment with PPARgamma agonists. |
| 5213 | 12145152 | Thiazolidinediones (TZDs), agonists of peroxisome proliferator-activated receptor-gamma (PPARgamma), improve insulin sensitivity in vivo, and the mechanism remains largely unknown. |
| 5214 | 12145152 | In this study, we showed that, in Zucker obese (fa/fa) rats, acute (1-day) treatment with both rosiglitazone (a TZD) and a non-TZD PPARgamma agonist (nTZD) reduced plasma free fatty acid and insulin levels and, concomitantly, potentiated insulin-stimulated Akt phosphorylation at threonine 308 (Akt-pT308) in adipose and muscle tissues. |
| 5215 | 12145152 | The increase in Akt-pT308 was correlated with an increase in Akt phosphorylation at serine 473 (Akt-pS473), tyrosine phosphorylation of insulin receptor beta subunit and insulin receptor substrate-1, and serine phosphorylation of glycogen synthase kinase-3alpha/beta. |
| 5216 | 12145152 | The agonists appeared to potentiate Akt1 phosphorylation in muscle and liver and both Akt1 and Akt2 in adipose. |
| 5217 | 12145152 | These results suggest that 1) PPARgamma agonists acutely potentiate insulin signaling in adipose and muscle tissues and such regulation may be physiologically relevant to insulin sensitization in vivo; 2) the agonists directly target adipose tissues; and 3) the metabolic and signaling effects of the agonists are mediated by structurally distinct PPARgamma agonists. |
| 5218 | 12166618 | Regulation of IRS-1/SHP2 interaction and AKT phosphorylation in animal models of insulin resistance. |
| 5219 | 12166618 | Insulin stimulates tyrosine kinase activity of its receptor, resulting in phosphorylation of its cytosolic substrate, insulin receptor substrate-1, which, in turn, associates with proteins containing SH2 domains, including phosphatidylinositol 3-kinase (PI 3-kinase) and the phosphotyrosine phosphatase SHP2. |
| 5220 | 12166618 | In the present study, we investigated insulin-induced IRS-1/SHP2 and IRS-1/PI 3-kinase associations and the regulation of a downstream serine-kinase AKT/PKB in liver and muscle of three animal models of insulin resistance: STZ diabetes, epinephrine-treated rats, and aging, which have alterations in IRS-1 tyrosine phosphorylation in common. |
| 5221 | 12166618 | The results demonstrated that insulin-induced IRS-1/PI 3-kinase association has a close correlation with IRS-1 tyrosine phosphorylation levels, but insulin-induced IRS-1/SHP2 association showed a modulation that did not parallel IRS-1 phosphorylation, with a tissue-specific regulation in aging. |
| 5222 | 12166618 | The integration of the behavior of IRS-1/PI 3-kinase and with IRS-1/SHP2 associations may be important for insulin signaling downstream as AKT phosphorylation. |
| 5223 | 12166618 | In conclusion, the results of the present study demonstrated that insulin-induced IRS-1/SHP2 association can be regulated in insulin-sensitive tissues of animal models of insulin resistance and may have a role in the control of AKT phosphorylation, which may be implicated in the control of glucose metabolism. |
| 5224 | 12166618 | Regulation of IRS-1/SHP2 interaction and AKT phosphorylation in animal models of insulin resistance. |
| 5225 | 12166618 | Insulin stimulates tyrosine kinase activity of its receptor, resulting in phosphorylation of its cytosolic substrate, insulin receptor substrate-1, which, in turn, associates with proteins containing SH2 domains, including phosphatidylinositol 3-kinase (PI 3-kinase) and the phosphotyrosine phosphatase SHP2. |
| 5226 | 12166618 | In the present study, we investigated insulin-induced IRS-1/SHP2 and IRS-1/PI 3-kinase associations and the regulation of a downstream serine-kinase AKT/PKB in liver and muscle of three animal models of insulin resistance: STZ diabetes, epinephrine-treated rats, and aging, which have alterations in IRS-1 tyrosine phosphorylation in common. |
| 5227 | 12166618 | The results demonstrated that insulin-induced IRS-1/PI 3-kinase association has a close correlation with IRS-1 tyrosine phosphorylation levels, but insulin-induced IRS-1/SHP2 association showed a modulation that did not parallel IRS-1 phosphorylation, with a tissue-specific regulation in aging. |
| 5228 | 12166618 | The integration of the behavior of IRS-1/PI 3-kinase and with IRS-1/SHP2 associations may be important for insulin signaling downstream as AKT phosphorylation. |
| 5229 | 12166618 | In conclusion, the results of the present study demonstrated that insulin-induced IRS-1/SHP2 association can be regulated in insulin-sensitive tissues of animal models of insulin resistance and may have a role in the control of AKT phosphorylation, which may be implicated in the control of glucose metabolism. |
| 5230 | 12166618 | Regulation of IRS-1/SHP2 interaction and AKT phosphorylation in animal models of insulin resistance. |
| 5231 | 12166618 | Insulin stimulates tyrosine kinase activity of its receptor, resulting in phosphorylation of its cytosolic substrate, insulin receptor substrate-1, which, in turn, associates with proteins containing SH2 domains, including phosphatidylinositol 3-kinase (PI 3-kinase) and the phosphotyrosine phosphatase SHP2. |
| 5232 | 12166618 | In the present study, we investigated insulin-induced IRS-1/SHP2 and IRS-1/PI 3-kinase associations and the regulation of a downstream serine-kinase AKT/PKB in liver and muscle of three animal models of insulin resistance: STZ diabetes, epinephrine-treated rats, and aging, which have alterations in IRS-1 tyrosine phosphorylation in common. |
| 5233 | 12166618 | The results demonstrated that insulin-induced IRS-1/PI 3-kinase association has a close correlation with IRS-1 tyrosine phosphorylation levels, but insulin-induced IRS-1/SHP2 association showed a modulation that did not parallel IRS-1 phosphorylation, with a tissue-specific regulation in aging. |
| 5234 | 12166618 | The integration of the behavior of IRS-1/PI 3-kinase and with IRS-1/SHP2 associations may be important for insulin signaling downstream as AKT phosphorylation. |
| 5235 | 12166618 | In conclusion, the results of the present study demonstrated that insulin-induced IRS-1/SHP2 association can be regulated in insulin-sensitive tissues of animal models of insulin resistance and may have a role in the control of AKT phosphorylation, which may be implicated in the control of glucose metabolism. |
| 5236 | 12166618 | Regulation of IRS-1/SHP2 interaction and AKT phosphorylation in animal models of insulin resistance. |
| 5237 | 12166618 | Insulin stimulates tyrosine kinase activity of its receptor, resulting in phosphorylation of its cytosolic substrate, insulin receptor substrate-1, which, in turn, associates with proteins containing SH2 domains, including phosphatidylinositol 3-kinase (PI 3-kinase) and the phosphotyrosine phosphatase SHP2. |
| 5238 | 12166618 | In the present study, we investigated insulin-induced IRS-1/SHP2 and IRS-1/PI 3-kinase associations and the regulation of a downstream serine-kinase AKT/PKB in liver and muscle of three animal models of insulin resistance: STZ diabetes, epinephrine-treated rats, and aging, which have alterations in IRS-1 tyrosine phosphorylation in common. |
| 5239 | 12166618 | The results demonstrated that insulin-induced IRS-1/PI 3-kinase association has a close correlation with IRS-1 tyrosine phosphorylation levels, but insulin-induced IRS-1/SHP2 association showed a modulation that did not parallel IRS-1 phosphorylation, with a tissue-specific regulation in aging. |
| 5240 | 12166618 | The integration of the behavior of IRS-1/PI 3-kinase and with IRS-1/SHP2 associations may be important for insulin signaling downstream as AKT phosphorylation. |
| 5241 | 12166618 | In conclusion, the results of the present study demonstrated that insulin-induced IRS-1/SHP2 association can be regulated in insulin-sensitive tissues of animal models of insulin resistance and may have a role in the control of AKT phosphorylation, which may be implicated in the control of glucose metabolism. |
| 5242 | 12166618 | Regulation of IRS-1/SHP2 interaction and AKT phosphorylation in animal models of insulin resistance. |
| 5243 | 12166618 | Insulin stimulates tyrosine kinase activity of its receptor, resulting in phosphorylation of its cytosolic substrate, insulin receptor substrate-1, which, in turn, associates with proteins containing SH2 domains, including phosphatidylinositol 3-kinase (PI 3-kinase) and the phosphotyrosine phosphatase SHP2. |
| 5244 | 12166618 | In the present study, we investigated insulin-induced IRS-1/SHP2 and IRS-1/PI 3-kinase associations and the regulation of a downstream serine-kinase AKT/PKB in liver and muscle of three animal models of insulin resistance: STZ diabetes, epinephrine-treated rats, and aging, which have alterations in IRS-1 tyrosine phosphorylation in common. |
| 5245 | 12166618 | The results demonstrated that insulin-induced IRS-1/PI 3-kinase association has a close correlation with IRS-1 tyrosine phosphorylation levels, but insulin-induced IRS-1/SHP2 association showed a modulation that did not parallel IRS-1 phosphorylation, with a tissue-specific regulation in aging. |
| 5246 | 12166618 | The integration of the behavior of IRS-1/PI 3-kinase and with IRS-1/SHP2 associations may be important for insulin signaling downstream as AKT phosphorylation. |
| 5247 | 12166618 | In conclusion, the results of the present study demonstrated that insulin-induced IRS-1/SHP2 association can be regulated in insulin-sensitive tissues of animal models of insulin resistance and may have a role in the control of AKT phosphorylation, which may be implicated in the control of glucose metabolism. |
| 5248 | 12166618 | Regulation of IRS-1/SHP2 interaction and AKT phosphorylation in animal models of insulin resistance. |
| 5249 | 12166618 | Insulin stimulates tyrosine kinase activity of its receptor, resulting in phosphorylation of its cytosolic substrate, insulin receptor substrate-1, which, in turn, associates with proteins containing SH2 domains, including phosphatidylinositol 3-kinase (PI 3-kinase) and the phosphotyrosine phosphatase SHP2. |
| 5250 | 12166618 | In the present study, we investigated insulin-induced IRS-1/SHP2 and IRS-1/PI 3-kinase associations and the regulation of a downstream serine-kinase AKT/PKB in liver and muscle of three animal models of insulin resistance: STZ diabetes, epinephrine-treated rats, and aging, which have alterations in IRS-1 tyrosine phosphorylation in common. |
| 5251 | 12166618 | The results demonstrated that insulin-induced IRS-1/PI 3-kinase association has a close correlation with IRS-1 tyrosine phosphorylation levels, but insulin-induced IRS-1/SHP2 association showed a modulation that did not parallel IRS-1 phosphorylation, with a tissue-specific regulation in aging. |
| 5252 | 12166618 | The integration of the behavior of IRS-1/PI 3-kinase and with IRS-1/SHP2 associations may be important for insulin signaling downstream as AKT phosphorylation. |
| 5253 | 12166618 | In conclusion, the results of the present study demonstrated that insulin-induced IRS-1/SHP2 association can be regulated in insulin-sensitive tissues of animal models of insulin resistance and may have a role in the control of AKT phosphorylation, which may be implicated in the control of glucose metabolism. |
| 5254 | 12169433 | Although a full understanding of insulin/insulin-like growth factor (IGF) action is evolving, the discovery of insulin receptor substrate (IRS) proteins and their role to link cell surface receptors to the intracellular signaling cascades provided an important step forward. |
| 5255 | 12169433 | Importantly, the IRS-2 branch of the insulin/IGF-signaling pathway is a common element in peripheral insulin response and pancreatic beta-cell growth and function. |
| 5256 | 12169433 | Failure of IRS-2 signaling might explain the eventual loss of compensatory hyperinsulinemia during prolonged periods of peripheral insulin resistance. |
| 5257 | 12169433 | Moreover, short-term inhibition of IRS protein functions by serine phosphorylation, or sustained inhibition by ubiquitin-targeted proteosome-mediated degradation suggests a common molecular mechanism for insulin resistance during acute injury or infection, or the sensitivity of beta-cells to autoimmune destruction. |
| 5258 | 12169433 | The broad role of IRS-1 and IRS-2 in cell growth and survival reveals a common regulatory pathway linking development, somatic growth, fertility, neuronal proliferation, and aging to the core mechanisms used by vertebrates for nutrient sensing. |
| 5259 | 12176670 | Heterozygous knockout of the IRS-1 gene in mice enhances obesity-linked insulin resistance: a possible model for the development of type 2 diabetes. |
| 5260 | 12176670 | Here we introduced obesity in heterozygous IRS-1 knockout (IRS-1(+/-)) mice by gold-thioglucose (GTG) injection and studied the impact of reduced IRS-1 expression on obesity-linked insulin resistance. |
| 5261 | 12176670 | There was no difference in insulin sensitivity between lean IRS-1(+/-) and lean WT. |
| 5262 | 12176670 | Elevated fasting insulin levels but no change in fasting glucose were noted in obese IRS-1(+/-) and WT compared with the respective lean controls. |
| 5263 | 12176670 | Importantly, fasting insulin in obese IRS-1(+/-) was 1.5-fold higher (P<0.05) than in obese WT, and an insulin tolerance test showed a profound insulin resistance in obese IRS-1(+/-) compared with obese WT. |
| 5264 | 12176670 | The expression of insulin receptor and IRS-1 and IRS-2 was decreased in obese IRS-1(+/-), which could in part explain the profound insulin resistance in these mice. |
| 5265 | 12176670 | Our results suggest that IRS-1 is the suspected gene for type 2 diabetes and its polymorphisms could worsen insulin resistance in the presence of other additional factors, such as obesity. |
| 5266 | 12176670 | Heterozygous knockout of the IRS-1 gene in mice enhances obesity-linked insulin resistance: a possible model for the development of type 2 diabetes. |
| 5267 | 12176670 | Here we introduced obesity in heterozygous IRS-1 knockout (IRS-1(+/-)) mice by gold-thioglucose (GTG) injection and studied the impact of reduced IRS-1 expression on obesity-linked insulin resistance. |
| 5268 | 12176670 | There was no difference in insulin sensitivity between lean IRS-1(+/-) and lean WT. |
| 5269 | 12176670 | Elevated fasting insulin levels but no change in fasting glucose were noted in obese IRS-1(+/-) and WT compared with the respective lean controls. |
| 5270 | 12176670 | Importantly, fasting insulin in obese IRS-1(+/-) was 1.5-fold higher (P<0.05) than in obese WT, and an insulin tolerance test showed a profound insulin resistance in obese IRS-1(+/-) compared with obese WT. |
| 5271 | 12176670 | The expression of insulin receptor and IRS-1 and IRS-2 was decreased in obese IRS-1(+/-), which could in part explain the profound insulin resistance in these mice. |
| 5272 | 12176670 | Our results suggest that IRS-1 is the suspected gene for type 2 diabetes and its polymorphisms could worsen insulin resistance in the presence of other additional factors, such as obesity. |
| 5273 | 12176670 | Heterozygous knockout of the IRS-1 gene in mice enhances obesity-linked insulin resistance: a possible model for the development of type 2 diabetes. |
| 5274 | 12176670 | Here we introduced obesity in heterozygous IRS-1 knockout (IRS-1(+/-)) mice by gold-thioglucose (GTG) injection and studied the impact of reduced IRS-1 expression on obesity-linked insulin resistance. |
| 5275 | 12176670 | There was no difference in insulin sensitivity between lean IRS-1(+/-) and lean WT. |
| 5276 | 12176670 | Elevated fasting insulin levels but no change in fasting glucose were noted in obese IRS-1(+/-) and WT compared with the respective lean controls. |
| 5277 | 12176670 | Importantly, fasting insulin in obese IRS-1(+/-) was 1.5-fold higher (P<0.05) than in obese WT, and an insulin tolerance test showed a profound insulin resistance in obese IRS-1(+/-) compared with obese WT. |
| 5278 | 12176670 | The expression of insulin receptor and IRS-1 and IRS-2 was decreased in obese IRS-1(+/-), which could in part explain the profound insulin resistance in these mice. |
| 5279 | 12176670 | Our results suggest that IRS-1 is the suspected gene for type 2 diabetes and its polymorphisms could worsen insulin resistance in the presence of other additional factors, such as obesity. |
| 5280 | 12176670 | Heterozygous knockout of the IRS-1 gene in mice enhances obesity-linked insulin resistance: a possible model for the development of type 2 diabetes. |
| 5281 | 12176670 | Here we introduced obesity in heterozygous IRS-1 knockout (IRS-1(+/-)) mice by gold-thioglucose (GTG) injection and studied the impact of reduced IRS-1 expression on obesity-linked insulin resistance. |
| 5282 | 12176670 | There was no difference in insulin sensitivity between lean IRS-1(+/-) and lean WT. |
| 5283 | 12176670 | Elevated fasting insulin levels but no change in fasting glucose were noted in obese IRS-1(+/-) and WT compared with the respective lean controls. |
| 5284 | 12176670 | Importantly, fasting insulin in obese IRS-1(+/-) was 1.5-fold higher (P<0.05) than in obese WT, and an insulin tolerance test showed a profound insulin resistance in obese IRS-1(+/-) compared with obese WT. |
| 5285 | 12176670 | The expression of insulin receptor and IRS-1 and IRS-2 was decreased in obese IRS-1(+/-), which could in part explain the profound insulin resistance in these mice. |
| 5286 | 12176670 | Our results suggest that IRS-1 is the suspected gene for type 2 diabetes and its polymorphisms could worsen insulin resistance in the presence of other additional factors, such as obesity. |
| 5287 | 12176670 | Heterozygous knockout of the IRS-1 gene in mice enhances obesity-linked insulin resistance: a possible model for the development of type 2 diabetes. |
| 5288 | 12176670 | Here we introduced obesity in heterozygous IRS-1 knockout (IRS-1(+/-)) mice by gold-thioglucose (GTG) injection and studied the impact of reduced IRS-1 expression on obesity-linked insulin resistance. |
| 5289 | 12176670 | There was no difference in insulin sensitivity between lean IRS-1(+/-) and lean WT. |
| 5290 | 12176670 | Elevated fasting insulin levels but no change in fasting glucose were noted in obese IRS-1(+/-) and WT compared with the respective lean controls. |
| 5291 | 12176670 | Importantly, fasting insulin in obese IRS-1(+/-) was 1.5-fold higher (P<0.05) than in obese WT, and an insulin tolerance test showed a profound insulin resistance in obese IRS-1(+/-) compared with obese WT. |
| 5292 | 12176670 | The expression of insulin receptor and IRS-1 and IRS-2 was decreased in obese IRS-1(+/-), which could in part explain the profound insulin resistance in these mice. |
| 5293 | 12176670 | Our results suggest that IRS-1 is the suspected gene for type 2 diabetes and its polymorphisms could worsen insulin resistance in the presence of other additional factors, such as obesity. |
| 5294 | 12176670 | Heterozygous knockout of the IRS-1 gene in mice enhances obesity-linked insulin resistance: a possible model for the development of type 2 diabetes. |
| 5295 | 12176670 | Here we introduced obesity in heterozygous IRS-1 knockout (IRS-1(+/-)) mice by gold-thioglucose (GTG) injection and studied the impact of reduced IRS-1 expression on obesity-linked insulin resistance. |
| 5296 | 12176670 | There was no difference in insulin sensitivity between lean IRS-1(+/-) and lean WT. |
| 5297 | 12176670 | Elevated fasting insulin levels but no change in fasting glucose were noted in obese IRS-1(+/-) and WT compared with the respective lean controls. |
| 5298 | 12176670 | Importantly, fasting insulin in obese IRS-1(+/-) was 1.5-fold higher (P<0.05) than in obese WT, and an insulin tolerance test showed a profound insulin resistance in obese IRS-1(+/-) compared with obese WT. |
| 5299 | 12176670 | The expression of insulin receptor and IRS-1 and IRS-2 was decreased in obese IRS-1(+/-), which could in part explain the profound insulin resistance in these mice. |
| 5300 | 12176670 | Our results suggest that IRS-1 is the suspected gene for type 2 diabetes and its polymorphisms could worsen insulin resistance in the presence of other additional factors, such as obesity. |
| 5301 | 12176670 | Heterozygous knockout of the IRS-1 gene in mice enhances obesity-linked insulin resistance: a possible model for the development of type 2 diabetes. |
| 5302 | 12176670 | Here we introduced obesity in heterozygous IRS-1 knockout (IRS-1(+/-)) mice by gold-thioglucose (GTG) injection and studied the impact of reduced IRS-1 expression on obesity-linked insulin resistance. |
| 5303 | 12176670 | There was no difference in insulin sensitivity between lean IRS-1(+/-) and lean WT. |
| 5304 | 12176670 | Elevated fasting insulin levels but no change in fasting glucose were noted in obese IRS-1(+/-) and WT compared with the respective lean controls. |
| 5305 | 12176670 | Importantly, fasting insulin in obese IRS-1(+/-) was 1.5-fold higher (P<0.05) than in obese WT, and an insulin tolerance test showed a profound insulin resistance in obese IRS-1(+/-) compared with obese WT. |
| 5306 | 12176670 | The expression of insulin receptor and IRS-1 and IRS-2 was decreased in obese IRS-1(+/-), which could in part explain the profound insulin resistance in these mice. |
| 5307 | 12176670 | Our results suggest that IRS-1 is the suspected gene for type 2 diabetes and its polymorphisms could worsen insulin resistance in the presence of other additional factors, such as obesity. |
| 5308 | 12196460 | In the biopsies, insulin receptor kinase (IRK) activity, insulin receptor substrate (IRS)-1-associated phosphatidylinositol 3-kinase (PI3K) activity, Ser(473) and Thr(308) phosphorylation of protein kinase B (PKB), and protein expression of IRS-1, IRS-2, phosphoinositol-dependent kinase-1 (PDK-1), PKB, and GLUT-4 were determined. |
| 5309 | 12196460 | IRK and PI3K activities were not altered by troglitazone, but PKB Ser(473) phosphorylation was enhanced compared with pretreatment and placebo at the clamp insulin level (138 +/- 36 vs. 77 +/- 16 and 55 +/- 13 internal standard units; both P < 0.05) and with pretreatment at the basal level (31 +/- 9 vs. 14 +/- 4 internal standard units; P < 0.05). |
| 5310 | 12196460 | Troglitazone did not alter insulin receptor number or IRS-1, IRS-2, PKB, PDK-1, or GLUT-4 protein expression. |
| 5311 | 12196460 | We conclude that increased PKB phosphorylation may contribute to the insulin-sensitizing effects of thiazolidinediones in human skeletal muscle. |
| 5312 | 12196460 | In the biopsies, insulin receptor kinase (IRK) activity, insulin receptor substrate (IRS)-1-associated phosphatidylinositol 3-kinase (PI3K) activity, Ser(473) and Thr(308) phosphorylation of protein kinase B (PKB), and protein expression of IRS-1, IRS-2, phosphoinositol-dependent kinase-1 (PDK-1), PKB, and GLUT-4 were determined. |
| 5313 | 12196460 | IRK and PI3K activities were not altered by troglitazone, but PKB Ser(473) phosphorylation was enhanced compared with pretreatment and placebo at the clamp insulin level (138 +/- 36 vs. 77 +/- 16 and 55 +/- 13 internal standard units; both P < 0.05) and with pretreatment at the basal level (31 +/- 9 vs. 14 +/- 4 internal standard units; P < 0.05). |
| 5314 | 12196460 | Troglitazone did not alter insulin receptor number or IRS-1, IRS-2, PKB, PDK-1, or GLUT-4 protein expression. |
| 5315 | 12196460 | We conclude that increased PKB phosphorylation may contribute to the insulin-sensitizing effects of thiazolidinediones in human skeletal muscle. |
| 5316 | 12213348 | Differential regulation of gene expression and insulin-induced activation of phosphodiesterase 3B in adipocytes of lean insulin-resistant IRS-1 (-/-) mice. |
| 5317 | 12213348 | PDE3B gene expression is generally reduced in adipocytes of either monogenic or polygenic rodent models of obese, insulin-resistance. |
| 5318 | 12213348 | To determine whether the regulation of PDE3B gene expression is correlated with fat cell size, we examined this gene expression in adipose tissues of IRS-1 (-/-) mice. |
| 5319 | 12213348 | In IRS-1 (-/-) mice, PDE3B mRNA and protein levels were increased 1.24- and 1.35-fold those in C57BL/6J control mice, respectively. |
| 5320 | 12213348 | Independently, the fold induction of PDE activity by insulin (insulin-induced/basal) was 1.7-fold in control mice, but was reduced to 1.35-fold in IRS-1 (-/-) mice. |
| 5321 | 12213348 | Thus, PDE3B gene expression may be inversely correlated with a fat cell size, whereas insulin-induced PDE3B activation is mediated through IRS-1. |
| 5322 | 12213348 | Differential regulation of gene expression and insulin-induced activation of phosphodiesterase 3B in adipocytes of lean insulin-resistant IRS-1 (-/-) mice. |
| 5323 | 12213348 | PDE3B gene expression is generally reduced in adipocytes of either monogenic or polygenic rodent models of obese, insulin-resistance. |
| 5324 | 12213348 | To determine whether the regulation of PDE3B gene expression is correlated with fat cell size, we examined this gene expression in adipose tissues of IRS-1 (-/-) mice. |
| 5325 | 12213348 | In IRS-1 (-/-) mice, PDE3B mRNA and protein levels were increased 1.24- and 1.35-fold those in C57BL/6J control mice, respectively. |
| 5326 | 12213348 | Independently, the fold induction of PDE activity by insulin (insulin-induced/basal) was 1.7-fold in control mice, but was reduced to 1.35-fold in IRS-1 (-/-) mice. |
| 5327 | 12213348 | Thus, PDE3B gene expression may be inversely correlated with a fat cell size, whereas insulin-induced PDE3B activation is mediated through IRS-1. |
| 5328 | 12213348 | Differential regulation of gene expression and insulin-induced activation of phosphodiesterase 3B in adipocytes of lean insulin-resistant IRS-1 (-/-) mice. |
| 5329 | 12213348 | PDE3B gene expression is generally reduced in adipocytes of either monogenic or polygenic rodent models of obese, insulin-resistance. |
| 5330 | 12213348 | To determine whether the regulation of PDE3B gene expression is correlated with fat cell size, we examined this gene expression in adipose tissues of IRS-1 (-/-) mice. |
| 5331 | 12213348 | In IRS-1 (-/-) mice, PDE3B mRNA and protein levels were increased 1.24- and 1.35-fold those in C57BL/6J control mice, respectively. |
| 5332 | 12213348 | Independently, the fold induction of PDE activity by insulin (insulin-induced/basal) was 1.7-fold in control mice, but was reduced to 1.35-fold in IRS-1 (-/-) mice. |
| 5333 | 12213348 | Thus, PDE3B gene expression may be inversely correlated with a fat cell size, whereas insulin-induced PDE3B activation is mediated through IRS-1. |
| 5334 | 12213348 | Differential regulation of gene expression and insulin-induced activation of phosphodiesterase 3B in adipocytes of lean insulin-resistant IRS-1 (-/-) mice. |
| 5335 | 12213348 | PDE3B gene expression is generally reduced in adipocytes of either monogenic or polygenic rodent models of obese, insulin-resistance. |
| 5336 | 12213348 | To determine whether the regulation of PDE3B gene expression is correlated with fat cell size, we examined this gene expression in adipose tissues of IRS-1 (-/-) mice. |
| 5337 | 12213348 | In IRS-1 (-/-) mice, PDE3B mRNA and protein levels were increased 1.24- and 1.35-fold those in C57BL/6J control mice, respectively. |
| 5338 | 12213348 | Independently, the fold induction of PDE activity by insulin (insulin-induced/basal) was 1.7-fold in control mice, but was reduced to 1.35-fold in IRS-1 (-/-) mice. |
| 5339 | 12213348 | Thus, PDE3B gene expression may be inversely correlated with a fat cell size, whereas insulin-induced PDE3B activation is mediated through IRS-1. |
| 5340 | 12213348 | Differential regulation of gene expression and insulin-induced activation of phosphodiesterase 3B in adipocytes of lean insulin-resistant IRS-1 (-/-) mice. |
| 5341 | 12213348 | PDE3B gene expression is generally reduced in adipocytes of either monogenic or polygenic rodent models of obese, insulin-resistance. |
| 5342 | 12213348 | To determine whether the regulation of PDE3B gene expression is correlated with fat cell size, we examined this gene expression in adipose tissues of IRS-1 (-/-) mice. |
| 5343 | 12213348 | In IRS-1 (-/-) mice, PDE3B mRNA and protein levels were increased 1.24- and 1.35-fold those in C57BL/6J control mice, respectively. |
| 5344 | 12213348 | Independently, the fold induction of PDE activity by insulin (insulin-induced/basal) was 1.7-fold in control mice, but was reduced to 1.35-fold in IRS-1 (-/-) mice. |
| 5345 | 12213348 | Thus, PDE3B gene expression may be inversely correlated with a fat cell size, whereas insulin-induced PDE3B activation is mediated through IRS-1. |
| 5346 | 12213887 | Polymorphisms in the genes encoding the insulin receptor substrate (IRS) proteins, IRS-1 (Gly(972)Arg) and IRS-2 (Gly(1057)Asp), influence susceptibility to type 2 diabetes. |
| 5347 | 12213887 | The IRS-1 Gly(972)Arg allele frequencies were identical in whites and African-Americans [0.95 (Gly) and 0.05 (Arg)]. |
| 5348 | 12213887 | Polymorphisms in the genes encoding the insulin receptor substrate (IRS) proteins, IRS-1 (Gly(972)Arg) and IRS-2 (Gly(1057)Asp), influence susceptibility to type 2 diabetes. |
| 5349 | 12213887 | The IRS-1 Gly(972)Arg allele frequencies were identical in whites and African-Americans [0.95 (Gly) and 0.05 (Arg)]. |
| 5350 | 12215475 | ACE inhibitor improves insulin resistance in diabetic mouse via bradykinin and NO. |
| 5351 | 12215475 | Improvement of insulin resistance by ACE inhibitors has been suggested; however, this mechanism has not been proved. |
| 5352 | 12215475 | We postulated that activation of the bradykinin-nitric oxide (NO) system by an ACE inhibitor enhances glucose uptake in peripheral tissues by means of an increase in translocation of glucose transporter 4 (GLUT4), resulting in improvement of insulin resistance. |
| 5353 | 12215475 | Administration of an ACE inhibitor, temocapril, significantly decreased plasma glucose and insulin concentrations in type 2 diabetic mouse KK-Ay. |
| 5354 | 12215475 | Moreover, we observed that translocation of GLUT4 to the plasma membrane was significantly enhanced by temocapril treatment without influencing insulin receptor substrate-1 phosphorylation. |
| 5355 | 12215475 | These results suggest that temocapril would improve insulin resistance and glucose intolerance through increasing glucose uptake, especially in skeletal muscle at least in part through enhancement of the bradykinin-NO system and consequently GLUT4 translocation. |
| 5356 | 12228220 | SOCS-1 and SOCS-3 block insulin signaling by ubiquitin-mediated degradation of IRS1 and IRS2. |
| 5357 | 12228220 | We show that SOCS1 or SOCS3 targeted IRS1 and IRS2, two critical signaling molecules for insulin action, for ubiquitin-mediated degradation. |
| 5358 | 12228220 | SOCS1 or SOCS3 bound both recombinant and endogenous IRS1 and IRS2 and promoted their ubiquitination and subsequent degradation in multiple cell types. |
| 5359 | 12228220 | Mutations in the conserved SOCS box of SOCS1 abrogated its interaction with the elongin BC ubiquitin-ligase complex without affecting its binding to IRS1 or IRS2. |
| 5360 | 12228220 | The SOCS1 mutants also failed to promote the ubiquitination and degradation of either IRS1 or IRS2. |
| 5361 | 12228220 | Adenoviral-mediated expression of SOCS1 in mouse liver dramatically reduced hepatic IRS1 and IRS2 protein levels and caused glucose intolerance; by contrast, expression of the SOCS1 mutants had no effect. |
| 5362 | 12228220 | Thus, SOCS-mediated degradation of IRS proteins, presumably via the elongin BC ubiquitin-ligase, might be a general mechanism of inflammation-induced insulin resistance, providing a target for therapy. |
| 5363 | 12228220 | SOCS-1 and SOCS-3 block insulin signaling by ubiquitin-mediated degradation of IRS1 and IRS2. |
| 5364 | 12228220 | We show that SOCS1 or SOCS3 targeted IRS1 and IRS2, two critical signaling molecules for insulin action, for ubiquitin-mediated degradation. |
| 5365 | 12228220 | SOCS1 or SOCS3 bound both recombinant and endogenous IRS1 and IRS2 and promoted their ubiquitination and subsequent degradation in multiple cell types. |
| 5366 | 12228220 | Mutations in the conserved SOCS box of SOCS1 abrogated its interaction with the elongin BC ubiquitin-ligase complex without affecting its binding to IRS1 or IRS2. |
| 5367 | 12228220 | The SOCS1 mutants also failed to promote the ubiquitination and degradation of either IRS1 or IRS2. |
| 5368 | 12228220 | Adenoviral-mediated expression of SOCS1 in mouse liver dramatically reduced hepatic IRS1 and IRS2 protein levels and caused glucose intolerance; by contrast, expression of the SOCS1 mutants had no effect. |
| 5369 | 12228220 | Thus, SOCS-mediated degradation of IRS proteins, presumably via the elongin BC ubiquitin-ligase, might be a general mechanism of inflammation-induced insulin resistance, providing a target for therapy. |
| 5370 | 12228220 | SOCS-1 and SOCS-3 block insulin signaling by ubiquitin-mediated degradation of IRS1 and IRS2. |
| 5371 | 12228220 | We show that SOCS1 or SOCS3 targeted IRS1 and IRS2, two critical signaling molecules for insulin action, for ubiquitin-mediated degradation. |
| 5372 | 12228220 | SOCS1 or SOCS3 bound both recombinant and endogenous IRS1 and IRS2 and promoted their ubiquitination and subsequent degradation in multiple cell types. |
| 5373 | 12228220 | Mutations in the conserved SOCS box of SOCS1 abrogated its interaction with the elongin BC ubiquitin-ligase complex without affecting its binding to IRS1 or IRS2. |
| 5374 | 12228220 | The SOCS1 mutants also failed to promote the ubiquitination and degradation of either IRS1 or IRS2. |
| 5375 | 12228220 | Adenoviral-mediated expression of SOCS1 in mouse liver dramatically reduced hepatic IRS1 and IRS2 protein levels and caused glucose intolerance; by contrast, expression of the SOCS1 mutants had no effect. |
| 5376 | 12228220 | Thus, SOCS-mediated degradation of IRS proteins, presumably via the elongin BC ubiquitin-ligase, might be a general mechanism of inflammation-induced insulin resistance, providing a target for therapy. |
| 5377 | 12228220 | SOCS-1 and SOCS-3 block insulin signaling by ubiquitin-mediated degradation of IRS1 and IRS2. |
| 5378 | 12228220 | We show that SOCS1 or SOCS3 targeted IRS1 and IRS2, two critical signaling molecules for insulin action, for ubiquitin-mediated degradation. |
| 5379 | 12228220 | SOCS1 or SOCS3 bound both recombinant and endogenous IRS1 and IRS2 and promoted their ubiquitination and subsequent degradation in multiple cell types. |
| 5380 | 12228220 | Mutations in the conserved SOCS box of SOCS1 abrogated its interaction with the elongin BC ubiquitin-ligase complex without affecting its binding to IRS1 or IRS2. |
| 5381 | 12228220 | The SOCS1 mutants also failed to promote the ubiquitination and degradation of either IRS1 or IRS2. |
| 5382 | 12228220 | Adenoviral-mediated expression of SOCS1 in mouse liver dramatically reduced hepatic IRS1 and IRS2 protein levels and caused glucose intolerance; by contrast, expression of the SOCS1 mutants had no effect. |
| 5383 | 12228220 | Thus, SOCS-mediated degradation of IRS proteins, presumably via the elongin BC ubiquitin-ligase, might be a general mechanism of inflammation-induced insulin resistance, providing a target for therapy. |
| 5384 | 12228220 | SOCS-1 and SOCS-3 block insulin signaling by ubiquitin-mediated degradation of IRS1 and IRS2. |
| 5385 | 12228220 | We show that SOCS1 or SOCS3 targeted IRS1 and IRS2, two critical signaling molecules for insulin action, for ubiquitin-mediated degradation. |
| 5386 | 12228220 | SOCS1 or SOCS3 bound both recombinant and endogenous IRS1 and IRS2 and promoted their ubiquitination and subsequent degradation in multiple cell types. |
| 5387 | 12228220 | Mutations in the conserved SOCS box of SOCS1 abrogated its interaction with the elongin BC ubiquitin-ligase complex without affecting its binding to IRS1 or IRS2. |
| 5388 | 12228220 | The SOCS1 mutants also failed to promote the ubiquitination and degradation of either IRS1 or IRS2. |
| 5389 | 12228220 | Adenoviral-mediated expression of SOCS1 in mouse liver dramatically reduced hepatic IRS1 and IRS2 protein levels and caused glucose intolerance; by contrast, expression of the SOCS1 mutants had no effect. |
| 5390 | 12228220 | Thus, SOCS-mediated degradation of IRS proteins, presumably via the elongin BC ubiquitin-ligase, might be a general mechanism of inflammation-induced insulin resistance, providing a target for therapy. |
| 5391 | 12228220 | SOCS-1 and SOCS-3 block insulin signaling by ubiquitin-mediated degradation of IRS1 and IRS2. |
| 5392 | 12228220 | We show that SOCS1 or SOCS3 targeted IRS1 and IRS2, two critical signaling molecules for insulin action, for ubiquitin-mediated degradation. |
| 5393 | 12228220 | SOCS1 or SOCS3 bound both recombinant and endogenous IRS1 and IRS2 and promoted their ubiquitination and subsequent degradation in multiple cell types. |
| 5394 | 12228220 | Mutations in the conserved SOCS box of SOCS1 abrogated its interaction with the elongin BC ubiquitin-ligase complex without affecting its binding to IRS1 or IRS2. |
| 5395 | 12228220 | The SOCS1 mutants also failed to promote the ubiquitination and degradation of either IRS1 or IRS2. |
| 5396 | 12228220 | Adenoviral-mediated expression of SOCS1 in mouse liver dramatically reduced hepatic IRS1 and IRS2 protein levels and caused glucose intolerance; by contrast, expression of the SOCS1 mutants had no effect. |
| 5397 | 12228220 | Thus, SOCS-mediated degradation of IRS proteins, presumably via the elongin BC ubiquitin-ligase, might be a general mechanism of inflammation-induced insulin resistance, providing a target for therapy. |
| 5398 | 12351658 | One mechanism mediating insulin resistance may involve the phosphorylation of serine residues in insulin receptor substrate-1 (IRS-1), leading to impairment in the ability of IRS-1 to activate downstream phosphatidylinositol 3-kinase-dependent pathways. |
| 5399 | 12351658 | Insulin-resistant states and serine phosphorylation of IRS-1 are associated with the activation of the inhibitor kappaB kinase (IKK) complex. |
| 5400 | 12351658 | In this study, using phosphospecific antibodies against rat IRS-1 phosphorylated at Ser(307) (equivalent to Ser(312) in human IRS-1), we observed serine phosphorylation of IRS-1 in response to TNF-alpha or calyculin A treatment that paralleled surrogate markers for IKK activation. |
| 5401 | 12351658 | The phosphorylation of human IRS-1 at Ser(312) in response to tumor necrosis factor-alpha was significantly reduced in cells pretreated with the IKK inhibitor 15 deoxy-prostaglandin J(2) as well as in cells derived from IKK knock-out mice. |
| 5402 | 12351658 | Taken together, our data suggest that IRS-1 is a novel direct substrate for IKK and that phosphorylation of IRS-1 at Ser(312) (and other sites) by IKK may contribute to the insulin resistance mediated by activation of inflammatory pathways. |
| 5403 | 12351658 | One mechanism mediating insulin resistance may involve the phosphorylation of serine residues in insulin receptor substrate-1 (IRS-1), leading to impairment in the ability of IRS-1 to activate downstream phosphatidylinositol 3-kinase-dependent pathways. |
| 5404 | 12351658 | Insulin-resistant states and serine phosphorylation of IRS-1 are associated with the activation of the inhibitor kappaB kinase (IKK) complex. |
| 5405 | 12351658 | In this study, using phosphospecific antibodies against rat IRS-1 phosphorylated at Ser(307) (equivalent to Ser(312) in human IRS-1), we observed serine phosphorylation of IRS-1 in response to TNF-alpha or calyculin A treatment that paralleled surrogate markers for IKK activation. |
| 5406 | 12351658 | The phosphorylation of human IRS-1 at Ser(312) in response to tumor necrosis factor-alpha was significantly reduced in cells pretreated with the IKK inhibitor 15 deoxy-prostaglandin J(2) as well as in cells derived from IKK knock-out mice. |
| 5407 | 12351658 | Taken together, our data suggest that IRS-1 is a novel direct substrate for IKK and that phosphorylation of IRS-1 at Ser(312) (and other sites) by IKK may contribute to the insulin resistance mediated by activation of inflammatory pathways. |
| 5408 | 12351658 | One mechanism mediating insulin resistance may involve the phosphorylation of serine residues in insulin receptor substrate-1 (IRS-1), leading to impairment in the ability of IRS-1 to activate downstream phosphatidylinositol 3-kinase-dependent pathways. |
| 5409 | 12351658 | Insulin-resistant states and serine phosphorylation of IRS-1 are associated with the activation of the inhibitor kappaB kinase (IKK) complex. |
| 5410 | 12351658 | In this study, using phosphospecific antibodies against rat IRS-1 phosphorylated at Ser(307) (equivalent to Ser(312) in human IRS-1), we observed serine phosphorylation of IRS-1 in response to TNF-alpha or calyculin A treatment that paralleled surrogate markers for IKK activation. |
| 5411 | 12351658 | The phosphorylation of human IRS-1 at Ser(312) in response to tumor necrosis factor-alpha was significantly reduced in cells pretreated with the IKK inhibitor 15 deoxy-prostaglandin J(2) as well as in cells derived from IKK knock-out mice. |
| 5412 | 12351658 | Taken together, our data suggest that IRS-1 is a novel direct substrate for IKK and that phosphorylation of IRS-1 at Ser(312) (and other sites) by IKK may contribute to the insulin resistance mediated by activation of inflammatory pathways. |
| 5413 | 12351658 | One mechanism mediating insulin resistance may involve the phosphorylation of serine residues in insulin receptor substrate-1 (IRS-1), leading to impairment in the ability of IRS-1 to activate downstream phosphatidylinositol 3-kinase-dependent pathways. |
| 5414 | 12351658 | Insulin-resistant states and serine phosphorylation of IRS-1 are associated with the activation of the inhibitor kappaB kinase (IKK) complex. |
| 5415 | 12351658 | In this study, using phosphospecific antibodies against rat IRS-1 phosphorylated at Ser(307) (equivalent to Ser(312) in human IRS-1), we observed serine phosphorylation of IRS-1 in response to TNF-alpha or calyculin A treatment that paralleled surrogate markers for IKK activation. |
| 5416 | 12351658 | The phosphorylation of human IRS-1 at Ser(312) in response to tumor necrosis factor-alpha was significantly reduced in cells pretreated with the IKK inhibitor 15 deoxy-prostaglandin J(2) as well as in cells derived from IKK knock-out mice. |
| 5417 | 12351658 | Taken together, our data suggest that IRS-1 is a novel direct substrate for IKK and that phosphorylation of IRS-1 at Ser(312) (and other sites) by IKK may contribute to the insulin resistance mediated by activation of inflammatory pathways. |
| 5418 | 12351658 | One mechanism mediating insulin resistance may involve the phosphorylation of serine residues in insulin receptor substrate-1 (IRS-1), leading to impairment in the ability of IRS-1 to activate downstream phosphatidylinositol 3-kinase-dependent pathways. |
| 5419 | 12351658 | Insulin-resistant states and serine phosphorylation of IRS-1 are associated with the activation of the inhibitor kappaB kinase (IKK) complex. |
| 5420 | 12351658 | In this study, using phosphospecific antibodies against rat IRS-1 phosphorylated at Ser(307) (equivalent to Ser(312) in human IRS-1), we observed serine phosphorylation of IRS-1 in response to TNF-alpha or calyculin A treatment that paralleled surrogate markers for IKK activation. |
| 5421 | 12351658 | The phosphorylation of human IRS-1 at Ser(312) in response to tumor necrosis factor-alpha was significantly reduced in cells pretreated with the IKK inhibitor 15 deoxy-prostaglandin J(2) as well as in cells derived from IKK knock-out mice. |
| 5422 | 12351658 | Taken together, our data suggest that IRS-1 is a novel direct substrate for IKK and that phosphorylation of IRS-1 at Ser(312) (and other sites) by IKK may contribute to the insulin resistance mediated by activation of inflammatory pathways. |
| 5423 | 12383882 | Low proliferation capacity of lymphocytes from alloxan-diabetic rats: involvement of high glucose and tyrosine phosphorylation of Shc and IRS-1. |
| 5424 | 12383882 | In cells from diabetic rats, the basal tyrosine phosphorylation of IRS-1 was higher than that of control rats, however, there was no further phosphorylation after insulin addition. |
| 5425 | 12383882 | Low proliferation capacity of lymphocytes from alloxan-diabetic rats: involvement of high glucose and tyrosine phosphorylation of Shc and IRS-1. |
| 5426 | 12383882 | In cells from diabetic rats, the basal tyrosine phosphorylation of IRS-1 was higher than that of control rats, however, there was no further phosphorylation after insulin addition. |
| 5427 | 12387679 | The fact that the function of two key targets of insulin action, glycogen synthase and insulin receptor substrate-1, are suppressed by GSK-3, as well as the fact that GSK-3 activity is higher in diabetic tissues, makes it a promising drug discovery target for insulin resistance and Type 2 diabetes. |
| 5428 | 12388133 | After treatments with cariporide or bafilomycin A1, insulin stimulation of insulin receptor and insulin receptor substrate-1 phosphorylation and Akt activity were normal. |
| 5429 | 12388133 | Immunocytochemical analysis revealed that insulin treatment caused a translocation of the GLUT4 from perinuclear structures and increased its co-localization with cell surface syntaxin 4. |
| 5430 | 12388133 | It is therefore hypothesized that insulin-stimulated cytosol alkalinization facilitates the final stages of translocation and incorporation of fully functional GLUT4 at the surface-limiting membrane. |
| 5431 | 12409308 | Salicylic acid reverses phorbol 12-myristate-13-acetate (PMA)- and tumor necrosis factor alpha (TNFalpha)-induced insulin receptor substrate 1 (IRS1) serine 307 phosphorylation and insulin resistance in human embryonic kidney 293 (HEK293) cells. |
| 5432 | 12409308 | Although it has been suggested that salicylates sensitize insulin action by inhibiting IkappaB kinase beta (IKKbeta), the detailed mechanisms remain unclear. |
| 5433 | 12409308 | Protein kinase C isoforms and tumor necrosis factor alpha (TNFalpha) signaling pathways are well described mediators of insulin resistance; they are implicated in the activation of IKKbeta and the subsequent inhibition of proximal insulin signaling via insulin receptor substrate 1 (IRS1) and Akt. |
| 5434 | 12409308 | This study investigated the effect of salicylic acid on phorbol 12-myristate 13-acetate (PMA)- and TNFalpha-induced insulin resistance in a human embryonic kidney 293 (HEK293) cell line stably expressing recombinant human IRS1. |
| 5435 | 12409308 | The results showed that both PMA and TNFalpha inhibited insulin-induced Akt phosphorylation and promoted IRS1 phosphorylation on Ser-307. |
| 5436 | 12409308 | Salicylic acid pretreatment completely reversed the effects of PMA and TNFalpha on both Akt and IRS1. |
| 5437 | 12409308 | Whereas PMA activated protein kinase C isoforms and IKKbeta, TNFalpha activated neither. |
| 5438 | 12409308 | On the other hand, both PMA and TNFalpha activated the c-Jun N-terminal kinase (JNK), which has been reported to directly phosphorylate IRS1 Ser-307. |
| 5439 | 12409308 | SP600125, a JNK inhibitor, prevented PMA and TNFalpha-induced IRS1 Ser-307 phosphorylation. |
| 5440 | 12409308 | Finally, salicylic acid inhibited JNK activation induced by both PMA and TNFalpha. |
| 5441 | 12409308 | Taken together, these observations suggest that salicylic acid can reverse the inhibitory effects of TNFalpha on insulin signaling via an IKKbeta-independent mechanism(s), potentially involving the inhibition of JNK activation. |
| 5442 | 12409308 | The role of JNK in salicylic acid-mediated insulin sensitization, however, requires further validation because the JNK inhibitor SP600125 appears to have other nonspecific activity in addition to inhibiting JNK activity. |
| 5443 | 12409308 | Salicylic acid reverses phorbol 12-myristate-13-acetate (PMA)- and tumor necrosis factor alpha (TNFalpha)-induced insulin receptor substrate 1 (IRS1) serine 307 phosphorylation and insulin resistance in human embryonic kidney 293 (HEK293) cells. |
| 5444 | 12409308 | Although it has been suggested that salicylates sensitize insulin action by inhibiting IkappaB kinase beta (IKKbeta), the detailed mechanisms remain unclear. |
| 5445 | 12409308 | Protein kinase C isoforms and tumor necrosis factor alpha (TNFalpha) signaling pathways are well described mediators of insulin resistance; they are implicated in the activation of IKKbeta and the subsequent inhibition of proximal insulin signaling via insulin receptor substrate 1 (IRS1) and Akt. |
| 5446 | 12409308 | This study investigated the effect of salicylic acid on phorbol 12-myristate 13-acetate (PMA)- and TNFalpha-induced insulin resistance in a human embryonic kidney 293 (HEK293) cell line stably expressing recombinant human IRS1. |
| 5447 | 12409308 | The results showed that both PMA and TNFalpha inhibited insulin-induced Akt phosphorylation and promoted IRS1 phosphorylation on Ser-307. |
| 5448 | 12409308 | Salicylic acid pretreatment completely reversed the effects of PMA and TNFalpha on both Akt and IRS1. |
| 5449 | 12409308 | Whereas PMA activated protein kinase C isoforms and IKKbeta, TNFalpha activated neither. |
| 5450 | 12409308 | On the other hand, both PMA and TNFalpha activated the c-Jun N-terminal kinase (JNK), which has been reported to directly phosphorylate IRS1 Ser-307. |
| 5451 | 12409308 | SP600125, a JNK inhibitor, prevented PMA and TNFalpha-induced IRS1 Ser-307 phosphorylation. |
| 5452 | 12409308 | Finally, salicylic acid inhibited JNK activation induced by both PMA and TNFalpha. |
| 5453 | 12409308 | Taken together, these observations suggest that salicylic acid can reverse the inhibitory effects of TNFalpha on insulin signaling via an IKKbeta-independent mechanism(s), potentially involving the inhibition of JNK activation. |
| 5454 | 12409308 | The role of JNK in salicylic acid-mediated insulin sensitization, however, requires further validation because the JNK inhibitor SP600125 appears to have other nonspecific activity in addition to inhibiting JNK activity. |
| 5455 | 12409308 | Salicylic acid reverses phorbol 12-myristate-13-acetate (PMA)- and tumor necrosis factor alpha (TNFalpha)-induced insulin receptor substrate 1 (IRS1) serine 307 phosphorylation and insulin resistance in human embryonic kidney 293 (HEK293) cells. |
| 5456 | 12409308 | Although it has been suggested that salicylates sensitize insulin action by inhibiting IkappaB kinase beta (IKKbeta), the detailed mechanisms remain unclear. |
| 5457 | 12409308 | Protein kinase C isoforms and tumor necrosis factor alpha (TNFalpha) signaling pathways are well described mediators of insulin resistance; they are implicated in the activation of IKKbeta and the subsequent inhibition of proximal insulin signaling via insulin receptor substrate 1 (IRS1) and Akt. |
| 5458 | 12409308 | This study investigated the effect of salicylic acid on phorbol 12-myristate 13-acetate (PMA)- and TNFalpha-induced insulin resistance in a human embryonic kidney 293 (HEK293) cell line stably expressing recombinant human IRS1. |
| 5459 | 12409308 | The results showed that both PMA and TNFalpha inhibited insulin-induced Akt phosphorylation and promoted IRS1 phosphorylation on Ser-307. |
| 5460 | 12409308 | Salicylic acid pretreatment completely reversed the effects of PMA and TNFalpha on both Akt and IRS1. |
| 5461 | 12409308 | Whereas PMA activated protein kinase C isoforms and IKKbeta, TNFalpha activated neither. |
| 5462 | 12409308 | On the other hand, both PMA and TNFalpha activated the c-Jun N-terminal kinase (JNK), which has been reported to directly phosphorylate IRS1 Ser-307. |
| 5463 | 12409308 | SP600125, a JNK inhibitor, prevented PMA and TNFalpha-induced IRS1 Ser-307 phosphorylation. |
| 5464 | 12409308 | Finally, salicylic acid inhibited JNK activation induced by both PMA and TNFalpha. |
| 5465 | 12409308 | Taken together, these observations suggest that salicylic acid can reverse the inhibitory effects of TNFalpha on insulin signaling via an IKKbeta-independent mechanism(s), potentially involving the inhibition of JNK activation. |
| 5466 | 12409308 | The role of JNK in salicylic acid-mediated insulin sensitization, however, requires further validation because the JNK inhibitor SP600125 appears to have other nonspecific activity in addition to inhibiting JNK activity. |
| 5467 | 12409308 | Salicylic acid reverses phorbol 12-myristate-13-acetate (PMA)- and tumor necrosis factor alpha (TNFalpha)-induced insulin receptor substrate 1 (IRS1) serine 307 phosphorylation and insulin resistance in human embryonic kidney 293 (HEK293) cells. |
| 5468 | 12409308 | Although it has been suggested that salicylates sensitize insulin action by inhibiting IkappaB kinase beta (IKKbeta), the detailed mechanisms remain unclear. |
| 5469 | 12409308 | Protein kinase C isoforms and tumor necrosis factor alpha (TNFalpha) signaling pathways are well described mediators of insulin resistance; they are implicated in the activation of IKKbeta and the subsequent inhibition of proximal insulin signaling via insulin receptor substrate 1 (IRS1) and Akt. |
| 5470 | 12409308 | This study investigated the effect of salicylic acid on phorbol 12-myristate 13-acetate (PMA)- and TNFalpha-induced insulin resistance in a human embryonic kidney 293 (HEK293) cell line stably expressing recombinant human IRS1. |
| 5471 | 12409308 | The results showed that both PMA and TNFalpha inhibited insulin-induced Akt phosphorylation and promoted IRS1 phosphorylation on Ser-307. |
| 5472 | 12409308 | Salicylic acid pretreatment completely reversed the effects of PMA and TNFalpha on both Akt and IRS1. |
| 5473 | 12409308 | Whereas PMA activated protein kinase C isoforms and IKKbeta, TNFalpha activated neither. |
| 5474 | 12409308 | On the other hand, both PMA and TNFalpha activated the c-Jun N-terminal kinase (JNK), which has been reported to directly phosphorylate IRS1 Ser-307. |
| 5475 | 12409308 | SP600125, a JNK inhibitor, prevented PMA and TNFalpha-induced IRS1 Ser-307 phosphorylation. |
| 5476 | 12409308 | Finally, salicylic acid inhibited JNK activation induced by both PMA and TNFalpha. |
| 5477 | 12409308 | Taken together, these observations suggest that salicylic acid can reverse the inhibitory effects of TNFalpha on insulin signaling via an IKKbeta-independent mechanism(s), potentially involving the inhibition of JNK activation. |
| 5478 | 12409308 | The role of JNK in salicylic acid-mediated insulin sensitization, however, requires further validation because the JNK inhibitor SP600125 appears to have other nonspecific activity in addition to inhibiting JNK activity. |
| 5479 | 12409308 | Salicylic acid reverses phorbol 12-myristate-13-acetate (PMA)- and tumor necrosis factor alpha (TNFalpha)-induced insulin receptor substrate 1 (IRS1) serine 307 phosphorylation and insulin resistance in human embryonic kidney 293 (HEK293) cells. |
| 5480 | 12409308 | Although it has been suggested that salicylates sensitize insulin action by inhibiting IkappaB kinase beta (IKKbeta), the detailed mechanisms remain unclear. |
| 5481 | 12409308 | Protein kinase C isoforms and tumor necrosis factor alpha (TNFalpha) signaling pathways are well described mediators of insulin resistance; they are implicated in the activation of IKKbeta and the subsequent inhibition of proximal insulin signaling via insulin receptor substrate 1 (IRS1) and Akt. |
| 5482 | 12409308 | This study investigated the effect of salicylic acid on phorbol 12-myristate 13-acetate (PMA)- and TNFalpha-induced insulin resistance in a human embryonic kidney 293 (HEK293) cell line stably expressing recombinant human IRS1. |
| 5483 | 12409308 | The results showed that both PMA and TNFalpha inhibited insulin-induced Akt phosphorylation and promoted IRS1 phosphorylation on Ser-307. |
| 5484 | 12409308 | Salicylic acid pretreatment completely reversed the effects of PMA and TNFalpha on both Akt and IRS1. |
| 5485 | 12409308 | Whereas PMA activated protein kinase C isoforms and IKKbeta, TNFalpha activated neither. |
| 5486 | 12409308 | On the other hand, both PMA and TNFalpha activated the c-Jun N-terminal kinase (JNK), which has been reported to directly phosphorylate IRS1 Ser-307. |
| 5487 | 12409308 | SP600125, a JNK inhibitor, prevented PMA and TNFalpha-induced IRS1 Ser-307 phosphorylation. |
| 5488 | 12409308 | Finally, salicylic acid inhibited JNK activation induced by both PMA and TNFalpha. |
| 5489 | 12409308 | Taken together, these observations suggest that salicylic acid can reverse the inhibitory effects of TNFalpha on insulin signaling via an IKKbeta-independent mechanism(s), potentially involving the inhibition of JNK activation. |
| 5490 | 12409308 | The role of JNK in salicylic acid-mediated insulin sensitization, however, requires further validation because the JNK inhibitor SP600125 appears to have other nonspecific activity in addition to inhibiting JNK activity. |
| 5491 | 12409308 | Salicylic acid reverses phorbol 12-myristate-13-acetate (PMA)- and tumor necrosis factor alpha (TNFalpha)-induced insulin receptor substrate 1 (IRS1) serine 307 phosphorylation and insulin resistance in human embryonic kidney 293 (HEK293) cells. |
| 5492 | 12409308 | Although it has been suggested that salicylates sensitize insulin action by inhibiting IkappaB kinase beta (IKKbeta), the detailed mechanisms remain unclear. |
| 5493 | 12409308 | Protein kinase C isoforms and tumor necrosis factor alpha (TNFalpha) signaling pathways are well described mediators of insulin resistance; they are implicated in the activation of IKKbeta and the subsequent inhibition of proximal insulin signaling via insulin receptor substrate 1 (IRS1) and Akt. |
| 5494 | 12409308 | This study investigated the effect of salicylic acid on phorbol 12-myristate 13-acetate (PMA)- and TNFalpha-induced insulin resistance in a human embryonic kidney 293 (HEK293) cell line stably expressing recombinant human IRS1. |
| 5495 | 12409308 | The results showed that both PMA and TNFalpha inhibited insulin-induced Akt phosphorylation and promoted IRS1 phosphorylation on Ser-307. |
| 5496 | 12409308 | Salicylic acid pretreatment completely reversed the effects of PMA and TNFalpha on both Akt and IRS1. |
| 5497 | 12409308 | Whereas PMA activated protein kinase C isoforms and IKKbeta, TNFalpha activated neither. |
| 5498 | 12409308 | On the other hand, both PMA and TNFalpha activated the c-Jun N-terminal kinase (JNK), which has been reported to directly phosphorylate IRS1 Ser-307. |
| 5499 | 12409308 | SP600125, a JNK inhibitor, prevented PMA and TNFalpha-induced IRS1 Ser-307 phosphorylation. |
| 5500 | 12409308 | Finally, salicylic acid inhibited JNK activation induced by both PMA and TNFalpha. |
| 5501 | 12409308 | Taken together, these observations suggest that salicylic acid can reverse the inhibitory effects of TNFalpha on insulin signaling via an IKKbeta-independent mechanism(s), potentially involving the inhibition of JNK activation. |
| 5502 | 12409308 | The role of JNK in salicylic acid-mediated insulin sensitization, however, requires further validation because the JNK inhibitor SP600125 appears to have other nonspecific activity in addition to inhibiting JNK activity. |
| 5503 | 12409308 | Salicylic acid reverses phorbol 12-myristate-13-acetate (PMA)- and tumor necrosis factor alpha (TNFalpha)-induced insulin receptor substrate 1 (IRS1) serine 307 phosphorylation and insulin resistance in human embryonic kidney 293 (HEK293) cells. |
| 5504 | 12409308 | Although it has been suggested that salicylates sensitize insulin action by inhibiting IkappaB kinase beta (IKKbeta), the detailed mechanisms remain unclear. |
| 5505 | 12409308 | Protein kinase C isoforms and tumor necrosis factor alpha (TNFalpha) signaling pathways are well described mediators of insulin resistance; they are implicated in the activation of IKKbeta and the subsequent inhibition of proximal insulin signaling via insulin receptor substrate 1 (IRS1) and Akt. |
| 5506 | 12409308 | This study investigated the effect of salicylic acid on phorbol 12-myristate 13-acetate (PMA)- and TNFalpha-induced insulin resistance in a human embryonic kidney 293 (HEK293) cell line stably expressing recombinant human IRS1. |
| 5507 | 12409308 | The results showed that both PMA and TNFalpha inhibited insulin-induced Akt phosphorylation and promoted IRS1 phosphorylation on Ser-307. |
| 5508 | 12409308 | Salicylic acid pretreatment completely reversed the effects of PMA and TNFalpha on both Akt and IRS1. |
| 5509 | 12409308 | Whereas PMA activated protein kinase C isoforms and IKKbeta, TNFalpha activated neither. |
| 5510 | 12409308 | On the other hand, both PMA and TNFalpha activated the c-Jun N-terminal kinase (JNK), which has been reported to directly phosphorylate IRS1 Ser-307. |
| 5511 | 12409308 | SP600125, a JNK inhibitor, prevented PMA and TNFalpha-induced IRS1 Ser-307 phosphorylation. |
| 5512 | 12409308 | Finally, salicylic acid inhibited JNK activation induced by both PMA and TNFalpha. |
| 5513 | 12409308 | Taken together, these observations suggest that salicylic acid can reverse the inhibitory effects of TNFalpha on insulin signaling via an IKKbeta-independent mechanism(s), potentially involving the inhibition of JNK activation. |
| 5514 | 12409308 | The role of JNK in salicylic acid-mediated insulin sensitization, however, requires further validation because the JNK inhibitor SP600125 appears to have other nonspecific activity in addition to inhibiting JNK activity. |
| 5515 | 12409500 | Gliclazide increases insulin receptor tyrosine phosphorylation but not p38 phosphorylation in insulin-resistant skeletal muscle cells. |
| 5516 | 12409500 | Although insulin receptor substrate-1 tyrosine phosphorylation was unaffected by gliclazide treatment, phosphatidylinositol 3-kinase activity was partially restored by treatment with gliclazide. |
| 5517 | 12409500 | Further investigations into the mitogen-activated protein kinase (MAPK) pathway revealed that insulin-stimulated p38 phosphorylation was impaired, as compared with extracellular-signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK), which were phosphorylated normally in insulin-resistant cells. |
| 5518 | 12409500 | Treatment with gliclazide could not restore p38 phosphorylation in insulin-resistant cells. |
| 5519 | 12409500 | We propose that gliclazide can regulate part of the insulin signaling in insulin-resistant skeletal muscle, and p38 could be a potential therapeutic target for glucose uptake to treat insulin resistance. |
| 5520 | 12417588 | c-Jun N-terminal kinase (JNK) mediates feedback inhibition of the insulin signaling cascade. |
| 5521 | 12417588 | Activation of the c-Jun N-terminal kinase (JNK) by proinflammatory cytokines inhibits insulin signaling, at least in part, by stimulating phosphorylation of rat/mouse insulin receptor substrate 1 (Irs1) at Ser(307) (Ser(312) in human IRS1). |
| 5522 | 12417588 | Here we show that JNK mediated feedback inhibition of the insulin signal in mouse embryo fibroblasts, 3T3-L1 adipocytes, and 32D(IR) cells. |
| 5523 | 12417588 | Insulin stimulation of JNK activity required phosphatidylinositol 3-kinase and Grb2 signaling. |
| 5524 | 12417588 | Moreover, activation of JNK by insulin was inhibited by a cell-permeable peptide that disrupted the interaction of JNK with cellular proteins. |
| 5525 | 12417588 | However, the direct binding of JNK to Irs1 was not required for its activation by insulin, whereas direct binding was required for Ser(307) phosphorylation of Irs1. |
| 5526 | 12417588 | Insulin-stimulated Ser(307) phosphorylation was reduced 80% in cells lacking JNK1 and JNK2 or in cells expressing a mutant Irs1 protein lacking the JNK binding site. |
| 5527 | 12417588 | Reduced Ser(307) phosphorylation was directly related to increased insulin-stimulated tyrosine phosphorylation, Akt phosphorylation, and glucose uptake. |
| 5528 | 12417588 | These results support the hypothesis that JNK is a negative feedback regulator of insulin action by phosphorylating Ser(307) in Irs1. |
| 5529 | 12417588 | c-Jun N-terminal kinase (JNK) mediates feedback inhibition of the insulin signaling cascade. |
| 5530 | 12417588 | Activation of the c-Jun N-terminal kinase (JNK) by proinflammatory cytokines inhibits insulin signaling, at least in part, by stimulating phosphorylation of rat/mouse insulin receptor substrate 1 (Irs1) at Ser(307) (Ser(312) in human IRS1). |
| 5531 | 12417588 | Here we show that JNK mediated feedback inhibition of the insulin signal in mouse embryo fibroblasts, 3T3-L1 adipocytes, and 32D(IR) cells. |
| 5532 | 12417588 | Insulin stimulation of JNK activity required phosphatidylinositol 3-kinase and Grb2 signaling. |
| 5533 | 12417588 | Moreover, activation of JNK by insulin was inhibited by a cell-permeable peptide that disrupted the interaction of JNK with cellular proteins. |
| 5534 | 12417588 | However, the direct binding of JNK to Irs1 was not required for its activation by insulin, whereas direct binding was required for Ser(307) phosphorylation of Irs1. |
| 5535 | 12417588 | Insulin-stimulated Ser(307) phosphorylation was reduced 80% in cells lacking JNK1 and JNK2 or in cells expressing a mutant Irs1 protein lacking the JNK binding site. |
| 5536 | 12417588 | Reduced Ser(307) phosphorylation was directly related to increased insulin-stimulated tyrosine phosphorylation, Akt phosphorylation, and glucose uptake. |
| 5537 | 12417588 | These results support the hypothesis that JNK is a negative feedback regulator of insulin action by phosphorylating Ser(307) in Irs1. |
| 5538 | 12417588 | c-Jun N-terminal kinase (JNK) mediates feedback inhibition of the insulin signaling cascade. |
| 5539 | 12417588 | Activation of the c-Jun N-terminal kinase (JNK) by proinflammatory cytokines inhibits insulin signaling, at least in part, by stimulating phosphorylation of rat/mouse insulin receptor substrate 1 (Irs1) at Ser(307) (Ser(312) in human IRS1). |
| 5540 | 12417588 | Here we show that JNK mediated feedback inhibition of the insulin signal in mouse embryo fibroblasts, 3T3-L1 adipocytes, and 32D(IR) cells. |
| 5541 | 12417588 | Insulin stimulation of JNK activity required phosphatidylinositol 3-kinase and Grb2 signaling. |
| 5542 | 12417588 | Moreover, activation of JNK by insulin was inhibited by a cell-permeable peptide that disrupted the interaction of JNK with cellular proteins. |
| 5543 | 12417588 | However, the direct binding of JNK to Irs1 was not required for its activation by insulin, whereas direct binding was required for Ser(307) phosphorylation of Irs1. |
| 5544 | 12417588 | Insulin-stimulated Ser(307) phosphorylation was reduced 80% in cells lacking JNK1 and JNK2 or in cells expressing a mutant Irs1 protein lacking the JNK binding site. |
| 5545 | 12417588 | Reduced Ser(307) phosphorylation was directly related to increased insulin-stimulated tyrosine phosphorylation, Akt phosphorylation, and glucose uptake. |
| 5546 | 12417588 | These results support the hypothesis that JNK is a negative feedback regulator of insulin action by phosphorylating Ser(307) in Irs1. |
| 5547 | 12417588 | c-Jun N-terminal kinase (JNK) mediates feedback inhibition of the insulin signaling cascade. |
| 5548 | 12417588 | Activation of the c-Jun N-terminal kinase (JNK) by proinflammatory cytokines inhibits insulin signaling, at least in part, by stimulating phosphorylation of rat/mouse insulin receptor substrate 1 (Irs1) at Ser(307) (Ser(312) in human IRS1). |
| 5549 | 12417588 | Here we show that JNK mediated feedback inhibition of the insulin signal in mouse embryo fibroblasts, 3T3-L1 adipocytes, and 32D(IR) cells. |
| 5550 | 12417588 | Insulin stimulation of JNK activity required phosphatidylinositol 3-kinase and Grb2 signaling. |
| 5551 | 12417588 | Moreover, activation of JNK by insulin was inhibited by a cell-permeable peptide that disrupted the interaction of JNK with cellular proteins. |
| 5552 | 12417588 | However, the direct binding of JNK to Irs1 was not required for its activation by insulin, whereas direct binding was required for Ser(307) phosphorylation of Irs1. |
| 5553 | 12417588 | Insulin-stimulated Ser(307) phosphorylation was reduced 80% in cells lacking JNK1 and JNK2 or in cells expressing a mutant Irs1 protein lacking the JNK binding site. |
| 5554 | 12417588 | Reduced Ser(307) phosphorylation was directly related to increased insulin-stimulated tyrosine phosphorylation, Akt phosphorylation, and glucose uptake. |
| 5555 | 12417588 | These results support the hypothesis that JNK is a negative feedback regulator of insulin action by phosphorylating Ser(307) in Irs1. |
| 5556 | 12453887 | Identification of the insulin-regulated interaction of phosphodiesterase 3B with 14-3-3 beta protein. |
| 5557 | 12453887 | Insulin-induced phosphorylation and activation of PDE3B is phosphatidylinositol 3-kinase (PI3-K) and Akt dependent, but the precise mechanism of PDE3B activation is not fully understood. |
| 5558 | 12453887 | The glutathione S-transferase (GST)-tagged 14-3-3 beta interacts with endogenous PDE3B of rat adipocytes, and this interaction is enhanced when adipocytes are treated with insulin. |
| 5559 | 12453887 | Synthetic 15 amino acid peptides of rat PDE3B containing phosphorylated Ser-279 or -302 inhibit this interaction, indicating that the insulin-regulated phosphorylation of these serine residues is involved. |
| 5560 | 12453887 | Because insulin receptor substrate-1 also associates with 14-3-3, the dimeric 14-3-3 beta could function as a scaffolding protein in the activation of PDE3B by insulin. |
| 5561 | 12453891 | Interleukin-6 induces cellular insulin resistance in hepatocytes. |
| 5562 | 12453891 | Interleukin (IL)-6 is one of several proinflammatory cytokines that have been associated with insulin resistance and type 2 diabetes. |
| 5563 | 12453891 | Nonetheless, little evidence supports a direct role for IL-6 in mediating insulin resistance. |
| 5564 | 12453891 | Here, we present data that IL-6 can inhibit insulin receptor (IR) signal transduction and insulin action in both primary mouse hepatocytes and the human hepatocarcinoma cell line, HepG2. |
| 5565 | 12453891 | The IL-6 effect is characterized by a decreased tyrosine phosphorylation of IR substrate (IRS)-1 and decreased association of the p85 subunit of phosphatidylinositol 3-kinase with IRS-1 in response to physiologic insulin levels. |
| 5566 | 12453891 | In addition, insulin-dependent activation of Akt, important in mediating insulin's downstream metabolic actions, is markedly inhibited by IL-6 treatment. |
| 5567 | 12453891 | Finally, a 1.5-h preincubation of primary hepatocytes with IL-6 inhibits insulin-induced glycogen synthesis by 75%. |
| 5568 | 12453891 | These data suggest that IL-6 plays a direct role in insulin resistance at the cellular level in both primary hepatocytes and HepG2 cell lines and may contribute to insulin resistance and type 2 diabetes. |
| 5569 | 12475767 | Increased insulin resistance in obese children who have both 972 IRS-1 and 1057 IRS-2 polymorphisms. |
| 5570 | 12475767 | In two cohorts of 174 and 165 obese Caucasian children, we measured insulin sensitivity and genotyped insulin receptor substrate IRS-1 and IRS-2 genes for the Arg972Gly and the Asp1057Gly variants, respectively. |
| 5571 | 12475767 | Because IRS-1 and IRS-2 have complementary roles in insulin signaling, we classified the genotypes in three categories: those with none of the variants in IRS-1 or IRS-2, those with one variant in IRS-1 or IRS-2, and those with variants in both IRS-1 and 2 proteins. |
| 5572 | 12475767 | The obese children with either the IRS-1 or IRS-2 variant had a mean insulin sensitivity index (2.9 +/- 0.2 in cohort 1, 2.7 +/- 0.1 in cohort 2) only slightly lower than the children having no variant in either gene (3.1 +/- 0.2 and 3.5 +/- 0.3, respectively). |
| 5573 | 12475767 | However, patients having variant alleles in both IRS-1 and IRS-2 genes showed a 25-35% decrease in sensitivity (2.3 +/- 0.2 and 2.0 +/- 0.2, respectively) when compared with nonvariant homozygotes (P < 0.001). |
| 5574 | 12475767 | These observations are reminiscent of the insulin sensitivity phenotypes in double IRS-1(+/-) IRS-2(+/-) heterozygous knockout mice. |
| 5575 | 12475767 | Increased insulin resistance in obese children who have both 972 IRS-1 and 1057 IRS-2 polymorphisms. |
| 5576 | 12475767 | In two cohorts of 174 and 165 obese Caucasian children, we measured insulin sensitivity and genotyped insulin receptor substrate IRS-1 and IRS-2 genes for the Arg972Gly and the Asp1057Gly variants, respectively. |
| 5577 | 12475767 | Because IRS-1 and IRS-2 have complementary roles in insulin signaling, we classified the genotypes in three categories: those with none of the variants in IRS-1 or IRS-2, those with one variant in IRS-1 or IRS-2, and those with variants in both IRS-1 and 2 proteins. |
| 5578 | 12475767 | The obese children with either the IRS-1 or IRS-2 variant had a mean insulin sensitivity index (2.9 +/- 0.2 in cohort 1, 2.7 +/- 0.1 in cohort 2) only slightly lower than the children having no variant in either gene (3.1 +/- 0.2 and 3.5 +/- 0.3, respectively). |
| 5579 | 12475767 | However, patients having variant alleles in both IRS-1 and IRS-2 genes showed a 25-35% decrease in sensitivity (2.3 +/- 0.2 and 2.0 +/- 0.2, respectively) when compared with nonvariant homozygotes (P < 0.001). |
| 5580 | 12475767 | These observations are reminiscent of the insulin sensitivity phenotypes in double IRS-1(+/-) IRS-2(+/-) heterozygous knockout mice. |
| 5581 | 12475767 | Increased insulin resistance in obese children who have both 972 IRS-1 and 1057 IRS-2 polymorphisms. |
| 5582 | 12475767 | In two cohorts of 174 and 165 obese Caucasian children, we measured insulin sensitivity and genotyped insulin receptor substrate IRS-1 and IRS-2 genes for the Arg972Gly and the Asp1057Gly variants, respectively. |
| 5583 | 12475767 | Because IRS-1 and IRS-2 have complementary roles in insulin signaling, we classified the genotypes in three categories: those with none of the variants in IRS-1 or IRS-2, those with one variant in IRS-1 or IRS-2, and those with variants in both IRS-1 and 2 proteins. |
| 5584 | 12475767 | The obese children with either the IRS-1 or IRS-2 variant had a mean insulin sensitivity index (2.9 +/- 0.2 in cohort 1, 2.7 +/- 0.1 in cohort 2) only slightly lower than the children having no variant in either gene (3.1 +/- 0.2 and 3.5 +/- 0.3, respectively). |
| 5585 | 12475767 | However, patients having variant alleles in both IRS-1 and IRS-2 genes showed a 25-35% decrease in sensitivity (2.3 +/- 0.2 and 2.0 +/- 0.2, respectively) when compared with nonvariant homozygotes (P < 0.001). |
| 5586 | 12475767 | These observations are reminiscent of the insulin sensitivity phenotypes in double IRS-1(+/-) IRS-2(+/-) heterozygous knockout mice. |
| 5587 | 12475767 | Increased insulin resistance in obese children who have both 972 IRS-1 and 1057 IRS-2 polymorphisms. |
| 5588 | 12475767 | In two cohorts of 174 and 165 obese Caucasian children, we measured insulin sensitivity and genotyped insulin receptor substrate IRS-1 and IRS-2 genes for the Arg972Gly and the Asp1057Gly variants, respectively. |
| 5589 | 12475767 | Because IRS-1 and IRS-2 have complementary roles in insulin signaling, we classified the genotypes in three categories: those with none of the variants in IRS-1 or IRS-2, those with one variant in IRS-1 or IRS-2, and those with variants in both IRS-1 and 2 proteins. |
| 5590 | 12475767 | The obese children with either the IRS-1 or IRS-2 variant had a mean insulin sensitivity index (2.9 +/- 0.2 in cohort 1, 2.7 +/- 0.1 in cohort 2) only slightly lower than the children having no variant in either gene (3.1 +/- 0.2 and 3.5 +/- 0.3, respectively). |
| 5591 | 12475767 | However, patients having variant alleles in both IRS-1 and IRS-2 genes showed a 25-35% decrease in sensitivity (2.3 +/- 0.2 and 2.0 +/- 0.2, respectively) when compared with nonvariant homozygotes (P < 0.001). |
| 5592 | 12475767 | These observations are reminiscent of the insulin sensitivity phenotypes in double IRS-1(+/-) IRS-2(+/-) heterozygous knockout mice. |
| 5593 | 12475767 | Increased insulin resistance in obese children who have both 972 IRS-1 and 1057 IRS-2 polymorphisms. |
| 5594 | 12475767 | In two cohorts of 174 and 165 obese Caucasian children, we measured insulin sensitivity and genotyped insulin receptor substrate IRS-1 and IRS-2 genes for the Arg972Gly and the Asp1057Gly variants, respectively. |
| 5595 | 12475767 | Because IRS-1 and IRS-2 have complementary roles in insulin signaling, we classified the genotypes in three categories: those with none of the variants in IRS-1 or IRS-2, those with one variant in IRS-1 or IRS-2, and those with variants in both IRS-1 and 2 proteins. |
| 5596 | 12475767 | The obese children with either the IRS-1 or IRS-2 variant had a mean insulin sensitivity index (2.9 +/- 0.2 in cohort 1, 2.7 +/- 0.1 in cohort 2) only slightly lower than the children having no variant in either gene (3.1 +/- 0.2 and 3.5 +/- 0.3, respectively). |
| 5597 | 12475767 | However, patients having variant alleles in both IRS-1 and IRS-2 genes showed a 25-35% decrease in sensitivity (2.3 +/- 0.2 and 2.0 +/- 0.2, respectively) when compared with nonvariant homozygotes (P < 0.001). |
| 5598 | 12475767 | These observations are reminiscent of the insulin sensitivity phenotypes in double IRS-1(+/-) IRS-2(+/-) heterozygous knockout mice. |
| 5599 | 12475767 | Increased insulin resistance in obese children who have both 972 IRS-1 and 1057 IRS-2 polymorphisms. |
| 5600 | 12475767 | In two cohorts of 174 and 165 obese Caucasian children, we measured insulin sensitivity and genotyped insulin receptor substrate IRS-1 and IRS-2 genes for the Arg972Gly and the Asp1057Gly variants, respectively. |
| 5601 | 12475767 | Because IRS-1 and IRS-2 have complementary roles in insulin signaling, we classified the genotypes in three categories: those with none of the variants in IRS-1 or IRS-2, those with one variant in IRS-1 or IRS-2, and those with variants in both IRS-1 and 2 proteins. |
| 5602 | 12475767 | The obese children with either the IRS-1 or IRS-2 variant had a mean insulin sensitivity index (2.9 +/- 0.2 in cohort 1, 2.7 +/- 0.1 in cohort 2) only slightly lower than the children having no variant in either gene (3.1 +/- 0.2 and 3.5 +/- 0.3, respectively). |
| 5603 | 12475767 | However, patients having variant alleles in both IRS-1 and IRS-2 genes showed a 25-35% decrease in sensitivity (2.3 +/- 0.2 and 2.0 +/- 0.2, respectively) when compared with nonvariant homozygotes (P < 0.001). |
| 5604 | 12475767 | These observations are reminiscent of the insulin sensitivity phenotypes in double IRS-1(+/-) IRS-2(+/-) heterozygous knockout mice. |
| 5605 | 12475786 | More recently, it has become apparent that the beta-cell also has many of the elements of the insulin receptor signal transduction pathway, including the insulin receptor and insulin receptor substrate (IRS) proteins 1 and 2. |
| 5606 | 12475786 | Studies with transgenic models have shown that the beta-cell-selective insulin receptor knockout and the IRS-1 knockout lead to reduced glucose-induced insulin secretion. |
| 5607 | 12475786 | Overexpression of the insulin receptor and IRS-1 in beta-cells results in increased insulin secretion and increased cytosolic Ca(2+). |
| 5608 | 12475786 | More recently, it has become apparent that the beta-cell also has many of the elements of the insulin receptor signal transduction pathway, including the insulin receptor and insulin receptor substrate (IRS) proteins 1 and 2. |
| 5609 | 12475786 | Studies with transgenic models have shown that the beta-cell-selective insulin receptor knockout and the IRS-1 knockout lead to reduced glucose-induced insulin secretion. |
| 5610 | 12475786 | Overexpression of the insulin receptor and IRS-1 in beta-cells results in increased insulin secretion and increased cytosolic Ca(2+). |
| 5611 | 12475786 | More recently, it has become apparent that the beta-cell also has many of the elements of the insulin receptor signal transduction pathway, including the insulin receptor and insulin receptor substrate (IRS) proteins 1 and 2. |
| 5612 | 12475786 | Studies with transgenic models have shown that the beta-cell-selective insulin receptor knockout and the IRS-1 knockout lead to reduced glucose-induced insulin secretion. |
| 5613 | 12475786 | Overexpression of the insulin receptor and IRS-1 in beta-cells results in increased insulin secretion and increased cytosolic Ca(2+). |
| 5614 | 12502742 | Based on the phenotypes of knockout mice and cell lines, as well as pathway-specific analysis, the insulin receptor substrates IRS-1, IRS-2, IRS-3, and IRS-4 have been shown to play unique roles in insulin signal transduction. |
| 5615 | 12502742 | To investigate possible functional complementarity within the IRS family, we generated mice with double knockout of the genes for IRS-1/IRS-3 and IRS-1/IRS-4. |
| 5616 | 12502742 | Mice with a combined deficiency of IRS-1 and IRS-4 showed no differences from Irs1(-/-) mice with respect to growth and glucose homeostasis. |
| 5617 | 12502742 | In contrast, mice with a combined deficiency of IRS-1 and IRS-3 developed early-onset severe lipoatrophy associated with marked hyperglycemia, hyperinsulinemia, and insulin resistance. |
| 5618 | 12502742 | Based on the phenotypes of knockout mice and cell lines, as well as pathway-specific analysis, the insulin receptor substrates IRS-1, IRS-2, IRS-3, and IRS-4 have been shown to play unique roles in insulin signal transduction. |
| 5619 | 12502742 | To investigate possible functional complementarity within the IRS family, we generated mice with double knockout of the genes for IRS-1/IRS-3 and IRS-1/IRS-4. |
| 5620 | 12502742 | Mice with a combined deficiency of IRS-1 and IRS-4 showed no differences from Irs1(-/-) mice with respect to growth and glucose homeostasis. |
| 5621 | 12502742 | In contrast, mice with a combined deficiency of IRS-1 and IRS-3 developed early-onset severe lipoatrophy associated with marked hyperglycemia, hyperinsulinemia, and insulin resistance. |
| 5622 | 12502742 | Based on the phenotypes of knockout mice and cell lines, as well as pathway-specific analysis, the insulin receptor substrates IRS-1, IRS-2, IRS-3, and IRS-4 have been shown to play unique roles in insulin signal transduction. |
| 5623 | 12502742 | To investigate possible functional complementarity within the IRS family, we generated mice with double knockout of the genes for IRS-1/IRS-3 and IRS-1/IRS-4. |
| 5624 | 12502742 | Mice with a combined deficiency of IRS-1 and IRS-4 showed no differences from Irs1(-/-) mice with respect to growth and glucose homeostasis. |
| 5625 | 12502742 | In contrast, mice with a combined deficiency of IRS-1 and IRS-3 developed early-onset severe lipoatrophy associated with marked hyperglycemia, hyperinsulinemia, and insulin resistance. |
| 5626 | 12502742 | Based on the phenotypes of knockout mice and cell lines, as well as pathway-specific analysis, the insulin receptor substrates IRS-1, IRS-2, IRS-3, and IRS-4 have been shown to play unique roles in insulin signal transduction. |
| 5627 | 12502742 | To investigate possible functional complementarity within the IRS family, we generated mice with double knockout of the genes for IRS-1/IRS-3 and IRS-1/IRS-4. |
| 5628 | 12502742 | Mice with a combined deficiency of IRS-1 and IRS-4 showed no differences from Irs1(-/-) mice with respect to growth and glucose homeostasis. |
| 5629 | 12502742 | In contrast, mice with a combined deficiency of IRS-1 and IRS-3 developed early-onset severe lipoatrophy associated with marked hyperglycemia, hyperinsulinemia, and insulin resistance. |
| 5630 | 12502902 | In vivo administration of glucosamine inhibited phosphatidylinositol 3-kinase activity without affecting tyrosine phosphorylation of the insulin receptor or insulin receptor substrate in rat adipocytes. |
| 5631 | 12502902 | Glucosamine had no effect on the insulin-stimulated tyrosine phosphorylation of the insulin receptor and insulin receptor substrate (IRS)-1. |
| 5632 | 12502902 | Glucosamine infusion also inhibited insulin-stimulated PI 3-kinase activity associated with IRS-1, 2, 3 by 30%, 43%, and 44%, respectively. |
| 5633 | 12502902 | There was no difference in the association of the 85kDa subunit of PI 3-kinase with the IRS-1 and IRS-2 protein. |
| 5634 | 12502902 | When we measured the kinase activity of protein kinase C (PKC) lamda, which is the downstream effector of PI 3-kinase in isolated adipocytes, we found that glucosamine inhibited insulin stimulated PKClamda kinase activity by 33%. |
| 5635 | 12502902 | In vivo administration of glucosamine inhibited phosphatidylinositol 3-kinase activity without affecting tyrosine phosphorylation of the insulin receptor or insulin receptor substrate in rat adipocytes. |
| 5636 | 12502902 | Glucosamine had no effect on the insulin-stimulated tyrosine phosphorylation of the insulin receptor and insulin receptor substrate (IRS)-1. |
| 5637 | 12502902 | Glucosamine infusion also inhibited insulin-stimulated PI 3-kinase activity associated with IRS-1, 2, 3 by 30%, 43%, and 44%, respectively. |
| 5638 | 12502902 | There was no difference in the association of the 85kDa subunit of PI 3-kinase with the IRS-1 and IRS-2 protein. |
| 5639 | 12502902 | When we measured the kinase activity of protein kinase C (PKC) lamda, which is the downstream effector of PI 3-kinase in isolated adipocytes, we found that glucosamine inhibited insulin stimulated PKClamda kinase activity by 33%. |
| 5640 | 12504077 | Reduction of protein-tyrosine phosphatase-1B increases insulin signaling in FAO hepatoma cells. |
| 5641 | 12504077 | Protein-tyrosine phosphatase-1B (PTP1B) has been implicated as a negative regulator of insulin signaling. |
| 5642 | 12504077 | PTP1B dephosphorylates the insulin receptor and insulin receptor substrates (IRS-1/2), inhibiting the insulin-signaling pathway. |
| 5643 | 12504077 | PTP1B has been reported to be elevated in diabetes and insulin-resistant states. |
| 5644 | 12504077 | Conversely, PTP1B null mice have increased insulin sensitivity. |
| 5645 | 12504077 | To further investigate the effect of PTP1B reduction on insulin signaling, FAO rat hepatoma cells were transfected, by electroporation, with a specific PTP1B antisense oligonucleotide (ASO), or a control oligonucleotide. |
| 5646 | 12504077 | Reduction of PTP1B expression in FAO cells also caused an increase in insulin-stimulated phosphorylation of PKB and GSK3, without any change in protein expression. |
| 5647 | 12504077 | These results demonstrate that reduction of PTP1B can modulate key insulin signaling events downstream of the insulin receptor. |
| 5648 | 12510059 | Modulation of insulin-stimulated degradation of human insulin receptor substrate-1 by Serine 312 phosphorylation. |
| 5649 | 12510059 | One potential mechanism for this is that Ser/Thr phosphorylation decreases the ability of IRS-1 to be tyrosine-phosphorylated by the insulin receptor. |
| 5650 | 12510059 | An additional mechanism for modulating insulin signaling is via the down-regulation of IRS-1 protein levels. |
| 5651 | 12510059 | Insulin-induced degradation of IRS-1 has been well documented, both in cells as well as in patients with diabetes. |
| 5652 | 12510059 | In the present study we have examined the potential role of different signaling cascades in the insulin-induced degradation of IRS-1. |
| 5653 | 12510059 | Second, knockout cells lacking one of the key effectors of this cascade, the phosphoinositide-dependent kinase-1, were found to be deficient in the insulin-stimulated degradation of IRS-1. |
| 5654 | 12510059 | Conversely, overexpression of this enzyme potentiated insulin-stimulated IRS-1 degradation. |
| 5655 | 12510059 | Third, concurrent with the decrease in IRS-1 degradation, the inhibitors of the phosphatidylinositol 3-kinase and mammalian target of rapamycin also blocked the insulin-stimulated increase in Ser(312) phosphorylation. |
| 5656 | 12510059 | Most important, an IRS-1 mutant in which Ser(312) was changed to alanine was found to be resistant to insulin-stimulated IRS-1 degradation. |
| 5657 | 12510059 | Finally, an inhibitor of c-Jun N-terminal kinase, SP600125, at 10 microm did not block IRS-1 degradation and IRS-1 Ser(312) phosphorylation yet completely blocked insulin-stimulated c-Jun phosphorylation. |
| 5658 | 12510059 | Further, insulin-stimulated c-Jun phosphorylation was not blocked by inhibitors of the phosphatidylinositol 3-kinase and mammalian target of rapamycin, indicating that c-Jun N-terminal kinase is unlikely to be the kinase phosphorylating IRS-1 Ser(312) in response to insulin. |
| 5659 | 12510059 | In summary, our results indicate that the insulin-stimulated degradation of IRS-1 via the phosphatidylinositol 3-kinase pathway is in part dependent upon the Ser(312) phosphorylation of IRS-1. |
| 5660 | 12510059 | Modulation of insulin-stimulated degradation of human insulin receptor substrate-1 by Serine 312 phosphorylation. |
| 5661 | 12510059 | One potential mechanism for this is that Ser/Thr phosphorylation decreases the ability of IRS-1 to be tyrosine-phosphorylated by the insulin receptor. |
| 5662 | 12510059 | An additional mechanism for modulating insulin signaling is via the down-regulation of IRS-1 protein levels. |
| 5663 | 12510059 | Insulin-induced degradation of IRS-1 has been well documented, both in cells as well as in patients with diabetes. |
| 5664 | 12510059 | In the present study we have examined the potential role of different signaling cascades in the insulin-induced degradation of IRS-1. |
| 5665 | 12510059 | Second, knockout cells lacking one of the key effectors of this cascade, the phosphoinositide-dependent kinase-1, were found to be deficient in the insulin-stimulated degradation of IRS-1. |
| 5666 | 12510059 | Conversely, overexpression of this enzyme potentiated insulin-stimulated IRS-1 degradation. |
| 5667 | 12510059 | Third, concurrent with the decrease in IRS-1 degradation, the inhibitors of the phosphatidylinositol 3-kinase and mammalian target of rapamycin also blocked the insulin-stimulated increase in Ser(312) phosphorylation. |
| 5668 | 12510059 | Most important, an IRS-1 mutant in which Ser(312) was changed to alanine was found to be resistant to insulin-stimulated IRS-1 degradation. |
| 5669 | 12510059 | Finally, an inhibitor of c-Jun N-terminal kinase, SP600125, at 10 microm did not block IRS-1 degradation and IRS-1 Ser(312) phosphorylation yet completely blocked insulin-stimulated c-Jun phosphorylation. |
| 5670 | 12510059 | Further, insulin-stimulated c-Jun phosphorylation was not blocked by inhibitors of the phosphatidylinositol 3-kinase and mammalian target of rapamycin, indicating that c-Jun N-terminal kinase is unlikely to be the kinase phosphorylating IRS-1 Ser(312) in response to insulin. |
| 5671 | 12510059 | In summary, our results indicate that the insulin-stimulated degradation of IRS-1 via the phosphatidylinositol 3-kinase pathway is in part dependent upon the Ser(312) phosphorylation of IRS-1. |
| 5672 | 12510059 | Modulation of insulin-stimulated degradation of human insulin receptor substrate-1 by Serine 312 phosphorylation. |
| 5673 | 12510059 | One potential mechanism for this is that Ser/Thr phosphorylation decreases the ability of IRS-1 to be tyrosine-phosphorylated by the insulin receptor. |
| 5674 | 12510059 | An additional mechanism for modulating insulin signaling is via the down-regulation of IRS-1 protein levels. |
| 5675 | 12510059 | Insulin-induced degradation of IRS-1 has been well documented, both in cells as well as in patients with diabetes. |
| 5676 | 12510059 | In the present study we have examined the potential role of different signaling cascades in the insulin-induced degradation of IRS-1. |
| 5677 | 12510059 | Second, knockout cells lacking one of the key effectors of this cascade, the phosphoinositide-dependent kinase-1, were found to be deficient in the insulin-stimulated degradation of IRS-1. |
| 5678 | 12510059 | Conversely, overexpression of this enzyme potentiated insulin-stimulated IRS-1 degradation. |
| 5679 | 12510059 | Third, concurrent with the decrease in IRS-1 degradation, the inhibitors of the phosphatidylinositol 3-kinase and mammalian target of rapamycin also blocked the insulin-stimulated increase in Ser(312) phosphorylation. |
| 5680 | 12510059 | Most important, an IRS-1 mutant in which Ser(312) was changed to alanine was found to be resistant to insulin-stimulated IRS-1 degradation. |
| 5681 | 12510059 | Finally, an inhibitor of c-Jun N-terminal kinase, SP600125, at 10 microm did not block IRS-1 degradation and IRS-1 Ser(312) phosphorylation yet completely blocked insulin-stimulated c-Jun phosphorylation. |
| 5682 | 12510059 | Further, insulin-stimulated c-Jun phosphorylation was not blocked by inhibitors of the phosphatidylinositol 3-kinase and mammalian target of rapamycin, indicating that c-Jun N-terminal kinase is unlikely to be the kinase phosphorylating IRS-1 Ser(312) in response to insulin. |
| 5683 | 12510059 | In summary, our results indicate that the insulin-stimulated degradation of IRS-1 via the phosphatidylinositol 3-kinase pathway is in part dependent upon the Ser(312) phosphorylation of IRS-1. |
| 5684 | 12510059 | Modulation of insulin-stimulated degradation of human insulin receptor substrate-1 by Serine 312 phosphorylation. |
| 5685 | 12510059 | One potential mechanism for this is that Ser/Thr phosphorylation decreases the ability of IRS-1 to be tyrosine-phosphorylated by the insulin receptor. |
| 5686 | 12510059 | An additional mechanism for modulating insulin signaling is via the down-regulation of IRS-1 protein levels. |
| 5687 | 12510059 | Insulin-induced degradation of IRS-1 has been well documented, both in cells as well as in patients with diabetes. |
| 5688 | 12510059 | In the present study we have examined the potential role of different signaling cascades in the insulin-induced degradation of IRS-1. |
| 5689 | 12510059 | Second, knockout cells lacking one of the key effectors of this cascade, the phosphoinositide-dependent kinase-1, were found to be deficient in the insulin-stimulated degradation of IRS-1. |
| 5690 | 12510059 | Conversely, overexpression of this enzyme potentiated insulin-stimulated IRS-1 degradation. |
| 5691 | 12510059 | Third, concurrent with the decrease in IRS-1 degradation, the inhibitors of the phosphatidylinositol 3-kinase and mammalian target of rapamycin also blocked the insulin-stimulated increase in Ser(312) phosphorylation. |
| 5692 | 12510059 | Most important, an IRS-1 mutant in which Ser(312) was changed to alanine was found to be resistant to insulin-stimulated IRS-1 degradation. |
| 5693 | 12510059 | Finally, an inhibitor of c-Jun N-terminal kinase, SP600125, at 10 microm did not block IRS-1 degradation and IRS-1 Ser(312) phosphorylation yet completely blocked insulin-stimulated c-Jun phosphorylation. |
| 5694 | 12510059 | Further, insulin-stimulated c-Jun phosphorylation was not blocked by inhibitors of the phosphatidylinositol 3-kinase and mammalian target of rapamycin, indicating that c-Jun N-terminal kinase is unlikely to be the kinase phosphorylating IRS-1 Ser(312) in response to insulin. |
| 5695 | 12510059 | In summary, our results indicate that the insulin-stimulated degradation of IRS-1 via the phosphatidylinositol 3-kinase pathway is in part dependent upon the Ser(312) phosphorylation of IRS-1. |
| 5696 | 12510059 | Modulation of insulin-stimulated degradation of human insulin receptor substrate-1 by Serine 312 phosphorylation. |
| 5697 | 12510059 | One potential mechanism for this is that Ser/Thr phosphorylation decreases the ability of IRS-1 to be tyrosine-phosphorylated by the insulin receptor. |
| 5698 | 12510059 | An additional mechanism for modulating insulin signaling is via the down-regulation of IRS-1 protein levels. |
| 5699 | 12510059 | Insulin-induced degradation of IRS-1 has been well documented, both in cells as well as in patients with diabetes. |
| 5700 | 12510059 | In the present study we have examined the potential role of different signaling cascades in the insulin-induced degradation of IRS-1. |
| 5701 | 12510059 | Second, knockout cells lacking one of the key effectors of this cascade, the phosphoinositide-dependent kinase-1, were found to be deficient in the insulin-stimulated degradation of IRS-1. |
| 5702 | 12510059 | Conversely, overexpression of this enzyme potentiated insulin-stimulated IRS-1 degradation. |
| 5703 | 12510059 | Third, concurrent with the decrease in IRS-1 degradation, the inhibitors of the phosphatidylinositol 3-kinase and mammalian target of rapamycin also blocked the insulin-stimulated increase in Ser(312) phosphorylation. |
| 5704 | 12510059 | Most important, an IRS-1 mutant in which Ser(312) was changed to alanine was found to be resistant to insulin-stimulated IRS-1 degradation. |
| 5705 | 12510059 | Finally, an inhibitor of c-Jun N-terminal kinase, SP600125, at 10 microm did not block IRS-1 degradation and IRS-1 Ser(312) phosphorylation yet completely blocked insulin-stimulated c-Jun phosphorylation. |
| 5706 | 12510059 | Further, insulin-stimulated c-Jun phosphorylation was not blocked by inhibitors of the phosphatidylinositol 3-kinase and mammalian target of rapamycin, indicating that c-Jun N-terminal kinase is unlikely to be the kinase phosphorylating IRS-1 Ser(312) in response to insulin. |
| 5707 | 12510059 | In summary, our results indicate that the insulin-stimulated degradation of IRS-1 via the phosphatidylinositol 3-kinase pathway is in part dependent upon the Ser(312) phosphorylation of IRS-1. |
| 5708 | 12510059 | Modulation of insulin-stimulated degradation of human insulin receptor substrate-1 by Serine 312 phosphorylation. |
| 5709 | 12510059 | One potential mechanism for this is that Ser/Thr phosphorylation decreases the ability of IRS-1 to be tyrosine-phosphorylated by the insulin receptor. |
| 5710 | 12510059 | An additional mechanism for modulating insulin signaling is via the down-regulation of IRS-1 protein levels. |
| 5711 | 12510059 | Insulin-induced degradation of IRS-1 has been well documented, both in cells as well as in patients with diabetes. |
| 5712 | 12510059 | In the present study we have examined the potential role of different signaling cascades in the insulin-induced degradation of IRS-1. |
| 5713 | 12510059 | Second, knockout cells lacking one of the key effectors of this cascade, the phosphoinositide-dependent kinase-1, were found to be deficient in the insulin-stimulated degradation of IRS-1. |
| 5714 | 12510059 | Conversely, overexpression of this enzyme potentiated insulin-stimulated IRS-1 degradation. |
| 5715 | 12510059 | Third, concurrent with the decrease in IRS-1 degradation, the inhibitors of the phosphatidylinositol 3-kinase and mammalian target of rapamycin also blocked the insulin-stimulated increase in Ser(312) phosphorylation. |
| 5716 | 12510059 | Most important, an IRS-1 mutant in which Ser(312) was changed to alanine was found to be resistant to insulin-stimulated IRS-1 degradation. |
| 5717 | 12510059 | Finally, an inhibitor of c-Jun N-terminal kinase, SP600125, at 10 microm did not block IRS-1 degradation and IRS-1 Ser(312) phosphorylation yet completely blocked insulin-stimulated c-Jun phosphorylation. |
| 5718 | 12510059 | Further, insulin-stimulated c-Jun phosphorylation was not blocked by inhibitors of the phosphatidylinositol 3-kinase and mammalian target of rapamycin, indicating that c-Jun N-terminal kinase is unlikely to be the kinase phosphorylating IRS-1 Ser(312) in response to insulin. |
| 5719 | 12510059 | In summary, our results indicate that the insulin-stimulated degradation of IRS-1 via the phosphatidylinositol 3-kinase pathway is in part dependent upon the Ser(312) phosphorylation of IRS-1. |
| 5720 | 12510059 | Modulation of insulin-stimulated degradation of human insulin receptor substrate-1 by Serine 312 phosphorylation. |
| 5721 | 12510059 | One potential mechanism for this is that Ser/Thr phosphorylation decreases the ability of IRS-1 to be tyrosine-phosphorylated by the insulin receptor. |
| 5722 | 12510059 | An additional mechanism for modulating insulin signaling is via the down-regulation of IRS-1 protein levels. |
| 5723 | 12510059 | Insulin-induced degradation of IRS-1 has been well documented, both in cells as well as in patients with diabetes. |
| 5724 | 12510059 | In the present study we have examined the potential role of different signaling cascades in the insulin-induced degradation of IRS-1. |
| 5725 | 12510059 | Second, knockout cells lacking one of the key effectors of this cascade, the phosphoinositide-dependent kinase-1, were found to be deficient in the insulin-stimulated degradation of IRS-1. |
| 5726 | 12510059 | Conversely, overexpression of this enzyme potentiated insulin-stimulated IRS-1 degradation. |
| 5727 | 12510059 | Third, concurrent with the decrease in IRS-1 degradation, the inhibitors of the phosphatidylinositol 3-kinase and mammalian target of rapamycin also blocked the insulin-stimulated increase in Ser(312) phosphorylation. |
| 5728 | 12510059 | Most important, an IRS-1 mutant in which Ser(312) was changed to alanine was found to be resistant to insulin-stimulated IRS-1 degradation. |
| 5729 | 12510059 | Finally, an inhibitor of c-Jun N-terminal kinase, SP600125, at 10 microm did not block IRS-1 degradation and IRS-1 Ser(312) phosphorylation yet completely blocked insulin-stimulated c-Jun phosphorylation. |
| 5730 | 12510059 | Further, insulin-stimulated c-Jun phosphorylation was not blocked by inhibitors of the phosphatidylinositol 3-kinase and mammalian target of rapamycin, indicating that c-Jun N-terminal kinase is unlikely to be the kinase phosphorylating IRS-1 Ser(312) in response to insulin. |
| 5731 | 12510059 | In summary, our results indicate that the insulin-stimulated degradation of IRS-1 via the phosphatidylinositol 3-kinase pathway is in part dependent upon the Ser(312) phosphorylation of IRS-1. |
| 5732 | 12510059 | Modulation of insulin-stimulated degradation of human insulin receptor substrate-1 by Serine 312 phosphorylation. |
| 5733 | 12510059 | One potential mechanism for this is that Ser/Thr phosphorylation decreases the ability of IRS-1 to be tyrosine-phosphorylated by the insulin receptor. |
| 5734 | 12510059 | An additional mechanism for modulating insulin signaling is via the down-regulation of IRS-1 protein levels. |
| 5735 | 12510059 | Insulin-induced degradation of IRS-1 has been well documented, both in cells as well as in patients with diabetes. |
| 5736 | 12510059 | In the present study we have examined the potential role of different signaling cascades in the insulin-induced degradation of IRS-1. |
| 5737 | 12510059 | Second, knockout cells lacking one of the key effectors of this cascade, the phosphoinositide-dependent kinase-1, were found to be deficient in the insulin-stimulated degradation of IRS-1. |
| 5738 | 12510059 | Conversely, overexpression of this enzyme potentiated insulin-stimulated IRS-1 degradation. |
| 5739 | 12510059 | Third, concurrent with the decrease in IRS-1 degradation, the inhibitors of the phosphatidylinositol 3-kinase and mammalian target of rapamycin also blocked the insulin-stimulated increase in Ser(312) phosphorylation. |
| 5740 | 12510059 | Most important, an IRS-1 mutant in which Ser(312) was changed to alanine was found to be resistant to insulin-stimulated IRS-1 degradation. |
| 5741 | 12510059 | Finally, an inhibitor of c-Jun N-terminal kinase, SP600125, at 10 microm did not block IRS-1 degradation and IRS-1 Ser(312) phosphorylation yet completely blocked insulin-stimulated c-Jun phosphorylation. |
| 5742 | 12510059 | Further, insulin-stimulated c-Jun phosphorylation was not blocked by inhibitors of the phosphatidylinositol 3-kinase and mammalian target of rapamycin, indicating that c-Jun N-terminal kinase is unlikely to be the kinase phosphorylating IRS-1 Ser(312) in response to insulin. |
| 5743 | 12510059 | In summary, our results indicate that the insulin-stimulated degradation of IRS-1 via the phosphatidylinositol 3-kinase pathway is in part dependent upon the Ser(312) phosphorylation of IRS-1. |
| 5744 | 12510059 | Modulation of insulin-stimulated degradation of human insulin receptor substrate-1 by Serine 312 phosphorylation. |
| 5745 | 12510059 | One potential mechanism for this is that Ser/Thr phosphorylation decreases the ability of IRS-1 to be tyrosine-phosphorylated by the insulin receptor. |
| 5746 | 12510059 | An additional mechanism for modulating insulin signaling is via the down-regulation of IRS-1 protein levels. |
| 5747 | 12510059 | Insulin-induced degradation of IRS-1 has been well documented, both in cells as well as in patients with diabetes. |
| 5748 | 12510059 | In the present study we have examined the potential role of different signaling cascades in the insulin-induced degradation of IRS-1. |
| 5749 | 12510059 | Second, knockout cells lacking one of the key effectors of this cascade, the phosphoinositide-dependent kinase-1, were found to be deficient in the insulin-stimulated degradation of IRS-1. |
| 5750 | 12510059 | Conversely, overexpression of this enzyme potentiated insulin-stimulated IRS-1 degradation. |
| 5751 | 12510059 | Third, concurrent with the decrease in IRS-1 degradation, the inhibitors of the phosphatidylinositol 3-kinase and mammalian target of rapamycin also blocked the insulin-stimulated increase in Ser(312) phosphorylation. |
| 5752 | 12510059 | Most important, an IRS-1 mutant in which Ser(312) was changed to alanine was found to be resistant to insulin-stimulated IRS-1 degradation. |
| 5753 | 12510059 | Finally, an inhibitor of c-Jun N-terminal kinase, SP600125, at 10 microm did not block IRS-1 degradation and IRS-1 Ser(312) phosphorylation yet completely blocked insulin-stimulated c-Jun phosphorylation. |
| 5754 | 12510059 | Further, insulin-stimulated c-Jun phosphorylation was not blocked by inhibitors of the phosphatidylinositol 3-kinase and mammalian target of rapamycin, indicating that c-Jun N-terminal kinase is unlikely to be the kinase phosphorylating IRS-1 Ser(312) in response to insulin. |
| 5755 | 12510059 | In summary, our results indicate that the insulin-stimulated degradation of IRS-1 via the phosphatidylinositol 3-kinase pathway is in part dependent upon the Ser(312) phosphorylation of IRS-1. |
| 5756 | 12510059 | Modulation of insulin-stimulated degradation of human insulin receptor substrate-1 by Serine 312 phosphorylation. |
| 5757 | 12510059 | One potential mechanism for this is that Ser/Thr phosphorylation decreases the ability of IRS-1 to be tyrosine-phosphorylated by the insulin receptor. |
| 5758 | 12510059 | An additional mechanism for modulating insulin signaling is via the down-regulation of IRS-1 protein levels. |
| 5759 | 12510059 | Insulin-induced degradation of IRS-1 has been well documented, both in cells as well as in patients with diabetes. |
| 5760 | 12510059 | In the present study we have examined the potential role of different signaling cascades in the insulin-induced degradation of IRS-1. |
| 5761 | 12510059 | Second, knockout cells lacking one of the key effectors of this cascade, the phosphoinositide-dependent kinase-1, were found to be deficient in the insulin-stimulated degradation of IRS-1. |
| 5762 | 12510059 | Conversely, overexpression of this enzyme potentiated insulin-stimulated IRS-1 degradation. |
| 5763 | 12510059 | Third, concurrent with the decrease in IRS-1 degradation, the inhibitors of the phosphatidylinositol 3-kinase and mammalian target of rapamycin also blocked the insulin-stimulated increase in Ser(312) phosphorylation. |
| 5764 | 12510059 | Most important, an IRS-1 mutant in which Ser(312) was changed to alanine was found to be resistant to insulin-stimulated IRS-1 degradation. |
| 5765 | 12510059 | Finally, an inhibitor of c-Jun N-terminal kinase, SP600125, at 10 microm did not block IRS-1 degradation and IRS-1 Ser(312) phosphorylation yet completely blocked insulin-stimulated c-Jun phosphorylation. |
| 5766 | 12510059 | Further, insulin-stimulated c-Jun phosphorylation was not blocked by inhibitors of the phosphatidylinositol 3-kinase and mammalian target of rapamycin, indicating that c-Jun N-terminal kinase is unlikely to be the kinase phosphorylating IRS-1 Ser(312) in response to insulin. |
| 5767 | 12510059 | In summary, our results indicate that the insulin-stimulated degradation of IRS-1 via the phosphatidylinositol 3-kinase pathway is in part dependent upon the Ser(312) phosphorylation of IRS-1. |
| 5768 | 12510059 | Modulation of insulin-stimulated degradation of human insulin receptor substrate-1 by Serine 312 phosphorylation. |
| 5769 | 12510059 | One potential mechanism for this is that Ser/Thr phosphorylation decreases the ability of IRS-1 to be tyrosine-phosphorylated by the insulin receptor. |
| 5770 | 12510059 | An additional mechanism for modulating insulin signaling is via the down-regulation of IRS-1 protein levels. |
| 5771 | 12510059 | Insulin-induced degradation of IRS-1 has been well documented, both in cells as well as in patients with diabetes. |
| 5772 | 12510059 | In the present study we have examined the potential role of different signaling cascades in the insulin-induced degradation of IRS-1. |
| 5773 | 12510059 | Second, knockout cells lacking one of the key effectors of this cascade, the phosphoinositide-dependent kinase-1, were found to be deficient in the insulin-stimulated degradation of IRS-1. |
| 5774 | 12510059 | Conversely, overexpression of this enzyme potentiated insulin-stimulated IRS-1 degradation. |
| 5775 | 12510059 | Third, concurrent with the decrease in IRS-1 degradation, the inhibitors of the phosphatidylinositol 3-kinase and mammalian target of rapamycin also blocked the insulin-stimulated increase in Ser(312) phosphorylation. |
| 5776 | 12510059 | Most important, an IRS-1 mutant in which Ser(312) was changed to alanine was found to be resistant to insulin-stimulated IRS-1 degradation. |
| 5777 | 12510059 | Finally, an inhibitor of c-Jun N-terminal kinase, SP600125, at 10 microm did not block IRS-1 degradation and IRS-1 Ser(312) phosphorylation yet completely blocked insulin-stimulated c-Jun phosphorylation. |
| 5778 | 12510059 | Further, insulin-stimulated c-Jun phosphorylation was not blocked by inhibitors of the phosphatidylinositol 3-kinase and mammalian target of rapamycin, indicating that c-Jun N-terminal kinase is unlikely to be the kinase phosphorylating IRS-1 Ser(312) in response to insulin. |
| 5779 | 12510059 | In summary, our results indicate that the insulin-stimulated degradation of IRS-1 via the phosphatidylinositol 3-kinase pathway is in part dependent upon the Ser(312) phosphorylation of IRS-1. |
| 5780 | 12510059 | Modulation of insulin-stimulated degradation of human insulin receptor substrate-1 by Serine 312 phosphorylation. |
| 5781 | 12510059 | One potential mechanism for this is that Ser/Thr phosphorylation decreases the ability of IRS-1 to be tyrosine-phosphorylated by the insulin receptor. |
| 5782 | 12510059 | An additional mechanism for modulating insulin signaling is via the down-regulation of IRS-1 protein levels. |
| 5783 | 12510059 | Insulin-induced degradation of IRS-1 has been well documented, both in cells as well as in patients with diabetes. |
| 5784 | 12510059 | In the present study we have examined the potential role of different signaling cascades in the insulin-induced degradation of IRS-1. |
| 5785 | 12510059 | Second, knockout cells lacking one of the key effectors of this cascade, the phosphoinositide-dependent kinase-1, were found to be deficient in the insulin-stimulated degradation of IRS-1. |
| 5786 | 12510059 | Conversely, overexpression of this enzyme potentiated insulin-stimulated IRS-1 degradation. |
| 5787 | 12510059 | Third, concurrent with the decrease in IRS-1 degradation, the inhibitors of the phosphatidylinositol 3-kinase and mammalian target of rapamycin also blocked the insulin-stimulated increase in Ser(312) phosphorylation. |
| 5788 | 12510059 | Most important, an IRS-1 mutant in which Ser(312) was changed to alanine was found to be resistant to insulin-stimulated IRS-1 degradation. |
| 5789 | 12510059 | Finally, an inhibitor of c-Jun N-terminal kinase, SP600125, at 10 microm did not block IRS-1 degradation and IRS-1 Ser(312) phosphorylation yet completely blocked insulin-stimulated c-Jun phosphorylation. |
| 5790 | 12510059 | Further, insulin-stimulated c-Jun phosphorylation was not blocked by inhibitors of the phosphatidylinositol 3-kinase and mammalian target of rapamycin, indicating that c-Jun N-terminal kinase is unlikely to be the kinase phosphorylating IRS-1 Ser(312) in response to insulin. |
| 5791 | 12510059 | In summary, our results indicate that the insulin-stimulated degradation of IRS-1 via the phosphatidylinositol 3-kinase pathway is in part dependent upon the Ser(312) phosphorylation of IRS-1. |
| 5792 | 12534369 | High glucose and insulin in combination cause insulin receptor substrate-1 and -2 depletion and protein kinase B desensitisation in primary cultured rat adipocytes: possible implications for insulin resistance in type 2 diabetes. |
| 5793 | 12540590 | Insulin activation of phosphatidylinositol 3-kinase in the hypothalamic arcuate nucleus: a key mediator of insulin-induced anorexia. |
| 5794 | 12540590 | In peripheral tissues, insulin signaling involves activation of the insulin receptor substrate (IRS)-phosphatidylinositol 3-kinase (PI3K) enzyme system. |
| 5795 | 12540590 | In the hypothalamus, insulin functions with leptin as an afferent adiposity signal important for the regulation of body fat stores and hepatic glucose metabolism. |
| 5796 | 12540590 | To test the hypothesis that hypothalamic insulin action involves intracellular PI3K signaling, we used histochemical and biochemical methods to determine the effect of insulin on hypothalamic IRS-PI3K activity. |
| 5797 | 12540590 | Here, we report that insulin induces tyrosine phosphorylation of the insulin receptor and IRS-1 and -2, increases binding of activated IRS-1 and -2 to the regulatory subunit of PI3K, and activates protein kinase B/Akt, a downstream target of PI3K. |
| 5798 | 12540590 | Using an immunohistochemical technique to detect PI 3,4,5-triphosphate, the main product of PI3K activity, we further demonstrate that in the arcuate nucleus, insulin-induced PI3K activity occurs preferentially within cells that contain IRS-2. |
| 5799 | 12540590 | Finally, we show that the food intake- lowering effects of insulin are reversed by intracerebroventricular infusion of either of two PI3K inhibitors at doses that have no independent feeding effects. |
| 5800 | 12540590 | These findings support the hypothesis that the IRS-PI3K pathway is a mediator of insulin action in the arcuate nucleus and, combined with recent evidence that leptin activates PI3K signaling in the hypothalamus, provide a plausible mechanism for neuronal cross-talk between insulin and leptin signaling. |
| 5801 | 12554784 | TNFalpha, which activates three different MAPKs [ERK, p38, and jun amino terminal kinase (JNK)], also induces insulin resistance. |
| 5802 | 12554784 | To better understand the respective roles of these three MAPK pathways in insulin signaling and their contribution to insulin resistance, constitutively active MAPK/ERK kinase (MEK)1, MAPK kinase (MKK6), and MKK7 mutants were overexpressed in 3T3-L1 adipocytes using an adenovirus-mediated transfection procedure. |
| 5803 | 12554784 | The MEK1 mutant, which activates ERK, markedly down-regulated expression of the insulin receptor (IR) and its major substrates, IRS-1 and IRS-2, mRNA and protein, and in turn reduced tyrosine phosphorylation of IR as well as IRS-1 and IRS-2 and their associated phosphatidyl inositol 3-kinase (PI3K) activity. |
| 5804 | 12554784 | The MKK6 mutant, which activates p38, moderately inhibited IRS-1 and IRS-2 expressions and IRS-1-associated PI3K activity without exerting a significant effect on the IR. |
| 5805 | 12554784 | Finally, the MKK7 mutant, which activates JNK, reduced tyrosine phosphorylation of IRS-1 and IRS-2 and IRS-associated PI3K activity without affecting expression of the IR, IRS-1, or IRS-2. |
| 5806 | 12554784 | In the context of our earlier report showing down-regulation of glucose transporter 4 by MEK1-ERK and MKK6/3-p38, the present findings suggest that chronic activation of ERK, p38, or JNK can induce insulin resistance by affecting glucose transporter expression and insulin signaling, though via distinctly different mechanisms. |
| 5807 | 12554784 | TNFalpha, which activates three different MAPKs [ERK, p38, and jun amino terminal kinase (JNK)], also induces insulin resistance. |
| 5808 | 12554784 | To better understand the respective roles of these three MAPK pathways in insulin signaling and their contribution to insulin resistance, constitutively active MAPK/ERK kinase (MEK)1, MAPK kinase (MKK6), and MKK7 mutants were overexpressed in 3T3-L1 adipocytes using an adenovirus-mediated transfection procedure. |
| 5809 | 12554784 | The MEK1 mutant, which activates ERK, markedly down-regulated expression of the insulin receptor (IR) and its major substrates, IRS-1 and IRS-2, mRNA and protein, and in turn reduced tyrosine phosphorylation of IR as well as IRS-1 and IRS-2 and their associated phosphatidyl inositol 3-kinase (PI3K) activity. |
| 5810 | 12554784 | The MKK6 mutant, which activates p38, moderately inhibited IRS-1 and IRS-2 expressions and IRS-1-associated PI3K activity without exerting a significant effect on the IR. |
| 5811 | 12554784 | Finally, the MKK7 mutant, which activates JNK, reduced tyrosine phosphorylation of IRS-1 and IRS-2 and IRS-associated PI3K activity without affecting expression of the IR, IRS-1, or IRS-2. |
| 5812 | 12554784 | In the context of our earlier report showing down-regulation of glucose transporter 4 by MEK1-ERK and MKK6/3-p38, the present findings suggest that chronic activation of ERK, p38, or JNK can induce insulin resistance by affecting glucose transporter expression and insulin signaling, though via distinctly different mechanisms. |
| 5813 | 12554784 | TNFalpha, which activates three different MAPKs [ERK, p38, and jun amino terminal kinase (JNK)], also induces insulin resistance. |
| 5814 | 12554784 | To better understand the respective roles of these three MAPK pathways in insulin signaling and their contribution to insulin resistance, constitutively active MAPK/ERK kinase (MEK)1, MAPK kinase (MKK6), and MKK7 mutants were overexpressed in 3T3-L1 adipocytes using an adenovirus-mediated transfection procedure. |
| 5815 | 12554784 | The MEK1 mutant, which activates ERK, markedly down-regulated expression of the insulin receptor (IR) and its major substrates, IRS-1 and IRS-2, mRNA and protein, and in turn reduced tyrosine phosphorylation of IR as well as IRS-1 and IRS-2 and their associated phosphatidyl inositol 3-kinase (PI3K) activity. |
| 5816 | 12554784 | The MKK6 mutant, which activates p38, moderately inhibited IRS-1 and IRS-2 expressions and IRS-1-associated PI3K activity without exerting a significant effect on the IR. |
| 5817 | 12554784 | Finally, the MKK7 mutant, which activates JNK, reduced tyrosine phosphorylation of IRS-1 and IRS-2 and IRS-associated PI3K activity without affecting expression of the IR, IRS-1, or IRS-2. |
| 5818 | 12554784 | In the context of our earlier report showing down-regulation of glucose transporter 4 by MEK1-ERK and MKK6/3-p38, the present findings suggest that chronic activation of ERK, p38, or JNK can induce insulin resistance by affecting glucose transporter expression and insulin signaling, though via distinctly different mechanisms. |
| 5819 | 12560330 | Suppressor of cytokine signaling-3 (SOCS-3), a potential mediator of interleukin-6-dependent insulin resistance in hepatocytes. |
| 5820 | 12560330 | Interleukin-6 (IL-6) is one of several pro-inflammatory cytokines implicated in insulin resistance during infection, cachexia, and obesity. |
| 5821 | 12560330 | We recently demonstrated that IL-6 inhibits insulin signaling in hepatocytes (Senn, J. |
| 5822 | 12560330 | Members of the suppressors of cytokine signaling (SOCS) family associate with the insulin receptor (IR), and their ectopic expression inhibits IR signaling. |
| 5823 | 12560330 | Since several SOCS proteins are induced by IL-6, a working hypothesis is that IL-6-dependent insulin resistance is mediated, at least in part, by induction of SOCS protein(s) in insulin target cells. |
| 5824 | 12560330 | To examine the involvement of SOCS protein(s) in IL-6-dependent inhibition of insulin receptor signaling, HepG2 cells were treated with IL-6 (20 ng/ml) for periods from 1 min to 8 h. |
| 5825 | 12560330 | IL-6 induced SOCS-3 transcript at 30 min with a maximum effect at 1 h. |
| 5826 | 12560330 | SOCS-3 induction by IL-6 paralleled IL-6-dependent inhibition of IR signal transduction. |
| 5827 | 12560330 | Ectopically expressed SOCS-3 associated with the IR and suppressed insulin-dependent receptor autophosphorylation, insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation, association of IRS-1 with the p85 subunit of phosphatidylinositol 3-kinase, and activation of Akt. |
| 5828 | 12560330 | SOCS-3 was also a direct inhibitor of insulin receptor autophosphorylation in vitro. |
| 5829 | 12560330 | In mice exposed to IL-6 for 60-90 min, hepatic SOCS-3 expression was increased. |
| 5830 | 12560330 | This was associated with inhibition of hepatic insulin-dependent receptor autophosphorylation and IRS-1 tyrosine phosphorylation. |
| 5831 | 12560330 | These data suggest that induction of SOCS-3 in liver may be an important mechanism of IL-6-mediated insulin resistance. |
| 5832 | 12560330 | Suppressor of cytokine signaling-3 (SOCS-3), a potential mediator of interleukin-6-dependent insulin resistance in hepatocytes. |
| 5833 | 12560330 | Interleukin-6 (IL-6) is one of several pro-inflammatory cytokines implicated in insulin resistance during infection, cachexia, and obesity. |
| 5834 | 12560330 | We recently demonstrated that IL-6 inhibits insulin signaling in hepatocytes (Senn, J. |
| 5835 | 12560330 | Members of the suppressors of cytokine signaling (SOCS) family associate with the insulin receptor (IR), and their ectopic expression inhibits IR signaling. |
| 5836 | 12560330 | Since several SOCS proteins are induced by IL-6, a working hypothesis is that IL-6-dependent insulin resistance is mediated, at least in part, by induction of SOCS protein(s) in insulin target cells. |
| 5837 | 12560330 | To examine the involvement of SOCS protein(s) in IL-6-dependent inhibition of insulin receptor signaling, HepG2 cells were treated with IL-6 (20 ng/ml) for periods from 1 min to 8 h. |
| 5838 | 12560330 | IL-6 induced SOCS-3 transcript at 30 min with a maximum effect at 1 h. |
| 5839 | 12560330 | SOCS-3 induction by IL-6 paralleled IL-6-dependent inhibition of IR signal transduction. |
| 5840 | 12560330 | Ectopically expressed SOCS-3 associated with the IR and suppressed insulin-dependent receptor autophosphorylation, insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation, association of IRS-1 with the p85 subunit of phosphatidylinositol 3-kinase, and activation of Akt. |
| 5841 | 12560330 | SOCS-3 was also a direct inhibitor of insulin receptor autophosphorylation in vitro. |
| 5842 | 12560330 | In mice exposed to IL-6 for 60-90 min, hepatic SOCS-3 expression was increased. |
| 5843 | 12560330 | This was associated with inhibition of hepatic insulin-dependent receptor autophosphorylation and IRS-1 tyrosine phosphorylation. |
| 5844 | 12560330 | These data suggest that induction of SOCS-3 in liver may be an important mechanism of IL-6-mediated insulin resistance. |
| 5845 | 12565902 | Reduced expression of PGC-1 and insulin-signaling molecules in adipose tissue is associated with insulin resistance. |
| 5846 | 12565902 | Peroxisome proliferator-activated receptor gamma (PPAR gamma) co-activator 1 (PGC-1) regulates glucose metabolism and energy expenditure and, thus, potentially insulin sensitivity. |
| 5847 | 12565902 | We examined the expression of PGC-1, PPAR gamma, insulin receptor substrate-1 (IRS-1), glucose transporter isoform-4 (GLUT-4), and mitochondrial uncoupling protein-1 (UCP-1) in adipose tissue and skeletal muscle from non-obese, non-diabetic insulin-resistant, and insulin-sensitive individuals. |
| 5848 | 12565902 | PGC-1, both mRNA and protein, was expressed in human adipose tissue and the expression was significantly reduced in insulin-resistant subjects. |
| 5849 | 12565902 | The expression of PGC-1 correlated with the mRNA levels of IRS-1, GLUT-4, and UCP-1 in adipose tissue. |
| 5850 | 12565902 | Furthermore, the adipose tissue expression of PGC-1 and IRS-1 correlated with insulin action in vivo. |
| 5851 | 12565902 | In contrast, no differential expression of PGC-1, GLUT-4, or IRS-1 was found in the skeletal muscle of insulin-resistant vs insulin-sensitive subjects. |
| 5852 | 12565902 | The combined reduction of PGC-1 and insulin signaling molecules in adipose tissue implicates adipose tissue dysfunction which, in turn, can impair the systemic insulin response in the insulin-resistant subjects. |
| 5853 | 12565902 | Reduced expression of PGC-1 and insulin-signaling molecules in adipose tissue is associated with insulin resistance. |
| 5854 | 12565902 | Peroxisome proliferator-activated receptor gamma (PPAR gamma) co-activator 1 (PGC-1) regulates glucose metabolism and energy expenditure and, thus, potentially insulin sensitivity. |
| 5855 | 12565902 | We examined the expression of PGC-1, PPAR gamma, insulin receptor substrate-1 (IRS-1), glucose transporter isoform-4 (GLUT-4), and mitochondrial uncoupling protein-1 (UCP-1) in adipose tissue and skeletal muscle from non-obese, non-diabetic insulin-resistant, and insulin-sensitive individuals. |
| 5856 | 12565902 | PGC-1, both mRNA and protein, was expressed in human adipose tissue and the expression was significantly reduced in insulin-resistant subjects. |
| 5857 | 12565902 | The expression of PGC-1 correlated with the mRNA levels of IRS-1, GLUT-4, and UCP-1 in adipose tissue. |
| 5858 | 12565902 | Furthermore, the adipose tissue expression of PGC-1 and IRS-1 correlated with insulin action in vivo. |
| 5859 | 12565902 | In contrast, no differential expression of PGC-1, GLUT-4, or IRS-1 was found in the skeletal muscle of insulin-resistant vs insulin-sensitive subjects. |
| 5860 | 12565902 | The combined reduction of PGC-1 and insulin signaling molecules in adipose tissue implicates adipose tissue dysfunction which, in turn, can impair the systemic insulin response in the insulin-resistant subjects. |
| 5861 | 12565902 | Reduced expression of PGC-1 and insulin-signaling molecules in adipose tissue is associated with insulin resistance. |
| 5862 | 12565902 | Peroxisome proliferator-activated receptor gamma (PPAR gamma) co-activator 1 (PGC-1) regulates glucose metabolism and energy expenditure and, thus, potentially insulin sensitivity. |
| 5863 | 12565902 | We examined the expression of PGC-1, PPAR gamma, insulin receptor substrate-1 (IRS-1), glucose transporter isoform-4 (GLUT-4), and mitochondrial uncoupling protein-1 (UCP-1) in adipose tissue and skeletal muscle from non-obese, non-diabetic insulin-resistant, and insulin-sensitive individuals. |
| 5864 | 12565902 | PGC-1, both mRNA and protein, was expressed in human adipose tissue and the expression was significantly reduced in insulin-resistant subjects. |
| 5865 | 12565902 | The expression of PGC-1 correlated with the mRNA levels of IRS-1, GLUT-4, and UCP-1 in adipose tissue. |
| 5866 | 12565902 | Furthermore, the adipose tissue expression of PGC-1 and IRS-1 correlated with insulin action in vivo. |
| 5867 | 12565902 | In contrast, no differential expression of PGC-1, GLUT-4, or IRS-1 was found in the skeletal muscle of insulin-resistant vs insulin-sensitive subjects. |
| 5868 | 12565902 | The combined reduction of PGC-1 and insulin signaling molecules in adipose tissue implicates adipose tissue dysfunction which, in turn, can impair the systemic insulin response in the insulin-resistant subjects. |
| 5869 | 12565902 | Reduced expression of PGC-1 and insulin-signaling molecules in adipose tissue is associated with insulin resistance. |
| 5870 | 12565902 | Peroxisome proliferator-activated receptor gamma (PPAR gamma) co-activator 1 (PGC-1) regulates glucose metabolism and energy expenditure and, thus, potentially insulin sensitivity. |
| 5871 | 12565902 | We examined the expression of PGC-1, PPAR gamma, insulin receptor substrate-1 (IRS-1), glucose transporter isoform-4 (GLUT-4), and mitochondrial uncoupling protein-1 (UCP-1) in adipose tissue and skeletal muscle from non-obese, non-diabetic insulin-resistant, and insulin-sensitive individuals. |
| 5872 | 12565902 | PGC-1, both mRNA and protein, was expressed in human adipose tissue and the expression was significantly reduced in insulin-resistant subjects. |
| 5873 | 12565902 | The expression of PGC-1 correlated with the mRNA levels of IRS-1, GLUT-4, and UCP-1 in adipose tissue. |
| 5874 | 12565902 | Furthermore, the adipose tissue expression of PGC-1 and IRS-1 correlated with insulin action in vivo. |
| 5875 | 12565902 | In contrast, no differential expression of PGC-1, GLUT-4, or IRS-1 was found in the skeletal muscle of insulin-resistant vs insulin-sensitive subjects. |
| 5876 | 12565902 | The combined reduction of PGC-1 and insulin signaling molecules in adipose tissue implicates adipose tissue dysfunction which, in turn, can impair the systemic insulin response in the insulin-resistant subjects. |
| 5877 | 12594228 | Phosphoinositide 3-kinase-mediated reduction of insulin receptor substrate-1/2 protein expression via different mechanisms contributes to the insulin-induced desensitization of its signaling pathways in L6 muscle cells. |
| 5878 | 12594228 | A 24-h long insulin treatment desensitized the phosphoinositide 3-kinase (PI3K)/protein kinase B (PKB) and p42/p44 MAPK pathways toward a second stimulation with insulin or insulin-like growth factor-1 and led to decreased insulin-induced glucose uptake. |
| 5879 | 12594228 | Desensitization was correlated to a reduction in insulin receptor substrate (IRS)-1 and IRS-2 protein levels, which was reversed by the PI3K inhibitor LY294002. |
| 5880 | 12594228 | Co-treatment of cells with insulin and LY294002, while reducing total IRS-1 phosphorylation, increased its phosphotyrosine content, enhancing IRS-1/PI3K association. |
| 5881 | 12594228 | PDK1, mTOR, and MAPK inhibitors did not block insulin-induced reduction of IRS-1, suggesting that the PI3K serine-kinase activity causes IRS-1 serine phosphorylation and its commitment to proteasomal degradation. |
| 5882 | 12594228 | Contrarily, insulin-induced IRS-2 down-regulation occurred via a PI3K/mTOR pathway. |
| 5883 | 12594228 | Suppression of IRS-1/2 down-regulation by LY294002 rescued the responsiveness of PKB and MAPK toward acute insulin stimulation. |
| 5884 | 12594228 | Conversely, adenoviral-driven expression of constitutively active PI3K induced an insulin-independent reduction in IRS-1/2 protein levels. |
| 5885 | 12594228 | IRS-2 appears to be the chief molecule responsible for MAPK and PKB activation by insulin, as knockdown of IRS-2 (but not IRS-1) by RNA interference severely impaired activation of both kinases. |
| 5886 | 12594228 | In summary, (i) PI3K mediates insulin-induced reduction of IRS-1 by phosphorylating it while a PI3K/mTOR pathway controls insulin-induced reduction of IRS-2, (ii) in L6 cells, IRS-2 is the major adapter molecule linking the insulin receptor to activation of PKB and MAPK, (iii) the mechanism of IRS-1/2 down-regulation is different in L6 cells compared with 3T3-L1 adipocytes. |
| 5887 | 12594228 | In conclusion, the reduction in IRS proteins via different PI3K-mediated mechanisms contributes to the development of an insulin-resistant state in L6 myoblasts. |
| 5888 | 12594228 | Phosphoinositide 3-kinase-mediated reduction of insulin receptor substrate-1/2 protein expression via different mechanisms contributes to the insulin-induced desensitization of its signaling pathways in L6 muscle cells. |
| 5889 | 12594228 | A 24-h long insulin treatment desensitized the phosphoinositide 3-kinase (PI3K)/protein kinase B (PKB) and p42/p44 MAPK pathways toward a second stimulation with insulin or insulin-like growth factor-1 and led to decreased insulin-induced glucose uptake. |
| 5890 | 12594228 | Desensitization was correlated to a reduction in insulin receptor substrate (IRS)-1 and IRS-2 protein levels, which was reversed by the PI3K inhibitor LY294002. |
| 5891 | 12594228 | Co-treatment of cells with insulin and LY294002, while reducing total IRS-1 phosphorylation, increased its phosphotyrosine content, enhancing IRS-1/PI3K association. |
| 5892 | 12594228 | PDK1, mTOR, and MAPK inhibitors did not block insulin-induced reduction of IRS-1, suggesting that the PI3K serine-kinase activity causes IRS-1 serine phosphorylation and its commitment to proteasomal degradation. |
| 5893 | 12594228 | Contrarily, insulin-induced IRS-2 down-regulation occurred via a PI3K/mTOR pathway. |
| 5894 | 12594228 | Suppression of IRS-1/2 down-regulation by LY294002 rescued the responsiveness of PKB and MAPK toward acute insulin stimulation. |
| 5895 | 12594228 | Conversely, adenoviral-driven expression of constitutively active PI3K induced an insulin-independent reduction in IRS-1/2 protein levels. |
| 5896 | 12594228 | IRS-2 appears to be the chief molecule responsible for MAPK and PKB activation by insulin, as knockdown of IRS-2 (but not IRS-1) by RNA interference severely impaired activation of both kinases. |
| 5897 | 12594228 | In summary, (i) PI3K mediates insulin-induced reduction of IRS-1 by phosphorylating it while a PI3K/mTOR pathway controls insulin-induced reduction of IRS-2, (ii) in L6 cells, IRS-2 is the major adapter molecule linking the insulin receptor to activation of PKB and MAPK, (iii) the mechanism of IRS-1/2 down-regulation is different in L6 cells compared with 3T3-L1 adipocytes. |
| 5898 | 12594228 | In conclusion, the reduction in IRS proteins via different PI3K-mediated mechanisms contributes to the development of an insulin-resistant state in L6 myoblasts. |
| 5899 | 12594228 | Phosphoinositide 3-kinase-mediated reduction of insulin receptor substrate-1/2 protein expression via different mechanisms contributes to the insulin-induced desensitization of its signaling pathways in L6 muscle cells. |
| 5900 | 12594228 | A 24-h long insulin treatment desensitized the phosphoinositide 3-kinase (PI3K)/protein kinase B (PKB) and p42/p44 MAPK pathways toward a second stimulation with insulin or insulin-like growth factor-1 and led to decreased insulin-induced glucose uptake. |
| 5901 | 12594228 | Desensitization was correlated to a reduction in insulin receptor substrate (IRS)-1 and IRS-2 protein levels, which was reversed by the PI3K inhibitor LY294002. |
| 5902 | 12594228 | Co-treatment of cells with insulin and LY294002, while reducing total IRS-1 phosphorylation, increased its phosphotyrosine content, enhancing IRS-1/PI3K association. |
| 5903 | 12594228 | PDK1, mTOR, and MAPK inhibitors did not block insulin-induced reduction of IRS-1, suggesting that the PI3K serine-kinase activity causes IRS-1 serine phosphorylation and its commitment to proteasomal degradation. |
| 5904 | 12594228 | Contrarily, insulin-induced IRS-2 down-regulation occurred via a PI3K/mTOR pathway. |
| 5905 | 12594228 | Suppression of IRS-1/2 down-regulation by LY294002 rescued the responsiveness of PKB and MAPK toward acute insulin stimulation. |
| 5906 | 12594228 | Conversely, adenoviral-driven expression of constitutively active PI3K induced an insulin-independent reduction in IRS-1/2 protein levels. |
| 5907 | 12594228 | IRS-2 appears to be the chief molecule responsible for MAPK and PKB activation by insulin, as knockdown of IRS-2 (but not IRS-1) by RNA interference severely impaired activation of both kinases. |
| 5908 | 12594228 | In summary, (i) PI3K mediates insulin-induced reduction of IRS-1 by phosphorylating it while a PI3K/mTOR pathway controls insulin-induced reduction of IRS-2, (ii) in L6 cells, IRS-2 is the major adapter molecule linking the insulin receptor to activation of PKB and MAPK, (iii) the mechanism of IRS-1/2 down-regulation is different in L6 cells compared with 3T3-L1 adipocytes. |
| 5909 | 12594228 | In conclusion, the reduction in IRS proteins via different PI3K-mediated mechanisms contributes to the development of an insulin-resistant state in L6 myoblasts. |
| 5910 | 12594228 | Phosphoinositide 3-kinase-mediated reduction of insulin receptor substrate-1/2 protein expression via different mechanisms contributes to the insulin-induced desensitization of its signaling pathways in L6 muscle cells. |
| 5911 | 12594228 | A 24-h long insulin treatment desensitized the phosphoinositide 3-kinase (PI3K)/protein kinase B (PKB) and p42/p44 MAPK pathways toward a second stimulation with insulin or insulin-like growth factor-1 and led to decreased insulin-induced glucose uptake. |
| 5912 | 12594228 | Desensitization was correlated to a reduction in insulin receptor substrate (IRS)-1 and IRS-2 protein levels, which was reversed by the PI3K inhibitor LY294002. |
| 5913 | 12594228 | Co-treatment of cells with insulin and LY294002, while reducing total IRS-1 phosphorylation, increased its phosphotyrosine content, enhancing IRS-1/PI3K association. |
| 5914 | 12594228 | PDK1, mTOR, and MAPK inhibitors did not block insulin-induced reduction of IRS-1, suggesting that the PI3K serine-kinase activity causes IRS-1 serine phosphorylation and its commitment to proteasomal degradation. |
| 5915 | 12594228 | Contrarily, insulin-induced IRS-2 down-regulation occurred via a PI3K/mTOR pathway. |
| 5916 | 12594228 | Suppression of IRS-1/2 down-regulation by LY294002 rescued the responsiveness of PKB and MAPK toward acute insulin stimulation. |
| 5917 | 12594228 | Conversely, adenoviral-driven expression of constitutively active PI3K induced an insulin-independent reduction in IRS-1/2 protein levels. |
| 5918 | 12594228 | IRS-2 appears to be the chief molecule responsible for MAPK and PKB activation by insulin, as knockdown of IRS-2 (but not IRS-1) by RNA interference severely impaired activation of both kinases. |
| 5919 | 12594228 | In summary, (i) PI3K mediates insulin-induced reduction of IRS-1 by phosphorylating it while a PI3K/mTOR pathway controls insulin-induced reduction of IRS-2, (ii) in L6 cells, IRS-2 is the major adapter molecule linking the insulin receptor to activation of PKB and MAPK, (iii) the mechanism of IRS-1/2 down-regulation is different in L6 cells compared with 3T3-L1 adipocytes. |
| 5920 | 12594228 | In conclusion, the reduction in IRS proteins via different PI3K-mediated mechanisms contributes to the development of an insulin-resistant state in L6 myoblasts. |
| 5921 | 12594228 | Phosphoinositide 3-kinase-mediated reduction of insulin receptor substrate-1/2 protein expression via different mechanisms contributes to the insulin-induced desensitization of its signaling pathways in L6 muscle cells. |
| 5922 | 12594228 | A 24-h long insulin treatment desensitized the phosphoinositide 3-kinase (PI3K)/protein kinase B (PKB) and p42/p44 MAPK pathways toward a second stimulation with insulin or insulin-like growth factor-1 and led to decreased insulin-induced glucose uptake. |
| 5923 | 12594228 | Desensitization was correlated to a reduction in insulin receptor substrate (IRS)-1 and IRS-2 protein levels, which was reversed by the PI3K inhibitor LY294002. |
| 5924 | 12594228 | Co-treatment of cells with insulin and LY294002, while reducing total IRS-1 phosphorylation, increased its phosphotyrosine content, enhancing IRS-1/PI3K association. |
| 5925 | 12594228 | PDK1, mTOR, and MAPK inhibitors did not block insulin-induced reduction of IRS-1, suggesting that the PI3K serine-kinase activity causes IRS-1 serine phosphorylation and its commitment to proteasomal degradation. |
| 5926 | 12594228 | Contrarily, insulin-induced IRS-2 down-regulation occurred via a PI3K/mTOR pathway. |
| 5927 | 12594228 | Suppression of IRS-1/2 down-regulation by LY294002 rescued the responsiveness of PKB and MAPK toward acute insulin stimulation. |
| 5928 | 12594228 | Conversely, adenoviral-driven expression of constitutively active PI3K induced an insulin-independent reduction in IRS-1/2 protein levels. |
| 5929 | 12594228 | IRS-2 appears to be the chief molecule responsible for MAPK and PKB activation by insulin, as knockdown of IRS-2 (but not IRS-1) by RNA interference severely impaired activation of both kinases. |
| 5930 | 12594228 | In summary, (i) PI3K mediates insulin-induced reduction of IRS-1 by phosphorylating it while a PI3K/mTOR pathway controls insulin-induced reduction of IRS-2, (ii) in L6 cells, IRS-2 is the major adapter molecule linking the insulin receptor to activation of PKB and MAPK, (iii) the mechanism of IRS-1/2 down-regulation is different in L6 cells compared with 3T3-L1 adipocytes. |
| 5931 | 12594228 | In conclusion, the reduction in IRS proteins via different PI3K-mediated mechanisms contributes to the development of an insulin-resistant state in L6 myoblasts. |
| 5932 | 12594228 | Phosphoinositide 3-kinase-mediated reduction of insulin receptor substrate-1/2 protein expression via different mechanisms contributes to the insulin-induced desensitization of its signaling pathways in L6 muscle cells. |
| 5933 | 12594228 | A 24-h long insulin treatment desensitized the phosphoinositide 3-kinase (PI3K)/protein kinase B (PKB) and p42/p44 MAPK pathways toward a second stimulation with insulin or insulin-like growth factor-1 and led to decreased insulin-induced glucose uptake. |
| 5934 | 12594228 | Desensitization was correlated to a reduction in insulin receptor substrate (IRS)-1 and IRS-2 protein levels, which was reversed by the PI3K inhibitor LY294002. |
| 5935 | 12594228 | Co-treatment of cells with insulin and LY294002, while reducing total IRS-1 phosphorylation, increased its phosphotyrosine content, enhancing IRS-1/PI3K association. |
| 5936 | 12594228 | PDK1, mTOR, and MAPK inhibitors did not block insulin-induced reduction of IRS-1, suggesting that the PI3K serine-kinase activity causes IRS-1 serine phosphorylation and its commitment to proteasomal degradation. |
| 5937 | 12594228 | Contrarily, insulin-induced IRS-2 down-regulation occurred via a PI3K/mTOR pathway. |
| 5938 | 12594228 | Suppression of IRS-1/2 down-regulation by LY294002 rescued the responsiveness of PKB and MAPK toward acute insulin stimulation. |
| 5939 | 12594228 | Conversely, adenoviral-driven expression of constitutively active PI3K induced an insulin-independent reduction in IRS-1/2 protein levels. |
| 5940 | 12594228 | IRS-2 appears to be the chief molecule responsible for MAPK and PKB activation by insulin, as knockdown of IRS-2 (but not IRS-1) by RNA interference severely impaired activation of both kinases. |
| 5941 | 12594228 | In summary, (i) PI3K mediates insulin-induced reduction of IRS-1 by phosphorylating it while a PI3K/mTOR pathway controls insulin-induced reduction of IRS-2, (ii) in L6 cells, IRS-2 is the major adapter molecule linking the insulin receptor to activation of PKB and MAPK, (iii) the mechanism of IRS-1/2 down-regulation is different in L6 cells compared with 3T3-L1 adipocytes. |
| 5942 | 12594228 | In conclusion, the reduction in IRS proteins via different PI3K-mediated mechanisms contributes to the development of an insulin-resistant state in L6 myoblasts. |
| 5943 | 12594228 | Phosphoinositide 3-kinase-mediated reduction of insulin receptor substrate-1/2 protein expression via different mechanisms contributes to the insulin-induced desensitization of its signaling pathways in L6 muscle cells. |
| 5944 | 12594228 | A 24-h long insulin treatment desensitized the phosphoinositide 3-kinase (PI3K)/protein kinase B (PKB) and p42/p44 MAPK pathways toward a second stimulation with insulin or insulin-like growth factor-1 and led to decreased insulin-induced glucose uptake. |
| 5945 | 12594228 | Desensitization was correlated to a reduction in insulin receptor substrate (IRS)-1 and IRS-2 protein levels, which was reversed by the PI3K inhibitor LY294002. |
| 5946 | 12594228 | Co-treatment of cells with insulin and LY294002, while reducing total IRS-1 phosphorylation, increased its phosphotyrosine content, enhancing IRS-1/PI3K association. |
| 5947 | 12594228 | PDK1, mTOR, and MAPK inhibitors did not block insulin-induced reduction of IRS-1, suggesting that the PI3K serine-kinase activity causes IRS-1 serine phosphorylation and its commitment to proteasomal degradation. |
| 5948 | 12594228 | Contrarily, insulin-induced IRS-2 down-regulation occurred via a PI3K/mTOR pathway. |
| 5949 | 12594228 | Suppression of IRS-1/2 down-regulation by LY294002 rescued the responsiveness of PKB and MAPK toward acute insulin stimulation. |
| 5950 | 12594228 | Conversely, adenoviral-driven expression of constitutively active PI3K induced an insulin-independent reduction in IRS-1/2 protein levels. |
| 5951 | 12594228 | IRS-2 appears to be the chief molecule responsible for MAPK and PKB activation by insulin, as knockdown of IRS-2 (but not IRS-1) by RNA interference severely impaired activation of both kinases. |
| 5952 | 12594228 | In summary, (i) PI3K mediates insulin-induced reduction of IRS-1 by phosphorylating it while a PI3K/mTOR pathway controls insulin-induced reduction of IRS-2, (ii) in L6 cells, IRS-2 is the major adapter molecule linking the insulin receptor to activation of PKB and MAPK, (iii) the mechanism of IRS-1/2 down-regulation is different in L6 cells compared with 3T3-L1 adipocytes. |
| 5953 | 12594228 | In conclusion, the reduction in IRS proteins via different PI3K-mediated mechanisms contributes to the development of an insulin-resistant state in L6 myoblasts. |
| 5954 | 12605345 | Dephosphorylation of immobilized tyrosine-phosphorylated insulin-receptor substrate-1 by the cell extracts was determined using a microwell plate-based method, and indinavir treatment did not alter this dephosphorylation. |
| 5955 | 12606502 | Enhanced basal activation of mitogen-activated protein kinases in adipocytes from type 2 diabetes: potential role of p38 in the downregulation of GLUT4 expression. |
| 5956 | 12606502 | To test the potential for members of the mitogen-activated protein (MAP) kinase family to contribute to type 2 diabetes, we examined basal and insulin-stimulated Erk 1/2, JNK, and p38 phosphorylation in adipocytes isolated from healthy and type 2 diabetic individuals. |
| 5957 | 12606502 | Maximal insulin stimulation increased the phosphorylation of Erk 1/2 and JNK in healthy control subjects but not type 2 diabetic patients. |
| 5958 | 12606502 | Insulin stimulation did not increase p38 phosphorylation in either healthy control subjects or type 2 diabetic patients. |
| 5959 | 12606502 | In type 2 diabetic adipocytes, the basal phosphorylation status of these MAP kinases was significantly elevated and was associated with decreased IRS-1 and GLUT4 in these fat cells. |
| 5960 | 12606502 | To determine whether MAP kinases were involved in the downregulation of IRS-1 and GLUT4 protein levels, selective inhibitors were used to inhibit these MAP kinases in 3T3-L1 adipocytes treated chronically with insulin. |
| 5961 | 12606502 | Inhibition of Erk 1/2, JNK, or p38 had no effect on insulin-stimulated reduction of IRS-1 protein levels. |
| 5962 | 12606502 | However, inhibition of the p38 pathway prevented the insulin-stimulated decrease in GLUT4 protein levels. |
| 5963 | 12606502 | In summary, type 2 diabetes is associated with an increased basal activation of the MAP kinase family. |
| 5964 | 12606502 | Furthermore, upregulation of the p38 pathway might contribute to the loss of GLUT4 expression observed in adipose tissue from type 2 diabetic patients. |
| 5965 | 12606502 | Enhanced basal activation of mitogen-activated protein kinases in adipocytes from type 2 diabetes: potential role of p38 in the downregulation of GLUT4 expression. |
| 5966 | 12606502 | To test the potential for members of the mitogen-activated protein (MAP) kinase family to contribute to type 2 diabetes, we examined basal and insulin-stimulated Erk 1/2, JNK, and p38 phosphorylation in adipocytes isolated from healthy and type 2 diabetic individuals. |
| 5967 | 12606502 | Maximal insulin stimulation increased the phosphorylation of Erk 1/2 and JNK in healthy control subjects but not type 2 diabetic patients. |
| 5968 | 12606502 | Insulin stimulation did not increase p38 phosphorylation in either healthy control subjects or type 2 diabetic patients. |
| 5969 | 12606502 | In type 2 diabetic adipocytes, the basal phosphorylation status of these MAP kinases was significantly elevated and was associated with decreased IRS-1 and GLUT4 in these fat cells. |
| 5970 | 12606502 | To determine whether MAP kinases were involved in the downregulation of IRS-1 and GLUT4 protein levels, selective inhibitors were used to inhibit these MAP kinases in 3T3-L1 adipocytes treated chronically with insulin. |
| 5971 | 12606502 | Inhibition of Erk 1/2, JNK, or p38 had no effect on insulin-stimulated reduction of IRS-1 protein levels. |
| 5972 | 12606502 | However, inhibition of the p38 pathway prevented the insulin-stimulated decrease in GLUT4 protein levels. |
| 5973 | 12606502 | In summary, type 2 diabetes is associated with an increased basal activation of the MAP kinase family. |
| 5974 | 12606502 | Furthermore, upregulation of the p38 pathway might contribute to the loss of GLUT4 expression observed in adipose tissue from type 2 diabetic patients. |
| 5975 | 12606502 | Enhanced basal activation of mitogen-activated protein kinases in adipocytes from type 2 diabetes: potential role of p38 in the downregulation of GLUT4 expression. |
| 5976 | 12606502 | To test the potential for members of the mitogen-activated protein (MAP) kinase family to contribute to type 2 diabetes, we examined basal and insulin-stimulated Erk 1/2, JNK, and p38 phosphorylation in adipocytes isolated from healthy and type 2 diabetic individuals. |
| 5977 | 12606502 | Maximal insulin stimulation increased the phosphorylation of Erk 1/2 and JNK in healthy control subjects but not type 2 diabetic patients. |
| 5978 | 12606502 | Insulin stimulation did not increase p38 phosphorylation in either healthy control subjects or type 2 diabetic patients. |
| 5979 | 12606502 | In type 2 diabetic adipocytes, the basal phosphorylation status of these MAP kinases was significantly elevated and was associated with decreased IRS-1 and GLUT4 in these fat cells. |
| 5980 | 12606502 | To determine whether MAP kinases were involved in the downregulation of IRS-1 and GLUT4 protein levels, selective inhibitors were used to inhibit these MAP kinases in 3T3-L1 adipocytes treated chronically with insulin. |
| 5981 | 12606502 | Inhibition of Erk 1/2, JNK, or p38 had no effect on insulin-stimulated reduction of IRS-1 protein levels. |
| 5982 | 12606502 | However, inhibition of the p38 pathway prevented the insulin-stimulated decrease in GLUT4 protein levels. |
| 5983 | 12606502 | In summary, type 2 diabetes is associated with an increased basal activation of the MAP kinase family. |
| 5984 | 12606502 | Furthermore, upregulation of the p38 pathway might contribute to the loss of GLUT4 expression observed in adipose tissue from type 2 diabetic patients. |
| 5985 | 12606535 | The Gly972-->Arg IRS-1 variant is associated with type 1 diabetes in continental Italy. |
| 5986 | 12606535 | We analyzed the relations between type 1 diabetes and the Arg(972) IRS-1 variant. |
| 5987 | 12606535 | The frequency of the IRS-1 Arg(972) variant was investigated in two independent sets of unrelated patients: a case-control study and a collection of type 1 diabetes simplex families. |
| 5988 | 12606535 | In the former group, frequency of the IRS-1 Arg(972) variant was significantly increased in the patients (P = 0.0008), conferring an OR of 2.5. |
| 5989 | 12606535 | Transmission disequilibrium analysis of data obtained from the family set revealed that the Arg(972) IRS-1 variant was transmitted from heterozygous parents to affected probands at a frequency of 70.2% (P < 0.02). |
| 5990 | 12606535 | Arg(972) IRS-1 frequency showed no significant correlation with HLA genotypic risk for type 1 diabetes. |
| 5991 | 12606535 | Arg(972) IRS-1 type 1 diabetic patients also had lower fasting plasma concentrations of C-peptide at the time of diagnosis with respect to patients carrying the wild-type IRS-1 (0.49 +/- 0.058, n = 34, and 0.76 +/- 0.066, n = 134, respectively [means +/- SE]; P = 0.051). |
| 5992 | 12606535 | Our findings suggest a role for Arg(972) IRS-1 in conferring risk for the development of type 1 diabetes. |
| 5993 | 12606535 | The Gly972-->Arg IRS-1 variant is associated with type 1 diabetes in continental Italy. |
| 5994 | 12606535 | We analyzed the relations between type 1 diabetes and the Arg(972) IRS-1 variant. |
| 5995 | 12606535 | The frequency of the IRS-1 Arg(972) variant was investigated in two independent sets of unrelated patients: a case-control study and a collection of type 1 diabetes simplex families. |
| 5996 | 12606535 | In the former group, frequency of the IRS-1 Arg(972) variant was significantly increased in the patients (P = 0.0008), conferring an OR of 2.5. |
| 5997 | 12606535 | Transmission disequilibrium analysis of data obtained from the family set revealed that the Arg(972) IRS-1 variant was transmitted from heterozygous parents to affected probands at a frequency of 70.2% (P < 0.02). |
| 5998 | 12606535 | Arg(972) IRS-1 frequency showed no significant correlation with HLA genotypic risk for type 1 diabetes. |
| 5999 | 12606535 | Arg(972) IRS-1 type 1 diabetic patients also had lower fasting plasma concentrations of C-peptide at the time of diagnosis with respect to patients carrying the wild-type IRS-1 (0.49 +/- 0.058, n = 34, and 0.76 +/- 0.066, n = 134, respectively [means +/- SE]; P = 0.051). |
| 6000 | 12606535 | Our findings suggest a role for Arg(972) IRS-1 in conferring risk for the development of type 1 diabetes. |
| 6001 | 12606535 | The Gly972-->Arg IRS-1 variant is associated with type 1 diabetes in continental Italy. |
| 6002 | 12606535 | We analyzed the relations between type 1 diabetes and the Arg(972) IRS-1 variant. |
| 6003 | 12606535 | The frequency of the IRS-1 Arg(972) variant was investigated in two independent sets of unrelated patients: a case-control study and a collection of type 1 diabetes simplex families. |
| 6004 | 12606535 | In the former group, frequency of the IRS-1 Arg(972) variant was significantly increased in the patients (P = 0.0008), conferring an OR of 2.5. |
| 6005 | 12606535 | Transmission disequilibrium analysis of data obtained from the family set revealed that the Arg(972) IRS-1 variant was transmitted from heterozygous parents to affected probands at a frequency of 70.2% (P < 0.02). |
| 6006 | 12606535 | Arg(972) IRS-1 frequency showed no significant correlation with HLA genotypic risk for type 1 diabetes. |
| 6007 | 12606535 | Arg(972) IRS-1 type 1 diabetic patients also had lower fasting plasma concentrations of C-peptide at the time of diagnosis with respect to patients carrying the wild-type IRS-1 (0.49 +/- 0.058, n = 34, and 0.76 +/- 0.066, n = 134, respectively [means +/- SE]; P = 0.051). |
| 6008 | 12606535 | Our findings suggest a role for Arg(972) IRS-1 in conferring risk for the development of type 1 diabetes. |
| 6009 | 12606535 | The Gly972-->Arg IRS-1 variant is associated with type 1 diabetes in continental Italy. |
| 6010 | 12606535 | We analyzed the relations between type 1 diabetes and the Arg(972) IRS-1 variant. |
| 6011 | 12606535 | The frequency of the IRS-1 Arg(972) variant was investigated in two independent sets of unrelated patients: a case-control study and a collection of type 1 diabetes simplex families. |
| 6012 | 12606535 | In the former group, frequency of the IRS-1 Arg(972) variant was significantly increased in the patients (P = 0.0008), conferring an OR of 2.5. |
| 6013 | 12606535 | Transmission disequilibrium analysis of data obtained from the family set revealed that the Arg(972) IRS-1 variant was transmitted from heterozygous parents to affected probands at a frequency of 70.2% (P < 0.02). |
| 6014 | 12606535 | Arg(972) IRS-1 frequency showed no significant correlation with HLA genotypic risk for type 1 diabetes. |
| 6015 | 12606535 | Arg(972) IRS-1 type 1 diabetic patients also had lower fasting plasma concentrations of C-peptide at the time of diagnosis with respect to patients carrying the wild-type IRS-1 (0.49 +/- 0.058, n = 34, and 0.76 +/- 0.066, n = 134, respectively [means +/- SE]; P = 0.051). |
| 6016 | 12606535 | Our findings suggest a role for Arg(972) IRS-1 in conferring risk for the development of type 1 diabetes. |
| 6017 | 12606535 | The Gly972-->Arg IRS-1 variant is associated with type 1 diabetes in continental Italy. |
| 6018 | 12606535 | We analyzed the relations between type 1 diabetes and the Arg(972) IRS-1 variant. |
| 6019 | 12606535 | The frequency of the IRS-1 Arg(972) variant was investigated in two independent sets of unrelated patients: a case-control study and a collection of type 1 diabetes simplex families. |
| 6020 | 12606535 | In the former group, frequency of the IRS-1 Arg(972) variant was significantly increased in the patients (P = 0.0008), conferring an OR of 2.5. |
| 6021 | 12606535 | Transmission disequilibrium analysis of data obtained from the family set revealed that the Arg(972) IRS-1 variant was transmitted from heterozygous parents to affected probands at a frequency of 70.2% (P < 0.02). |
| 6022 | 12606535 | Arg(972) IRS-1 frequency showed no significant correlation with HLA genotypic risk for type 1 diabetes. |
| 6023 | 12606535 | Arg(972) IRS-1 type 1 diabetic patients also had lower fasting plasma concentrations of C-peptide at the time of diagnosis with respect to patients carrying the wild-type IRS-1 (0.49 +/- 0.058, n = 34, and 0.76 +/- 0.066, n = 134, respectively [means +/- SE]; P = 0.051). |
| 6024 | 12606535 | Our findings suggest a role for Arg(972) IRS-1 in conferring risk for the development of type 1 diabetes. |
| 6025 | 12606535 | The Gly972-->Arg IRS-1 variant is associated with type 1 diabetes in continental Italy. |
| 6026 | 12606535 | We analyzed the relations between type 1 diabetes and the Arg(972) IRS-1 variant. |
| 6027 | 12606535 | The frequency of the IRS-1 Arg(972) variant was investigated in two independent sets of unrelated patients: a case-control study and a collection of type 1 diabetes simplex families. |
| 6028 | 12606535 | In the former group, frequency of the IRS-1 Arg(972) variant was significantly increased in the patients (P = 0.0008), conferring an OR of 2.5. |
| 6029 | 12606535 | Transmission disequilibrium analysis of data obtained from the family set revealed that the Arg(972) IRS-1 variant was transmitted from heterozygous parents to affected probands at a frequency of 70.2% (P < 0.02). |
| 6030 | 12606535 | Arg(972) IRS-1 frequency showed no significant correlation with HLA genotypic risk for type 1 diabetes. |
| 6031 | 12606535 | Arg(972) IRS-1 type 1 diabetic patients also had lower fasting plasma concentrations of C-peptide at the time of diagnosis with respect to patients carrying the wild-type IRS-1 (0.49 +/- 0.058, n = 34, and 0.76 +/- 0.066, n = 134, respectively [means +/- SE]; P = 0.051). |
| 6032 | 12606535 | Our findings suggest a role for Arg(972) IRS-1 in conferring risk for the development of type 1 diabetes. |
| 6033 | 12606535 | The Gly972-->Arg IRS-1 variant is associated with type 1 diabetes in continental Italy. |
| 6034 | 12606535 | We analyzed the relations between type 1 diabetes and the Arg(972) IRS-1 variant. |
| 6035 | 12606535 | The frequency of the IRS-1 Arg(972) variant was investigated in two independent sets of unrelated patients: a case-control study and a collection of type 1 diabetes simplex families. |
| 6036 | 12606535 | In the former group, frequency of the IRS-1 Arg(972) variant was significantly increased in the patients (P = 0.0008), conferring an OR of 2.5. |
| 6037 | 12606535 | Transmission disequilibrium analysis of data obtained from the family set revealed that the Arg(972) IRS-1 variant was transmitted from heterozygous parents to affected probands at a frequency of 70.2% (P < 0.02). |
| 6038 | 12606535 | Arg(972) IRS-1 frequency showed no significant correlation with HLA genotypic risk for type 1 diabetes. |
| 6039 | 12606535 | Arg(972) IRS-1 type 1 diabetic patients also had lower fasting plasma concentrations of C-peptide at the time of diagnosis with respect to patients carrying the wild-type IRS-1 (0.49 +/- 0.058, n = 34, and 0.76 +/- 0.066, n = 134, respectively [means +/- SE]; P = 0.051). |
| 6040 | 12606535 | Our findings suggest a role for Arg(972) IRS-1 in conferring risk for the development of type 1 diabetes. |
| 6041 | 12606535 | The Gly972-->Arg IRS-1 variant is associated with type 1 diabetes in continental Italy. |
| 6042 | 12606535 | We analyzed the relations between type 1 diabetes and the Arg(972) IRS-1 variant. |
| 6043 | 12606535 | The frequency of the IRS-1 Arg(972) variant was investigated in two independent sets of unrelated patients: a case-control study and a collection of type 1 diabetes simplex families. |
| 6044 | 12606535 | In the former group, frequency of the IRS-1 Arg(972) variant was significantly increased in the patients (P = 0.0008), conferring an OR of 2.5. |
| 6045 | 12606535 | Transmission disequilibrium analysis of data obtained from the family set revealed that the Arg(972) IRS-1 variant was transmitted from heterozygous parents to affected probands at a frequency of 70.2% (P < 0.02). |
| 6046 | 12606535 | Arg(972) IRS-1 frequency showed no significant correlation with HLA genotypic risk for type 1 diabetes. |
| 6047 | 12606535 | Arg(972) IRS-1 type 1 diabetic patients also had lower fasting plasma concentrations of C-peptide at the time of diagnosis with respect to patients carrying the wild-type IRS-1 (0.49 +/- 0.058, n = 34, and 0.76 +/- 0.066, n = 134, respectively [means +/- SE]; P = 0.051). |
| 6048 | 12606535 | Our findings suggest a role for Arg(972) IRS-1 in conferring risk for the development of type 1 diabetes. |
| 6049 | 12618360 | Resistin inhibits glucose uptake in L6 cells independently of changes in insulin signaling and GLUT4 translocation. |
| 6050 | 12618360 | Elevated levels of resistin have been proposed to cause insulin resistance and therefore may serve as a link between obesity and type 2 diabetes. |
| 6051 | 12618360 | In this study, we examined the effect of resistin on insulin-stimulated glucose uptake and the upstream insulin-signaling components in L6 rat skeletal muscle cells that were either incubated with recombinant resistin or stably transfected with a vector containing the myc-tagged mouse resistin gene. |
| 6052 | 12618360 | Incubation with recombinant resistin resulted in a dose-dependent inhibition of insulin-stimulated 2-deoxyglucose (2-DG) uptake. |
| 6053 | 12618360 | The inhibitory effect of resistin on insulin-stimulated 2-DG uptake was not the result of impaired GLUT4 translocation to the plasma membrane. |
| 6054 | 12618360 | Furthermore, resistin did not alter the insulin receptor (IR) content and its phosphorylation, nor did it affect insulin-stimulated insulin receptor substrate (IRS)-1 tyrosine phosphorylation, its association with the p85 subunit of phosphatidylinositol (PI) 3-kinase, or IRS-1-associated PI 3-kinase enzymatic activity. |
| 6055 | 12618360 | Insulin-stimulated phosphorylation of Akt/protein kinase B-alpha, one of the downstream targets of PI 3-kinase and p38 MAPK phosphorylation, was also not affected by resistin. |
| 6056 | 12618360 | Expression of resistin also inhibited insulin-stimulated 2-DG uptake when compared with cells expressing the empty vector (L6Neo) without affecting GLUT4 translocation, GLUT1 content, and IRS-1/PI 3-kinase signaling. |
| 6057 | 12618360 | We conclude that resistin does not alter IR signaling but does affect insulin-stimulated glucose uptake, presumably by decreasing the intrinsic activity of cell surface glucose transporters. |
| 6058 | 12639902 | In contrast to IRS-1 and IRS-2, IRS-4 exhibits a limited tissue expression, and IRS-4 protein has not been detected in any mouse or primary human tissue so far. |
| 6059 | 12639902 | The purpose of the present study was to analyze the expression of IRS-4 in rat muscle and human skeletal muscle cells and assess involvement of IRS-4 in initial insulin signaling. |
| 6060 | 12639902 | In human skeletal muscle cells, both IRS-1 and IRS-2 are rapidly phosphorylated on tyrosine in response to insulin, whereas essentially no tyrosine phosphorylation of IRS-4 was observed in response to both insulin and IGF-I. |
| 6061 | 12639902 | Our data suggest that IRS-4 does not function as a substrate of the insulin and the IGF-I receptor in primary muscle cells but may be involved in nonreceptor tyrosine kinase signaling. |
| 6062 | 12639902 | In contrast to IRS-1 and IRS-2, IRS-4 exhibits a limited tissue expression, and IRS-4 protein has not been detected in any mouse or primary human tissue so far. |
| 6063 | 12639902 | The purpose of the present study was to analyze the expression of IRS-4 in rat muscle and human skeletal muscle cells and assess involvement of IRS-4 in initial insulin signaling. |
| 6064 | 12639902 | In human skeletal muscle cells, both IRS-1 and IRS-2 are rapidly phosphorylated on tyrosine in response to insulin, whereas essentially no tyrosine phosphorylation of IRS-4 was observed in response to both insulin and IGF-I. |
| 6065 | 12639902 | Our data suggest that IRS-4 does not function as a substrate of the insulin and the IGF-I receptor in primary muscle cells but may be involved in nonreceptor tyrosine kinase signaling. |
| 6066 | 12644458 | High glucose inhibits insulin-stimulated nitric oxide production without reducing endothelial nitric-oxide synthase Ser1177 phosphorylation in human aortic endothelial cells. |
| 6067 | 12644458 | Recent studies have indicated that insulin activates endothelial nitric-oxide synthase (eNOS) by protein kinase B (PKB)-mediated phosphorylation at Ser1177 in endothelial cells. |
| 6068 | 12644458 | This was accompanied by reduced expression of IRS-2 and attenuated insulin-stimulated recruitment of PI3K to IRS-1 and IRS-2, yet insulin-stimulated PKB activity and phosphorylation of eNOS at Ser1177 were unaffected. |
| 6069 | 12644458 | Furthermore, high glucose down-regulated the expression of CAP and Cbl, and insulin-stimulated Cbl phosphorylation, components of an insulin signaling cascade previously characterized in adipocytes. |
| 6070 | 12644458 | These data suggest that high glucose specifically inhibits insulin-stimulated NO synthesis and down-regulates some aspects of insulin signaling, including the CAP-Cbl signaling pathway, yet this is not a result of reduced PKB-mediated eNOS phosphorylation at Ser1177. |
| 6071 | 12663464 | Defective signaling through Akt-2 and -3 but not Akt-1 in insulin-resistant human skeletal muscle: potential role in insulin resistance. |
| 6072 | 12663464 | Recent evidence has shown that activation of phosphatidyinositol-3-kinase (PI3K) and Akt, necessary for insulin stimulation of glucose transport, is impaired in insulin resistance. |
| 6073 | 12663464 | It is unknown, however, which Akt isoform shows impaired activation in insulin resistance. |
| 6074 | 12663464 | Additionally, related growth factors (epidermal or platelet-derived vascular) also stimulate PI3K, but it is unknown whether production of 3,4,5 phosphatidyinositol is sufficient to stimulate glucose transport in insulin-resistant muscle. |
| 6075 | 12663464 | Hence, we investigated the stimulation of PI3K and Akt-1, -2, and -3 by insulin and epidermal growth factors (EGFs) in skeletal muscles from lean and obese insulin-resistant humans. |
| 6076 | 12663464 | Insulin activated all Akt isoforms in lean muscles, whereas only Akt-1 was activated in obese muscles. |
| 6077 | 12663464 | Insulin receptor substrate (IRS)-1 was associated with PI3K activity, which is necessary for Akt activation by insulin, and was reduced in obese muscles, and this was accompanied by decreased IRS-1 expression. |
| 6078 | 12663464 | In contrast, insulin- or EGF-stimulated phosphotyrosine-associated PI3K activity was not different between lean and obese muscles. |
| 6079 | 12679424 | To investigate whether the T608R mutation impairs insulin signaling, we transiently transfected NIH-3T3(IR) cells with hemagglutinin-tagged wild-type or T608R mutant IRS-1 constructs. |
| 6080 | 12679424 | Recombinant IRS-1 immunoprecipitated from transfected cells treated with or without insulin was subjected to immunoblotting for the p85 regulatory subunit of PI 3-kinase as well as a PI 3-kinase assay. |
| 6081 | 12679424 | As expected, in control cells transfected with wild-type IRS-1, insulin stimulation caused an increase in p85 coimmunoprecipitated with IRS-1 as well as a 10-fold increase in IRS-1-associated PI 3-kinase activity. |
| 6082 | 12679424 | Interestingly, when cells transfected with IRS1-T608R were stimulated with insulin, both the amount of p85 coimmunoprecipitated with IRS1-T608R as well as the associated PI 3-kinase activity were approximately 50% less than those observed with wild-type IRS-1. |
| 6083 | 12679424 | Moreover, in rat adipose cells, overexpression of IRS1-T608R resulted in significantly less translocation of GLUT4 to the cell surface than comparable overexpression of wild-type IRS-1. |
| 6084 | 12679424 | We conclude that a naturally occurring substitution of Arg for Thr(608) in IRS-1 is a rare human mutation that may contribute to insulin resistance by impairing metabolic signaling through PI 3-kinase-dependent pathways. |
| 6085 | 12679424 | To investigate whether the T608R mutation impairs insulin signaling, we transiently transfected NIH-3T3(IR) cells with hemagglutinin-tagged wild-type or T608R mutant IRS-1 constructs. |
| 6086 | 12679424 | Recombinant IRS-1 immunoprecipitated from transfected cells treated with or without insulin was subjected to immunoblotting for the p85 regulatory subunit of PI 3-kinase as well as a PI 3-kinase assay. |
| 6087 | 12679424 | As expected, in control cells transfected with wild-type IRS-1, insulin stimulation caused an increase in p85 coimmunoprecipitated with IRS-1 as well as a 10-fold increase in IRS-1-associated PI 3-kinase activity. |
| 6088 | 12679424 | Interestingly, when cells transfected with IRS1-T608R were stimulated with insulin, both the amount of p85 coimmunoprecipitated with IRS1-T608R as well as the associated PI 3-kinase activity were approximately 50% less than those observed with wild-type IRS-1. |
| 6089 | 12679424 | Moreover, in rat adipose cells, overexpression of IRS1-T608R resulted in significantly less translocation of GLUT4 to the cell surface than comparable overexpression of wild-type IRS-1. |
| 6090 | 12679424 | We conclude that a naturally occurring substitution of Arg for Thr(608) in IRS-1 is a rare human mutation that may contribute to insulin resistance by impairing metabolic signaling through PI 3-kinase-dependent pathways. |
| 6091 | 12679424 | To investigate whether the T608R mutation impairs insulin signaling, we transiently transfected NIH-3T3(IR) cells with hemagglutinin-tagged wild-type or T608R mutant IRS-1 constructs. |
| 6092 | 12679424 | Recombinant IRS-1 immunoprecipitated from transfected cells treated with or without insulin was subjected to immunoblotting for the p85 regulatory subunit of PI 3-kinase as well as a PI 3-kinase assay. |
| 6093 | 12679424 | As expected, in control cells transfected with wild-type IRS-1, insulin stimulation caused an increase in p85 coimmunoprecipitated with IRS-1 as well as a 10-fold increase in IRS-1-associated PI 3-kinase activity. |
| 6094 | 12679424 | Interestingly, when cells transfected with IRS1-T608R were stimulated with insulin, both the amount of p85 coimmunoprecipitated with IRS1-T608R as well as the associated PI 3-kinase activity were approximately 50% less than those observed with wild-type IRS-1. |
| 6095 | 12679424 | Moreover, in rat adipose cells, overexpression of IRS1-T608R resulted in significantly less translocation of GLUT4 to the cell surface than comparable overexpression of wild-type IRS-1. |
| 6096 | 12679424 | We conclude that a naturally occurring substitution of Arg for Thr(608) in IRS-1 is a rare human mutation that may contribute to insulin resistance by impairing metabolic signaling through PI 3-kinase-dependent pathways. |
| 6097 | 12679424 | To investigate whether the T608R mutation impairs insulin signaling, we transiently transfected NIH-3T3(IR) cells with hemagglutinin-tagged wild-type or T608R mutant IRS-1 constructs. |
| 6098 | 12679424 | Recombinant IRS-1 immunoprecipitated from transfected cells treated with or without insulin was subjected to immunoblotting for the p85 regulatory subunit of PI 3-kinase as well as a PI 3-kinase assay. |
| 6099 | 12679424 | As expected, in control cells transfected with wild-type IRS-1, insulin stimulation caused an increase in p85 coimmunoprecipitated with IRS-1 as well as a 10-fold increase in IRS-1-associated PI 3-kinase activity. |
| 6100 | 12679424 | Interestingly, when cells transfected with IRS1-T608R were stimulated with insulin, both the amount of p85 coimmunoprecipitated with IRS1-T608R as well as the associated PI 3-kinase activity were approximately 50% less than those observed with wild-type IRS-1. |
| 6101 | 12679424 | Moreover, in rat adipose cells, overexpression of IRS1-T608R resulted in significantly less translocation of GLUT4 to the cell surface than comparable overexpression of wild-type IRS-1. |
| 6102 | 12679424 | We conclude that a naturally occurring substitution of Arg for Thr(608) in IRS-1 is a rare human mutation that may contribute to insulin resistance by impairing metabolic signaling through PI 3-kinase-dependent pathways. |
| 6103 | 12679424 | To investigate whether the T608R mutation impairs insulin signaling, we transiently transfected NIH-3T3(IR) cells with hemagglutinin-tagged wild-type or T608R mutant IRS-1 constructs. |
| 6104 | 12679424 | Recombinant IRS-1 immunoprecipitated from transfected cells treated with or without insulin was subjected to immunoblotting for the p85 regulatory subunit of PI 3-kinase as well as a PI 3-kinase assay. |
| 6105 | 12679424 | As expected, in control cells transfected with wild-type IRS-1, insulin stimulation caused an increase in p85 coimmunoprecipitated with IRS-1 as well as a 10-fold increase in IRS-1-associated PI 3-kinase activity. |
| 6106 | 12679424 | Interestingly, when cells transfected with IRS1-T608R were stimulated with insulin, both the amount of p85 coimmunoprecipitated with IRS1-T608R as well as the associated PI 3-kinase activity were approximately 50% less than those observed with wild-type IRS-1. |
| 6107 | 12679424 | Moreover, in rat adipose cells, overexpression of IRS1-T608R resulted in significantly less translocation of GLUT4 to the cell surface than comparable overexpression of wild-type IRS-1. |
| 6108 | 12679424 | We conclude that a naturally occurring substitution of Arg for Thr(608) in IRS-1 is a rare human mutation that may contribute to insulin resistance by impairing metabolic signaling through PI 3-kinase-dependent pathways. |
| 6109 | 12679424 | To investigate whether the T608R mutation impairs insulin signaling, we transiently transfected NIH-3T3(IR) cells with hemagglutinin-tagged wild-type or T608R mutant IRS-1 constructs. |
| 6110 | 12679424 | Recombinant IRS-1 immunoprecipitated from transfected cells treated with or without insulin was subjected to immunoblotting for the p85 regulatory subunit of PI 3-kinase as well as a PI 3-kinase assay. |
| 6111 | 12679424 | As expected, in control cells transfected with wild-type IRS-1, insulin stimulation caused an increase in p85 coimmunoprecipitated with IRS-1 as well as a 10-fold increase in IRS-1-associated PI 3-kinase activity. |
| 6112 | 12679424 | Interestingly, when cells transfected with IRS1-T608R were stimulated with insulin, both the amount of p85 coimmunoprecipitated with IRS1-T608R as well as the associated PI 3-kinase activity were approximately 50% less than those observed with wild-type IRS-1. |
| 6113 | 12679424 | Moreover, in rat adipose cells, overexpression of IRS1-T608R resulted in significantly less translocation of GLUT4 to the cell surface than comparable overexpression of wild-type IRS-1. |
| 6114 | 12679424 | We conclude that a naturally occurring substitution of Arg for Thr(608) in IRS-1 is a rare human mutation that may contribute to insulin resistance by impairing metabolic signaling through PI 3-kinase-dependent pathways. |
| 6115 | 12686100 | Semicarbazide-sensitive amine oxidase activity exerts insulin-like effects on glucose metabolism and insulin-signaling pathways in adipose cells. |
| 6116 | 12686100 | Semicarbazide-sensitive amine oxidase (SSAO) is very abundant at the plasma membrane in adipocytes. |
| 6117 | 12686100 | The combination of SSAO substrates and low concentrations of vanadate markedly stimulates glucose transport and GLUT4 glucose transporter recruitment to the cell surface in rat adipocytes by a mechanism that requires SSAO activity and hydrogen peroxide formation. |
| 6118 | 12686100 | Substrates of SSAO such as benzylamine or tyramine in combination with vanadate potently stimulate tyrosine phosphorylation of both insulin-receptor substrates 1 (IRS-1) and 3 (IRS-3) and phosphatidylinositol 3-kinase (PI 3-kinase) activity in adipose cells, which occurs in the presence of a weak stimulation of insulin-receptor kinase. |
| 6119 | 12686100 | Based on these observations, we propose that SSAO activity and vanadate potently mimic insulin effects in adipose cells and exert an anti-diabetic action in an animal model of type 1 diabetes mellitus. |
| 6120 | 12714600 | Aspirin inhibits serine phosphorylation of insulin receptor substrate 1 in tumor necrosis factor-treated cells through targeting multiple serine kinases. |
| 6121 | 12714600 | In this study, we analyzed the effects of aspirin (acetylsalicylic acid) on serine phosphorylation of insulin receptor substrate 1 (IRS-1) in cells treated with tumor necrosis factor (TNF)-alpha. |
| 6122 | 12714600 | In 3T3-L1 and Hep G2 cells, phosphorylation of IRS-1 at Ser307 in response to TNF-alpha treatment correlated with phosphorylation of JNK, c-Jun, and degradation of IkappaBalpha. |
| 6123 | 12714600 | Moreover, phosphorylation of IRS-1 at Ser307 in embryo fibroblasts derived from either JNK or IKK knockout mice was reduced when compared with that in the wild-type controls. |
| 6124 | 12714600 | Taken together, these data suggest that serine phosphorylation of IRS-1 in response to TNF-alpha is mediated, in part, by JNK and IKK. |
| 6125 | 12714600 | Interestingly, aspirin treatment inhibited the phosphorylation of IRS-1 at Ser307 as well as the phosphorylation of JNK, c-Jun, and degradation of IkappaBalpha. |
| 6126 | 12714600 | Furthermore, other serine kinases including Akt, extracellular regulated kinase, mammalian target of rapamycin, and PKCzeta were also activated by TNF-alpha (as assessed by phospho-specific antibodies). |
| 6127 | 12714600 | Phosphorylation of Akt and the mammalian target of rapamycin (but not extracellular regulated kinase or PKCzeta) in response to TNF-alpha was inhibited by aspirin treatment. |
| 6128 | 12714600 | Finally, aspirin rescued insulin-induced glucose uptake in 3T3-L1 adipocytes pretreated with TNF-alpha. |
| 6129 | 12714600 | Aspirin inhibits serine phosphorylation of insulin receptor substrate 1 in tumor necrosis factor-treated cells through targeting multiple serine kinases. |
| 6130 | 12714600 | In this study, we analyzed the effects of aspirin (acetylsalicylic acid) on serine phosphorylation of insulin receptor substrate 1 (IRS-1) in cells treated with tumor necrosis factor (TNF)-alpha. |
| 6131 | 12714600 | In 3T3-L1 and Hep G2 cells, phosphorylation of IRS-1 at Ser307 in response to TNF-alpha treatment correlated with phosphorylation of JNK, c-Jun, and degradation of IkappaBalpha. |
| 6132 | 12714600 | Moreover, phosphorylation of IRS-1 at Ser307 in embryo fibroblasts derived from either JNK or IKK knockout mice was reduced when compared with that in the wild-type controls. |
| 6133 | 12714600 | Taken together, these data suggest that serine phosphorylation of IRS-1 in response to TNF-alpha is mediated, in part, by JNK and IKK. |
| 6134 | 12714600 | Interestingly, aspirin treatment inhibited the phosphorylation of IRS-1 at Ser307 as well as the phosphorylation of JNK, c-Jun, and degradation of IkappaBalpha. |
| 6135 | 12714600 | Furthermore, other serine kinases including Akt, extracellular regulated kinase, mammalian target of rapamycin, and PKCzeta were also activated by TNF-alpha (as assessed by phospho-specific antibodies). |
| 6136 | 12714600 | Phosphorylation of Akt and the mammalian target of rapamycin (but not extracellular regulated kinase or PKCzeta) in response to TNF-alpha was inhibited by aspirin treatment. |
| 6137 | 12714600 | Finally, aspirin rescued insulin-induced glucose uptake in 3T3-L1 adipocytes pretreated with TNF-alpha. |
| 6138 | 12714600 | Aspirin inhibits serine phosphorylation of insulin receptor substrate 1 in tumor necrosis factor-treated cells through targeting multiple serine kinases. |
| 6139 | 12714600 | In this study, we analyzed the effects of aspirin (acetylsalicylic acid) on serine phosphorylation of insulin receptor substrate 1 (IRS-1) in cells treated with tumor necrosis factor (TNF)-alpha. |
| 6140 | 12714600 | In 3T3-L1 and Hep G2 cells, phosphorylation of IRS-1 at Ser307 in response to TNF-alpha treatment correlated with phosphorylation of JNK, c-Jun, and degradation of IkappaBalpha. |
| 6141 | 12714600 | Moreover, phosphorylation of IRS-1 at Ser307 in embryo fibroblasts derived from either JNK or IKK knockout mice was reduced when compared with that in the wild-type controls. |
| 6142 | 12714600 | Taken together, these data suggest that serine phosphorylation of IRS-1 in response to TNF-alpha is mediated, in part, by JNK and IKK. |
| 6143 | 12714600 | Interestingly, aspirin treatment inhibited the phosphorylation of IRS-1 at Ser307 as well as the phosphorylation of JNK, c-Jun, and degradation of IkappaBalpha. |
| 6144 | 12714600 | Furthermore, other serine kinases including Akt, extracellular regulated kinase, mammalian target of rapamycin, and PKCzeta were also activated by TNF-alpha (as assessed by phospho-specific antibodies). |
| 6145 | 12714600 | Phosphorylation of Akt and the mammalian target of rapamycin (but not extracellular regulated kinase or PKCzeta) in response to TNF-alpha was inhibited by aspirin treatment. |
| 6146 | 12714600 | Finally, aspirin rescued insulin-induced glucose uptake in 3T3-L1 adipocytes pretreated with TNF-alpha. |
| 6147 | 12714600 | Aspirin inhibits serine phosphorylation of insulin receptor substrate 1 in tumor necrosis factor-treated cells through targeting multiple serine kinases. |
| 6148 | 12714600 | In this study, we analyzed the effects of aspirin (acetylsalicylic acid) on serine phosphorylation of insulin receptor substrate 1 (IRS-1) in cells treated with tumor necrosis factor (TNF)-alpha. |
| 6149 | 12714600 | In 3T3-L1 and Hep G2 cells, phosphorylation of IRS-1 at Ser307 in response to TNF-alpha treatment correlated with phosphorylation of JNK, c-Jun, and degradation of IkappaBalpha. |
| 6150 | 12714600 | Moreover, phosphorylation of IRS-1 at Ser307 in embryo fibroblasts derived from either JNK or IKK knockout mice was reduced when compared with that in the wild-type controls. |
| 6151 | 12714600 | Taken together, these data suggest that serine phosphorylation of IRS-1 in response to TNF-alpha is mediated, in part, by JNK and IKK. |
| 6152 | 12714600 | Interestingly, aspirin treatment inhibited the phosphorylation of IRS-1 at Ser307 as well as the phosphorylation of JNK, c-Jun, and degradation of IkappaBalpha. |
| 6153 | 12714600 | Furthermore, other serine kinases including Akt, extracellular regulated kinase, mammalian target of rapamycin, and PKCzeta were also activated by TNF-alpha (as assessed by phospho-specific antibodies). |
| 6154 | 12714600 | Phosphorylation of Akt and the mammalian target of rapamycin (but not extracellular regulated kinase or PKCzeta) in response to TNF-alpha was inhibited by aspirin treatment. |
| 6155 | 12714600 | Finally, aspirin rescued insulin-induced glucose uptake in 3T3-L1 adipocytes pretreated with TNF-alpha. |
| 6156 | 12714600 | Aspirin inhibits serine phosphorylation of insulin receptor substrate 1 in tumor necrosis factor-treated cells through targeting multiple serine kinases. |
| 6157 | 12714600 | In this study, we analyzed the effects of aspirin (acetylsalicylic acid) on serine phosphorylation of insulin receptor substrate 1 (IRS-1) in cells treated with tumor necrosis factor (TNF)-alpha. |
| 6158 | 12714600 | In 3T3-L1 and Hep G2 cells, phosphorylation of IRS-1 at Ser307 in response to TNF-alpha treatment correlated with phosphorylation of JNK, c-Jun, and degradation of IkappaBalpha. |
| 6159 | 12714600 | Moreover, phosphorylation of IRS-1 at Ser307 in embryo fibroblasts derived from either JNK or IKK knockout mice was reduced when compared with that in the wild-type controls. |
| 6160 | 12714600 | Taken together, these data suggest that serine phosphorylation of IRS-1 in response to TNF-alpha is mediated, in part, by JNK and IKK. |
| 6161 | 12714600 | Interestingly, aspirin treatment inhibited the phosphorylation of IRS-1 at Ser307 as well as the phosphorylation of JNK, c-Jun, and degradation of IkappaBalpha. |
| 6162 | 12714600 | Furthermore, other serine kinases including Akt, extracellular regulated kinase, mammalian target of rapamycin, and PKCzeta were also activated by TNF-alpha (as assessed by phospho-specific antibodies). |
| 6163 | 12714600 | Phosphorylation of Akt and the mammalian target of rapamycin (but not extracellular regulated kinase or PKCzeta) in response to TNF-alpha was inhibited by aspirin treatment. |
| 6164 | 12714600 | Finally, aspirin rescued insulin-induced glucose uptake in 3T3-L1 adipocytes pretreated with TNF-alpha. |
| 6165 | 12714600 | Aspirin inhibits serine phosphorylation of insulin receptor substrate 1 in tumor necrosis factor-treated cells through targeting multiple serine kinases. |
| 6166 | 12714600 | In this study, we analyzed the effects of aspirin (acetylsalicylic acid) on serine phosphorylation of insulin receptor substrate 1 (IRS-1) in cells treated with tumor necrosis factor (TNF)-alpha. |
| 6167 | 12714600 | In 3T3-L1 and Hep G2 cells, phosphorylation of IRS-1 at Ser307 in response to TNF-alpha treatment correlated with phosphorylation of JNK, c-Jun, and degradation of IkappaBalpha. |
| 6168 | 12714600 | Moreover, phosphorylation of IRS-1 at Ser307 in embryo fibroblasts derived from either JNK or IKK knockout mice was reduced when compared with that in the wild-type controls. |
| 6169 | 12714600 | Taken together, these data suggest that serine phosphorylation of IRS-1 in response to TNF-alpha is mediated, in part, by JNK and IKK. |
| 6170 | 12714600 | Interestingly, aspirin treatment inhibited the phosphorylation of IRS-1 at Ser307 as well as the phosphorylation of JNK, c-Jun, and degradation of IkappaBalpha. |
| 6171 | 12714600 | Furthermore, other serine kinases including Akt, extracellular regulated kinase, mammalian target of rapamycin, and PKCzeta were also activated by TNF-alpha (as assessed by phospho-specific antibodies). |
| 6172 | 12714600 | Phosphorylation of Akt and the mammalian target of rapamycin (but not extracellular regulated kinase or PKCzeta) in response to TNF-alpha was inhibited by aspirin treatment. |
| 6173 | 12714600 | Finally, aspirin rescued insulin-induced glucose uptake in 3T3-L1 adipocytes pretreated with TNF-alpha. |
| 6174 | 12730241 | Because the other known PH-PTB proteins (insulin receptor substrates: IRS-1, IRS-2, IRS-3, and IRS-4, and the downstream of kinases: DOK-1, DOK-2, and DOK-3) are substrates of insulin and insulin-like growth factor (IGF)-1 receptors, we asked whether these new proteins, termed IRS5/DOK4 and IRS6/DOK5, might also have roles in insulin and IGF-1 signaling. |
| 6175 | 12730241 | Both proteins are tyrosine-phosphorylated in response to insulin and IGF-1 in transfected cells, although the kinetics differ. |
| 6176 | 12730241 | Insulin receptor-phosphorylated IRS5/DOK4 associates with RasGAP, Crk, Src, and Fyn, but not phosphatidylinositol 3-kinase p85, Grb2, SHP-2, Nck, or phospholipase Cgamma Src homology 2 domains, and activates MAPK in cells. |
| 6177 | 12730241 | IRS5/DOK4 and IRS6/DOK5 represent two new signaling proteins with potential roles in insulin and IGF-1 action. |
| 6178 | 12734206 | Interaction of filamin A with the insulin receptor alters insulin-dependent activation of the mitogen-activated protein kinase pathway. |
| 6179 | 12734206 | Even though this event requires the participation of actin-binding proteins, the effect of filamin A (FLNa) on insulin-mediated signaling events is still unknown. |
| 6180 | 12734206 | We report here that human melanoma M2 cells lacking FLNa expression exhibited normal insulin receptor (IR) signaling, whereas FLNa-expressing A7 cells were unable to elicit insulin-dependent Shc tyrosine phosphorylation and p42/44 MAPK activation despite no significant defect in IR-stimulated phosphorylation of insulin receptor substrate-1 or activation of the phosphatidylinositol 3-kinase/AKT cascade. |
| 6181 | 12734206 | Insulin-dependent translocation of Shc, SOS1, and MAPK to lipid raft microdomains was markedly attenuated by FLNa expression. |
| 6182 | 12734206 | Coimmunoprecipitation experiments and in vitro binding assays demonstrated that FLNa binds constitutively to IR and that neither insulin nor depolymerization of actin by cytochalasin D affected this interaction. |
| 6183 | 12734206 | Ectopic expression of a C-terminal fragment of FLNa (FLNaCT) in HepG2 cells blocked the endogenous IR-FLNa interaction and potentiated insulin-stimulated MAPK phosphorylation and transactivation of Elk-1 compared with vector-transfected cells. |
| 6184 | 12734206 | Expression of FLNaCT had no major effect on insulin-induced phosphorylation of the IR, insulin receptor substrate-1, or AKT, but it elicited changes in actin cytoskeletal structure and ruffle formation in HepG2 cells. |
| 6185 | 12734206 | Taken together, these results indicate that FLNa interacts constitutively with the IR to exert an inhibitory tone along the MAPK activation pathway. |
| 6186 | 12734206 | Interaction of filamin A with the insulin receptor alters insulin-dependent activation of the mitogen-activated protein kinase pathway. |
| 6187 | 12734206 | Even though this event requires the participation of actin-binding proteins, the effect of filamin A (FLNa) on insulin-mediated signaling events is still unknown. |
| 6188 | 12734206 | We report here that human melanoma M2 cells lacking FLNa expression exhibited normal insulin receptor (IR) signaling, whereas FLNa-expressing A7 cells were unable to elicit insulin-dependent Shc tyrosine phosphorylation and p42/44 MAPK activation despite no significant defect in IR-stimulated phosphorylation of insulin receptor substrate-1 or activation of the phosphatidylinositol 3-kinase/AKT cascade. |
| 6189 | 12734206 | Insulin-dependent translocation of Shc, SOS1, and MAPK to lipid raft microdomains was markedly attenuated by FLNa expression. |
| 6190 | 12734206 | Coimmunoprecipitation experiments and in vitro binding assays demonstrated that FLNa binds constitutively to IR and that neither insulin nor depolymerization of actin by cytochalasin D affected this interaction. |
| 6191 | 12734206 | Ectopic expression of a C-terminal fragment of FLNa (FLNaCT) in HepG2 cells blocked the endogenous IR-FLNa interaction and potentiated insulin-stimulated MAPK phosphorylation and transactivation of Elk-1 compared with vector-transfected cells. |
| 6192 | 12734206 | Expression of FLNaCT had no major effect on insulin-induced phosphorylation of the IR, insulin receptor substrate-1, or AKT, but it elicited changes in actin cytoskeletal structure and ruffle formation in HepG2 cells. |
| 6193 | 12734206 | Taken together, these results indicate that FLNa interacts constitutively with the IR to exert an inhibitory tone along the MAPK activation pathway. |
| 6194 | 12765939 | Reduced activation of phosphatidylinositol-3 kinase and increased serine 636 phosphorylation of insulin receptor substrate-1 in primary culture of skeletal muscle cells from patients with type 2 diabetes. |
| 6195 | 12765939 | When compared with cells from control subjects, myotubes established from patients with type 2 diabetes presented the same defects as those previously evidenced in vivo in muscle biopsies, including defective stimulation of phosphatidylinositol (PI) 3-kinase activity, decreased association of PI 3-kinase with insulin receptor substrate (IRS)-1 and reduced IRS-1 tyrosine phosphorylation during insulin stimulation. |
| 6196 | 12765939 | In contrast to IRS-1, the signaling through IRS-2 was not altered. |
| 6197 | 12765939 | These results suggest that IRS-1 phosphorylation on serine 636 might be involved in the reduced phosphorylation of IRS-1 on tyrosine and in the subsequent alteration of insulin-induced PI 3-kinase activation. |
| 6198 | 12765939 | Moreover, increased MAPK activity seems to play a role in the phosphorylation of IRS-1 on serine residue in human muscle cells. |
| 6199 | 12765939 | Reduced activation of phosphatidylinositol-3 kinase and increased serine 636 phosphorylation of insulin receptor substrate-1 in primary culture of skeletal muscle cells from patients with type 2 diabetes. |
| 6200 | 12765939 | When compared with cells from control subjects, myotubes established from patients with type 2 diabetes presented the same defects as those previously evidenced in vivo in muscle biopsies, including defective stimulation of phosphatidylinositol (PI) 3-kinase activity, decreased association of PI 3-kinase with insulin receptor substrate (IRS)-1 and reduced IRS-1 tyrosine phosphorylation during insulin stimulation. |
| 6201 | 12765939 | In contrast to IRS-1, the signaling through IRS-2 was not altered. |
| 6202 | 12765939 | These results suggest that IRS-1 phosphorylation on serine 636 might be involved in the reduced phosphorylation of IRS-1 on tyrosine and in the subsequent alteration of insulin-induced PI 3-kinase activation. |
| 6203 | 12765939 | Moreover, increased MAPK activity seems to play a role in the phosphorylation of IRS-1 on serine residue in human muscle cells. |
| 6204 | 12765939 | Reduced activation of phosphatidylinositol-3 kinase and increased serine 636 phosphorylation of insulin receptor substrate-1 in primary culture of skeletal muscle cells from patients with type 2 diabetes. |
| 6205 | 12765939 | When compared with cells from control subjects, myotubes established from patients with type 2 diabetes presented the same defects as those previously evidenced in vivo in muscle biopsies, including defective stimulation of phosphatidylinositol (PI) 3-kinase activity, decreased association of PI 3-kinase with insulin receptor substrate (IRS)-1 and reduced IRS-1 tyrosine phosphorylation during insulin stimulation. |
| 6206 | 12765939 | In contrast to IRS-1, the signaling through IRS-2 was not altered. |
| 6207 | 12765939 | These results suggest that IRS-1 phosphorylation on serine 636 might be involved in the reduced phosphorylation of IRS-1 on tyrosine and in the subsequent alteration of insulin-induced PI 3-kinase activation. |
| 6208 | 12765939 | Moreover, increased MAPK activity seems to play a role in the phosphorylation of IRS-1 on serine residue in human muscle cells. |
| 6209 | 12765939 | Reduced activation of phosphatidylinositol-3 kinase and increased serine 636 phosphorylation of insulin receptor substrate-1 in primary culture of skeletal muscle cells from patients with type 2 diabetes. |
| 6210 | 12765939 | When compared with cells from control subjects, myotubes established from patients with type 2 diabetes presented the same defects as those previously evidenced in vivo in muscle biopsies, including defective stimulation of phosphatidylinositol (PI) 3-kinase activity, decreased association of PI 3-kinase with insulin receptor substrate (IRS)-1 and reduced IRS-1 tyrosine phosphorylation during insulin stimulation. |
| 6211 | 12765939 | In contrast to IRS-1, the signaling through IRS-2 was not altered. |
| 6212 | 12765939 | These results suggest that IRS-1 phosphorylation on serine 636 might be involved in the reduced phosphorylation of IRS-1 on tyrosine and in the subsequent alteration of insulin-induced PI 3-kinase activation. |
| 6213 | 12765939 | Moreover, increased MAPK activity seems to play a role in the phosphorylation of IRS-1 on serine residue in human muscle cells. |
| 6214 | 12765939 | Reduced activation of phosphatidylinositol-3 kinase and increased serine 636 phosphorylation of insulin receptor substrate-1 in primary culture of skeletal muscle cells from patients with type 2 diabetes. |
| 6215 | 12765939 | When compared with cells from control subjects, myotubes established from patients with type 2 diabetes presented the same defects as those previously evidenced in vivo in muscle biopsies, including defective stimulation of phosphatidylinositol (PI) 3-kinase activity, decreased association of PI 3-kinase with insulin receptor substrate (IRS)-1 and reduced IRS-1 tyrosine phosphorylation during insulin stimulation. |
| 6216 | 12765939 | In contrast to IRS-1, the signaling through IRS-2 was not altered. |
| 6217 | 12765939 | These results suggest that IRS-1 phosphorylation on serine 636 might be involved in the reduced phosphorylation of IRS-1 on tyrosine and in the subsequent alteration of insulin-induced PI 3-kinase activation. |
| 6218 | 12765939 | Moreover, increased MAPK activity seems to play a role in the phosphorylation of IRS-1 on serine residue in human muscle cells. |
| 6219 | 12765944 | Involvement of AMP-activated protein kinase in glucose uptake stimulated by the globular domain of adiponectin in primary rat adipocytes. |
| 6220 | 12765944 | Adiponectin is an abundant adipocyte-derived plasma protein with anti-atherosclerotic and insulin-sensitizing properties that suppresses hepatic glucose production and enhances glucose uptake into skeletal muscle. |
| 6221 | 12765944 | Globular adiponectin increased glucose uptake in adipocytes without stimulating tyrosine phosphorylation of the insulin receptor or insulin receptor substrate-1, and without enhancing phosphorylation of Akt on Ser-473. |
| 6222 | 12765944 | Globular adiponectin further enhanced insulin-stimulated glucose uptake at submaximal insulin concentrations and reversed the inhibitory effect of tumor necrosis factor-alpha on insulin-stimulated glucose uptake. |
| 6223 | 12765944 | Cellular treatment with globular adiponectin increased the Thr-172 phosphorylation and catalytic activity of AMP-activated protein kinase and enhanced the Ser-79 phosphorylation of acetyl CoA carboxylase, an enzyme downstream of AMP kinase in adipose cells. |
| 6224 | 12767053 | Angiotensin converting enzyme (ACE) inhibitors are a widely used intervention for blood pressure control, and are particularly beneficial in hypertensive type 2 diabetic subjects with insulin resistance. |
| 6225 | 12767053 | The hemodynamic effects of ACE inhibitors are associated with enhanced levels of the vasodilator bradykinin and decreased production of the vasoconstrictor and growth factor angiotensin II (ATII). |
| 6226 | 12767053 | In insulin-resistant conditions, ACE inhibitors can also enhance whole-body glucose disposal and glucose transport activity in skeletal muscle. |
| 6227 | 12767053 | This review will focus on the metabolic consequences of ACE inhibition in insulin resistance. |
| 6228 | 12767053 | At the cellular level, ACE inhibitors acutely enhance glucose uptake in insulin-resistant skeletal muscle via two mechanisms. |
| 6229 | 12767053 | The acute actions of ACE inhibitors on skeletal muscle glucose transport are associated with upregulation of insulin signaling, including enhanced IRS-1 tyrosine phosphorylation and phosphatidylinositol-3-kinase activity, and ultimately with increased cell-surface GLUT-4 glucose transporter protein. |
| 6230 | 12767053 | Chronic administration of ACE inhibitors or AT(1) antagonists to insulin-resistant rodents can increase protein expression of GLUT-4 in skeletal muscle and myocardium. |
| 6231 | 12767053 | These data support the concept that ACE inhibitors can beneficially modulate glucose control in insulin-resistant states, possibly through a NO-dependent effect of bradykinin and/or antagonism of ATII action on skeletal muscle. |
| 6232 | 12775712 | Characterization of multiple signaling pathways of insulin in the regulation of vascular endothelial growth factor expression in vascular cells and angiogenesis. |
| 6233 | 12775712 | The effects of insulin on vascular endothelial growth factor (VEGF) expression in cultured vascular cells and in angiogenesis were characterized. |
| 6234 | 12775712 | Insulin increased VEGF mRNA levels in mouse aortic smooth muscle cells from 10(-9) to 10(-7) m with an initial peak of 3.7-fold increases at 1 h and a second peak of 2.8-fold after 12 h. |
| 6235 | 12775712 | The first peak of VEGF expression was inhibited by LY294002, an inhibitor of phosphatidylinositol (PI) 3-kinase, and by the overexpression of dominant negative forms of p85 subunit of PI 3-kinase or Akt. |
| 6236 | 12775712 | In contrast, the chronic effect of insulin on VEGF expression was partially inhibited by both LY294002 or PD98059 as well as by the overexpression of dominant negatives of PI 3-kinase or Ras. |
| 6237 | 12775712 | The importance of PI 3-kinase-Akt pathway on VEGF expression was confirmed in mouse aortic smooth muscle cells isolated from insulin receptor substrate -1 knockout (IRS-1-/-) mice that showed parallel reductions of 46-49% in insulin-stimulated VEGF expression and PI 3-kinase-Akt activation. |
| 6238 | 12775712 | Insulin-induced activation of PI 3-kinase-Akt on hypoxia-induced VEGF expression and neovascularization was reduced by 40% in the retina of neonatal hypoxia model using IRS-1-/- mice. |
| 6239 | 12775712 | Thus, unlike other cells, insulin can regulate VEGF expression by both IRS-1/PI 3-kinase-Akt cascade and Ras-MAPK pathways in aortic smooth muscle cells. |
| 6240 | 12775712 | The in vivo results provide direct evidence that insulin can modulate hypoxia-induced angiogenesis via reduction in VEGF expression in vivo. |
| 6241 | 12775712 | Characterization of multiple signaling pathways of insulin in the regulation of vascular endothelial growth factor expression in vascular cells and angiogenesis. |
| 6242 | 12775712 | The effects of insulin on vascular endothelial growth factor (VEGF) expression in cultured vascular cells and in angiogenesis were characterized. |
| 6243 | 12775712 | Insulin increased VEGF mRNA levels in mouse aortic smooth muscle cells from 10(-9) to 10(-7) m with an initial peak of 3.7-fold increases at 1 h and a second peak of 2.8-fold after 12 h. |
| 6244 | 12775712 | The first peak of VEGF expression was inhibited by LY294002, an inhibitor of phosphatidylinositol (PI) 3-kinase, and by the overexpression of dominant negative forms of p85 subunit of PI 3-kinase or Akt. |
| 6245 | 12775712 | In contrast, the chronic effect of insulin on VEGF expression was partially inhibited by both LY294002 or PD98059 as well as by the overexpression of dominant negatives of PI 3-kinase or Ras. |
| 6246 | 12775712 | The importance of PI 3-kinase-Akt pathway on VEGF expression was confirmed in mouse aortic smooth muscle cells isolated from insulin receptor substrate -1 knockout (IRS-1-/-) mice that showed parallel reductions of 46-49% in insulin-stimulated VEGF expression and PI 3-kinase-Akt activation. |
| 6247 | 12775712 | Insulin-induced activation of PI 3-kinase-Akt on hypoxia-induced VEGF expression and neovascularization was reduced by 40% in the retina of neonatal hypoxia model using IRS-1-/- mice. |
| 6248 | 12775712 | Thus, unlike other cells, insulin can regulate VEGF expression by both IRS-1/PI 3-kinase-Akt cascade and Ras-MAPK pathways in aortic smooth muscle cells. |
| 6249 | 12775712 | The in vivo results provide direct evidence that insulin can modulate hypoxia-induced angiogenesis via reduction in VEGF expression in vivo. |
| 6250 | 12800089 | Here we show that simultaneous inhibition of IRS-1 tyrosine dephosphorylation and proteasomal degradation synergistically augments insulin-responsive glucose uptake. |
| 6251 | 12800089 | L6 skeletal muscle cells (L6 cells) were treated with inhibitors of protein-tyrosine phosphatases, proteasomal degradation, and mammalian target of rapamycin (mTOR), and the effects of insulin on glucose uptake, IRS-1 tyrosine phosphorylation, phosphatidylinositol (PI) 3-kinase activity, and IRS-1 mass were examined. |
| 6252 | 12800089 | Evaluation of IRS-1 associated PI 3-kinase activity, IRS-1-associated p85 mass, and IRS-1 tyrosine phosphorylation showed that 2 hours after insulin addition they were reduced by 70% from maximal activity. |
| 6253 | 12800089 | When L6 cells were pretreated with Na(3)VO(4) plus the proteasome inhibitor MG-132 or the mTOR inhibitor rapamycin prior to insulin addition, IRS-1 mass loss as well as IRS-1/PI-3 kinase complex decay was blocked at 2 hours and PI 3-kinase activity was increased 2.5-fold and 4-fold, respectively, over insulin alone. |
| 6254 | 12800089 | Here we show that simultaneous inhibition of IRS-1 tyrosine dephosphorylation and proteasomal degradation synergistically augments insulin-responsive glucose uptake. |
| 6255 | 12800089 | L6 skeletal muscle cells (L6 cells) were treated with inhibitors of protein-tyrosine phosphatases, proteasomal degradation, and mammalian target of rapamycin (mTOR), and the effects of insulin on glucose uptake, IRS-1 tyrosine phosphorylation, phosphatidylinositol (PI) 3-kinase activity, and IRS-1 mass were examined. |
| 6256 | 12800089 | Evaluation of IRS-1 associated PI 3-kinase activity, IRS-1-associated p85 mass, and IRS-1 tyrosine phosphorylation showed that 2 hours after insulin addition they were reduced by 70% from maximal activity. |
| 6257 | 12800089 | When L6 cells were pretreated with Na(3)VO(4) plus the proteasome inhibitor MG-132 or the mTOR inhibitor rapamycin prior to insulin addition, IRS-1 mass loss as well as IRS-1/PI-3 kinase complex decay was blocked at 2 hours and PI 3-kinase activity was increased 2.5-fold and 4-fold, respectively, over insulin alone. |
| 6258 | 12800089 | Here we show that simultaneous inhibition of IRS-1 tyrosine dephosphorylation and proteasomal degradation synergistically augments insulin-responsive glucose uptake. |
| 6259 | 12800089 | L6 skeletal muscle cells (L6 cells) were treated with inhibitors of protein-tyrosine phosphatases, proteasomal degradation, and mammalian target of rapamycin (mTOR), and the effects of insulin on glucose uptake, IRS-1 tyrosine phosphorylation, phosphatidylinositol (PI) 3-kinase activity, and IRS-1 mass were examined. |
| 6260 | 12800089 | Evaluation of IRS-1 associated PI 3-kinase activity, IRS-1-associated p85 mass, and IRS-1 tyrosine phosphorylation showed that 2 hours after insulin addition they were reduced by 70% from maximal activity. |
| 6261 | 12800089 | When L6 cells were pretreated with Na(3)VO(4) plus the proteasome inhibitor MG-132 or the mTOR inhibitor rapamycin prior to insulin addition, IRS-1 mass loss as well as IRS-1/PI-3 kinase complex decay was blocked at 2 hours and PI 3-kinase activity was increased 2.5-fold and 4-fold, respectively, over insulin alone. |
| 6262 | 12800089 | Here we show that simultaneous inhibition of IRS-1 tyrosine dephosphorylation and proteasomal degradation synergistically augments insulin-responsive glucose uptake. |
| 6263 | 12800089 | L6 skeletal muscle cells (L6 cells) were treated with inhibitors of protein-tyrosine phosphatases, proteasomal degradation, and mammalian target of rapamycin (mTOR), and the effects of insulin on glucose uptake, IRS-1 tyrosine phosphorylation, phosphatidylinositol (PI) 3-kinase activity, and IRS-1 mass were examined. |
| 6264 | 12800089 | Evaluation of IRS-1 associated PI 3-kinase activity, IRS-1-associated p85 mass, and IRS-1 tyrosine phosphorylation showed that 2 hours after insulin addition they were reduced by 70% from maximal activity. |
| 6265 | 12800089 | When L6 cells were pretreated with Na(3)VO(4) plus the proteasome inhibitor MG-132 or the mTOR inhibitor rapamycin prior to insulin addition, IRS-1 mass loss as well as IRS-1/PI-3 kinase complex decay was blocked at 2 hours and PI 3-kinase activity was increased 2.5-fold and 4-fold, respectively, over insulin alone. |
| 6266 | 12807888 | Insulin is a potent inducer of adipogenesis, and differentiation of adipocytes requires many components of the insulin signaling pathway, including the insulin receptor substrate IRS-1 and phosphatidylinositol 3-kinase (PI3K). |
| 6267 | 12807888 | Likewise, overexpression of IR in control IRlox cells also results in inhibition of differentiation and a failure to accumulate expression of the adipogenic markers peroxisome proliferator-activated receptor gamma, Glut4, and fatty acid synthase, although cells overexpressing IR retain the ability to activate PI3K and down-regulate mitogen-activated protein kinase (MAPK) phosphorylation. |
| 6268 | 12843189 | To investigate the relationship between the common Gly(972)Arg IRS-1 variant and the presence of cardiovascular risk factors, 153 glucose-tolerant, unrelated offspring of type 2 diabetic patients were studied. |
| 6269 | 12843189 | There were no differences between Arg(972) IRS-1 carriers and noncarriers in age, gender, body mass index, waist/hip ratio, body composition, fasting glucose and insulin levels, and glucose or insulin levels during the oral glucose tolerance test. |
| 6270 | 12843189 | Insulin sensitivity, assessed by hyperinsulinemic-euglycemic clamp, was significantly reduced in carriers of Arg(972) IRS-1 (P < 0.03). |
| 6271 | 12843189 | Carriers of Arg(972) IRS-1 displayed many features of the insulin resistance syndrome, including higher values for serum triglycerides (P < 0.01), total/high density lipoprotein cholesterol ratio (P < 0.01), free fatty acid levels (P < 0.04), systolic blood pressure (P < 0.04), microalbuminuria (P < 0.003), and intima-media thickness (P < 0.02). |
| 6272 | 12843189 | These results suggest that the Arg(972) IRS-1 variant could contribute to the risk for atherosclerotic cardiovascular diseases associated with type 2 diabetes by producing a cluster of insulin resistance-related metabolic abnormalities. |
| 6273 | 12843189 | To investigate the relationship between the common Gly(972)Arg IRS-1 variant and the presence of cardiovascular risk factors, 153 glucose-tolerant, unrelated offspring of type 2 diabetic patients were studied. |
| 6274 | 12843189 | There were no differences between Arg(972) IRS-1 carriers and noncarriers in age, gender, body mass index, waist/hip ratio, body composition, fasting glucose and insulin levels, and glucose or insulin levels during the oral glucose tolerance test. |
| 6275 | 12843189 | Insulin sensitivity, assessed by hyperinsulinemic-euglycemic clamp, was significantly reduced in carriers of Arg(972) IRS-1 (P < 0.03). |
| 6276 | 12843189 | Carriers of Arg(972) IRS-1 displayed many features of the insulin resistance syndrome, including higher values for serum triglycerides (P < 0.01), total/high density lipoprotein cholesterol ratio (P < 0.01), free fatty acid levels (P < 0.04), systolic blood pressure (P < 0.04), microalbuminuria (P < 0.003), and intima-media thickness (P < 0.02). |
| 6277 | 12843189 | These results suggest that the Arg(972) IRS-1 variant could contribute to the risk for atherosclerotic cardiovascular diseases associated with type 2 diabetes by producing a cluster of insulin resistance-related metabolic abnormalities. |
| 6278 | 12843189 | To investigate the relationship between the common Gly(972)Arg IRS-1 variant and the presence of cardiovascular risk factors, 153 glucose-tolerant, unrelated offspring of type 2 diabetic patients were studied. |
| 6279 | 12843189 | There were no differences between Arg(972) IRS-1 carriers and noncarriers in age, gender, body mass index, waist/hip ratio, body composition, fasting glucose and insulin levels, and glucose or insulin levels during the oral glucose tolerance test. |
| 6280 | 12843189 | Insulin sensitivity, assessed by hyperinsulinemic-euglycemic clamp, was significantly reduced in carriers of Arg(972) IRS-1 (P < 0.03). |
| 6281 | 12843189 | Carriers of Arg(972) IRS-1 displayed many features of the insulin resistance syndrome, including higher values for serum triglycerides (P < 0.01), total/high density lipoprotein cholesterol ratio (P < 0.01), free fatty acid levels (P < 0.04), systolic blood pressure (P < 0.04), microalbuminuria (P < 0.003), and intima-media thickness (P < 0.02). |
| 6282 | 12843189 | These results suggest that the Arg(972) IRS-1 variant could contribute to the risk for atherosclerotic cardiovascular diseases associated with type 2 diabetes by producing a cluster of insulin resistance-related metabolic abnormalities. |
| 6283 | 12843189 | To investigate the relationship between the common Gly(972)Arg IRS-1 variant and the presence of cardiovascular risk factors, 153 glucose-tolerant, unrelated offspring of type 2 diabetic patients were studied. |
| 6284 | 12843189 | There were no differences between Arg(972) IRS-1 carriers and noncarriers in age, gender, body mass index, waist/hip ratio, body composition, fasting glucose and insulin levels, and glucose or insulin levels during the oral glucose tolerance test. |
| 6285 | 12843189 | Insulin sensitivity, assessed by hyperinsulinemic-euglycemic clamp, was significantly reduced in carriers of Arg(972) IRS-1 (P < 0.03). |
| 6286 | 12843189 | Carriers of Arg(972) IRS-1 displayed many features of the insulin resistance syndrome, including higher values for serum triglycerides (P < 0.01), total/high density lipoprotein cholesterol ratio (P < 0.01), free fatty acid levels (P < 0.04), systolic blood pressure (P < 0.04), microalbuminuria (P < 0.003), and intima-media thickness (P < 0.02). |
| 6287 | 12843189 | These results suggest that the Arg(972) IRS-1 variant could contribute to the risk for atherosclerotic cardiovascular diseases associated with type 2 diabetes by producing a cluster of insulin resistance-related metabolic abnormalities. |
| 6288 | 12843189 | To investigate the relationship between the common Gly(972)Arg IRS-1 variant and the presence of cardiovascular risk factors, 153 glucose-tolerant, unrelated offspring of type 2 diabetic patients were studied. |
| 6289 | 12843189 | There were no differences between Arg(972) IRS-1 carriers and noncarriers in age, gender, body mass index, waist/hip ratio, body composition, fasting glucose and insulin levels, and glucose or insulin levels during the oral glucose tolerance test. |
| 6290 | 12843189 | Insulin sensitivity, assessed by hyperinsulinemic-euglycemic clamp, was significantly reduced in carriers of Arg(972) IRS-1 (P < 0.03). |
| 6291 | 12843189 | Carriers of Arg(972) IRS-1 displayed many features of the insulin resistance syndrome, including higher values for serum triglycerides (P < 0.01), total/high density lipoprotein cholesterol ratio (P < 0.01), free fatty acid levels (P < 0.04), systolic blood pressure (P < 0.04), microalbuminuria (P < 0.003), and intima-media thickness (P < 0.02). |
| 6292 | 12843189 | These results suggest that the Arg(972) IRS-1 variant could contribute to the risk for atherosclerotic cardiovascular diseases associated with type 2 diabetes by producing a cluster of insulin resistance-related metabolic abnormalities. |
| 6293 | 12866995 | The mechanism by which elevated plasma FFA levels cause insulin resistance in skeletal muscle includes intramyocellular accumulation of diacylglycerol, which activates protein kinase C (the b II and d isoforms). |
| 6294 | 12866995 | This results in reduction of tyrosine phosphorylation of the insulin receptor substrate-1 and inhibits activation of phosphoinositol-3 kinase, an enzyme that is essential for normal insulin-stimulated glucose uptake. |
| 6295 | 12882908 | Insulin-stimulated protein kinase C lambda/zeta activity is reduced in skeletal muscle of humans with obesity and type 2 diabetes: reversal with weight reduction. |
| 6296 | 12882908 | The atypical protein kinase C (PKC) isoforms lambda and zeta are downstream of phosphatidylinositol-3 kinase (PI3K) and are required for maximal insulin stimulation of glucose uptake. |
| 6297 | 12882908 | Phosphoinositide-dependent protein kinase-1 (PDK-1), also downstream of PI3K, mediates activation of atypical PKC isoforms and Akt. |
| 6298 | 12882908 | To determine whether impaired PKClambda/zeta or PDK-1 activation plays a role in the pathogenesis of insulin resistance, we measured the activities of PKClambda/zeta and PDK-1 in vastus lateralis muscle of lean, obese, and obese/type 2 diabetic humans. |
| 6299 | 12882908 | Insulin-stimulated insulin receptor substrate (IRS)-1 tyrosine phosphorylation and PI3K activity are impaired 40-50% in diabetic subjects compared with lean or obese subjects. |
| 6300 | 12882908 | Importantly, weight loss in obese subjects normalizes PKClambda/zeta activation and increases IRS-1 phosphorylation and PI3K activity. |
| 6301 | 12882908 | Insulin also stimulates PDK-1 activity approximately twofold with no impairment in obese or diabetic subjects. |
| 6302 | 12882908 | In contrast to our previous data on Akt, reduced insulin-stimulated PKClambda/zeta activity could play a role in the pathogenesis of insulin resistance in muscle of obese and type 2 diabetic subjects. |
| 6303 | 12882909 | To determine whether the TZD-induced improvement in glycemic control is associated with enhanced insulin receptor signaling in skeletal muscle, 20 type 2 diabetic patients received a 75-g oral glucose tolerance test (OGTT) and euglycemic insulin (80 mU x m(-2) x min(-1)) clamp with [3-(3)H]glucose/indirect calorimetry/vastus lateralis muscle biopsies before and after 16 weeks of rosiglitazone treatment. |
| 6304 | 12882909 | Before RSG treatment, insulin infusion did not significantly increase insulin receptor tyrosine phosphorylation (0.95 +/- 0.10 to 1.08 +/- 0.13 density units; NS) but had a small stimulatory effect on insulin receptor substrate (IRS)-1 tyrosine phosphorylation (1.05 +/- 0.10 to 1.21 +/- 0.12 density units; P < 0.01) and the association of p85 with IRS-1 (0.94 +/- 0.06 to 1.08 +/- 0.06 activity units; P < 0.01). |
| 6305 | 12882909 | RSG therapy had no effect on basal or insulin-stimulated insulin receptor tyrosine phosphorylation but increased insulin stimulation of IRS-1 tyrosine phosphorylation (1.13 +/- 0.11 to 1.56 +/- 0.17 density units; P < 0.01 vs. prerosiglitazone) and p85 association with IRS-1 (1.00 +/- 0.06 to 1.27 +/- 0.07 activity units; P < 0.05 vs. prerosiglitazone). |
| 6306 | 12882909 | In control and type 2 diabetic subjects, TGD/nonoxidative glucose disposal correlated positively with the insulin-stimulated increments in IRS-1 tyrosine phosphorylation (r = 0.52/r = 0.57, P < 0.01) and inversely with the plasma FFA concentration during the insulin clamp (r = -0.55/r = -0.53, P < 0.01). |
| 6307 | 12882909 | However, no significant association between plasma FFA concentrations during the insulin clamp and the increment in either IRS-1 tyrosine phosphorylation or the association of p85 with IRS-1 was observed. |
| 6308 | 12882909 | To determine whether the TZD-induced improvement in glycemic control is associated with enhanced insulin receptor signaling in skeletal muscle, 20 type 2 diabetic patients received a 75-g oral glucose tolerance test (OGTT) and euglycemic insulin (80 mU x m(-2) x min(-1)) clamp with [3-(3)H]glucose/indirect calorimetry/vastus lateralis muscle biopsies before and after 16 weeks of rosiglitazone treatment. |
| 6309 | 12882909 | Before RSG treatment, insulin infusion did not significantly increase insulin receptor tyrosine phosphorylation (0.95 +/- 0.10 to 1.08 +/- 0.13 density units; NS) but had a small stimulatory effect on insulin receptor substrate (IRS)-1 tyrosine phosphorylation (1.05 +/- 0.10 to 1.21 +/- 0.12 density units; P < 0.01) and the association of p85 with IRS-1 (0.94 +/- 0.06 to 1.08 +/- 0.06 activity units; P < 0.01). |
| 6310 | 12882909 | RSG therapy had no effect on basal or insulin-stimulated insulin receptor tyrosine phosphorylation but increased insulin stimulation of IRS-1 tyrosine phosphorylation (1.13 +/- 0.11 to 1.56 +/- 0.17 density units; P < 0.01 vs. prerosiglitazone) and p85 association with IRS-1 (1.00 +/- 0.06 to 1.27 +/- 0.07 activity units; P < 0.05 vs. prerosiglitazone). |
| 6311 | 12882909 | In control and type 2 diabetic subjects, TGD/nonoxidative glucose disposal correlated positively with the insulin-stimulated increments in IRS-1 tyrosine phosphorylation (r = 0.52/r = 0.57, P < 0.01) and inversely with the plasma FFA concentration during the insulin clamp (r = -0.55/r = -0.53, P < 0.01). |
| 6312 | 12882909 | However, no significant association between plasma FFA concentrations during the insulin clamp and the increment in either IRS-1 tyrosine phosphorylation or the association of p85 with IRS-1 was observed. |
| 6313 | 12882909 | To determine whether the TZD-induced improvement in glycemic control is associated with enhanced insulin receptor signaling in skeletal muscle, 20 type 2 diabetic patients received a 75-g oral glucose tolerance test (OGTT) and euglycemic insulin (80 mU x m(-2) x min(-1)) clamp with [3-(3)H]glucose/indirect calorimetry/vastus lateralis muscle biopsies before and after 16 weeks of rosiglitazone treatment. |
| 6314 | 12882909 | Before RSG treatment, insulin infusion did not significantly increase insulin receptor tyrosine phosphorylation (0.95 +/- 0.10 to 1.08 +/- 0.13 density units; NS) but had a small stimulatory effect on insulin receptor substrate (IRS)-1 tyrosine phosphorylation (1.05 +/- 0.10 to 1.21 +/- 0.12 density units; P < 0.01) and the association of p85 with IRS-1 (0.94 +/- 0.06 to 1.08 +/- 0.06 activity units; P < 0.01). |
| 6315 | 12882909 | RSG therapy had no effect on basal or insulin-stimulated insulin receptor tyrosine phosphorylation but increased insulin stimulation of IRS-1 tyrosine phosphorylation (1.13 +/- 0.11 to 1.56 +/- 0.17 density units; P < 0.01 vs. prerosiglitazone) and p85 association with IRS-1 (1.00 +/- 0.06 to 1.27 +/- 0.07 activity units; P < 0.05 vs. prerosiglitazone). |
| 6316 | 12882909 | In control and type 2 diabetic subjects, TGD/nonoxidative glucose disposal correlated positively with the insulin-stimulated increments in IRS-1 tyrosine phosphorylation (r = 0.52/r = 0.57, P < 0.01) and inversely with the plasma FFA concentration during the insulin clamp (r = -0.55/r = -0.53, P < 0.01). |
| 6317 | 12882909 | However, no significant association between plasma FFA concentrations during the insulin clamp and the increment in either IRS-1 tyrosine phosphorylation or the association of p85 with IRS-1 was observed. |
| 6318 | 12882909 | To determine whether the TZD-induced improvement in glycemic control is associated with enhanced insulin receptor signaling in skeletal muscle, 20 type 2 diabetic patients received a 75-g oral glucose tolerance test (OGTT) and euglycemic insulin (80 mU x m(-2) x min(-1)) clamp with [3-(3)H]glucose/indirect calorimetry/vastus lateralis muscle biopsies before and after 16 weeks of rosiglitazone treatment. |
| 6319 | 12882909 | Before RSG treatment, insulin infusion did not significantly increase insulin receptor tyrosine phosphorylation (0.95 +/- 0.10 to 1.08 +/- 0.13 density units; NS) but had a small stimulatory effect on insulin receptor substrate (IRS)-1 tyrosine phosphorylation (1.05 +/- 0.10 to 1.21 +/- 0.12 density units; P < 0.01) and the association of p85 with IRS-1 (0.94 +/- 0.06 to 1.08 +/- 0.06 activity units; P < 0.01). |
| 6320 | 12882909 | RSG therapy had no effect on basal or insulin-stimulated insulin receptor tyrosine phosphorylation but increased insulin stimulation of IRS-1 tyrosine phosphorylation (1.13 +/- 0.11 to 1.56 +/- 0.17 density units; P < 0.01 vs. prerosiglitazone) and p85 association with IRS-1 (1.00 +/- 0.06 to 1.27 +/- 0.07 activity units; P < 0.05 vs. prerosiglitazone). |
| 6321 | 12882909 | In control and type 2 diabetic subjects, TGD/nonoxidative glucose disposal correlated positively with the insulin-stimulated increments in IRS-1 tyrosine phosphorylation (r = 0.52/r = 0.57, P < 0.01) and inversely with the plasma FFA concentration during the insulin clamp (r = -0.55/r = -0.53, P < 0.01). |
| 6322 | 12882909 | However, no significant association between plasma FFA concentrations during the insulin clamp and the increment in either IRS-1 tyrosine phosphorylation or the association of p85 with IRS-1 was observed. |
| 6323 | 12890697 | A novel cellular marker of insulin resistance and early atherosclerosis in humans is related to impaired fat cell differentiation and low adiponectin. |
| 6324 | 12890697 | In contrast to the commonly used risk marker, known heredity for diabetes, low cellular IRS-1 identified individuals who were markedly insulin resistant, had high proinsulin and insulin levels, and exhibited evidence of early atherosclerosis measured as increased intima media thickness in the carotid artery bulb. |
| 6325 | 12890697 | Gene analyses of fat cells in a parallel study showed attenuated expression of several genes related to fat cell differentiation (adiponectin, aP2, PPARgamma, and lipoprotein lipase) in the group of individuals characterized by a low IRS-1 expression and insulin resistance. |
| 6326 | 12890697 | A low IRS-1 expression in fat cells is a marker of insulin resistance and risk for type 2 diabetes and is associated with evidence of early vascular complications. |
| 6327 | 12890697 | A novel cellular marker of insulin resistance and early atherosclerosis in humans is related to impaired fat cell differentiation and low adiponectin. |
| 6328 | 12890697 | In contrast to the commonly used risk marker, known heredity for diabetes, low cellular IRS-1 identified individuals who were markedly insulin resistant, had high proinsulin and insulin levels, and exhibited evidence of early atherosclerosis measured as increased intima media thickness in the carotid artery bulb. |
| 6329 | 12890697 | Gene analyses of fat cells in a parallel study showed attenuated expression of several genes related to fat cell differentiation (adiponectin, aP2, PPARgamma, and lipoprotein lipase) in the group of individuals characterized by a low IRS-1 expression and insulin resistance. |
| 6330 | 12890697 | A low IRS-1 expression in fat cells is a marker of insulin resistance and risk for type 2 diabetes and is associated with evidence of early vascular complications. |
| 6331 | 12890697 | A novel cellular marker of insulin resistance and early atherosclerosis in humans is related to impaired fat cell differentiation and low adiponectin. |
| 6332 | 12890697 | In contrast to the commonly used risk marker, known heredity for diabetes, low cellular IRS-1 identified individuals who were markedly insulin resistant, had high proinsulin and insulin levels, and exhibited evidence of early atherosclerosis measured as increased intima media thickness in the carotid artery bulb. |
| 6333 | 12890697 | Gene analyses of fat cells in a parallel study showed attenuated expression of several genes related to fat cell differentiation (adiponectin, aP2, PPARgamma, and lipoprotein lipase) in the group of individuals characterized by a low IRS-1 expression and insulin resistance. |
| 6334 | 12890697 | A low IRS-1 expression in fat cells is a marker of insulin resistance and risk for type 2 diabetes and is associated with evidence of early vascular complications. |
| 6335 | 12898468 | Physical exercise enhances protein kinase C delta activity and insulin receptor tyrosine phosphorylation in diabetes-prone psammomys obesus. |
| 6336 | 12898468 | In the present study we characterized the effect of physical exercise on protein kinase C delta (PKC delta) activity, as a mediator of the insulin-signaling cascade in vivo. |
| 6337 | 12898468 | Tyrosine phosphorylation of insulin receptor (IR), insulin receptor substrate-1 (IRS-1), and phosphatidylinositol 3 kinase (PI3 kinase) was significantly higher in the HE/EX and LE/C groups compared with the HE/C group. |
| 6338 | 12909611 | Exercise synergistically enhanced insulin-stimulated insulin receptor substrate 1-associated phosphatidylinositol 3-kinase activity (P < 0.05) and Akt Ser473 phosphorylation (P < 0.05) in nondiabetic subjects but had little effect in diabetic subjects. |
| 6339 | 12909611 | In nondiabetic, but not diabetic, subjects, exercise-induced enhancement of insulin stimulation of the phosphatidylinositol 3-kinase pathway is also likely to be involved in the exercise-induced synergistic enhancement of glucose disposal. |
| 6340 | 12941761 | A novel insulin analog with unique properties: LysB3,GluB29 insulin induces prominent activation of insulin receptor substrate 2, but marginal phosphorylation of insulin receptor substrate 1. |
| 6341 | 12941761 | We assessed the signaling properties and mitogenic potency of two novel rapid-acting insulin analogs, Lys(B3),Glu(B29) insulin (HMR 1964) and Lys(B3),Ile(B28) insulin (HMR 1153) using myoblasts and cardiomyocytes. |
| 6342 | 12941761 | This finding correlated with a prominent Shc/IGF-I receptor interaction, tyrosine phosphorylation of Shc, activation of extracellular signal-regulated protein kinase (ERK)-1 and -2, and stimulation of DNA synthesis by HMR 1153 and Asp(B10) insulin. |
| 6343 | 12941761 | In contrast, HMR 1964 produced a marginal activation of the Shc/ERK kinase cascade and was equipotent to insulin in stimulating DNA synthesis in myoblasts. |
| 6344 | 12941761 | In myoblasts, HMR 1964 produced a minor activation of insulin receptor substrate (IRS)-1 tyrosine phosphorylation, but a prominent activation of IRS-2, with a significantly stronger effect than insulin in human myoblasts. |
| 6345 | 12941761 | Predominant activation of IRS-2 was also observed in adult cardiomyocytes where HMR 1964 increased 3-O-methylglucose transport and the activation of Akt and glycogen synthase kinase-3 to the same extent as human insulin. |
| 6346 | 12941761 | We concluded that 1) the mitogenic properties of insulin analogs may result from a series of initial receptor interactions, including internalization and phosphorylation; 2) the mitogenic and metabolic potential of HMR 1964 is identical to that of insulin; and 3) predominant activation of IRS-2 may open new avenues for optimized insulin therapies. |
| 6347 | 12941762 | To assess the role of insulin receptor (IR) substrate (IRS)-2 in insulin action and resistance in the liver, immortalized neonatal hepatocyte cell lines have been generated from IRS-2(-/-), IRS-2(+/-), and wild-type mice. |
| 6348 | 12941762 | The lack of IRS-2 did not result in enhanced IRS-1 tyrosine phosphorylation or IRS-1-associated phosphatidylinositol (PI) 3-kinase activity on insulin stimulation. |
| 6349 | 12941762 | Total insulin-induced PI 3-kinase activity was decreased by 50% in IRS-2(-/-) hepatocytes, but the translocation of PI-3,4,5-trisphosphate to the plasma membrane in these cells was almost completely abolished. |
| 6350 | 12941762 | Downstream PI 3-kinase, activation of Akt, glycogen synthase kinase (GSK)-3 (alpha and beta isoforms), Foxo1, and atypical protein kinase C were blunted in insulin-stimulated IRS-2(-/-) cells. |
| 6351 | 12941762 | Reconstitution of IRS-2(-/-) hepatocytes with adenoviral IRS-2 restored activation of these pathways, demonstrating that IRS-2 is essential for functional insulin signaling in hepatocytes. |
| 6352 | 12941762 | Insulin induced a marked glycogen synthase activity in wild-type and heterozygous primary hepatocytes; interestingly, this response was absent in IRS-2(-/-) cells but was rescued by infection with adenoviral IRS-2. |
| 6353 | 12941762 | However, insulin was not able to suppress gluconeogenic gene expression in primary hepatocytes lacking IRS-2, but when IRS-2 signaling was reconstituted, these cells recovered this response to insulin. |
| 6354 | 12952969 | Interleukin-6 (IL-6) induces insulin resistance in 3T3-L1 adipocytes and is, like IL-8 and tumor necrosis factor-alpha, overexpressed in human fat cells from insulin-resistant subjects. |
| 6355 | 12952969 | Several studies have shown a relationship between interleukin (IL) 6 levels and insulin resistance. |
| 6356 | 12952969 | To examine putative mechanisms and cross-talk with insulin, 3T3-L1 adipocytes were cultured for different times with IL-6 and tumor necrosis factor alpha (TNF-alpha). |
| 6357 | 12952969 | IL-6, in contrast to TNF-alpha, did not increase pS-307 of insulin-receptor substrate (IRS)-1 or JNK activation. |
| 6358 | 12952969 | However, IL-6, like TNF-alpha exerted long term inhibitory effects on the gene transcription of IRS-1, GLUT-4, and peroxisome proliferator-activated receptor gamma. |
| 6359 | 12952969 | This effect of IL-6 was accompanied by a marked reduction in IRS-1, but not IRS-2, protein expression, and insulin-stimulated tyrosine phosphorylation, whereas no inhibitory effect was seen on the insulin receptor tyrosine phosphorylation. |
| 6360 | 12952969 | Consistent with the reduced GLUT-4 mRNA, insulin-stimulated glucose transport was also significantly reduced by IL-6. |
| 6361 | 12952969 | An important interaction with TNF-alpha was found because TNF-alpha markedly increased IL-6 mRNA and protein secretion. |
| 6362 | 12952969 | These results show that IL-6, through effects on gene transcription, is capable of impairing insulin signaling and action but, in contrast to TNF-alpha, IL-6 does not increase pS-307 (or pS-612) of IRS-1. |
| 6363 | 12952969 | The link between IL-6 and insulin resistance in man was further corroborated by the finding that the expression of IL-6, like that of TNF-alpha and IL-8, was markedly increased ( approximately 15-fold) in human fat cells from insulin-resistant individuals. |
| 6364 | 12952969 | We conclude that IL-6 can play an important role in insulin resistance in man and, furthermore, that it may act in concert with other cytokines that also are up-regulated in adipose cells in insulin resistance. |
| 6365 | 12952969 | Interleukin-6 (IL-6) induces insulin resistance in 3T3-L1 adipocytes and is, like IL-8 and tumor necrosis factor-alpha, overexpressed in human fat cells from insulin-resistant subjects. |
| 6366 | 12952969 | Several studies have shown a relationship between interleukin (IL) 6 levels and insulin resistance. |
| 6367 | 12952969 | To examine putative mechanisms and cross-talk with insulin, 3T3-L1 adipocytes were cultured for different times with IL-6 and tumor necrosis factor alpha (TNF-alpha). |
| 6368 | 12952969 | IL-6, in contrast to TNF-alpha, did not increase pS-307 of insulin-receptor substrate (IRS)-1 or JNK activation. |
| 6369 | 12952969 | However, IL-6, like TNF-alpha exerted long term inhibitory effects on the gene transcription of IRS-1, GLUT-4, and peroxisome proliferator-activated receptor gamma. |
| 6370 | 12952969 | This effect of IL-6 was accompanied by a marked reduction in IRS-1, but not IRS-2, protein expression, and insulin-stimulated tyrosine phosphorylation, whereas no inhibitory effect was seen on the insulin receptor tyrosine phosphorylation. |
| 6371 | 12952969 | Consistent with the reduced GLUT-4 mRNA, insulin-stimulated glucose transport was also significantly reduced by IL-6. |
| 6372 | 12952969 | An important interaction with TNF-alpha was found because TNF-alpha markedly increased IL-6 mRNA and protein secretion. |
| 6373 | 12952969 | These results show that IL-6, through effects on gene transcription, is capable of impairing insulin signaling and action but, in contrast to TNF-alpha, IL-6 does not increase pS-307 (or pS-612) of IRS-1. |
| 6374 | 12952969 | The link between IL-6 and insulin resistance in man was further corroborated by the finding that the expression of IL-6, like that of TNF-alpha and IL-8, was markedly increased ( approximately 15-fold) in human fat cells from insulin-resistant individuals. |
| 6375 | 12952969 | We conclude that IL-6 can play an important role in insulin resistance in man and, furthermore, that it may act in concert with other cytokines that also are up-regulated in adipose cells in insulin resistance. |
| 6376 | 12952969 | Interleukin-6 (IL-6) induces insulin resistance in 3T3-L1 adipocytes and is, like IL-8 and tumor necrosis factor-alpha, overexpressed in human fat cells from insulin-resistant subjects. |
| 6377 | 12952969 | Several studies have shown a relationship between interleukin (IL) 6 levels and insulin resistance. |
| 6378 | 12952969 | To examine putative mechanisms and cross-talk with insulin, 3T3-L1 adipocytes were cultured for different times with IL-6 and tumor necrosis factor alpha (TNF-alpha). |
| 6379 | 12952969 | IL-6, in contrast to TNF-alpha, did not increase pS-307 of insulin-receptor substrate (IRS)-1 or JNK activation. |
| 6380 | 12952969 | However, IL-6, like TNF-alpha exerted long term inhibitory effects on the gene transcription of IRS-1, GLUT-4, and peroxisome proliferator-activated receptor gamma. |
| 6381 | 12952969 | This effect of IL-6 was accompanied by a marked reduction in IRS-1, but not IRS-2, protein expression, and insulin-stimulated tyrosine phosphorylation, whereas no inhibitory effect was seen on the insulin receptor tyrosine phosphorylation. |
| 6382 | 12952969 | Consistent with the reduced GLUT-4 mRNA, insulin-stimulated glucose transport was also significantly reduced by IL-6. |
| 6383 | 12952969 | An important interaction with TNF-alpha was found because TNF-alpha markedly increased IL-6 mRNA and protein secretion. |
| 6384 | 12952969 | These results show that IL-6, through effects on gene transcription, is capable of impairing insulin signaling and action but, in contrast to TNF-alpha, IL-6 does not increase pS-307 (or pS-612) of IRS-1. |
| 6385 | 12952969 | The link between IL-6 and insulin resistance in man was further corroborated by the finding that the expression of IL-6, like that of TNF-alpha and IL-8, was markedly increased ( approximately 15-fold) in human fat cells from insulin-resistant individuals. |
| 6386 | 12952969 | We conclude that IL-6 can play an important role in insulin resistance in man and, furthermore, that it may act in concert with other cytokines that also are up-regulated in adipose cells in insulin resistance. |
| 6387 | 12957877 | Myosin bound phosphatase (MBP) dephosphorylates myosin light chains which play a dominant role in vascular smooth muscle (VSM) contraction. |
| 6388 | 12957877 | Using two distinct approaches, we have demonstrated that insulin rapidly stimulates MBP and simultaneously inhibits RhoA/Rho kinase signaling via the nitric oxide (NO)/cGMP signaling pathway. |
| 6389 | 12957877 | Insulin activates MBP by decreasing Thr695 phosphorylation of myosin-bound subunit (MBS) via two different but cross-talking signaling pathways. |
| 6390 | 12957877 | Secondly, insulin induces iNOS expression via PI3-kinase signaling leading to generation of NO/cGMP which activates MBP via cGK-1( mediated inhibition of MBSThr695 phosphorylation via Rho kinase inactivation. |
| 6391 | 12957877 | The defects appear to be at the level of PI3-kinase activation due to impaired insulin-induced IRS-1 tyrosine phosphorylation because of increased association of active Rho kinase with the IRS-1 leading to increased IRS-1 serine phosphorylation, which interrupts with downstream insulin signaling. |
| 6392 | 12970360 | Human glycated albumin affects glucose metabolism in L6 skeletal muscle cells by impairing insulin-induced insulin receptor substrate (IRS) signaling through a protein kinase C alpha-mediated mechanism. |
| 6393 | 12970360 | Here, we have investigated the action of human glycated albumin (HGA) on insulin signaling in L6 skeletal muscle cells. |
| 6394 | 12970360 | Further, HGA reduced insulin-stimulated serine phosphorylation of PKB and GSK3, but did not alter ERK1/2 activation. |
| 6395 | 12970360 | HGA did not affect either insulin receptor kinase activity or insulin-induced Shc phosphorylation on tyrosine. |
| 6396 | 12970360 | In contrast, insulin-dependent IRS-1 and IRS-2 tyrosine phosphorylation was severely reduced in cells preincubated with HGA for 24 h. |
| 6397 | 12970360 | Insulin-stimulated association of PI3K with IRS-1 and IRS-2, and PI3K activity were reduced by HGA in parallel with the changes in IRS tyrosine phosphorylation, while Grb2-IRS association was unchanged. |
| 6398 | 12970360 | In L6 myotubes, exposure to HGA increased PKC activity by 2-fold resulting in a similar increase in Ser/Thr phosphorylation of IRS-1 and IRS-2. |
| 6399 | 12970360 | BDM also blocked the action of HGA on insulin-stimulated PKB and GSK3 alpha. |
| 6400 | 12970360 | Human glycated albumin affects glucose metabolism in L6 skeletal muscle cells by impairing insulin-induced insulin receptor substrate (IRS) signaling through a protein kinase C alpha-mediated mechanism. |
| 6401 | 12970360 | Here, we have investigated the action of human glycated albumin (HGA) on insulin signaling in L6 skeletal muscle cells. |
| 6402 | 12970360 | Further, HGA reduced insulin-stimulated serine phosphorylation of PKB and GSK3, but did not alter ERK1/2 activation. |
| 6403 | 12970360 | HGA did not affect either insulin receptor kinase activity or insulin-induced Shc phosphorylation on tyrosine. |
| 6404 | 12970360 | In contrast, insulin-dependent IRS-1 and IRS-2 tyrosine phosphorylation was severely reduced in cells preincubated with HGA for 24 h. |
| 6405 | 12970360 | Insulin-stimulated association of PI3K with IRS-1 and IRS-2, and PI3K activity were reduced by HGA in parallel with the changes in IRS tyrosine phosphorylation, while Grb2-IRS association was unchanged. |
| 6406 | 12970360 | In L6 myotubes, exposure to HGA increased PKC activity by 2-fold resulting in a similar increase in Ser/Thr phosphorylation of IRS-1 and IRS-2. |
| 6407 | 12970360 | BDM also blocked the action of HGA on insulin-stimulated PKB and GSK3 alpha. |
| 6408 | 12970360 | Human glycated albumin affects glucose metabolism in L6 skeletal muscle cells by impairing insulin-induced insulin receptor substrate (IRS) signaling through a protein kinase C alpha-mediated mechanism. |
| 6409 | 12970360 | Here, we have investigated the action of human glycated albumin (HGA) on insulin signaling in L6 skeletal muscle cells. |
| 6410 | 12970360 | Further, HGA reduced insulin-stimulated serine phosphorylation of PKB and GSK3, but did not alter ERK1/2 activation. |
| 6411 | 12970360 | HGA did not affect either insulin receptor kinase activity or insulin-induced Shc phosphorylation on tyrosine. |
| 6412 | 12970360 | In contrast, insulin-dependent IRS-1 and IRS-2 tyrosine phosphorylation was severely reduced in cells preincubated with HGA for 24 h. |
| 6413 | 12970360 | Insulin-stimulated association of PI3K with IRS-1 and IRS-2, and PI3K activity were reduced by HGA in parallel with the changes in IRS tyrosine phosphorylation, while Grb2-IRS association was unchanged. |
| 6414 | 12970360 | In L6 myotubes, exposure to HGA increased PKC activity by 2-fold resulting in a similar increase in Ser/Thr phosphorylation of IRS-1 and IRS-2. |
| 6415 | 12970360 | BDM also blocked the action of HGA on insulin-stimulated PKB and GSK3 alpha. |
| 6416 | 14514640 | Inhibition of net HepG2 cell apolipoprotein B secretion by the citrus flavonoid naringenin involves activation of phosphatidylinositol 3-kinase, independent of insulin receptor substrate-1 phosphorylation. |
| 6417 | 14514640 | In HepG2 human hepatoma cells, naringenin inhibits apolipoprotein B (apoB) secretion primarily by inhibiting microsomal triglyceride transfer protein and enhances LDL receptor (LDLr)-mediated apoB-containing lipoprotein uptake. |
| 6418 | 14514640 | Phosphatidylinositol 3-kinase (PI3K) activation by insulin increases sterol regulatory element-binding protein (SREBP)-1 and LDLr expression and inhibits apoB secretion in hepatocytes. |
| 6419 | 14514640 | Insulin and naringenin induced PI3K-dependent increases in cytosolic and nuclear SREBP-1 and LDLr expression. |
| 6420 | 14514640 | Similar PI3K-mediated increases in SREBP-1 were observed in McA-RH7777 rat hepatoma cells, which express predominantly SREBP-1c. |
| 6421 | 14514640 | Reductions in HepG2 cell media apoB with naringenin were partially attenuated by wortmannin, whereas the effect of insulin was completely blocked. |
| 6422 | 14514640 | Both treatments reduced apoB100 secretion in wild-type and LDLr(-/-) mouse hepatocytes to the same extent. |
| 6423 | 14514640 | Insulin and naringenin increased HepG2 cell PI3K activity and decreased insulin receptor substrate (IRS)-2 levels. |
| 6424 | 14514640 | In sharp contrast to insulin, naringenin did not induce tyrosine phosphorylation of IRS-1. |
| 6425 | 14514640 | We conclude that naringenin increases LDLr expression in HepG2 cells via PI3K-mediated upregulation of SREBP-1, independent of IRS-1 phosphorylation. |
| 6426 | 14514640 | Although this pathway may not regulate apoB secretion in primary hepatocytes, PI3K activation by this novel mechanism may explain the insulin-like effects of naringenin in vivo. |
| 6427 | 14514640 | Inhibition of net HepG2 cell apolipoprotein B secretion by the citrus flavonoid naringenin involves activation of phosphatidylinositol 3-kinase, independent of insulin receptor substrate-1 phosphorylation. |
| 6428 | 14514640 | In HepG2 human hepatoma cells, naringenin inhibits apolipoprotein B (apoB) secretion primarily by inhibiting microsomal triglyceride transfer protein and enhances LDL receptor (LDLr)-mediated apoB-containing lipoprotein uptake. |
| 6429 | 14514640 | Phosphatidylinositol 3-kinase (PI3K) activation by insulin increases sterol regulatory element-binding protein (SREBP)-1 and LDLr expression and inhibits apoB secretion in hepatocytes. |
| 6430 | 14514640 | Insulin and naringenin induced PI3K-dependent increases in cytosolic and nuclear SREBP-1 and LDLr expression. |
| 6431 | 14514640 | Similar PI3K-mediated increases in SREBP-1 were observed in McA-RH7777 rat hepatoma cells, which express predominantly SREBP-1c. |
| 6432 | 14514640 | Reductions in HepG2 cell media apoB with naringenin were partially attenuated by wortmannin, whereas the effect of insulin was completely blocked. |
| 6433 | 14514640 | Both treatments reduced apoB100 secretion in wild-type and LDLr(-/-) mouse hepatocytes to the same extent. |
| 6434 | 14514640 | Insulin and naringenin increased HepG2 cell PI3K activity and decreased insulin receptor substrate (IRS)-2 levels. |
| 6435 | 14514640 | In sharp contrast to insulin, naringenin did not induce tyrosine phosphorylation of IRS-1. |
| 6436 | 14514640 | We conclude that naringenin increases LDLr expression in HepG2 cells via PI3K-mediated upregulation of SREBP-1, independent of IRS-1 phosphorylation. |
| 6437 | 14514640 | Although this pathway may not regulate apoB secretion in primary hepatocytes, PI3K activation by this novel mechanism may explain the insulin-like effects of naringenin in vivo. |
| 6438 | 14514640 | Inhibition of net HepG2 cell apolipoprotein B secretion by the citrus flavonoid naringenin involves activation of phosphatidylinositol 3-kinase, independent of insulin receptor substrate-1 phosphorylation. |
| 6439 | 14514640 | In HepG2 human hepatoma cells, naringenin inhibits apolipoprotein B (apoB) secretion primarily by inhibiting microsomal triglyceride transfer protein and enhances LDL receptor (LDLr)-mediated apoB-containing lipoprotein uptake. |
| 6440 | 14514640 | Phosphatidylinositol 3-kinase (PI3K) activation by insulin increases sterol regulatory element-binding protein (SREBP)-1 and LDLr expression and inhibits apoB secretion in hepatocytes. |
| 6441 | 14514640 | Insulin and naringenin induced PI3K-dependent increases in cytosolic and nuclear SREBP-1 and LDLr expression. |
| 6442 | 14514640 | Similar PI3K-mediated increases in SREBP-1 were observed in McA-RH7777 rat hepatoma cells, which express predominantly SREBP-1c. |
| 6443 | 14514640 | Reductions in HepG2 cell media apoB with naringenin were partially attenuated by wortmannin, whereas the effect of insulin was completely blocked. |
| 6444 | 14514640 | Both treatments reduced apoB100 secretion in wild-type and LDLr(-/-) mouse hepatocytes to the same extent. |
| 6445 | 14514640 | Insulin and naringenin increased HepG2 cell PI3K activity and decreased insulin receptor substrate (IRS)-2 levels. |
| 6446 | 14514640 | In sharp contrast to insulin, naringenin did not induce tyrosine phosphorylation of IRS-1. |
| 6447 | 14514640 | We conclude that naringenin increases LDLr expression in HepG2 cells via PI3K-mediated upregulation of SREBP-1, independent of IRS-1 phosphorylation. |
| 6448 | 14514640 | Although this pathway may not regulate apoB secretion in primary hepatocytes, PI3K activation by this novel mechanism may explain the insulin-like effects of naringenin in vivo. |
| 6449 | 14550282 | Here we tested the hypothesis that the novel analog [LysB3, GluB29] insulin (insulin glulisine, IG) might mediate an enhanced beta-cell protective effect due to its unique property of preferential IRS-2 phosphorylation. |
| 6450 | 14550282 | We assessed IRS activation by IG and its anti-apoptotic activity against cytokines or palmitic acid in comparison to insulin, insulin analogs, and insulin-like growth factor (IGF)-I using INS-1 cells. |
| 6451 | 14550282 | IG induced a prominent IRS-2 activation without significant IRS-1 stimulation. |
| 6452 | 14556646 | Rosiglitazone, an agonist of peroxisome-proliferator-activated receptor gamma (PPARgamma), decreases inhibitory serine phosphorylation of IRS1 in vitro and in vivo. |
| 6453 | 14556646 | Peroxisome-proliferator-activated receptor gamma agonists such as rosiglitazone, a thiazolidinedione, improve insulin sensitivity in vivo, but the underlying mechanism(s) remains unclear. |
| 6454 | 14556646 | Phosphorylation of IRS1 (insulin receptor substrate protein 1) on certain serine residues, including S307 and S612 in rodent IRS1 (equivalent to S312 and S616 in human IRS1), has been shown to play a negative role in insulin signalling. |
| 6455 | 14556646 | In the present study, we investigated whether rosiglitazone improves insulin sensitivity by decreasing IRS1 inhibitory serine phosphorylation. |
| 6456 | 14556646 | In HEK-293 (human embryonic kidney 293) cells stably expressing recombinant IRS1 and in 3T3L1 adipocytes, rosiglitazone attenuated PMA-induced IRS1 S307/S612 phosphorylation and decreased insulin-stimulated Akt phosphorylation. |
| 6457 | 14556646 | We observed increased IRS1 S307 phosphorylation and concomitant decrease in insulin signalling as measured by insulin-stimulated IRS1 tyrosine phosphorylation, and Akt threonine phosphorylation in adipose tissues of Zucker obese rats compared with lean control rats. |
| 6458 | 14556646 | Treatment with rosiglitazone at 30 mg/kg body weight for 24 and 48 h increased insulin signalling and decreased IRS1 S307 phosphorylation concomitantly. |
| 6459 | 14556646 | Whereas the 48 h treatment reversed hyper-phosphorylation (and activation) of both c-Jun N-terminal kinase and p38 mitogen-activated protein kinase, the 24 h treatments only decreased hyper-phosphorylation of p38 mitogen-activated protein kinase. |
| 6460 | 14556646 | Taken together, these results suggest that IRS1 inhibitory serine phosphorylation is a key component of insulin resistance and its reversal contributes to the insulin sensitizing effects by rosiglitazone. |
| 6461 | 14556646 | Rosiglitazone, an agonist of peroxisome-proliferator-activated receptor gamma (PPARgamma), decreases inhibitory serine phosphorylation of IRS1 in vitro and in vivo. |
| 6462 | 14556646 | Peroxisome-proliferator-activated receptor gamma agonists such as rosiglitazone, a thiazolidinedione, improve insulin sensitivity in vivo, but the underlying mechanism(s) remains unclear. |
| 6463 | 14556646 | Phosphorylation of IRS1 (insulin receptor substrate protein 1) on certain serine residues, including S307 and S612 in rodent IRS1 (equivalent to S312 and S616 in human IRS1), has been shown to play a negative role in insulin signalling. |
| 6464 | 14556646 | In the present study, we investigated whether rosiglitazone improves insulin sensitivity by decreasing IRS1 inhibitory serine phosphorylation. |
| 6465 | 14556646 | In HEK-293 (human embryonic kidney 293) cells stably expressing recombinant IRS1 and in 3T3L1 adipocytes, rosiglitazone attenuated PMA-induced IRS1 S307/S612 phosphorylation and decreased insulin-stimulated Akt phosphorylation. |
| 6466 | 14556646 | We observed increased IRS1 S307 phosphorylation and concomitant decrease in insulin signalling as measured by insulin-stimulated IRS1 tyrosine phosphorylation, and Akt threonine phosphorylation in adipose tissues of Zucker obese rats compared with lean control rats. |
| 6467 | 14556646 | Treatment with rosiglitazone at 30 mg/kg body weight for 24 and 48 h increased insulin signalling and decreased IRS1 S307 phosphorylation concomitantly. |
| 6468 | 14556646 | Whereas the 48 h treatment reversed hyper-phosphorylation (and activation) of both c-Jun N-terminal kinase and p38 mitogen-activated protein kinase, the 24 h treatments only decreased hyper-phosphorylation of p38 mitogen-activated protein kinase. |
| 6469 | 14556646 | Taken together, these results suggest that IRS1 inhibitory serine phosphorylation is a key component of insulin resistance and its reversal contributes to the insulin sensitizing effects by rosiglitazone. |
| 6470 | 14556646 | Rosiglitazone, an agonist of peroxisome-proliferator-activated receptor gamma (PPARgamma), decreases inhibitory serine phosphorylation of IRS1 in vitro and in vivo. |
| 6471 | 14556646 | Peroxisome-proliferator-activated receptor gamma agonists such as rosiglitazone, a thiazolidinedione, improve insulin sensitivity in vivo, but the underlying mechanism(s) remains unclear. |
| 6472 | 14556646 | Phosphorylation of IRS1 (insulin receptor substrate protein 1) on certain serine residues, including S307 and S612 in rodent IRS1 (equivalent to S312 and S616 in human IRS1), has been shown to play a negative role in insulin signalling. |
| 6473 | 14556646 | In the present study, we investigated whether rosiglitazone improves insulin sensitivity by decreasing IRS1 inhibitory serine phosphorylation. |
| 6474 | 14556646 | In HEK-293 (human embryonic kidney 293) cells stably expressing recombinant IRS1 and in 3T3L1 adipocytes, rosiglitazone attenuated PMA-induced IRS1 S307/S612 phosphorylation and decreased insulin-stimulated Akt phosphorylation. |
| 6475 | 14556646 | We observed increased IRS1 S307 phosphorylation and concomitant decrease in insulin signalling as measured by insulin-stimulated IRS1 tyrosine phosphorylation, and Akt threonine phosphorylation in adipose tissues of Zucker obese rats compared with lean control rats. |
| 6476 | 14556646 | Treatment with rosiglitazone at 30 mg/kg body weight for 24 and 48 h increased insulin signalling and decreased IRS1 S307 phosphorylation concomitantly. |
| 6477 | 14556646 | Whereas the 48 h treatment reversed hyper-phosphorylation (and activation) of both c-Jun N-terminal kinase and p38 mitogen-activated protein kinase, the 24 h treatments only decreased hyper-phosphorylation of p38 mitogen-activated protein kinase. |
| 6478 | 14556646 | Taken together, these results suggest that IRS1 inhibitory serine phosphorylation is a key component of insulin resistance and its reversal contributes to the insulin sensitizing effects by rosiglitazone. |
| 6479 | 14556646 | Rosiglitazone, an agonist of peroxisome-proliferator-activated receptor gamma (PPARgamma), decreases inhibitory serine phosphorylation of IRS1 in vitro and in vivo. |
| 6480 | 14556646 | Peroxisome-proliferator-activated receptor gamma agonists such as rosiglitazone, a thiazolidinedione, improve insulin sensitivity in vivo, but the underlying mechanism(s) remains unclear. |
| 6481 | 14556646 | Phosphorylation of IRS1 (insulin receptor substrate protein 1) on certain serine residues, including S307 and S612 in rodent IRS1 (equivalent to S312 and S616 in human IRS1), has been shown to play a negative role in insulin signalling. |
| 6482 | 14556646 | In the present study, we investigated whether rosiglitazone improves insulin sensitivity by decreasing IRS1 inhibitory serine phosphorylation. |
| 6483 | 14556646 | In HEK-293 (human embryonic kidney 293) cells stably expressing recombinant IRS1 and in 3T3L1 adipocytes, rosiglitazone attenuated PMA-induced IRS1 S307/S612 phosphorylation and decreased insulin-stimulated Akt phosphorylation. |
| 6484 | 14556646 | We observed increased IRS1 S307 phosphorylation and concomitant decrease in insulin signalling as measured by insulin-stimulated IRS1 tyrosine phosphorylation, and Akt threonine phosphorylation in adipose tissues of Zucker obese rats compared with lean control rats. |
| 6485 | 14556646 | Treatment with rosiglitazone at 30 mg/kg body weight for 24 and 48 h increased insulin signalling and decreased IRS1 S307 phosphorylation concomitantly. |
| 6486 | 14556646 | Whereas the 48 h treatment reversed hyper-phosphorylation (and activation) of both c-Jun N-terminal kinase and p38 mitogen-activated protein kinase, the 24 h treatments only decreased hyper-phosphorylation of p38 mitogen-activated protein kinase. |
| 6487 | 14556646 | Taken together, these results suggest that IRS1 inhibitory serine phosphorylation is a key component of insulin resistance and its reversal contributes to the insulin sensitizing effects by rosiglitazone. |
| 6488 | 14556646 | Rosiglitazone, an agonist of peroxisome-proliferator-activated receptor gamma (PPARgamma), decreases inhibitory serine phosphorylation of IRS1 in vitro and in vivo. |
| 6489 | 14556646 | Peroxisome-proliferator-activated receptor gamma agonists such as rosiglitazone, a thiazolidinedione, improve insulin sensitivity in vivo, but the underlying mechanism(s) remains unclear. |
| 6490 | 14556646 | Phosphorylation of IRS1 (insulin receptor substrate protein 1) on certain serine residues, including S307 and S612 in rodent IRS1 (equivalent to S312 and S616 in human IRS1), has been shown to play a negative role in insulin signalling. |
| 6491 | 14556646 | In the present study, we investigated whether rosiglitazone improves insulin sensitivity by decreasing IRS1 inhibitory serine phosphorylation. |
| 6492 | 14556646 | In HEK-293 (human embryonic kidney 293) cells stably expressing recombinant IRS1 and in 3T3L1 adipocytes, rosiglitazone attenuated PMA-induced IRS1 S307/S612 phosphorylation and decreased insulin-stimulated Akt phosphorylation. |
| 6493 | 14556646 | We observed increased IRS1 S307 phosphorylation and concomitant decrease in insulin signalling as measured by insulin-stimulated IRS1 tyrosine phosphorylation, and Akt threonine phosphorylation in adipose tissues of Zucker obese rats compared with lean control rats. |
| 6494 | 14556646 | Treatment with rosiglitazone at 30 mg/kg body weight for 24 and 48 h increased insulin signalling and decreased IRS1 S307 phosphorylation concomitantly. |
| 6495 | 14556646 | Whereas the 48 h treatment reversed hyper-phosphorylation (and activation) of both c-Jun N-terminal kinase and p38 mitogen-activated protein kinase, the 24 h treatments only decreased hyper-phosphorylation of p38 mitogen-activated protein kinase. |
| 6496 | 14556646 | Taken together, these results suggest that IRS1 inhibitory serine phosphorylation is a key component of insulin resistance and its reversal contributes to the insulin sensitizing effects by rosiglitazone. |
| 6497 | 14556646 | Rosiglitazone, an agonist of peroxisome-proliferator-activated receptor gamma (PPARgamma), decreases inhibitory serine phosphorylation of IRS1 in vitro and in vivo. |
| 6498 | 14556646 | Peroxisome-proliferator-activated receptor gamma agonists such as rosiglitazone, a thiazolidinedione, improve insulin sensitivity in vivo, but the underlying mechanism(s) remains unclear. |
| 6499 | 14556646 | Phosphorylation of IRS1 (insulin receptor substrate protein 1) on certain serine residues, including S307 and S612 in rodent IRS1 (equivalent to S312 and S616 in human IRS1), has been shown to play a negative role in insulin signalling. |
| 6500 | 14556646 | In the present study, we investigated whether rosiglitazone improves insulin sensitivity by decreasing IRS1 inhibitory serine phosphorylation. |
| 6501 | 14556646 | In HEK-293 (human embryonic kidney 293) cells stably expressing recombinant IRS1 and in 3T3L1 adipocytes, rosiglitazone attenuated PMA-induced IRS1 S307/S612 phosphorylation and decreased insulin-stimulated Akt phosphorylation. |
| 6502 | 14556646 | We observed increased IRS1 S307 phosphorylation and concomitant decrease in insulin signalling as measured by insulin-stimulated IRS1 tyrosine phosphorylation, and Akt threonine phosphorylation in adipose tissues of Zucker obese rats compared with lean control rats. |
| 6503 | 14556646 | Treatment with rosiglitazone at 30 mg/kg body weight for 24 and 48 h increased insulin signalling and decreased IRS1 S307 phosphorylation concomitantly. |
| 6504 | 14556646 | Whereas the 48 h treatment reversed hyper-phosphorylation (and activation) of both c-Jun N-terminal kinase and p38 mitogen-activated protein kinase, the 24 h treatments only decreased hyper-phosphorylation of p38 mitogen-activated protein kinase. |
| 6505 | 14556646 | Taken together, these results suggest that IRS1 inhibitory serine phosphorylation is a key component of insulin resistance and its reversal contributes to the insulin sensitizing effects by rosiglitazone. |
| 6506 | 14556646 | Rosiglitazone, an agonist of peroxisome-proliferator-activated receptor gamma (PPARgamma), decreases inhibitory serine phosphorylation of IRS1 in vitro and in vivo. |
| 6507 | 14556646 | Peroxisome-proliferator-activated receptor gamma agonists such as rosiglitazone, a thiazolidinedione, improve insulin sensitivity in vivo, but the underlying mechanism(s) remains unclear. |
| 6508 | 14556646 | Phosphorylation of IRS1 (insulin receptor substrate protein 1) on certain serine residues, including S307 and S612 in rodent IRS1 (equivalent to S312 and S616 in human IRS1), has been shown to play a negative role in insulin signalling. |
| 6509 | 14556646 | In the present study, we investigated whether rosiglitazone improves insulin sensitivity by decreasing IRS1 inhibitory serine phosphorylation. |
| 6510 | 14556646 | In HEK-293 (human embryonic kidney 293) cells stably expressing recombinant IRS1 and in 3T3L1 adipocytes, rosiglitazone attenuated PMA-induced IRS1 S307/S612 phosphorylation and decreased insulin-stimulated Akt phosphorylation. |
| 6511 | 14556646 | We observed increased IRS1 S307 phosphorylation and concomitant decrease in insulin signalling as measured by insulin-stimulated IRS1 tyrosine phosphorylation, and Akt threonine phosphorylation in adipose tissues of Zucker obese rats compared with lean control rats. |
| 6512 | 14556646 | Treatment with rosiglitazone at 30 mg/kg body weight for 24 and 48 h increased insulin signalling and decreased IRS1 S307 phosphorylation concomitantly. |
| 6513 | 14556646 | Whereas the 48 h treatment reversed hyper-phosphorylation (and activation) of both c-Jun N-terminal kinase and p38 mitogen-activated protein kinase, the 24 h treatments only decreased hyper-phosphorylation of p38 mitogen-activated protein kinase. |
| 6514 | 14556646 | Taken together, these results suggest that IRS1 inhibitory serine phosphorylation is a key component of insulin resistance and its reversal contributes to the insulin sensitizing effects by rosiglitazone. |
| 6515 | 14563700 | The following results were obtained: 1) gliclazide stimulates insulin receptor substrate (IRS)-1-phosphatidylinositol 3 (PI3)-kinase-associated activity, and this activity is necessary for gliclazide-stimulated glucose transport; 2) gliclazide treatment produces a gradual translocation of the diacylglycerol (DAG)-dependent isoforms protein kinase C (PKC) alpha, theta, and epsilon from cytosolic to membrane fraction that is dependent on PI3-kinase and phospholipase C (PLC)-gamma activation; and 3) PKC and PLC-gamma activation is necessary for gliclazide-stimulated glucose transport. |
| 6516 | 14563700 | We propose a hypothetical signaling pathway by which gliclazide could stimulate IRS-1 that would allow its association with PI3-kinase, promoting its activation. |
| 6517 | 14563700 | PI3-kinase products could induce PLC-gamma activation, whose hydrolytic activity could activate the DAG-dependent isoforms PKC alpha, theta, and epsilon. |
| 6518 | 14578283 | Increased insulin sensitivity and hypoinsulinemia in APS knockout mice. |
| 6519 | 14578283 | A tyrosine kinase adaptor protein containing pleckstrin homology and SH2 domains (APS) is rapidly and strongly tyrosine phosphorylated by insulin receptor kinase upon insulin stimulation. |
| 6520 | 14578283 | The function of APS in insulin signaling has heretofore remained unknown. |
| 6521 | 14578283 | The blood glucose-lowering effect of insulin, as assessed by the intraperitoneal insulin tolerance test, was increased in APS(-/-) mice. |
| 6522 | 14578283 | Plasma insulin levels during fasting and in the intraperitoneal glucose tolerance test were lower in APS(-/-) mice. |
| 6523 | 14578283 | However, overexpression of wild-type or dominant-negative APS in 3T3L1 adipocytes did not affect insulin receptor numbers, phosphorylations of insulin receptor, insulin receptor substrate-1, or Akt and mitogen-activated protein kinase. |
| 6524 | 14578283 | The glucose uptake and GLUT4 translocation were not affected by insulin stimulation in these cells. |
| 6525 | 14578283 | Nevertheless, the insulin-stimulated glucose transport in isolated adipocytes of APS(-/-) mice was increased over that of APS(+/+) mice. |
| 6526 | 14578283 | APS(-/-) mice also showed increased serum levels of leptin and adiponectin, which might explain the increased insulin sensitivity of adipocytes. |
| 6527 | 14579029 | MAP kinases and mTOR mediate insulin-induced phosphorylation of insulin receptor substrate-1 on serine residues 307, 612 and 632. |
| 6528 | 14584587 | This controls many aspects of IRS-1, including its interaction with the insulin receptor and subsequent tyrosine phosphorylation, as well as its subcellular distribution and targeting for degradation by the proteasome. |
| 6529 | 14584587 | Emerging evidence indicates that 'diabetogenic factors' associated with insulin resistance, such as TNFalpha and elevated circulating fatty acids, impact on insulin signalling at the level of IRS-1 serine/threonine phosphorylation. |
| 6530 | 14584587 | The expression and/or activity of several kinases, such as IkappaB kinase beta (IKKbeta) and salt-induced kinase 2 (SIK2), and the phosphorylation of IRS-1 at key sites, such as Ser307 and Ser789, are increased in states of insulin resistance. |
| 6531 | 14584587 | This controls many aspects of IRS-1, including its interaction with the insulin receptor and subsequent tyrosine phosphorylation, as well as its subcellular distribution and targeting for degradation by the proteasome. |
| 6532 | 14584587 | Emerging evidence indicates that 'diabetogenic factors' associated with insulin resistance, such as TNFalpha and elevated circulating fatty acids, impact on insulin signalling at the level of IRS-1 serine/threonine phosphorylation. |
| 6533 | 14584587 | The expression and/or activity of several kinases, such as IkappaB kinase beta (IKKbeta) and salt-induced kinase 2 (SIK2), and the phosphorylation of IRS-1 at key sites, such as Ser307 and Ser789, are increased in states of insulin resistance. |
| 6534 | 14584587 | This controls many aspects of IRS-1, including its interaction with the insulin receptor and subsequent tyrosine phosphorylation, as well as its subcellular distribution and targeting for degradation by the proteasome. |
| 6535 | 14584587 | Emerging evidence indicates that 'diabetogenic factors' associated with insulin resistance, such as TNFalpha and elevated circulating fatty acids, impact on insulin signalling at the level of IRS-1 serine/threonine phosphorylation. |
| 6536 | 14584587 | The expression and/or activity of several kinases, such as IkappaB kinase beta (IKKbeta) and salt-induced kinase 2 (SIK2), and the phosphorylation of IRS-1 at key sites, such as Ser307 and Ser789, are increased in states of insulin resistance. |
| 6537 | 14592424 | Chronic interleukin-6 (IL-6) treatment increased IL-6 secretion and induced insulin resistance in adipocyte: prevention by rosiglitazone. |
| 6538 | 14592424 | IL-6 has emerged as an important cytokine upregulated in states of insulin resistance such as type 2 diabetes. |
| 6539 | 14592424 | We evaluated the chronic effect of IL-6 on insulin signaling in 3T3-F442A and 3T3-L1 adipocytes. |
| 6540 | 14592424 | Second, IL-6-treated adipocytes showed a decreased protein expression of IR-beta subunit and IRS-1 but also an inhibition of the insulin-induced activation of IR-beta, Akt/PKB, and ERK1/2. |
| 6541 | 14592424 | Moreover, IL-6 suppressed the insulin-induced lipogenesis and glucose transport consistent with a diminished expression of GLUT4. |
| 6542 | 14592424 | IL-6-treated adipocytes failed to maintain their adipocyte phenotype as shown by the downregulation of the adipogenic markers FAS, GAPDH, aP2, PPAR-gamma, and C/EBP-alpha. |
| 6543 | 14592424 | IL-6 also induced the expression of SOCS-3, a potential inhibitor of insulin signaling. |
| 6544 | 14592424 | Finally, the effects of IL-6 could be prevented by rosiglitazone, an insulin-sensitizing agent. |
| 6545 | 14592424 | Thus, IL-6 may play an important role in the set-up of insulin resistance in adipose cell. |
| 6546 | 14596593 | Cellular effects of small molecule PTP1B inhibitors on insulin signaling. |
| 6547 | 14596593 | Protein tyrosine phosphatase 1B (PTP1B) is implicated as a negative regulator of insulin receptor (IR) signaling and a potential drug target for the treatment of type 2 diabetes and other associated metabolic syndromes. |
| 6548 | 14596593 | To further define the role of PTP1B in insulin signaling and to test the hypothesis that blocking the activity of PTP1B would augment the action of insulin, we prepared several cell permeable, potent and selective, small molecule PTP1B inhibitors, and evaluated their biological effects in several insulin sensitive cell lines. |
| 6549 | 14596593 | Our data indicate that PTP1B inhibitors bind to and colocalize with PTP1B on the surface of the endoplasmic reticulum and PTP1B exerts its negative effect on insulin signaling upstream of phosphatidylinositol 3-kinase and MEK1. |
| 6550 | 14596593 | Treatment of cells with PTP1B inhibitors, both in the presence and in the absence of insulin, markedly enhances IRbeta and IRS-1 phosphorylation, Akt and ERK1/2 activation, Glut4 translocation, glucose uptake, and Elk1 transcriptional activation and cell proliferation. |
| 6551 | 14596593 | These results indicate that small molecule inhibitors targeted to PTP1B can act as both insulin mimetics and insulin sensitizers. |
| 6552 | 14596593 | Taken together, our findings combined with results from PTP1B knockout, antisense, and biochemical studies provide strong evidence that PTP1B negatively regulates insulin signaling and that small molecule PTP1B inhibitors have the ability to potentiate and augment the action of insulin. |
| 6553 | 14604996 | Role of insulin receptor substrates and protein kinase C-zeta in vascular permeability factor/vascular endothelial growth factor expression in pancreatic cancer cells. |
| 6554 | 14604996 | Previously we have shown that in AsPC-1 pancreatic adenocarcinoma cells, insulin-like growth factor receptor (IGF-IR) regulates VPF/VEGF expression. |
| 6555 | 14604996 | Insulin receptor substrate-1 and -2 (IRS-1 and IRS-2), two major downstream molecules of IGF-1R, are known to be important in the genesis of diabetes. |
| 6556 | 14604996 | The Sp1-dependent VPF/VEGF transcription is regulated mainly by IRS-2. |
| 6557 | 14604996 | Protein kinase C-zeta (PKC-zeta) plays a central role in VPF/VEGF expression and acts as a switching element. |
| 6558 | 14604996 | Furthermore, we have also demonstrated that the phosphatidylinositol 3-kinase pathway, but not the Ras pathway, is a downstream event of IRS proteins for VPF/VEGF expression in AsPC-1 cells. |
| 6559 | 14604996 | Interestingly, like renal cancer cells, in AsPC-1 cells PKC-zeta leads to direct Sp1-dependent VPF/VEGF transcription; in addition, it also promotes a negative feedback loop to IRS-2 that decreases the association of IRS-2/IGF-1R and IRS-2/p85. |
| 6560 | 14604996 | Taken together, our results show that in AsPC-1 pancreatic carcinoma cells, Sp1-dependent VPF/VEGF transcription is controlled by IGF-1R signaling through IRS-2 proteins and modulated by a negative feedback loop of PKC-zeta to IRS-2. |
| 6561 | 14623341 | Overexpression of Fer increases the association of tyrosine-phosphorylated IRS-1 with P85 phosphatidylinositol kinase via SH2 domain of Fer in transfected cells. |
| 6562 | 14623341 | We have reported that the protein-tyrosine kinase Fer is associated with signaling complexes containing insulin receptor substrate-1 (IRS-1) and phosphatidylinositol 3-kinase (PI-3 kinase) in insulin-stimulated 3T3-L1 adipocytes [J. |
| 6563 | 14623341 | Based on transfection study, we have demonstrated that overexpression of both Fer and IRS-1 can induce Fer/IRS-1/P85 complexes without insulin stimulation and SH2 domain of Fer is essential for this complex. |
| 6564 | 14623341 | Taken together, these data suggested that Fer may play a critically important role to form Fer/IRS-1/P85 complex in LDM of insulin-stimulated adipocytes and elicit biological effect through PI-3 kinase activity in LDM. |
| 6565 | 14623341 | Overexpression of Fer increases the association of tyrosine-phosphorylated IRS-1 with P85 phosphatidylinositol kinase via SH2 domain of Fer in transfected cells. |
| 6566 | 14623341 | We have reported that the protein-tyrosine kinase Fer is associated with signaling complexes containing insulin receptor substrate-1 (IRS-1) and phosphatidylinositol 3-kinase (PI-3 kinase) in insulin-stimulated 3T3-L1 adipocytes [J. |
| 6567 | 14623341 | Based on transfection study, we have demonstrated that overexpression of both Fer and IRS-1 can induce Fer/IRS-1/P85 complexes without insulin stimulation and SH2 domain of Fer is essential for this complex. |
| 6568 | 14623341 | Taken together, these data suggested that Fer may play a critically important role to form Fer/IRS-1/P85 complex in LDM of insulin-stimulated adipocytes and elicit biological effect through PI-3 kinase activity in LDM. |
| 6569 | 14623341 | Overexpression of Fer increases the association of tyrosine-phosphorylated IRS-1 with P85 phosphatidylinositol kinase via SH2 domain of Fer in transfected cells. |
| 6570 | 14623341 | We have reported that the protein-tyrosine kinase Fer is associated with signaling complexes containing insulin receptor substrate-1 (IRS-1) and phosphatidylinositol 3-kinase (PI-3 kinase) in insulin-stimulated 3T3-L1 adipocytes [J. |
| 6571 | 14623341 | Based on transfection study, we have demonstrated that overexpression of both Fer and IRS-1 can induce Fer/IRS-1/P85 complexes without insulin stimulation and SH2 domain of Fer is essential for this complex. |
| 6572 | 14623341 | Taken together, these data suggested that Fer may play a critically important role to form Fer/IRS-1/P85 complex in LDM of insulin-stimulated adipocytes and elicit biological effect through PI-3 kinase activity in LDM. |
| 6573 | 14623341 | Overexpression of Fer increases the association of tyrosine-phosphorylated IRS-1 with P85 phosphatidylinositol kinase via SH2 domain of Fer in transfected cells. |
| 6574 | 14623341 | We have reported that the protein-tyrosine kinase Fer is associated with signaling complexes containing insulin receptor substrate-1 (IRS-1) and phosphatidylinositol 3-kinase (PI-3 kinase) in insulin-stimulated 3T3-L1 adipocytes [J. |
| 6575 | 14623341 | Based on transfection study, we have demonstrated that overexpression of both Fer and IRS-1 can induce Fer/IRS-1/P85 complexes without insulin stimulation and SH2 domain of Fer is essential for this complex. |
| 6576 | 14623341 | Taken together, these data suggested that Fer may play a critically important role to form Fer/IRS-1/P85 complex in LDM of insulin-stimulated adipocytes and elicit biological effect through PI-3 kinase activity in LDM. |
| 6577 | 14623899 | Nutrient-dependent and insulin-stimulated phosphorylation of insulin receptor substrate-1 on serine 302 correlates with increased insulin signaling. |
| 6578 | 14623899 | Ser/Thr phosphorylation of insulin receptor substrate IRS-1 regulates insulin signaling, but the relevant phosphorylated residues and their potential functions during insulin-stimulated signal transduction are difficult to resolve. |
| 6579 | 14623899 | We used a sequence-specific polyclonal antibody directed against phosphorylated Ser(302) to study IRS-1-mediated signaling during insulin and insulin-like growth factor IGF-I stimulation. |
| 6580 | 14623899 | Insulin or IGF-I stimulated phosphorylation of Ser(302) in various cell backgrounds and in murine muscle. |
| 6581 | 14623899 | The NH(2)-terminal c-Jun kinase did not phosphorylate Ser(302). |
| 6582 | 14623899 | Replacing Ser(302) with alanine significantly reduced insulin-stimulated tyrosine phosphorylation of IRS-1 and p85 binding and reduced insulin-stimulated phosphorylation of p70(S6K), ribosomal S6 protein, and 4E-BP1; however, this mutation had no effect on insulin-stimulated Akt or glycogen synthase kinase 3beta phosphorylation. |
| 6583 | 14623899 | Replacing Ser(302) with alanine reduced insulin/IGF-I-stimulated DNA synthesis. |
| 6584 | 14623899 | We conclude that Ser(302) phosphorylation integrates nutrient availability with insulin/IGF-I signaling to promote mitogenesis and cell growth. |
| 6585 | 14623899 | Nutrient-dependent and insulin-stimulated phosphorylation of insulin receptor substrate-1 on serine 302 correlates with increased insulin signaling. |
| 6586 | 14623899 | Ser/Thr phosphorylation of insulin receptor substrate IRS-1 regulates insulin signaling, but the relevant phosphorylated residues and their potential functions during insulin-stimulated signal transduction are difficult to resolve. |
| 6587 | 14623899 | We used a sequence-specific polyclonal antibody directed against phosphorylated Ser(302) to study IRS-1-mediated signaling during insulin and insulin-like growth factor IGF-I stimulation. |
| 6588 | 14623899 | Insulin or IGF-I stimulated phosphorylation of Ser(302) in various cell backgrounds and in murine muscle. |
| 6589 | 14623899 | The NH(2)-terminal c-Jun kinase did not phosphorylate Ser(302). |
| 6590 | 14623899 | Replacing Ser(302) with alanine significantly reduced insulin-stimulated tyrosine phosphorylation of IRS-1 and p85 binding and reduced insulin-stimulated phosphorylation of p70(S6K), ribosomal S6 protein, and 4E-BP1; however, this mutation had no effect on insulin-stimulated Akt or glycogen synthase kinase 3beta phosphorylation. |
| 6591 | 14623899 | Replacing Ser(302) with alanine reduced insulin/IGF-I-stimulated DNA synthesis. |
| 6592 | 14623899 | We conclude that Ser(302) phosphorylation integrates nutrient availability with insulin/IGF-I signaling to promote mitogenesis and cell growth. |
| 6593 | 14623899 | Nutrient-dependent and insulin-stimulated phosphorylation of insulin receptor substrate-1 on serine 302 correlates with increased insulin signaling. |
| 6594 | 14623899 | Ser/Thr phosphorylation of insulin receptor substrate IRS-1 regulates insulin signaling, but the relevant phosphorylated residues and their potential functions during insulin-stimulated signal transduction are difficult to resolve. |
| 6595 | 14623899 | We used a sequence-specific polyclonal antibody directed against phosphorylated Ser(302) to study IRS-1-mediated signaling during insulin and insulin-like growth factor IGF-I stimulation. |
| 6596 | 14623899 | Insulin or IGF-I stimulated phosphorylation of Ser(302) in various cell backgrounds and in murine muscle. |
| 6597 | 14623899 | The NH(2)-terminal c-Jun kinase did not phosphorylate Ser(302). |
| 6598 | 14623899 | Replacing Ser(302) with alanine significantly reduced insulin-stimulated tyrosine phosphorylation of IRS-1 and p85 binding and reduced insulin-stimulated phosphorylation of p70(S6K), ribosomal S6 protein, and 4E-BP1; however, this mutation had no effect on insulin-stimulated Akt or glycogen synthase kinase 3beta phosphorylation. |
| 6599 | 14623899 | Replacing Ser(302) with alanine reduced insulin/IGF-I-stimulated DNA synthesis. |
| 6600 | 14623899 | We conclude that Ser(302) phosphorylation integrates nutrient availability with insulin/IGF-I signaling to promote mitogenesis and cell growth. |
| 6601 | 14625128 | However, the skeletal muscle insulin-stimulated IR-beta and the IRS-1 tyrosine phosphorylation levels in C300 rats were 18 and 33% higher, respectively, added to 41% higher IRS-1/PI 3-kinase association. |
| 6602 | 14633864 | In gene expression studies of tissue biopsies from nondiabetic Pima Indians, IRS1 mRNA levels were reduced in adipocytes from obese subjects compared with lean subjects, and IRS1 mRNA levels were also reduced in skeletal muscle from insulin-resistant subjects compared with insulin-sensitive subjects (all P < 0.05). |
| 6603 | 14641015 | Tyrosine phosphorylation of IRS-1 (insulin receptor substrate 1) and its binding to PI 3-kinase (phosphoinositide 3-kinase) are critical events in the insulin signalling cascade leading to insulin-stimulated glucose transport. |
| 6604 | 14641043 | Down-regulation of insulin receptor tyrosine phosphorylation and subsequent steps in the insulin signalling pathway, including insulin receptor substrate-1 (IRS-1)-associated phosphoinositide 3-kinase (PI3K), Akt kinase serine phosphorylation and activity and glucose transporter (GLUT-4) protein content, are evident in skeletal muscle after eccentric exercise. |
| 6605 | 14641043 | Furthermore, increased tumour necrosis factor alpha (TNF-alpha) secretion from monocytes is associated with the decrease in PI3K activity after this type of exercise. |
| 6606 | 14641043 | Recent studies have shown that TNF-alpha can increase IRS-1 serine/threonine phosphorylation, which impairs IRS-1 docking to the insulin receptor, and this inhibits insulin signalling. |
| 6607 | 14641043 | Thus a unifying hypothesis to explain insulin resistance after eccentric exercise may include inflammation arising from the disruption of muscle-cell integrity, leading to an acute-phase response that includes TNF-alpha, with the latter inhibiting insulin signalling and subsequent metabolic events. |
| 6608 | 14641043 | In contrast, exercise training increases insulin signalling and GLUT-4 expression, decreases TNF-alpha expression in skeletal muscle, and is associated with enhanced insulin sensitivity. |
| 6609 | 14641043 | Down-regulation of insulin receptor tyrosine phosphorylation and subsequent steps in the insulin signalling pathway, including insulin receptor substrate-1 (IRS-1)-associated phosphoinositide 3-kinase (PI3K), Akt kinase serine phosphorylation and activity and glucose transporter (GLUT-4) protein content, are evident in skeletal muscle after eccentric exercise. |
| 6610 | 14641043 | Furthermore, increased tumour necrosis factor alpha (TNF-alpha) secretion from monocytes is associated with the decrease in PI3K activity after this type of exercise. |
| 6611 | 14641043 | Recent studies have shown that TNF-alpha can increase IRS-1 serine/threonine phosphorylation, which impairs IRS-1 docking to the insulin receptor, and this inhibits insulin signalling. |
| 6612 | 14641043 | Thus a unifying hypothesis to explain insulin resistance after eccentric exercise may include inflammation arising from the disruption of muscle-cell integrity, leading to an acute-phase response that includes TNF-alpha, with the latter inhibiting insulin signalling and subsequent metabolic events. |
| 6613 | 14641043 | In contrast, exercise training increases insulin signalling and GLUT-4 expression, decreases TNF-alpha expression in skeletal muscle, and is associated with enhanced insulin sensitivity. |
| 6614 | 14647049 | Impaired IRS-1/PI3-kinase signaling in patients with HCV: a mechanism for increased prevalence of type 2 diabetes. |
| 6615 | 14647049 | In contrast, insulin-stimulated IRS-1 tyrosine phosphorylation was decreased by 2-fold in HCV-infected subjects compared with non-HCV-infected subjects (P <.05). |
| 6616 | 14647049 | The observed reductions in IRS-1 tyrosine phosphorylation were accompanied by a 3.4-fold decrease in IRS-1/p85 phosphatidylinositol 3-kinase (PI3-kinase) association and a 2.5-fold decrease in IRS-1-associated PI3-kinase enzymatic activity (P <.05 vs. non-HCV). |
| 6617 | 14647049 | This was accompanied by a marked reduction in insulin-stimulated Akt phosphorylation without any alterations in mitogen-activated protein kinase (MAPK) phosphorylation. |
| 6618 | 14647049 | Cellular contents of the hepatic p85 subunit of PI3-kinase were comparable between HCV-infected and non-HCV-infected subjects. |
| 6619 | 14647049 | HCV infection leads to a postreceptor defect in IRS-1 association with the IR and (2). insulin signaling defects in hepatic IRS-1 tyrosine phosphorylation and PI3-kinase association/activation may contribute to insulin resistance, which leads to the development of type 2 diabetes mellitus in patients with HCV infection. |
| 6620 | 14647049 | Impaired IRS-1/PI3-kinase signaling in patients with HCV: a mechanism for increased prevalence of type 2 diabetes. |
| 6621 | 14647049 | In contrast, insulin-stimulated IRS-1 tyrosine phosphorylation was decreased by 2-fold in HCV-infected subjects compared with non-HCV-infected subjects (P <.05). |
| 6622 | 14647049 | The observed reductions in IRS-1 tyrosine phosphorylation were accompanied by a 3.4-fold decrease in IRS-1/p85 phosphatidylinositol 3-kinase (PI3-kinase) association and a 2.5-fold decrease in IRS-1-associated PI3-kinase enzymatic activity (P <.05 vs. non-HCV). |
| 6623 | 14647049 | This was accompanied by a marked reduction in insulin-stimulated Akt phosphorylation without any alterations in mitogen-activated protein kinase (MAPK) phosphorylation. |
| 6624 | 14647049 | Cellular contents of the hepatic p85 subunit of PI3-kinase were comparable between HCV-infected and non-HCV-infected subjects. |
| 6625 | 14647049 | HCV infection leads to a postreceptor defect in IRS-1 association with the IR and (2). insulin signaling defects in hepatic IRS-1 tyrosine phosphorylation and PI3-kinase association/activation may contribute to insulin resistance, which leads to the development of type 2 diabetes mellitus in patients with HCV infection. |
| 6626 | 14647049 | Impaired IRS-1/PI3-kinase signaling in patients with HCV: a mechanism for increased prevalence of type 2 diabetes. |
| 6627 | 14647049 | In contrast, insulin-stimulated IRS-1 tyrosine phosphorylation was decreased by 2-fold in HCV-infected subjects compared with non-HCV-infected subjects (P <.05). |
| 6628 | 14647049 | The observed reductions in IRS-1 tyrosine phosphorylation were accompanied by a 3.4-fold decrease in IRS-1/p85 phosphatidylinositol 3-kinase (PI3-kinase) association and a 2.5-fold decrease in IRS-1-associated PI3-kinase enzymatic activity (P <.05 vs. non-HCV). |
| 6629 | 14647049 | This was accompanied by a marked reduction in insulin-stimulated Akt phosphorylation without any alterations in mitogen-activated protein kinase (MAPK) phosphorylation. |
| 6630 | 14647049 | Cellular contents of the hepatic p85 subunit of PI3-kinase were comparable between HCV-infected and non-HCV-infected subjects. |
| 6631 | 14647049 | HCV infection leads to a postreceptor defect in IRS-1 association with the IR and (2). insulin signaling defects in hepatic IRS-1 tyrosine phosphorylation and PI3-kinase association/activation may contribute to insulin resistance, which leads to the development of type 2 diabetes mellitus in patients with HCV infection. |
| 6632 | 14647049 | Impaired IRS-1/PI3-kinase signaling in patients with HCV: a mechanism for increased prevalence of type 2 diabetes. |
| 6633 | 14647049 | In contrast, insulin-stimulated IRS-1 tyrosine phosphorylation was decreased by 2-fold in HCV-infected subjects compared with non-HCV-infected subjects (P <.05). |
| 6634 | 14647049 | The observed reductions in IRS-1 tyrosine phosphorylation were accompanied by a 3.4-fold decrease in IRS-1/p85 phosphatidylinositol 3-kinase (PI3-kinase) association and a 2.5-fold decrease in IRS-1-associated PI3-kinase enzymatic activity (P <.05 vs. non-HCV). |
| 6635 | 14647049 | This was accompanied by a marked reduction in insulin-stimulated Akt phosphorylation without any alterations in mitogen-activated protein kinase (MAPK) phosphorylation. |
| 6636 | 14647049 | Cellular contents of the hepatic p85 subunit of PI3-kinase were comparable between HCV-infected and non-HCV-infected subjects. |
| 6637 | 14647049 | HCV infection leads to a postreceptor defect in IRS-1 association with the IR and (2). insulin signaling defects in hepatic IRS-1 tyrosine phosphorylation and PI3-kinase association/activation may contribute to insulin resistance, which leads to the development of type 2 diabetes mellitus in patients with HCV infection. |
| 6638 | 14673165 | p50alpha/p55alpha phosphoinositide 3-kinase knockout mice exhibit enhanced insulin sensitivity. |
| 6639 | 14673165 | In addition to p85alpha and p85beta, insulin-sensitive tissues such as fat, muscle, and liver express the splice variants of the pik3r1 gene, p50alpha and p55alpha. |
| 6640 | 14673165 | Results of an insulin tolerance test indicate that p50alpha/p55alpha knockout mice have enhanced insulin sensitivity in vivo, and there is an increase in insulin-stimulated glucose transport in isolated extensor digitorum longus muscle tissues and adipocytes. |
| 6641 | 14673165 | In muscle, loss of p50alpha/p55alpha results in reduced levels of insulin-stimulated insulin receptor substrate 1 (IRS-1) and phosphotyrosine-associated PI 3-kinase but enhanced levels of IRS-2-associated PI 3-kinase and Akt activation, whereas in adipocytes levels of both insulin-stimulated PI 3-kinase and Akt are unchanged. |
| 6642 | 14673165 | Taken together, these data indicate that p50alpha and p55alpha play an important role in insulin signaling and action, especially in lipid and glucose metabolism. |
| 6643 | 14693412 | The insulin gene (INS), insulin receptor gene (INSR) and insulin receptor substrate 1 gene (IRS1) have been proposed as candidate genes. |
| 6644 | 14693412 | Restriction fragment length polymorphisms in INS, INSR and IRS1 were identified by polymerase chain reaction and digestion with selected restriction enzymes. |
| 6645 | 14693412 | None of the polymorphisms in INSR or IRS1 was associated with any of these traits. |
| 6646 | 14693412 | The insulin gene (INS), insulin receptor gene (INSR) and insulin receptor substrate 1 gene (IRS1) have been proposed as candidate genes. |
| 6647 | 14693412 | Restriction fragment length polymorphisms in INS, INSR and IRS1 were identified by polymerase chain reaction and digestion with selected restriction enzymes. |
| 6648 | 14693412 | None of the polymorphisms in INSR or IRS1 was associated with any of these traits. |
| 6649 | 14693412 | The insulin gene (INS), insulin receptor gene (INSR) and insulin receptor substrate 1 gene (IRS1) have been proposed as candidate genes. |
| 6650 | 14693412 | Restriction fragment length polymorphisms in INS, INSR and IRS1 were identified by polymerase chain reaction and digestion with selected restriction enzymes. |
| 6651 | 14693412 | None of the polymorphisms in INSR or IRS1 was associated with any of these traits. |
| 6652 | 14693422 | In cultured adrenocortical cells, SIK1 is rapidly but transiently induced by adrenocorticotropin (ACTH) treatment, suggesting that it contributes to ACTH-mediated induction of steroidogenic enzymes. |
| 6653 | 14693422 | However, ACTH treatment of Y1 mouse adrenocortical cells stimulates a rapid translocation of SIK1 from the nucleus to the cytoplasm, and SIK1 represses the transcription of a steroidogenic enzyme by inhibiting the action of cAMP-responsive elements in the promoter. |
| 6654 | 14693422 | SIK2 is found in adipocytes and phosphorylates a specific serine residue in insulin receptor substrate-1. |
| 6655 | 14693422 | Thus, members of the SIK family are emerging as important modulators of key processes such as steroid hormone biosynthesis by the adrenal cortex and insulin signaling in adipocytes. |
| 6656 | 14693698 | Islet-sparing effects of protein tyrosine phosphatase-1b deficiency delays onset of diabetes in IRS2 knockout mice. |
| 6657 | 14693698 | Protein tyrosine phosphatase-1b (Ptp1b) inhibits insulin and leptin signaling by dephosphorylating specific tyrosine residues in their activated receptor complexes. |
| 6658 | 14693698 | Insulin signals are mediated by tyrosine phosphorylation of the insulin receptor and its downstream targets, such as Irs1 and Irs2. |
| 6659 | 14693698 | Irs2 plays an especially important role in glucose homeostasis because it mediates some peripheral actions of insulin and promotes pancreatic beta-cell function. |
| 6660 | 14693698 | To determine whether the deletion of Ptp1b compensates for the absence of Irs2, we analyzed mice deficient in both Ptp1b and Irs2. |
| 6661 | 14693698 | Pancreatic beta-cell area decreased in Ptp1b(-/-) mice, consistent with decreased insulin requirements owing to increased peripheral insulin sensitivity. |
| 6662 | 14693698 | By contrast, peripheral insulin sensitivity and beta-cell area increased in Irs2(-/-)::Ptp1b(-/-) mice, which improved glucose tolerance in Irs2(-/-)::Ptp1b(-/-) mice and delayed diabetes until 3 months of age. |
| 6663 | 14693698 | Our studies demonstrate a novel role for Ptp1b in regulating beta-cell homeostasis and indicate that Ptp1b deficiency can partially compensate for lack of Irs2. |
| 6664 | 14707885 | Glucose uptake induced by insulin is largely dependent on the PI 3-kinase/PKB pathway. |
| 6665 | 14707885 | In both adipocyte and muscle cells, hyperosmolarity promotes glucose uptake by multiple mechanisms which do not require PI 3-kinase/PKB pathway but are dependent on the cell type. |
| 6666 | 14707885 | Apart of its insulin-like effects, hyperosmolarity can lead to cellular insulin resistance mediated by both prevention of PKB activation and inhibition of the Insulin Receptor Substrate-1 (IRS1) function. |
| 6667 | 14749734 | Adult male Grb14(-/-) mice displayed improved glucose tolerance, lower circulating insulin levels, and increased incorporation of glucose into glycogen in the liver and skeletal muscle. |
| 6668 | 14749734 | In the liver, despite lower IR autophosphorylation, enhanced insulin-induced tyrosine phosphorylation of insulin receptor substrate (IRS)-1 and activation of protein kinase B (PKB) was observed. |
| 6669 | 14749734 | In skeletal muscle, IR tyrosine phosphorylation was normal, but signalling via IRS-1 and PKB was increased. |
| 6670 | 14749734 | Finally, no effect of Grb14 ablation was observed on insulin signalling in white adipose tissue. |
| 6671 | 14749734 | These findings demonstrate that Grb14 functions in vivo as a tissue-specific modulator of insulin action, most likely via repression of IR-mediated IRS-1 tyrosine phosphorylation, and highlight this protein as a potential target for therapeutic intervention. |
| 6672 | 14749734 | Adult male Grb14(-/-) mice displayed improved glucose tolerance, lower circulating insulin levels, and increased incorporation of glucose into glycogen in the liver and skeletal muscle. |
| 6673 | 14749734 | In the liver, despite lower IR autophosphorylation, enhanced insulin-induced tyrosine phosphorylation of insulin receptor substrate (IRS)-1 and activation of protein kinase B (PKB) was observed. |
| 6674 | 14749734 | In skeletal muscle, IR tyrosine phosphorylation was normal, but signalling via IRS-1 and PKB was increased. |
| 6675 | 14749734 | Finally, no effect of Grb14 ablation was observed on insulin signalling in white adipose tissue. |
| 6676 | 14749734 | These findings demonstrate that Grb14 functions in vivo as a tissue-specific modulator of insulin action, most likely via repression of IR-mediated IRS-1 tyrosine phosphorylation, and highlight this protein as a potential target for therapeutic intervention. |
| 6677 | 14966267 | The NAD(P)H oxidase homolog Nox4 modulates insulin-stimulated generation of H2O2 and plays an integral role in insulin signal transduction. |
| 6678 | 14966267 | Insulin stimulation of target cells elicits a burst of H(2)O(2) that enhances tyrosine phosphorylation of the insulin receptor and its cellular substrate proteins as well as distal signaling events in the insulin action cascade. |
| 6679 | 14966267 | Using reverse transcription-PCR and Northern blot analyses, we found that Nox4, a homolog of gp91phox, the phagocytic NAD(P)H oxidase catalytic subunit, is prominently expressed in insulin-sensitive adipose cells. |
| 6680 | 14966267 | Adenovirus-mediated expression of Nox4 deletion constructs lacking NAD(P)H or FAD/NAD(P)H cofactor binding domains acted in a dominant-negative fashion in differentiated 3T3-L1 adipocytes and attenuated insulin-stimulated H(2)O(2) generation, insulin receptor (IR) and IRS-1 tyrosine phosphorylation, activation of downstream serine kinases, and glucose uptake. |
| 6681 | 14966267 | Transfection of specific small interfering RNA oligonucleotides reduced Nox4 protein abundance and also inhibited the insulin signaling cascade. |
| 6682 | 14966267 | Overexpression of Nox4 also significantly reversed the inhibition of insulin-stimulated IR tyrosine phosphorylation induced by coexpression of PTP1B by inhibiting PTP1B catalytic activity. |
| 6683 | 14966267 | These data suggest that Nox4 provides a novel link between the IR and the generation of cellular reactive oxygen species that enhance insulin signal transduction, at least in part via the oxidative inhibition of cellular protein-tyrosine phosphatases (PTPases), including PTP1B, a PTPase that has been previously implicated in the regulation of insulin action. |
| 6684 | 14966273 | Differential roles of insulin receptor substrates in brown adipocyte differentiation. |
| 6685 | 14966273 | Insulin promotes adipocyte differentiation via a complex signaling network involving multiple insulin receptor substrates (IRSs). |
| 6686 | 14966273 | In cultured brown preadipocytes, expression of IRS-1 and IRS-2 mRNAs and proteins was at relatively high levels before and after differentiation into mature fat cells, while IRS-3 transcript was not detectable in preadipocytes but increased during the course of differentiation, and IRS-4 mRNA was barely detected in both states. |
| 6687 | 14966273 | While wild-type, IRS-2 KO, and IRS-4 KO cells fully differentiated into mature adipocytes, IRS-3 KO cells showed a moderate defect in differentiation and IRS-1 KO cells exhibited a severe defect in the process. |
| 6688 | 14966273 | Expression of the adipogenic markers peroxisome proliferator-activated receptor gamma (PPARgamma), CCAAT/enhancer-binding protein alpha, fatty acid synthase, glucose transporter 4, and the transcription factor signal transducer and activator of transcription 5, as well as the brown-fat-specific markers PPARgamma coactivator 1 alpha and uncoupling protein 1, mirrored the differentiation pattern. |
| 6689 | 14966273 | Reconstitution of the IRS-1 KO cells with IRS-1 and IRS-4, but not IRS-2 or IRS-3, compensated for the lack of differentiation in IRS-1 KO cells. |
| 6690 | 14966273 | A chimeric molecule containing the N terminus of IRS-1 and the C terminus of IRS-2, but not one with the N terminus of IRS-2 and the C terminus of IRS-1, also rescued differentiation. |
| 6691 | 14966273 | Expression of Wnt 10a, a molecule known to inhibit adipogenesis, was dramatically increased in the IRS-1 KO cells, and this could be reduced by overexpression of IRS-1 or IRS-4, which was correlated with restoration of differentiation. |
| 6692 | 14966273 | Although IRS-4 is not essential for the process, overexpression of IRS-4 can compensate for the deficiency in differentiation in IRS-1 KO cells. |
| 6693 | 14966273 | Differential roles of insulin receptor substrates in brown adipocyte differentiation. |
| 6694 | 14966273 | Insulin promotes adipocyte differentiation via a complex signaling network involving multiple insulin receptor substrates (IRSs). |
| 6695 | 14966273 | In cultured brown preadipocytes, expression of IRS-1 and IRS-2 mRNAs and proteins was at relatively high levels before and after differentiation into mature fat cells, while IRS-3 transcript was not detectable in preadipocytes but increased during the course of differentiation, and IRS-4 mRNA was barely detected in both states. |
| 6696 | 14966273 | While wild-type, IRS-2 KO, and IRS-4 KO cells fully differentiated into mature adipocytes, IRS-3 KO cells showed a moderate defect in differentiation and IRS-1 KO cells exhibited a severe defect in the process. |
| 6697 | 14966273 | Expression of the adipogenic markers peroxisome proliferator-activated receptor gamma (PPARgamma), CCAAT/enhancer-binding protein alpha, fatty acid synthase, glucose transporter 4, and the transcription factor signal transducer and activator of transcription 5, as well as the brown-fat-specific markers PPARgamma coactivator 1 alpha and uncoupling protein 1, mirrored the differentiation pattern. |
| 6698 | 14966273 | Reconstitution of the IRS-1 KO cells with IRS-1 and IRS-4, but not IRS-2 or IRS-3, compensated for the lack of differentiation in IRS-1 KO cells. |
| 6699 | 14966273 | A chimeric molecule containing the N terminus of IRS-1 and the C terminus of IRS-2, but not one with the N terminus of IRS-2 and the C terminus of IRS-1, also rescued differentiation. |
| 6700 | 14966273 | Expression of Wnt 10a, a molecule known to inhibit adipogenesis, was dramatically increased in the IRS-1 KO cells, and this could be reduced by overexpression of IRS-1 or IRS-4, which was correlated with restoration of differentiation. |
| 6701 | 14966273 | Although IRS-4 is not essential for the process, overexpression of IRS-4 can compensate for the deficiency in differentiation in IRS-1 KO cells. |
| 6702 | 14966273 | Differential roles of insulin receptor substrates in brown adipocyte differentiation. |
| 6703 | 14966273 | Insulin promotes adipocyte differentiation via a complex signaling network involving multiple insulin receptor substrates (IRSs). |
| 6704 | 14966273 | In cultured brown preadipocytes, expression of IRS-1 and IRS-2 mRNAs and proteins was at relatively high levels before and after differentiation into mature fat cells, while IRS-3 transcript was not detectable in preadipocytes but increased during the course of differentiation, and IRS-4 mRNA was barely detected in both states. |
| 6705 | 14966273 | While wild-type, IRS-2 KO, and IRS-4 KO cells fully differentiated into mature adipocytes, IRS-3 KO cells showed a moderate defect in differentiation and IRS-1 KO cells exhibited a severe defect in the process. |
| 6706 | 14966273 | Expression of the adipogenic markers peroxisome proliferator-activated receptor gamma (PPARgamma), CCAAT/enhancer-binding protein alpha, fatty acid synthase, glucose transporter 4, and the transcription factor signal transducer and activator of transcription 5, as well as the brown-fat-specific markers PPARgamma coactivator 1 alpha and uncoupling protein 1, mirrored the differentiation pattern. |
| 6707 | 14966273 | Reconstitution of the IRS-1 KO cells with IRS-1 and IRS-4, but not IRS-2 or IRS-3, compensated for the lack of differentiation in IRS-1 KO cells. |
| 6708 | 14966273 | A chimeric molecule containing the N terminus of IRS-1 and the C terminus of IRS-2, but not one with the N terminus of IRS-2 and the C terminus of IRS-1, also rescued differentiation. |
| 6709 | 14966273 | Expression of Wnt 10a, a molecule known to inhibit adipogenesis, was dramatically increased in the IRS-1 KO cells, and this could be reduced by overexpression of IRS-1 or IRS-4, which was correlated with restoration of differentiation. |
| 6710 | 14966273 | Although IRS-4 is not essential for the process, overexpression of IRS-4 can compensate for the deficiency in differentiation in IRS-1 KO cells. |
| 6711 | 14966273 | Differential roles of insulin receptor substrates in brown adipocyte differentiation. |
| 6712 | 14966273 | Insulin promotes adipocyte differentiation via a complex signaling network involving multiple insulin receptor substrates (IRSs). |
| 6713 | 14966273 | In cultured brown preadipocytes, expression of IRS-1 and IRS-2 mRNAs and proteins was at relatively high levels before and after differentiation into mature fat cells, while IRS-3 transcript was not detectable in preadipocytes but increased during the course of differentiation, and IRS-4 mRNA was barely detected in both states. |
| 6714 | 14966273 | While wild-type, IRS-2 KO, and IRS-4 KO cells fully differentiated into mature adipocytes, IRS-3 KO cells showed a moderate defect in differentiation and IRS-1 KO cells exhibited a severe defect in the process. |
| 6715 | 14966273 | Expression of the adipogenic markers peroxisome proliferator-activated receptor gamma (PPARgamma), CCAAT/enhancer-binding protein alpha, fatty acid synthase, glucose transporter 4, and the transcription factor signal transducer and activator of transcription 5, as well as the brown-fat-specific markers PPARgamma coactivator 1 alpha and uncoupling protein 1, mirrored the differentiation pattern. |
| 6716 | 14966273 | Reconstitution of the IRS-1 KO cells with IRS-1 and IRS-4, but not IRS-2 or IRS-3, compensated for the lack of differentiation in IRS-1 KO cells. |
| 6717 | 14966273 | A chimeric molecule containing the N terminus of IRS-1 and the C terminus of IRS-2, but not one with the N terminus of IRS-2 and the C terminus of IRS-1, also rescued differentiation. |
| 6718 | 14966273 | Expression of Wnt 10a, a molecule known to inhibit adipogenesis, was dramatically increased in the IRS-1 KO cells, and this could be reduced by overexpression of IRS-1 or IRS-4, which was correlated with restoration of differentiation. |
| 6719 | 14966273 | Although IRS-4 is not essential for the process, overexpression of IRS-4 can compensate for the deficiency in differentiation in IRS-1 KO cells. |
| 6720 | 14966273 | Differential roles of insulin receptor substrates in brown adipocyte differentiation. |
| 6721 | 14966273 | Insulin promotes adipocyte differentiation via a complex signaling network involving multiple insulin receptor substrates (IRSs). |
| 6722 | 14966273 | In cultured brown preadipocytes, expression of IRS-1 and IRS-2 mRNAs and proteins was at relatively high levels before and after differentiation into mature fat cells, while IRS-3 transcript was not detectable in preadipocytes but increased during the course of differentiation, and IRS-4 mRNA was barely detected in both states. |
| 6723 | 14966273 | While wild-type, IRS-2 KO, and IRS-4 KO cells fully differentiated into mature adipocytes, IRS-3 KO cells showed a moderate defect in differentiation and IRS-1 KO cells exhibited a severe defect in the process. |
| 6724 | 14966273 | Expression of the adipogenic markers peroxisome proliferator-activated receptor gamma (PPARgamma), CCAAT/enhancer-binding protein alpha, fatty acid synthase, glucose transporter 4, and the transcription factor signal transducer and activator of transcription 5, as well as the brown-fat-specific markers PPARgamma coactivator 1 alpha and uncoupling protein 1, mirrored the differentiation pattern. |
| 6725 | 14966273 | Reconstitution of the IRS-1 KO cells with IRS-1 and IRS-4, but not IRS-2 or IRS-3, compensated for the lack of differentiation in IRS-1 KO cells. |
| 6726 | 14966273 | A chimeric molecule containing the N terminus of IRS-1 and the C terminus of IRS-2, but not one with the N terminus of IRS-2 and the C terminus of IRS-1, also rescued differentiation. |
| 6727 | 14966273 | Expression of Wnt 10a, a molecule known to inhibit adipogenesis, was dramatically increased in the IRS-1 KO cells, and this could be reduced by overexpression of IRS-1 or IRS-4, which was correlated with restoration of differentiation. |
| 6728 | 14966273 | Although IRS-4 is not essential for the process, overexpression of IRS-4 can compensate for the deficiency in differentiation in IRS-1 KO cells. |
| 6729 | 14966273 | Differential roles of insulin receptor substrates in brown adipocyte differentiation. |
| 6730 | 14966273 | Insulin promotes adipocyte differentiation via a complex signaling network involving multiple insulin receptor substrates (IRSs). |
| 6731 | 14966273 | In cultured brown preadipocytes, expression of IRS-1 and IRS-2 mRNAs and proteins was at relatively high levels before and after differentiation into mature fat cells, while IRS-3 transcript was not detectable in preadipocytes but increased during the course of differentiation, and IRS-4 mRNA was barely detected in both states. |
| 6732 | 14966273 | While wild-type, IRS-2 KO, and IRS-4 KO cells fully differentiated into mature adipocytes, IRS-3 KO cells showed a moderate defect in differentiation and IRS-1 KO cells exhibited a severe defect in the process. |
| 6733 | 14966273 | Expression of the adipogenic markers peroxisome proliferator-activated receptor gamma (PPARgamma), CCAAT/enhancer-binding protein alpha, fatty acid synthase, glucose transporter 4, and the transcription factor signal transducer and activator of transcription 5, as well as the brown-fat-specific markers PPARgamma coactivator 1 alpha and uncoupling protein 1, mirrored the differentiation pattern. |
| 6734 | 14966273 | Reconstitution of the IRS-1 KO cells with IRS-1 and IRS-4, but not IRS-2 or IRS-3, compensated for the lack of differentiation in IRS-1 KO cells. |
| 6735 | 14966273 | A chimeric molecule containing the N terminus of IRS-1 and the C terminus of IRS-2, but not one with the N terminus of IRS-2 and the C terminus of IRS-1, also rescued differentiation. |
| 6736 | 14966273 | Expression of Wnt 10a, a molecule known to inhibit adipogenesis, was dramatically increased in the IRS-1 KO cells, and this could be reduced by overexpression of IRS-1 or IRS-4, which was correlated with restoration of differentiation. |
| 6737 | 14966273 | Although IRS-4 is not essential for the process, overexpression of IRS-4 can compensate for the deficiency in differentiation in IRS-1 KO cells. |
| 6738 | 14988278 | Analysis of the type 2 diabetes-associated single nucleotide polymorphisms in the genes IRS1, KCNJ11, and PPARG2 in type 1 diabetes. |
| 6739 | 14988278 | We have genotyped three single nucleotide polymorphisms associated with type 2 diabetes in a large type 1 diabetic family collection of European descent: Gly972Arg in the insulin receptor substrate 1 (IRS1) gene, Glu23Lys in the potassium inwardly-rectifying channel gene (KCNJ11), and Pro12Ala in the peroxisome proliferative-activated receptor gamma2 gene (PPARG2). |
| 6740 | 14988278 | Analysis of the type 2 diabetes-associated single nucleotide polymorphisms in the genes IRS1, KCNJ11, and PPARG2 in type 1 diabetes. |
| 6741 | 14988278 | We have genotyped three single nucleotide polymorphisms associated with type 2 diabetes in a large type 1 diabetic family collection of European descent: Gly972Arg in the insulin receptor substrate 1 (IRS1) gene, Glu23Lys in the potassium inwardly-rectifying channel gene (KCNJ11), and Pro12Ala in the peroxisome proliferative-activated receptor gamma2 gene (PPARG2). |
| 6742 | 14998989 | Activation of both the insulin receptor substrates (IRSs)/Akt and the c-Cbl-associated protein (CAP)/c-Cbl pathways are important in regulating insulin-stimulated glucose transport. |
| 6743 | 14998989 | Treatment with LG268 increases insulin-stimulated IRS-1 tyrosine phosphorylation and Akt phosphorylation in skeletal muscle without affecting the activity of the CAP/c-Cbl pathway. |
| 6744 | 14998989 | In contrast, rosiglitazone increases the levels of CAP expression and insulin-stimulated c-Cbl phosphorylation without affecting the IRS-1/Akt pathway. |
| 6745 | 14998989 | The effects of LG268 on the IRS-1/Akt pathway were associated with a decrease in the level of IRS-1 Ser(307) phosphorylation. |
| 6746 | 14998989 | Activation of both the insulin receptor substrates (IRSs)/Akt and the c-Cbl-associated protein (CAP)/c-Cbl pathways are important in regulating insulin-stimulated glucose transport. |
| 6747 | 14998989 | Treatment with LG268 increases insulin-stimulated IRS-1 tyrosine phosphorylation and Akt phosphorylation in skeletal muscle without affecting the activity of the CAP/c-Cbl pathway. |
| 6748 | 14998989 | In contrast, rosiglitazone increases the levels of CAP expression and insulin-stimulated c-Cbl phosphorylation without affecting the IRS-1/Akt pathway. |
| 6749 | 14998989 | The effects of LG268 on the IRS-1/Akt pathway were associated with a decrease in the level of IRS-1 Ser(307) phosphorylation. |
| 6750 | 14998989 | Activation of both the insulin receptor substrates (IRSs)/Akt and the c-Cbl-associated protein (CAP)/c-Cbl pathways are important in regulating insulin-stimulated glucose transport. |
| 6751 | 14998989 | Treatment with LG268 increases insulin-stimulated IRS-1 tyrosine phosphorylation and Akt phosphorylation in skeletal muscle without affecting the activity of the CAP/c-Cbl pathway. |
| 6752 | 14998989 | In contrast, rosiglitazone increases the levels of CAP expression and insulin-stimulated c-Cbl phosphorylation without affecting the IRS-1/Akt pathway. |
| 6753 | 14998989 | The effects of LG268 on the IRS-1/Akt pathway were associated with a decrease in the level of IRS-1 Ser(307) phosphorylation. |
| 6754 | 15001626 | Short- or long-term infusion did not affect the absolute values of basal or insulin-stimulated insulin receptor substrate-1 tyrosine phosphorylation, tyrosine-associated phosphoinositide 3-kinase (PI 3-kinase) activity, insulin receptor substrate-1-associated PI 3-kinase activity, or Akt serine phosphorylation in IGT relatives or matched controls. |
| 6755 | 15037562 | Angiotensin II type-1 receptor blocker valsartan enhances insulin sensitivity in skeletal muscles of diabetic mice. |
| 6756 | 15037562 | Angiotensin II has been shown to contribute to the pathogenesis of insulin resistance; however, the mechanism is not well understood. |
| 6757 | 15037562 | The present study was undertaken to investigate the potential effect of an angiotensin II type-1 (AT1) receptor blocker, valsartan, to improve insulin resistance and to explore the signaling basis of cross-talk of the AT1 receptor- and insulin-mediated signaling in type 2 diabetic KK-Ay mice. |
| 6758 | 15037562 | In contrast, insulin-mediated 2-[3H]DG uptake into skeletal muscle was not influenced in AT2 receptor null mice, and an AT2 receptor blocker, PD123319, did not affect 2-[3H]DG uptake and superoxide production in skeletal muscle of KK-Ay mice. |
| 6759 | 15037562 | Moreover, we observed that valsartan treatment exaggerated the insulin-induced phosphorylation of IRS-1, the association of IRS-1 with the p85 regulatory subunit of phosphoinositide 3 kinase (PI 3-K), PI 3-K activity, and translocation of GLUT4 to the plasma membrane. |
| 6760 | 15037562 | Specific AT1 receptor blockade increases insulin sensitivity and glucose uptake in skeletal muscle of KK-Ay mice via stimulating the insulin signaling cascade and consequent enhancement of GLUT4 translocation to the plasma membrane. |
| 6761 | 15056942 | On the other hand, PAC1 receptor is expressed in adipocytes. |
| 6762 | 15056942 | PACAP enhances insulin-stimulated glucose uptake in an adipocyte cell-line, 3T3-L1 cells. |
| 6763 | 15056942 | PACAP does not alter the tyrosine phosphorylation of insulin receptor and IRS-1, but increases the activity of PI-3 kinase, a distal site of insulin signaling. |
| 6764 | 15056942 | These results demonstrate that PACAP enhances glucose-stimulated insulin secretion in islets, enhances insulin action inadipocytes, and prevents hyperglycemia in diabetic animals. |
| 6765 | 15082116 | Elevated sympathetic activity may promote insulin resistance syndrome by activating alpha-1 adrenergic receptors on adipocytes. |
| 6766 | 15082116 | An excess of free intracellular calcium can reduce the efficiency of insulin-mediated glucose transport by blocking the dephosphorylation of GLUT-4. |
| 6767 | 15082116 | Classical isoforms of protein kinase C (PKC) can interfere with insulin signalling via serine phosphorylation of IRS-1 and the insulin receptor. |
| 6768 | 15082116 | Parathyroid hormone (PTH), by activating phospholipase C-beta in adipocytes, can promote a sustained increase in intracellular free calcium in these cells, while also activating classical PKCs. |
| 6769 | 15082116 | This may rationalize the fact that insulin resistance is a typical feature of hyperparathyroidism, as well as epidemiological evidence that regular ingestion of dairy products or of ethanol--which down-regulates PTH secretion--reduces risk for insulin resistance syndrome and diabetes. |
| 6770 | 15082116 | Alpha-1 adrenergic receptors of adipocytes--like PTH receptors--also activate phospholipase C-beta, and thus have an effect analogous to PTH on intracellular free calcium and PKC activity in adipocytes. |
| 6771 | 15082116 | This suggests that, via activation of alpha-1 adrenergic receptors, increased sympathetic activity in adipose tissue may promote insulin resistance syndrome. |
| 6772 | 15082116 | In fact, measures which provoke increased sympathetic output--such as diuretic use and severe salt restriction--are known to compromise insulin sensitivity, whereas alpha-1 antagonist drugs, as well as drugs that act centrally to suppress sympathetic activity, typically have a favorable effect on insulin function. |
| 6773 | 15082116 | When insulin resistance syndrome is associated with elevated sympathetic activity--for example, in hypertensives who are obese or on diuretic therapy--measures which down-regulate sympathetic activity, or, more specifically, alpha-1 adrenergic activity, may be warranted. |
| 6774 | 15114471 | For the purpose of this review, four molecules (adiponectin [APM1], stearoyl CoA desaturase-1 [SCD1], insulin receptor substrate-1 [IRS1], peroxisome proliferator-activated receptor-gamma [PPARG]), each with a plausible role in the disease process, have been selected to illustrate the use of such techniques in humans. |
| 6775 | 15114471 | IRS-1 and PPAR gamma), multivariate correlational analyses (as with plasma adiponectin), magnetic resonance spectroscopy to quantify intra-tissue lipid deposition and regional fat distribution, and gas chromatography to determine fatty acid patterns in selected lipid fractions as proxy for intrahepatic enzyme activity. |
| 6776 | 15114471 | For the purpose of this review, four molecules (adiponectin [APM1], stearoyl CoA desaturase-1 [SCD1], insulin receptor substrate-1 [IRS1], peroxisome proliferator-activated receptor-gamma [PPARG]), each with a plausible role in the disease process, have been selected to illustrate the use of such techniques in humans. |
| 6777 | 15114471 | IRS-1 and PPAR gamma), multivariate correlational analyses (as with plasma adiponectin), magnetic resonance spectroscopy to quantify intra-tissue lipid deposition and regional fat distribution, and gas chromatography to determine fatty acid patterns in selected lipid fractions as proxy for intrahepatic enzyme activity. |
| 6778 | 15118277 | Aldosterone stimulates gene expression of hepatic gluconeogenic enzymes through the glucocorticoid receptor in a manner independent of the protein kinase B cascade. |
| 6779 | 15118277 | In contrast, aldosterone had no effects on major insulin signaling pathways including insulin receptor substrate-1, protein kinase B, and forkhead transcription factor. |
| 6780 | 15118277 | These results suggest that aldosterone may affect the inhibitory effect of insulin on hepatic gluconeogenesis through the glucocorticoid receptor, which may be one of the causes of impaired glucose metabolism in primary aldosteronism. |
| 6781 | 15122091 | Alteration in insulin action: role of IRS-1 serine phosphorylation in the retroregulation of insulin signalling. |
| 6782 | 15122091 | Tyrosine phosphorylation of insulin receptor substrate 1 (IRS-1) and its binding to phosphatidylinositol 3-kinase (PI 3-kinase) are critical events in the insulin signalling cascade leading to insulin-stimulated glucose transport. |
| 6783 | 15122091 | Recent findings demonstrate that "diabetogenic" factors such as FFA, TNFalpha, hyperinsulinemia and cellular stress, increase the serine phosphorylation of IRS-1 and identified Ser307/612/632 as phosphorylated sites. |
| 6784 | 15122091 | These exciting results suggest that serine phosphorylation of IRS-1 is a possible hallmark of insulin resistance in biologically insulin responsive cells or tIssues. |
| 6785 | 15122091 | Alteration in insulin action: role of IRS-1 serine phosphorylation in the retroregulation of insulin signalling. |
| 6786 | 15122091 | Tyrosine phosphorylation of insulin receptor substrate 1 (IRS-1) and its binding to phosphatidylinositol 3-kinase (PI 3-kinase) are critical events in the insulin signalling cascade leading to insulin-stimulated glucose transport. |
| 6787 | 15122091 | Recent findings demonstrate that "diabetogenic" factors such as FFA, TNFalpha, hyperinsulinemia and cellular stress, increase the serine phosphorylation of IRS-1 and identified Ser307/612/632 as phosphorylated sites. |
| 6788 | 15122091 | These exciting results suggest that serine phosphorylation of IRS-1 is a possible hallmark of insulin resistance in biologically insulin responsive cells or tIssues. |
| 6789 | 15122091 | Alteration in insulin action: role of IRS-1 serine phosphorylation in the retroregulation of insulin signalling. |
| 6790 | 15122091 | Tyrosine phosphorylation of insulin receptor substrate 1 (IRS-1) and its binding to phosphatidylinositol 3-kinase (PI 3-kinase) are critical events in the insulin signalling cascade leading to insulin-stimulated glucose transport. |
| 6791 | 15122091 | Recent findings demonstrate that "diabetogenic" factors such as FFA, TNFalpha, hyperinsulinemia and cellular stress, increase the serine phosphorylation of IRS-1 and identified Ser307/612/632 as phosphorylated sites. |
| 6792 | 15122091 | These exciting results suggest that serine phosphorylation of IRS-1 is a possible hallmark of insulin resistance in biologically insulin responsive cells or tIssues. |
| 6793 | 15122091 | Alteration in insulin action: role of IRS-1 serine phosphorylation in the retroregulation of insulin signalling. |
| 6794 | 15122091 | Tyrosine phosphorylation of insulin receptor substrate 1 (IRS-1) and its binding to phosphatidylinositol 3-kinase (PI 3-kinase) are critical events in the insulin signalling cascade leading to insulin-stimulated glucose transport. |
| 6795 | 15122091 | Recent findings demonstrate that "diabetogenic" factors such as FFA, TNFalpha, hyperinsulinemia and cellular stress, increase the serine phosphorylation of IRS-1 and identified Ser307/612/632 as phosphorylated sites. |
| 6796 | 15122091 | These exciting results suggest that serine phosphorylation of IRS-1 is a possible hallmark of insulin resistance in biologically insulin responsive cells or tIssues. |
| 6797 | 15126243 | LIP in CON reduced insulin-stimulated glucose disposal (Rd) by 25%, insulin-stimulated insulin receptor tyrosine phosphorylation by 17%, phosphatidylinositol 3-kinase activity associated with insulin receptor substrate-1 by 20%, and insulin-stimulated glycogen synthase fractional velocity over baseline (44 vs. 15%; all P < 0.05). |
| 6798 | 15134463 | In vitro phosphorylation of insulin receptor substrate 1 by protein kinase C-zeta: functional analysis and identification of novel phosphorylation sites. |
| 6799 | 15134463 | Protein kinase C-zeta (PKC-zeta) participates both in downstream insulin signaling and in the negative feedback control of insulin action. |
| 6800 | 15134463 | Here we used an in vitro approach to identify PKC-zeta phosphorylation sites within insulin receptor substrate 1 (IRS-1) and to characterize the functional implications. |
| 6801 | 15134463 | A recombinant IRS-1 fragment (rIRS-1(449)(-)(664)) containing major tyrosine motifs for interaction with phosphatidylinositol (PI) 3-kinase strongly associated to the p85alpha subunit of PI 3-kinase after Tyr phosphorylation by the insulin receptor. |
| 6802 | 15134463 | However, modification of this residue did not reduce the affinity of p85alpha binding to pTyr-containing peptides (amino acids 605-615 of rat IRS-1), as determined by surface plasmon resonance. rIRS-1(449)(-)(664) was then phosphorylated by PKC-zeta using [(32)P]ATP and subjected to tryptic phosphopeptide mapping based on two-dimensional HPLC coupled to mass spectrometry. |
| 6803 | 15134463 | Ser(570) was specifically targeted by PKC-zeta, as shown by immunoblotting with a phosphospecific antiserum against Ser(570) of IRS-1. |
| 6804 | 15134463 | Binding of p85alpha to the S570A mutant was less susceptible to inhibition by PKC-zeta, when compared to the S612A mutant. |
| 6805 | 15134463 | In conclusion, our in vitro data demonstrate a strong inhibitory action of PKC-zeta at the level of IRS-1/PI 3-kinase interaction involving multiple serine phosphorylation sites. |
| 6806 | 15134463 | In vitro phosphorylation of insulin receptor substrate 1 by protein kinase C-zeta: functional analysis and identification of novel phosphorylation sites. |
| 6807 | 15134463 | Protein kinase C-zeta (PKC-zeta) participates both in downstream insulin signaling and in the negative feedback control of insulin action. |
| 6808 | 15134463 | Here we used an in vitro approach to identify PKC-zeta phosphorylation sites within insulin receptor substrate 1 (IRS-1) and to characterize the functional implications. |
| 6809 | 15134463 | A recombinant IRS-1 fragment (rIRS-1(449)(-)(664)) containing major tyrosine motifs for interaction with phosphatidylinositol (PI) 3-kinase strongly associated to the p85alpha subunit of PI 3-kinase after Tyr phosphorylation by the insulin receptor. |
| 6810 | 15134463 | However, modification of this residue did not reduce the affinity of p85alpha binding to pTyr-containing peptides (amino acids 605-615 of rat IRS-1), as determined by surface plasmon resonance. rIRS-1(449)(-)(664) was then phosphorylated by PKC-zeta using [(32)P]ATP and subjected to tryptic phosphopeptide mapping based on two-dimensional HPLC coupled to mass spectrometry. |
| 6811 | 15134463 | Ser(570) was specifically targeted by PKC-zeta, as shown by immunoblotting with a phosphospecific antiserum against Ser(570) of IRS-1. |
| 6812 | 15134463 | Binding of p85alpha to the S570A mutant was less susceptible to inhibition by PKC-zeta, when compared to the S612A mutant. |
| 6813 | 15134463 | In conclusion, our in vitro data demonstrate a strong inhibitory action of PKC-zeta at the level of IRS-1/PI 3-kinase interaction involving multiple serine phosphorylation sites. |
| 6814 | 15134463 | In vitro phosphorylation of insulin receptor substrate 1 by protein kinase C-zeta: functional analysis and identification of novel phosphorylation sites. |
| 6815 | 15134463 | Protein kinase C-zeta (PKC-zeta) participates both in downstream insulin signaling and in the negative feedback control of insulin action. |
| 6816 | 15134463 | Here we used an in vitro approach to identify PKC-zeta phosphorylation sites within insulin receptor substrate 1 (IRS-1) and to characterize the functional implications. |
| 6817 | 15134463 | A recombinant IRS-1 fragment (rIRS-1(449)(-)(664)) containing major tyrosine motifs for interaction with phosphatidylinositol (PI) 3-kinase strongly associated to the p85alpha subunit of PI 3-kinase after Tyr phosphorylation by the insulin receptor. |
| 6818 | 15134463 | However, modification of this residue did not reduce the affinity of p85alpha binding to pTyr-containing peptides (amino acids 605-615 of rat IRS-1), as determined by surface plasmon resonance. rIRS-1(449)(-)(664) was then phosphorylated by PKC-zeta using [(32)P]ATP and subjected to tryptic phosphopeptide mapping based on two-dimensional HPLC coupled to mass spectrometry. |
| 6819 | 15134463 | Ser(570) was specifically targeted by PKC-zeta, as shown by immunoblotting with a phosphospecific antiserum against Ser(570) of IRS-1. |
| 6820 | 15134463 | Binding of p85alpha to the S570A mutant was less susceptible to inhibition by PKC-zeta, when compared to the S612A mutant. |
| 6821 | 15134463 | In conclusion, our in vitro data demonstrate a strong inhibitory action of PKC-zeta at the level of IRS-1/PI 3-kinase interaction involving multiple serine phosphorylation sites. |
| 6822 | 15134463 | In vitro phosphorylation of insulin receptor substrate 1 by protein kinase C-zeta: functional analysis and identification of novel phosphorylation sites. |
| 6823 | 15134463 | Protein kinase C-zeta (PKC-zeta) participates both in downstream insulin signaling and in the negative feedback control of insulin action. |
| 6824 | 15134463 | Here we used an in vitro approach to identify PKC-zeta phosphorylation sites within insulin receptor substrate 1 (IRS-1) and to characterize the functional implications. |
| 6825 | 15134463 | A recombinant IRS-1 fragment (rIRS-1(449)(-)(664)) containing major tyrosine motifs for interaction with phosphatidylinositol (PI) 3-kinase strongly associated to the p85alpha subunit of PI 3-kinase after Tyr phosphorylation by the insulin receptor. |
| 6826 | 15134463 | However, modification of this residue did not reduce the affinity of p85alpha binding to pTyr-containing peptides (amino acids 605-615 of rat IRS-1), as determined by surface plasmon resonance. rIRS-1(449)(-)(664) was then phosphorylated by PKC-zeta using [(32)P]ATP and subjected to tryptic phosphopeptide mapping based on two-dimensional HPLC coupled to mass spectrometry. |
| 6827 | 15134463 | Ser(570) was specifically targeted by PKC-zeta, as shown by immunoblotting with a phosphospecific antiserum against Ser(570) of IRS-1. |
| 6828 | 15134463 | Binding of p85alpha to the S570A mutant was less susceptible to inhibition by PKC-zeta, when compared to the S612A mutant. |
| 6829 | 15134463 | In conclusion, our in vitro data demonstrate a strong inhibitory action of PKC-zeta at the level of IRS-1/PI 3-kinase interaction involving multiple serine phosphorylation sites. |
| 6830 | 15134463 | In vitro phosphorylation of insulin receptor substrate 1 by protein kinase C-zeta: functional analysis and identification of novel phosphorylation sites. |
| 6831 | 15134463 | Protein kinase C-zeta (PKC-zeta) participates both in downstream insulin signaling and in the negative feedback control of insulin action. |
| 6832 | 15134463 | Here we used an in vitro approach to identify PKC-zeta phosphorylation sites within insulin receptor substrate 1 (IRS-1) and to characterize the functional implications. |
| 6833 | 15134463 | A recombinant IRS-1 fragment (rIRS-1(449)(-)(664)) containing major tyrosine motifs for interaction with phosphatidylinositol (PI) 3-kinase strongly associated to the p85alpha subunit of PI 3-kinase after Tyr phosphorylation by the insulin receptor. |
| 6834 | 15134463 | However, modification of this residue did not reduce the affinity of p85alpha binding to pTyr-containing peptides (amino acids 605-615 of rat IRS-1), as determined by surface plasmon resonance. rIRS-1(449)(-)(664) was then phosphorylated by PKC-zeta using [(32)P]ATP and subjected to tryptic phosphopeptide mapping based on two-dimensional HPLC coupled to mass spectrometry. |
| 6835 | 15134463 | Ser(570) was specifically targeted by PKC-zeta, as shown by immunoblotting with a phosphospecific antiserum against Ser(570) of IRS-1. |
| 6836 | 15134463 | Binding of p85alpha to the S570A mutant was less susceptible to inhibition by PKC-zeta, when compared to the S612A mutant. |
| 6837 | 15134463 | In conclusion, our in vitro data demonstrate a strong inhibitory action of PKC-zeta at the level of IRS-1/PI 3-kinase interaction involving multiple serine phosphorylation sites. |
| 6838 | 15134463 | In vitro phosphorylation of insulin receptor substrate 1 by protein kinase C-zeta: functional analysis and identification of novel phosphorylation sites. |
| 6839 | 15134463 | Protein kinase C-zeta (PKC-zeta) participates both in downstream insulin signaling and in the negative feedback control of insulin action. |
| 6840 | 15134463 | Here we used an in vitro approach to identify PKC-zeta phosphorylation sites within insulin receptor substrate 1 (IRS-1) and to characterize the functional implications. |
| 6841 | 15134463 | A recombinant IRS-1 fragment (rIRS-1(449)(-)(664)) containing major tyrosine motifs for interaction with phosphatidylinositol (PI) 3-kinase strongly associated to the p85alpha subunit of PI 3-kinase after Tyr phosphorylation by the insulin receptor. |
| 6842 | 15134463 | However, modification of this residue did not reduce the affinity of p85alpha binding to pTyr-containing peptides (amino acids 605-615 of rat IRS-1), as determined by surface plasmon resonance. rIRS-1(449)(-)(664) was then phosphorylated by PKC-zeta using [(32)P]ATP and subjected to tryptic phosphopeptide mapping based on two-dimensional HPLC coupled to mass spectrometry. |
| 6843 | 15134463 | Ser(570) was specifically targeted by PKC-zeta, as shown by immunoblotting with a phosphospecific antiserum against Ser(570) of IRS-1. |
| 6844 | 15134463 | Binding of p85alpha to the S570A mutant was less susceptible to inhibition by PKC-zeta, when compared to the S612A mutant. |
| 6845 | 15134463 | In conclusion, our in vitro data demonstrate a strong inhibitory action of PKC-zeta at the level of IRS-1/PI 3-kinase interaction involving multiple serine phosphorylation sites. |
| 6846 | 15153564 | Regulation of muscle protein degradation: coordinated control of apoptotic and ubiquitin-proteasome systems by phosphatidylinositol 3 kinase. |
| 6847 | 15153564 | As expected, phosphatidylinositol 3 kinase activity (PI3K) was suppressed in muscle; in addition to decreased insulin, the mechanism includes IRS-1 phosphorylation at serine-307. |
| 6848 | 15153564 | Caspase-3 activity was also increased, and the authors linked it to a low PI3K-induced activation of the apoptotic system that includes a conformational change in Bax and release of cytochrome C. |
| 6849 | 15153564 | Atrogin-1/MAFbx expression increased when the authors suppressed PI3K activity in muscle cells. |
| 6850 | 15153564 | The forkhead transcriptional factor, a downstream substrate of PI3K, stimulated atrogin-1/MAFbx promoter transcriptional activity markedly. |
| 6851 | 15161747 | Mice that lack acyl CoA:diacylglycerol acyltransferase 1 (DGAT1), a key enzyme in mammalian triglyceride synthesis, have decreased adiposity and increased insulin sensitivity. |
| 6852 | 15161747 | Here we show that insulin-stimulated glucose transport is increased in the skeletal muscle and white adipose tissue (WAT) of chow-fed DGAT1-deficient mice. |
| 6853 | 15161747 | This increase in glucose transport correlated with enhanced insulin-stimulated activities of phosphatidylinositol 3-kinase, protein kinase B (or Akt), and protein kinase Clambda (PKC-lambda), three key molecules in the insulin-signaling pathway, and was associated with decreased levels of serine-phosphorylated insulin receptor substrate 1 (IRS-1), a molecule implicated in insulin resistance. |
| 6854 | 15161747 | Similar findings in insulin signaling were also observed in DGAT1-deficient mice fed a high-fat diet. |
| 6855 | 15161747 | Interestingly, the increased PKC-lambda activity and decreased serine phosphorylation of IRS-1 were observed in chow-fed wild-type mice transplanted with DGAT1-deficient WAT, consistent with our previous finding that transplantation of DGAT1-deficient WAT enhances glucose disposal in wild-type recipient mice. |
| 6856 | 15161747 | Our findings demonstrate that DGAT1 deficiency enhances insulin signaling in the skeletal muscle and WAT, in part through altered expression of adipocyte-derived factors that modulate insulin signaling in peripheral tissues. |
| 6857 | 15161747 | Mice that lack acyl CoA:diacylglycerol acyltransferase 1 (DGAT1), a key enzyme in mammalian triglyceride synthesis, have decreased adiposity and increased insulin sensitivity. |
| 6858 | 15161747 | Here we show that insulin-stimulated glucose transport is increased in the skeletal muscle and white adipose tissue (WAT) of chow-fed DGAT1-deficient mice. |
| 6859 | 15161747 | This increase in glucose transport correlated with enhanced insulin-stimulated activities of phosphatidylinositol 3-kinase, protein kinase B (or Akt), and protein kinase Clambda (PKC-lambda), three key molecules in the insulin-signaling pathway, and was associated with decreased levels of serine-phosphorylated insulin receptor substrate 1 (IRS-1), a molecule implicated in insulin resistance. |
| 6860 | 15161747 | Similar findings in insulin signaling were also observed in DGAT1-deficient mice fed a high-fat diet. |
| 6861 | 15161747 | Interestingly, the increased PKC-lambda activity and decreased serine phosphorylation of IRS-1 were observed in chow-fed wild-type mice transplanted with DGAT1-deficient WAT, consistent with our previous finding that transplantation of DGAT1-deficient WAT enhances glucose disposal in wild-type recipient mice. |
| 6862 | 15161747 | Our findings demonstrate that DGAT1 deficiency enhances insulin signaling in the skeletal muscle and WAT, in part through altered expression of adipocyte-derived factors that modulate insulin signaling in peripheral tissues. |
| 6863 | 15161756 | Mice with deletion of insulin receptor substrate (IRS)-1 (IRS-1 knockout [KO] mice) show mild insulin resistance and defective glucose-stimulated insulin secretion and reduced insulin synthesis. |
| 6864 | 15161756 | To further define the role of IRS-1 in islet function, we examined the insulin secretory defect in the knockouts using freshly isolated islets and primary beta-cells. |
| 6865 | 15161756 | These data provide evidence that IRS-1 modulation of insulin secretion is associated with Ca(2+) signaling and expression of SERCA-2b and -3 genes in pancreatic islets and provides a direct link between insulin resistance and defective insulin secretion. |
| 6866 | 15161756 | Mice with deletion of insulin receptor substrate (IRS)-1 (IRS-1 knockout [KO] mice) show mild insulin resistance and defective glucose-stimulated insulin secretion and reduced insulin synthesis. |
| 6867 | 15161756 | To further define the role of IRS-1 in islet function, we examined the insulin secretory defect in the knockouts using freshly isolated islets and primary beta-cells. |
| 6868 | 15161756 | These data provide evidence that IRS-1 modulation of insulin secretion is associated with Ca(2+) signaling and expression of SERCA-2b and -3 genes in pancreatic islets and provides a direct link between insulin resistance and defective insulin secretion. |
| 6869 | 15161756 | Mice with deletion of insulin receptor substrate (IRS)-1 (IRS-1 knockout [KO] mice) show mild insulin resistance and defective glucose-stimulated insulin secretion and reduced insulin synthesis. |
| 6870 | 15161756 | To further define the role of IRS-1 in islet function, we examined the insulin secretory defect in the knockouts using freshly isolated islets and primary beta-cells. |
| 6871 | 15161756 | These data provide evidence that IRS-1 modulation of insulin secretion is associated with Ca(2+) signaling and expression of SERCA-2b and -3 genes in pancreatic islets and provides a direct link between insulin resistance and defective insulin secretion. |
| 6872 | 15169905 | Suppressor of cytokine signaling 1 (SOCS-1) and SOCS-3 cause insulin resistance through inhibition of tyrosine phosphorylation of insulin receptor substrate proteins by discrete mechanisms. |
| 6873 | 15169905 | Here we show that in both obesity and lipopolysaccharide (LPS)-induced endotoxemia there is an increase in suppressor of cytokine signaling (SOCS) proteins, SOCS-1 and SOCS-3, in liver, muscle, and, to a lesser extent, fat. |
| 6874 | 15169905 | Direct overexpression of SOCS-3 in liver by adenoviral-mediated gene transfer markedly decreases tyrosine phosphorylation of both IRS-1 and IRS-2, while SOCS-1 overexpression preferentially inhibits IRS-2 phosphorylation. |
| 6875 | 15169905 | Neither affects IR phosphorylation, although both SOCS-1 and SOCS-3 bind to the insulin receptor in vivo in an insulin-dependent fashion. |
| 6876 | 15169905 | Experiments with cultured cells expressing mutant insulin receptors reveal that SOCS-3 binds to Tyr960 of IR, a key residue for the recognition of IRS-1 and IRS-2, whereas SOCS-1 binds to the domain in the catalytic loop essential for IRS-2 recognition in vitro. |
| 6877 | 15169905 | Moreover, overexpression of either SOCS-1 or SOCS-3 attenuates insulin-induced glycogen synthesis in L6 myotubes and activation of glucose uptake in 3T3L1 adipocytes. |
| 6878 | 15169905 | By contrast, a reduction of SOCS-1 or SOCS-3 by antisense treatment partially restores tumor necrosis factor alpha-induced downregulation of tyrosine phosphorylation of IRS proteins in 3T3L1 adipocytes. |
| 6879 | 15169905 | These data indicate that SOCS-1 and SOCS-3 act as negative regulators in insulin signaling and serve as one of the missing links between insulin resistance and cytokine signaling. |
| 6880 | 15169905 | Suppressor of cytokine signaling 1 (SOCS-1) and SOCS-3 cause insulin resistance through inhibition of tyrosine phosphorylation of insulin receptor substrate proteins by discrete mechanisms. |
| 6881 | 15169905 | Here we show that in both obesity and lipopolysaccharide (LPS)-induced endotoxemia there is an increase in suppressor of cytokine signaling (SOCS) proteins, SOCS-1 and SOCS-3, in liver, muscle, and, to a lesser extent, fat. |
| 6882 | 15169905 | Direct overexpression of SOCS-3 in liver by adenoviral-mediated gene transfer markedly decreases tyrosine phosphorylation of both IRS-1 and IRS-2, while SOCS-1 overexpression preferentially inhibits IRS-2 phosphorylation. |
| 6883 | 15169905 | Neither affects IR phosphorylation, although both SOCS-1 and SOCS-3 bind to the insulin receptor in vivo in an insulin-dependent fashion. |
| 6884 | 15169905 | Experiments with cultured cells expressing mutant insulin receptors reveal that SOCS-3 binds to Tyr960 of IR, a key residue for the recognition of IRS-1 and IRS-2, whereas SOCS-1 binds to the domain in the catalytic loop essential for IRS-2 recognition in vitro. |
| 6885 | 15169905 | Moreover, overexpression of either SOCS-1 or SOCS-3 attenuates insulin-induced glycogen synthesis in L6 myotubes and activation of glucose uptake in 3T3L1 adipocytes. |
| 6886 | 15169905 | By contrast, a reduction of SOCS-1 or SOCS-3 by antisense treatment partially restores tumor necrosis factor alpha-induced downregulation of tyrosine phosphorylation of IRS proteins in 3T3L1 adipocytes. |
| 6887 | 15169905 | These data indicate that SOCS-1 and SOCS-3 act as negative regulators in insulin signaling and serve as one of the missing links between insulin resistance and cytokine signaling. |
| 6888 | 15180298 | The discovery of insulin receptor substrate (IRS) proteins and their role to link cell surface receptors to the intracellular signaling cascades is a key step to understanding insulin and insulin-like growth factor (IGF) action. |
| 6889 | 15180298 | The IRS2-branch of the insulin/IGF signaling cascade has an important role in both peripheral insulin response and pancreatic beta-cell growth and function. |
| 6890 | 15180298 | Dysregulation of IRS2 signaling in mice causes the failure of compensatory hyperinsulinemia during peripheral insulin resistance. |
| 6891 | 15180298 | Understanding the regulation and signaling by IRS1 and IRS2 in cell growth, metabolism and survival will reveal new strategies to prevent or cure diabetes and other metabolic diseases. |
| 6892 | 15181014 | Suppressor of cytokine signaling 3 is a physiological regulator of adipocyte insulin signaling. |
| 6893 | 15181014 | We observed that several cytokines and hormones that induce insulin resistance also stimulate SOCS3 expression in 3T3-L1 adipocytes and that SOCS3 mRNA is increased in adipose tissue of obese/diabetic mice. |
| 6894 | 15181014 | We then hypothesized that SOCS3 may mediate cytokine- and hormone-induced insulin resistance. |
| 6895 | 15181014 | By using SOCS3-deficient adipocytes differentiated from mouse embryonic fibroblasts, we found that SOCS3 deficiency increases insulin-stimulated IRS1 and IRS2 phosphorylation, IRS-associated phosphatidylinositol 3-kinase activity, and insulin-stimulated glucose uptake. |
| 6896 | 15181014 | Moreover, lack of SOCS3 substantially limits the inhibitory effects of tumor necrosis factor-alpha to suppress IRS1 and IRS2 tyrosine phosphorylation, phosphatidylinositol 3-kinase activity, and glucose uptake in adipocytes. |
| 6897 | 15181014 | The ameliorated insulin signaling in SOCS3-deficient adipocytes is mainly due to the suppression of tumor necrosis factor-alpha-induced IRS1 and IRS2 protein degradation. |
| 6898 | 15181014 | Therefore, our data suggest that endogenous SOCS3 expression is a key determinant of basal insulin signaling and is an important molecular mediator of cytokine-induced insulin resistance in adipocytes. |
| 6899 | 15181014 | We conclude that SOCS3 plays an important role in mediating insulin resistance and may be an excellent target for therapeutic intervention in insulin resistance and type II diabetes. |
| 6900 | 15181014 | Suppressor of cytokine signaling 3 is a physiological regulator of adipocyte insulin signaling. |
| 6901 | 15181014 | We observed that several cytokines and hormones that induce insulin resistance also stimulate SOCS3 expression in 3T3-L1 adipocytes and that SOCS3 mRNA is increased in adipose tissue of obese/diabetic mice. |
| 6902 | 15181014 | We then hypothesized that SOCS3 may mediate cytokine- and hormone-induced insulin resistance. |
| 6903 | 15181014 | By using SOCS3-deficient adipocytes differentiated from mouse embryonic fibroblasts, we found that SOCS3 deficiency increases insulin-stimulated IRS1 and IRS2 phosphorylation, IRS-associated phosphatidylinositol 3-kinase activity, and insulin-stimulated glucose uptake. |
| 6904 | 15181014 | Moreover, lack of SOCS3 substantially limits the inhibitory effects of tumor necrosis factor-alpha to suppress IRS1 and IRS2 tyrosine phosphorylation, phosphatidylinositol 3-kinase activity, and glucose uptake in adipocytes. |
| 6905 | 15181014 | The ameliorated insulin signaling in SOCS3-deficient adipocytes is mainly due to the suppression of tumor necrosis factor-alpha-induced IRS1 and IRS2 protein degradation. |
| 6906 | 15181014 | Therefore, our data suggest that endogenous SOCS3 expression is a key determinant of basal insulin signaling and is an important molecular mediator of cytokine-induced insulin resistance in adipocytes. |
| 6907 | 15181014 | We conclude that SOCS3 plays an important role in mediating insulin resistance and may be an excellent target for therapeutic intervention in insulin resistance and type II diabetes. |
| 6908 | 15181014 | Suppressor of cytokine signaling 3 is a physiological regulator of adipocyte insulin signaling. |
| 6909 | 15181014 | We observed that several cytokines and hormones that induce insulin resistance also stimulate SOCS3 expression in 3T3-L1 adipocytes and that SOCS3 mRNA is increased in adipose tissue of obese/diabetic mice. |
| 6910 | 15181014 | We then hypothesized that SOCS3 may mediate cytokine- and hormone-induced insulin resistance. |
| 6911 | 15181014 | By using SOCS3-deficient adipocytes differentiated from mouse embryonic fibroblasts, we found that SOCS3 deficiency increases insulin-stimulated IRS1 and IRS2 phosphorylation, IRS-associated phosphatidylinositol 3-kinase activity, and insulin-stimulated glucose uptake. |
| 6912 | 15181014 | Moreover, lack of SOCS3 substantially limits the inhibitory effects of tumor necrosis factor-alpha to suppress IRS1 and IRS2 tyrosine phosphorylation, phosphatidylinositol 3-kinase activity, and glucose uptake in adipocytes. |
| 6913 | 15181014 | The ameliorated insulin signaling in SOCS3-deficient adipocytes is mainly due to the suppression of tumor necrosis factor-alpha-induced IRS1 and IRS2 protein degradation. |
| 6914 | 15181014 | Therefore, our data suggest that endogenous SOCS3 expression is a key determinant of basal insulin signaling and is an important molecular mediator of cytokine-induced insulin resistance in adipocytes. |
| 6915 | 15181014 | We conclude that SOCS3 plays an important role in mediating insulin resistance and may be an excellent target for therapeutic intervention in insulin resistance and type II diabetes. |
| 6916 | 15181089 | After washing, basal and insulin-stimulated [14C]glucose uptake as well as cellular content of insulin signaling proteins and glucose transporter 4 (GLUT4) was assessed. |
| 6917 | 15181089 | The cellular content of insulin receptor substrate 1 and phosphatidylinositol 3-kinase did not differ significantly between the depots, but the expression of protein kinase B (PKB) tended to be increased in omental compared with s.c. adipocytes (P = 0.09). |
| 6918 | 15181089 | Dexamethasone treatment decreased the expression of insulin receptor substrate 1 (by approximately 40%; P < 0.05) and PKB (by approximately 20%; P < 0.05) in omental but not in s.c. adipocytes. |
| 6919 | 15181089 | In contrast, dexamethasone pretreatment had no effect on insulin-stimulated Ser473 phosphorylation of PKB. |
| 6920 | 15181089 | After washing, basal and insulin-stimulated [14C]glucose uptake as well as cellular content of insulin signaling proteins and glucose transporter 4 (GLUT4) was assessed. |
| 6921 | 15181089 | The cellular content of insulin receptor substrate 1 and phosphatidylinositol 3-kinase did not differ significantly between the depots, but the expression of protein kinase B (PKB) tended to be increased in omental compared with s.c. adipocytes (P = 0.09). |
| 6922 | 15181089 | Dexamethasone treatment decreased the expression of insulin receptor substrate 1 (by approximately 40%; P < 0.05) and PKB (by approximately 20%; P < 0.05) in omental but not in s.c. adipocytes. |
| 6923 | 15181089 | In contrast, dexamethasone pretreatment had no effect on insulin-stimulated Ser473 phosphorylation of PKB. |
| 6924 | 15182363 | Depletion of cholesterol from the cells using beta-cyclodextrin blocked insulin stimulation of glucose uptake, insulin inhibition of perilipin phosphorylation in response to isoproterenol, and insulin stimulation of protein kinase B and Map-kinases extracellular signal-related kinase (ERK)1/2 phosphorylation. |
| 6925 | 15182363 | Insulin-stimulated phosphorylation of the insulin receptor and IRS1 was not affected, indicating that caveolae integrity is required downstream of IRS1. |
| 6926 | 15182363 | In conclusion we show that insulin receptor and IRS1 are both caveolar proteins and that caveolae are required for both metabolic and mitogenic control in human adipocytes. |
| 6927 | 15182363 | Depletion of cholesterol from the cells using beta-cyclodextrin blocked insulin stimulation of glucose uptake, insulin inhibition of perilipin phosphorylation in response to isoproterenol, and insulin stimulation of protein kinase B and Map-kinases extracellular signal-related kinase (ERK)1/2 phosphorylation. |
| 6928 | 15182363 | Insulin-stimulated phosphorylation of the insulin receptor and IRS1 was not affected, indicating that caveolae integrity is required downstream of IRS1. |
| 6929 | 15182363 | In conclusion we show that insulin receptor and IRS1 are both caveolar proteins and that caveolae are required for both metabolic and mitogenic control in human adipocytes. |
| 6930 | 15199052 | We have developed a new variant of the yeast two-hybrid method, referred to as disruptive yeast tri-hybrid (Y3H), to identify inhibitory kinases and sites of phosphorylation in insulin receptors (IR) and IR substrates, IRS-1. |
| 6931 | 15199052 | Using IR and IRS-1 as bait and prey, respectively, and c-Jun NH(2)-terminal kinase (JNK1) as the disruptor, we now show that phosphorylation of IRS-1 Ser-307, a previously identified site, is necessary but not sufficient for JNK1-mediated disruption of IR/IRS-1 binding. |
| 6932 | 15199052 | Seven additional kinases potentially linked to insulin resistance similarly block IR/IRS-1 binding in the disruptive Y3H, but through distinct Ser-302- and Ser-307-independent mechanisms. |
| 6933 | 15199052 | These findings demonstrate that phosphorylation at both Ser-302 and Ser-307 is necessary for JNK1-mediated inhibition of the IR/IRS-1 interaction and that Ser-302 and Ser-307 are phosphorylated in parallel in cultured cells and in vivo under conditions that lead to insulin resistance. |
| 6934 | 15199052 | We have developed a new variant of the yeast two-hybrid method, referred to as disruptive yeast tri-hybrid (Y3H), to identify inhibitory kinases and sites of phosphorylation in insulin receptors (IR) and IR substrates, IRS-1. |
| 6935 | 15199052 | Using IR and IRS-1 as bait and prey, respectively, and c-Jun NH(2)-terminal kinase (JNK1) as the disruptor, we now show that phosphorylation of IRS-1 Ser-307, a previously identified site, is necessary but not sufficient for JNK1-mediated disruption of IR/IRS-1 binding. |
| 6936 | 15199052 | Seven additional kinases potentially linked to insulin resistance similarly block IR/IRS-1 binding in the disruptive Y3H, but through distinct Ser-302- and Ser-307-independent mechanisms. |
| 6937 | 15199052 | These findings demonstrate that phosphorylation at both Ser-302 and Ser-307 is necessary for JNK1-mediated inhibition of the IR/IRS-1 interaction and that Ser-302 and Ser-307 are phosphorylated in parallel in cultured cells and in vivo under conditions that lead to insulin resistance. |
| 6938 | 15199052 | We have developed a new variant of the yeast two-hybrid method, referred to as disruptive yeast tri-hybrid (Y3H), to identify inhibitory kinases and sites of phosphorylation in insulin receptors (IR) and IR substrates, IRS-1. |
| 6939 | 15199052 | Using IR and IRS-1 as bait and prey, respectively, and c-Jun NH(2)-terminal kinase (JNK1) as the disruptor, we now show that phosphorylation of IRS-1 Ser-307, a previously identified site, is necessary but not sufficient for JNK1-mediated disruption of IR/IRS-1 binding. |
| 6940 | 15199052 | Seven additional kinases potentially linked to insulin resistance similarly block IR/IRS-1 binding in the disruptive Y3H, but through distinct Ser-302- and Ser-307-independent mechanisms. |
| 6941 | 15199052 | These findings demonstrate that phosphorylation at both Ser-302 and Ser-307 is necessary for JNK1-mediated inhibition of the IR/IRS-1 interaction and that Ser-302 and Ser-307 are phosphorylated in parallel in cultured cells and in vivo under conditions that lead to insulin resistance. |
| 6942 | 15199052 | We have developed a new variant of the yeast two-hybrid method, referred to as disruptive yeast tri-hybrid (Y3H), to identify inhibitory kinases and sites of phosphorylation in insulin receptors (IR) and IR substrates, IRS-1. |
| 6943 | 15199052 | Using IR and IRS-1 as bait and prey, respectively, and c-Jun NH(2)-terminal kinase (JNK1) as the disruptor, we now show that phosphorylation of IRS-1 Ser-307, a previously identified site, is necessary but not sufficient for JNK1-mediated disruption of IR/IRS-1 binding. |
| 6944 | 15199052 | Seven additional kinases potentially linked to insulin resistance similarly block IR/IRS-1 binding in the disruptive Y3H, but through distinct Ser-302- and Ser-307-independent mechanisms. |
| 6945 | 15199052 | These findings demonstrate that phosphorylation at both Ser-302 and Ser-307 is necessary for JNK1-mediated inhibition of the IR/IRS-1 interaction and that Ser-302 and Ser-307 are phosphorylated in parallel in cultured cells and in vivo under conditions that lead to insulin resistance. |
| 6946 | 15201286 | In streptozotocin mice, in both retina and liver, insulin receptor (IR) and insulin receptor substrate (IRS)-2 protein and tyrosine phosphorylation were increased by insulin, while IRS-1 protein and its phosphorylation were maintained. |
| 6947 | 15201286 | By contrast, in ob/ob mice, there was marked down-regulation of IR, IRS-1, and IRS-2 protein and phosphorylation in liver; these were maintained or increased in retina. |
| 6948 | 15201286 | On the other hand, protein levels and phosphorylation of PDK1 and Akt were decreased in retina of both mice. |
| 6949 | 15201286 | Interestingly, phosphorylation of p38 mitogen-activated protein kinase and ERK1 were responsive to insulin in retina of both mice but were unresponsive in liver. |
| 6950 | 15201286 | HIF-1alpha and vascular endothelial growth factor were increased and endothelial nitric-oxide synthase was decreased in retina. |
| 6951 | 15201286 | These observations indicate that, in both insulin-resistant and insulin-deficient diabetic states, there are alterations in insulin signaling, such as impaired PDK/Akt responses and enhanced mitogen-activated protein kinases responses that could contribute to the retinopathy. |
| 6952 | 15201286 | In streptozotocin mice, in both retina and liver, insulin receptor (IR) and insulin receptor substrate (IRS)-2 protein and tyrosine phosphorylation were increased by insulin, while IRS-1 protein and its phosphorylation were maintained. |
| 6953 | 15201286 | By contrast, in ob/ob mice, there was marked down-regulation of IR, IRS-1, and IRS-2 protein and phosphorylation in liver; these were maintained or increased in retina. |
| 6954 | 15201286 | On the other hand, protein levels and phosphorylation of PDK1 and Akt were decreased in retina of both mice. |
| 6955 | 15201286 | Interestingly, phosphorylation of p38 mitogen-activated protein kinase and ERK1 were responsive to insulin in retina of both mice but were unresponsive in liver. |
| 6956 | 15201286 | HIF-1alpha and vascular endothelial growth factor were increased and endothelial nitric-oxide synthase was decreased in retina. |
| 6957 | 15201286 | These observations indicate that, in both insulin-resistant and insulin-deficient diabetic states, there are alterations in insulin signaling, such as impaired PDK/Akt responses and enhanced mitogen-activated protein kinases responses that could contribute to the retinopathy. |
| 6958 | 15222685 | The most common IRS1 variant, a Gly --> Arg substitution at codon 972 (Arg972 IRS1), is more prevalent among subjects who have features of insulin resistance syndrome associated, or not, with type 2 diabetes in European populations. |
| 6959 | 15235328 | Insulin receptor substrate (IRS-1) phosphorylation, phosphatidylinositol (PI) 3-kinase activity, and glucose transport activity are impaired as a consequence of functional defects, whereas insulin receptor tyrosine phosphorylation, mitogen-activated protein kinase (MAPK) phosphorylation, and glycogen synthase activity are normal. |
| 6960 | 15235328 | Using biotinylated photoaffinity labeling, we have shown that reduced cell surface GLUT4 levels can explain glucose transport defects in skeletal muscle from Type 2 diabetic patients under insulin-stimulated conditions. |
| 6961 | 15235328 | We have recently determined the independent effects of insulin and hypoxia/AICAR exposure on glucose transport and cell surface GLUT4 content in skeletal muscle from nondiabetic and Type 2 diabetic subjects. |
| 6962 | 15235328 | Hypoxia and AICAR increase glucose transport via an insulin-independent mechanism involving activation of 5'-AMP-activated kinase (AMPK). |
| 6963 | 15235328 | AMPK signaling is intact, because 5-aminoimidazole-4-carboxamide 1-beta-D-ribonucleoside (AICAR) increased AMPK and acetyl-CoA carboxylase (ACC) phosphorylation to a similar extent in Type 2 diabetic and nondiabetic subjects. |
| 6964 | 15235328 | Our studies highlight important AMPK-dependent and independent pathways in the regulation of GLUT4 and glucose transport activity in insulin resistant skeletal muscle. |
| 6965 | 15247278 | Differential roles of the insulin and insulin-like growth factor-I (IGF-I) receptors in response to insulin and IGF-I. |
| 6966 | 15247278 | Insulin and insulin-like growth factor-I (IGF-I) receptors are highly homologous tyrosine kinase receptors that share many common steps in their signaling pathways and have ligands that can bind to either receptor with differing affinities. |
| 6967 | 15247278 | To define precisely the signaling specific to the insulin receptor (IR) or the IGF-I receptor, we have generated brown preadipocyte cell lines that lack either receptor (insulin receptor knockout (IRKO) or insulin-like growth factor receptor knockout (IGFRKO)). |
| 6968 | 15247278 | Control preadipocytes expressed fewer insulin receptors than IGF-I receptors (20,000 versus 60,000), but during differentiation, insulin receptor levels increased so that mature adipocytes expressed slightly more insulin receptors than IGF-I receptors (120,000 versus 100,000). |
| 6969 | 15247278 | In these cells, insulin stimulated IR homodimer phosphorylation, whereas IGF-I activated both IGF-I receptor homodimers and hybrid receptors. |
| 6970 | 15247278 | Insulin-stimulated IRS-1 phosphorylation was significantly impaired in IRKO cells but was surprisingly elevated in IGFRKO cells. |
| 6971 | 15247278 | IRS-2 phosphorylation was unchanged in either cell line upon insulin stimulation. |
| 6972 | 15247278 | IGF-I-dependent phosphorylation of IRS-1 and IRS-2 was ablated in IGFRKO cells but not in IRKO cells. |
| 6973 | 15247278 | In control cells, both insulin and IGF-I produced a dose-dependent increase in phosphorylated Akt and MAPK, although IGF-I elicited a stronger response at an equivalent dose. |
| 6974 | 15247278 | Most interestingly, the response to IGF-I was also impaired at low doses, suggesting that IR is required for both insulin- and IGF-I-dependent phosphorylation of Akt. |
| 6975 | 15247278 | Most surprisingly, insulin- or IGF-I-dependent phosphorylation of MAPK was unaltered in either receptor-deficient cell line. |
| 6976 | 15247278 | Taken together, these results indicate that the insulin and IGF-I receptors contribute distinct signals to common downstream components in response to both insulin and IGF-I. |
| 6977 | 15247278 | Differential roles of the insulin and insulin-like growth factor-I (IGF-I) receptors in response to insulin and IGF-I. |
| 6978 | 15247278 | Insulin and insulin-like growth factor-I (IGF-I) receptors are highly homologous tyrosine kinase receptors that share many common steps in their signaling pathways and have ligands that can bind to either receptor with differing affinities. |
| 6979 | 15247278 | To define precisely the signaling specific to the insulin receptor (IR) or the IGF-I receptor, we have generated brown preadipocyte cell lines that lack either receptor (insulin receptor knockout (IRKO) or insulin-like growth factor receptor knockout (IGFRKO)). |
| 6980 | 15247278 | Control preadipocytes expressed fewer insulin receptors than IGF-I receptors (20,000 versus 60,000), but during differentiation, insulin receptor levels increased so that mature adipocytes expressed slightly more insulin receptors than IGF-I receptors (120,000 versus 100,000). |
| 6981 | 15247278 | In these cells, insulin stimulated IR homodimer phosphorylation, whereas IGF-I activated both IGF-I receptor homodimers and hybrid receptors. |
| 6982 | 15247278 | Insulin-stimulated IRS-1 phosphorylation was significantly impaired in IRKO cells but was surprisingly elevated in IGFRKO cells. |
| 6983 | 15247278 | IRS-2 phosphorylation was unchanged in either cell line upon insulin stimulation. |
| 6984 | 15247278 | IGF-I-dependent phosphorylation of IRS-1 and IRS-2 was ablated in IGFRKO cells but not in IRKO cells. |
| 6985 | 15247278 | In control cells, both insulin and IGF-I produced a dose-dependent increase in phosphorylated Akt and MAPK, although IGF-I elicited a stronger response at an equivalent dose. |
| 6986 | 15247278 | Most interestingly, the response to IGF-I was also impaired at low doses, suggesting that IR is required for both insulin- and IGF-I-dependent phosphorylation of Akt. |
| 6987 | 15247278 | Most surprisingly, insulin- or IGF-I-dependent phosphorylation of MAPK was unaltered in either receptor-deficient cell line. |
| 6988 | 15247278 | Taken together, these results indicate that the insulin and IGF-I receptors contribute distinct signals to common downstream components in response to both insulin and IGF-I. |
| 6989 | 15249658 | Selective disruption of PPARgamma 2 impairs the development of adipose tissue and insulin sensitivity. |
| 6990 | 15249658 | In addition, insulin sensitivity was impaired in male PPARgamma2(-/-) mice, with dramatically decreased expression of insulin receptor substrate 1 and glucose transporter 4 in the skeletal muscle, but thiazolidinediones were able to normalize this insulin resistance. |
| 6991 | 15254873 | Hepatic phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) activity was measured. |
| 6992 | 15254873 | Insulin signaling response was examined after insulin injection in the fast state by analyzing tyrosine phosphorylation of insulin receptor (IR) and the association between insulin receptor substrate-1 (IRS-1) and IRS-2 with phosphatidylinositol 3 kinase (PI3-K). |
| 6993 | 15254873 | After insulin administration in the fast state, tyrosine phosphorylation of IR and association of IRS-2 with PI3-K were higher in the EH and CL groups than in the CH group. |
| 6994 | 15306563 | TNFalpha-induced insulin resistance in adipocytes as a membrane microdomain disorder: involvement of ganglioside GM3. |
| 6995 | 15306563 | Tumor necrosis factor alpha (TNFalpha) induces insulin resistance in type 2 diabetes, but its mechanism of action is not fully understood. |
| 6996 | 15306563 | In the DRMs from TNFalpha-treated 3T3-L1 adipocytes, GM3 levels were doubled compared with results in normal adipocytes. |
| 6997 | 15306563 | Furthermore, insulin-dependent IR internalization and intracellular movement of the IR substrate 1(IRS-1) were both greatly suppressed in the treated cells, leading to an uncoupling of IR-IRS-1 signaling. |
| 6998 | 15306821 | Nevertheless, S6K1-deficient mice remain sensitive to insulin owing to the apparent loss of a negative feedback loop from S6K1 to insulin receptor substrate 1 (IRS1), which blunts S307 and S636/S639 phosphorylation; sites involved in insulin resistance. |
| 6999 | 15306821 | Moreover, wild-type mice on a high fat diet as well as K/K A(y) and ob/ob (also known as Lep/Lep) mice-two genetic models of obesity-have markedly elevated S6K1 activity and, unlike S6K1-deficient mice, increased phosphorylation of IRS1 S307 and S636/S639. |
| 7000 | 15306821 | Nevertheless, S6K1-deficient mice remain sensitive to insulin owing to the apparent loss of a negative feedback loop from S6K1 to insulin receptor substrate 1 (IRS1), which blunts S307 and S636/S639 phosphorylation; sites involved in insulin resistance. |
| 7001 | 15306821 | Moreover, wild-type mice on a high fat diet as well as K/K A(y) and ob/ob (also known as Lep/Lep) mice-two genetic models of obesity-have markedly elevated S6K1 activity and, unlike S6K1-deficient mice, increased phosphorylation of IRS1 S307 and S636/S639. |
| 7002 | 15314024 | An essential role of the JIP1 scaffold protein for JNK activation in adipose tissue. |
| 7003 | 15314024 | The c-Jun NH2-terminal kinase (JNK) is activated during obesity. |
| 7004 | 15314024 | One consequence of obesity is that JNK phosphorylates the adapter protein insulin receptor substrate 1 (IRS-1) on Ser 307 and inhibits signaling by the insulin receptor. |
| 7005 | 15314024 | JNK can therefore cause peripheral insulin resistance during obesity and may contribute to the development of type 2 diabetes. |
| 7006 | 15314024 | Here we report that the JNK-interacting protein 1 (JIP1) scaffold protein, which binds components of the JNK signaling module, is essential for JNK activation in the adipose tissue of obese mice. |
| 7007 | 15314154 | Disruption of the SH2-B gene causes age-dependent insulin resistance and glucose intolerance. |
| 7008 | 15314154 | SH2-B, an Src homology 2 (SH2) and pleckstrin homology domain-containing adaptor protein, binds via its SH2 domain to insulin receptor in response to insulin; however, its physiological role remains unclear. |
| 7009 | 15314154 | Systemic deletion of SH2-B impaired insulin receptor activation and signaling in the liver, skeletal muscle, and fat, including tyrosine phosphorylation of insulin receptor substrate 1 (IRS1) and IRS2 and activation of the phosphatidylinositol 3-kinase/Akt and the Erk1/2 pathways. |
| 7010 | 15314154 | Moreover, SH2-B directly enhanced autophosphorylation of insulin receptor and tyrosine phosphorylation of IRS1 and IRS2 in an SH2 domain-dependent manner in cultured cells. |
| 7011 | 15314154 | Our data suggest that SH2-B is a physiological enhancer of insulin receptor activation and is required for maintaining normal insulin sensitivity and glucose homeostasis during aging. |
| 7012 | 15314154 | Disruption of the SH2-B gene causes age-dependent insulin resistance and glucose intolerance. |
| 7013 | 15314154 | SH2-B, an Src homology 2 (SH2) and pleckstrin homology domain-containing adaptor protein, binds via its SH2 domain to insulin receptor in response to insulin; however, its physiological role remains unclear. |
| 7014 | 15314154 | Systemic deletion of SH2-B impaired insulin receptor activation and signaling in the liver, skeletal muscle, and fat, including tyrosine phosphorylation of insulin receptor substrate 1 (IRS1) and IRS2 and activation of the phosphatidylinositol 3-kinase/Akt and the Erk1/2 pathways. |
| 7015 | 15314154 | Moreover, SH2-B directly enhanced autophosphorylation of insulin receptor and tyrosine phosphorylation of IRS1 and IRS2 in an SH2 domain-dependent manner in cultured cells. |
| 7016 | 15314154 | Our data suggest that SH2-B is a physiological enhancer of insulin receptor activation and is required for maintaining normal insulin sensitivity and glucose homeostasis during aging. |
| 7017 | 15314230 | Insulin resistance in skeletal muscles of caveolin-3-null mice. |
| 7018 | 15314230 | Cav is also known as growth signal inhibitor, although it was recently demonstrated that the genetic disruption of Cav3 did not augment growth in mice. |
| 7019 | 15314230 | We found, however, that the lack of Cav3 led to the development of insulin resistance, as exemplified by decreased glucose uptake in skeletal muscles, impaired glucose tolerance test performance, and increases in serum lipids. |
| 7020 | 15314230 | Insulin-stimulated activation of insulin receptors and downstream molecules, such as IRS-1 and Akt, was attenuated in the skeletal muscles of Cav3 null mice, but not in the liver, without affecting protein expression or subcellular localization. |
| 7021 | 15314230 | Genetic transfer of Cav3 by needle injection restored insulin signaling in skeletal muscles. |
| 7022 | 15314230 | Our findings suggest that Cav3 is an enhancer of insulin signaling in skeletal muscles but does not act as a scaffolding molecule for insulin receptors. |
| 7023 | 15322693 | The specific inhibition of angiotensin II action at AT(1) receptors by losartan has been shown to decrease peripheral insulin resistance in type 2 diabetic patients and animal models. |
| 7024 | 15322693 | We examined the effect of losartan on the expression of insulin receptor substrate 1 (IRS-1), protein kinase B (PKB) and glucose transporter 4 (GLUT4), as well as the phosphorylation status of IRS-1 and the association between IRS-1 and phosphatidylinositol (PI) 3-kinase in skeletal muscle from fat-fed and-streptozotocin (STZ)-treated rats, an animal model of type 2 diabetes mellitus. |
| 7025 | 15322693 | In addition, the effects of losartan on GLUT4 translocation in muscle cells and on insulin sensitivity were also evaluated. |
| 7026 | 15322693 | In skeletal muscles, the protein levels of IRS-1, PKB and GLUT4 in NIDDM rats were not significantly different from those of the control rats, and they were not affected by losartan. |
| 7027 | 15322693 | The levels of IRS-1 tyrosine phosphorylation, PI 3-kinase activity associated with IRS-1 and PKB activation after stimulation with insulin in muscle tissue of NIDDM rats were significantly decreased (P<0.01) compared with those in the control rats, while they were not increased by losartan. |
| 7028 | 15322693 | Losartan had a major effect on GLUT4 translocation in myocytes, as it significantly increased (P<0.05) the insulin-induced amounts of GLUT4 in plasma membrane (PM) and T-tubules (TT) in myocytes from NIDDM rats. |
| 7029 | 15322693 | Our results suggest that losartan may exert beneficial effects on insulin resistance by increasing the translocation of GLUT4 in muscle tissue, which is probably associated with a non-PI 3-kinase-dependent mechanism. |
| 7030 | 15322693 | The specific inhibition of angiotensin II action at AT(1) receptors by losartan has been shown to decrease peripheral insulin resistance in type 2 diabetic patients and animal models. |
| 7031 | 15322693 | We examined the effect of losartan on the expression of insulin receptor substrate 1 (IRS-1), protein kinase B (PKB) and glucose transporter 4 (GLUT4), as well as the phosphorylation status of IRS-1 and the association between IRS-1 and phosphatidylinositol (PI) 3-kinase in skeletal muscle from fat-fed and-streptozotocin (STZ)-treated rats, an animal model of type 2 diabetes mellitus. |
| 7032 | 15322693 | In addition, the effects of losartan on GLUT4 translocation in muscle cells and on insulin sensitivity were also evaluated. |
| 7033 | 15322693 | In skeletal muscles, the protein levels of IRS-1, PKB and GLUT4 in NIDDM rats were not significantly different from those of the control rats, and they were not affected by losartan. |
| 7034 | 15322693 | The levels of IRS-1 tyrosine phosphorylation, PI 3-kinase activity associated with IRS-1 and PKB activation after stimulation with insulin in muscle tissue of NIDDM rats were significantly decreased (P<0.01) compared with those in the control rats, while they were not increased by losartan. |
| 7035 | 15322693 | Losartan had a major effect on GLUT4 translocation in myocytes, as it significantly increased (P<0.05) the insulin-induced amounts of GLUT4 in plasma membrane (PM) and T-tubules (TT) in myocytes from NIDDM rats. |
| 7036 | 15322693 | Our results suggest that losartan may exert beneficial effects on insulin resistance by increasing the translocation of GLUT4 in muscle tissue, which is probably associated with a non-PI 3-kinase-dependent mechanism. |
| 7037 | 15322693 | The specific inhibition of angiotensin II action at AT(1) receptors by losartan has been shown to decrease peripheral insulin resistance in type 2 diabetic patients and animal models. |
| 7038 | 15322693 | We examined the effect of losartan on the expression of insulin receptor substrate 1 (IRS-1), protein kinase B (PKB) and glucose transporter 4 (GLUT4), as well as the phosphorylation status of IRS-1 and the association between IRS-1 and phosphatidylinositol (PI) 3-kinase in skeletal muscle from fat-fed and-streptozotocin (STZ)-treated rats, an animal model of type 2 diabetes mellitus. |
| 7039 | 15322693 | In addition, the effects of losartan on GLUT4 translocation in muscle cells and on insulin sensitivity were also evaluated. |
| 7040 | 15322693 | In skeletal muscles, the protein levels of IRS-1, PKB and GLUT4 in NIDDM rats were not significantly different from those of the control rats, and they were not affected by losartan. |
| 7041 | 15322693 | The levels of IRS-1 tyrosine phosphorylation, PI 3-kinase activity associated with IRS-1 and PKB activation after stimulation with insulin in muscle tissue of NIDDM rats were significantly decreased (P<0.01) compared with those in the control rats, while they were not increased by losartan. |
| 7042 | 15322693 | Losartan had a major effect on GLUT4 translocation in myocytes, as it significantly increased (P<0.05) the insulin-induced amounts of GLUT4 in plasma membrane (PM) and T-tubules (TT) in myocytes from NIDDM rats. |
| 7043 | 15322693 | Our results suggest that losartan may exert beneficial effects on insulin resistance by increasing the translocation of GLUT4 in muscle tissue, which is probably associated with a non-PI 3-kinase-dependent mechanism. |
| 7044 | 15326562 | Western blot analysis and immunoprecipitation were performed to determine protein content of IRS-1, IRS-2, p85, phosphorylation of IRS-1, IRS-2, Akt and MAPK as well as association between p85 and IRS-1/IRS-2. |
| 7045 | 15326562 | Furthermore, long-term treatment with insulin in diabetic adipocytes led to a significant reduction in the phosphorylation of IRS-1(68 +/- 11%), IRS-2 (82 +/- 11%), Akt (42 +/- 2%), and MAPK (92 +/- 12%) and in the subsequent association between p85 to IRS-1 and IRS-2 (100 +/- 16% and 96 +/- 12%) in comparison to controls. |
| 7046 | 15326562 | Western blot analysis and immunoprecipitation were performed to determine protein content of IRS-1, IRS-2, p85, phosphorylation of IRS-1, IRS-2, Akt and MAPK as well as association between p85 and IRS-1/IRS-2. |
| 7047 | 15326562 | Furthermore, long-term treatment with insulin in diabetic adipocytes led to a significant reduction in the phosphorylation of IRS-1(68 +/- 11%), IRS-2 (82 +/- 11%), Akt (42 +/- 2%), and MAPK (92 +/- 12%) and in the subsequent association between p85 to IRS-1 and IRS-2 (100 +/- 16% and 96 +/- 12%) in comparison to controls. |
| 7048 | 15326564 | These diabetes-related abnormalities in glucose disposal were associated with a marked diminution in the insulin-mediated enhancement of protein kinase B (Akt/PKB) and insulin receptor substrate-1 (IRS-1)-associated phosphatidylinostol 3-kinase (PI 3-kinase) activities; these two kinases are key elements in the insulin signalling pathway. |
| 7049 | 15326564 | Chronic administration of the hydrophobic/hydrophilic antioxidant alpha -lipoic-acid (ALA, 100 mg/kg, i.p.) partly ameliorated the diabetes-related deficit in glucose metabolism, protein oxidation as well as the activation by insulin of the various steps of the insulin signalling pathway, including the enzymes Akt/PKB and PI-3 kinase. |
| 7050 | 15364919 | Protein kinase C Theta inhibits insulin signaling by phosphorylating IRS1 at Ser(1101). |
| 7051 | 15364919 | Obesity and stress inhibit insulin action by activating protein kinases that enhance serine phosphorylation of IRS1 and have been thus associated to insulin resistance and the development of type II diabetes. |
| 7052 | 15364919 | Here we show that PKC phosphorylates IRS1 at serine 1101 blocking IRS1 tyrosine phosphorylation and downstream activation of the Akt pathway. |
| 7053 | 15364919 | Mutation of Ser(1101) to alanine makes IRS1 insensitive to the effect of PKC and restores insulin signaling in culture cells. |
| 7054 | 15364919 | Protein kinase C Theta inhibits insulin signaling by phosphorylating IRS1 at Ser(1101). |
| 7055 | 15364919 | Obesity and stress inhibit insulin action by activating protein kinases that enhance serine phosphorylation of IRS1 and have been thus associated to insulin resistance and the development of type II diabetes. |
| 7056 | 15364919 | Here we show that PKC phosphorylates IRS1 at serine 1101 blocking IRS1 tyrosine phosphorylation and downstream activation of the Akt pathway. |
| 7057 | 15364919 | Mutation of Ser(1101) to alanine makes IRS1 insensitive to the effect of PKC and restores insulin signaling in culture cells. |
| 7058 | 15364919 | Protein kinase C Theta inhibits insulin signaling by phosphorylating IRS1 at Ser(1101). |
| 7059 | 15364919 | Obesity and stress inhibit insulin action by activating protein kinases that enhance serine phosphorylation of IRS1 and have been thus associated to insulin resistance and the development of type II diabetes. |
| 7060 | 15364919 | Here we show that PKC phosphorylates IRS1 at serine 1101 blocking IRS1 tyrosine phosphorylation and downstream activation of the Akt pathway. |
| 7061 | 15364919 | Mutation of Ser(1101) to alanine makes IRS1 insensitive to the effect of PKC and restores insulin signaling in culture cells. |
| 7062 | 15364919 | Protein kinase C Theta inhibits insulin signaling by phosphorylating IRS1 at Ser(1101). |
| 7063 | 15364919 | Obesity and stress inhibit insulin action by activating protein kinases that enhance serine phosphorylation of IRS1 and have been thus associated to insulin resistance and the development of type II diabetes. |
| 7064 | 15364919 | Here we show that PKC phosphorylates IRS1 at serine 1101 blocking IRS1 tyrosine phosphorylation and downstream activation of the Akt pathway. |
| 7065 | 15364919 | Mutation of Ser(1101) to alanine makes IRS1 insensitive to the effect of PKC and restores insulin signaling in culture cells. |
| 7066 | 15372106 | Recent studies have suggested that local accumulation of fat metabolites inside skeletal muscle may activate a serine kinase cascade involving protein kinase C-theta (PKC-theta), leading to defects in insulin signaling and glucose transport in skeletal muscle. |
| 7067 | 15372106 | A 5-hour lipid infusion decreased insulin-stimulated skeletal muscle glucose uptake in the WT mice that was associated with 40-50% decreases in insulin-stimulated tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and IRS-1-associated PI3K activity. |
| 7068 | 15372107 | PDX-1 haploinsufficiency limits the compensatory islet hyperplasia that occurs in response to insulin resistance. |
| 7069 | 15372107 | Here we show that the compensatory islet-growth response to insulin resistance in 2 models--insulin receptor (IR)/IR substrate-1 (IRS-1) double heterozygous mice and liver-specific IR KO (LIRKO) mice--is severely restricted by PDX-1 heterozygosity. |
| 7070 | 15372107 | In both models, superimposition of PDX-1 haploinsufficiency upon the background of insulin resistance completely abrogated the adaptive islet hyperplastic response, and instead the beta cells showed apoptosis resulting in premature death of the mice. |
| 7071 | 15372107 | This study shows that, in postdevelopmental states of beta cell growth, PDX-1 is a critical regulator of beta cell replication and is required for the compensatory response to insulin resistance. |
| 7072 | 15375789 | The male GSK-3beta transgenic mice had significantly raised plasma insulin levels and by 24 weeks of age became glucose-intolerant as determined by a 50% increase in the area under their oral glucose tolerance curve (P < .001). |
| 7073 | 15375789 | At 29 weeks of age, GSK-3beta protein levels were 5-fold higher, and glycogen synthase activation (-27%), glycogen levels (-58%) and insulin receptor substrate-1 (IRS-1) protein levels (-67%) were significantly reduced in skeletal muscle. |
| 7074 | 15375789 | We conclude that overexpression of human GSK-3beta in skeletal muscle of male mice resulted in impaired glucose tolerance despite raised insulin levels, consistent with the possibility that elevated levels of GSK-3 in type 2 diabetes are partly responsible for insulin resistance. |
| 7075 | 15474483 | Transcriptome and proteome expression in activated human CD4 and CD8 T-lymphocytes. |
| 7076 | 15474483 | T-lymphocytes (T-cells) are unique in that unlike monocytes, they have no insulin receptors, and are insulin insensitive, but upon activation with antigens develop insulin, IGF-1, and IL-2 receptors, and become insulin sensitive tissues. |
| 7077 | 15474483 | We analyzed the genomics and proteomics of activated and non-activated CD4+ and CD8+ T-cells of normal subjects using Affymetrix microarray gene chips and proteomes by SELDI-TOF mass spectrometry analysis. |
| 7078 | 15474483 | Genes for IL-2, insulin, and IGF-1 receptors were increased at least 2-fold in activated vs non-activated T-cells. |
| 7079 | 15474483 | Among activated ontologies were signal transduction pathways such as IRS-1, IRS-2, Akt, and glycolytic pathways. |
| 7080 | 15486293 | This stress in turn leads to suppression of insulin receptor signaling through hyperactivation of c-Jun N-terminal kinase (JNK) and subsequent serine phosphorylation of insulin receptor substrate-1 (IRS-1). |
| 7081 | 15486293 | Mice deficient in X-box-binding protein-1 (XBP-1), a transcription factor that modulates the ER stress response, develop insulin resistance. |
| 7082 | 15509553 | In this study, we have shown that endoplasmic reticulum (ER) stress, which is provoked under diabetic conditions, plays a crucial role in the insulin resistance found in diabetes by modifying the expression of oxygen-regulated protein 150 (ORP150), a molecular chaperone that protects cells from ER stress. |
| 7083 | 15509553 | Conversely, expression of antisense ORP150 in the liver of normal mice decreased insulin sensitivity. |
| 7084 | 15509553 | The phosphorylation state of IRS-1 and Akt, which are key molecules for insulin signaling, and the expression levels of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase, key enzymes of gluconeogenesis, were also altered by ORP150 overexpression. |
| 7085 | 15516700 | Both of the metal ions were also found to potentiate insulin-mediated activation of IRS-1. |
| 7086 | 15520221 | Insulin receptor, insulin receptor substrate-1, Raf-1, and Mek-1 during hormonal hepatocarcinogenesis by intrahepatic pancreatic islet transplantation in diabetic rats. |
| 7087 | 15520221 | Thus, we investigated FAHs, HCAs, and HCCs for altered expression of insulin receptor, insulin receptor substrate-1 (IRS-1), Raf-1 and Mek-1. |
| 7088 | 15520221 | IRS-1, Raf-1, and Mek-1 proteins were strongly overexpressed in FAHs and tumors, as compared with the unaltered liver tissue. |
| 7089 | 15520221 | Insulin receptor, insulin receptor substrate-1, Raf-1, and Mek-1 during hormonal hepatocarcinogenesis by intrahepatic pancreatic islet transplantation in diabetic rats. |
| 7090 | 15520221 | Thus, we investigated FAHs, HCAs, and HCCs for altered expression of insulin receptor, insulin receptor substrate-1 (IRS-1), Raf-1 and Mek-1. |
| 7091 | 15520221 | IRS-1, Raf-1, and Mek-1 proteins were strongly overexpressed in FAHs and tumors, as compared with the unaltered liver tissue. |
| 7092 | 15520221 | Insulin receptor, insulin receptor substrate-1, Raf-1, and Mek-1 during hormonal hepatocarcinogenesis by intrahepatic pancreatic islet transplantation in diabetic rats. |
| 7093 | 15520221 | Thus, we investigated FAHs, HCAs, and HCCs for altered expression of insulin receptor, insulin receptor substrate-1 (IRS-1), Raf-1 and Mek-1. |
| 7094 | 15520221 | IRS-1, Raf-1, and Mek-1 proteins were strongly overexpressed in FAHs and tumors, as compared with the unaltered liver tissue. |
| 7095 | 15523593 | Met326Ile aminoacid polymorphism in the human p85 alpha gene has no major impact on early insulin signaling in type 2 diabetes. |
| 7096 | 15523593 | This mutation resulted in a homozygous missense amino acid change Met --> Ile in one subject with type 2 diabetes and heterozygous variant in two other diabetic patients and one with severe insulin resistance. |
| 7097 | 15523593 | Interestingly, those patients revealed an impaired insulin-mediated insulin receptor substrate (IRS)-1 binding to p85 alpha without any alteration in IRS-2/p85 alpha association. |
| 7098 | 15523593 | Furthermore, IRS-1, IRS-2, p85 alpha and MAPK protein contents were not significantly changed, and neither were MAPK or Akt phosphorylation. |
| 7099 | 15530428 | Glucagon release is regulated by tyrosine phosphatase and PI3-kinase activity. |
| 7100 | 15530428 | In In-R1-G9 glucagonoma cells, the inhibitory effect of pV (0.01 mM) on glucagon response to arginine was also observed and paralleled by increased IRS-1 and IRS-2 associated PI3-kinase activity. |
| 7101 | 15530428 | PI3-kinase activity seems to play an important role in pV-induced inhibition of glucagon release. |
| 7102 | 15561934 | Hepatic PTP-1B expression regulates the assembly and secretion of apolipoprotein B-containing lipoproteins: evidence from protein tyrosine phosphatase-1B overexpression, knockout, and RNAi studies. |
| 7103 | 15561934 | Protein tyrosine phosphatase-1B (PTP-1B) plays an important role in regulation of insulin signal transduction, and modulation of PTP-1B expression seems to have a profound effect on insulin sensitivity and diet-induced weight gain. |
| 7104 | 15561934 | The molecular link between PTP-1B expression and metabolic dyslipidemia, a major complication of insulin resistance, was investigated in the present study using PTP-1B knockout mice as well as overexpression and suppression of PTP-1B. |
| 7105 | 15561934 | Lipoprotein profile analysis of plasma from PTP-1B knockout mice revealed a significant reduction in apolipoprotein B (apoB100) lipoproteins, associated with reduced hepatic apoB100 secretion from isolated primary hepatocytes. |
| 7106 | 15561934 | Conversely, adenoviral-mediated overexpression of PTP-1B in HepG2 cells downregulated the phosphorylation of insulin receptor and insulin receptor substrate-1 and caused increases in cellular and secreted apoB100 as a result of increased intracellular apoB100 stability. |
| 7107 | 15561958 | Postclamp liver but not muscle phosphorylated/total Akt protein was increased, whereas basal c-Jun NH2-terminal kinase-1 and -2 protein expression were reduced (by 39 and 53%, respectively; P < 0.05). |
| 7108 | 15561958 | Metformin also increased hepatic basal IkappaBalpha levels (by 260%; P < 0.001) but had no effect on tyrosine phosphorylation or expression of insulin receptor substrate-1 (IRS-1). |
| 7109 | 15572028 | To investigate if IRS2 autonomously affects beta-cells, we have studied proliferation, apoptosis, and beta-cell function in isolated rat and human islets after overexpression of IRS2 or IRS1. |
| 7110 | 15572028 | We found that beta-cell proliferation was significantly increased in rat islets overexpressing IRS2 while IRS1 was less effective. |
| 7111 | 15572028 | Overexpression of IRS2 in isolated rat islets significantly increased basal and D-glucose-stimulated insulin secretion as determined in perifusion experiments. |
| 7112 | 15572028 | To investigate if IRS2 autonomously affects beta-cells, we have studied proliferation, apoptosis, and beta-cell function in isolated rat and human islets after overexpression of IRS2 or IRS1. |
| 7113 | 15572028 | We found that beta-cell proliferation was significantly increased in rat islets overexpressing IRS2 while IRS1 was less effective. |
| 7114 | 15572028 | Overexpression of IRS2 in isolated rat islets significantly increased basal and D-glucose-stimulated insulin secretion as determined in perifusion experiments. |
| 7115 | 15574412 | Using an N-terminal deleted IRS-1 mutant and two IRS-1 fragments, PTB-1 1-320 and PTB-2 1-350, we localized GSK-3 phosphorylation site(s) within amino acid sequence 320-350. |
| 7116 | 15574412 | Mutations of serine 332 or 336, which lie in the GSK-3 consensus motif (SXXXS) within PTB-2 or IRS-1, to alanine abolished their phosphorylation by GSK-3. |
| 7117 | 15574412 | When IRS-1 mutants S332A(IRS-1), S336A(IRS-1), or S332A/336A(IRS-1) were expressed in Chinese hamster ovary cells overexpressing insulin receptors, their insulin-induced tyrosine phosphorylation levels increased compared with that of wild-type (WT) IRS-1. |
| 7118 | 15574412 | This effect was stronger in the double mutant S332A/336A(IRS-1) and led to enhanced insulin-mediated activation of protein kinase B. |
| 7119 | 15574412 | In summary, our studies identify Ser332 as the GSK-3 phosphorylation target in IRS-1, indicating its physiological relevance and demonstrating its novel inhibitory role in insulin signaling. |
| 7120 | 15574412 | Using an N-terminal deleted IRS-1 mutant and two IRS-1 fragments, PTB-1 1-320 and PTB-2 1-350, we localized GSK-3 phosphorylation site(s) within amino acid sequence 320-350. |
| 7121 | 15574412 | Mutations of serine 332 or 336, which lie in the GSK-3 consensus motif (SXXXS) within PTB-2 or IRS-1, to alanine abolished their phosphorylation by GSK-3. |
| 7122 | 15574412 | When IRS-1 mutants S332A(IRS-1), S336A(IRS-1), or S332A/336A(IRS-1) were expressed in Chinese hamster ovary cells overexpressing insulin receptors, their insulin-induced tyrosine phosphorylation levels increased compared with that of wild-type (WT) IRS-1. |
| 7123 | 15574412 | This effect was stronger in the double mutant S332A/336A(IRS-1) and led to enhanced insulin-mediated activation of protein kinase B. |
| 7124 | 15574412 | In summary, our studies identify Ser332 as the GSK-3 phosphorylation target in IRS-1, indicating its physiological relevance and demonstrating its novel inhibitory role in insulin signaling. |
| 7125 | 15574412 | Using an N-terminal deleted IRS-1 mutant and two IRS-1 fragments, PTB-1 1-320 and PTB-2 1-350, we localized GSK-3 phosphorylation site(s) within amino acid sequence 320-350. |
| 7126 | 15574412 | Mutations of serine 332 or 336, which lie in the GSK-3 consensus motif (SXXXS) within PTB-2 or IRS-1, to alanine abolished their phosphorylation by GSK-3. |
| 7127 | 15574412 | When IRS-1 mutants S332A(IRS-1), S336A(IRS-1), or S332A/336A(IRS-1) were expressed in Chinese hamster ovary cells overexpressing insulin receptors, their insulin-induced tyrosine phosphorylation levels increased compared with that of wild-type (WT) IRS-1. |
| 7128 | 15574412 | This effect was stronger in the double mutant S332A/336A(IRS-1) and led to enhanced insulin-mediated activation of protein kinase B. |
| 7129 | 15574412 | In summary, our studies identify Ser332 as the GSK-3 phosphorylation target in IRS-1, indicating its physiological relevance and demonstrating its novel inhibitory role in insulin signaling. |
| 7130 | 15574412 | Using an N-terminal deleted IRS-1 mutant and two IRS-1 fragments, PTB-1 1-320 and PTB-2 1-350, we localized GSK-3 phosphorylation site(s) within amino acid sequence 320-350. |
| 7131 | 15574412 | Mutations of serine 332 or 336, which lie in the GSK-3 consensus motif (SXXXS) within PTB-2 or IRS-1, to alanine abolished their phosphorylation by GSK-3. |
| 7132 | 15574412 | When IRS-1 mutants S332A(IRS-1), S336A(IRS-1), or S332A/336A(IRS-1) were expressed in Chinese hamster ovary cells overexpressing insulin receptors, their insulin-induced tyrosine phosphorylation levels increased compared with that of wild-type (WT) IRS-1. |
| 7133 | 15574412 | This effect was stronger in the double mutant S332A/336A(IRS-1) and led to enhanced insulin-mediated activation of protein kinase B. |
| 7134 | 15574412 | In summary, our studies identify Ser332 as the GSK-3 phosphorylation target in IRS-1, indicating its physiological relevance and demonstrating its novel inhibitory role in insulin signaling. |
| 7135 | 15574412 | Using an N-terminal deleted IRS-1 mutant and two IRS-1 fragments, PTB-1 1-320 and PTB-2 1-350, we localized GSK-3 phosphorylation site(s) within amino acid sequence 320-350. |
| 7136 | 15574412 | Mutations of serine 332 or 336, which lie in the GSK-3 consensus motif (SXXXS) within PTB-2 or IRS-1, to alanine abolished their phosphorylation by GSK-3. |
| 7137 | 15574412 | When IRS-1 mutants S332A(IRS-1), S336A(IRS-1), or S332A/336A(IRS-1) were expressed in Chinese hamster ovary cells overexpressing insulin receptors, their insulin-induced tyrosine phosphorylation levels increased compared with that of wild-type (WT) IRS-1. |
| 7138 | 15574412 | This effect was stronger in the double mutant S332A/336A(IRS-1) and led to enhanced insulin-mediated activation of protein kinase B. |
| 7139 | 15574412 | In summary, our studies identify Ser332 as the GSK-3 phosphorylation target in IRS-1, indicating its physiological relevance and demonstrating its novel inhibitory role in insulin signaling. |
| 7140 | 15590636 | To determine the molecular mechanism by which this polymorphism may be linked to insulin resistance, we produced recombinant peptides comprising amino acid residues 925-1008 from IRS-1 that contain either a glycine or arginine at codon 972 and the two nearby tyrosine phosphorylation consensus sites (EY(941)MLM and DY(989)MTM), which are known binding sites for the p85alpha regulatory subunit of phosphatidylinositol 3-kinase. |
| 7141 | 15590636 | The use of additional overlapping fragments localized this interaction to domains between residues 950-986 of IRS-1 and residues 966-1271 of the insulin receptor, containing the tyrosine kinase domain of the receptor. |
| 7142 | 15590636 | In addition, the IRS-1-(925-1008) G972R peptide acted as a competitive inhibitor of insulin receptor and insulin-like growth factor-1 receptor autophosphorylation. |
| 7143 | 15590636 | Taken together, these data indicate that the G972R naturally occurring polymorphism of IRS-1 not only reduces phosphorylation of the substrate but allows IRS-1 to act as an inhibitor of the insulin receptor kinase, producing global insulin resistance. |
| 7144 | 15590636 | To determine the molecular mechanism by which this polymorphism may be linked to insulin resistance, we produced recombinant peptides comprising amino acid residues 925-1008 from IRS-1 that contain either a glycine or arginine at codon 972 and the two nearby tyrosine phosphorylation consensus sites (EY(941)MLM and DY(989)MTM), which are known binding sites for the p85alpha regulatory subunit of phosphatidylinositol 3-kinase. |
| 7145 | 15590636 | The use of additional overlapping fragments localized this interaction to domains between residues 950-986 of IRS-1 and residues 966-1271 of the insulin receptor, containing the tyrosine kinase domain of the receptor. |
| 7146 | 15590636 | In addition, the IRS-1-(925-1008) G972R peptide acted as a competitive inhibitor of insulin receptor and insulin-like growth factor-1 receptor autophosphorylation. |
| 7147 | 15590636 | Taken together, these data indicate that the G972R naturally occurring polymorphism of IRS-1 not only reduces phosphorylation of the substrate but allows IRS-1 to act as an inhibitor of the insulin receptor kinase, producing global insulin resistance. |
| 7148 | 15590636 | To determine the molecular mechanism by which this polymorphism may be linked to insulin resistance, we produced recombinant peptides comprising amino acid residues 925-1008 from IRS-1 that contain either a glycine or arginine at codon 972 and the two nearby tyrosine phosphorylation consensus sites (EY(941)MLM and DY(989)MTM), which are known binding sites for the p85alpha regulatory subunit of phosphatidylinositol 3-kinase. |
| 7149 | 15590636 | The use of additional overlapping fragments localized this interaction to domains between residues 950-986 of IRS-1 and residues 966-1271 of the insulin receptor, containing the tyrosine kinase domain of the receptor. |
| 7150 | 15590636 | In addition, the IRS-1-(925-1008) G972R peptide acted as a competitive inhibitor of insulin receptor and insulin-like growth factor-1 receptor autophosphorylation. |
| 7151 | 15590636 | Taken together, these data indicate that the G972R naturally occurring polymorphism of IRS-1 not only reduces phosphorylation of the substrate but allows IRS-1 to act as an inhibitor of the insulin receptor kinase, producing global insulin resistance. |
| 7152 | 15592487 | In skeletal muscle, the increase in LC-CoA and diacylglycerol translocates and activates specific protein kinase C (PKC) isoforms, which will phosphorylate IRS-1 on serine, preventing its phosphorylation on tyrosine and association with PI3 kinase. |
| 7153 | 15606684 | The ability of these compounds to stimulate glucose uptake, glycogen and lipid synthesis in muscle, adipose and hepatic tissues and to inhibit gluconeogenesis, and the activities of the gluconeogenic enzymes: phosphoenol pyruvate carboxykinase and glucose-6-phosphatase in the liver and kidney as well as lipolysis in fat cells contributes as potential mechanisms to their anti-diabetic insulin-like effects. |
| 7154 | 15606684 | At the cellular level, vanadium activates several key elements of the insulin signal transduction pathway, such as the tyrosine phosphorylation of insulin receptor substrate-1, and extracellular signal-regulated kinase 1 and 2, phosphatidylinositol 3-kinase and protein kinase B activation. |
| 7155 | 15610610 | In HepG2 cells transduced with adeno-associated viral (AAV) vectors encoding LFv2IRE, AP20187 induces LFv2IRE homodimerization and transphosphorylation minutes after drug administration, resulting in the phosphorylation of a canonical substrate of the insulin receptor tyrosine kinase, IRS-1. |
| 7156 | 15613682 | Insulin resistance in polycystic ovary syndrome (PCOS) is due to a postbinding defect in signaling that persists in cultured skin fibroblasts and is associated with constitutive serine phosphorylation of the insulin receptor (IR). |
| 7157 | 15613682 | Basal and insulin-stimulated glucose transport and GLUT1 abundance were significantly increased in cultured myotubes from women with PCOS. |
| 7158 | 15613682 | Insulin signaling via IRS-2 was also decreased in myotubes from women with PCOS. |
| 7159 | 15613682 | Nevertheless, there are intrinsic abnormalities in glucose transport and insulin signaling in myotubes from affected women, including increased phosphorylation of IRS-1 Ser312, that may confer increased susceptibility to insulin resistance-inducing factors in the in vivo environment. |
| 7160 | 15634339 | Insulin resistance in human adipocytes occurs downstream of IRS1 after surgical cell isolation but at the level of phosphorylation of IRS1 in type 2 diabetes. |
| 7161 | 15634339 | Tyrosine phosphorylation of the insulin receptor and insulin receptor substrate (IRS)1 was insulin sensitive, but protein kinase B (PKB) and downstream metabolic effects exhibited insulin resistance that was reversed by overnight incubation. |
| 7162 | 15634339 | MAP-kinases ERK1/2 and p38 were strongly phosphorylated after surgery, but was dephosphorylated during reversal of insulin resistance. |
| 7163 | 15634339 | Phosphorylation of MAP-kinase was not caused by collagenase treatment during cell isolation and was present also in tissue pieces that were not subjected to cell isolation procedures. |
| 7164 | 15634339 | IRS1, PKB, and downstream metabolic effects, but not insulin-stimulated tyrosine phosphorylation of insulin receptor, exhibited insulin resistance. |
| 7165 | 15634339 | Moreover, we pinpoint the signalling dysregulation in type 2 diabetes to be the insulin-stimulated phosphorylation of IRS1 in human adipocytes. |
| 7166 | 15634339 | Insulin resistance in human adipocytes occurs downstream of IRS1 after surgical cell isolation but at the level of phosphorylation of IRS1 in type 2 diabetes. |
| 7167 | 15634339 | Tyrosine phosphorylation of the insulin receptor and insulin receptor substrate (IRS)1 was insulin sensitive, but protein kinase B (PKB) and downstream metabolic effects exhibited insulin resistance that was reversed by overnight incubation. |
| 7168 | 15634339 | MAP-kinases ERK1/2 and p38 were strongly phosphorylated after surgery, but was dephosphorylated during reversal of insulin resistance. |
| 7169 | 15634339 | Phosphorylation of MAP-kinase was not caused by collagenase treatment during cell isolation and was present also in tissue pieces that were not subjected to cell isolation procedures. |
| 7170 | 15634339 | IRS1, PKB, and downstream metabolic effects, but not insulin-stimulated tyrosine phosphorylation of insulin receptor, exhibited insulin resistance. |
| 7171 | 15634339 | Moreover, we pinpoint the signalling dysregulation in type 2 diabetes to be the insulin-stimulated phosphorylation of IRS1 in human adipocytes. |
| 7172 | 15634339 | Insulin resistance in human adipocytes occurs downstream of IRS1 after surgical cell isolation but at the level of phosphorylation of IRS1 in type 2 diabetes. |
| 7173 | 15634339 | Tyrosine phosphorylation of the insulin receptor and insulin receptor substrate (IRS)1 was insulin sensitive, but protein kinase B (PKB) and downstream metabolic effects exhibited insulin resistance that was reversed by overnight incubation. |
| 7174 | 15634339 | MAP-kinases ERK1/2 and p38 were strongly phosphorylated after surgery, but was dephosphorylated during reversal of insulin resistance. |
| 7175 | 15634339 | Phosphorylation of MAP-kinase was not caused by collagenase treatment during cell isolation and was present also in tissue pieces that were not subjected to cell isolation procedures. |
| 7176 | 15634339 | IRS1, PKB, and downstream metabolic effects, but not insulin-stimulated tyrosine phosphorylation of insulin receptor, exhibited insulin resistance. |
| 7177 | 15634339 | Moreover, we pinpoint the signalling dysregulation in type 2 diabetes to be the insulin-stimulated phosphorylation of IRS1 in human adipocytes. |
| 7178 | 15636429 | Our results demonstrate the association of the G972R variant of the IRS-1 gene with reduced insulin sensitivity in obese subjects, and indicate a possible interaction between the IRS-1 variant and obesity in worsening of insulin sensitivity. |
| 7179 | 15664450 | Distinct Grb10 domain requirements for effects on glucose uptake and insulin signaling. |
| 7180 | 15664450 | The adapter protein Grb10 binds to phosphotyrosine residues in insulin receptors via its C-terminal region and regulates insulin signaling. |
| 7181 | 15664450 | Overexpression of FL-Grb10 inhibited insulin-stimulated receptor autophosphorylation and glucose uptake. |
| 7182 | 15664450 | In spite of these differences, both FL-Grb10 and the BPS-SH2 fragment inhibited insulin-stimulated phosphorylation of IRS1, IRS2, Akt/PKB, Shc, ERK1/2, APS, and c-Cbl to a similar extent. |
| 7183 | 15664450 | Co-precipitation studies demonstrated more sustained binding of the BPS-SH2 fragment than FL-Grb10 to insulin receptors. |
| 7184 | 15664450 | Although receptor binding domains of Grb10 are sufficient to inhibit insulin effects on proximal post-receptor signaling responses, N-terminal domains of Grb10 are essential for the effects of this adapter protein on receptor phosphorylation and glucose uptake. |
| 7185 | 15671078 | Type I soleus and type IIb epitrochlearis muscles from female obese Zucker rats were incubated in the absence or presence of a selective, small organic GSK3 inhibitor (1 microM CT118637, Ki < 10 nM for GSK3alpha and GSK3beta). |
| 7186 | 15671078 | Maximal insulin stimulation (5 mU/ml) of glucose transport activity, glycogen synthase activity, and selected insulin-signaling factors [tyrosine phosphorylation of insulin receptor (IR) and IRS-1, IRS-1 associated with p85 subunit of phosphatidylinositol 3-kinase, and serine phosphorylation of Akt and GSK3] were assessed. |
| 7187 | 15671078 | However, in obese soleus, GSK3 inhibition enhanced (all P < 0.05) insulin-stimulated IRS-1 tyrosine phosphorylation (45%), IRS-1-associated p85 (72%), Akt1/2 serine phosphorylation (30%), and GSK3beta serine phosphorylation (39%). |
| 7188 | 15671078 | Type I soleus and type IIb epitrochlearis muscles from female obese Zucker rats were incubated in the absence or presence of a selective, small organic GSK3 inhibitor (1 microM CT118637, Ki < 10 nM for GSK3alpha and GSK3beta). |
| 7189 | 15671078 | Maximal insulin stimulation (5 mU/ml) of glucose transport activity, glycogen synthase activity, and selected insulin-signaling factors [tyrosine phosphorylation of insulin receptor (IR) and IRS-1, IRS-1 associated with p85 subunit of phosphatidylinositol 3-kinase, and serine phosphorylation of Akt and GSK3] were assessed. |
| 7190 | 15671078 | However, in obese soleus, GSK3 inhibition enhanced (all P < 0.05) insulin-stimulated IRS-1 tyrosine phosphorylation (45%), IRS-1-associated p85 (72%), Akt1/2 serine phosphorylation (30%), and GSK3beta serine phosphorylation (39%). |
| 7191 | 15671479 | Foxo1, a member of the Fox0 subfamily of winged-helix forkhead transcription factors, is a target of insulin and insulin-like growth factor-1 (IGF-1) signal transduction pathways that activate protein kinase B (PKB) in pancreatic beta cells. |
| 7192 | 15671479 | Foxo1 is a substrate for PKB, and its phosphorylation results in nuclear exclusion with concomitant alterations in gene expression that are important to cellular growth and differentiation. |
| 7193 | 15671479 | Because activation of PKB can require insulin receptor substrate proteins (IRS-1 and IRS-2) and phosphatidylinositol 3-kinase (PI3K), it is of interest to determine whether the activity of Foxo1 is also regulated by heterotrimeric G protein-coupled receptors (GPCRs) with IRS-1 or -2, PI3K, or PKB signaling potential. |
| 7194 | 15671479 | Indeed, studies of beta cells have demonstrated that activation of a GPCR for the blood glucose-lowering hormone GLP-1 leads to major alterations of IRS-2, PI3K, and PKB activity. |
| 7195 | 15671479 | By promoting nuclear exclusion of Foxo1 in a PKB-mediated manner, GLP-1 may up-regulate the expression of a homeodomain transcription factor (PDX-1) that serves as a master regulator of beta-cell growth and differentiation. |
| 7196 | 15711641 | Complementary roles of IRS-1 and IRS-2 in the hepatic regulation of metabolism. |
| 7197 | 15711641 | In many cases, insulin resistance in liver is associated with reduced expression of both major insulin receptor substrate (IRS) proteins, IRS-1 and IRS-2. |
| 7198 | 15711641 | To investigate the specific functions of IRS-1 and IRS-2 in regulating liver function in vivo, we developed an adenovirus-mediated RNA interference technique in which short hairpin RNAs (shRNAs) are used to knock down IRS-1, IRS-2, or both, by 70-80% in livers of WT mice. |
| 7199 | 15711641 | The knockdown of IRS-1 resulted in an upregulation of the gluconeogenic enzymes glucose-6 phosphatase and phosphoenolpyruvate carboxykinase, as well as a marked increase in hepatic nuclear factor-4 alpha. |
| 7200 | 15711641 | Decreased IRS-1 was also associated with a decrease in glucokinase expression and a trend toward increased blood glucose, whereas knockdown of IRS-2 resulted in the upregulation of lipogenic enzymes SREBP-1c and fatty acid synthase, as well as increased hepatic lipid accumulation. |
| 7201 | 15711641 | The concomitant injection of IRS-1 and IRS-2 adenoviral shRNAs resulted in systemic insulin resistance, glucose intolerance, and hepatic steatosis. |
| 7202 | 15711641 | Taken together, our results demonstrate that hepatic IRS-1 and IRS-2 have complementary roles in the control of hepatic metabolism, with IRS-1 more closely linked to glucose homeostasis and IRS-2 more closely linked to lipid metabolism. |
| 7203 | 15711641 | Complementary roles of IRS-1 and IRS-2 in the hepatic regulation of metabolism. |
| 7204 | 15711641 | In many cases, insulin resistance in liver is associated with reduced expression of both major insulin receptor substrate (IRS) proteins, IRS-1 and IRS-2. |
| 7205 | 15711641 | To investigate the specific functions of IRS-1 and IRS-2 in regulating liver function in vivo, we developed an adenovirus-mediated RNA interference technique in which short hairpin RNAs (shRNAs) are used to knock down IRS-1, IRS-2, or both, by 70-80% in livers of WT mice. |
| 7206 | 15711641 | The knockdown of IRS-1 resulted in an upregulation of the gluconeogenic enzymes glucose-6 phosphatase and phosphoenolpyruvate carboxykinase, as well as a marked increase in hepatic nuclear factor-4 alpha. |
| 7207 | 15711641 | Decreased IRS-1 was also associated with a decrease in glucokinase expression and a trend toward increased blood glucose, whereas knockdown of IRS-2 resulted in the upregulation of lipogenic enzymes SREBP-1c and fatty acid synthase, as well as increased hepatic lipid accumulation. |
| 7208 | 15711641 | The concomitant injection of IRS-1 and IRS-2 adenoviral shRNAs resulted in systemic insulin resistance, glucose intolerance, and hepatic steatosis. |
| 7209 | 15711641 | Taken together, our results demonstrate that hepatic IRS-1 and IRS-2 have complementary roles in the control of hepatic metabolism, with IRS-1 more closely linked to glucose homeostasis and IRS-2 more closely linked to lipid metabolism. |
| 7210 | 15711641 | Complementary roles of IRS-1 and IRS-2 in the hepatic regulation of metabolism. |
| 7211 | 15711641 | In many cases, insulin resistance in liver is associated with reduced expression of both major insulin receptor substrate (IRS) proteins, IRS-1 and IRS-2. |
| 7212 | 15711641 | To investigate the specific functions of IRS-1 and IRS-2 in regulating liver function in vivo, we developed an adenovirus-mediated RNA interference technique in which short hairpin RNAs (shRNAs) are used to knock down IRS-1, IRS-2, or both, by 70-80% in livers of WT mice. |
| 7213 | 15711641 | The knockdown of IRS-1 resulted in an upregulation of the gluconeogenic enzymes glucose-6 phosphatase and phosphoenolpyruvate carboxykinase, as well as a marked increase in hepatic nuclear factor-4 alpha. |
| 7214 | 15711641 | Decreased IRS-1 was also associated with a decrease in glucokinase expression and a trend toward increased blood glucose, whereas knockdown of IRS-2 resulted in the upregulation of lipogenic enzymes SREBP-1c and fatty acid synthase, as well as increased hepatic lipid accumulation. |
| 7215 | 15711641 | The concomitant injection of IRS-1 and IRS-2 adenoviral shRNAs resulted in systemic insulin resistance, glucose intolerance, and hepatic steatosis. |
| 7216 | 15711641 | Taken together, our results demonstrate that hepatic IRS-1 and IRS-2 have complementary roles in the control of hepatic metabolism, with IRS-1 more closely linked to glucose homeostasis and IRS-2 more closely linked to lipid metabolism. |
| 7217 | 15711641 | Complementary roles of IRS-1 and IRS-2 in the hepatic regulation of metabolism. |
| 7218 | 15711641 | In many cases, insulin resistance in liver is associated with reduced expression of both major insulin receptor substrate (IRS) proteins, IRS-1 and IRS-2. |
| 7219 | 15711641 | To investigate the specific functions of IRS-1 and IRS-2 in regulating liver function in vivo, we developed an adenovirus-mediated RNA interference technique in which short hairpin RNAs (shRNAs) are used to knock down IRS-1, IRS-2, or both, by 70-80% in livers of WT mice. |
| 7220 | 15711641 | The knockdown of IRS-1 resulted in an upregulation of the gluconeogenic enzymes glucose-6 phosphatase and phosphoenolpyruvate carboxykinase, as well as a marked increase in hepatic nuclear factor-4 alpha. |
| 7221 | 15711641 | Decreased IRS-1 was also associated with a decrease in glucokinase expression and a trend toward increased blood glucose, whereas knockdown of IRS-2 resulted in the upregulation of lipogenic enzymes SREBP-1c and fatty acid synthase, as well as increased hepatic lipid accumulation. |
| 7222 | 15711641 | The concomitant injection of IRS-1 and IRS-2 adenoviral shRNAs resulted in systemic insulin resistance, glucose intolerance, and hepatic steatosis. |
| 7223 | 15711641 | Taken together, our results demonstrate that hepatic IRS-1 and IRS-2 have complementary roles in the control of hepatic metabolism, with IRS-1 more closely linked to glucose homeostasis and IRS-2 more closely linked to lipid metabolism. |
| 7224 | 15711641 | Complementary roles of IRS-1 and IRS-2 in the hepatic regulation of metabolism. |
| 7225 | 15711641 | In many cases, insulin resistance in liver is associated with reduced expression of both major insulin receptor substrate (IRS) proteins, IRS-1 and IRS-2. |
| 7226 | 15711641 | To investigate the specific functions of IRS-1 and IRS-2 in regulating liver function in vivo, we developed an adenovirus-mediated RNA interference technique in which short hairpin RNAs (shRNAs) are used to knock down IRS-1, IRS-2, or both, by 70-80% in livers of WT mice. |
| 7227 | 15711641 | The knockdown of IRS-1 resulted in an upregulation of the gluconeogenic enzymes glucose-6 phosphatase and phosphoenolpyruvate carboxykinase, as well as a marked increase in hepatic nuclear factor-4 alpha. |
| 7228 | 15711641 | Decreased IRS-1 was also associated with a decrease in glucokinase expression and a trend toward increased blood glucose, whereas knockdown of IRS-2 resulted in the upregulation of lipogenic enzymes SREBP-1c and fatty acid synthase, as well as increased hepatic lipid accumulation. |
| 7229 | 15711641 | The concomitant injection of IRS-1 and IRS-2 adenoviral shRNAs resulted in systemic insulin resistance, glucose intolerance, and hepatic steatosis. |
| 7230 | 15711641 | Taken together, our results demonstrate that hepatic IRS-1 and IRS-2 have complementary roles in the control of hepatic metabolism, with IRS-1 more closely linked to glucose homeostasis and IRS-2 more closely linked to lipid metabolism. |
| 7231 | 15711641 | Complementary roles of IRS-1 and IRS-2 in the hepatic regulation of metabolism. |
| 7232 | 15711641 | In many cases, insulin resistance in liver is associated with reduced expression of both major insulin receptor substrate (IRS) proteins, IRS-1 and IRS-2. |
| 7233 | 15711641 | To investigate the specific functions of IRS-1 and IRS-2 in regulating liver function in vivo, we developed an adenovirus-mediated RNA interference technique in which short hairpin RNAs (shRNAs) are used to knock down IRS-1, IRS-2, or both, by 70-80% in livers of WT mice. |
| 7234 | 15711641 | The knockdown of IRS-1 resulted in an upregulation of the gluconeogenic enzymes glucose-6 phosphatase and phosphoenolpyruvate carboxykinase, as well as a marked increase in hepatic nuclear factor-4 alpha. |
| 7235 | 15711641 | Decreased IRS-1 was also associated with a decrease in glucokinase expression and a trend toward increased blood glucose, whereas knockdown of IRS-2 resulted in the upregulation of lipogenic enzymes SREBP-1c and fatty acid synthase, as well as increased hepatic lipid accumulation. |
| 7236 | 15711641 | The concomitant injection of IRS-1 and IRS-2 adenoviral shRNAs resulted in systemic insulin resistance, glucose intolerance, and hepatic steatosis. |
| 7237 | 15711641 | Taken together, our results demonstrate that hepatic IRS-1 and IRS-2 have complementary roles in the control of hepatic metabolism, with IRS-1 more closely linked to glucose homeostasis and IRS-2 more closely linked to lipid metabolism. |
| 7238 | 15711641 | Complementary roles of IRS-1 and IRS-2 in the hepatic regulation of metabolism. |
| 7239 | 15711641 | In many cases, insulin resistance in liver is associated with reduced expression of both major insulin receptor substrate (IRS) proteins, IRS-1 and IRS-2. |
| 7240 | 15711641 | To investigate the specific functions of IRS-1 and IRS-2 in regulating liver function in vivo, we developed an adenovirus-mediated RNA interference technique in which short hairpin RNAs (shRNAs) are used to knock down IRS-1, IRS-2, or both, by 70-80% in livers of WT mice. |
| 7241 | 15711641 | The knockdown of IRS-1 resulted in an upregulation of the gluconeogenic enzymes glucose-6 phosphatase and phosphoenolpyruvate carboxykinase, as well as a marked increase in hepatic nuclear factor-4 alpha. |
| 7242 | 15711641 | Decreased IRS-1 was also associated with a decrease in glucokinase expression and a trend toward increased blood glucose, whereas knockdown of IRS-2 resulted in the upregulation of lipogenic enzymes SREBP-1c and fatty acid synthase, as well as increased hepatic lipid accumulation. |
| 7243 | 15711641 | The concomitant injection of IRS-1 and IRS-2 adenoviral shRNAs resulted in systemic insulin resistance, glucose intolerance, and hepatic steatosis. |
| 7244 | 15711641 | Taken together, our results demonstrate that hepatic IRS-1 and IRS-2 have complementary roles in the control of hepatic metabolism, with IRS-1 more closely linked to glucose homeostasis and IRS-2 more closely linked to lipid metabolism. |
| 7245 | 15764607 | The plasma membrane (PM) GLUT4 in the basal state was decreased, and the insulin-stimulated GLUT4 translocation to the PM was drastically reduced by mtDNA depletion. |
| 7246 | 15764607 | Moreover, insulin-stimulated phosphorylation of IRS-1 and Akt2/protein kinase B were drastically reduced in the depleted cells. |
| 7247 | 15764607 | Taken together, our data suggest that PM GLUT4 content and insulin signal pathway intermediates are modulated by the alteration of cellular mtDNA content, and the reductions in the expression of IRS-1 and insulin-stimulated phosphorylation of IRS-1 and Akt2/protein kinase B are associated with insulin resistance in the mtDNA-depleted L6 GLUT4myc myocytes. |
| 7248 | 15764607 | The plasma membrane (PM) GLUT4 in the basal state was decreased, and the insulin-stimulated GLUT4 translocation to the PM was drastically reduced by mtDNA depletion. |
| 7249 | 15764607 | Moreover, insulin-stimulated phosphorylation of IRS-1 and Akt2/protein kinase B were drastically reduced in the depleted cells. |
| 7250 | 15764607 | Taken together, our data suggest that PM GLUT4 content and insulin signal pathway intermediates are modulated by the alteration of cellular mtDNA content, and the reductions in the expression of IRS-1 and insulin-stimulated phosphorylation of IRS-1 and Akt2/protein kinase B are associated with insulin resistance in the mtDNA-depleted L6 GLUT4myc myocytes. |
| 7251 | 15781195 | Common polymorphisms in the PPARgamma2 and IRS-1 genes and their interaction influence serum adiponectin concentration in young Finnish men. |
| 7252 | 15781195 | The Gly972Arg substitution of the insulin receptor substrate-1 (IRS-1) gene and the Pro12Pro genotype of the peroxisome proliferator-activated receptor gamma 2 (PPARgamma2) gene have been suggested to be associated with type 2 diabetes mellitus. |
| 7253 | 15781195 | No difference was observed in serum adiponectin level between the IRS-1 genotype groups. |
| 7254 | 15781195 | The interaction between the PPARgamma2 and IRS-1 genes with respect to their effects on adiponectin levels was statistically significant (p=0.02). |
| 7255 | 15781195 | Adiponectin was significantly higher (p<0.05) in subjects who simultaneously had the Ala/Ala (PPARgamma2)+Gly/Gly (IRS-1) genotype combination compared to subjects with the Pro/Pro+Gly/Gly and Pro/Ala+Gly/Gly genotype combinations. |
| 7256 | 15781195 | We conclude that the Ala12Ala genotype of PPARgamma2 is associated with elevated adiponectin level, and that the PPARgamma2 and IRS-1 genes have a possible interaction in their effects on adiponectin concentration. |
| 7257 | 15781195 | Common polymorphisms in the PPARgamma2 and IRS-1 genes and their interaction influence serum adiponectin concentration in young Finnish men. |
| 7258 | 15781195 | The Gly972Arg substitution of the insulin receptor substrate-1 (IRS-1) gene and the Pro12Pro genotype of the peroxisome proliferator-activated receptor gamma 2 (PPARgamma2) gene have been suggested to be associated with type 2 diabetes mellitus. |
| 7259 | 15781195 | No difference was observed in serum adiponectin level between the IRS-1 genotype groups. |
| 7260 | 15781195 | The interaction between the PPARgamma2 and IRS-1 genes with respect to their effects on adiponectin levels was statistically significant (p=0.02). |
| 7261 | 15781195 | Adiponectin was significantly higher (p<0.05) in subjects who simultaneously had the Ala/Ala (PPARgamma2)+Gly/Gly (IRS-1) genotype combination compared to subjects with the Pro/Pro+Gly/Gly and Pro/Ala+Gly/Gly genotype combinations. |
| 7262 | 15781195 | We conclude that the Ala12Ala genotype of PPARgamma2 is associated with elevated adiponectin level, and that the PPARgamma2 and IRS-1 genes have a possible interaction in their effects on adiponectin concentration. |
| 7263 | 15781195 | Common polymorphisms in the PPARgamma2 and IRS-1 genes and their interaction influence serum adiponectin concentration in young Finnish men. |
| 7264 | 15781195 | The Gly972Arg substitution of the insulin receptor substrate-1 (IRS-1) gene and the Pro12Pro genotype of the peroxisome proliferator-activated receptor gamma 2 (PPARgamma2) gene have been suggested to be associated with type 2 diabetes mellitus. |
| 7265 | 15781195 | No difference was observed in serum adiponectin level between the IRS-1 genotype groups. |
| 7266 | 15781195 | The interaction between the PPARgamma2 and IRS-1 genes with respect to their effects on adiponectin levels was statistically significant (p=0.02). |
| 7267 | 15781195 | Adiponectin was significantly higher (p<0.05) in subjects who simultaneously had the Ala/Ala (PPARgamma2)+Gly/Gly (IRS-1) genotype combination compared to subjects with the Pro/Pro+Gly/Gly and Pro/Ala+Gly/Gly genotype combinations. |
| 7268 | 15781195 | We conclude that the Ala12Ala genotype of PPARgamma2 is associated with elevated adiponectin level, and that the PPARgamma2 and IRS-1 genes have a possible interaction in their effects on adiponectin concentration. |
| 7269 | 15781195 | Common polymorphisms in the PPARgamma2 and IRS-1 genes and their interaction influence serum adiponectin concentration in young Finnish men. |
| 7270 | 15781195 | The Gly972Arg substitution of the insulin receptor substrate-1 (IRS-1) gene and the Pro12Pro genotype of the peroxisome proliferator-activated receptor gamma 2 (PPARgamma2) gene have been suggested to be associated with type 2 diabetes mellitus. |
| 7271 | 15781195 | No difference was observed in serum adiponectin level between the IRS-1 genotype groups. |
| 7272 | 15781195 | The interaction between the PPARgamma2 and IRS-1 genes with respect to their effects on adiponectin levels was statistically significant (p=0.02). |
| 7273 | 15781195 | Adiponectin was significantly higher (p<0.05) in subjects who simultaneously had the Ala/Ala (PPARgamma2)+Gly/Gly (IRS-1) genotype combination compared to subjects with the Pro/Pro+Gly/Gly and Pro/Ala+Gly/Gly genotype combinations. |
| 7274 | 15781195 | We conclude that the Ala12Ala genotype of PPARgamma2 is associated with elevated adiponectin level, and that the PPARgamma2 and IRS-1 genes have a possible interaction in their effects on adiponectin concentration. |
| 7275 | 15781195 | Common polymorphisms in the PPARgamma2 and IRS-1 genes and their interaction influence serum adiponectin concentration in young Finnish men. |
| 7276 | 15781195 | The Gly972Arg substitution of the insulin receptor substrate-1 (IRS-1) gene and the Pro12Pro genotype of the peroxisome proliferator-activated receptor gamma 2 (PPARgamma2) gene have been suggested to be associated with type 2 diabetes mellitus. |
| 7277 | 15781195 | No difference was observed in serum adiponectin level between the IRS-1 genotype groups. |
| 7278 | 15781195 | The interaction between the PPARgamma2 and IRS-1 genes with respect to their effects on adiponectin levels was statistically significant (p=0.02). |
| 7279 | 15781195 | Adiponectin was significantly higher (p<0.05) in subjects who simultaneously had the Ala/Ala (PPARgamma2)+Gly/Gly (IRS-1) genotype combination compared to subjects with the Pro/Pro+Gly/Gly and Pro/Ala+Gly/Gly genotype combinations. |
| 7280 | 15781195 | We conclude that the Ala12Ala genotype of PPARgamma2 is associated with elevated adiponectin level, and that the PPARgamma2 and IRS-1 genes have a possible interaction in their effects on adiponectin concentration. |
| 7281 | 15781195 | Common polymorphisms in the PPARgamma2 and IRS-1 genes and their interaction influence serum adiponectin concentration in young Finnish men. |
| 7282 | 15781195 | The Gly972Arg substitution of the insulin receptor substrate-1 (IRS-1) gene and the Pro12Pro genotype of the peroxisome proliferator-activated receptor gamma 2 (PPARgamma2) gene have been suggested to be associated with type 2 diabetes mellitus. |
| 7283 | 15781195 | No difference was observed in serum adiponectin level between the IRS-1 genotype groups. |
| 7284 | 15781195 | The interaction between the PPARgamma2 and IRS-1 genes with respect to their effects on adiponectin levels was statistically significant (p=0.02). |
| 7285 | 15781195 | Adiponectin was significantly higher (p<0.05) in subjects who simultaneously had the Ala/Ala (PPARgamma2)+Gly/Gly (IRS-1) genotype combination compared to subjects with the Pro/Pro+Gly/Gly and Pro/Ala+Gly/Gly genotype combinations. |
| 7286 | 15781195 | We conclude that the Ala12Ala genotype of PPARgamma2 is associated with elevated adiponectin level, and that the PPARgamma2 and IRS-1 genes have a possible interaction in their effects on adiponectin concentration. |
| 7287 | 15787604 | Atypical protein kinase C in insulin action and insulin resistance. |
| 7288 | 15787604 | It now seems clear that aPKC (atypical protein kinase C) isoforms are required for insulin-stimulated glucose transport in muscle and adipocytes. |
| 7289 | 15787604 | These defects in muscle aPKC activation are due to both impaired activation of insulin receptor substrate-1-dependent PI3K (phosphoinositide 3-kinase) and the direct activation of aPKCs by the lipid product of PI3K, PI-3,4,5-(PO4)3. |
| 7290 | 15787606 | It is well documented that insulin sensitizers such as peroxisome-proliferator-activated receptor gamma agonists and aspirin improve insulin action in vivo. |
| 7291 | 15787606 | In 3T3-L1 adipocytes and/or in HEK-293 cells stably expressing recombinant IRS1 protein (insulin receptor substrate protein 1), the peroxisome-proliferator-activated receptor gamma agonist rosiglitazone and aspirin promote insulin signalling by decreasing inhibitory IRS1 serine phosphorylation. |
| 7292 | 15787606 | Increased IRS1 Ser-307 phosphorylation and concomitant decreased insulin signalling as measured by insulin-stimulated IRS1 tyrosine phosphorylation and Akt threonine phosphorylation were observed in adipose tissues of Zucker obese rats compared with lean control rats. |
| 7293 | 15787606 | Treatment with rosiglitazone for 24 and 48 h increased insulin signalling and decreased IRS1 Ser-307 phosphorylation concomitantly. |
| 7294 | 15787606 | Taken together, the results suggest that IRS1 inhibitory serine phosphorylation is a key component of insulin resistance and its reversal may be physiologically relevant to insulin sensitization in vivo. |
| 7295 | 15787606 | It is well documented that insulin sensitizers such as peroxisome-proliferator-activated receptor gamma agonists and aspirin improve insulin action in vivo. |
| 7296 | 15787606 | In 3T3-L1 adipocytes and/or in HEK-293 cells stably expressing recombinant IRS1 protein (insulin receptor substrate protein 1), the peroxisome-proliferator-activated receptor gamma agonist rosiglitazone and aspirin promote insulin signalling by decreasing inhibitory IRS1 serine phosphorylation. |
| 7297 | 15787606 | Increased IRS1 Ser-307 phosphorylation and concomitant decreased insulin signalling as measured by insulin-stimulated IRS1 tyrosine phosphorylation and Akt threonine phosphorylation were observed in adipose tissues of Zucker obese rats compared with lean control rats. |
| 7298 | 15787606 | Treatment with rosiglitazone for 24 and 48 h increased insulin signalling and decreased IRS1 Ser-307 phosphorylation concomitantly. |
| 7299 | 15787606 | Taken together, the results suggest that IRS1 inhibitory serine phosphorylation is a key component of insulin resistance and its reversal may be physiologically relevant to insulin sensitization in vivo. |
| 7300 | 15787606 | It is well documented that insulin sensitizers such as peroxisome-proliferator-activated receptor gamma agonists and aspirin improve insulin action in vivo. |
| 7301 | 15787606 | In 3T3-L1 adipocytes and/or in HEK-293 cells stably expressing recombinant IRS1 protein (insulin receptor substrate protein 1), the peroxisome-proliferator-activated receptor gamma agonist rosiglitazone and aspirin promote insulin signalling by decreasing inhibitory IRS1 serine phosphorylation. |
| 7302 | 15787606 | Increased IRS1 Ser-307 phosphorylation and concomitant decreased insulin signalling as measured by insulin-stimulated IRS1 tyrosine phosphorylation and Akt threonine phosphorylation were observed in adipose tissues of Zucker obese rats compared with lean control rats. |
| 7303 | 15787606 | Treatment with rosiglitazone for 24 and 48 h increased insulin signalling and decreased IRS1 Ser-307 phosphorylation concomitantly. |
| 7304 | 15787606 | Taken together, the results suggest that IRS1 inhibitory serine phosphorylation is a key component of insulin resistance and its reversal may be physiologically relevant to insulin sensitization in vivo. |
| 7305 | 15787606 | It is well documented that insulin sensitizers such as peroxisome-proliferator-activated receptor gamma agonists and aspirin improve insulin action in vivo. |
| 7306 | 15787606 | In 3T3-L1 adipocytes and/or in HEK-293 cells stably expressing recombinant IRS1 protein (insulin receptor substrate protein 1), the peroxisome-proliferator-activated receptor gamma agonist rosiglitazone and aspirin promote insulin signalling by decreasing inhibitory IRS1 serine phosphorylation. |
| 7307 | 15787606 | Increased IRS1 Ser-307 phosphorylation and concomitant decreased insulin signalling as measured by insulin-stimulated IRS1 tyrosine phosphorylation and Akt threonine phosphorylation were observed in adipose tissues of Zucker obese rats compared with lean control rats. |
| 7308 | 15787606 | Treatment with rosiglitazone for 24 and 48 h increased insulin signalling and decreased IRS1 Ser-307 phosphorylation concomitantly. |
| 7309 | 15787606 | Taken together, the results suggest that IRS1 inhibitory serine phosphorylation is a key component of insulin resistance and its reversal may be physiologically relevant to insulin sensitization in vivo. |
| 7310 | 15790685 | In vivo insulin signaling through PI3-kinase is impaired in skeletal muscle of adult rat offspring exposed to ethanol in utero. |
| 7311 | 15790685 | To test the hypothesis that in vivo insulin signaling through phosphatidylinositol 3 (PI3)-kinase is reduced in skeletal muscle of adult rat offspring exposed to EtOH in utero, we gave insulin intravenously to these rats and probed steps in the PI3-kinase insulin signaling pathway. |
| 7312 | 15790685 | After insulin treatment, EtOH-exposed rats had decreased tyrosine phosphorylation of the insulin receptor beta-subunit and of insulin receptor substrate-1 (IRS-1), as well as reduced IRS-1-associated PI3-kinase in the gastrocnemius muscle compared with control rats. |
| 7313 | 15790685 | There was no significant difference in basal or insulin-stimulated Akt activity between EtOH-exposed rats and controls. |
| 7314 | 15790685 | Muscle insulin binding and peptide contents of insulin receptor, IRS-1, p85 subunit of PI3-kinase, Akt/PKB, and atypical PKC isoform zeta were not different between EtOH-exposed rats and controls. |
| 7315 | 15790685 | Thus insulin resistance in rat offspring exposed to EtOH in utero may be explained, at least in part, by impaired insulin signaling through the PI3-kinase pathway in skeletal muscle. |
| 7316 | 15790685 | In vivo insulin signaling through PI3-kinase is impaired in skeletal muscle of adult rat offspring exposed to ethanol in utero. |
| 7317 | 15790685 | To test the hypothesis that in vivo insulin signaling through phosphatidylinositol 3 (PI3)-kinase is reduced in skeletal muscle of adult rat offspring exposed to EtOH in utero, we gave insulin intravenously to these rats and probed steps in the PI3-kinase insulin signaling pathway. |
| 7318 | 15790685 | After insulin treatment, EtOH-exposed rats had decreased tyrosine phosphorylation of the insulin receptor beta-subunit and of insulin receptor substrate-1 (IRS-1), as well as reduced IRS-1-associated PI3-kinase in the gastrocnemius muscle compared with control rats. |
| 7319 | 15790685 | There was no significant difference in basal or insulin-stimulated Akt activity between EtOH-exposed rats and controls. |
| 7320 | 15790685 | Muscle insulin binding and peptide contents of insulin receptor, IRS-1, p85 subunit of PI3-kinase, Akt/PKB, and atypical PKC isoform zeta were not different between EtOH-exposed rats and controls. |
| 7321 | 15790685 | Thus insulin resistance in rat offspring exposed to EtOH in utero may be explained, at least in part, by impaired insulin signaling through the PI3-kinase pathway in skeletal muscle. |
| 7322 | 15793233 | S-nitrosation of the insulin receptor, insulin receptor substrate 1, and protein kinase B/Akt: a novel mechanism of insulin resistance. |
| 7323 | 15793233 | Evidence demonstrates that exogenous nitric oxide (NO) and the NO produced by inducible nitric oxide synthase (iNOS) can induce insulin resistance in muscle. |
| 7324 | 15793233 | Exogenous NO donated by S-nitrosoglutathione (GSNO) induced in vitro and in vivo S-nitrosation of the insulin receptor beta subunit (IRbeta) and protein kinase B/Akt (Akt) and reduced their kinase activity in muscle. |
| 7325 | 15793233 | In two distinct models of insulin resistance associated with enhanced iNOS expression-diet-induced obesity and the ob/ob diabetic mice-we observed enhanced S-nitrosation of IRbeta/IRS-1 and Akt in muscle. |
| 7326 | 15793233 | Reversal of S-nitrosation of these proteins by reducing iNOS expression yielded an improvement in insulin action in both animal models. |
| 7327 | 15793233 | Thus, S-nitrosation of proteins involved in insulin signal transduction is a novel molecular mechanism of iNOS-induced insulin resistance. |
| 7328 | 15793233 | S-nitrosation of the insulin receptor, insulin receptor substrate 1, and protein kinase B/Akt: a novel mechanism of insulin resistance. |
| 7329 | 15793233 | Evidence demonstrates that exogenous nitric oxide (NO) and the NO produced by inducible nitric oxide synthase (iNOS) can induce insulin resistance in muscle. |
| 7330 | 15793233 | Exogenous NO donated by S-nitrosoglutathione (GSNO) induced in vitro and in vivo S-nitrosation of the insulin receptor beta subunit (IRbeta) and protein kinase B/Akt (Akt) and reduced their kinase activity in muscle. |
| 7331 | 15793233 | In two distinct models of insulin resistance associated with enhanced iNOS expression-diet-induced obesity and the ob/ob diabetic mice-we observed enhanced S-nitrosation of IRbeta/IRS-1 and Akt in muscle. |
| 7332 | 15793233 | Reversal of S-nitrosation of these proteins by reducing iNOS expression yielded an improvement in insulin action in both animal models. |
| 7333 | 15793233 | Thus, S-nitrosation of proteins involved in insulin signal transduction is a novel molecular mechanism of iNOS-induced insulin resistance. |
| 7334 | 15823284 | Low adipocyte IRS-1 protein expression is associated with an increased arterial stiffness in non-diabetic males. |
| 7335 | 15823385 | Several mechanisms have been proposed, including increased non-esterified fatty acids, inflammatory cytokines, adipokines, and mitochondrial dysfunction for insulin resistance, and glucotoxicity, lipotoxicity, and amyloid formation for beta-cell dysfunction. |
| 7336 | 15823385 | Moreover, the disease has a strong genetic component, but only a handful of genes have been identified so far: genes for calpain 10, potassium inward-rectifier 6.2, peroxisome proliferator-activated receptor gamma, insulin receptor substrate-1, and others. |
| 7337 | 15824195 | Fatty acids appear to cause this defect in glucose transport by inhibiting insulin-stimulated tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and IRS-1 associated phosphatidylinositol 3-kinase activity. |
| 7338 | 15827066 | Insulin and IGF-I activate antiapoptotic pathways via insulin receptor substrate (IRS) proteins in most mammalian cells, including beta-cells. |
| 7339 | 15827066 | IRS-1 knockout (IRS-1KO) mice show growth retardation, hyperinsulinemia, and hyperplastic but dysfunctional islets without developing overt diabetes, whereas IRS-2KOs develop insulin resistance and islet hypoplasia leading to diabetes. |
| 7340 | 15827066 | We used a transplantation approach, as a means of separating host insulin resistance from islet function, to examine alterations in proteins in insulin/IGF-I signaling pathways that may contribute to beta-cell proliferation and/or apoptosis in IRS-1KO islets. |
| 7341 | 15827066 | Furthermore, enhanced cytosolic forkhead transcription factor (FoxO1) staining in IRS-1KO grafts suggests intact Akt/PKB activity. |
| 7342 | 15827066 | Together, these data indicate that, even in the absence of insulin resistance, beta-cells deficient in IRS-1 exhibit a compensatory increase in IRS-2, which is associated with islet growth and is characterized by both proliferative and antiapoptotic effects that likely occur via an insulin/IGF-I/IRS-2 pathway. |
| 7343 | 15827066 | Insulin and IGF-I activate antiapoptotic pathways via insulin receptor substrate (IRS) proteins in most mammalian cells, including beta-cells. |
| 7344 | 15827066 | IRS-1 knockout (IRS-1KO) mice show growth retardation, hyperinsulinemia, and hyperplastic but dysfunctional islets without developing overt diabetes, whereas IRS-2KOs develop insulin resistance and islet hypoplasia leading to diabetes. |
| 7345 | 15827066 | We used a transplantation approach, as a means of separating host insulin resistance from islet function, to examine alterations in proteins in insulin/IGF-I signaling pathways that may contribute to beta-cell proliferation and/or apoptosis in IRS-1KO islets. |
| 7346 | 15827066 | Furthermore, enhanced cytosolic forkhead transcription factor (FoxO1) staining in IRS-1KO grafts suggests intact Akt/PKB activity. |
| 7347 | 15827066 | Together, these data indicate that, even in the absence of insulin resistance, beta-cells deficient in IRS-1 exhibit a compensatory increase in IRS-2, which is associated with islet growth and is characterized by both proliferative and antiapoptotic effects that likely occur via an insulin/IGF-I/IRS-2 pathway. |
| 7348 | 15841260 | Additionally, the increased tyrosine phosphorylation levels of IR-beta and IRS-1 were significantly inhibited in insulin combined with GJG treated diabetes. |
| 7349 | 15845625 | Alterations in muscle and adipose tissue insulin receptor substrate (IRS)-1 and IRS-2 are associated with, and commonly believed to contribute to, development of insulin resistance. |
| 7350 | 15845625 | Semiquantitative RT-PCR analysis showed that insulin (10(4) microU/ml) alone or in combination with glucose (15 mm) markedly suppressed IRS-2 gene expression, whereas IRS-1 mRNA was unaffected by the culture conditions. |
| 7351 | 15845625 | The negative effect of a high glucose/high insulin setting on IRS-1 protein level was still exerted when protein synthesis was inhibited with cycloheximide. |
| 7352 | 15845625 | Impairment of glucose uptake capacity after treatment with high glucose and insulin was most pronounced after 3 h, whereas IRS-1 and IRS-2 protein levels were unaffected up to 6 h but were reduced after 16 h. |
| 7353 | 15845625 | These novel results suggest that: 1) in a high glucose/high insulin setting depletion of IRS-1 and IRS-2 protein, respectively, occurs via different mechanisms, and IRS-2 gene expression is suppressed, whereas IRS-1 depletion is due to posttranslational mechanisms; 2) IRS-1 and IRS-2 protein depletion is a secondary event in the development of insulin resistance in this model of hyperglycemia/hyperinsulinemia; and 3) depletion of cellular IRS in adipose tissue may be a consequence rather than a cause of insulin resistance and hyperinsulinemia in type 2 diabetes. |
| 7354 | 15845625 | Alterations in muscle and adipose tissue insulin receptor substrate (IRS)-1 and IRS-2 are associated with, and commonly believed to contribute to, development of insulin resistance. |
| 7355 | 15845625 | Semiquantitative RT-PCR analysis showed that insulin (10(4) microU/ml) alone or in combination with glucose (15 mm) markedly suppressed IRS-2 gene expression, whereas IRS-1 mRNA was unaffected by the culture conditions. |
| 7356 | 15845625 | The negative effect of a high glucose/high insulin setting on IRS-1 protein level was still exerted when protein synthesis was inhibited with cycloheximide. |
| 7357 | 15845625 | Impairment of glucose uptake capacity after treatment with high glucose and insulin was most pronounced after 3 h, whereas IRS-1 and IRS-2 protein levels were unaffected up to 6 h but were reduced after 16 h. |
| 7358 | 15845625 | These novel results suggest that: 1) in a high glucose/high insulin setting depletion of IRS-1 and IRS-2 protein, respectively, occurs via different mechanisms, and IRS-2 gene expression is suppressed, whereas IRS-1 depletion is due to posttranslational mechanisms; 2) IRS-1 and IRS-2 protein depletion is a secondary event in the development of insulin resistance in this model of hyperglycemia/hyperinsulinemia; and 3) depletion of cellular IRS in adipose tissue may be a consequence rather than a cause of insulin resistance and hyperinsulinemia in type 2 diabetes. |
| 7359 | 15845625 | Alterations in muscle and adipose tissue insulin receptor substrate (IRS)-1 and IRS-2 are associated with, and commonly believed to contribute to, development of insulin resistance. |
| 7360 | 15845625 | Semiquantitative RT-PCR analysis showed that insulin (10(4) microU/ml) alone or in combination with glucose (15 mm) markedly suppressed IRS-2 gene expression, whereas IRS-1 mRNA was unaffected by the culture conditions. |
| 7361 | 15845625 | The negative effect of a high glucose/high insulin setting on IRS-1 protein level was still exerted when protein synthesis was inhibited with cycloheximide. |
| 7362 | 15845625 | Impairment of glucose uptake capacity after treatment with high glucose and insulin was most pronounced after 3 h, whereas IRS-1 and IRS-2 protein levels were unaffected up to 6 h but were reduced after 16 h. |
| 7363 | 15845625 | These novel results suggest that: 1) in a high glucose/high insulin setting depletion of IRS-1 and IRS-2 protein, respectively, occurs via different mechanisms, and IRS-2 gene expression is suppressed, whereas IRS-1 depletion is due to posttranslational mechanisms; 2) IRS-1 and IRS-2 protein depletion is a secondary event in the development of insulin resistance in this model of hyperglycemia/hyperinsulinemia; and 3) depletion of cellular IRS in adipose tissue may be a consequence rather than a cause of insulin resistance and hyperinsulinemia in type 2 diabetes. |
| 7364 | 15845625 | Alterations in muscle and adipose tissue insulin receptor substrate (IRS)-1 and IRS-2 are associated with, and commonly believed to contribute to, development of insulin resistance. |
| 7365 | 15845625 | Semiquantitative RT-PCR analysis showed that insulin (10(4) microU/ml) alone or in combination with glucose (15 mm) markedly suppressed IRS-2 gene expression, whereas IRS-1 mRNA was unaffected by the culture conditions. |
| 7366 | 15845625 | The negative effect of a high glucose/high insulin setting on IRS-1 protein level was still exerted when protein synthesis was inhibited with cycloheximide. |
| 7367 | 15845625 | Impairment of glucose uptake capacity after treatment with high glucose and insulin was most pronounced after 3 h, whereas IRS-1 and IRS-2 protein levels were unaffected up to 6 h but were reduced after 16 h. |
| 7368 | 15845625 | These novel results suggest that: 1) in a high glucose/high insulin setting depletion of IRS-1 and IRS-2 protein, respectively, occurs via different mechanisms, and IRS-2 gene expression is suppressed, whereas IRS-1 depletion is due to posttranslational mechanisms; 2) IRS-1 and IRS-2 protein depletion is a secondary event in the development of insulin resistance in this model of hyperglycemia/hyperinsulinemia; and 3) depletion of cellular IRS in adipose tissue may be a consequence rather than a cause of insulin resistance and hyperinsulinemia in type 2 diabetes. |
| 7369 | 15849359 | Phosphorylation of Ser24 in the pleckstrin homology domain of insulin receptor substrate-1 by Mouse Pelle-like kinase/interleukin-1 receptor-associated kinase: cross-talk between inflammatory signaling and insulin signaling that may contribute to insulin resistance. |
| 7370 | 15849359 | Mouse Pelle-like kinase (mPLK, homolog of human IL-1 receptor-associated kinase (IRAK)) participates in inflammatory signaling. |
| 7371 | 15849359 | We evaluated IRS-1 as a novel substrate for mPLK that may contribute to linking inflammation with insulin resistance. |
| 7372 | 15849359 | Wild-type mPLK, but not a kinase-inactive mutant (mPLK-KD), directly phosphorylated full-length IRS-1 in vitro. |
| 7373 | 15849359 | This in vitro phosphorylation was increased when mPLK was immunoprecipitated from tumor necrosis factor (TNF)-alpha-treated cells. |
| 7374 | 15849359 | In NIH-3T3(IR) cells, wild-type mPLK (but not mPLK-KD) co-immunoprecipitated with IRS-1. |
| 7375 | 15849359 | Using mass spectrometry, we identified Ser(24) in the pleckstrin homology (PH) domain of IRS-1 as a specific phosphorylation site for mPLK. |
| 7376 | 15849359 | IRS-1 mutants S24D or S24E (mimicking phosphorylation at Ser(24)) had impaired ability to associate with insulin receptors resulting in diminished tyrosine phosphorylation of IRS-1 and impaired ability of IRS-1 to bind and activate PI-3 kinase in response to insulin. |
| 7377 | 15849359 | IRS-1-S24D also had an impaired ability to mediate insulin-stimulated translocation of GLUT4 in rat adipose cells. |
| 7378 | 15849359 | Importantly, endogenous mPLK/IRAK was activated in response to TNF-alpha or interleukin 1 treatment of primary adipose cells. |
| 7379 | 15849359 | In addition, using a phospho-specific antibody against IRS-1 phosphorylated at Ser(24), we found that interleukin-1 or TNF-alpha treatment of Fao cells stimulated increased phosphorylation of endogenous IRS-1 at Ser(24). |
| 7380 | 15849359 | We conclude that IRS-1 is a novel physiological substrate for mPLK. |
| 7381 | 15849359 | TNF-alpha-regulated phosphorylation at Ser(24) in the pleckstrin homology domain of IRS-1 by mPLK/IRAK represents an additional mechanism for cross-talk between inflammatory signaling and insulin signaling that may contribute to metabolic insulin resistance. |
| 7382 | 15849359 | Phosphorylation of Ser24 in the pleckstrin homology domain of insulin receptor substrate-1 by Mouse Pelle-like kinase/interleukin-1 receptor-associated kinase: cross-talk between inflammatory signaling and insulin signaling that may contribute to insulin resistance. |
| 7383 | 15849359 | Mouse Pelle-like kinase (mPLK, homolog of human IL-1 receptor-associated kinase (IRAK)) participates in inflammatory signaling. |
| 7384 | 15849359 | We evaluated IRS-1 as a novel substrate for mPLK that may contribute to linking inflammation with insulin resistance. |
| 7385 | 15849359 | Wild-type mPLK, but not a kinase-inactive mutant (mPLK-KD), directly phosphorylated full-length IRS-1 in vitro. |
| 7386 | 15849359 | This in vitro phosphorylation was increased when mPLK was immunoprecipitated from tumor necrosis factor (TNF)-alpha-treated cells. |
| 7387 | 15849359 | In NIH-3T3(IR) cells, wild-type mPLK (but not mPLK-KD) co-immunoprecipitated with IRS-1. |
| 7388 | 15849359 | Using mass spectrometry, we identified Ser(24) in the pleckstrin homology (PH) domain of IRS-1 as a specific phosphorylation site for mPLK. |
| 7389 | 15849359 | IRS-1 mutants S24D or S24E (mimicking phosphorylation at Ser(24)) had impaired ability to associate with insulin receptors resulting in diminished tyrosine phosphorylation of IRS-1 and impaired ability of IRS-1 to bind and activate PI-3 kinase in response to insulin. |
| 7390 | 15849359 | IRS-1-S24D also had an impaired ability to mediate insulin-stimulated translocation of GLUT4 in rat adipose cells. |
| 7391 | 15849359 | Importantly, endogenous mPLK/IRAK was activated in response to TNF-alpha or interleukin 1 treatment of primary adipose cells. |
| 7392 | 15849359 | In addition, using a phospho-specific antibody against IRS-1 phosphorylated at Ser(24), we found that interleukin-1 or TNF-alpha treatment of Fao cells stimulated increased phosphorylation of endogenous IRS-1 at Ser(24). |
| 7393 | 15849359 | We conclude that IRS-1 is a novel physiological substrate for mPLK. |
| 7394 | 15849359 | TNF-alpha-regulated phosphorylation at Ser(24) in the pleckstrin homology domain of IRS-1 by mPLK/IRAK represents an additional mechanism for cross-talk between inflammatory signaling and insulin signaling that may contribute to metabolic insulin resistance. |
| 7395 | 15849359 | Phosphorylation of Ser24 in the pleckstrin homology domain of insulin receptor substrate-1 by Mouse Pelle-like kinase/interleukin-1 receptor-associated kinase: cross-talk between inflammatory signaling and insulin signaling that may contribute to insulin resistance. |
| 7396 | 15849359 | Mouse Pelle-like kinase (mPLK, homolog of human IL-1 receptor-associated kinase (IRAK)) participates in inflammatory signaling. |
| 7397 | 15849359 | We evaluated IRS-1 as a novel substrate for mPLK that may contribute to linking inflammation with insulin resistance. |
| 7398 | 15849359 | Wild-type mPLK, but not a kinase-inactive mutant (mPLK-KD), directly phosphorylated full-length IRS-1 in vitro. |
| 7399 | 15849359 | This in vitro phosphorylation was increased when mPLK was immunoprecipitated from tumor necrosis factor (TNF)-alpha-treated cells. |
| 7400 | 15849359 | In NIH-3T3(IR) cells, wild-type mPLK (but not mPLK-KD) co-immunoprecipitated with IRS-1. |
| 7401 | 15849359 | Using mass spectrometry, we identified Ser(24) in the pleckstrin homology (PH) domain of IRS-1 as a specific phosphorylation site for mPLK. |
| 7402 | 15849359 | IRS-1 mutants S24D or S24E (mimicking phosphorylation at Ser(24)) had impaired ability to associate with insulin receptors resulting in diminished tyrosine phosphorylation of IRS-1 and impaired ability of IRS-1 to bind and activate PI-3 kinase in response to insulin. |
| 7403 | 15849359 | IRS-1-S24D also had an impaired ability to mediate insulin-stimulated translocation of GLUT4 in rat adipose cells. |
| 7404 | 15849359 | Importantly, endogenous mPLK/IRAK was activated in response to TNF-alpha or interleukin 1 treatment of primary adipose cells. |
| 7405 | 15849359 | In addition, using a phospho-specific antibody against IRS-1 phosphorylated at Ser(24), we found that interleukin-1 or TNF-alpha treatment of Fao cells stimulated increased phosphorylation of endogenous IRS-1 at Ser(24). |
| 7406 | 15849359 | We conclude that IRS-1 is a novel physiological substrate for mPLK. |
| 7407 | 15849359 | TNF-alpha-regulated phosphorylation at Ser(24) in the pleckstrin homology domain of IRS-1 by mPLK/IRAK represents an additional mechanism for cross-talk between inflammatory signaling and insulin signaling that may contribute to metabolic insulin resistance. |
| 7408 | 15849359 | Phosphorylation of Ser24 in the pleckstrin homology domain of insulin receptor substrate-1 by Mouse Pelle-like kinase/interleukin-1 receptor-associated kinase: cross-talk between inflammatory signaling and insulin signaling that may contribute to insulin resistance. |
| 7409 | 15849359 | Mouse Pelle-like kinase (mPLK, homolog of human IL-1 receptor-associated kinase (IRAK)) participates in inflammatory signaling. |
| 7410 | 15849359 | We evaluated IRS-1 as a novel substrate for mPLK that may contribute to linking inflammation with insulin resistance. |
| 7411 | 15849359 | Wild-type mPLK, but not a kinase-inactive mutant (mPLK-KD), directly phosphorylated full-length IRS-1 in vitro. |
| 7412 | 15849359 | This in vitro phosphorylation was increased when mPLK was immunoprecipitated from tumor necrosis factor (TNF)-alpha-treated cells. |
| 7413 | 15849359 | In NIH-3T3(IR) cells, wild-type mPLK (but not mPLK-KD) co-immunoprecipitated with IRS-1. |
| 7414 | 15849359 | Using mass spectrometry, we identified Ser(24) in the pleckstrin homology (PH) domain of IRS-1 as a specific phosphorylation site for mPLK. |
| 7415 | 15849359 | IRS-1 mutants S24D or S24E (mimicking phosphorylation at Ser(24)) had impaired ability to associate with insulin receptors resulting in diminished tyrosine phosphorylation of IRS-1 and impaired ability of IRS-1 to bind and activate PI-3 kinase in response to insulin. |
| 7416 | 15849359 | IRS-1-S24D also had an impaired ability to mediate insulin-stimulated translocation of GLUT4 in rat adipose cells. |
| 7417 | 15849359 | Importantly, endogenous mPLK/IRAK was activated in response to TNF-alpha or interleukin 1 treatment of primary adipose cells. |
| 7418 | 15849359 | In addition, using a phospho-specific antibody against IRS-1 phosphorylated at Ser(24), we found that interleukin-1 or TNF-alpha treatment of Fao cells stimulated increased phosphorylation of endogenous IRS-1 at Ser(24). |
| 7419 | 15849359 | We conclude that IRS-1 is a novel physiological substrate for mPLK. |
| 7420 | 15849359 | TNF-alpha-regulated phosphorylation at Ser(24) in the pleckstrin homology domain of IRS-1 by mPLK/IRAK represents an additional mechanism for cross-talk between inflammatory signaling and insulin signaling that may contribute to metabolic insulin resistance. |
| 7421 | 15849359 | Phosphorylation of Ser24 in the pleckstrin homology domain of insulin receptor substrate-1 by Mouse Pelle-like kinase/interleukin-1 receptor-associated kinase: cross-talk between inflammatory signaling and insulin signaling that may contribute to insulin resistance. |
| 7422 | 15849359 | Mouse Pelle-like kinase (mPLK, homolog of human IL-1 receptor-associated kinase (IRAK)) participates in inflammatory signaling. |
| 7423 | 15849359 | We evaluated IRS-1 as a novel substrate for mPLK that may contribute to linking inflammation with insulin resistance. |
| 7424 | 15849359 | Wild-type mPLK, but not a kinase-inactive mutant (mPLK-KD), directly phosphorylated full-length IRS-1 in vitro. |
| 7425 | 15849359 | This in vitro phosphorylation was increased when mPLK was immunoprecipitated from tumor necrosis factor (TNF)-alpha-treated cells. |
| 7426 | 15849359 | In NIH-3T3(IR) cells, wild-type mPLK (but not mPLK-KD) co-immunoprecipitated with IRS-1. |
| 7427 | 15849359 | Using mass spectrometry, we identified Ser(24) in the pleckstrin homology (PH) domain of IRS-1 as a specific phosphorylation site for mPLK. |
| 7428 | 15849359 | IRS-1 mutants S24D or S24E (mimicking phosphorylation at Ser(24)) had impaired ability to associate with insulin receptors resulting in diminished tyrosine phosphorylation of IRS-1 and impaired ability of IRS-1 to bind and activate PI-3 kinase in response to insulin. |
| 7429 | 15849359 | IRS-1-S24D also had an impaired ability to mediate insulin-stimulated translocation of GLUT4 in rat adipose cells. |
| 7430 | 15849359 | Importantly, endogenous mPLK/IRAK was activated in response to TNF-alpha or interleukin 1 treatment of primary adipose cells. |
| 7431 | 15849359 | In addition, using a phospho-specific antibody against IRS-1 phosphorylated at Ser(24), we found that interleukin-1 or TNF-alpha treatment of Fao cells stimulated increased phosphorylation of endogenous IRS-1 at Ser(24). |
| 7432 | 15849359 | We conclude that IRS-1 is a novel physiological substrate for mPLK. |
| 7433 | 15849359 | TNF-alpha-regulated phosphorylation at Ser(24) in the pleckstrin homology domain of IRS-1 by mPLK/IRAK represents an additional mechanism for cross-talk between inflammatory signaling and insulin signaling that may contribute to metabolic insulin resistance. |
| 7434 | 15849359 | Phosphorylation of Ser24 in the pleckstrin homology domain of insulin receptor substrate-1 by Mouse Pelle-like kinase/interleukin-1 receptor-associated kinase: cross-talk between inflammatory signaling and insulin signaling that may contribute to insulin resistance. |
| 7435 | 15849359 | Mouse Pelle-like kinase (mPLK, homolog of human IL-1 receptor-associated kinase (IRAK)) participates in inflammatory signaling. |
| 7436 | 15849359 | We evaluated IRS-1 as a novel substrate for mPLK that may contribute to linking inflammation with insulin resistance. |
| 7437 | 15849359 | Wild-type mPLK, but not a kinase-inactive mutant (mPLK-KD), directly phosphorylated full-length IRS-1 in vitro. |
| 7438 | 15849359 | This in vitro phosphorylation was increased when mPLK was immunoprecipitated from tumor necrosis factor (TNF)-alpha-treated cells. |
| 7439 | 15849359 | In NIH-3T3(IR) cells, wild-type mPLK (but not mPLK-KD) co-immunoprecipitated with IRS-1. |
| 7440 | 15849359 | Using mass spectrometry, we identified Ser(24) in the pleckstrin homology (PH) domain of IRS-1 as a specific phosphorylation site for mPLK. |
| 7441 | 15849359 | IRS-1 mutants S24D or S24E (mimicking phosphorylation at Ser(24)) had impaired ability to associate with insulin receptors resulting in diminished tyrosine phosphorylation of IRS-1 and impaired ability of IRS-1 to bind and activate PI-3 kinase in response to insulin. |
| 7442 | 15849359 | IRS-1-S24D also had an impaired ability to mediate insulin-stimulated translocation of GLUT4 in rat adipose cells. |
| 7443 | 15849359 | Importantly, endogenous mPLK/IRAK was activated in response to TNF-alpha or interleukin 1 treatment of primary adipose cells. |
| 7444 | 15849359 | In addition, using a phospho-specific antibody against IRS-1 phosphorylated at Ser(24), we found that interleukin-1 or TNF-alpha treatment of Fao cells stimulated increased phosphorylation of endogenous IRS-1 at Ser(24). |
| 7445 | 15849359 | We conclude that IRS-1 is a novel physiological substrate for mPLK. |
| 7446 | 15849359 | TNF-alpha-regulated phosphorylation at Ser(24) in the pleckstrin homology domain of IRS-1 by mPLK/IRAK represents an additional mechanism for cross-talk between inflammatory signaling and insulin signaling that may contribute to metabolic insulin resistance. |
| 7447 | 15849359 | Phosphorylation of Ser24 in the pleckstrin homology domain of insulin receptor substrate-1 by Mouse Pelle-like kinase/interleukin-1 receptor-associated kinase: cross-talk between inflammatory signaling and insulin signaling that may contribute to insulin resistance. |
| 7448 | 15849359 | Mouse Pelle-like kinase (mPLK, homolog of human IL-1 receptor-associated kinase (IRAK)) participates in inflammatory signaling. |
| 7449 | 15849359 | We evaluated IRS-1 as a novel substrate for mPLK that may contribute to linking inflammation with insulin resistance. |
| 7450 | 15849359 | Wild-type mPLK, but not a kinase-inactive mutant (mPLK-KD), directly phosphorylated full-length IRS-1 in vitro. |
| 7451 | 15849359 | This in vitro phosphorylation was increased when mPLK was immunoprecipitated from tumor necrosis factor (TNF)-alpha-treated cells. |
| 7452 | 15849359 | In NIH-3T3(IR) cells, wild-type mPLK (but not mPLK-KD) co-immunoprecipitated with IRS-1. |
| 7453 | 15849359 | Using mass spectrometry, we identified Ser(24) in the pleckstrin homology (PH) domain of IRS-1 as a specific phosphorylation site for mPLK. |
| 7454 | 15849359 | IRS-1 mutants S24D or S24E (mimicking phosphorylation at Ser(24)) had impaired ability to associate with insulin receptors resulting in diminished tyrosine phosphorylation of IRS-1 and impaired ability of IRS-1 to bind and activate PI-3 kinase in response to insulin. |
| 7455 | 15849359 | IRS-1-S24D also had an impaired ability to mediate insulin-stimulated translocation of GLUT4 in rat adipose cells. |
| 7456 | 15849359 | Importantly, endogenous mPLK/IRAK was activated in response to TNF-alpha or interleukin 1 treatment of primary adipose cells. |
| 7457 | 15849359 | In addition, using a phospho-specific antibody against IRS-1 phosphorylated at Ser(24), we found that interleukin-1 or TNF-alpha treatment of Fao cells stimulated increased phosphorylation of endogenous IRS-1 at Ser(24). |
| 7458 | 15849359 | We conclude that IRS-1 is a novel physiological substrate for mPLK. |
| 7459 | 15849359 | TNF-alpha-regulated phosphorylation at Ser(24) in the pleckstrin homology domain of IRS-1 by mPLK/IRAK represents an additional mechanism for cross-talk between inflammatory signaling and insulin signaling that may contribute to metabolic insulin resistance. |
| 7460 | 15849359 | Phosphorylation of Ser24 in the pleckstrin homology domain of insulin receptor substrate-1 by Mouse Pelle-like kinase/interleukin-1 receptor-associated kinase: cross-talk between inflammatory signaling and insulin signaling that may contribute to insulin resistance. |
| 7461 | 15849359 | Mouse Pelle-like kinase (mPLK, homolog of human IL-1 receptor-associated kinase (IRAK)) participates in inflammatory signaling. |
| 7462 | 15849359 | We evaluated IRS-1 as a novel substrate for mPLK that may contribute to linking inflammation with insulin resistance. |
| 7463 | 15849359 | Wild-type mPLK, but not a kinase-inactive mutant (mPLK-KD), directly phosphorylated full-length IRS-1 in vitro. |
| 7464 | 15849359 | This in vitro phosphorylation was increased when mPLK was immunoprecipitated from tumor necrosis factor (TNF)-alpha-treated cells. |
| 7465 | 15849359 | In NIH-3T3(IR) cells, wild-type mPLK (but not mPLK-KD) co-immunoprecipitated with IRS-1. |
| 7466 | 15849359 | Using mass spectrometry, we identified Ser(24) in the pleckstrin homology (PH) domain of IRS-1 as a specific phosphorylation site for mPLK. |
| 7467 | 15849359 | IRS-1 mutants S24D or S24E (mimicking phosphorylation at Ser(24)) had impaired ability to associate with insulin receptors resulting in diminished tyrosine phosphorylation of IRS-1 and impaired ability of IRS-1 to bind and activate PI-3 kinase in response to insulin. |
| 7468 | 15849359 | IRS-1-S24D also had an impaired ability to mediate insulin-stimulated translocation of GLUT4 in rat adipose cells. |
| 7469 | 15849359 | Importantly, endogenous mPLK/IRAK was activated in response to TNF-alpha or interleukin 1 treatment of primary adipose cells. |
| 7470 | 15849359 | In addition, using a phospho-specific antibody against IRS-1 phosphorylated at Ser(24), we found that interleukin-1 or TNF-alpha treatment of Fao cells stimulated increased phosphorylation of endogenous IRS-1 at Ser(24). |
| 7471 | 15849359 | We conclude that IRS-1 is a novel physiological substrate for mPLK. |
| 7472 | 15849359 | TNF-alpha-regulated phosphorylation at Ser(24) in the pleckstrin homology domain of IRS-1 by mPLK/IRAK represents an additional mechanism for cross-talk between inflammatory signaling and insulin signaling that may contribute to metabolic insulin resistance. |
| 7473 | 15849359 | Phosphorylation of Ser24 in the pleckstrin homology domain of insulin receptor substrate-1 by Mouse Pelle-like kinase/interleukin-1 receptor-associated kinase: cross-talk between inflammatory signaling and insulin signaling that may contribute to insulin resistance. |
| 7474 | 15849359 | Mouse Pelle-like kinase (mPLK, homolog of human IL-1 receptor-associated kinase (IRAK)) participates in inflammatory signaling. |
| 7475 | 15849359 | We evaluated IRS-1 as a novel substrate for mPLK that may contribute to linking inflammation with insulin resistance. |
| 7476 | 15849359 | Wild-type mPLK, but not a kinase-inactive mutant (mPLK-KD), directly phosphorylated full-length IRS-1 in vitro. |
| 7477 | 15849359 | This in vitro phosphorylation was increased when mPLK was immunoprecipitated from tumor necrosis factor (TNF)-alpha-treated cells. |
| 7478 | 15849359 | In NIH-3T3(IR) cells, wild-type mPLK (but not mPLK-KD) co-immunoprecipitated with IRS-1. |
| 7479 | 15849359 | Using mass spectrometry, we identified Ser(24) in the pleckstrin homology (PH) domain of IRS-1 as a specific phosphorylation site for mPLK. |
| 7480 | 15849359 | IRS-1 mutants S24D or S24E (mimicking phosphorylation at Ser(24)) had impaired ability to associate with insulin receptors resulting in diminished tyrosine phosphorylation of IRS-1 and impaired ability of IRS-1 to bind and activate PI-3 kinase in response to insulin. |
| 7481 | 15849359 | IRS-1-S24D also had an impaired ability to mediate insulin-stimulated translocation of GLUT4 in rat adipose cells. |
| 7482 | 15849359 | Importantly, endogenous mPLK/IRAK was activated in response to TNF-alpha or interleukin 1 treatment of primary adipose cells. |
| 7483 | 15849359 | In addition, using a phospho-specific antibody against IRS-1 phosphorylated at Ser(24), we found that interleukin-1 or TNF-alpha treatment of Fao cells stimulated increased phosphorylation of endogenous IRS-1 at Ser(24). |
| 7484 | 15849359 | We conclude that IRS-1 is a novel physiological substrate for mPLK. |
| 7485 | 15849359 | TNF-alpha-regulated phosphorylation at Ser(24) in the pleckstrin homology domain of IRS-1 by mPLK/IRAK represents an additional mechanism for cross-talk between inflammatory signaling and insulin signaling that may contribute to metabolic insulin resistance. |
| 7486 | 15855318 | A role for iNOS in fasting hyperglycemia and impaired insulin signaling in the liver of obese diabetic mice. |
| 7487 | 15855318 | Inducible nitric oxide synthase (iNOS) has been implicated in many human diseases associated with inflammation. iNOS deficiency was shown to prevent high-fat diet-induced insulin resistance in skeletal muscle but not in the liver. |
| 7488 | 15855318 | A role for iNOS in fasting hyperglycemia and hepatic insulin resistance, however, remains to be investigated in obesity-related diabetes. |
| 7489 | 15855318 | Treatment with iNOS inhibitor reversed fasting hyperglycemia with concomitant amelioration of hyperinsulinemia and improved insulin sensitivity in ob/ob mice. iNOS inhibitor also increased the protein expression of insulin receptor substrate (IRS)-1 and -2 1.5- and 2-fold, respectively, and enhanced IRS-1- and IRS-2-mediated insulin signaling in the liver of ob/ob mice. |
| 7490 | 15855318 | Exposure to NO donor and ectopically expressed iNOS decreased the protein expression of IRS-1 and -2 in cultured hepatocytes. |
| 7491 | 15855318 | These results suggest that iNOS plays a role in fasting hyperglycemia and contributes to hepatic insulin resistance in ob/ob mice. |
| 7492 | 15855334 | Insulin increased insulin receptor substrate 1 (IRS-1) tyrosine phosphorylation, IRS-1-associated phosphatidylinositol (PI) 3-kinase activity, and phosphorylation of Akt Ser473 and AS160, a newly described Akt substrate that plays a role in GLUT4 exocytosis, approximately 2.3 fold before treatment. |
| 7493 | 15855334 | In conclusion, the insulin-sensitizing effects of rosiglitazone are independent of enhanced signaling of IRS-1/PI 3-kinase/Akt/AS160 in patients with newly diagnosed type 2 diabetes. |
| 7494 | 15855334 | Insulin increased insulin receptor substrate 1 (IRS-1) tyrosine phosphorylation, IRS-1-associated phosphatidylinositol (PI) 3-kinase activity, and phosphorylation of Akt Ser473 and AS160, a newly described Akt substrate that plays a role in GLUT4 exocytosis, approximately 2.3 fold before treatment. |
| 7495 | 15855334 | In conclusion, the insulin-sensitizing effects of rosiglitazone are independent of enhanced signaling of IRS-1/PI 3-kinase/Akt/AS160 in patients with newly diagnosed type 2 diabetes. |
| 7496 | 15889998 | Insulin signal transduction in adipocytes is accompanied by a burst of cellular hydrogen peroxide (H(2)O(2)) that facilitates insulin signaling by inhibiting thiol-dependent protein-tyrosine phosphatases (PTPs) that are negative regulators of insulin action. |
| 7497 | 15889998 | Basal endogenous total PTP activity and the activity of PTP1B, a PTP implicated in the negative regulation of insulin signaling, were reduced in high glucose conditions, and their further reduction by insulin stimulation was more enhanced in high versus low glucose medium. |
| 7498 | 15889998 | Phosphorylation of the insulin receptor, IRS-1, and Akt in response to insulin was also significantly enhanced in high glucose conditions, especially at submaximal insulin concentrations. |
| 7499 | 15889998 | In primary rat adipocytes, high glucose increased insulin-stimulated H(2)O(2) production and potentiated the oxidative inhibition of total PTP and PTP1B activity; however, insulin signaling was not enhanced in the primary cells in high glucose apparently due to cross-regulation of insulin-stimulated protein phosphorylation by activation of protein kinase C (PKC). |
| 7500 | 15889998 | These studies indicate that high glucose can enhance insulin stimulated H(2)O(2) generation and augment oxidative PTP inhibition in cultured and primary adipocytes, but the overall balance of insulin signal transduction is determined by additional signal effects in high glucose, including the activation of PKC. |
| 7501 | 15919784 | At the lowest lipid infusion rate (30 ml/h), insulin receptor and insulin receptor substrate (IRS)-1 tyrosine phosphorylation, phosphatidylinositol (PI) 3-kinase activity associated with IRS-1, and Akt serine phosphorylation were all significantly impaired (P < 0.05-0.01). |
| 7502 | 15919784 | PI 3-kinase activity associated with IRS-1 correlated with insulin-stimulated glucose disposal (r = 0.45, P < 0.01) and inversely with both the plasma FFA concentration after 4 h of lipid infusion (r = -0.39, P = 0.01) and during the last 30 min of the insulin clamp (r = -0.43, P < 0.01). |
| 7503 | 15919784 | At the lowest lipid infusion rate (30 ml/h), insulin receptor and insulin receptor substrate (IRS)-1 tyrosine phosphorylation, phosphatidylinositol (PI) 3-kinase activity associated with IRS-1, and Akt serine phosphorylation were all significantly impaired (P < 0.05-0.01). |
| 7504 | 15919784 | PI 3-kinase activity associated with IRS-1 correlated with insulin-stimulated glucose disposal (r = 0.45, P < 0.01) and inversely with both the plasma FFA concentration after 4 h of lipid infusion (r = -0.39, P = 0.01) and during the last 30 min of the insulin clamp (r = -0.43, P < 0.01). |
| 7505 | 15919788 | Inhibition of microsomal triglyceride transfer protein expression and apolipoprotein B100 secretion by the citrus flavonoid naringenin and by insulin involves activation of the mitogen-activated protein kinase pathway in hepatocytes. |
| 7506 | 15919788 | Microsomal triglyceride transfer protein (MTP) is necessary for hepatocyte assembly and secretion of apolipoprotein (apo)B100-containing lipoproteins. |
| 7507 | 15919788 | The citrus flavonoid naringenin, like insulin, decreased MTP expression in HepG2 cells, resulting in inhibition of apoB100 secretion; however, the mechanism for naringenin is independent of insulin receptor substrate-1/2. |
| 7508 | 15919788 | Recently, it was reported that insulin decreased MTP expression in HepG2 cells via the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) (MAPK(erk)) pathway. |
| 7509 | 15919788 | Inhibition of MAPK kinase (MEK) 1/2 in HepG2 cells significantly attenuated the naringenin- and insulin-induced reduction in MTP expression. |
| 7510 | 15919788 | Both naringenin and insulin increased ERK1/2 phosphorylation, which was completely inhibited by MEK1/2 inhibition and enhanced by inhibition of MAPK(p38), a negative regulator of MAPK(erk) activity. |
| 7511 | 15919788 | Inhibition of MEK1/2 significantly attenuated both the naringenin- and insulin-induced decrease in apoB100 secretion demonstrating a direct link between MAPK(erk) activation and apoB100 secretion. |
| 7512 | 15919788 | Furthermore, both compounds increased MAPK(p38) activation, and therefore inhibition of MAPK(p38) amplified thenaringenin- and insulin-induced decrease in apoB100 secretion. |
| 7513 | 15919788 | We conclude that MAPK(erk) signaling in hepatocytes is critical for inhibition of apoB100 secretion by naringenin and insulin. |
| 7514 | 15924436 | The level of insulin receptor phosphorylation in cells can be increased by inhibition of the opposing protein tyrosine phosphatase (PTP1B), a target for drug development. |
| 7515 | 15924436 | However, chromium did not inhibit recombinant human PTP1B using either p-nitrophenyl phosphate or the tyrosine-phosphorylated insulin receptor as the substrate. |
| 7516 | 15924436 | Purified plasma membranes exhibited insulin-dependent kinase activity in assays using substrate peptides mimicking sites of Tyr phosphorylation in the endogenous substrate IRS-1. |
| 7517 | 15929863 | Fatty acids appear to cause this defect in glucose transport by inhibiting insulin-stimulated tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and IRS-1-associated phosphatidylinositol 3-kinase activity. |
| 7518 | 15950750 | Early signaling interactions between the insulin and leptin pathways in bovine myogenic cells. |
| 7519 | 15950750 | One function of insulin is to signal high extracellular glucose, while leptin may signal the abundance of extracellular lipid, both energy sources being readily utilized by muscle. |
| 7520 | 15950750 | The present study reports early signaling events in the insulin and leptin cascades in primary bovine myogenic cells (BMC). |
| 7521 | 15950750 | BMC were treated with insulin, or leptin for 1, 10, 30 and 120 min, or pretreated with leptin for 10 min followed by insulin for 1, 10, 30 and 120 min. |
| 7522 | 15950750 | BMC were insulin resistant, showing a significant inhibition of IRS-1 association with the insulin receptor (IR) following insulin stimulation, a corresponding increase in PI 3-kinase association with the IR, and a slow and modest increase in GLUT4 recruitment to the plasma membrane. |
| 7523 | 15950750 | Pretreatment of BMC for 10 min leptin, followed by insulin time-course, caused IRS-1 recruitment to be unresponsive, but evoked a rapid, phasic response of PI 3-kinase recruitment to the IR and abrogated the response of GLUT4 translocation to the plasma membrane evoked by insulin alone. |
| 7524 | 15950750 | JAK-2 association with the ObR and JAK-2 tyrosine phosphorylation were responsive to all three treatments. |
| 7525 | 15950750 | Insulin alone down-regulated the leptin signaling pathway, JAK-2 association with ObR decreased at all time-points, and JAK-2 phosphorylation decreased similarly. |
| 7526 | 15950750 | Leptin alone also appeared to down-regulate JAK-2 association with the ObR, but stimulated the down-regulated pathway to signal, JAK-2 tyrosine phosphorylation being increased at later time-points. |
| 7527 | 15950750 | Pretreatment with leptin followed by insulin time-course showed marked up-regulation of the early leptin signaling pathway, JAK-2 association with the ObR being increased by insulin while JAK-2 tyrosine phosphorylation was also increased. |
| 7528 | 15950750 | The contrasting responses of BMC to insulin alone, leptin alone and the sequential leptin-insulin treatment may point to the ability of these cells to respond to energy substrate availability, as bovine muscle has evolved to utilize lipids and fatty acids in response to a metabolism which provides only limited glucose. |
| 7529 | 15950750 | This cross-talk between insulin and leptin signaling pathways points to a better understanding of the mechanisms driving energy substrate utilization in ruminant muscle and may provide a useful model for greater understanding of the molecular mechanisms underlying the development of insulin resistance and Type 2 diabetes in man. |
| 7530 | 15950750 | Early signaling interactions between the insulin and leptin pathways in bovine myogenic cells. |
| 7531 | 15950750 | One function of insulin is to signal high extracellular glucose, while leptin may signal the abundance of extracellular lipid, both energy sources being readily utilized by muscle. |
| 7532 | 15950750 | The present study reports early signaling events in the insulin and leptin cascades in primary bovine myogenic cells (BMC). |
| 7533 | 15950750 | BMC were treated with insulin, or leptin for 1, 10, 30 and 120 min, or pretreated with leptin for 10 min followed by insulin for 1, 10, 30 and 120 min. |
| 7534 | 15950750 | BMC were insulin resistant, showing a significant inhibition of IRS-1 association with the insulin receptor (IR) following insulin stimulation, a corresponding increase in PI 3-kinase association with the IR, and a slow and modest increase in GLUT4 recruitment to the plasma membrane. |
| 7535 | 15950750 | Pretreatment of BMC for 10 min leptin, followed by insulin time-course, caused IRS-1 recruitment to be unresponsive, but evoked a rapid, phasic response of PI 3-kinase recruitment to the IR and abrogated the response of GLUT4 translocation to the plasma membrane evoked by insulin alone. |
| 7536 | 15950750 | JAK-2 association with the ObR and JAK-2 tyrosine phosphorylation were responsive to all three treatments. |
| 7537 | 15950750 | Insulin alone down-regulated the leptin signaling pathway, JAK-2 association with ObR decreased at all time-points, and JAK-2 phosphorylation decreased similarly. |
| 7538 | 15950750 | Leptin alone also appeared to down-regulate JAK-2 association with the ObR, but stimulated the down-regulated pathway to signal, JAK-2 tyrosine phosphorylation being increased at later time-points. |
| 7539 | 15950750 | Pretreatment with leptin followed by insulin time-course showed marked up-regulation of the early leptin signaling pathway, JAK-2 association with the ObR being increased by insulin while JAK-2 tyrosine phosphorylation was also increased. |
| 7540 | 15950750 | The contrasting responses of BMC to insulin alone, leptin alone and the sequential leptin-insulin treatment may point to the ability of these cells to respond to energy substrate availability, as bovine muscle has evolved to utilize lipids and fatty acids in response to a metabolism which provides only limited glucose. |
| 7541 | 15950750 | This cross-talk between insulin and leptin signaling pathways points to a better understanding of the mechanisms driving energy substrate utilization in ruminant muscle and may provide a useful model for greater understanding of the molecular mechanisms underlying the development of insulin resistance and Type 2 diabetes in man. |
| 7542 | 15955369 | The majority of proteins associated with MODY are transcription factors, such as hepatocyte nuclear factor 4alpha (HNF-4alpha), HNF-1alpha, insulin promoter factor-1 (IPF-1), HNF-1beta, and NEUROD1. |
| 7543 | 15955369 | In addition, some evidence exists that genes, such as adiponectin, IRS-1, and some others may also influence the susceptibility to T2DM. |
| 7544 | 15978611 | Activation of IKKbeta by glucose is necessary and sufficient to impair insulin signaling and nitric oxide production in endothelial cells. |
| 7545 | 15978611 | In skeletal muscle, diabetes induces activation of inhibitor kappaB kinase (IKKbeta), a key cellular mediator of the response to inflammatory stimuli, and this impairs insulin signal transduction via the insulin receptor substrate-phosphatidylinositol 3-OH kinase (IRS-1/PI3-kinase) pathway. |
| 7546 | 15978611 | Since activation of endothelial nitric oxide synthase (eNOS) is dependent on IRS-1/PI3-kinase signaling, we hypothesized that activation of IKKbeta may contribute to the effect of glucose to impair NO production. |
| 7547 | 15978611 | Here, we show that exposure of bovine aortic endothelial cells to high glucose (25 mM) for 24 h impaired insulin-mediated tyrosine phosphorylation of IRS-1, serine phosphorylation of Akt, activation of eNOS, and production of NO. |
| 7548 | 15978611 | High glucose treatment also activated IKKbeta, and pretreatment with aspirin, a pharmacological inhibitor of IKKbeta, prevented both glucose-induced IKKbeta activation and the effect of high glucose to impair insulin-mediated NO production. |
| 7549 | 15978611 | Conversely, overexpression of wild-type IKKbeta recapitulated the deleterious effect of high glucose on insulin-mediated activation of eNOS. |
| 7550 | 15978611 | Activation of IKKbeta by glucose is necessary and sufficient to impair insulin signaling and nitric oxide production in endothelial cells. |
| 7551 | 15978611 | In skeletal muscle, diabetes induces activation of inhibitor kappaB kinase (IKKbeta), a key cellular mediator of the response to inflammatory stimuli, and this impairs insulin signal transduction via the insulin receptor substrate-phosphatidylinositol 3-OH kinase (IRS-1/PI3-kinase) pathway. |
| 7552 | 15978611 | Since activation of endothelial nitric oxide synthase (eNOS) is dependent on IRS-1/PI3-kinase signaling, we hypothesized that activation of IKKbeta may contribute to the effect of glucose to impair NO production. |
| 7553 | 15978611 | Here, we show that exposure of bovine aortic endothelial cells to high glucose (25 mM) for 24 h impaired insulin-mediated tyrosine phosphorylation of IRS-1, serine phosphorylation of Akt, activation of eNOS, and production of NO. |
| 7554 | 15978611 | High glucose treatment also activated IKKbeta, and pretreatment with aspirin, a pharmacological inhibitor of IKKbeta, prevented both glucose-induced IKKbeta activation and the effect of high glucose to impair insulin-mediated NO production. |
| 7555 | 15978611 | Conversely, overexpression of wild-type IKKbeta recapitulated the deleterious effect of high glucose on insulin-mediated activation of eNOS. |
| 7556 | 15978611 | Activation of IKKbeta by glucose is necessary and sufficient to impair insulin signaling and nitric oxide production in endothelial cells. |
| 7557 | 15978611 | In skeletal muscle, diabetes induces activation of inhibitor kappaB kinase (IKKbeta), a key cellular mediator of the response to inflammatory stimuli, and this impairs insulin signal transduction via the insulin receptor substrate-phosphatidylinositol 3-OH kinase (IRS-1/PI3-kinase) pathway. |
| 7558 | 15978611 | Since activation of endothelial nitric oxide synthase (eNOS) is dependent on IRS-1/PI3-kinase signaling, we hypothesized that activation of IKKbeta may contribute to the effect of glucose to impair NO production. |
| 7559 | 15978611 | Here, we show that exposure of bovine aortic endothelial cells to high glucose (25 mM) for 24 h impaired insulin-mediated tyrosine phosphorylation of IRS-1, serine phosphorylation of Akt, activation of eNOS, and production of NO. |
| 7560 | 15978611 | High glucose treatment also activated IKKbeta, and pretreatment with aspirin, a pharmacological inhibitor of IKKbeta, prevented both glucose-induced IKKbeta activation and the effect of high glucose to impair insulin-mediated NO production. |
| 7561 | 15978611 | Conversely, overexpression of wild-type IKKbeta recapitulated the deleterious effect of high glucose on insulin-mediated activation of eNOS. |
| 7562 | 15980869 | These effects of FSE on GLUT4 translocation and glucose uptake were inhibited by wortmannin, a phosphatidylinositol 3-kinase (PI3-K) inhibitor, and bisindolylmaleimide 1, a protein kinase C (PKC)-specific inhibitor. |
| 7563 | 15980869 | In vitro phosphorylation analysis revealed that, like insulin, FSE also induces tyrosine phosphorylation of a number of proteins including the insulin receptor, insulin receptor substrate 1 and p85 subunit of PI3-K, in both 3T3-L1 adipocytes and human hepatoma cells, HepG2. |
| 7564 | 15980869 | However, unlike insulin, FSE had no effect on protein kinase B (Akt) activation. |
| 7565 | 15997237 | Protein tyrosine phosphatase 1B (PTP1B) acts as a physiological negative regulator of insulin signaling by dephosphorylating the activated insulin receptor (IR). |
| 7566 | 15997237 | Here we examine the role of PTP1B in the insulin-sensitizing action of rosiglitazone (RSG) in skeletal muscle and liver. |
| 7567 | 15997237 | Diabetic rats showed significantly increased levels and activities of PTP1B in the skeletal muscle (1.6- and 2-fold, respectively) and liver (1.7- and 1.8-fold, respectively), thus diminishing insulin signaling in the target tissues. |
| 7568 | 15997237 | We found that the decreases in insulin-stimulated glucose uptake (55%), tyrosine phosphorylation of IRbeta-subunits (48%), and IR substrate-1 (IRS-1) (39%) in muscles of diabetic rats were normalized after RSG treatment. |
| 7569 | 15997237 | In contrast, RSG did not affect the increased PTP1B levels and activities or the already reduced insulin-stimulated glycogen synthesis and tyrosine phosphorylation of IRbeta-subunits and IRS-2 in livers of diabetic rats. |
| 7570 | 15997237 | RSG treatment in normal rats did not significantly change PTP1B activities and levels or protein levels of IRbeta, IRS-1, and -2 in diabetic rats. |
| 7571 | 15997237 | These data suggest that RSG enhances insulin activity in skeletal muscle of diabetic rats possibly by ameliorating abnormal levels and activities of PTP1B. |
| 7572 | 15997237 | Protein tyrosine phosphatase 1B (PTP1B) acts as a physiological negative regulator of insulin signaling by dephosphorylating the activated insulin receptor (IR). |
| 7573 | 15997237 | Here we examine the role of PTP1B in the insulin-sensitizing action of rosiglitazone (RSG) in skeletal muscle and liver. |
| 7574 | 15997237 | Diabetic rats showed significantly increased levels and activities of PTP1B in the skeletal muscle (1.6- and 2-fold, respectively) and liver (1.7- and 1.8-fold, respectively), thus diminishing insulin signaling in the target tissues. |
| 7575 | 15997237 | We found that the decreases in insulin-stimulated glucose uptake (55%), tyrosine phosphorylation of IRbeta-subunits (48%), and IR substrate-1 (IRS-1) (39%) in muscles of diabetic rats were normalized after RSG treatment. |
| 7576 | 15997237 | In contrast, RSG did not affect the increased PTP1B levels and activities or the already reduced insulin-stimulated glycogen synthesis and tyrosine phosphorylation of IRbeta-subunits and IRS-2 in livers of diabetic rats. |
| 7577 | 15997237 | RSG treatment in normal rats did not significantly change PTP1B activities and levels or protein levels of IRbeta, IRS-1, and -2 in diabetic rats. |
| 7578 | 15997237 | These data suggest that RSG enhances insulin activity in skeletal muscle of diabetic rats possibly by ameliorating abnormal levels and activities of PTP1B. |
| 7579 | 15998259 | An increased concentration of reactive molecules triggers the activation of serine/threonine kinase cascades such as c-Jun N-terminal kinase, nuclear factor-kappaB, and others that in turn phosphorylate multiple targets, including the insulin receptor and the insulin receptor substrate (IRS) proteins. |
| 7580 | 15998259 | Increased serine phosphorylation of IRS reduces its ability to undergo tyrosine phosphorylation and may accelerate the degradation of IRS-1, offering an attractive explanation for the molecular basis of oxidative stress-induced insulin resistance. |
| 7581 | 15998260 | Recently, we reported that lysophosphatidylcholine, a major bioactive product of oxidized low-density lipoprotein, and angiotensin II, a vasoactive hormone and a potent inducer of reactive oxygen species (ROS), negatively regulate insulin signaling in vascular smooth muscle cells (VSMCs). |
| 7582 | 15998260 | Other data suggest that angiotensin II inhibits the vasodilator effects of insulin through insulin receptor substrate-1 phosphorylation at Ser312 and Ser616. |
| 7583 | 16036906 | One mechanism is insulin-activated signaling through insulin receptor substrate-1 and phosphatidylinositol 3-kinase. |
| 7584 | 16036906 | However, more recent studies in transgenic and knockout animals show that AMP-activated protein kinase is not the sole mediator of the signal to GLUT4 translocation and suggest that there may be redundant signaling pathways leading to contraction-stimulated glucose transport. |
| 7585 | 16046301 | Increased p85/55/50 expression and decreased phosphotidylinositol 3-kinase activity in insulin-resistant human skeletal muscle. |
| 7586 | 16046301 | We found a highly significant inverse correlation between in vivo insulin sensitivity (as measured by the glucose infusion rate) and increased protein expression of p85/55/50, protein kinase C (PKC)-theta activity, levels of pSer307 insulin receptor substrate (IRS)-1 and p-Jun NH2-terminal kinase (JNK)-1, and myosin heavy chain IIx fibers. |
| 7587 | 16046301 | Increased basal phosphorylation of Ser307 IRS-1 in the obese and type 2 diabetic subjects corresponds with decrease in insulin-stimulated IRS-1 tyrosine phosphorylation, PI 3-kinase activity, and insulin-induced activation of Akt and, more prominently, PKC-zeta/lambda. |
| 7588 | 16046301 | In summary, increased expression of the PI 3-kinase adaptor subunits p85/55/50, as well as increased activity of the proinflammatory kinases JNK-1, PKC-theta, and, to a lesser extent, inhibitor of kappaB kinase-beta, are associated with increased basal Ser307 IRS-1 phosphorylation and decreased PI 3-kinase activity and may follow a common pathway to attenuate in vivo insulin sensitivity in insulin-resistant subjects. |
| 7589 | 16046301 | Increased p85/55/50 expression and decreased phosphotidylinositol 3-kinase activity in insulin-resistant human skeletal muscle. |
| 7590 | 16046301 | We found a highly significant inverse correlation between in vivo insulin sensitivity (as measured by the glucose infusion rate) and increased protein expression of p85/55/50, protein kinase C (PKC)-theta activity, levels of pSer307 insulin receptor substrate (IRS)-1 and p-Jun NH2-terminal kinase (JNK)-1, and myosin heavy chain IIx fibers. |
| 7591 | 16046301 | Increased basal phosphorylation of Ser307 IRS-1 in the obese and type 2 diabetic subjects corresponds with decrease in insulin-stimulated IRS-1 tyrosine phosphorylation, PI 3-kinase activity, and insulin-induced activation of Akt and, more prominently, PKC-zeta/lambda. |
| 7592 | 16046301 | In summary, increased expression of the PI 3-kinase adaptor subunits p85/55/50, as well as increased activity of the proinflammatory kinases JNK-1, PKC-theta, and, to a lesser extent, inhibitor of kappaB kinase-beta, are associated with increased basal Ser307 IRS-1 phosphorylation and decreased PI 3-kinase activity and may follow a common pathway to attenuate in vivo insulin sensitivity in insulin-resistant subjects. |
| 7593 | 16055077 | Since inorganic vanadium compounds have been found to activate several key components of the insulin signaling cascade, such as protein kinase B (PKB), the objective of the present study was to investigate if stimulation of PKB and its downstream target glycogen synthase kinase-3 (GSK-3), are responsible for the more potent insulinomimetic effects of OVC. |
| 7594 | 16055077 | Among several vanadium compounds tested, vanadium (IV) oxo bis (acetylacetonate) and vanadium (IV) oxo bis(maltolato) markedly induced the phosphorylation of PKB as well as GSK-3beta compared to vanadyl sulfate (VS), an inorganic vanadium salts in Chinese hamster ovary cells overexpressing the insulin receptor (IR). |
| 7595 | 16055077 | In addition, greater IRS-1/p85alpha interaction was elicited by the OVC than by VS. |
| 7596 | 16055077 | These data indicate that the higher PTPase inhibitory potential of OVC translates into greater phosphorylation of PKB and GSK-3beta, which, in turn, may contribute to a more potent effect of OVC on glucose homeostasis. |
| 7597 | 16084832 | Upon activation by phytohemagglutine (PHA), T-lymphocytes (T-cells) express receptors for growth factors, insulin, IGF-1 and IL2 and become insulin sensitive. |
| 7598 | 16084832 | The activation was also associated with incremental changes in GLUT 4, IRS-1, proinflammatory cytokines, and oxidative stress components. |
| 7599 | 16098829 | Accumulating evidence indicates an important role for serine phosphorylation of IRS-1 in the regulation of insulin action. |
| 7600 | 16098829 | Recent studies suggest that Rho-kinase (ROK) is a mediator of insulin signaling, via interaction with IRS-1. |
| 7601 | 16098829 | Inactivation of ROK also reduces insulin-stimulated IRS-1 tyrosine phosphorylation and PI3K activity. |
| 7602 | 16098829 | Mass spectrometry analysis identifies IRS-1 Ser632/635 as substrates of ROK in vitro, and mutation of these sites inhibits insulin signaling. |
| 7603 | 16098829 | Accumulating evidence indicates an important role for serine phosphorylation of IRS-1 in the regulation of insulin action. |
| 7604 | 16098829 | Recent studies suggest that Rho-kinase (ROK) is a mediator of insulin signaling, via interaction with IRS-1. |
| 7605 | 16098829 | Inactivation of ROK also reduces insulin-stimulated IRS-1 tyrosine phosphorylation and PI3K activity. |
| 7606 | 16098829 | Mass spectrometry analysis identifies IRS-1 Ser632/635 as substrates of ROK in vitro, and mutation of these sites inhibits insulin signaling. |
| 7607 | 16098829 | Accumulating evidence indicates an important role for serine phosphorylation of IRS-1 in the regulation of insulin action. |
| 7608 | 16098829 | Recent studies suggest that Rho-kinase (ROK) is a mediator of insulin signaling, via interaction with IRS-1. |
| 7609 | 16098829 | Inactivation of ROK also reduces insulin-stimulated IRS-1 tyrosine phosphorylation and PI3K activity. |
| 7610 | 16098829 | Mass spectrometry analysis identifies IRS-1 Ser632/635 as substrates of ROK in vitro, and mutation of these sites inhibits insulin signaling. |
| 7611 | 16098829 | Accumulating evidence indicates an important role for serine phosphorylation of IRS-1 in the regulation of insulin action. |
| 7612 | 16098829 | Recent studies suggest that Rho-kinase (ROK) is a mediator of insulin signaling, via interaction with IRS-1. |
| 7613 | 16098829 | Inactivation of ROK also reduces insulin-stimulated IRS-1 tyrosine phosphorylation and PI3K activity. |
| 7614 | 16098829 | Mass spectrometry analysis identifies IRS-1 Ser632/635 as substrates of ROK in vitro, and mutation of these sites inhibits insulin signaling. |
| 7615 | 16105663 | Gastric inhibitory polypeptide modulates adiposity and fat oxidation under diminished insulin action. |
| 7616 | 16105663 | Gut hormone gastric inhibitory polypeptide (GIP) stimulates insulin secretion from pancreatic beta-cells upon ingestion of nutrients. |
| 7617 | 16105663 | Inhibition of GIP signaling prevents the onset of obesity and consequent insulin resistance induced by high-fat diet. |
| 7618 | 16105663 | In this study, we investigated the role of GIP in accumulation of triglycerides into adipocytes and in fat oxidation peripherally using insulin receptor substrate (IRS)-1-deficient mice and revealed that IRS-1(-/-)GIPR(-/-) mice exhibited both reduced adiposity and ameliorated insulin resistance. |
| 7619 | 16105663 | Furthermore, increased gene expression of CD36 and UCP2 in liver, and increased expression and enzyme activity of 3-hydroxyacyl-CoA dehydrogenase in skeletal muscle of IRS-1(-/-)GIPR(-/-) mice might contribute to the lower respiratory quotient and the higher fat oxidation in light phase. |
| 7620 | 16105663 | These results suggest that GIP plays a crucial role in switching from fat oxidation to fat accumulation under the diminished insulin action as a potential target for secondary prevention of insulin resistance. |
| 7621 | 16105663 | Gastric inhibitory polypeptide modulates adiposity and fat oxidation under diminished insulin action. |
| 7622 | 16105663 | Gut hormone gastric inhibitory polypeptide (GIP) stimulates insulin secretion from pancreatic beta-cells upon ingestion of nutrients. |
| 7623 | 16105663 | Inhibition of GIP signaling prevents the onset of obesity and consequent insulin resistance induced by high-fat diet. |
| 7624 | 16105663 | In this study, we investigated the role of GIP in accumulation of triglycerides into adipocytes and in fat oxidation peripherally using insulin receptor substrate (IRS)-1-deficient mice and revealed that IRS-1(-/-)GIPR(-/-) mice exhibited both reduced adiposity and ameliorated insulin resistance. |
| 7625 | 16105663 | Furthermore, increased gene expression of CD36 and UCP2 in liver, and increased expression and enzyme activity of 3-hydroxyacyl-CoA dehydrogenase in skeletal muscle of IRS-1(-/-)GIPR(-/-) mice might contribute to the lower respiratory quotient and the higher fat oxidation in light phase. |
| 7626 | 16105663 | These results suggest that GIP plays a crucial role in switching from fat oxidation to fat accumulation under the diminished insulin action as a potential target for secondary prevention of insulin resistance. |
| 7627 | 16123357 | Somatostatin-insulin-glucose clamps created conditions of low peripheral hyperinsulinemia ( approximately 100 pmol/l, 0-180 min) and prandial-like peripheral hyperinsulinemia ( approximately 430 pmol/l, 180-360 min). |
| 7628 | 16123357 | Furthermore, amino acid infusion increased the inhibitory insulin receptor substrate-1 phosphorylation at Ser312 and Ser636/639 and decreased insulin-induced phosphoinositide 3-kinase activity. |
| 7629 | 16123357 | However, plasma amino acid elevation failed to reduce insulin-induced Akt/protein kinase B and glycogen synthase kinase 3alpha phosphorylation. |
| 7630 | 16127460 | Additionally, SOCS7 associated with the INSR and IRS1--molecules that are essential for normal regulation of insulin action. |
| 7631 | 16128672 | Conversely, increased serine/threonine phosphorylation of IRS1 following prolonged insulin exposure (or in obesity) reduces signalling capacity, partly by stimulating IRS1 degradation. |
| 7632 | 16128672 | Similarly, transient induction of IRS1 (3-fold) in the liver or muscle of rodents occurs following feeding or insulin injection respectively. |
| 7633 | 16128672 | Elucidation of the mechanism by which insulin promotes IRS1 stability will permit characterization of the importance of this novel signalling event in insulin regulation of liver and muscle function. |
| 7634 | 16128672 | Impairment of this process would reduce IRS1 signalling capacity, thereby contributing to the development of hyperinsulinaemia/insulin resistance prior to the appearance of T2DM. |
| 7635 | 16128672 | Conversely, increased serine/threonine phosphorylation of IRS1 following prolonged insulin exposure (or in obesity) reduces signalling capacity, partly by stimulating IRS1 degradation. |
| 7636 | 16128672 | Similarly, transient induction of IRS1 (3-fold) in the liver or muscle of rodents occurs following feeding or insulin injection respectively. |
| 7637 | 16128672 | Elucidation of the mechanism by which insulin promotes IRS1 stability will permit characterization of the importance of this novel signalling event in insulin regulation of liver and muscle function. |
| 7638 | 16128672 | Impairment of this process would reduce IRS1 signalling capacity, thereby contributing to the development of hyperinsulinaemia/insulin resistance prior to the appearance of T2DM. |
| 7639 | 16128672 | Conversely, increased serine/threonine phosphorylation of IRS1 following prolonged insulin exposure (or in obesity) reduces signalling capacity, partly by stimulating IRS1 degradation. |
| 7640 | 16128672 | Similarly, transient induction of IRS1 (3-fold) in the liver or muscle of rodents occurs following feeding or insulin injection respectively. |
| 7641 | 16128672 | Elucidation of the mechanism by which insulin promotes IRS1 stability will permit characterization of the importance of this novel signalling event in insulin regulation of liver and muscle function. |
| 7642 | 16128672 | Impairment of this process would reduce IRS1 signalling capacity, thereby contributing to the development of hyperinsulinaemia/insulin resistance prior to the appearance of T2DM. |
| 7643 | 16128672 | Conversely, increased serine/threonine phosphorylation of IRS1 following prolonged insulin exposure (or in obesity) reduces signalling capacity, partly by stimulating IRS1 degradation. |
| 7644 | 16128672 | Similarly, transient induction of IRS1 (3-fold) in the liver or muscle of rodents occurs following feeding or insulin injection respectively. |
| 7645 | 16128672 | Elucidation of the mechanism by which insulin promotes IRS1 stability will permit characterization of the importance of this novel signalling event in insulin regulation of liver and muscle function. |
| 7646 | 16128672 | Impairment of this process would reduce IRS1 signalling capacity, thereby contributing to the development of hyperinsulinaemia/insulin resistance prior to the appearance of T2DM. |
| 7647 | 16129690 | Attenuation of insulin-stimulated insulin receptor substrate-1 serine 307 phosphorylation in insulin resistance of type 2 diabetes. |
| 7648 | 16129690 | We found that insulin-stimulated phosphorylation of serine 307 (corresponding to serine 302 in the murine sequence) in the immediate downstream mediator protein of the insulin receptor, insulin receptor substrate-1 (IRS1), is required for efficient insulin signaling and that this phosphorylation is attenuated in adipocytes from patients with type 2 diabetes. |
| 7649 | 16129690 | Inhibition of serine 307 phosphorylation by rapamycin mimicked type 2 diabetes and reduced the sensitivity of IRS1 tyrosine phosphorylation in response to insulin, while stimulation of the phosphorylation by okadaic acid, in cells from patients with type 2 diabetes, rescued cells from insulin resistance. |
| 7650 | 16129690 | Attenuation of insulin-stimulated insulin receptor substrate-1 serine 307 phosphorylation in insulin resistance of type 2 diabetes. |
| 7651 | 16129690 | We found that insulin-stimulated phosphorylation of serine 307 (corresponding to serine 302 in the murine sequence) in the immediate downstream mediator protein of the insulin receptor, insulin receptor substrate-1 (IRS1), is required for efficient insulin signaling and that this phosphorylation is attenuated in adipocytes from patients with type 2 diabetes. |
| 7652 | 16129690 | Inhibition of serine 307 phosphorylation by rapamycin mimicked type 2 diabetes and reduced the sensitivity of IRS1 tyrosine phosphorylation in response to insulin, while stimulation of the phosphorylation by okadaic acid, in cells from patients with type 2 diabetes, rescued cells from insulin resistance. |
| 7653 | 16129690 | Attenuation of insulin-stimulated insulin receptor substrate-1 serine 307 phosphorylation in insulin resistance of type 2 diabetes. |
| 7654 | 16129690 | We found that insulin-stimulated phosphorylation of serine 307 (corresponding to serine 302 in the murine sequence) in the immediate downstream mediator protein of the insulin receptor, insulin receptor substrate-1 (IRS1), is required for efficient insulin signaling and that this phosphorylation is attenuated in adipocytes from patients with type 2 diabetes. |
| 7655 | 16129690 | Inhibition of serine 307 phosphorylation by rapamycin mimicked type 2 diabetes and reduced the sensitivity of IRS1 tyrosine phosphorylation in response to insulin, while stimulation of the phosphorylation by okadaic acid, in cells from patients with type 2 diabetes, rescued cells from insulin resistance. |
| 7656 | 16130009 | Within the insulin-signaling cascade IRS-1 tyrosine phosphorylation was induced several fold by insulin and was diminished by preincubation with olanzapine. |
| 7657 | 16130009 | IRS-1-associated PI3K activity was stimulated by insulin three-fold in L6 myotubes. |
| 7658 | 16130009 | Olanzapine inhibited insulin-stimulated IRS-1-associated PI3K activity in a dose-dependent manner. |
| 7659 | 16150913 | Both saturated and n-6 polyunsaturated fat diets reduce phosphorylation of insulin receptor substrate-1 and protein kinase B in muscle during the initial stages of in vivo insulin stimulation. |
| 7660 | 16150913 | Interestingly, phosphorylation of IRS-1 at Tyr895 continued to increase over the 20-min period, and protein kinase B (PKB) phosphorylation at Ser473 reached a plateau by 5 min, demonstrating that different profiles of phosphorylation are involved in transmission of the insulin signal despite a constant level of insulin stimulation. |
| 7661 | 16150913 | In muscle from rats fed high n-6 polyunsaturated or saturated fat diets, however, there was no insulin-stimulated increase in IRS-1 Tyr612 phosphorylation and a temporal difference in PKB Ser473 phosphorylation despite no difference in IR Tyr1162/1163 phosphorylation, IRS-1 Tyr895 phosphorylation, and ERK phosphorylation. |
| 7662 | 16150913 | These results demonstrate that under conditions of increased insulin, similar to those used to assess insulin action in vivo, chronic high-fat feeding impairs insulin signal transduction related to glucose metabolism at the level of IRS-1 Tyr612 and PKB Ser473 and that these effects are independent of the type of fat used in the high-fat diet. |
| 7663 | 16150913 | Both saturated and n-6 polyunsaturated fat diets reduce phosphorylation of insulin receptor substrate-1 and protein kinase B in muscle during the initial stages of in vivo insulin stimulation. |
| 7664 | 16150913 | Interestingly, phosphorylation of IRS-1 at Tyr895 continued to increase over the 20-min period, and protein kinase B (PKB) phosphorylation at Ser473 reached a plateau by 5 min, demonstrating that different profiles of phosphorylation are involved in transmission of the insulin signal despite a constant level of insulin stimulation. |
| 7665 | 16150913 | In muscle from rats fed high n-6 polyunsaturated or saturated fat diets, however, there was no insulin-stimulated increase in IRS-1 Tyr612 phosphorylation and a temporal difference in PKB Ser473 phosphorylation despite no difference in IR Tyr1162/1163 phosphorylation, IRS-1 Tyr895 phosphorylation, and ERK phosphorylation. |
| 7666 | 16150913 | These results demonstrate that under conditions of increased insulin, similar to those used to assess insulin action in vivo, chronic high-fat feeding impairs insulin signal transduction related to glucose metabolism at the level of IRS-1 Tyr612 and PKB Ser473 and that these effects are independent of the type of fat used in the high-fat diet. |
| 7667 | 16150913 | Both saturated and n-6 polyunsaturated fat diets reduce phosphorylation of insulin receptor substrate-1 and protein kinase B in muscle during the initial stages of in vivo insulin stimulation. |
| 7668 | 16150913 | Interestingly, phosphorylation of IRS-1 at Tyr895 continued to increase over the 20-min period, and protein kinase B (PKB) phosphorylation at Ser473 reached a plateau by 5 min, demonstrating that different profiles of phosphorylation are involved in transmission of the insulin signal despite a constant level of insulin stimulation. |
| 7669 | 16150913 | In muscle from rats fed high n-6 polyunsaturated or saturated fat diets, however, there was no insulin-stimulated increase in IRS-1 Tyr612 phosphorylation and a temporal difference in PKB Ser473 phosphorylation despite no difference in IR Tyr1162/1163 phosphorylation, IRS-1 Tyr895 phosphorylation, and ERK phosphorylation. |
| 7670 | 16150913 | These results demonstrate that under conditions of increased insulin, similar to those used to assess insulin action in vivo, chronic high-fat feeding impairs insulin signal transduction related to glucose metabolism at the level of IRS-1 Tyr612 and PKB Ser473 and that these effects are independent of the type of fat used in the high-fat diet. |
| 7671 | 16150913 | Both saturated and n-6 polyunsaturated fat diets reduce phosphorylation of insulin receptor substrate-1 and protein kinase B in muscle during the initial stages of in vivo insulin stimulation. |
| 7672 | 16150913 | Interestingly, phosphorylation of IRS-1 at Tyr895 continued to increase over the 20-min period, and protein kinase B (PKB) phosphorylation at Ser473 reached a plateau by 5 min, demonstrating that different profiles of phosphorylation are involved in transmission of the insulin signal despite a constant level of insulin stimulation. |
| 7673 | 16150913 | In muscle from rats fed high n-6 polyunsaturated or saturated fat diets, however, there was no insulin-stimulated increase in IRS-1 Tyr612 phosphorylation and a temporal difference in PKB Ser473 phosphorylation despite no difference in IR Tyr1162/1163 phosphorylation, IRS-1 Tyr895 phosphorylation, and ERK phosphorylation. |
| 7674 | 16150913 | These results demonstrate that under conditions of increased insulin, similar to those used to assess insulin action in vivo, chronic high-fat feeding impairs insulin signal transduction related to glucose metabolism at the level of IRS-1 Tyr612 and PKB Ser473 and that these effects are independent of the type of fat used in the high-fat diet. |
| 7675 | 16151974 | This was paralleled by robust induction of insulin receptor kinase activity, insulin receptor substrate-1-associated phosphatidylinositol-3 kinase activity, and protein kinase B phosphorylation. |
| 7676 | 16151974 | By contrast, pretreatment with the beta (3)-adrenoceptor agonist inhibited the insulin-induced insulin receptor substrate-1-associated phosphatidylinositol-3 kinase activity by 50 % and protein kinase B phosphorylation by 40 % without affecting insulin receptor kinase activity upstream. |
| 7677 | 16151974 | This was paralleled by robust induction of insulin receptor kinase activity, insulin receptor substrate-1-associated phosphatidylinositol-3 kinase activity, and protein kinase B phosphorylation. |
| 7678 | 16151974 | By contrast, pretreatment with the beta (3)-adrenoceptor agonist inhibited the insulin-induced insulin receptor substrate-1-associated phosphatidylinositol-3 kinase activity by 50 % and protein kinase B phosphorylation by 40 % without affecting insulin receptor kinase activity upstream. |
| 7679 | 16151975 | The metabolisable hexoses D-glucose and D-mannose enhance the expression of IRS-2 but not of IRS-1 in pancreatic beta-cells. |
| 7680 | 16151975 | Several studies have shown that IRS-2, but not IRS-1, is necessary to maintain and sufficient to expand functional beta-cell mass. |
| 7681 | 16151975 | We therefore analyzed the expression of IRS-2 and IRS-1 in beta-cells after culture in the presence of various concentrations of D-glucose and other metabolisable or non-metabolisable hexoses. |
| 7682 | 16151975 | D-glucose-mediated elevation and phosphorylation of IRS-2 were independent of autocrine insulin action although insulin itself could transiently and slightly enhance IRS-2 expression. |
| 7683 | 16151975 | The metabolisable hexoses D-glucose and D-mannose enhance the expression of IRS-2 but not of IRS-1 in pancreatic beta-cells. |
| 7684 | 16151975 | Several studies have shown that IRS-2, but not IRS-1, is necessary to maintain and sufficient to expand functional beta-cell mass. |
| 7685 | 16151975 | We therefore analyzed the expression of IRS-2 and IRS-1 in beta-cells after culture in the presence of various concentrations of D-glucose and other metabolisable or non-metabolisable hexoses. |
| 7686 | 16151975 | D-glucose-mediated elevation and phosphorylation of IRS-2 were independent of autocrine insulin action although insulin itself could transiently and slightly enhance IRS-2 expression. |
| 7687 | 16151975 | The metabolisable hexoses D-glucose and D-mannose enhance the expression of IRS-2 but not of IRS-1 in pancreatic beta-cells. |
| 7688 | 16151975 | Several studies have shown that IRS-2, but not IRS-1, is necessary to maintain and sufficient to expand functional beta-cell mass. |
| 7689 | 16151975 | We therefore analyzed the expression of IRS-2 and IRS-1 in beta-cells after culture in the presence of various concentrations of D-glucose and other metabolisable or non-metabolisable hexoses. |
| 7690 | 16151975 | D-glucose-mediated elevation and phosphorylation of IRS-2 were independent of autocrine insulin action although insulin itself could transiently and slightly enhance IRS-2 expression. |
| 7691 | 16179348 | Agonists for the nuclear receptor peroxisomal proliferator-activated receptor-gamma (PPARgamma) and its heterodimeric partner, retinoid X receptor (RXR), are effective agents for the treatment of type 2 diabetes. |
| 7692 | 16179348 | Troglitazone increased skeletal muscle Irs-1 and phospho-Akt levels following in vivo insulin treatment, whereas AGN194204 increased hepatic Irs-2 and insulin stimulated phospho-Akt in liver. |
| 7693 | 16179348 | Gene profiles of AGN194204-treated mouse liver analyzed by Ingenuity Pathway Analysis identified increases in fatty acid synthetic genes, including Srebp-1 and fatty acid synthase, a pathway previously shown to be induced by RXR agonists. |
| 7694 | 16179348 | A network of down-regulated genes containing Foxa2, Foxa3, and G-protein subunits was identified, and decreases in these mRNA levels were confirmed by quantitative reverse transcription-PCR. |
| 7695 | 16179348 | These studies demonstrate distinct molecular events lead to insulin sensitization by high affinity RXR and PPARgamma agonists. |
| 7696 | 16179727 | Insulin-sensitive protein kinases (atypical protein kinase C and protein kinase B/Akt): actions and defects in obesity and type II diabetes. |
| 7697 | 16179727 | Insulin regulates glucose transport by activating insulin receptor substrate-1 (IRS-1)-dependent phosphatidylinositol 3-kinase (PI3K) which, via increases in PI-3,4,5-triphosphate (PIP(3)), activates atypical protein kinase C (aPKC) and protein kinase B (PKB/Akt). |
| 7698 | 16179727 | Here, we review (i) the evidence that both aPKC and PKB are required for insulin-stimulated glucose transport, (ii) abnormalities in muscle aPKC/PKB activation seen in obesity and diabetes, and (iii) mechanisms for impaired aPKC activation in insulin-resistant conditions. |
| 7699 | 16179727 | In most cases, defective muscle aPKC/PKB activation reflects both impaired activation of IRS-1/PI3K, the upstream activator of aPKC and PKB in muscle and, in the case of aPKC, poor responsiveness to PIP(3), the lipid product of PI3K. |
| 7700 | 16179727 | Differently from muscle, aPKC activation in the liver is dependent on IRS-2/PI3K rather than IRS-1/PI3K and, surprisingly, the activation of IRS-2/PI3K and aPKC is conserved in high-fat feeding, obesity, and diabetes. |
| 7701 | 16179727 | On the other hand, the defective activation of IRS-1/PI3K and PKB, as seen in diabetic liver, undoubtedly and importantly contributes to increases in hepatic glucose output. |
| 7702 | 16179727 | Thus, the divergent activation of aPKC and PKB in the liver may explain why some hepatic actions of insulin (e.g., aPKC-dependent lipid synthesis) are increased while other actions (e.g., PKB-dependent glucose metabolism) are diminished. |
| 7703 | 16179727 | Insulin-sensitive protein kinases (atypical protein kinase C and protein kinase B/Akt): actions and defects in obesity and type II diabetes. |
| 7704 | 16179727 | Insulin regulates glucose transport by activating insulin receptor substrate-1 (IRS-1)-dependent phosphatidylinositol 3-kinase (PI3K) which, via increases in PI-3,4,5-triphosphate (PIP(3)), activates atypical protein kinase C (aPKC) and protein kinase B (PKB/Akt). |
| 7705 | 16179727 | Here, we review (i) the evidence that both aPKC and PKB are required for insulin-stimulated glucose transport, (ii) abnormalities in muscle aPKC/PKB activation seen in obesity and diabetes, and (iii) mechanisms for impaired aPKC activation in insulin-resistant conditions. |
| 7706 | 16179727 | In most cases, defective muscle aPKC/PKB activation reflects both impaired activation of IRS-1/PI3K, the upstream activator of aPKC and PKB in muscle and, in the case of aPKC, poor responsiveness to PIP(3), the lipid product of PI3K. |
| 7707 | 16179727 | Differently from muscle, aPKC activation in the liver is dependent on IRS-2/PI3K rather than IRS-1/PI3K and, surprisingly, the activation of IRS-2/PI3K and aPKC is conserved in high-fat feeding, obesity, and diabetes. |
| 7708 | 16179727 | On the other hand, the defective activation of IRS-1/PI3K and PKB, as seen in diabetic liver, undoubtedly and importantly contributes to increases in hepatic glucose output. |
| 7709 | 16179727 | Thus, the divergent activation of aPKC and PKB in the liver may explain why some hepatic actions of insulin (e.g., aPKC-dependent lipid synthesis) are increased while other actions (e.g., PKB-dependent glucose metabolism) are diminished. |
| 7710 | 16179727 | Insulin-sensitive protein kinases (atypical protein kinase C and protein kinase B/Akt): actions and defects in obesity and type II diabetes. |
| 7711 | 16179727 | Insulin regulates glucose transport by activating insulin receptor substrate-1 (IRS-1)-dependent phosphatidylinositol 3-kinase (PI3K) which, via increases in PI-3,4,5-triphosphate (PIP(3)), activates atypical protein kinase C (aPKC) and protein kinase B (PKB/Akt). |
| 7712 | 16179727 | Here, we review (i) the evidence that both aPKC and PKB are required for insulin-stimulated glucose transport, (ii) abnormalities in muscle aPKC/PKB activation seen in obesity and diabetes, and (iii) mechanisms for impaired aPKC activation in insulin-resistant conditions. |
| 7713 | 16179727 | In most cases, defective muscle aPKC/PKB activation reflects both impaired activation of IRS-1/PI3K, the upstream activator of aPKC and PKB in muscle and, in the case of aPKC, poor responsiveness to PIP(3), the lipid product of PI3K. |
| 7714 | 16179727 | Differently from muscle, aPKC activation in the liver is dependent on IRS-2/PI3K rather than IRS-1/PI3K and, surprisingly, the activation of IRS-2/PI3K and aPKC is conserved in high-fat feeding, obesity, and diabetes. |
| 7715 | 16179727 | On the other hand, the defective activation of IRS-1/PI3K and PKB, as seen in diabetic liver, undoubtedly and importantly contributes to increases in hepatic glucose output. |
| 7716 | 16179727 | Thus, the divergent activation of aPKC and PKB in the liver may explain why some hepatic actions of insulin (e.g., aPKC-dependent lipid synthesis) are increased while other actions (e.g., PKB-dependent glucose metabolism) are diminished. |
| 7717 | 16179727 | Insulin-sensitive protein kinases (atypical protein kinase C and protein kinase B/Akt): actions and defects in obesity and type II diabetes. |
| 7718 | 16179727 | Insulin regulates glucose transport by activating insulin receptor substrate-1 (IRS-1)-dependent phosphatidylinositol 3-kinase (PI3K) which, via increases in PI-3,4,5-triphosphate (PIP(3)), activates atypical protein kinase C (aPKC) and protein kinase B (PKB/Akt). |
| 7719 | 16179727 | Here, we review (i) the evidence that both aPKC and PKB are required for insulin-stimulated glucose transport, (ii) abnormalities in muscle aPKC/PKB activation seen in obesity and diabetes, and (iii) mechanisms for impaired aPKC activation in insulin-resistant conditions. |
| 7720 | 16179727 | In most cases, defective muscle aPKC/PKB activation reflects both impaired activation of IRS-1/PI3K, the upstream activator of aPKC and PKB in muscle and, in the case of aPKC, poor responsiveness to PIP(3), the lipid product of PI3K. |
| 7721 | 16179727 | Differently from muscle, aPKC activation in the liver is dependent on IRS-2/PI3K rather than IRS-1/PI3K and, surprisingly, the activation of IRS-2/PI3K and aPKC is conserved in high-fat feeding, obesity, and diabetes. |
| 7722 | 16179727 | On the other hand, the defective activation of IRS-1/PI3K and PKB, as seen in diabetic liver, undoubtedly and importantly contributes to increases in hepatic glucose output. |
| 7723 | 16179727 | Thus, the divergent activation of aPKC and PKB in the liver may explain why some hepatic actions of insulin (e.g., aPKC-dependent lipid synthesis) are increased while other actions (e.g., PKB-dependent glucose metabolism) are diminished. |
| 7724 | 16186396 | Tumor necrosis factor-alpha induces skeletal muscle insulin resistance in healthy human subjects via inhibition of Akt substrate 160 phosphorylation. |
| 7725 | 16186396 | Excessive tumor necrosis factor-alpha (TNF-alpha) concentrations have been implicated in the development of insulin resistance, but direct evidence in humans is lacking. |
| 7726 | 16186396 | Here, we demonstrate that TNF-alpha infusion in healthy humans induces insulin resistance in skeletal muscle, without effect on endogenous glucose production, as estimated by a combined euglycemic insulin clamp and stable isotope tracer method. |
| 7727 | 16186396 | TNF-alpha directly impairs glucose uptake and metabolism by altering insulin signal transduction. |
| 7728 | 16186396 | TNF-alpha infusion increases phosphorylation of p70 S6 kinase, extracellular signal-regulated kinase-1/2, and c-Jun NH(2)-terminal kinase, concomitant with increased serine and reduced tyrosine phosphorylation of insulin receptor substrate-1. |
| 7729 | 16186396 | These signaling effects are associated with impaired phosphorylation of Akt substrate 160, the most proximal step identified in the canonical insulin signaling cascade regulating GLUT4 translocation and glucose uptake. |
| 7730 | 16186396 | Thus, excessive concentrations of TNF-alpha negatively regulate insulin signaling and whole-body glucose uptake in humans. |
| 7731 | 16198620 | This results in down regulation of insulin receptor substance 1 (IRS-1) signaling by excess free fatty acids. |
| 7732 | 16198620 | In muscle, activated IRS-1 promotes translocation of glucose transporter protein 4 (GLUT4) to cell membrane. |
| 7733 | 16198620 | This results in down regulation of insulin receptor substance 1 (IRS-1) signaling by excess free fatty acids. |
| 7734 | 16198620 | In muscle, activated IRS-1 promotes translocation of glucose transporter protein 4 (GLUT4) to cell membrane. |
| 7735 | 16217126 | It is a direct scavenger of free radicals and has indirect antioxidant effects due to its stimulation of the expression and activity of antioxidative enzymes such as glutathione peroxidase, superoxide dismutase and catalase, and NO synthase, in mammalian cells. |
| 7736 | 16217126 | It was recently reported that melatonin enhanced insulin-receptor kinase and IRS-1 phosphorylation, suggesting the potential existence of signaling pathway cross-talk between melatonin and insulin. |
| 7737 | 16217126 | Because TNF-alpha has been shown to impair insulin action by suppressing insulin receptor-tyrosine kinase activity and its IRS-1 tyrosine phosphorylation in peripheral tissues such as skeletal muscle cells, it was speculated that melatonin might counteract TNF-alpha-associated insulin resistance in type 2 diabetes. |
| 7738 | 16217126 | It is a direct scavenger of free radicals and has indirect antioxidant effects due to its stimulation of the expression and activity of antioxidative enzymes such as glutathione peroxidase, superoxide dismutase and catalase, and NO synthase, in mammalian cells. |
| 7739 | 16217126 | It was recently reported that melatonin enhanced insulin-receptor kinase and IRS-1 phosphorylation, suggesting the potential existence of signaling pathway cross-talk between melatonin and insulin. |
| 7740 | 16217126 | Because TNF-alpha has been shown to impair insulin action by suppressing insulin receptor-tyrosine kinase activity and its IRS-1 tyrosine phosphorylation in peripheral tissues such as skeletal muscle cells, it was speculated that melatonin might counteract TNF-alpha-associated insulin resistance in type 2 diabetes. |
| 7741 | 16225464 | Oxidative stress and inflammation through activtion of IKK-beta could determine insulin resistance impairing IRS-1 ability to activate the metabolic branch of insulin signalling. |
| 7742 | 16227617 | Mice with muscle-specific knockout of the Glut4 glucose transporter (muscle-G4KO) are insulin resistant and mildly diabetic. |
| 7743 | 16227617 | The increased glycogen synthase activity occurs in spite of decreased signaling through the insulin receptor substrate 1 (IRS-1)-phosphoinositide (PI) 3-kinase-Akt pathway and increased glycogen synthase kinase 3beta (GSK3beta) activity in the basal state. |
| 7744 | 16227617 | In addition, the levels of two scaffolding proteins that are glycogen-targeting subunits of protein phosphatase 1 (PP1), the muscle-specific regulatory subunit (RGL) and the protein targeting to glycogen (PTG), are strikingly increased by 3.2- to 4.2-fold in muscle of muscle-G4KO mice compared to wild-type mice. |
| 7745 | 16233930 | Variation of the insulin receptor substrate gene (IRS-1) in African Pygmies and Bantus. |
| 7746 | 16240321 | Endothelin-1 (ET-1) disrupts insulin-regulated glucose transporter GLUT4 trafficking. |
| 7747 | 16240321 | Since the negative consequence of chronic ET-1 exposure appears to be independent of signal disturbance along the insulin receptor substrate-1/phosphatidylinositol (PI) 3-kinase (PI3K)/Akt-2 pathway of insulin action, we tested if ET-1 altered GLUT4 regulation engaged by osmotic shock, a PI3K-independent stimulus that mimics insulin action. |
| 7748 | 16240321 | Regulation of GLUT4 by hyperosmotic stress was impaired by ET-1. |
| 7749 | 16240321 | Because of the mutual disruption of both insulin- and hyperosmolarity-stimulated GLUT4 translocation, we tested whether shared signaling and/or key phosphatidylinositol 4,5-bisphosphate (PIP2)-regulated cytoskeletal events of GLUT4 trafficking were targets of ET-1. |
| 7750 | 16240321 | Both insulin and hyperosmotic stress signaling to Cbl were impaired by ET-1. |
| 7751 | 16240321 | These data show that ET-1-induced PIP2/actin disruption impairs GLUT4 trafficking elicited by insulin and hyperosmolarity. |
| 7752 | 16240321 | In addition to showing for the first time the important role of PIP2-regulated cytoskeletal events in GLUT4 regulation by stimuli other than insulin, these studies reveal a novel function of PIP2/actin structure in signal transduction. |
| 7753 | 16243841 | Resistin-like molecule beta activates MAPKs, suppresses insulin signaling in hepatocytes, and induces diabetes, hyperlipidemia, and fatty liver in transgenic mice on a high fat diet. |
| 7754 | 16243841 | Resistin and resistin-like molecules (RELMs) are a family of proteins reportedly related to insulin resistance and inflammation. |
| 7755 | 16243841 | Because the serum concentration and intestinal expression level of RELMbeta were elevated in insulin-resistant rodent models, in this study we investigated the effect of RELMbeta on insulin signaling and metabolism using transgenic mice and primary cultured hepatocytes. |
| 7756 | 16243841 | In addition, the expression levels of IRS-1 and IRS-2 proteins as well as the degrees of insulin-induced phosphatidylinositol 3-kinase and Akt activations were attenuated in RELMbeta transgenic mice. |
| 7757 | 16243841 | Similar down-regulations of IRS-1 and IRS-2 proteins were observed in primary cultured hepatocytes chronically treated (for 24 h) with RELMbeta, suggesting the insulin resistance-inducing effect of RELMbeta to be direct. |
| 7758 | 16243841 | Furthermore, it was shown that RELMbeta acutely and markedly activates ERK and p38, while weakly activating JNK, in primary cultured hepatocytes. |
| 7759 | 16243841 | This increased basal p38 phosphorylation level was also observed in the livers of RELMbeta transgenic mice. |
| 7760 | 16243841 | In conclusion, RELMbeta, a gut-derived hormone, impairs insulin signaling probably via the activations of classic MAPKs, and increased expression of RELMbeta may be involved in the pathogenesis of glucose intolerance and hyperlipidemia in some insulin-resistant models. |
| 7761 | 16243841 | Thus, RELMbeta is a potentially useful marker for assessing insulin resistance and may also be a target for future novel anti-diabetic agents. |
| 7762 | 16243841 | Resistin-like molecule beta activates MAPKs, suppresses insulin signaling in hepatocytes, and induces diabetes, hyperlipidemia, and fatty liver in transgenic mice on a high fat diet. |
| 7763 | 16243841 | Resistin and resistin-like molecules (RELMs) are a family of proteins reportedly related to insulin resistance and inflammation. |
| 7764 | 16243841 | Because the serum concentration and intestinal expression level of RELMbeta were elevated in insulin-resistant rodent models, in this study we investigated the effect of RELMbeta on insulin signaling and metabolism using transgenic mice and primary cultured hepatocytes. |
| 7765 | 16243841 | In addition, the expression levels of IRS-1 and IRS-2 proteins as well as the degrees of insulin-induced phosphatidylinositol 3-kinase and Akt activations were attenuated in RELMbeta transgenic mice. |
| 7766 | 16243841 | Similar down-regulations of IRS-1 and IRS-2 proteins were observed in primary cultured hepatocytes chronically treated (for 24 h) with RELMbeta, suggesting the insulin resistance-inducing effect of RELMbeta to be direct. |
| 7767 | 16243841 | Furthermore, it was shown that RELMbeta acutely and markedly activates ERK and p38, while weakly activating JNK, in primary cultured hepatocytes. |
| 7768 | 16243841 | This increased basal p38 phosphorylation level was also observed in the livers of RELMbeta transgenic mice. |
| 7769 | 16243841 | In conclusion, RELMbeta, a gut-derived hormone, impairs insulin signaling probably via the activations of classic MAPKs, and increased expression of RELMbeta may be involved in the pathogenesis of glucose intolerance and hyperlipidemia in some insulin-resistant models. |
| 7770 | 16243841 | Thus, RELMbeta is a potentially useful marker for assessing insulin resistance and may also be a target for future novel anti-diabetic agents. |
| 7771 | 16244361 | To identify sites of O-GlcNAc modification in IRS-1, recombinant rat IRS-1 isolated from HEK293 cells was analyzed by two complementary mass spectrometric methods. |
| 7772 | 16244361 | This methodology provided sequence coverage of 84% of the protein, permitted identification of a novel site of phosphorylation at Thr-1045, and facilitated the detection of an O-GlcNAc-modified peptide of IRS-1 at residues 1027-1073. |
| 7773 | 16244361 | The level of O-GlcNAc modification of this peptide increased when cells were grown under conditions of high glucose with or without chronic insulin stimulation or in the presence of an inhibitor of the O-GlcNAcase enzyme. |
| 7774 | 16244361 | To map the exact site of O-GlcNAc modification, IRS-1 peptides were chemically derivatized with dithiothreitol following beta-elimination and Michael addition prior to LC-MS/MS. |
| 7775 | 16244361 | Site-directed mutagenesis and Western blotting with an anti-O-GlcNAc antibody suggested that Ser-1036 is the major site of O-GlcNAc modification of IRS-1. |
| 7776 | 16244361 | To identify sites of O-GlcNAc modification in IRS-1, recombinant rat IRS-1 isolated from HEK293 cells was analyzed by two complementary mass spectrometric methods. |
| 7777 | 16244361 | This methodology provided sequence coverage of 84% of the protein, permitted identification of a novel site of phosphorylation at Thr-1045, and facilitated the detection of an O-GlcNAc-modified peptide of IRS-1 at residues 1027-1073. |
| 7778 | 16244361 | The level of O-GlcNAc modification of this peptide increased when cells were grown under conditions of high glucose with or without chronic insulin stimulation or in the presence of an inhibitor of the O-GlcNAcase enzyme. |
| 7779 | 16244361 | To map the exact site of O-GlcNAc modification, IRS-1 peptides were chemically derivatized with dithiothreitol following beta-elimination and Michael addition prior to LC-MS/MS. |
| 7780 | 16244361 | Site-directed mutagenesis and Western blotting with an anti-O-GlcNAc antibody suggested that Ser-1036 is the major site of O-GlcNAc modification of IRS-1. |
| 7781 | 16244361 | To identify sites of O-GlcNAc modification in IRS-1, recombinant rat IRS-1 isolated from HEK293 cells was analyzed by two complementary mass spectrometric methods. |
| 7782 | 16244361 | This methodology provided sequence coverage of 84% of the protein, permitted identification of a novel site of phosphorylation at Thr-1045, and facilitated the detection of an O-GlcNAc-modified peptide of IRS-1 at residues 1027-1073. |
| 7783 | 16244361 | The level of O-GlcNAc modification of this peptide increased when cells were grown under conditions of high glucose with or without chronic insulin stimulation or in the presence of an inhibitor of the O-GlcNAcase enzyme. |
| 7784 | 16244361 | To map the exact site of O-GlcNAc modification, IRS-1 peptides were chemically derivatized with dithiothreitol following beta-elimination and Michael addition prior to LC-MS/MS. |
| 7785 | 16244361 | Site-directed mutagenesis and Western blotting with an anti-O-GlcNAc antibody suggested that Ser-1036 is the major site of O-GlcNAc modification of IRS-1. |
| 7786 | 16244361 | To identify sites of O-GlcNAc modification in IRS-1, recombinant rat IRS-1 isolated from HEK293 cells was analyzed by two complementary mass spectrometric methods. |
| 7787 | 16244361 | This methodology provided sequence coverage of 84% of the protein, permitted identification of a novel site of phosphorylation at Thr-1045, and facilitated the detection of an O-GlcNAc-modified peptide of IRS-1 at residues 1027-1073. |
| 7788 | 16244361 | The level of O-GlcNAc modification of this peptide increased when cells were grown under conditions of high glucose with or without chronic insulin stimulation or in the presence of an inhibitor of the O-GlcNAcase enzyme. |
| 7789 | 16244361 | To map the exact site of O-GlcNAc modification, IRS-1 peptides were chemically derivatized with dithiothreitol following beta-elimination and Michael addition prior to LC-MS/MS. |
| 7790 | 16244361 | Site-directed mutagenesis and Western blotting with an anti-O-GlcNAc antibody suggested that Ser-1036 is the major site of O-GlcNAc modification of IRS-1. |
| 7791 | 16248779 | There is increasing evidence to suggest that chronic activation of the endothelin-1 system can lead to heterologous desensitization of the glucose-regulatory and mitogenic actions of insulin with subsequent development of glucose intolerance, hyperinsulinemia, impaired endothelial function and exacerbation of cardiovascular disease. |
| 7792 | 16248779 | Effects are mediated through a variety of mechanisms that include attenuation of key insulin signalling pathways and decreased tyrosine phosphorylation of insulin receptor substrates IRS-1, SHC and G alpha q/11. |
| 7793 | 16248779 | Overall the data suggest that ET-1 antagonists may provide an effective means of improving cardiac dysfunction and favourably influencing glucose tolerance in obese humans and patients with early insulin sensitivity where there is clear evidence for activation of the ET-1 system. |
| 7794 | 16248779 | Although most effects of ET-1 that modulate mechanisms leading to glucose intolerance appear to involve the ETA receptor subtype recent data indicates that combined ETA/ETB receptor antagonists may function as effectively as selective ETA blockers. |
| 7795 | 16248779 | Prospective trials are needed to assess whether ET-1 antagonists, either alone or in combination, are superior to other more conventional therapies such as insulin sensitizers and to evaluate effects of combined treatments on the development of insulin resistance and the progression of diabetes. |
| 7796 | 16249255 | Increased collagen content in insulin-resistant skeletal muscle. |
| 7797 | 16249255 | Because evidence indicates that lipid oversupply can produce abnormalities in extracellular matrix composition and matrix changes can affect the function of mitochondria, the present study was undertaken to determine whether muscle from insulin-resistant, nondiabetic obese subjects and patients with type 2 diabetes mellitus had increased collagen content. |
| 7798 | 16249255 | Compared with lean control subjects, obese and type 2 diabetic subjects had reduced muscle glucose uptake (P<0.01) and decreased insulin stimulation of tyrosine phosphorylation of insulin receptor substrate-1 and its ability to associate with phosphatidylinositol 3-kinase (P<0.01 and P<.05). |
| 7799 | 16284649 | Reduced mitochondrial density and increased IRS-1 serine phosphorylation in muscle of insulin-resistant offspring of type 2 diabetic parents. |
| 7800 | 16284649 | These changes were associated with a 50% increase in IRS-1 Ser312 and IRS-1 Ser636 phosphorylation and an approximately 60% reduction in insulin-stimulated Akt activation in the IR offspring. |
| 7801 | 16284649 | Reduced mitochondrial density and increased IRS-1 serine phosphorylation in muscle of insulin-resistant offspring of type 2 diabetic parents. |
| 7802 | 16284649 | These changes were associated with a 50% increase in IRS-1 Ser312 and IRS-1 Ser636 phosphorylation and an approximately 60% reduction in insulin-stimulated Akt activation in the IR offspring. |
| 7803 | 16287721 | Learning-specific increases in levels of downstream molecules such as IRS-1 and Akt were detected in the synaptic membrane accompanied by decreases in Akt phosphorylation. |
| 7804 | 16287721 | Translocation of Shc protein to the synaptic membrane and activation of Erk1/2 were also observed after long-term memory formation. |
| 7805 | 16287721 | This may be due to higher glucose levels in the DM brain, and to compensatory mechanisms from other signaling pathways such as the insulin-like growth factor-1 receptor (IGF-1R) system. |
| 7806 | 16301821 | This was followed by the inhibition of insulin-stimulated IRbeta tyrosine phosphorylation that consequently resulted inhibition of insulin receptor substrate 1 (IRS 1) and IRS 1 associated phosphatidylinositol-3 kinase (PI3 Kinase), phosphoinositide dependent kinase-1 (PDK 1) phosphorylation. |
| 7807 | 16301821 | PDK 1 dependent phosphorylation of PKCzeta and Akt/PKB were also inhibited by palmitate. |
| 7808 | 16306364 | Skeletal muscle insulin signaling defects downstream of phosphatidylinositol 3-kinase at the level of Akt are associated with impaired nonoxidative glucose disposal in HIV lipodystrophy. |
| 7809 | 16306364 | Insulin-stimulated Akt Ser473 and Akt Thr308 phosphorylation was decreased in LIPO patients (P < 0.05), whereas insulin receptor substrate-1-associated phosphatidylinositol (PI) 3-kinase activity increased significantly (P < 0.001) and similarly (NS) in both groups during clamp. |
| 7810 | 16306364 | Thus, low glycogen synthase activity explained impaired NOGM(ins) in HIV lipodystrophy, and insulin signaling defects were downstream of PI 3-kinase at the level of Akt. |
| 7811 | 16307847 | In rodent studies, measures which increase [Ca2+]i in adipocytes and skeletal muscle are associated with impaired insulin signaling, attributable at least in part to diminished ability of insulin to activate phosphoserine phosphatase-1 (PP-1). |
| 7812 | 16307847 | Clinical insulin resistance is associated with increased levels of triglycerides and other fatty acid metabolites in muscle fibers; this can give rise to diacylglycerol-mediated activation of PKC, which in turn compromises insulin signaling by triggering kinase cascades that phosphorylate IRS-1 on key serine residues. |
| 7813 | 16307847 | Thus, the PKC activation associated with fat overexposure might be expected to boost basal [Ca2+]i in skeletal muscle, potentially impeding insulin-mediated activation of PP-1. |
| 7814 | 16307847 | Since parathyroid hormone can act on adipocytes and muscle to boost [Ca2+]i, mild secondary hyperparathyroidism associated with low calcium intakes and poor vitamin D status may contribute to insulin resistance, consistent with certain clinical and epidemiological findings. |
| 7815 | 16309849 | The molecular mechanism responsible for obesity-associated insulin resistance has been partially clarified: increased fatty acid levels in muscle fibers promote diacylglycerol synthesis, which activates certain isoforms of protein kinase C (PKC). |
| 7816 | 16309849 | This in turn triggers a kinase cascade which activates both IkappaB kinase-beta (IKK-beta) and c-Jun N-terminal kinase (JNK), each of which can phosphorylate a key serine residue in IRS-1, rendering it a poor substrate for the activated insulin receptor. |
| 7817 | 16309849 | Heat shock proteins Hsp27 and Hsp72 have the potential to prevent the activation of IKK-beta and JNK, respectively; this suggests that induction of heat shock proteins may blunt the adverse impact of fat overexposure on insulin function. |
| 7818 | 16311102 | Insulin signaling and expression of GLUT-4, FAT/CD36, and triglycerides were assessed in muscle biopsies, obtained before the clamp and after 30 minutes of hyperinsulinemia. |
| 7819 | 16311102 | No diet effect was found on the expression of the insulin receptor and insulin receptor substrate-1 or on phosphatidylinositol 3'-kinase activity, or on FAT/CD36 expression pattern, GLUT-4 translocation, or triglyceride distribution in either the basal or insulin-stimulated situation. |
| 7820 | 16311102 | Accordingly, no changes in activation of phosphatidylinositol 3'-kinase, triglyceride distribution, FAT/CD36 expression, and GLUT-4 translocation were found in skeletal muscle biopsies. |
| 7821 | 16311104 | Continually high insulin levels impair Akt phosphorylation and glucose transport in human myoblasts. |
| 7822 | 16311104 | Glucose transport, insulin receptor (IR), and IR substrate 1 (IRS1) phosphorylation, phosphatidylinositol 3'-kinase (PI3K) activity, as well as Akt-Ser473 phosphorylation have been investigated at the end of the incubation period and after a further short-term insulin stimulation. |
| 7823 | 16311104 | At the end of the incubation period, IR, IRS1, p85/PI3K, Akt, and GLUT4 protein expression levels were similar in both culture conditions. |
| 7824 | 16311104 | IR binding was down-regulated in SkMC-H (P < .01), but IR and IRS1 tyrosine phosphorylation and PI3K activity were significantly higher (P < .01) in SkMC-H than SkMC-L. |
| 7825 | 16311104 | Despite increased PI3K activation, Akt-Ser473 phosphorylation was similar in SkMC-L and SkMC-H. |
| 7826 | 16311104 | After a short-term insulin stimulation (10 nmol/L insulin for 10 minutes), IR and IRS1 tyrosine phosphorylation, PI3K activation, and Akt-Ser473 phosphorylation significantly increased (P < .01 and P < .05 for Akt) in SkMC-L but not in SkMC-H. |
| 7827 | 16311104 | Moreover, in the SkMC-H, insulin stimulation was associated with the inhibition of IRS1 tyrosine dephosphorylation (P < .05). |
| 7828 | 16311104 | In summary, continuous exposure of cultured myoblasts to high insulin levels induces a persistent up-regulation of IR, IRS1, and PI3K activity associated with the demodulation of insulin signaling. |
| 7829 | 16311104 | Moreover, the impairment of the insulin-signaling steps between PI3K and Akt is concomitant with the desensitization of glucose transport. |
| 7830 | 16311104 | Continually high insulin levels impair Akt phosphorylation and glucose transport in human myoblasts. |
| 7831 | 16311104 | Glucose transport, insulin receptor (IR), and IR substrate 1 (IRS1) phosphorylation, phosphatidylinositol 3'-kinase (PI3K) activity, as well as Akt-Ser473 phosphorylation have been investigated at the end of the incubation period and after a further short-term insulin stimulation. |
| 7832 | 16311104 | At the end of the incubation period, IR, IRS1, p85/PI3K, Akt, and GLUT4 protein expression levels were similar in both culture conditions. |
| 7833 | 16311104 | IR binding was down-regulated in SkMC-H (P < .01), but IR and IRS1 tyrosine phosphorylation and PI3K activity were significantly higher (P < .01) in SkMC-H than SkMC-L. |
| 7834 | 16311104 | Despite increased PI3K activation, Akt-Ser473 phosphorylation was similar in SkMC-L and SkMC-H. |
| 7835 | 16311104 | After a short-term insulin stimulation (10 nmol/L insulin for 10 minutes), IR and IRS1 tyrosine phosphorylation, PI3K activation, and Akt-Ser473 phosphorylation significantly increased (P < .01 and P < .05 for Akt) in SkMC-L but not in SkMC-H. |
| 7836 | 16311104 | Moreover, in the SkMC-H, insulin stimulation was associated with the inhibition of IRS1 tyrosine dephosphorylation (P < .05). |
| 7837 | 16311104 | In summary, continuous exposure of cultured myoblasts to high insulin levels induces a persistent up-regulation of IR, IRS1, and PI3K activity associated with the demodulation of insulin signaling. |
| 7838 | 16311104 | Moreover, the impairment of the insulin-signaling steps between PI3K and Akt is concomitant with the desensitization of glucose transport. |
| 7839 | 16311104 | Continually high insulin levels impair Akt phosphorylation and glucose transport in human myoblasts. |
| 7840 | 16311104 | Glucose transport, insulin receptor (IR), and IR substrate 1 (IRS1) phosphorylation, phosphatidylinositol 3'-kinase (PI3K) activity, as well as Akt-Ser473 phosphorylation have been investigated at the end of the incubation period and after a further short-term insulin stimulation. |
| 7841 | 16311104 | At the end of the incubation period, IR, IRS1, p85/PI3K, Akt, and GLUT4 protein expression levels were similar in both culture conditions. |
| 7842 | 16311104 | IR binding was down-regulated in SkMC-H (P < .01), but IR and IRS1 tyrosine phosphorylation and PI3K activity were significantly higher (P < .01) in SkMC-H than SkMC-L. |
| 7843 | 16311104 | Despite increased PI3K activation, Akt-Ser473 phosphorylation was similar in SkMC-L and SkMC-H. |
| 7844 | 16311104 | After a short-term insulin stimulation (10 nmol/L insulin for 10 minutes), IR and IRS1 tyrosine phosphorylation, PI3K activation, and Akt-Ser473 phosphorylation significantly increased (P < .01 and P < .05 for Akt) in SkMC-L but not in SkMC-H. |
| 7845 | 16311104 | Moreover, in the SkMC-H, insulin stimulation was associated with the inhibition of IRS1 tyrosine dephosphorylation (P < .05). |
| 7846 | 16311104 | In summary, continuous exposure of cultured myoblasts to high insulin levels induces a persistent up-regulation of IR, IRS1, and PI3K activity associated with the demodulation of insulin signaling. |
| 7847 | 16311104 | Moreover, the impairment of the insulin-signaling steps between PI3K and Akt is concomitant with the desensitization of glucose transport. |
| 7848 | 16311104 | Continually high insulin levels impair Akt phosphorylation and glucose transport in human myoblasts. |
| 7849 | 16311104 | Glucose transport, insulin receptor (IR), and IR substrate 1 (IRS1) phosphorylation, phosphatidylinositol 3'-kinase (PI3K) activity, as well as Akt-Ser473 phosphorylation have been investigated at the end of the incubation period and after a further short-term insulin stimulation. |
| 7850 | 16311104 | At the end of the incubation period, IR, IRS1, p85/PI3K, Akt, and GLUT4 protein expression levels were similar in both culture conditions. |
| 7851 | 16311104 | IR binding was down-regulated in SkMC-H (P < .01), but IR and IRS1 tyrosine phosphorylation and PI3K activity were significantly higher (P < .01) in SkMC-H than SkMC-L. |
| 7852 | 16311104 | Despite increased PI3K activation, Akt-Ser473 phosphorylation was similar in SkMC-L and SkMC-H. |
| 7853 | 16311104 | After a short-term insulin stimulation (10 nmol/L insulin for 10 minutes), IR and IRS1 tyrosine phosphorylation, PI3K activation, and Akt-Ser473 phosphorylation significantly increased (P < .01 and P < .05 for Akt) in SkMC-L but not in SkMC-H. |
| 7854 | 16311104 | Moreover, in the SkMC-H, insulin stimulation was associated with the inhibition of IRS1 tyrosine dephosphorylation (P < .05). |
| 7855 | 16311104 | In summary, continuous exposure of cultured myoblasts to high insulin levels induces a persistent up-regulation of IR, IRS1, and PI3K activity associated with the demodulation of insulin signaling. |
| 7856 | 16311104 | Moreover, the impairment of the insulin-signaling steps between PI3K and Akt is concomitant with the desensitization of glucose transport. |
| 7857 | 16311104 | Continually high insulin levels impair Akt phosphorylation and glucose transport in human myoblasts. |
| 7858 | 16311104 | Glucose transport, insulin receptor (IR), and IR substrate 1 (IRS1) phosphorylation, phosphatidylinositol 3'-kinase (PI3K) activity, as well as Akt-Ser473 phosphorylation have been investigated at the end of the incubation period and after a further short-term insulin stimulation. |
| 7859 | 16311104 | At the end of the incubation period, IR, IRS1, p85/PI3K, Akt, and GLUT4 protein expression levels were similar in both culture conditions. |
| 7860 | 16311104 | IR binding was down-regulated in SkMC-H (P < .01), but IR and IRS1 tyrosine phosphorylation and PI3K activity were significantly higher (P < .01) in SkMC-H than SkMC-L. |
| 7861 | 16311104 | Despite increased PI3K activation, Akt-Ser473 phosphorylation was similar in SkMC-L and SkMC-H. |
| 7862 | 16311104 | After a short-term insulin stimulation (10 nmol/L insulin for 10 minutes), IR and IRS1 tyrosine phosphorylation, PI3K activation, and Akt-Ser473 phosphorylation significantly increased (P < .01 and P < .05 for Akt) in SkMC-L but not in SkMC-H. |
| 7863 | 16311104 | Moreover, in the SkMC-H, insulin stimulation was associated with the inhibition of IRS1 tyrosine dephosphorylation (P < .05). |
| 7864 | 16311104 | In summary, continuous exposure of cultured myoblasts to high insulin levels induces a persistent up-regulation of IR, IRS1, and PI3K activity associated with the demodulation of insulin signaling. |
| 7865 | 16311104 | Moreover, the impairment of the insulin-signaling steps between PI3K and Akt is concomitant with the desensitization of glucose transport. |
| 7866 | 16311104 | Continually high insulin levels impair Akt phosphorylation and glucose transport in human myoblasts. |
| 7867 | 16311104 | Glucose transport, insulin receptor (IR), and IR substrate 1 (IRS1) phosphorylation, phosphatidylinositol 3'-kinase (PI3K) activity, as well as Akt-Ser473 phosphorylation have been investigated at the end of the incubation period and after a further short-term insulin stimulation. |
| 7868 | 16311104 | At the end of the incubation period, IR, IRS1, p85/PI3K, Akt, and GLUT4 protein expression levels were similar in both culture conditions. |
| 7869 | 16311104 | IR binding was down-regulated in SkMC-H (P < .01), but IR and IRS1 tyrosine phosphorylation and PI3K activity were significantly higher (P < .01) in SkMC-H than SkMC-L. |
| 7870 | 16311104 | Despite increased PI3K activation, Akt-Ser473 phosphorylation was similar in SkMC-L and SkMC-H. |
| 7871 | 16311104 | After a short-term insulin stimulation (10 nmol/L insulin for 10 minutes), IR and IRS1 tyrosine phosphorylation, PI3K activation, and Akt-Ser473 phosphorylation significantly increased (P < .01 and P < .05 for Akt) in SkMC-L but not in SkMC-H. |
| 7872 | 16311104 | Moreover, in the SkMC-H, insulin stimulation was associated with the inhibition of IRS1 tyrosine dephosphorylation (P < .05). |
| 7873 | 16311104 | In summary, continuous exposure of cultured myoblasts to high insulin levels induces a persistent up-regulation of IR, IRS1, and PI3K activity associated with the demodulation of insulin signaling. |
| 7874 | 16311104 | Moreover, the impairment of the insulin-signaling steps between PI3K and Akt is concomitant with the desensitization of glucose transport. |
| 7875 | 16335791 | Is insulin signaling molecules misguided in diabetes for ubiquitin-proteasome mediated degradation? |
| 7876 | 16335791 | Inappropriate degradation of insulin signaling molecules such as insulin receptor substrates (IRS-1 and IRS-2) has been demonstrated in experimental diabetes, mediated in part through the up-regulation of suppressors of cytokine signaling (SOCS). |
| 7877 | 16335791 | It appears that altered ubiquitin-proteasome system might be one of the molecular mechanisms of insulin resistance in many pathological situations. |
| 7878 | 16335791 | Drugs that modulate the SOCS action and/or proteasomal degradation of proteins could become novel agents for the treatment of insulin resistance and Type 2 diabetes. |
| 7879 | 16339278 | Chromium activates glucose transporter 4 trafficking and enhances insulin-stimulated glucose transport in 3T3-L1 adipocytes via a cholesterol-dependent mechanism. |
| 7880 | 16339278 | Concomitant with an increase in GLUT4 at the plasma membrane, insulin-stimulated glucose transport was enhanced by chromium treatment. |
| 7881 | 16339278 | Regulation of GLUT4 translocation by chromium did not involve known insulin signaling proteins such as the insulin receptor, insulin receptor substrate-1, phosphatidylinositol 3-kinase, and Akt. |
| 7882 | 16339278 | Interestingly, cholesterol add-back to the plasma membrane prevented the beneficial effect of chromium on both GLUT4 mobilization and insulin-stimulated glucose transport. |
| 7883 | 16339278 | Together, these data reveal a novel mechanism by which chromium may enhance GLUT4 trafficking and insulin-stimulated glucose transport. |
| 7884 | 16350721 | Several genes from these pathways have been tested include genes involved in steroid hormone biosynthesis and metabolism (StAR, CYP11, CYP17, CYP19 HSD17B1-3, HSD3B1-2), gonadotropin and gonadal hormones action (ACTR1, ACTR2A-B, FS, INHA, INHBA-B, INHC, SHBG, LHCGR, FSHR, MADH4, AR), obesity and energy regulation (MC4R, OB, OBR, POMC, UCP2-3), insulin secretion and action (IGF1, IGF1R, IGFBPI1-3, INS VNTR, IR, INSL, IRS1-2, PPARG) and many others. |
| 7885 | 16350721 | Polymorphic alleles of both IRS-1 and IRS-2 (insulin receptor substrate 1 - 2), alone or in combination, may have a functional impact on the insulin-resistant component of PCOS. |
| 7886 | 16350721 | There is no evidence to suggest that follistatin gene polymorphisms play a role in the pathogenesis of insulin resistance in PCOS women. |
| 7887 | 16350721 | The results of this study demonstrate that there are significant alterations in the expression of ERalpha and ERbeta in PCOS that may be related to abnormal follicular development. |
| 7888 | 16354680 | Nutrients suppress phosphatidylinositol 3-kinase/Akt signaling via raptor-dependent mTOR-mediated insulin receptor substrate 1 phosphorylation. |
| 7889 | 16354680 | Here, we demonstrate that nutrients suppress phosphatidylinositol 3 (PI3)-kinase/Akt signaling via Raptor-dependent mTOR (mammalian target of rapamycin)-mediated phosphorylation of insulin receptor substrate 1 (IRS-1). |
| 7890 | 16354680 | These serines lie close to the Y(632)MPM motif that is implicated in the binding of p85alpha/p110alpha PI3-kinase to IRS-1 upon insulin stimulation. |
| 7891 | 16354680 | Phosphomimicking mutations of these serines block insulin-stimulated activation of IRS-1-associated PI3-kinase. |
| 7892 | 16354680 | Knockdown of Raptor as well as activators of the LKB1/AMPK pathway, such as the widely used antidiabetic compound metformin, suppress IRS-1 Ser636/639 phosphorylation and reverse mTOR-mediated inhibition on PI3-kinase/Akt signaling. |
| 7893 | 16354680 | Thus, diabetes-related hyperglycemia hyperactivates the mTOR pathway and may lead to insulin resistance due to suppression of IRS-1-dependent PI3-kinase/Akt signaling. |
| 7894 | 16354680 | Nutrients suppress phosphatidylinositol 3-kinase/Akt signaling via raptor-dependent mTOR-mediated insulin receptor substrate 1 phosphorylation. |
| 7895 | 16354680 | Here, we demonstrate that nutrients suppress phosphatidylinositol 3 (PI3)-kinase/Akt signaling via Raptor-dependent mTOR (mammalian target of rapamycin)-mediated phosphorylation of insulin receptor substrate 1 (IRS-1). |
| 7896 | 16354680 | These serines lie close to the Y(632)MPM motif that is implicated in the binding of p85alpha/p110alpha PI3-kinase to IRS-1 upon insulin stimulation. |
| 7897 | 16354680 | Phosphomimicking mutations of these serines block insulin-stimulated activation of IRS-1-associated PI3-kinase. |
| 7898 | 16354680 | Knockdown of Raptor as well as activators of the LKB1/AMPK pathway, such as the widely used antidiabetic compound metformin, suppress IRS-1 Ser636/639 phosphorylation and reverse mTOR-mediated inhibition on PI3-kinase/Akt signaling. |
| 7899 | 16354680 | Thus, diabetes-related hyperglycemia hyperactivates the mTOR pathway and may lead to insulin resistance due to suppression of IRS-1-dependent PI3-kinase/Akt signaling. |
| 7900 | 16354680 | Nutrients suppress phosphatidylinositol 3-kinase/Akt signaling via raptor-dependent mTOR-mediated insulin receptor substrate 1 phosphorylation. |
| 7901 | 16354680 | Here, we demonstrate that nutrients suppress phosphatidylinositol 3 (PI3)-kinase/Akt signaling via Raptor-dependent mTOR (mammalian target of rapamycin)-mediated phosphorylation of insulin receptor substrate 1 (IRS-1). |
| 7902 | 16354680 | These serines lie close to the Y(632)MPM motif that is implicated in the binding of p85alpha/p110alpha PI3-kinase to IRS-1 upon insulin stimulation. |
| 7903 | 16354680 | Phosphomimicking mutations of these serines block insulin-stimulated activation of IRS-1-associated PI3-kinase. |
| 7904 | 16354680 | Knockdown of Raptor as well as activators of the LKB1/AMPK pathway, such as the widely used antidiabetic compound metformin, suppress IRS-1 Ser636/639 phosphorylation and reverse mTOR-mediated inhibition on PI3-kinase/Akt signaling. |
| 7905 | 16354680 | Thus, diabetes-related hyperglycemia hyperactivates the mTOR pathway and may lead to insulin resistance due to suppression of IRS-1-dependent PI3-kinase/Akt signaling. |
| 7906 | 16354680 | Nutrients suppress phosphatidylinositol 3-kinase/Akt signaling via raptor-dependent mTOR-mediated insulin receptor substrate 1 phosphorylation. |
| 7907 | 16354680 | Here, we demonstrate that nutrients suppress phosphatidylinositol 3 (PI3)-kinase/Akt signaling via Raptor-dependent mTOR (mammalian target of rapamycin)-mediated phosphorylation of insulin receptor substrate 1 (IRS-1). |
| 7908 | 16354680 | These serines lie close to the Y(632)MPM motif that is implicated in the binding of p85alpha/p110alpha PI3-kinase to IRS-1 upon insulin stimulation. |
| 7909 | 16354680 | Phosphomimicking mutations of these serines block insulin-stimulated activation of IRS-1-associated PI3-kinase. |
| 7910 | 16354680 | Knockdown of Raptor as well as activators of the LKB1/AMPK pathway, such as the widely used antidiabetic compound metformin, suppress IRS-1 Ser636/639 phosphorylation and reverse mTOR-mediated inhibition on PI3-kinase/Akt signaling. |
| 7911 | 16354680 | Thus, diabetes-related hyperglycemia hyperactivates the mTOR pathway and may lead to insulin resistance due to suppression of IRS-1-dependent PI3-kinase/Akt signaling. |
| 7912 | 16356119 | Exposure of different cell lines to micromolar concentrations of hydrogen peroxide leads to the activation of stress kinases such as c-Jun N-terminal kinase, p38, I kappaB kinase, and extracellular receptor kinase 1/2. |
| 7913 | 16356119 | The mechanisms leading to this down-regulation in oxidized cells are complicated, involving increased serine/threonine phosphorylation of insulin receptor substrate-1 (IRS1), impaired insulin-stimulated redistribution of IRS1 and phosphatidylinositol-kinase between cytosol and low-density microsomal fraction, followed by a reduced protein kinase-B phosphorylation and GLUT4 translocation to the plasma membrane. |
| 7914 | 16356119 | In addition, prolonged exposure to ROS affects transcription of glucose transporters: whereas the level of GLUT1 is increased, GLUT4 level is reduced. |
| 7915 | 16367885 | IRS1, KCNJ11, PPARgamma2 and HNF-1alpha: do amino acid polymorphisms in these candidate genes support a shared aetiology between type 1 and type 2 diabetes? |
| 7916 | 16374520 | Irs1 and Irs2 signaling is essential for hepatic glucose homeostasis and systemic growth. |
| 7917 | 16374520 | Insulin receptor substrates, including Irs1 and Irs2, integrate insulin and IGF receptor signals with heterologous pathways to coordinate growth and metabolism. |
| 7918 | 16374520 | Since Irs2 is thought to be especially important in hepatic nutrient homeostasis, we deleted Irs2 [corrected] from hepatocytes of WT mice (called LKO) or genetically insulin-resistant Irs1-/- mice (called LKO::Irs1-/-). |
| 7919 | 16374520 | Hepatic insulin receptors were functional in all the mice, but insulin signaling via the Akt-FoxO1 pathway was reduced in Irs1-/- and LKO liver, and undetected in LKO::Irs1-/- liver; however, Gsk3beta phosphorylation (Ser9) and hepatic glycogen stores were nearly normal in all of the mice. |
| 7920 | 16374520 | Regardless, few hepatic genes changed expression significantly in Irs1-/- or LKO mice, whereas hundreds of genes changed in LKO::Irs1-/- mice--including elevated levels of Pck1, G6pc, Ppargc1, Pparg, and Igfbp1. |
| 7921 | 16374520 | Thus, signals delivered by Irs1 or Irs2 regulate hepatic gene expression that coordinates glucose homeostasis and systemic growth. |
| 7922 | 16374520 | Irs1 and Irs2 signaling is essential for hepatic glucose homeostasis and systemic growth. |
| 7923 | 16374520 | Insulin receptor substrates, including Irs1 and Irs2, integrate insulin and IGF receptor signals with heterologous pathways to coordinate growth and metabolism. |
| 7924 | 16374520 | Since Irs2 is thought to be especially important in hepatic nutrient homeostasis, we deleted Irs2 [corrected] from hepatocytes of WT mice (called LKO) or genetically insulin-resistant Irs1-/- mice (called LKO::Irs1-/-). |
| 7925 | 16374520 | Hepatic insulin receptors were functional in all the mice, but insulin signaling via the Akt-FoxO1 pathway was reduced in Irs1-/- and LKO liver, and undetected in LKO::Irs1-/- liver; however, Gsk3beta phosphorylation (Ser9) and hepatic glycogen stores were nearly normal in all of the mice. |
| 7926 | 16374520 | Regardless, few hepatic genes changed expression significantly in Irs1-/- or LKO mice, whereas hundreds of genes changed in LKO::Irs1-/- mice--including elevated levels of Pck1, G6pc, Ppargc1, Pparg, and Igfbp1. |
| 7927 | 16374520 | Thus, signals delivered by Irs1 or Irs2 regulate hepatic gene expression that coordinates glucose homeostasis and systemic growth. |
| 7928 | 16374520 | Irs1 and Irs2 signaling is essential for hepatic glucose homeostasis and systemic growth. |
| 7929 | 16374520 | Insulin receptor substrates, including Irs1 and Irs2, integrate insulin and IGF receptor signals with heterologous pathways to coordinate growth and metabolism. |
| 7930 | 16374520 | Since Irs2 is thought to be especially important in hepatic nutrient homeostasis, we deleted Irs2 [corrected] from hepatocytes of WT mice (called LKO) or genetically insulin-resistant Irs1-/- mice (called LKO::Irs1-/-). |
| 7931 | 16374520 | Hepatic insulin receptors were functional in all the mice, but insulin signaling via the Akt-FoxO1 pathway was reduced in Irs1-/- and LKO liver, and undetected in LKO::Irs1-/- liver; however, Gsk3beta phosphorylation (Ser9) and hepatic glycogen stores were nearly normal in all of the mice. |
| 7932 | 16374520 | Regardless, few hepatic genes changed expression significantly in Irs1-/- or LKO mice, whereas hundreds of genes changed in LKO::Irs1-/- mice--including elevated levels of Pck1, G6pc, Ppargc1, Pparg, and Igfbp1. |
| 7933 | 16374520 | Thus, signals delivered by Irs1 or Irs2 regulate hepatic gene expression that coordinates glucose homeostasis and systemic growth. |
| 7934 | 16376341 | The following parameters were examined: morphological analysis of endocrine pancreata by immunohistochemistry; protein levels of insulin receptor, IRS-1, IRS-2, PI 3-kinase, Akt-1, and Akt-2; and static insulin secretion in isolated pancreatic islets. |
| 7935 | 16376341 | Pancreatic islets from DHEA-treated rats showed an increased beta-cell mass accompanied by increased Akt-1 protein level but reduced IR, IRS-1, and IRS-2 protein levels and enhanced glucose-stimulated insulin secretion. |
| 7936 | 16376341 | The following parameters were examined: morphological analysis of endocrine pancreata by immunohistochemistry; protein levels of insulin receptor, IRS-1, IRS-2, PI 3-kinase, Akt-1, and Akt-2; and static insulin secretion in isolated pancreatic islets. |
| 7937 | 16376341 | Pancreatic islets from DHEA-treated rats showed an increased beta-cell mass accompanied by increased Akt-1 protein level but reduced IR, IRS-1, and IRS-2 protein levels and enhanced glucose-stimulated insulin secretion. |
| 7938 | 16389635 | The multi-faceted cross-talk between the insulin and angiotensin II signaling systems. |
| 7939 | 16389635 | Insulin and angiotensin II are hormones that play pivotal roles in the control of two vital and closely related systems, the metabolic and the circulatory systems, respectively. |
| 7940 | 16389635 | In recent years, a series of studies has revealed a tight connection between the signal transduction pathways that mediate insulin and angiotensin II actions in target tissues. |
| 7941 | 16389635 | At the extracellular level, the angiotensin-converting enzyme controls angiotensin II synthesis but also interferes with insulin signaling through the proper regulation of angiotensin II and through the accumulation of bradykinin. |
| 7942 | 16389635 | At an early intracellular level, angiotensin II, acting through JAK-2/IRS-1/PI3-kinase, JNK and ERK, may induce the serine phosphorylation and inhibition of key elements of the insulin-signaling pathway. |
| 7943 | 16389635 | Finally, by inducing the expression of the regulatory protein SOCS-3, angiotensin II may impose a late control on the insulin signal. |
| 7944 | 16449300 | The altered in utero hormonal/metabolic milieu was associated with no change in basal total IRS-1, p85, and p110beta subunits of PI 3-kinase, PKCtheta, and PKCzeta concentrations but an increase in basal IRS-2 (P < 0.05) only in the CM/SP group and an increase in basal phospho (p)-PDK-1 (P < 0.05), p-Akt (P < 0.05), and p-PKCzeta (P < 0.05) concentrations in the CM/SP and SM/SP groups. |
| 7945 | 16449300 | SHP2 (P < 0.03) and PTP1B (P < 0.03) increased only in SM/SP with no change in PTEN in CM/SP and SM/SP groups. |
| 7946 | 16449300 | The inability to further respond to exogenous insulin was due to the key molecular distal roadblock consisting of resistance to phosphorylate and activate PKCzeta necessary for GLUT4 translocation. |
| 7947 | 16452245 | After low-number islet transplantation (n = 450), the liver acini downstream of the islets show insulin-induced alterations: massive glycogen and/or fat accumulation, translocation of the insulin receptor, decrease in glucose-6-phosphatase activity, increase in expression of insulin-like growth factor (IGF)-I, IGF-II/mannose-6-phosphate receptor, insulin receptor substrate-1, Raf-1, and Mek-1, corresponding to clear cell preneoplastic foci of altered hepatocytes known from chemical hepatocarcinogenesis and identical to that in streptozotocin-diabetic Lewis rats. |
| 7948 | 16452245 | After 6 months, many altered liver acini progressed to other types of preneoplasias often accompanied by an overexpression of the glutathione-S transferase (placental form), IGF-I receptor, and transforming growth factor (TGF)-alpha. |
| 7949 | 16452245 | Hepatocarcinogenesis is independent from additional genotoxic compounds (i.e., streptozotocin), but is primarily triggered by increased intracellular insulin signaling via pathways associated with cell growth and proliferation, such as the Ras-Raf-mitogen-activated protein kinase pathway and the IGF system, and secondarily involves other growth factors, such as TGF-alpha. |
| 7950 | 16458527 | IRS1 and IRS2 are the major insulin receptor substrates leading to glucose homeostasis, and have distinct and overlapping roles in diverse organs. |
| 7951 | 16458527 | The majority of the published literature in this field suggests that IRS1 is the major substrate leading to stimulation of glucose transport in muscle and adipose tissues, whereas in liver, IRS1 and IRS2 have complementary roles in insulin signaling and metabolism. |
| 7952 | 16458527 | IRS1 and IRS2 are the major insulin receptor substrates leading to glucose homeostasis, and have distinct and overlapping roles in diverse organs. |
| 7953 | 16458527 | The majority of the published literature in this field suggests that IRS1 is the major substrate leading to stimulation of glucose transport in muscle and adipose tissues, whereas in liver, IRS1 and IRS2 have complementary roles in insulin signaling and metabolism. |
| 7954 | 16470420 | IRS-1 is important in the insulin-mediated signal transduction pathway in both liver and skeletal muscle. |
| 7955 | 16470420 | Exogenous NO donated by S-nitroso-N-acetylpenicillamine (SNAP) and S-nitrosoglutathione (GSNO) resulted in significant reduction in levels of IRS-1 in both cells, when compared to the insulin-stimulated control (p<0.001). |
| 7956 | 16470420 | IRS-1 is important in the insulin-mediated signal transduction pathway in both liver and skeletal muscle. |
| 7957 | 16470420 | Exogenous NO donated by S-nitroso-N-acetylpenicillamine (SNAP) and S-nitrosoglutathione (GSNO) resulted in significant reduction in levels of IRS-1 in both cells, when compared to the insulin-stimulated control (p<0.001). |
| 7958 | 16489531 | PPARgamma and colon and rectal cancer: associations with specific tumor mutations, aspirin, ibuprofen and insulin-related genes (United States). |
| 7959 | 16489531 | We hypothesize that the peroxisome proliferator-activated receptor-gamma (PPARgamma) is associated with colorectal cancer given its association with insulin, diabetes, obesity, and inflammation. |
| 7960 | 16489531 | In this study, we evaluated the association between colorectal cancer and specific tumor mutations and the Pro12Ala (P12A) PPARgamma polymorphism. |
| 7961 | 16489531 | We also evaluated interactions between the PPARgamma gene and other insulin-related genes and use of aspirin and non-steroidal anti-inflammatory drug use. |
| 7962 | 16489531 | Colon tumors from the case subjects were evaluated for p53 and Ki-ras mutations and microsatellite instability (MSI). |
| 7963 | 16489531 | Insulin-related genes evaluated were the Bsm1, polyA, and Fok1 polymorphisms of the VDR gene; the G972R IRS1 polymorphism; the G1057D IRS2 polymorphism; the 19CA repeat polymorphism of the IGF1 gene; and the -200A>C IGFBP3 polymorphism. |
| 7964 | 16489531 | Colon cancer cases also were less likely to have a tumor with MSI if they had the PA or AA PPARgamma genotype (OR 0.68; 95% CI: 0.47-0.98); differences in Ki-ras mutations were not seen in colon tumors by PPARgamma genotype. |
| 7965 | 16489531 | There was a significant interaction between the -200A>C IGFBP3 polymorphism and the Pro12Ala PPARgamma polymorphism and risk of colon cancer (p for interaction = 0.02) with individuals being at significantly lower risk if they had both the CC IGFBP3 genotype and the PA/AA PPARgamma genotype. |
| 7966 | 16489531 | For rectal cancer there was a significant interaction between the Bsm1/polyA polymorphisms (p = 0.001) of the VDR gene and the PA/AA Pro12Ala PPARgamma polymorphism with the highest risk group being those with both the PA/AA Pro12Ala PPARgamma and the BB/SS VDR genotypes. |
| 7967 | 16489531 | These data suggest that PPARgamma may be associated with many aspects of colorectal cancer including insulin- and inflammation-related mechanisms. |
| 7968 | 16505233 | Overexpression of suppressor of cytokine signaling 3 in adipose tissue causes local but not systemic insulin resistance. |
| 7969 | 16505233 | In adipocytes, suppressor of cytokine signaling (SOCS)3 deficiency increases insulin-stimulated insulin receptor substrate (IRS)-1 and -2 phosphorylation, IRS-associated phosphatidylinositol 3 kinase activity, and insulin-stimulated glucose uptake. |
| 7970 | 16505233 | Moreover, SOCS3 is required for tumor necrosis factor-alpha full inhibition of insulin-stimulated IRS-1 and -2 phosphorylation, phosphatidylinositol 3 kinase activity, and glucose uptake. |
| 7971 | 16505233 | Whether SOCS3 also inhibits adipocyte insulin signaling in vivo and whether this action further affects systemic insulin sensitivity is not clear. |
| 7972 | 16505233 | Overexpression of SOCS3 in adipocytes decreases IRS1 protein levels and subsequent insulin-stimulated IRS-1 and -2 phosphorylation, decreases p85 binding to IRS-1, and leads to decreased insulin-stimulated glucose uptake in adipocytes. |
| 7973 | 16505233 | This impaired insulin signaling in adipose tissue of aP2-SOCS3 mice causes decreased lipogenesis and blocks insulin's antilipolytic action. |
| 7974 | 16505233 | However, because of decreased energy partitioning in adipose tissue, aP2-SOCS3 mice are resistant to diet-induced obesity and are protected against systemic insulin resistance caused by a high-fat diet. |
| 7975 | 16505233 | Therefore, overexpression of SOCS3 in adipocytes causes local adipocyte insulin resistance, but it is not sufficient to cause systemic insulin resistance. |
| 7976 | 16505233 | Overexpression of suppressor of cytokine signaling 3 in adipose tissue causes local but not systemic insulin resistance. |
| 7977 | 16505233 | In adipocytes, suppressor of cytokine signaling (SOCS)3 deficiency increases insulin-stimulated insulin receptor substrate (IRS)-1 and -2 phosphorylation, IRS-associated phosphatidylinositol 3 kinase activity, and insulin-stimulated glucose uptake. |
| 7978 | 16505233 | Moreover, SOCS3 is required for tumor necrosis factor-alpha full inhibition of insulin-stimulated IRS-1 and -2 phosphorylation, phosphatidylinositol 3 kinase activity, and glucose uptake. |
| 7979 | 16505233 | Whether SOCS3 also inhibits adipocyte insulin signaling in vivo and whether this action further affects systemic insulin sensitivity is not clear. |
| 7980 | 16505233 | Overexpression of SOCS3 in adipocytes decreases IRS1 protein levels and subsequent insulin-stimulated IRS-1 and -2 phosphorylation, decreases p85 binding to IRS-1, and leads to decreased insulin-stimulated glucose uptake in adipocytes. |
| 7981 | 16505233 | This impaired insulin signaling in adipose tissue of aP2-SOCS3 mice causes decreased lipogenesis and blocks insulin's antilipolytic action. |
| 7982 | 16505233 | However, because of decreased energy partitioning in adipose tissue, aP2-SOCS3 mice are resistant to diet-induced obesity and are protected against systemic insulin resistance caused by a high-fat diet. |
| 7983 | 16505233 | Therefore, overexpression of SOCS3 in adipocytes causes local adipocyte insulin resistance, but it is not sufficient to cause systemic insulin resistance. |
| 7984 | 16505239 | Extracellular signal-regulated kinase (ERK)1/2 activation was increased in skeletal muscle tissue and in cultured myotubes basally and in response to insulin in women with PCOS compared with control women. |
| 7985 | 16505239 | Mitogen-activated/extracellular signal-regulated kinase kinase (MEK)1/2 was also activated in PCOS, whereas p38 mitogen-activated protein kinase phosphorylation and signaling from the insulin receptor to Grb2 was similar in both groups. |
| 7986 | 16505239 | MEK1/2 inhibition reduced IRS-1 Ser312 phosphorylation and increased IRS-1 association with the p85 subunit of phosphatidylinositol 3-kinase in both groups. |
| 7987 | 16505239 | We conclude that in PCOS skeletal muscle, 1) mitogenic signaling is enhanced in vivo and in culture, 2) ERK1/2 activation inhibits association of IRS-1 with p85 via IRS-1 Ser312 phosphorylation, and 3) ERK1/2 activation may play a role in normal feedback of insulin signaling and contribute to resistance to insulin's metabolic actions in PCOS. |
| 7988 | 16505239 | Extracellular signal-regulated kinase (ERK)1/2 activation was increased in skeletal muscle tissue and in cultured myotubes basally and in response to insulin in women with PCOS compared with control women. |
| 7989 | 16505239 | Mitogen-activated/extracellular signal-regulated kinase kinase (MEK)1/2 was also activated in PCOS, whereas p38 mitogen-activated protein kinase phosphorylation and signaling from the insulin receptor to Grb2 was similar in both groups. |
| 7990 | 16505239 | MEK1/2 inhibition reduced IRS-1 Ser312 phosphorylation and increased IRS-1 association with the p85 subunit of phosphatidylinositol 3-kinase in both groups. |
| 7991 | 16505239 | We conclude that in PCOS skeletal muscle, 1) mitogenic signaling is enhanced in vivo and in culture, 2) ERK1/2 activation inhibits association of IRS-1 with p85 via IRS-1 Ser312 phosphorylation, and 3) ERK1/2 activation may play a role in normal feedback of insulin signaling and contribute to resistance to insulin's metabolic actions in PCOS. |
| 7992 | 16505244 | IRS-1 serine phosphorylation and insulin resistance in skeletal muscle from pancreas transplant recipients. |
| 7993 | 16505244 | Basal insulin receptor substrate (IRS)-1 Ser (312) and Ser (616) phosphorylation, IRS-1-associated phosphatidylinositol 3-kinase activity, and extracellular signal-regulated kinase (ERK)-1/2 phosphorylation were elevated in pancreas-kidney transplant recipients, coincident with fasting hyperinsulinemia. |
| 7994 | 16505244 | Insulin increased phosphorylation of IRS-1 at Ser (312) but not Ser (616) in healthy subjects, with impairments noted in nondiabetic kidney and pancreas-kidney transplant recipients. |
| 7995 | 16505244 | Insulin action on ERK-1/2 and Akt phosphorylation was impaired in pancreas-kidney transplant recipients and was preserved in nondiabetic kidney transplant recipients. |
| 7996 | 16505244 | Importantly, insulin stimulation of the Akt substrate AS160 was impaired in nondiabetic kidney and pancreas-kidney transplant recipients. |
| 7997 | 16505244 | In conclusion, peripheral insulin resistance in pancreas-kidney transplant recipients may arise from a negative feedback regulation of the canonical insulin-signaling cascade from excessive serine phosphorylation of IRS-1, possibly as a consequence of immunosuppressive therapy and hyperinsulinemia. |
| 7998 | 16505244 | IRS-1 serine phosphorylation and insulin resistance in skeletal muscle from pancreas transplant recipients. |
| 7999 | 16505244 | Basal insulin receptor substrate (IRS)-1 Ser (312) and Ser (616) phosphorylation, IRS-1-associated phosphatidylinositol 3-kinase activity, and extracellular signal-regulated kinase (ERK)-1/2 phosphorylation were elevated in pancreas-kidney transplant recipients, coincident with fasting hyperinsulinemia. |
| 8000 | 16505244 | Insulin increased phosphorylation of IRS-1 at Ser (312) but not Ser (616) in healthy subjects, with impairments noted in nondiabetic kidney and pancreas-kidney transplant recipients. |
| 8001 | 16505244 | Insulin action on ERK-1/2 and Akt phosphorylation was impaired in pancreas-kidney transplant recipients and was preserved in nondiabetic kidney transplant recipients. |
| 8002 | 16505244 | Importantly, insulin stimulation of the Akt substrate AS160 was impaired in nondiabetic kidney and pancreas-kidney transplant recipients. |
| 8003 | 16505244 | In conclusion, peripheral insulin resistance in pancreas-kidney transplant recipients may arise from a negative feedback regulation of the canonical insulin-signaling cascade from excessive serine phosphorylation of IRS-1, possibly as a consequence of immunosuppressive therapy and hyperinsulinemia. |
| 8004 | 16505244 | IRS-1 serine phosphorylation and insulin resistance in skeletal muscle from pancreas transplant recipients. |
| 8005 | 16505244 | Basal insulin receptor substrate (IRS)-1 Ser (312) and Ser (616) phosphorylation, IRS-1-associated phosphatidylinositol 3-kinase activity, and extracellular signal-regulated kinase (ERK)-1/2 phosphorylation were elevated in pancreas-kidney transplant recipients, coincident with fasting hyperinsulinemia. |
| 8006 | 16505244 | Insulin increased phosphorylation of IRS-1 at Ser (312) but not Ser (616) in healthy subjects, with impairments noted in nondiabetic kidney and pancreas-kidney transplant recipients. |
| 8007 | 16505244 | Insulin action on ERK-1/2 and Akt phosphorylation was impaired in pancreas-kidney transplant recipients and was preserved in nondiabetic kidney transplant recipients. |
| 8008 | 16505244 | Importantly, insulin stimulation of the Akt substrate AS160 was impaired in nondiabetic kidney and pancreas-kidney transplant recipients. |
| 8009 | 16505244 | In conclusion, peripheral insulin resistance in pancreas-kidney transplant recipients may arise from a negative feedback regulation of the canonical insulin-signaling cascade from excessive serine phosphorylation of IRS-1, possibly as a consequence of immunosuppressive therapy and hyperinsulinemia. |
| 8010 | 16507892 | Severely impaired insulin signaling in chronic wounds of diabetic ob/ob mice: a potential role of tumor necrosis factor-alpha. |
| 8011 | 16507892 | Here, we investigated insulin-mediated signaling in nonwounded skin and in cutaneous tissue regeneration of healthy C57BL/6 and diabetes-impaired leptin-deficient obese/obese (ob/ob) mice. |
| 8012 | 16507892 | Remarkably, active signaling from the InsR, as assessed by phosphorylation of downstream targets such as protein tyrosine phosphatase-1B, glycogen synthase (GS), and GS kinase, was nearly absent in nonwounded and acutely healing skin from ob/ob mice. |
| 8013 | 16507892 | Systemic leptin administration to ob/ob mice reverted the diabetic phenotype and improved tissue regeneration as well as the impaired expression of InsR, insulin receptor substrate-1 and insulin receptor substrate-2, and downstream signaling (phosphorylation of GS kinase and GS) in late wounds and nonwounded skin of ob/ob mice. |
| 8014 | 16507892 | Importantly, tumor necrosis factor (TNF)-alpha was a mediator of insulin resistance in keratinocytes in vitro and in ob/ob wound tissue in vivo. |
| 8015 | 16507892 | Systemic administration of a monoclonal anti-TNF-alpha antibody (V1q) in wounded ob/ob mice attenuated wound inflammation, improved re-epithelialization, and restored InsR expression and signaling in wound tissue of ob/ob mice. |
| 8016 | 16507892 | These data suggest that InsR signaling in diabetes-impaired wounds is sensitive to inflammatory conditions and that anti-inflammatory approaches, such as anti-TNF-alpha strategies, improve diabetic wound healing. |
| 8017 | 16516141 | Phosphorylation of IRS1 at serine 307 and serine 312 in response to insulin in human adipocytes. |
| 8018 | 16516141 | By analyzing the insulin-induced phosphorylation of IRS1 at serine 307, serine 312, and tyrosine in the same primary human adipocytes, we now report that negative feedback phosphorylation of serine 312 (corresponding to murine serine 307) required relatively high concentrations of insulin (EC(50)=3 nM) for a long time (t(1/2) ca. 30 min) and reduced the steady-state tyrosine phosphorylation, without affecting the cellular concentration, of IRS1. |
| 8019 | 16516141 | Phosphorylation of IRS1 at serine 307 and serine 312 in response to insulin in human adipocytes. |
| 8020 | 16516141 | By analyzing the insulin-induced phosphorylation of IRS1 at serine 307, serine 312, and tyrosine in the same primary human adipocytes, we now report that negative feedback phosphorylation of serine 312 (corresponding to murine serine 307) required relatively high concentrations of insulin (EC(50)=3 nM) for a long time (t(1/2) ca. 30 min) and reduced the steady-state tyrosine phosphorylation, without affecting the cellular concentration, of IRS1. |
| 8021 | 16545776 | PKCtheta overexpression induced reduction of IRS-1 protein levels with a decrease in insulin-induced p85 binding to IRS-1, phosphorylation of PKB and its substrates, p70 and GSK3. |
| 8022 | 16545776 | PKCtheta was found to be expressed in liver and treatment of human hepatoma cells (HepG2) with high insulin and glucose resulted in an increase in PKCtheta expression that correlated with a decrease in IRS-1 protein levels and the development of insulin resistance. |
| 8023 | 16545776 | Reduction of PKCtheta expression using RNAi technology significantly inhibited the degradation of IRS-1 and enhanced insulin-induced IRS-1 tyrosine phosphorylation, p85 association to IRS-1 and PKB phosphorylation. |
| 8024 | 16545776 | PKCtheta overexpression induced reduction of IRS-1 protein levels with a decrease in insulin-induced p85 binding to IRS-1, phosphorylation of PKB and its substrates, p70 and GSK3. |
| 8025 | 16545776 | PKCtheta was found to be expressed in liver and treatment of human hepatoma cells (HepG2) with high insulin and glucose resulted in an increase in PKCtheta expression that correlated with a decrease in IRS-1 protein levels and the development of insulin resistance. |
| 8026 | 16545776 | Reduction of PKCtheta expression using RNAi technology significantly inhibited the degradation of IRS-1 and enhanced insulin-induced IRS-1 tyrosine phosphorylation, p85 association to IRS-1 and PKB phosphorylation. |
| 8027 | 16545776 | PKCtheta overexpression induced reduction of IRS-1 protein levels with a decrease in insulin-induced p85 binding to IRS-1, phosphorylation of PKB and its substrates, p70 and GSK3. |
| 8028 | 16545776 | PKCtheta was found to be expressed in liver and treatment of human hepatoma cells (HepG2) with high insulin and glucose resulted in an increase in PKCtheta expression that correlated with a decrease in IRS-1 protein levels and the development of insulin resistance. |
| 8029 | 16545776 | Reduction of PKCtheta expression using RNAi technology significantly inhibited the degradation of IRS-1 and enhanced insulin-induced IRS-1 tyrosine phosphorylation, p85 association to IRS-1 and PKB phosphorylation. |
| 8030 | 16556765 | Low insulin-like growth factor binding protein-2 expression is responsible for increased insulin receptor substrate-1 phosphorylation in mesangial cells from mice susceptible to glomerulosclerosis. |
| 8031 | 16556765 | However, IGF-I, IGF-I receptor, and IRS-1 protein levels were induced by exposure to 25 mm glucose in both cell lines. |
| 8032 | 16556765 | Addition of exogenous IGFBP-2 partially blunted the effect of 25 mm glucose on IRS-1 phosphorylation in ROP MC. |
| 8033 | 16556765 | Finally, addition of exogenous IGFBP-2 in ROP MC partially blunted the effect of high glucose on IRS-1 phosphorylation and might have a protective role. |
| 8034 | 16556765 | Low insulin-like growth factor binding protein-2 expression is responsible for increased insulin receptor substrate-1 phosphorylation in mesangial cells from mice susceptible to glomerulosclerosis. |
| 8035 | 16556765 | However, IGF-I, IGF-I receptor, and IRS-1 protein levels were induced by exposure to 25 mm glucose in both cell lines. |
| 8036 | 16556765 | Addition of exogenous IGFBP-2 partially blunted the effect of 25 mm glucose on IRS-1 phosphorylation in ROP MC. |
| 8037 | 16556765 | Finally, addition of exogenous IGFBP-2 in ROP MC partially blunted the effect of high glucose on IRS-1 phosphorylation and might have a protective role. |
| 8038 | 16556765 | Low insulin-like growth factor binding protein-2 expression is responsible for increased insulin receptor substrate-1 phosphorylation in mesangial cells from mice susceptible to glomerulosclerosis. |
| 8039 | 16556765 | However, IGF-I, IGF-I receptor, and IRS-1 protein levels were induced by exposure to 25 mm glucose in both cell lines. |
| 8040 | 16556765 | Addition of exogenous IGFBP-2 partially blunted the effect of 25 mm glucose on IRS-1 phosphorylation in ROP MC. |
| 8041 | 16556765 | Finally, addition of exogenous IGFBP-2 in ROP MC partially blunted the effect of high glucose on IRS-1 phosphorylation and might have a protective role. |
| 8042 | 16556765 | Low insulin-like growth factor binding protein-2 expression is responsible for increased insulin receptor substrate-1 phosphorylation in mesangial cells from mice susceptible to glomerulosclerosis. |
| 8043 | 16556765 | However, IGF-I, IGF-I receptor, and IRS-1 protein levels were induced by exposure to 25 mm glucose in both cell lines. |
| 8044 | 16556765 | Addition of exogenous IGFBP-2 partially blunted the effect of 25 mm glucose on IRS-1 phosphorylation in ROP MC. |
| 8045 | 16556765 | Finally, addition of exogenous IGFBP-2 in ROP MC partially blunted the effect of high glucose on IRS-1 phosphorylation and might have a protective role. |
| 8046 | 16567515 | Opposite effect of JAK2 on insulin-dependent activation of mitogen-activated protein kinases and Akt in muscle cells: possible target to ameliorate insulin resistance. |
| 8047 | 16567515 | Activated JAK binds to signal transducers and activators of transcription, insulin receptor substrates (IRSs), and Shc. |
| 8048 | 16567515 | Intriguingly, insulin acting through its own receptor kinase also activates JAK2. |
| 8049 | 16567515 | To determine the contribution of JAK2 to insulin signaling, we transfected L6 myotubes with siRNA against JAK2 (siJAK2), reducing JAK2 protein expression by 75%. |
| 8050 | 16567515 | Insulin-dependent phosphorylation of IRS1/2 and Shc was not affected by siJAK2, but insulin-induced phosphorylation of the mitogen-activated protein kinases (MAPKs) extracellular signal-related kinase, p38, and Jun NH2-terminal kinase and their respective upstream kinases MKK1/2, MKK3/6, and MKK4/7 was significantly lowered when JAK2 was depleted, correlating with a significant drop in insulin-mediated cell proliferation. |
| 8051 | 16567515 | Conversely, insulin-stimulated Akt phosphorylation, glucose uptake, and GLUT4 translocation were not affected by siJAK2. |
| 8052 | 16567515 | Interestingly, in two insulin-resistant states, siJAK2 led to partial restoration of Akt phosphorylation and glucose uptake stimulation but not of the MAPK pathway. |
| 8053 | 16567515 | These results suggest that JAK2 may depress the Akt to glucose uptake signaling axis selectively in insulin-resistant states. |
| 8054 | 16567515 | Inhibition of JAK2 may be a useful strategy to relieve insulin resistance of metabolic outcomes. |
| 8055 | 16567541 | We previously showed that insulin mediates a prosurvival pathway in retinal neurons and that normal retina expresses a highly active basal insulin receptor/Akt signaling pathway that is stable throughout feeding and fasting. |
| 8056 | 16567541 | The expression, phosphorylation status, and/or kinase activity of the insulin receptor and downstream signaling proteins were investigated in retinas of age-matched control, diabetic, and insulin-treated diabetic rats. |
| 8057 | 16567541 | Four weeks of diabetes reduced basal insulin receptor kinase, insulin receptor substrate (IRS)-1/2-associated phosphatidylinositol 3-kinase, and Akt kinase activity without altering insulin receptor or IRS-1/2 expression or tyrosine phosphorylation. |
| 8058 | 16567541 | After 12 weeks of diabetes, constitutive insulin receptor autophosphorylation and IRS-2 expression were reduced, without changes in p42/p44 mitogen-activated protein kinase or IRS-1. |
| 8059 | 16567541 | Sustained systemic insulin treatment of diabetic rats prevented loss of insulin receptor and Akt kinase activity, and acute intravitreal insulin administration restored insulin receptor kinase activity. |
| 8060 | 16567541 | Insulin treatment restored insulin receptor-beta autophosphorylation in rat retinas maintained ex vivo, demonstrating functional receptors and suggesting loss of ligand as a cause for reduced retinal insulin receptor/Akt pathway activity. |
| 8061 | 16567541 | These results demonstrate that diabetes progressively impairs the constitutive retinal insulin receptor signaling pathway through Akt and suggests that loss of this survival pathway may contribute to the initial stages of diabetic retinopathy. |
| 8062 | 16567541 | We previously showed that insulin mediates a prosurvival pathway in retinal neurons and that normal retina expresses a highly active basal insulin receptor/Akt signaling pathway that is stable throughout feeding and fasting. |
| 8063 | 16567541 | The expression, phosphorylation status, and/or kinase activity of the insulin receptor and downstream signaling proteins were investigated in retinas of age-matched control, diabetic, and insulin-treated diabetic rats. |
| 8064 | 16567541 | Four weeks of diabetes reduced basal insulin receptor kinase, insulin receptor substrate (IRS)-1/2-associated phosphatidylinositol 3-kinase, and Akt kinase activity without altering insulin receptor or IRS-1/2 expression or tyrosine phosphorylation. |
| 8065 | 16567541 | After 12 weeks of diabetes, constitutive insulin receptor autophosphorylation and IRS-2 expression were reduced, without changes in p42/p44 mitogen-activated protein kinase or IRS-1. |
| 8066 | 16567541 | Sustained systemic insulin treatment of diabetic rats prevented loss of insulin receptor and Akt kinase activity, and acute intravitreal insulin administration restored insulin receptor kinase activity. |
| 8067 | 16567541 | Insulin treatment restored insulin receptor-beta autophosphorylation in rat retinas maintained ex vivo, demonstrating functional receptors and suggesting loss of ligand as a cause for reduced retinal insulin receptor/Akt pathway activity. |
| 8068 | 16567541 | These results demonstrate that diabetes progressively impairs the constitutive retinal insulin receptor signaling pathway through Akt and suggests that loss of this survival pathway may contribute to the initial stages of diabetic retinopathy. |
| 8069 | 16574795 | We recently reported that disruption of FAK impairs insulin-mediated glycogen synthesis in hepatocytes. |
| 8070 | 16574795 | To test the hypothesis that FAK regulates skeletal muscle insulin action, we reduced FAK expression in L6 myotubes using FAK antisense. |
| 8071 | 16574795 | In untransfected myotubes, insulin stimulated both FAK tyrosine phosphorylation and kinase activity. |
| 8072 | 16574795 | Cells treated with antisense FAK showed 78 and 53% reductions in FAK mRNA and FAK protein, respectively, whereas insulin receptor substrate 1/2 and paxillin abundance were unaffected. |
| 8073 | 16574795 | Insulin-stimulated U-(14)C-glucose incorporation into glycogen was abolished by FAK antisense, and 2-deoxy-glucose uptake and glucose transporter 4 (GLUT4) translocation were both markedly attenuated. |
| 8074 | 16574795 | Antisense FAK did not alter GLUT1 or GLUT3 protein abundance. |
| 8075 | 16574795 | Thus, in skeletal myotubes, FAK regulates the insulin-mediated cytoskeletal rearrangement essential for normal glucose transport and glycogen synthesis. |
| 8076 | 16601979 | During the next 12-24 months, many peri-insular ductules progressed via tumor-like cystic lesions to large cystic cholangiomas, accompanied by a translocation of the insulin receptor into the cytoplasm and an increase in expression of insulin-related signaling proteins (Insulin-receptor-substrate-1, Raf-1, Mek-1). |
| 8077 | 16611834 | Leptin down-regulates insulin action through phosphorylation of serine-318 in insulin receptor substrate 1. |
| 8078 | 16611834 | Recently, we described serine-318 as a protein kinase C (PKC)-dependent phosphorylation site in Irs1 (Ser-318) activated by hyperinsulinemia. |
| 8079 | 16611834 | Here we show in various cell models that the adipose hormone leptin, a putative mediator in obesity-related insulin resistance, promotes phosphorylation of Ser-318 in Irs1 by a janus kinase 2, Irs2, and PKC-dependent pathway. |
| 8080 | 16611834 | Mutation of Ser-318 to alanine abrogates the inhibitory effect of leptin on insulin-induced Irs1 tyrosine phosphorylation and glucose uptake in L6 myoblasts. |
| 8081 | 16611834 | In C57Bl/6 mice, Ser-318 phosphorylation levels in muscle tissue were enhanced by leptin and insulin administration in lean animals while in diet-induced obesity Ser-318 phosphorylation levels were already up-regulated in the basal state, and further stimulation was diminished. |
| 8082 | 16611834 | In summary, these data suggest that phosphorylation of Ser-318 in Irs1 mediates the inhibitory signal of leptin on the insulin-signaling cascade in obese subjects. |
| 8083 | 16611834 | Leptin down-regulates insulin action through phosphorylation of serine-318 in insulin receptor substrate 1. |
| 8084 | 16611834 | Recently, we described serine-318 as a protein kinase C (PKC)-dependent phosphorylation site in Irs1 (Ser-318) activated by hyperinsulinemia. |
| 8085 | 16611834 | Here we show in various cell models that the adipose hormone leptin, a putative mediator in obesity-related insulin resistance, promotes phosphorylation of Ser-318 in Irs1 by a janus kinase 2, Irs2, and PKC-dependent pathway. |
| 8086 | 16611834 | Mutation of Ser-318 to alanine abrogates the inhibitory effect of leptin on insulin-induced Irs1 tyrosine phosphorylation and glucose uptake in L6 myoblasts. |
| 8087 | 16611834 | In C57Bl/6 mice, Ser-318 phosphorylation levels in muscle tissue were enhanced by leptin and insulin administration in lean animals while in diet-induced obesity Ser-318 phosphorylation levels were already up-regulated in the basal state, and further stimulation was diminished. |
| 8088 | 16611834 | In summary, these data suggest that phosphorylation of Ser-318 in Irs1 mediates the inhibitory signal of leptin on the insulin-signaling cascade in obese subjects. |
| 8089 | 16611834 | Leptin down-regulates insulin action through phosphorylation of serine-318 in insulin receptor substrate 1. |
| 8090 | 16611834 | Recently, we described serine-318 as a protein kinase C (PKC)-dependent phosphorylation site in Irs1 (Ser-318) activated by hyperinsulinemia. |
| 8091 | 16611834 | Here we show in various cell models that the adipose hormone leptin, a putative mediator in obesity-related insulin resistance, promotes phosphorylation of Ser-318 in Irs1 by a janus kinase 2, Irs2, and PKC-dependent pathway. |
| 8092 | 16611834 | Mutation of Ser-318 to alanine abrogates the inhibitory effect of leptin on insulin-induced Irs1 tyrosine phosphorylation and glucose uptake in L6 myoblasts. |
| 8093 | 16611834 | In C57Bl/6 mice, Ser-318 phosphorylation levels in muscle tissue were enhanced by leptin and insulin administration in lean animals while in diet-induced obesity Ser-318 phosphorylation levels were already up-regulated in the basal state, and further stimulation was diminished. |
| 8094 | 16611834 | In summary, these data suggest that phosphorylation of Ser-318 in Irs1 mediates the inhibitory signal of leptin on the insulin-signaling cascade in obese subjects. |
| 8095 | 16611834 | Leptin down-regulates insulin action through phosphorylation of serine-318 in insulin receptor substrate 1. |
| 8096 | 16611834 | Recently, we described serine-318 as a protein kinase C (PKC)-dependent phosphorylation site in Irs1 (Ser-318) activated by hyperinsulinemia. |
| 8097 | 16611834 | Here we show in various cell models that the adipose hormone leptin, a putative mediator in obesity-related insulin resistance, promotes phosphorylation of Ser-318 in Irs1 by a janus kinase 2, Irs2, and PKC-dependent pathway. |
| 8098 | 16611834 | Mutation of Ser-318 to alanine abrogates the inhibitory effect of leptin on insulin-induced Irs1 tyrosine phosphorylation and glucose uptake in L6 myoblasts. |
| 8099 | 16611834 | In C57Bl/6 mice, Ser-318 phosphorylation levels in muscle tissue were enhanced by leptin and insulin administration in lean animals while in diet-induced obesity Ser-318 phosphorylation levels were already up-regulated in the basal state, and further stimulation was diminished. |
| 8100 | 16611834 | In summary, these data suggest that phosphorylation of Ser-318 in Irs1 mediates the inhibitory signal of leptin on the insulin-signaling cascade in obese subjects. |
| 8101 | 16611834 | Leptin down-regulates insulin action through phosphorylation of serine-318 in insulin receptor substrate 1. |
| 8102 | 16611834 | Recently, we described serine-318 as a protein kinase C (PKC)-dependent phosphorylation site in Irs1 (Ser-318) activated by hyperinsulinemia. |
| 8103 | 16611834 | Here we show in various cell models that the adipose hormone leptin, a putative mediator in obesity-related insulin resistance, promotes phosphorylation of Ser-318 in Irs1 by a janus kinase 2, Irs2, and PKC-dependent pathway. |
| 8104 | 16611834 | Mutation of Ser-318 to alanine abrogates the inhibitory effect of leptin on insulin-induced Irs1 tyrosine phosphorylation and glucose uptake in L6 myoblasts. |
| 8105 | 16611834 | In C57Bl/6 mice, Ser-318 phosphorylation levels in muscle tissue were enhanced by leptin and insulin administration in lean animals while in diet-induced obesity Ser-318 phosphorylation levels were already up-regulated in the basal state, and further stimulation was diminished. |
| 8106 | 16611834 | In summary, these data suggest that phosphorylation of Ser-318 in Irs1 mediates the inhibitory signal of leptin on the insulin-signaling cascade in obese subjects. |
| 8107 | 16622294 | Insulin-resistant muscle has defects at several steps of the insulin-signaling pathway, including decreases in insulin-stimulated insulin receptor and insulin receptor substrate-1 tyrosine phosphorylation, and phosphatidylinositol 3-kinase (PI 3-kinase) activation. |
| 8108 | 16622294 | Weight loss and thiazolidinediones (TZDs) improve glucose disposal, in part, by increasing insulin-stimulated insulin receptor and IRS-1 tyrosine phosphorylation and PI 3-kinase activity. |
| 8109 | 16622294 | A novel approach to reverse insulin resistance involves inhibition of the stress-activated protein kinase Jun N-terminal kinase (JNK) and the protein tyrosine phosphatases (PTPs). |
| 8110 | 16622294 | AMPK activation is also involved in the mechanism of action of metformin and adiponectin. |
| 8111 | 16622294 | Insulin-resistant muscle has defects at several steps of the insulin-signaling pathway, including decreases in insulin-stimulated insulin receptor and insulin receptor substrate-1 tyrosine phosphorylation, and phosphatidylinositol 3-kinase (PI 3-kinase) activation. |
| 8112 | 16622294 | Weight loss and thiazolidinediones (TZDs) improve glucose disposal, in part, by increasing insulin-stimulated insulin receptor and IRS-1 tyrosine phosphorylation and PI 3-kinase activity. |
| 8113 | 16622294 | A novel approach to reverse insulin resistance involves inhibition of the stress-activated protein kinase Jun N-terminal kinase (JNK) and the protein tyrosine phosphatases (PTPs). |
| 8114 | 16622294 | AMPK activation is also involved in the mechanism of action of metformin and adiponectin. |
| 8115 | 16627931 | More recently, studies with human postmortem brain tissue linked many of the characteristic molecular and pathological features of AD to reduced expression of the insulin and insulin-like growth factor (IGF) genes and their corresponding receptors. |
| 8116 | 16627931 | The ic-STZ-injected rats did not have elevated blood glucose levels, and pancreatic architecture and insulin immunoreactivity were similar to control, yet their brains were reduced in size and exhibited neurodegeneration associated with cell loss, gliosis, and increased immunoreactivity for p53, active glycogen synthase kinase 3beta, phospho-tau, ubiquitin, and amyloid-beta. |
| 8117 | 16627931 | Real time quantitative RT-PCR studies demonstrated that the ic-STZ-treated brains had significantly reduced expression of genes corresponding to neurons, oligodendroglia, and choline acetyltransferase, and increased expression of genes encoding glial fibrillary acidic protein, microglia-specific proteins, acetylcholinesterase, tau, and amyloid precursor protein. |
| 8118 | 16627931 | These abnormalities were associated reduced expression of genes encoding insulin, IGF-II, insulin receptor, IGF-I receptor, and insulin receptor substrate-1, and reduced ligand binding to the insulin and IGF-II receptors. |
| 8119 | 16644673 | Impact of mitochondrial reactive oxygen species and apoptosis signal-regulating kinase 1 on insulin signaling. |
| 8120 | 16644673 | Tumor necrosis factor (TNF)-alpha inhibits insulin action; however, the precise mechanisms are unknown. |
| 8121 | 16644673 | It was reported that TNF-alpha could increase mitochondrial reactive oxygen species (ROS) production, and apoptosis signal-regulating kinase 1 (ASK1) was reported to be required for TNF-alpha-induced apoptosis. |
| 8122 | 16644673 | Here, we examined roles of mitochondrial ROS and ASK1 in TNF-alpha-induced impaired insulin signaling in cultured human hepatoma (Huh7) cells. |
| 8123 | 16644673 | Using reduced MitoTracker Red probe, we confirmed that TNF-alpha increased mitochondrial ROS production, which was suppressed by overexpression of either uncoupling protein-1 (UCP)-1 or manganese superoxide dismutase (MnSOD). |
| 8124 | 16644673 | TNF-alpha significantly activated ASK1, increased serine phosphorylation of insulin receptor substrate (IRS)-1, and decreased insulin-stimulated tyrosine phosphorylation of IRS-1 and serine phosphorylation of Akt, and all of these effects were inhibited by overexpression of either UCP-1 or MnSOD. |
| 8125 | 16644673 | Similar to TNF-alpha, overexpression of wild-type ASK1 increased serine phosphorylation of IRS-1 and decreased insulin-stimulated tyrosine phosphorylation of IRS-1, whereas overexpression of dominant-negative ASK1 ameliorated these TNF-alpha-induced events. |
| 8126 | 16644673 | In addition, TNF-alpha activated c-jun NH(2)-terminal kinases (JNKs), and this observation was partially inhibited by overexpression of UCP-1, MnSOD, or dominant-negative ASK1. |
| 8127 | 16644673 | These results suggest that TNF-alpha increases mitochondrial ROS and activates ASK1 in Huh7 cells and that these TNF-alpha-induced phenomena contribute, at least in part, to impaired insulin signaling. |
| 8128 | 16644673 | Impact of mitochondrial reactive oxygen species and apoptosis signal-regulating kinase 1 on insulin signaling. |
| 8129 | 16644673 | Tumor necrosis factor (TNF)-alpha inhibits insulin action; however, the precise mechanisms are unknown. |
| 8130 | 16644673 | It was reported that TNF-alpha could increase mitochondrial reactive oxygen species (ROS) production, and apoptosis signal-regulating kinase 1 (ASK1) was reported to be required for TNF-alpha-induced apoptosis. |
| 8131 | 16644673 | Here, we examined roles of mitochondrial ROS and ASK1 in TNF-alpha-induced impaired insulin signaling in cultured human hepatoma (Huh7) cells. |
| 8132 | 16644673 | Using reduced MitoTracker Red probe, we confirmed that TNF-alpha increased mitochondrial ROS production, which was suppressed by overexpression of either uncoupling protein-1 (UCP)-1 or manganese superoxide dismutase (MnSOD). |
| 8133 | 16644673 | TNF-alpha significantly activated ASK1, increased serine phosphorylation of insulin receptor substrate (IRS)-1, and decreased insulin-stimulated tyrosine phosphorylation of IRS-1 and serine phosphorylation of Akt, and all of these effects were inhibited by overexpression of either UCP-1 or MnSOD. |
| 8134 | 16644673 | Similar to TNF-alpha, overexpression of wild-type ASK1 increased serine phosphorylation of IRS-1 and decreased insulin-stimulated tyrosine phosphorylation of IRS-1, whereas overexpression of dominant-negative ASK1 ameliorated these TNF-alpha-induced events. |
| 8135 | 16644673 | In addition, TNF-alpha activated c-jun NH(2)-terminal kinases (JNKs), and this observation was partially inhibited by overexpression of UCP-1, MnSOD, or dominant-negative ASK1. |
| 8136 | 16644673 | These results suggest that TNF-alpha increases mitochondrial ROS and activates ASK1 in Huh7 cells and that these TNF-alpha-induced phenomena contribute, at least in part, to impaired insulin signaling. |
| 8137 | 16644685 | We demonstrate that a short exposure to methylglyoxal induces an inhibition of insulin-stimulated phosphorylation of protein kinase B and extracellular-regulated kinase 1/2, without affecting insulin receptor tyrosine phosphorylation. |
| 8138 | 16644685 | Importantly, these deleterious effects of methylglyoxal are independent of reactive oxygen species produced by methylglyoxal but appear to be the direct consequence of an impairment of insulin-induced insulin receptor substrate-1 tyrosine phosphorylation subsequent to the binding of methylglyoxal to these proteins. |
| 8139 | 16644688 | Intestinal insulin resistance and aberrant production of apolipoprotein B48 lipoproteins in an animal model of insulin resistance and metabolic dyslipidemia: evidence for activation of protein tyrosine phosphatase-1B, extracellular signal-related kinase, and sterol regulatory element-binding protein-1c in the fructose-fed hamster intestine. |
| 8140 | 16644688 | Intestinal lipoprotein production in chow-fed hamsters was responsive to the inhibitory effects of insulin, and a decrease in circulating levels of triglyceride-rich apolipoprotein (apo)B48-containing lipoproteins occurred 60 min after insulin administration. |
| 8141 | 16644688 | However, fructose-fed hamster intestine was not responsive to the insulin-induced downregulation of apoB48-lipoprotein production, suggesting insulin insensitivity at the level of the intestine. |
| 8142 | 16644688 | Enterocytes from the fructose-fed hamster exhibited normal activity of the insulin receptor but reduced levels of insulin receptor substrate-1 phosphorylation and mass and Akt protein mass. |
| 8143 | 16644688 | Conversely, the protein mass of the p110 subunit of phosphatidylinositol 3-kinase, protein tyrosine phosphatase-1B, and basal levels of phosphorylated extracellular signal-related kinase (ERK) were significantly increased in the fructose-fed hamster intestine. |
| 8144 | 16644688 | Modulating the ERK pathway through in vivo inhibition of mitogen-activated protein/ERK kinase 1/2, the upstream activator of ERK1/2, we observed a significant decrease in intestinal apoB48 synthesis and secretion. |
| 8145 | 16644688 | Interestingly, enhanced basal ERK activity in the fructose-fed hamster intestine was accompanied by an increased activation of sterol regulatory element-binding protein. |
| 8146 | 16644688 | In summary, these data suggest that insulin insensitivity at the level of the intestine and aberrant insulin signaling are important underlying factors in intestinal overproduction of highly atherogenic apoB48-containing lipoproteins in the insulin-resistant state. |
| 8147 | 16644688 | Basal activation of the ERK pathway may be an important contributor to the aberrant insulin signaling and lipoprotein overproduction in this model. |
| 8148 | 16702017 | The prototypical insulin receptor substrate, IRS-1 plays a central role in insulin signaling. |
| 8149 | 16702017 | By subcellular fractionation IRS-1 is enriched in a particulate fraction, termed the high speed pellet (HSP), and its redistribution from this fraction is associated with signal attenuation and insulin resistance. |
| 8150 | 16702017 | By standard microscopy or immunoprecipitation we were unable to detect evidence to support a specific interaction between IRS-1 and the major cytoskeletal components actin (microfilaments), vimentin (intermediate filaments), and tubulin (microtubules) in 3T3-L1 adipocytes or in CHO.IR.IRS-1 cells. |
| 8151 | 16702017 | Pharmacological disruption of microfilaments and microtubules, individually or in combination, was without effect on the subcellular distribution of IRS-1 or insulin-stimulated tyrosine phosphorylation in either cell type. |
| 8152 | 16702017 | In cells lacking intermediate filaments (Vim(-/-)) IRS-1 expression, distribution and insulin-stimulated phosphorylation appeared normal. |
| 8153 | 16702017 | Even after depolymerisation of microfilaments and microtubules, insulin-stimulated phosphorylation of IRS-1 and Akt were maintained in Vim(-/-) cells. |
| 8154 | 16702017 | Taken together these data indicate that the characteristic subcellular fractionation properties and function of IRS-1 are unlikely to be mediated by cytoskeletal networks and that proximal insulin signaling does not require an intact cytoskeleton. |
| 8155 | 16702017 | The prototypical insulin receptor substrate, IRS-1 plays a central role in insulin signaling. |
| 8156 | 16702017 | By subcellular fractionation IRS-1 is enriched in a particulate fraction, termed the high speed pellet (HSP), and its redistribution from this fraction is associated with signal attenuation and insulin resistance. |
| 8157 | 16702017 | By standard microscopy or immunoprecipitation we were unable to detect evidence to support a specific interaction between IRS-1 and the major cytoskeletal components actin (microfilaments), vimentin (intermediate filaments), and tubulin (microtubules) in 3T3-L1 adipocytes or in CHO.IR.IRS-1 cells. |
| 8158 | 16702017 | Pharmacological disruption of microfilaments and microtubules, individually or in combination, was without effect on the subcellular distribution of IRS-1 or insulin-stimulated tyrosine phosphorylation in either cell type. |
| 8159 | 16702017 | In cells lacking intermediate filaments (Vim(-/-)) IRS-1 expression, distribution and insulin-stimulated phosphorylation appeared normal. |
| 8160 | 16702017 | Even after depolymerisation of microfilaments and microtubules, insulin-stimulated phosphorylation of IRS-1 and Akt were maintained in Vim(-/-) cells. |
| 8161 | 16702017 | Taken together these data indicate that the characteristic subcellular fractionation properties and function of IRS-1 are unlikely to be mediated by cytoskeletal networks and that proximal insulin signaling does not require an intact cytoskeleton. |
| 8162 | 16702017 | The prototypical insulin receptor substrate, IRS-1 plays a central role in insulin signaling. |
| 8163 | 16702017 | By subcellular fractionation IRS-1 is enriched in a particulate fraction, termed the high speed pellet (HSP), and its redistribution from this fraction is associated with signal attenuation and insulin resistance. |
| 8164 | 16702017 | By standard microscopy or immunoprecipitation we were unable to detect evidence to support a specific interaction between IRS-1 and the major cytoskeletal components actin (microfilaments), vimentin (intermediate filaments), and tubulin (microtubules) in 3T3-L1 adipocytes or in CHO.IR.IRS-1 cells. |
| 8165 | 16702017 | Pharmacological disruption of microfilaments and microtubules, individually or in combination, was without effect on the subcellular distribution of IRS-1 or insulin-stimulated tyrosine phosphorylation in either cell type. |
| 8166 | 16702017 | In cells lacking intermediate filaments (Vim(-/-)) IRS-1 expression, distribution and insulin-stimulated phosphorylation appeared normal. |
| 8167 | 16702017 | Even after depolymerisation of microfilaments and microtubules, insulin-stimulated phosphorylation of IRS-1 and Akt were maintained in Vim(-/-) cells. |
| 8168 | 16702017 | Taken together these data indicate that the characteristic subcellular fractionation properties and function of IRS-1 are unlikely to be mediated by cytoskeletal networks and that proximal insulin signaling does not require an intact cytoskeleton. |
| 8169 | 16702017 | The prototypical insulin receptor substrate, IRS-1 plays a central role in insulin signaling. |
| 8170 | 16702017 | By subcellular fractionation IRS-1 is enriched in a particulate fraction, termed the high speed pellet (HSP), and its redistribution from this fraction is associated with signal attenuation and insulin resistance. |
| 8171 | 16702017 | By standard microscopy or immunoprecipitation we were unable to detect evidence to support a specific interaction between IRS-1 and the major cytoskeletal components actin (microfilaments), vimentin (intermediate filaments), and tubulin (microtubules) in 3T3-L1 adipocytes or in CHO.IR.IRS-1 cells. |
| 8172 | 16702017 | Pharmacological disruption of microfilaments and microtubules, individually or in combination, was without effect on the subcellular distribution of IRS-1 or insulin-stimulated tyrosine phosphorylation in either cell type. |
| 8173 | 16702017 | In cells lacking intermediate filaments (Vim(-/-)) IRS-1 expression, distribution and insulin-stimulated phosphorylation appeared normal. |
| 8174 | 16702017 | Even after depolymerisation of microfilaments and microtubules, insulin-stimulated phosphorylation of IRS-1 and Akt were maintained in Vim(-/-) cells. |
| 8175 | 16702017 | Taken together these data indicate that the characteristic subcellular fractionation properties and function of IRS-1 are unlikely to be mediated by cytoskeletal networks and that proximal insulin signaling does not require an intact cytoskeleton. |
| 8176 | 16702017 | The prototypical insulin receptor substrate, IRS-1 plays a central role in insulin signaling. |
| 8177 | 16702017 | By subcellular fractionation IRS-1 is enriched in a particulate fraction, termed the high speed pellet (HSP), and its redistribution from this fraction is associated with signal attenuation and insulin resistance. |
| 8178 | 16702017 | By standard microscopy or immunoprecipitation we were unable to detect evidence to support a specific interaction between IRS-1 and the major cytoskeletal components actin (microfilaments), vimentin (intermediate filaments), and tubulin (microtubules) in 3T3-L1 adipocytes or in CHO.IR.IRS-1 cells. |
| 8179 | 16702017 | Pharmacological disruption of microfilaments and microtubules, individually or in combination, was without effect on the subcellular distribution of IRS-1 or insulin-stimulated tyrosine phosphorylation in either cell type. |
| 8180 | 16702017 | In cells lacking intermediate filaments (Vim(-/-)) IRS-1 expression, distribution and insulin-stimulated phosphorylation appeared normal. |
| 8181 | 16702017 | Even after depolymerisation of microfilaments and microtubules, insulin-stimulated phosphorylation of IRS-1 and Akt were maintained in Vim(-/-) cells. |
| 8182 | 16702017 | Taken together these data indicate that the characteristic subcellular fractionation properties and function of IRS-1 are unlikely to be mediated by cytoskeletal networks and that proximal insulin signaling does not require an intact cytoskeleton. |
| 8183 | 16702017 | The prototypical insulin receptor substrate, IRS-1 plays a central role in insulin signaling. |
| 8184 | 16702017 | By subcellular fractionation IRS-1 is enriched in a particulate fraction, termed the high speed pellet (HSP), and its redistribution from this fraction is associated with signal attenuation and insulin resistance. |
| 8185 | 16702017 | By standard microscopy or immunoprecipitation we were unable to detect evidence to support a specific interaction between IRS-1 and the major cytoskeletal components actin (microfilaments), vimentin (intermediate filaments), and tubulin (microtubules) in 3T3-L1 adipocytes or in CHO.IR.IRS-1 cells. |
| 8186 | 16702017 | Pharmacological disruption of microfilaments and microtubules, individually or in combination, was without effect on the subcellular distribution of IRS-1 or insulin-stimulated tyrosine phosphorylation in either cell type. |
| 8187 | 16702017 | In cells lacking intermediate filaments (Vim(-/-)) IRS-1 expression, distribution and insulin-stimulated phosphorylation appeared normal. |
| 8188 | 16702017 | Even after depolymerisation of microfilaments and microtubules, insulin-stimulated phosphorylation of IRS-1 and Akt were maintained in Vim(-/-) cells. |
| 8189 | 16702017 | Taken together these data indicate that the characteristic subcellular fractionation properties and function of IRS-1 are unlikely to be mediated by cytoskeletal networks and that proximal insulin signaling does not require an intact cytoskeleton. |
| 8190 | 16702017 | The prototypical insulin receptor substrate, IRS-1 plays a central role in insulin signaling. |
| 8191 | 16702017 | By subcellular fractionation IRS-1 is enriched in a particulate fraction, termed the high speed pellet (HSP), and its redistribution from this fraction is associated with signal attenuation and insulin resistance. |
| 8192 | 16702017 | By standard microscopy or immunoprecipitation we were unable to detect evidence to support a specific interaction between IRS-1 and the major cytoskeletal components actin (microfilaments), vimentin (intermediate filaments), and tubulin (microtubules) in 3T3-L1 adipocytes or in CHO.IR.IRS-1 cells. |
| 8193 | 16702017 | Pharmacological disruption of microfilaments and microtubules, individually or in combination, was without effect on the subcellular distribution of IRS-1 or insulin-stimulated tyrosine phosphorylation in either cell type. |
| 8194 | 16702017 | In cells lacking intermediate filaments (Vim(-/-)) IRS-1 expression, distribution and insulin-stimulated phosphorylation appeared normal. |
| 8195 | 16702017 | Even after depolymerisation of microfilaments and microtubules, insulin-stimulated phosphorylation of IRS-1 and Akt were maintained in Vim(-/-) cells. |
| 8196 | 16702017 | Taken together these data indicate that the characteristic subcellular fractionation properties and function of IRS-1 are unlikely to be mediated by cytoskeletal networks and that proximal insulin signaling does not require an intact cytoskeleton. |
| 8197 | 16753575 | Nutrient overload, insulin resistance, and ribosomal protein S6 kinase 1, S6K1. |
| 8198 | 16753575 | Recent studies have revealed that ribosomal protein S6 kinase 1, S6K1, an effector of mTOR, is sensitive to both insulin and nutrients, including amino acids. |
| 8199 | 16753575 | Although S6K1 is an effector of growth, recent reports show that amino acids also negatively affect insulin signaling through mTOR/S6K1 phosphorylation of IRS1. |
| 8200 | 16753575 | Moreover, rather than signaling through the class 1 PI3K pathway, amino acids appear to mediate mTOR activation through class 3 PI3K, or hVps34. |
| 8201 | 16753575 | Consistent with this, infusion of amino acids into humans leads to S6K1 activation, inhibition of insulin-induced class 1 PI3K activation, and insulin resistance. |
| 8202 | 16753575 | Thus, S6K1 may mediate deleterious effects, like insulin resistance, and potentially type 2 diabetes in the face of nutrient excess. |
| 8203 | 16754202 | Differential phosphorylation of IRS-1 and IRS-2 by insulin and IGF-I receptors. |
| 8204 | 16754202 | The specific contribution of insulin and IGF-I receptors to IRS-protein activation remains elusive. |
| 8205 | 16754202 | We studied the signalling properties of AspB10-insulin, an analog with enhanced affinity for the IGF-I receptor, in comparison to native insulin using primary human skeletal muscle cells. |
| 8206 | 16754202 | In myoblasts regular insulin and AspB10-insulin were equipotent in stimulating the IRS cascade, whereas this analog induced a significantly higher Shc phosphorylation. |
| 8207 | 16754202 | Phosphorylation of IRS-1 in response to insulin was inhibited equally by blocking either the insulin or the IGF-I receptor. |
| 8208 | 16754202 | IRS-1 activation by AspB10-insulin was only inhibited by blocking the IGF-I receptor. |
| 8209 | 16754202 | IRS-2 phosphorylation induced by both insulin and AspB10-insulin was nearly insensitive to blocking the insulin receptor, being predominantly mediated by the IGF-I receptor. |
| 8210 | 16754202 | We conclude that in myoblasts IRS-2, but not IRS-1, functions as preferred substrate for the IGF-I receptor. |
| 8211 | 16754202 | Differential phosphorylation of IRS-1 and IRS-2 by insulin and IGF-I receptors. |
| 8212 | 16754202 | The specific contribution of insulin and IGF-I receptors to IRS-protein activation remains elusive. |
| 8213 | 16754202 | We studied the signalling properties of AspB10-insulin, an analog with enhanced affinity for the IGF-I receptor, in comparison to native insulin using primary human skeletal muscle cells. |
| 8214 | 16754202 | In myoblasts regular insulin and AspB10-insulin were equipotent in stimulating the IRS cascade, whereas this analog induced a significantly higher Shc phosphorylation. |
| 8215 | 16754202 | Phosphorylation of IRS-1 in response to insulin was inhibited equally by blocking either the insulin or the IGF-I receptor. |
| 8216 | 16754202 | IRS-1 activation by AspB10-insulin was only inhibited by blocking the IGF-I receptor. |
| 8217 | 16754202 | IRS-2 phosphorylation induced by both insulin and AspB10-insulin was nearly insensitive to blocking the insulin receptor, being predominantly mediated by the IGF-I receptor. |
| 8218 | 16754202 | We conclude that in myoblasts IRS-2, but not IRS-1, functions as preferred substrate for the IGF-I receptor. |
| 8219 | 16754202 | Differential phosphorylation of IRS-1 and IRS-2 by insulin and IGF-I receptors. |
| 8220 | 16754202 | The specific contribution of insulin and IGF-I receptors to IRS-protein activation remains elusive. |
| 8221 | 16754202 | We studied the signalling properties of AspB10-insulin, an analog with enhanced affinity for the IGF-I receptor, in comparison to native insulin using primary human skeletal muscle cells. |
| 8222 | 16754202 | In myoblasts regular insulin and AspB10-insulin were equipotent in stimulating the IRS cascade, whereas this analog induced a significantly higher Shc phosphorylation. |
| 8223 | 16754202 | Phosphorylation of IRS-1 in response to insulin was inhibited equally by blocking either the insulin or the IGF-I receptor. |
| 8224 | 16754202 | IRS-1 activation by AspB10-insulin was only inhibited by blocking the IGF-I receptor. |
| 8225 | 16754202 | IRS-2 phosphorylation induced by both insulin and AspB10-insulin was nearly insensitive to blocking the insulin receptor, being predominantly mediated by the IGF-I receptor. |
| 8226 | 16754202 | We conclude that in myoblasts IRS-2, but not IRS-1, functions as preferred substrate for the IGF-I receptor. |
| 8227 | 16754202 | Differential phosphorylation of IRS-1 and IRS-2 by insulin and IGF-I receptors. |
| 8228 | 16754202 | The specific contribution of insulin and IGF-I receptors to IRS-protein activation remains elusive. |
| 8229 | 16754202 | We studied the signalling properties of AspB10-insulin, an analog with enhanced affinity for the IGF-I receptor, in comparison to native insulin using primary human skeletal muscle cells. |
| 8230 | 16754202 | In myoblasts regular insulin and AspB10-insulin were equipotent in stimulating the IRS cascade, whereas this analog induced a significantly higher Shc phosphorylation. |
| 8231 | 16754202 | Phosphorylation of IRS-1 in response to insulin was inhibited equally by blocking either the insulin or the IGF-I receptor. |
| 8232 | 16754202 | IRS-1 activation by AspB10-insulin was only inhibited by blocking the IGF-I receptor. |
| 8233 | 16754202 | IRS-2 phosphorylation induced by both insulin and AspB10-insulin was nearly insensitive to blocking the insulin receptor, being predominantly mediated by the IGF-I receptor. |
| 8234 | 16754202 | We conclude that in myoblasts IRS-2, but not IRS-1, functions as preferred substrate for the IGF-I receptor. |
| 8235 | 16777978 | C-jun N-terminal kinase mediates tumor necrosis factor-alpha suppression of differentiation in myoblasts. |
| 8236 | 16777978 | The stress kinase c-jun N-terminal kinase (JNK) was recently shown to be involved in the pathophysiology of major inflammatory conditions, including Alzheimer's disease, stroke, obesity, and type II diabetes. |
| 8237 | 16777978 | Here we used a novel, JNK interacting protein (JIP)-derived JNK peptide inhibitor to establish that JNK suppresses the biological activity of IGF-I in skeletal muscle progenitor cells. |
| 8238 | 16777978 | In these myoblasts, TNFalpha and its downstream receptor substrates, neutral-sphingomyelinase (N-SMase) and N-acetyl-d-sphingosine (C2-ceramide), induce JNK kinase activity in a time-dependent manner. |
| 8239 | 16777978 | Consistent with these results, TNFalpha induces JNK binding to insulin receptor substrate 1 (IRS-1) but is unable to inhibit IGF-I-induced IRS-1 tyrosine phosphorylation in myoblasts that are treated with the JNK peptide inhibitor. |
| 8240 | 16777978 | More importantly, JNK activation induced by TNFalpha, C2-ceramide, and N-SMase is associated with reduced expression of the critical muscle transcription factor myogenin as well as the differentiation marker myosin heavy chain (MHC). |
| 8241 | 16777978 | The JNK peptide inhibitor, but not the control peptide, completely reverses this inhibition of both myogenin and MHC. |
| 8242 | 16777978 | In the absence of IGF-I, TNFalpha, C2-ceramide, N-SMase and the JNK inhibitor are inactive, as shown by their inability to affect IRS tyrosine phosphorylation and protein expression of myogenin and MHC. |
| 8243 | 16777978 | These results establish that the resistance of muscle progenitor cells to IGF-I, which is caused by inflammatory stimuli, is mediated by the JNK stress kinase pathway. |
| 8244 | 16782068 | These cells in presence of palmitate, but not UFA, exhibited time, and concentration-dependent emergence of insulin receptors, GLUT 4 expression, generation of ROS, cytokines, lipid peroxidation, and IRS-1. |
| 8245 | 16807405 | Chronic inhibition of mammalian target of rapamycin signaling downregulates insulin receptor substrates 1 and 2 and AKT activation: A crossroad between cancer and diabetes? |
| 8246 | 16807405 | Overactivation of the mammalian target of rapamycin (mTOR) branch downstream of the phosphatidylinositol 3-kinase-AKT pathway critically modulates insulin and growth factor signaling by insulin receptor substrates (IRS). |
| 8247 | 16807405 | In view of the critical role of AKT in insulin signaling and tumorigenesis, the in vivo expression and activation of this kinase and of IRS-1 and IRS-2 were explored in PBMC of 30 patients who were treated long term with rapamycin. |
| 8248 | 16807405 | A marked decrease of basal and insulin-stimulated AKT phosphorylation, which correlated with the increase of patients' insulin resistance, and a significant increase of IRS total protein expression, together with a lower (IRS-2) or absent (IRS-1) increase of insulin-induced tyrosine phosphorylation, were found. |
| 8249 | 16807405 | Chronic inhibition of mammalian target of rapamycin signaling downregulates insulin receptor substrates 1 and 2 and AKT activation: A crossroad between cancer and diabetes? |
| 8250 | 16807405 | Overactivation of the mammalian target of rapamycin (mTOR) branch downstream of the phosphatidylinositol 3-kinase-AKT pathway critically modulates insulin and growth factor signaling by insulin receptor substrates (IRS). |
| 8251 | 16807405 | In view of the critical role of AKT in insulin signaling and tumorigenesis, the in vivo expression and activation of this kinase and of IRS-1 and IRS-2 were explored in PBMC of 30 patients who were treated long term with rapamycin. |
| 8252 | 16807405 | A marked decrease of basal and insulin-stimulated AKT phosphorylation, which correlated with the increase of patients' insulin resistance, and a significant increase of IRS total protein expression, together with a lower (IRS-2) or absent (IRS-1) increase of insulin-induced tyrosine phosphorylation, were found. |
| 8253 | 16814735 | siRNA-based gene silencing reveals specialized roles of IRS-1/Akt2 and IRS-2/Akt1 in glucose and lipid metabolism in human skeletal muscle. |
| 8254 | 16814735 | We utilized siRNA to decipher the specific role of predominant insulin receptor substrates and Akt isoforms expressed in human skeletal muscle. |
| 8255 | 16814735 | IRS-1 and Akt2 were required for myoblast differentiation and glucose metabolism, whereas IRS-2 and Akt1 were dispensable. |
| 8256 | 16814735 | A key role of IRS-2 and Akt1 in lipid metabolism was revealed, highlighting reciprocal relationships between metabolic pathways. |
| 8257 | 16814735 | siRNA-based gene silencing reveals specialized roles of IRS-1/Akt2 and IRS-2/Akt1 in glucose and lipid metabolism in human skeletal muscle. |
| 8258 | 16814735 | We utilized siRNA to decipher the specific role of predominant insulin receptor substrates and Akt isoforms expressed in human skeletal muscle. |
| 8259 | 16814735 | IRS-1 and Akt2 were required for myoblast differentiation and glucose metabolism, whereas IRS-2 and Akt1 were dispensable. |
| 8260 | 16814735 | A key role of IRS-2 and Akt1 in lipid metabolism was revealed, highlighting reciprocal relationships between metabolic pathways. |
| 8261 | 16839860 | Insulin mediates its action on target organs through phosphorylation of a transmembrane-spanning tyrosine kinase receptor, the insulin receptor (IR). |
| 8262 | 16839860 | In particular, phosphorylation of IRS-1 on serine Ser612 causes dissociation of the p85 subunit of phosphatidylinositol 3-kinase, inhibiting further signaling. |
| 8263 | 16839860 | Dysregulation of sympathetic nervous and renin-angiotensin systems resulting in enhanced stimulation of both adrenergic and angiotensin II receptors is a typical feature of several cardiovascular diseases and, at the same time, is involved in the pathogenesis of insulin resistance. |
| 8264 | 16842543 | Melatonin stimulates glucose transport via insulin receptor substrate-1/phosphatidylinositol 3-kinase pathway in C2C12 murine skeletal muscle cells. |
| 8265 | 16842543 | However, 3',5'-cyclic adenosine monophosphate-activated protein kinase (AMPK), another important glucose transport stimulatory mediator via an insulin-independent pathway, was not influenced by melatonin treatment. |
| 8266 | 16842543 | Activity of p38 mitogen-activated protein kinase (MAPK), a downstream mediator of AMPK, was also not changed by melatonin. |
| 8267 | 16849561 | Absence of the full-length breast cancer-associated gene-1 leads to increased expression of insulin-like growth factor signaling axis members. |
| 8268 | 16849561 | The breast cancer-associated gene-1 (BRCA1) plays many important functions in multiple biological processes/pathways. |
| 8269 | 16849561 | Here, we show that Brca1 deficiency leads to increased expression of several insulin-like growth factor (IGF) signaling axis members in multiple experimental systems, including BRCA1-deficient mice, primary mammary tumors, and cultured human cells. |
| 8270 | 16849561 | Furthermore, we provide evidence that activation of IGF signaling by BRCA1 deficiency can also occur in a p53-independent fashion. |
| 8271 | 16849561 | Our data indicate that BRCA1 interacts with the IRS-1 promoter and inhibits its activity that is associated with epigenetic modification of histone H3 and histone H4 to a transcriptional repression chromatin configuration. |
| 8272 | 16849561 | We further show that BRCA1-deficient mammary tumor cells exhibit high levels of IRS-1, and acute suppression of Irs-1 using RNA interference significantly inhibits growth of these cells. |
| 8273 | 16849561 | Absence of the full-length breast cancer-associated gene-1 leads to increased expression of insulin-like growth factor signaling axis members. |
| 8274 | 16849561 | The breast cancer-associated gene-1 (BRCA1) plays many important functions in multiple biological processes/pathways. |
| 8275 | 16849561 | Here, we show that Brca1 deficiency leads to increased expression of several insulin-like growth factor (IGF) signaling axis members in multiple experimental systems, including BRCA1-deficient mice, primary mammary tumors, and cultured human cells. |
| 8276 | 16849561 | Furthermore, we provide evidence that activation of IGF signaling by BRCA1 deficiency can also occur in a p53-independent fashion. |
| 8277 | 16849561 | Our data indicate that BRCA1 interacts with the IRS-1 promoter and inhibits its activity that is associated with epigenetic modification of histone H3 and histone H4 to a transcriptional repression chromatin configuration. |
| 8278 | 16849561 | We further show that BRCA1-deficient mammary tumor cells exhibit high levels of IRS-1, and acute suppression of Irs-1 using RNA interference significantly inhibits growth of these cells. |
| 8279 | 16860589 | In light of recent epidemiological studies that associate diabetes mellitus with increased risk for oral cancer, we investigated in diabetic (type I) and normal rats with induced oral squamous cell carcinoma whether the molecular basis for that putative association involves insulin receptor substrate-1 (IRS-1) and focal adhesion kinase (FAK). |
| 8280 | 16860589 | Oral sections were studied using monoclonal antibodies against IRS-1 and FAK proteins. |
| 8281 | 16860589 | These data suggest that the IRS-1/FAK pathway is altered by diabetes resulting in reduced cell adhesion and possibly increasing risk for oral cancer. |
| 8282 | 16860589 | In light of recent epidemiological studies that associate diabetes mellitus with increased risk for oral cancer, we investigated in diabetic (type I) and normal rats with induced oral squamous cell carcinoma whether the molecular basis for that putative association involves insulin receptor substrate-1 (IRS-1) and focal adhesion kinase (FAK). |
| 8283 | 16860589 | Oral sections were studied using monoclonal antibodies against IRS-1 and FAK proteins. |
| 8284 | 16860589 | These data suggest that the IRS-1/FAK pathway is altered by diabetes resulting in reduced cell adhesion and possibly increasing risk for oral cancer. |
| 8285 | 16860589 | In light of recent epidemiological studies that associate diabetes mellitus with increased risk for oral cancer, we investigated in diabetic (type I) and normal rats with induced oral squamous cell carcinoma whether the molecular basis for that putative association involves insulin receptor substrate-1 (IRS-1) and focal adhesion kinase (FAK). |
| 8286 | 16860589 | Oral sections were studied using monoclonal antibodies against IRS-1 and FAK proteins. |
| 8287 | 16860589 | These data suggest that the IRS-1/FAK pathway is altered by diabetes resulting in reduced cell adhesion and possibly increasing risk for oral cancer. |
| 8288 | 16873706 | Subsequent studies in insulin-resistant animal models and humans have consistently demonstrated a reduced strength of insulin signaling via the insulin receptor substrate (IRS)-1/phosphatidylinositol (PI) 3-kinase pathway, resulting in diminished glucose uptake and utilization in insulin target tissues. |
| 8289 | 16873706 | A number of serine kinases that phosphorylate serine residues of IRS-1 and weaken insulin signal transduction have been identified. |
| 8290 | 16873706 | Conceivably, a combination of both increased expression of p85alpha and increased serine phosphorylation of IRS-1 is needed to induce clinically apparent insulin resistance. |
| 8291 | 16873706 | Subsequent studies in insulin-resistant animal models and humans have consistently demonstrated a reduced strength of insulin signaling via the insulin receptor substrate (IRS)-1/phosphatidylinositol (PI) 3-kinase pathway, resulting in diminished glucose uptake and utilization in insulin target tissues. |
| 8292 | 16873706 | A number of serine kinases that phosphorylate serine residues of IRS-1 and weaken insulin signal transduction have been identified. |
| 8293 | 16873706 | Conceivably, a combination of both increased expression of p85alpha and increased serine phosphorylation of IRS-1 is needed to induce clinically apparent insulin resistance. |
| 8294 | 16877540 | Furthermore, insulin increased spontaneous cortical activity (beta band) in carriers of wild-type IRS-1, whereas, in carriers of the 972Arg allele, this insulin effect was absent (P = 0.01). |
| 8295 | 16877540 | Moreover, cerebrocortical insulin resistance is found in individuals with the Gly972Arg polymorphism in IRS-1, which is considered a type 2 diabetes risk gene. |
| 8296 | 16877540 | Furthermore, insulin increased spontaneous cortical activity (beta band) in carriers of wild-type IRS-1, whereas, in carriers of the 972Arg allele, this insulin effect was absent (P = 0.01). |
| 8297 | 16877540 | Moreover, cerebrocortical insulin resistance is found in individuals with the Gly972Arg polymorphism in IRS-1, which is considered a type 2 diabetes risk gene. |
| 8298 | 16931448 | It can change adaptively to meet demand and studies in vivo indicate that the regulation of beta-cell mass involves IRS2, while IRS1 is only required for proper insulin production in beta-cells. |
| 8299 | 16931448 | Overexpression studies in isolated islets have shown that IRS2, but not IRS1 or Shc, is sufficient to induce proliferation of beta-cells and to protect against d-glucose-induced apoptosis. |
| 8300 | 16931448 | In light of the finding that many growth factors can regulate Irs2 in islets, this signalling intermediate could balance capacity for insulin production with demand. |
| 8301 | 16931448 | It can change adaptively to meet demand and studies in vivo indicate that the regulation of beta-cell mass involves IRS2, while IRS1 is only required for proper insulin production in beta-cells. |
| 8302 | 16931448 | Overexpression studies in isolated islets have shown that IRS2, but not IRS1 or Shc, is sufficient to induce proliferation of beta-cells and to protect against d-glucose-induced apoptosis. |
| 8303 | 16931448 | In light of the finding that many growth factors can regulate Irs2 in islets, this signalling intermediate could balance capacity for insulin production with demand. |
| 8304 | 16934905 | The levels of the medial outgrowth rate of VSMCs and Ang II type-1 receptors (AT1R) in aortae from WF were more enhanced than those in aortae from WL, but the level of Ang II type-2 receptors (AT2R) was not different. |
| 8305 | 16934905 | A mixture of insulin and Ang II additively increased the values of [(3)H]-thymidine incorporation in WF and WL, which was inhibited by olmesartan, an AT1 receptor blockade (ARB), but not by PD123,319, an AT2 receptor blockade. |
| 8306 | 16934905 | Similarly, insulin and Ang II phosphorylated extracellular-regulated protein kinase 1/2, retinoblastoma tumor suppressor protein, and cyclic AMP response element binding protein, and these levels were higher in WF than in WL. |
| 8307 | 16934905 | Insulin-stimulated Akt phosphorylation and 2-deoxy-d-glucose uptake in WF were significantly reduced by Ang II, and the reduction was ameliorated by olmesartan but not PD123,319. |
| 8308 | 16934905 | Differently from the result of Akt, the phosphorylation of the insulin-stimulated insulin receptor beta-subunit was not affected by Ang II, olmesartan, or PD123,319. |
| 8309 | 16934905 | However, the phosphorylation of insulin-stimulated insulin-related substrate (IRS)-1 was suppressed by Ang II, and the suppression was ameliorated by olmesartan, but not PD123,319, in both WF and WL. |
| 8310 | 16934905 | In contrast, the phosphorylation of IRS-1 on Ser(307) was elevated by the Ang II, and the elevation was suppressed by olmesartan, but not by PD123,319, in both WF and WL. |
| 8311 | 16934905 | These findings demonstrated that Ang II signaling contributes to cell proliferation and inhibition of the insulin signaling pathways through AT1R, but not trough AT2R, in both non-diabetic and diabetic VSMCs. |
| 8312 | 16960657 | Chronic exposure to ketone bodies impairs glucose uptake in adult cardiomyocytes in response to insulin but not vanadate: the role of PI3-K. |
| 8313 | 16960657 | We have already shown that chronic exposure to the ketone body beta-hydroxybutyrate (OHB) decreases insulin-mediated activation of protein kinase B (PKB) and glucose uptake in cardiomyocytes. |
| 8314 | 16960657 | While chronic exposure to OHB did not alter insulin- or vanadate-mediated activation of the insulin receptor, it suppressed insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation in response to both agonists. |
| 8315 | 16960657 | Furthermore, this treatment decreased by 54 and 36% the phosphorylation of the p85 regulatory subunit of phosphatidylinositol 3-kinase (PI3-K) and PKB in response to insulin, whereas it did not alter vanadate-mediated activation of these enzymes. |
| 8316 | 16960657 | Though OHB induced a 2.1-fold increase of basal ERK1/2 phosphorylation, inhibition of this enzyme with the MEK inhibitor PD98059 demonstrated that ERK1/2 did not participate in OHB-induced insulin resistance. |
| 8317 | 16960657 | In conclusion, ketone bodies promote insulin resistance probably through decreased activation of the PI3-K/PKB signaling cascade. |
| 8318 | 16960890 | Long-term effects of tumor necrosis factor-alpha treatment on insulin signaling pathway in HepG2 cells and HepG2 cells overexpressing constitutively active Akt/PKB. |
| 8319 | 16960890 | Tumor necrosis factor-alpha (TNF-alpha) mediated attenuation of insulin signaling pathway is an important cause in several disorders like obesity, obesity linked diabetes mellitus. |
| 8320 | 16960890 | In the present study, the effects of long-term TNF-alpha (1 ng/ml) exposure on the components of insulin signaling pathway in HepG2 and HepG2 cells overexpressing constitutively active Akt1/PKB-alpha (HepG2-CA-Akt/PKB) have been investigated. |
| 8321 | 16960890 | In parental HepG2 cells, TNF-alpha treatment for 24 h reduced the phosphorylation of Akt1/PKB-alpha and GSK-3beta and under these conditions cells also showed reduced insulin responsiveness in terms of Akt1/PKB-alpha and GSK-3beta phosphorylation. |
| 8322 | 16960890 | TNF-alpha pre-incubated HepG2-CA-Akt/PKB cells showed lower reduction in Akt1/PKB-alpha and GSK-3beta phosphorylation and insulin responsiveness after 24 h as compared to parental HepG2 cells. |
| 8323 | 16960890 | We report that the long-term TNF-alpha pre-incubation in both parental HepG2 and HepG2-CA-Akt/PKB-alpha cells leads to the reduction in the levels of IRS-1 without altering the levels of IRS-2. |
| 8324 | 16960890 | In order to understand the reason for the differential insulin resistance in both the cell types, the effect of long-term TNF-alpha treatment on the proteins upstream to Akt/PKB was investigated. |
| 8325 | 16960890 | TNF-alpha pre-incubation also showed reduced insulin-stimulated Tyr phosphorylation of insulin receptor (IR-beta) in both the cell types, moreover hyperphosphorylation of IRS-1 at Ser 312 residue was observed in TNF-alpha pre-incubated cells. |
| 8326 | 16960890 | As hyperphosphorylation of IRS-1 at Ser 312 can induce its degradation, it is possible that reduced insulin responsiveness after long-term TNF-alpha pre-incubation observed in this study is due to the decrease in IRS-1 levels. |
| 8327 | 16960890 | Long-term effects of tumor necrosis factor-alpha treatment on insulin signaling pathway in HepG2 cells and HepG2 cells overexpressing constitutively active Akt/PKB. |
| 8328 | 16960890 | Tumor necrosis factor-alpha (TNF-alpha) mediated attenuation of insulin signaling pathway is an important cause in several disorders like obesity, obesity linked diabetes mellitus. |
| 8329 | 16960890 | In the present study, the effects of long-term TNF-alpha (1 ng/ml) exposure on the components of insulin signaling pathway in HepG2 and HepG2 cells overexpressing constitutively active Akt1/PKB-alpha (HepG2-CA-Akt/PKB) have been investigated. |
| 8330 | 16960890 | In parental HepG2 cells, TNF-alpha treatment for 24 h reduced the phosphorylation of Akt1/PKB-alpha and GSK-3beta and under these conditions cells also showed reduced insulin responsiveness in terms of Akt1/PKB-alpha and GSK-3beta phosphorylation. |
| 8331 | 16960890 | TNF-alpha pre-incubated HepG2-CA-Akt/PKB cells showed lower reduction in Akt1/PKB-alpha and GSK-3beta phosphorylation and insulin responsiveness after 24 h as compared to parental HepG2 cells. |
| 8332 | 16960890 | We report that the long-term TNF-alpha pre-incubation in both parental HepG2 and HepG2-CA-Akt/PKB-alpha cells leads to the reduction in the levels of IRS-1 without altering the levels of IRS-2. |
| 8333 | 16960890 | In order to understand the reason for the differential insulin resistance in both the cell types, the effect of long-term TNF-alpha treatment on the proteins upstream to Akt/PKB was investigated. |
| 8334 | 16960890 | TNF-alpha pre-incubation also showed reduced insulin-stimulated Tyr phosphorylation of insulin receptor (IR-beta) in both the cell types, moreover hyperphosphorylation of IRS-1 at Ser 312 residue was observed in TNF-alpha pre-incubated cells. |
| 8335 | 16960890 | As hyperphosphorylation of IRS-1 at Ser 312 can induce its degradation, it is possible that reduced insulin responsiveness after long-term TNF-alpha pre-incubation observed in this study is due to the decrease in IRS-1 levels. |
| 8336 | 16960890 | Long-term effects of tumor necrosis factor-alpha treatment on insulin signaling pathway in HepG2 cells and HepG2 cells overexpressing constitutively active Akt/PKB. |
| 8337 | 16960890 | Tumor necrosis factor-alpha (TNF-alpha) mediated attenuation of insulin signaling pathway is an important cause in several disorders like obesity, obesity linked diabetes mellitus. |
| 8338 | 16960890 | In the present study, the effects of long-term TNF-alpha (1 ng/ml) exposure on the components of insulin signaling pathway in HepG2 and HepG2 cells overexpressing constitutively active Akt1/PKB-alpha (HepG2-CA-Akt/PKB) have been investigated. |
| 8339 | 16960890 | In parental HepG2 cells, TNF-alpha treatment for 24 h reduced the phosphorylation of Akt1/PKB-alpha and GSK-3beta and under these conditions cells also showed reduced insulin responsiveness in terms of Akt1/PKB-alpha and GSK-3beta phosphorylation. |
| 8340 | 16960890 | TNF-alpha pre-incubated HepG2-CA-Akt/PKB cells showed lower reduction in Akt1/PKB-alpha and GSK-3beta phosphorylation and insulin responsiveness after 24 h as compared to parental HepG2 cells. |
| 8341 | 16960890 | We report that the long-term TNF-alpha pre-incubation in both parental HepG2 and HepG2-CA-Akt/PKB-alpha cells leads to the reduction in the levels of IRS-1 without altering the levels of IRS-2. |
| 8342 | 16960890 | In order to understand the reason for the differential insulin resistance in both the cell types, the effect of long-term TNF-alpha treatment on the proteins upstream to Akt/PKB was investigated. |
| 8343 | 16960890 | TNF-alpha pre-incubation also showed reduced insulin-stimulated Tyr phosphorylation of insulin receptor (IR-beta) in both the cell types, moreover hyperphosphorylation of IRS-1 at Ser 312 residue was observed in TNF-alpha pre-incubated cells. |
| 8344 | 16960890 | As hyperphosphorylation of IRS-1 at Ser 312 can induce its degradation, it is possible that reduced insulin responsiveness after long-term TNF-alpha pre-incubation observed in this study is due to the decrease in IRS-1 levels. |
| 8345 | 16981720 | Involvement of insulin-like growth factor type 1 receptor and protein kinase Cdelta in bis(maltolato)oxovanadium(IV)-induced phosphorylation of protein kinase B in HepG2 cells. |
| 8346 | 16981720 | In contrast, AG1295 and AG1478, specific inhibitors of PDGFR and EGFR, respectively, were unable to block the BMOV response. |
| 8347 | 16981720 | Moreover, efficient reduction of the level of IGF-1R protein expression by antisense oligonucleotides (ASO) attenuated BMOV-induced PKB phosphorylation. |
| 8348 | 16981720 | BMOV-induced PKB phosphorylation was associated with an increased level of tyrosine phosphorylation of the IRbeta subunit, IGF-1Rbeta subunit, IRS-1, and p85alpha subunit of PI3-kinase. |
| 8349 | 16981720 | However, this response was independent of IR-PTK activity because in cells overexpressing a PTK-inactive form of IR, insulin response was attenuated while the effect of BMOV remained intact. |
| 8350 | 16981720 | Taken together, these data suggest that IGF-1R and PKCdelta are required to stimulate PKB phosphorylation in response to BMOV in HepG2 cells and provide new insights into the molecular mechanism by which this compound exerts its insulinomimetic effects. |
| 8351 | 16990512 | The potential combined effect and mechanism of calcium channel blockers (CCB) and angiotensin II type 1 receptor blockers (ARB) to improve insulin resistance were investigated in type 2 diabetic KK-Ay mice, focusing on their antioxidative action. |
| 8352 | 16990512 | Treatment of KK-Ay mice with a CCB, azelnidipine (3 mg/kg/day), or with an ARB, olmesartan (3 mg/kg/day), for 2 weeks lowered the plasma concentrations of glucose and insulin in the fed state, attenuated the increase in plasma glucose in the oral glucose tolerance test (OGTT), and increased 2-[(3)H]deoxy-d-glucose (2-[(3)H]DG) uptake into skeletal muscle with the increase in translocation of glucose transporter 4 (GLUT4) to the plasma membrane. |
| 8353 | 16990512 | The decrease in plasma concentrations of glucose and insulin in the fed state and superoxide production in skeletal muscle, as well as GLUT4 translocation to the plasma membrane, after azelnidipine administration was not significantly affected by coadministration of an antioxidant, 2,2,6,6-tetramethyl-1-piperidinyloxy (tempol). |
| 8354 | 16990512 | Moreover, olmesartan enhanced the insulin-induced tyrosine phosphorylation of insulin receptor substrate-1 induced in skeletal muscle, whereas azelnidipine did not change it. |
| 8355 | 17003331 | Bradykinin augments insulin-stimulated glucose transport in rat adipocytes via endothelial nitric oxide synthase-mediated inhibition of Jun NH2-terminal kinase. |
| 8356 | 17003331 | An increase in bradykinin has been suggested to contribute to the enhanced insulin sensitivity observed in the presence of ACE inhibitors. |
| 8357 | 17003331 | Investigation of insulin signaling revealed that bradykinin enhanced insulin receptor substrate-1 (IRS-1) Tyr phosphorylation, Akt/protein kinase B phosphorylation, and GLUT4 translocation. |
| 8358 | 17003331 | In contrast, insulin-stimulated extracellular signal-regulated kinase1/2 and Jun NH2-terminal kinase (JNK) activation were decreased in the presence of bradykinin, accompanied by decreased IRS-1 Ser307 phosphorylation. |
| 8359 | 17003331 | Furthermore, bradykinin did not enhance insulin action in the presence of the JNK inhibitor, SP-600125, or in adipocytes from JNK1-/- mice. |
| 8360 | 17003331 | These data indicate that bradykinin enhances insulin sensitivity in adipocytes via an NO-dependent pathway that acts by modulating the feedback inhibition of insulin signaling at the level of IRS-1. |
| 8361 | 17003331 | Bradykinin augments insulin-stimulated glucose transport in rat adipocytes via endothelial nitric oxide synthase-mediated inhibition of Jun NH2-terminal kinase. |
| 8362 | 17003331 | An increase in bradykinin has been suggested to contribute to the enhanced insulin sensitivity observed in the presence of ACE inhibitors. |
| 8363 | 17003331 | Investigation of insulin signaling revealed that bradykinin enhanced insulin receptor substrate-1 (IRS-1) Tyr phosphorylation, Akt/protein kinase B phosphorylation, and GLUT4 translocation. |
| 8364 | 17003331 | In contrast, insulin-stimulated extracellular signal-regulated kinase1/2 and Jun NH2-terminal kinase (JNK) activation were decreased in the presence of bradykinin, accompanied by decreased IRS-1 Ser307 phosphorylation. |
| 8365 | 17003331 | Furthermore, bradykinin did not enhance insulin action in the presence of the JNK inhibitor, SP-600125, or in adipocytes from JNK1-/- mice. |
| 8366 | 17003331 | These data indicate that bradykinin enhances insulin sensitivity in adipocytes via an NO-dependent pathway that acts by modulating the feedback inhibition of insulin signaling at the level of IRS-1. |
| 8367 | 17003331 | Bradykinin augments insulin-stimulated glucose transport in rat adipocytes via endothelial nitric oxide synthase-mediated inhibition of Jun NH2-terminal kinase. |
| 8368 | 17003331 | An increase in bradykinin has been suggested to contribute to the enhanced insulin sensitivity observed in the presence of ACE inhibitors. |
| 8369 | 17003331 | Investigation of insulin signaling revealed that bradykinin enhanced insulin receptor substrate-1 (IRS-1) Tyr phosphorylation, Akt/protein kinase B phosphorylation, and GLUT4 translocation. |
| 8370 | 17003331 | In contrast, insulin-stimulated extracellular signal-regulated kinase1/2 and Jun NH2-terminal kinase (JNK) activation were decreased in the presence of bradykinin, accompanied by decreased IRS-1 Ser307 phosphorylation. |
| 8371 | 17003331 | Furthermore, bradykinin did not enhance insulin action in the presence of the JNK inhibitor, SP-600125, or in adipocytes from JNK1-/- mice. |
| 8372 | 17003331 | These data indicate that bradykinin enhances insulin sensitivity in adipocytes via an NO-dependent pathway that acts by modulating the feedback inhibition of insulin signaling at the level of IRS-1. |
| 8373 | 17008371 | Reversal of diet-induced insulin resistance with a single bout of exercise in the rat: the role of PTP1B and IRS-1 serine phosphorylation. |
| 8374 | 17008371 | Diet-induced obesity (DIO) increased the expression and activity of the protein tyrosine phosphatase 1B (PTP1B) and attenuated insulin signalling in gastrocnemius muscle of rats, a phenomenon which was reversed by a single session of exercise. |
| 8375 | 17008371 | In addition, DIO was observed to lead to serine phosphorylation of insulin receptor substrate 1 (IRS-1), which was also reversed by exercise in muscle in parallel with a reduction in c-Jun N-terminal kinase (JNK) activity. |
| 8376 | 17008371 | Reversal of diet-induced insulin resistance with a single bout of exercise in the rat: the role of PTP1B and IRS-1 serine phosphorylation. |
| 8377 | 17008371 | Diet-induced obesity (DIO) increased the expression and activity of the protein tyrosine phosphatase 1B (PTP1B) and attenuated insulin signalling in gastrocnemius muscle of rats, a phenomenon which was reversed by a single session of exercise. |
| 8378 | 17008371 | In addition, DIO was observed to lead to serine phosphorylation of insulin receptor substrate 1 (IRS-1), which was also reversed by exercise in muscle in parallel with a reduction in c-Jun N-terminal kinase (JNK) activity. |
| 8379 | 17021050 | Functional studies of Akt isoform specificity in skeletal muscle in vivo; maintained insulin sensitivity despite reduced insulin receptor substrate-1 expression. |
| 8380 | 17021050 | The phosphoinositide 3-kinase/Akt pathway is thought to be essential for normal insulin action and glucose metabolism in skeletal muscle and has been shown to be dysregulated in insulin resistance. |
| 8381 | 17021050 | We overexpressed constitutively active (ca-) Akt-1 or Akt-2 constructs in muscle using in vivo electrotransfer and, after 1 wk, assessed the roles of each isoform on glucose metabolism and fiber growth. |
| 8382 | 17021050 | These data indicate distinct roles for Akt-1 and Akt-2 in muscle glucose metabolism and that moderate reductions in IRS-1 expression do not result in the development of insulin resistance in skeletal muscle in vivo. |
| 8383 | 17021050 | Functional studies of Akt isoform specificity in skeletal muscle in vivo; maintained insulin sensitivity despite reduced insulin receptor substrate-1 expression. |
| 8384 | 17021050 | The phosphoinositide 3-kinase/Akt pathway is thought to be essential for normal insulin action and glucose metabolism in skeletal muscle and has been shown to be dysregulated in insulin resistance. |
| 8385 | 17021050 | We overexpressed constitutively active (ca-) Akt-1 or Akt-2 constructs in muscle using in vivo electrotransfer and, after 1 wk, assessed the roles of each isoform on glucose metabolism and fiber growth. |
| 8386 | 17021050 | These data indicate distinct roles for Akt-1 and Akt-2 in muscle glucose metabolism and that moderate reductions in IRS-1 expression do not result in the development of insulin resistance in skeletal muscle in vivo. |
| 8387 | 17038556 | However, the ability of IL-1beta to alter insulin signaling and action remains to be explored. |
| 8388 | 17038556 | Importantly, we found that prolonged IL-1beta treatment reduced the insulin-induced glucose uptake, whereas an acute treatment had no effect. |
| 8389 | 17038556 | This inhibitory effect was due to a decrease in the amount of insulin receptor substrate (IRS)-1 but not IRS-2 expression in both 3T3-L1 and human adipocytes. |
| 8390 | 17038556 | The decrease in IRS-1 amount resulted in a reduction in its tyrosine phosphorylation and the alteration of insulin-induced protein kinase B activation and AS160 phosphorylation. |
| 8391 | 17038556 | Pharmacological inhibition of ERK totally inhibited IL-1beta-induced down-regulation of IRS-1 mRNA. |
| 8392 | 17038556 | Moreover, IRS-1 protein expression and insulin-induced protein kinase B activation, AS160 phosphorylation, and Glut 4 translocation were partially recovered after treatment with the ERK inhibitor. |
| 8393 | 17038556 | These results demonstrate that IL-1beta reduces IRS-1 expression at a transcriptional level through a mechanism that is ERK dependent and at a posttranscriptional level independently of ERK activation. |
| 8394 | 17038556 | By targeting IRS-1, IL-1beta is capable of impairing insulin signaling and action, and could thus participate in concert with other cytokines, in the development of insulin resistance in adipocytes. |
| 8395 | 17038556 | However, the ability of IL-1beta to alter insulin signaling and action remains to be explored. |
| 8396 | 17038556 | Importantly, we found that prolonged IL-1beta treatment reduced the insulin-induced glucose uptake, whereas an acute treatment had no effect. |
| 8397 | 17038556 | This inhibitory effect was due to a decrease in the amount of insulin receptor substrate (IRS)-1 but not IRS-2 expression in both 3T3-L1 and human adipocytes. |
| 8398 | 17038556 | The decrease in IRS-1 amount resulted in a reduction in its tyrosine phosphorylation and the alteration of insulin-induced protein kinase B activation and AS160 phosphorylation. |
| 8399 | 17038556 | Pharmacological inhibition of ERK totally inhibited IL-1beta-induced down-regulation of IRS-1 mRNA. |
| 8400 | 17038556 | Moreover, IRS-1 protein expression and insulin-induced protein kinase B activation, AS160 phosphorylation, and Glut 4 translocation were partially recovered after treatment with the ERK inhibitor. |
| 8401 | 17038556 | These results demonstrate that IL-1beta reduces IRS-1 expression at a transcriptional level through a mechanism that is ERK dependent and at a posttranscriptional level independently of ERK activation. |
| 8402 | 17038556 | By targeting IRS-1, IL-1beta is capable of impairing insulin signaling and action, and could thus participate in concert with other cytokines, in the development of insulin resistance in adipocytes. |
| 8403 | 17038556 | However, the ability of IL-1beta to alter insulin signaling and action remains to be explored. |
| 8404 | 17038556 | Importantly, we found that prolonged IL-1beta treatment reduced the insulin-induced glucose uptake, whereas an acute treatment had no effect. |
| 8405 | 17038556 | This inhibitory effect was due to a decrease in the amount of insulin receptor substrate (IRS)-1 but not IRS-2 expression in both 3T3-L1 and human adipocytes. |
| 8406 | 17038556 | The decrease in IRS-1 amount resulted in a reduction in its tyrosine phosphorylation and the alteration of insulin-induced protein kinase B activation and AS160 phosphorylation. |
| 8407 | 17038556 | Pharmacological inhibition of ERK totally inhibited IL-1beta-induced down-regulation of IRS-1 mRNA. |
| 8408 | 17038556 | Moreover, IRS-1 protein expression and insulin-induced protein kinase B activation, AS160 phosphorylation, and Glut 4 translocation were partially recovered after treatment with the ERK inhibitor. |
| 8409 | 17038556 | These results demonstrate that IL-1beta reduces IRS-1 expression at a transcriptional level through a mechanism that is ERK dependent and at a posttranscriptional level independently of ERK activation. |
| 8410 | 17038556 | By targeting IRS-1, IL-1beta is capable of impairing insulin signaling and action, and could thus participate in concert with other cytokines, in the development of insulin resistance in adipocytes. |
| 8411 | 17038556 | However, the ability of IL-1beta to alter insulin signaling and action remains to be explored. |
| 8412 | 17038556 | Importantly, we found that prolonged IL-1beta treatment reduced the insulin-induced glucose uptake, whereas an acute treatment had no effect. |
| 8413 | 17038556 | This inhibitory effect was due to a decrease in the amount of insulin receptor substrate (IRS)-1 but not IRS-2 expression in both 3T3-L1 and human adipocytes. |
| 8414 | 17038556 | The decrease in IRS-1 amount resulted in a reduction in its tyrosine phosphorylation and the alteration of insulin-induced protein kinase B activation and AS160 phosphorylation. |
| 8415 | 17038556 | Pharmacological inhibition of ERK totally inhibited IL-1beta-induced down-regulation of IRS-1 mRNA. |
| 8416 | 17038556 | Moreover, IRS-1 protein expression and insulin-induced protein kinase B activation, AS160 phosphorylation, and Glut 4 translocation were partially recovered after treatment with the ERK inhibitor. |
| 8417 | 17038556 | These results demonstrate that IL-1beta reduces IRS-1 expression at a transcriptional level through a mechanism that is ERK dependent and at a posttranscriptional level independently of ERK activation. |
| 8418 | 17038556 | By targeting IRS-1, IL-1beta is capable of impairing insulin signaling and action, and could thus participate in concert with other cytokines, in the development of insulin resistance in adipocytes. |
| 8419 | 17038556 | However, the ability of IL-1beta to alter insulin signaling and action remains to be explored. |
| 8420 | 17038556 | Importantly, we found that prolonged IL-1beta treatment reduced the insulin-induced glucose uptake, whereas an acute treatment had no effect. |
| 8421 | 17038556 | This inhibitory effect was due to a decrease in the amount of insulin receptor substrate (IRS)-1 but not IRS-2 expression in both 3T3-L1 and human adipocytes. |
| 8422 | 17038556 | The decrease in IRS-1 amount resulted in a reduction in its tyrosine phosphorylation and the alteration of insulin-induced protein kinase B activation and AS160 phosphorylation. |
| 8423 | 17038556 | Pharmacological inhibition of ERK totally inhibited IL-1beta-induced down-regulation of IRS-1 mRNA. |
| 8424 | 17038556 | Moreover, IRS-1 protein expression and insulin-induced protein kinase B activation, AS160 phosphorylation, and Glut 4 translocation were partially recovered after treatment with the ERK inhibitor. |
| 8425 | 17038556 | These results demonstrate that IL-1beta reduces IRS-1 expression at a transcriptional level through a mechanism that is ERK dependent and at a posttranscriptional level independently of ERK activation. |
| 8426 | 17038556 | By targeting IRS-1, IL-1beta is capable of impairing insulin signaling and action, and could thus participate in concert with other cytokines, in the development of insulin resistance in adipocytes. |
| 8427 | 17046546 | We studied possible relations between GDM and both insulin receptor substrate 1 (IRS-1) (Gly972Arg) and beta3-adrenergic receptor (ADRB3 Trp64Arg, beta3-AR) gene mutations, considered potential modifying factors in the etiology of type 2 diabetes mellitus. |
| 8428 | 17046546 | Age, family history of diabetes, prepregnancy body mass index, weight gain during pregnancy, plasma glucose levels, hemoglobin A1c, islet autoantibody levels, and insulin treatment during pregnancy were all evaluated. |
| 8429 | 17046546 | All pregnant women were genotyped for IRS-1 (Gly972Arg) and beta3-AR (ADRB3 Trp64Arg) polymorphisms. |
| 8430 | 17046546 | We studied possible relations between GDM and both insulin receptor substrate 1 (IRS-1) (Gly972Arg) and beta3-adrenergic receptor (ADRB3 Trp64Arg, beta3-AR) gene mutations, considered potential modifying factors in the etiology of type 2 diabetes mellitus. |
| 8431 | 17046546 | Age, family history of diabetes, prepregnancy body mass index, weight gain during pregnancy, plasma glucose levels, hemoglobin A1c, islet autoantibody levels, and insulin treatment during pregnancy were all evaluated. |
| 8432 | 17046546 | All pregnant women were genotyped for IRS-1 (Gly972Arg) and beta3-AR (ADRB3 Trp64Arg) polymorphisms. |
| 8433 | 17068137 | Developmental switch from prolonged insulin action to increased insulin sensitivity in protein tyrosine phosphatase 1B-deficient hepatocytes. |
| 8434 | 17068137 | Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of insulin signaling and a therapeutic target for type 2 diabetes. |
| 8435 | 17068137 | The purpose of this study was to evaluate the differences in insulin sensitivity between neonate and adult hepatocytes lacking PTP1B. |
| 8436 | 17068137 | PTP1B deficiency in immortalized neonatal hepatocytes prolonged insulin-induced tyrosine phosphorylation of the insulin receptor (IR) and IR substrates (IRS) -1, -2 compared with wild-type control cells. |
| 8437 | 17068137 | Endogenous IR and IRS-2 were down-regulated, whereas IRS-1 was up-regulated in PTP1B(-/-) neonatal hepatocytes and livers of PTP1B(-/-) neonates. |
| 8438 | 17068137 | Insulin-induced activation of phosphatidylinositol 3-kinase/Akt pathway was prolonged in PTP1B(-/-) immortalized neonatal hepatocytes. |
| 8439 | 17068137 | Rescue of PTP1B in deficient cells suppressed the prolonged insulin signaling, whereas RNA interference in wild-type cells promoted prolonged signaling. |
| 8440 | 17068137 | In primary neonatal PTP1B(-/-) hepatocytes, insulin prolonged the inhibition of gluconeogenic mRNAs, but the sensitivity to this inhibition was similar to wild-type cells. |
| 8441 | 17068137 | By contrast, in adult PTP1B-deficient livers, p85alpha was down-regulated compared with the wild type. |
| 8442 | 17068137 | Moreover, primary hepatocytes from adult PTP1B(-/-) mice displayed enhanced Akt phosphorylation and a more pronounced inhibition of gluconeogenic mRNAs than wild-type cells. |
| 8443 | 17068137 | Hepatic insulin sensitivity due to PTP1B deficiency is acquired through postnatal development. |
| 8444 | 17068137 | Thus, changes in IR and IRS-2 expression and in the balance between regulatory and catalytic subunits of phosphatidylinositol 3-kinase are necessary to achieve insulin sensitization in adult PTP1B(-/-) hepatocytes. |
| 8445 | 17077083 | Interaction of FoxO1 and TSC2 induces insulin resistance through activation of the mammalian target of rapamycin/p70 S6K pathway. |
| 8446 | 17077083 | Both TSC2 (tuberin) and forkhead transcription factor FoxO1 are phosphorylated and inhibited by Akt and play important roles in insulin signaling. |
| 8447 | 17077083 | However, little is known about the relationship between TSC2 and FoxO1. |
| 8448 | 17077083 | Here we identified TSC2 as a FoxO1-binding protein by using a yeast two-hybrid screening with a murine islet cDNA library. |
| 8449 | 17077083 | Among FoxOs, only FoxO1 can be associated with TSC2. |
| 8450 | 17077083 | The physical association between the C terminus of TSC2 (amino acids 1280-1499) and FoxO1 degrades the TSC1-TSC2 complex and inhibits GTPase-activating protein activity of TSC2 toward Rheb. |
| 8451 | 17077083 | Overexpression of wild type FoxO1 enhances p70 S6K phosphorylation, whereas overexpression of TSC2 can reverse these effects. |
| 8452 | 17077083 | Knockdown of endogenous FOXO1 in human vascular endothelial cells decreased phosphorylation of p70 S6K. |
| 8453 | 17077083 | Prolonged overexpression of wild type FoxO1 enhanced phosphorylation of serine 307 of IRS1 and decreased phosphorylation of Akt and FoxO1 itself even in the presence of serum. |
| 8454 | 17077083 | These data suggest a novel mechanism by which FoxO1 regulates the insulin signaling pathway through negative regulation of TSC2 function. |
| 8455 | 17116401 | Activation of N-terminal C-Jun kinase is known to be associated with unfolded protein response activation, and has been shown to participate in the inhibition of insulin action by stimulating serine phosphorylation of the insulin receptor substrate 1, an event that attenuates insulin signaling. |
| 8456 | 17135326 | We have previously reported that HCV core gene-transgenic (PA28gamma(+/+)CoreTg) mice develop marked insulin resistance and that the HCV core protein is degraded in the nucleus through a PA28gamma-dependent pathway. |
| 8457 | 17135326 | In this study, we examined whether PA28gamma is required for HCV core-induced insulin resistance in vivo. |
| 8458 | 17135326 | Although there was no significant difference in the glucose tolerance test results among the mice, the insulin sensitivity in PA28gamma(-/-)CoreTg mice was recovered to a normal level in the insulin tolerance test. |
| 8459 | 17135326 | Tyrosine phosphorylation of insulin receptor substrate 1 (IRS1), production of IRS2, and phosphorylation of Akt were suppressed in the livers of PA28gamma(+/+)CoreTg mice in response to insulin stimulation, whereas they were restored in the livers of PA28gamma(-/-)CoreTg mice. |
| 8460 | 17135326 | Furthermore, activation of the tumor necrosis factor alpha promoter in human liver cell lines or mice by the HCV core protein was suppressed by the knockdown or knockout of the PA28gamma gene. |
| 8461 | 17184170 | Inducible nitric oxide synthase (iNOS), a mediator of inflammation, has emerged as an important player in insulin resistance. |
| 8462 | 17184170 | Obesity is associated with increased iNOS expression in insulin-sensitive tissues in rodents and humans. |
| 8463 | 17184170 | Inhibition of iNOS ameliorates obesity-induced insulin resistance. |
| 8464 | 17184170 | However, molecular mechanisms by which iNOS mediates insulin resistance remain largely unknown. |
| 8465 | 17184170 | S-nitrosylation is elevated in patients with type 2 diabetes, and increased S-nitrosylation of insulin signaling molecules, including insulin receptor, insulin receptor substrate-1, and Akt/PKB, has been shown in skeletal muscle of obese, diabetic mice. |
| 8466 | 17184177 | In endothelial cells, high-glucose treatment increases mitochondrial ROS and normalization of the ROS production by inhibitors of mitochondrial metabolism, or by overexpression of UCP-1 or MnSOD, prevents glucose-induced activation of PKC, formation of AGE, and accumulation of sorbitol, all of which are believed to be the main molecular mechanisms of diabetic complications. |
| 8467 | 17184177 | In pancreatic beta cells, hyperglycemia also increases mitochondrial ROS, which suppresses the first phase of glucose-induced insulin secretion, at least in part, through the suppression of GAPDH activity. |
| 8468 | 17184177 | In liver cells, similar to that in hyperglycemia, TNF-alpha increases mitochondrial ROS, which in turn activates apoptosis signal-regulating kinase 1 (ASK1) and c-jun NH2-terminal kinases (JNK), increases serine phosphorylation of IRS-1, and decreases insulin-stimulated tyrosine phosphorylation of IRS-1, leading to insulin resistance. |
| 8469 | 17208384 | Adipocyte-derived hormones, including adiponectin and leptin, regulate systemic insulin sensitivity in accordance to existing triglyceride reserves. |
| 8470 | 17208384 | Leptin levels reflect existing fat mass and the adipokine negatively regulates insulin action in adipose tissue. |
| 8471 | 17208384 | Adiponectin, on the other hand, preserves insulin sensitivity via transient increments of AMPK activity and its circulating levels seem to reflect the adipogenic capacity of adipose tissue. |
| 8472 | 17208384 | Because adiponectin and insulin synergize in their postprandial actions, it seems evident that inadequate adiponectin production causes systemic insulin resistance. |
| 8473 | 17208384 | As a consequence, compounds that either increase adiponectin production or mimic its actions can be considered as an efficient strategy for improving insulin sensitivity in type 2 diabetics. |
| 8474 | 17208384 | Finally, after delineating critical nodes of insulin and adipokine crosstalk, putative pathways are proposed by which adiponectin and leptin cooperatively regulate systemic insulin sensitivity in accordance to existing fat mass. |
| 8475 | 17208384 | By amplifying insulin action downstream of PI3K, leptin exerts negative feedback on insulin signaling via mTOR-dependent pathways that target IRS-1 for serine phosphorylation and protein degradation. |
| 8476 | 17208384 | Adiponectin-mediated increments of AMPK activity, on the other hand, may attenuate mTOR signaling, leading to the preservation of insulin sensitivity in periods of increased nutrient availability. |
| 8477 | 17208384 | Considering that leptin and adiponectin are inversely associated with BMI, the proposed model provides a plausible explanation for the observation that leptin exerts strong negative feedback on systemic insulin sensitivity, while increasing PIP3 availability. |
| 8478 | 17222824 | Insulin receptor substrates 1 and 2 but not Shc can activate the insulin receptor independent of insulin and induce proliferation in CHO-IR cells. |
| 8479 | 17222824 | Ligand-activated insulin receptor (IR) attracts and phosphorylates various substrates such as insulin receptor substrates 1-4 (IRS) and Shc. |
| 8480 | 17222824 | We found that the extent of receptor tyrosine phosphorylation positively correlates with binding affinity towards IRS1/2 but not towards Shc. |
| 8481 | 17222824 | Moreover, overexpression of IRS1 or IRS2 but not of Shc increased IR tyrosine phosphorylation in a dose-dependent manner, also independent of insulin. |
| 8482 | 17222824 | Molecular truncations of IRS1 revealed that neither the isolated PH and PTB domains nor the C-terminus with the tyrosine phosphorylation sites alone are sufficient for substrate-dependent receptor activation. |
| 8483 | 17222824 | Overexpression of IRS1 and IRS2 impaired insulin-induced internalization of the IR in a dose-dependent manner suggesting that IRS proteins prevent endosome-associated receptor dephosphorylation/inactivation. |
| 8484 | 17222824 | IRS1 and IRS2 could therefore target the activated IR to different cellular compartments. |
| 8485 | 17222824 | Overexpression of IRS1 and IRS2 inhibited insulin-stimulated activation of the MAP kinases Erk1/2 while it increased/induced activation of Akt/PKB. |
| 8486 | 17222824 | Finally, overexpression of IRS1 and IRS2 but not of Shc induced DNA synthesis in starved CHO-IR cells independent of exogenous growth factors. |
| 8487 | 17222824 | Our results demonstrate that variations in cellular IRS1 and IRS2 concentration affect insulin signalling both upstream and downstream and that IRS proteins could play instructive rather than just permissive roles in signal transmission. |
| 8488 | 17222824 | Insulin receptor substrates 1 and 2 but not Shc can activate the insulin receptor independent of insulin and induce proliferation in CHO-IR cells. |
| 8489 | 17222824 | Ligand-activated insulin receptor (IR) attracts and phosphorylates various substrates such as insulin receptor substrates 1-4 (IRS) and Shc. |
| 8490 | 17222824 | We found that the extent of receptor tyrosine phosphorylation positively correlates with binding affinity towards IRS1/2 but not towards Shc. |
| 8491 | 17222824 | Moreover, overexpression of IRS1 or IRS2 but not of Shc increased IR tyrosine phosphorylation in a dose-dependent manner, also independent of insulin. |
| 8492 | 17222824 | Molecular truncations of IRS1 revealed that neither the isolated PH and PTB domains nor the C-terminus with the tyrosine phosphorylation sites alone are sufficient for substrate-dependent receptor activation. |
| 8493 | 17222824 | Overexpression of IRS1 and IRS2 impaired insulin-induced internalization of the IR in a dose-dependent manner suggesting that IRS proteins prevent endosome-associated receptor dephosphorylation/inactivation. |
| 8494 | 17222824 | IRS1 and IRS2 could therefore target the activated IR to different cellular compartments. |
| 8495 | 17222824 | Overexpression of IRS1 and IRS2 inhibited insulin-stimulated activation of the MAP kinases Erk1/2 while it increased/induced activation of Akt/PKB. |
| 8496 | 17222824 | Finally, overexpression of IRS1 and IRS2 but not of Shc induced DNA synthesis in starved CHO-IR cells independent of exogenous growth factors. |
| 8497 | 17222824 | Our results demonstrate that variations in cellular IRS1 and IRS2 concentration affect insulin signalling both upstream and downstream and that IRS proteins could play instructive rather than just permissive roles in signal transmission. |
| 8498 | 17222824 | Insulin receptor substrates 1 and 2 but not Shc can activate the insulin receptor independent of insulin and induce proliferation in CHO-IR cells. |
| 8499 | 17222824 | Ligand-activated insulin receptor (IR) attracts and phosphorylates various substrates such as insulin receptor substrates 1-4 (IRS) and Shc. |
| 8500 | 17222824 | We found that the extent of receptor tyrosine phosphorylation positively correlates with binding affinity towards IRS1/2 but not towards Shc. |
| 8501 | 17222824 | Moreover, overexpression of IRS1 or IRS2 but not of Shc increased IR tyrosine phosphorylation in a dose-dependent manner, also independent of insulin. |
| 8502 | 17222824 | Molecular truncations of IRS1 revealed that neither the isolated PH and PTB domains nor the C-terminus with the tyrosine phosphorylation sites alone are sufficient for substrate-dependent receptor activation. |
| 8503 | 17222824 | Overexpression of IRS1 and IRS2 impaired insulin-induced internalization of the IR in a dose-dependent manner suggesting that IRS proteins prevent endosome-associated receptor dephosphorylation/inactivation. |
| 8504 | 17222824 | IRS1 and IRS2 could therefore target the activated IR to different cellular compartments. |
| 8505 | 17222824 | Overexpression of IRS1 and IRS2 inhibited insulin-stimulated activation of the MAP kinases Erk1/2 while it increased/induced activation of Akt/PKB. |
| 8506 | 17222824 | Finally, overexpression of IRS1 and IRS2 but not of Shc induced DNA synthesis in starved CHO-IR cells independent of exogenous growth factors. |
| 8507 | 17222824 | Our results demonstrate that variations in cellular IRS1 and IRS2 concentration affect insulin signalling both upstream and downstream and that IRS proteins could play instructive rather than just permissive roles in signal transmission. |
| 8508 | 17222824 | Insulin receptor substrates 1 and 2 but not Shc can activate the insulin receptor independent of insulin and induce proliferation in CHO-IR cells. |
| 8509 | 17222824 | Ligand-activated insulin receptor (IR) attracts and phosphorylates various substrates such as insulin receptor substrates 1-4 (IRS) and Shc. |
| 8510 | 17222824 | We found that the extent of receptor tyrosine phosphorylation positively correlates with binding affinity towards IRS1/2 but not towards Shc. |
| 8511 | 17222824 | Moreover, overexpression of IRS1 or IRS2 but not of Shc increased IR tyrosine phosphorylation in a dose-dependent manner, also independent of insulin. |
| 8512 | 17222824 | Molecular truncations of IRS1 revealed that neither the isolated PH and PTB domains nor the C-terminus with the tyrosine phosphorylation sites alone are sufficient for substrate-dependent receptor activation. |
| 8513 | 17222824 | Overexpression of IRS1 and IRS2 impaired insulin-induced internalization of the IR in a dose-dependent manner suggesting that IRS proteins prevent endosome-associated receptor dephosphorylation/inactivation. |
| 8514 | 17222824 | IRS1 and IRS2 could therefore target the activated IR to different cellular compartments. |
| 8515 | 17222824 | Overexpression of IRS1 and IRS2 inhibited insulin-stimulated activation of the MAP kinases Erk1/2 while it increased/induced activation of Akt/PKB. |
| 8516 | 17222824 | Finally, overexpression of IRS1 and IRS2 but not of Shc induced DNA synthesis in starved CHO-IR cells independent of exogenous growth factors. |
| 8517 | 17222824 | Our results demonstrate that variations in cellular IRS1 and IRS2 concentration affect insulin signalling both upstream and downstream and that IRS proteins could play instructive rather than just permissive roles in signal transmission. |
| 8518 | 17222824 | Insulin receptor substrates 1 and 2 but not Shc can activate the insulin receptor independent of insulin and induce proliferation in CHO-IR cells. |
| 8519 | 17222824 | Ligand-activated insulin receptor (IR) attracts and phosphorylates various substrates such as insulin receptor substrates 1-4 (IRS) and Shc. |
| 8520 | 17222824 | We found that the extent of receptor tyrosine phosphorylation positively correlates with binding affinity towards IRS1/2 but not towards Shc. |
| 8521 | 17222824 | Moreover, overexpression of IRS1 or IRS2 but not of Shc increased IR tyrosine phosphorylation in a dose-dependent manner, also independent of insulin. |
| 8522 | 17222824 | Molecular truncations of IRS1 revealed that neither the isolated PH and PTB domains nor the C-terminus with the tyrosine phosphorylation sites alone are sufficient for substrate-dependent receptor activation. |
| 8523 | 17222824 | Overexpression of IRS1 and IRS2 impaired insulin-induced internalization of the IR in a dose-dependent manner suggesting that IRS proteins prevent endosome-associated receptor dephosphorylation/inactivation. |
| 8524 | 17222824 | IRS1 and IRS2 could therefore target the activated IR to different cellular compartments. |
| 8525 | 17222824 | Overexpression of IRS1 and IRS2 inhibited insulin-stimulated activation of the MAP kinases Erk1/2 while it increased/induced activation of Akt/PKB. |
| 8526 | 17222824 | Finally, overexpression of IRS1 and IRS2 but not of Shc induced DNA synthesis in starved CHO-IR cells independent of exogenous growth factors. |
| 8527 | 17222824 | Our results demonstrate that variations in cellular IRS1 and IRS2 concentration affect insulin signalling both upstream and downstream and that IRS proteins could play instructive rather than just permissive roles in signal transmission. |
| 8528 | 17222824 | Insulin receptor substrates 1 and 2 but not Shc can activate the insulin receptor independent of insulin and induce proliferation in CHO-IR cells. |
| 8529 | 17222824 | Ligand-activated insulin receptor (IR) attracts and phosphorylates various substrates such as insulin receptor substrates 1-4 (IRS) and Shc. |
| 8530 | 17222824 | We found that the extent of receptor tyrosine phosphorylation positively correlates with binding affinity towards IRS1/2 but not towards Shc. |
| 8531 | 17222824 | Moreover, overexpression of IRS1 or IRS2 but not of Shc increased IR tyrosine phosphorylation in a dose-dependent manner, also independent of insulin. |
| 8532 | 17222824 | Molecular truncations of IRS1 revealed that neither the isolated PH and PTB domains nor the C-terminus with the tyrosine phosphorylation sites alone are sufficient for substrate-dependent receptor activation. |
| 8533 | 17222824 | Overexpression of IRS1 and IRS2 impaired insulin-induced internalization of the IR in a dose-dependent manner suggesting that IRS proteins prevent endosome-associated receptor dephosphorylation/inactivation. |
| 8534 | 17222824 | IRS1 and IRS2 could therefore target the activated IR to different cellular compartments. |
| 8535 | 17222824 | Overexpression of IRS1 and IRS2 inhibited insulin-stimulated activation of the MAP kinases Erk1/2 while it increased/induced activation of Akt/PKB. |
| 8536 | 17222824 | Finally, overexpression of IRS1 and IRS2 but not of Shc induced DNA synthesis in starved CHO-IR cells independent of exogenous growth factors. |
| 8537 | 17222824 | Our results demonstrate that variations in cellular IRS1 and IRS2 concentration affect insulin signalling both upstream and downstream and that IRS proteins could play instructive rather than just permissive roles in signal transmission. |
| 8538 | 17222824 | Insulin receptor substrates 1 and 2 but not Shc can activate the insulin receptor independent of insulin and induce proliferation in CHO-IR cells. |
| 8539 | 17222824 | Ligand-activated insulin receptor (IR) attracts and phosphorylates various substrates such as insulin receptor substrates 1-4 (IRS) and Shc. |
| 8540 | 17222824 | We found that the extent of receptor tyrosine phosphorylation positively correlates with binding affinity towards IRS1/2 but not towards Shc. |
| 8541 | 17222824 | Moreover, overexpression of IRS1 or IRS2 but not of Shc increased IR tyrosine phosphorylation in a dose-dependent manner, also independent of insulin. |
| 8542 | 17222824 | Molecular truncations of IRS1 revealed that neither the isolated PH and PTB domains nor the C-terminus with the tyrosine phosphorylation sites alone are sufficient for substrate-dependent receptor activation. |
| 8543 | 17222824 | Overexpression of IRS1 and IRS2 impaired insulin-induced internalization of the IR in a dose-dependent manner suggesting that IRS proteins prevent endosome-associated receptor dephosphorylation/inactivation. |
| 8544 | 17222824 | IRS1 and IRS2 could therefore target the activated IR to different cellular compartments. |
| 8545 | 17222824 | Overexpression of IRS1 and IRS2 inhibited insulin-stimulated activation of the MAP kinases Erk1/2 while it increased/induced activation of Akt/PKB. |
| 8546 | 17222824 | Finally, overexpression of IRS1 and IRS2 but not of Shc induced DNA synthesis in starved CHO-IR cells independent of exogenous growth factors. |
| 8547 | 17222824 | Our results demonstrate that variations in cellular IRS1 and IRS2 concentration affect insulin signalling both upstream and downstream and that IRS proteins could play instructive rather than just permissive roles in signal transmission. |
| 8548 | 17222824 | Insulin receptor substrates 1 and 2 but not Shc can activate the insulin receptor independent of insulin and induce proliferation in CHO-IR cells. |
| 8549 | 17222824 | Ligand-activated insulin receptor (IR) attracts and phosphorylates various substrates such as insulin receptor substrates 1-4 (IRS) and Shc. |
| 8550 | 17222824 | We found that the extent of receptor tyrosine phosphorylation positively correlates with binding affinity towards IRS1/2 but not towards Shc. |
| 8551 | 17222824 | Moreover, overexpression of IRS1 or IRS2 but not of Shc increased IR tyrosine phosphorylation in a dose-dependent manner, also independent of insulin. |
| 8552 | 17222824 | Molecular truncations of IRS1 revealed that neither the isolated PH and PTB domains nor the C-terminus with the tyrosine phosphorylation sites alone are sufficient for substrate-dependent receptor activation. |
| 8553 | 17222824 | Overexpression of IRS1 and IRS2 impaired insulin-induced internalization of the IR in a dose-dependent manner suggesting that IRS proteins prevent endosome-associated receptor dephosphorylation/inactivation. |
| 8554 | 17222824 | IRS1 and IRS2 could therefore target the activated IR to different cellular compartments. |
| 8555 | 17222824 | Overexpression of IRS1 and IRS2 inhibited insulin-stimulated activation of the MAP kinases Erk1/2 while it increased/induced activation of Akt/PKB. |
| 8556 | 17222824 | Finally, overexpression of IRS1 and IRS2 but not of Shc induced DNA synthesis in starved CHO-IR cells independent of exogenous growth factors. |
| 8557 | 17222824 | Our results demonstrate that variations in cellular IRS1 and IRS2 concentration affect insulin signalling both upstream and downstream and that IRS proteins could play instructive rather than just permissive roles in signal transmission. |
| 8558 | 17229938 | Defective insulin and acetylcholine induction of endothelial cell-nitric oxide synthase through insulin receptor substrate/Akt signaling pathway in aorta of obese rats. |
| 8559 | 17229938 | Upon JAK2 activation, tyrosine phosphorylation of insulin receptor substrate (IRS)-1 is detected. |
| 8560 | 17229938 | In addition, ACh induces JAK2/IRS-1 and IRS-1/phosphatidylinositol (PI) 3-kinase associations, downstream activation of Akt/protein kinase B, endothelial cell-nitric oxide synthase (eNOS), and extracellular signal-regulated kinase (ERK)-1/2. |
| 8561 | 17229938 | The pharmacological blockade of JAK2 or PI 3-kinase reduced ACh-stimulated eNOS phosphorylation, NOS activity, and aorta relaxation. |
| 8562 | 17229938 | These data indicate a new signal transduction pathway for IRS-1/PI 3-kinase/Akt/eNOS activation and ERK1/2 by means of JAK2 tyrosine phosphorylation stimulated by ACh in vessels. |
| 8563 | 17229938 | Moreover, we demonstrate that in aorta of obese rats (high-fat diet), there is an impairment in the insulin- and ACh-stimulated IRS-1/PI 3-kinase pathway, leading to reduced activation with lower protein levels of eNOS associated with a hyperactivated ERK/mitogen-activated protein kinase pathway. |
| 8564 | 17229938 | These results suggest that in aorta of obese rats, there not only is insulin resistance but also ACh resistance, probably mediated by a common signaling pathway that controls the activity and the protein levels of eNOS. |
| 8565 | 17229938 | Defective insulin and acetylcholine induction of endothelial cell-nitric oxide synthase through insulin receptor substrate/Akt signaling pathway in aorta of obese rats. |
| 8566 | 17229938 | Upon JAK2 activation, tyrosine phosphorylation of insulin receptor substrate (IRS)-1 is detected. |
| 8567 | 17229938 | In addition, ACh induces JAK2/IRS-1 and IRS-1/phosphatidylinositol (PI) 3-kinase associations, downstream activation of Akt/protein kinase B, endothelial cell-nitric oxide synthase (eNOS), and extracellular signal-regulated kinase (ERK)-1/2. |
| 8568 | 17229938 | The pharmacological blockade of JAK2 or PI 3-kinase reduced ACh-stimulated eNOS phosphorylation, NOS activity, and aorta relaxation. |
| 8569 | 17229938 | These data indicate a new signal transduction pathway for IRS-1/PI 3-kinase/Akt/eNOS activation and ERK1/2 by means of JAK2 tyrosine phosphorylation stimulated by ACh in vessels. |
| 8570 | 17229938 | Moreover, we demonstrate that in aorta of obese rats (high-fat diet), there is an impairment in the insulin- and ACh-stimulated IRS-1/PI 3-kinase pathway, leading to reduced activation with lower protein levels of eNOS associated with a hyperactivated ERK/mitogen-activated protein kinase pathway. |
| 8571 | 17229938 | These results suggest that in aorta of obese rats, there not only is insulin resistance but also ACh resistance, probably mediated by a common signaling pathway that controls the activity and the protein levels of eNOS. |
| 8572 | 17229938 | Defective insulin and acetylcholine induction of endothelial cell-nitric oxide synthase through insulin receptor substrate/Akt signaling pathway in aorta of obese rats. |
| 8573 | 17229938 | Upon JAK2 activation, tyrosine phosphorylation of insulin receptor substrate (IRS)-1 is detected. |
| 8574 | 17229938 | In addition, ACh induces JAK2/IRS-1 and IRS-1/phosphatidylinositol (PI) 3-kinase associations, downstream activation of Akt/protein kinase B, endothelial cell-nitric oxide synthase (eNOS), and extracellular signal-regulated kinase (ERK)-1/2. |
| 8575 | 17229938 | The pharmacological blockade of JAK2 or PI 3-kinase reduced ACh-stimulated eNOS phosphorylation, NOS activity, and aorta relaxation. |
| 8576 | 17229938 | These data indicate a new signal transduction pathway for IRS-1/PI 3-kinase/Akt/eNOS activation and ERK1/2 by means of JAK2 tyrosine phosphorylation stimulated by ACh in vessels. |
| 8577 | 17229938 | Moreover, we demonstrate that in aorta of obese rats (high-fat diet), there is an impairment in the insulin- and ACh-stimulated IRS-1/PI 3-kinase pathway, leading to reduced activation with lower protein levels of eNOS associated with a hyperactivated ERK/mitogen-activated protein kinase pathway. |
| 8578 | 17229938 | These results suggest that in aorta of obese rats, there not only is insulin resistance but also ACh resistance, probably mediated by a common signaling pathway that controls the activity and the protein levels of eNOS. |
| 8579 | 17242212 | Interleukin-6 impairs the insulin signaling pathway, promoting production of nitric oxide in human umbilical vein endothelial cells. |
| 8580 | 17242212 | Interleukin 6 (IL-6) is an independent predictor of type 2 diabetes and cardiovascular disease and is correlated with insulin resistance. |
| 8581 | 17242212 | Insulin stimulates nitric oxide (NO) production through the IRS-1/PI3-kinase/Akt/eNOS pathway (where IRS-1 is insulin receptor substrate 1, PI3-kinase is phosphatidylinositol 3-kinase, and eNOS is endothelial NO synthase). |
| 8582 | 17242212 | We asked if IL-6 affects insulin vasodilator action both in human umbilical vein endothelial cells (HUVEC) and in the aortas of C57BL/6J mice and whether this inhibitory effect was caused by increased Ser phosphorylation of IRS-1. |
| 8583 | 17242212 | We observed that IL-6 increased IRS-1 phosphorylation at Ser(312) and Ser(616); these effects were paralleled by increased Jun N-terminal protein kinase (JNK) and extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation and reversed by JNK and ERK1/2 inhibition. |
| 8584 | 17242212 | In addition, IL-6 treatment resulted in impaired IRS-1 phosphorylation at Tyr(612), a site essential for engaging PI3-kinase. |
| 8585 | 17242212 | Furthermore, IL-6 treatment reduced insulin-stimulated phosphorylation of eNOS at the stimulatory Ser(1177) site and impaired insulin-stimulated eNOS dephosphorylation at the inhibitory Thr(495) site. |
| 8586 | 17242212 | Insulin-stimulated eNOS activation and NO production were also inhibited by IL-6; these effects were reversed by inhibition of JNK and ERK1/2. |
| 8587 | 17242212 | Treatment of C57BL/6J mice with IL-6 resulted in impaired insulin-dependent activation of the Akt/eNOS pathway in the aorta as a result of JNK and ERK1/2 activation. |
| 8588 | 17242212 | Our data suggest that IL-6 impairs the vasodilator effects of insulin that are mediated by the IRS-1/PI3-kinase/Akt/eNOS pathway through activation of JNK and ERK1/2. |
| 8589 | 17242212 | Interleukin-6 impairs the insulin signaling pathway, promoting production of nitric oxide in human umbilical vein endothelial cells. |
| 8590 | 17242212 | Interleukin 6 (IL-6) is an independent predictor of type 2 diabetes and cardiovascular disease and is correlated with insulin resistance. |
| 8591 | 17242212 | Insulin stimulates nitric oxide (NO) production through the IRS-1/PI3-kinase/Akt/eNOS pathway (where IRS-1 is insulin receptor substrate 1, PI3-kinase is phosphatidylinositol 3-kinase, and eNOS is endothelial NO synthase). |
| 8592 | 17242212 | We asked if IL-6 affects insulin vasodilator action both in human umbilical vein endothelial cells (HUVEC) and in the aortas of C57BL/6J mice and whether this inhibitory effect was caused by increased Ser phosphorylation of IRS-1. |
| 8593 | 17242212 | We observed that IL-6 increased IRS-1 phosphorylation at Ser(312) and Ser(616); these effects were paralleled by increased Jun N-terminal protein kinase (JNK) and extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation and reversed by JNK and ERK1/2 inhibition. |
| 8594 | 17242212 | In addition, IL-6 treatment resulted in impaired IRS-1 phosphorylation at Tyr(612), a site essential for engaging PI3-kinase. |
| 8595 | 17242212 | Furthermore, IL-6 treatment reduced insulin-stimulated phosphorylation of eNOS at the stimulatory Ser(1177) site and impaired insulin-stimulated eNOS dephosphorylation at the inhibitory Thr(495) site. |
| 8596 | 17242212 | Insulin-stimulated eNOS activation and NO production were also inhibited by IL-6; these effects were reversed by inhibition of JNK and ERK1/2. |
| 8597 | 17242212 | Treatment of C57BL/6J mice with IL-6 resulted in impaired insulin-dependent activation of the Akt/eNOS pathway in the aorta as a result of JNK and ERK1/2 activation. |
| 8598 | 17242212 | Our data suggest that IL-6 impairs the vasodilator effects of insulin that are mediated by the IRS-1/PI3-kinase/Akt/eNOS pathway through activation of JNK and ERK1/2. |
| 8599 | 17242212 | Interleukin-6 impairs the insulin signaling pathway, promoting production of nitric oxide in human umbilical vein endothelial cells. |
| 8600 | 17242212 | Interleukin 6 (IL-6) is an independent predictor of type 2 diabetes and cardiovascular disease and is correlated with insulin resistance. |
| 8601 | 17242212 | Insulin stimulates nitric oxide (NO) production through the IRS-1/PI3-kinase/Akt/eNOS pathway (where IRS-1 is insulin receptor substrate 1, PI3-kinase is phosphatidylinositol 3-kinase, and eNOS is endothelial NO synthase). |
| 8602 | 17242212 | We asked if IL-6 affects insulin vasodilator action both in human umbilical vein endothelial cells (HUVEC) and in the aortas of C57BL/6J mice and whether this inhibitory effect was caused by increased Ser phosphorylation of IRS-1. |
| 8603 | 17242212 | We observed that IL-6 increased IRS-1 phosphorylation at Ser(312) and Ser(616); these effects were paralleled by increased Jun N-terminal protein kinase (JNK) and extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation and reversed by JNK and ERK1/2 inhibition. |
| 8604 | 17242212 | In addition, IL-6 treatment resulted in impaired IRS-1 phosphorylation at Tyr(612), a site essential for engaging PI3-kinase. |
| 8605 | 17242212 | Furthermore, IL-6 treatment reduced insulin-stimulated phosphorylation of eNOS at the stimulatory Ser(1177) site and impaired insulin-stimulated eNOS dephosphorylation at the inhibitory Thr(495) site. |
| 8606 | 17242212 | Insulin-stimulated eNOS activation and NO production were also inhibited by IL-6; these effects were reversed by inhibition of JNK and ERK1/2. |
| 8607 | 17242212 | Treatment of C57BL/6J mice with IL-6 resulted in impaired insulin-dependent activation of the Akt/eNOS pathway in the aorta as a result of JNK and ERK1/2 activation. |
| 8608 | 17242212 | Our data suggest that IL-6 impairs the vasodilator effects of insulin that are mediated by the IRS-1/PI3-kinase/Akt/eNOS pathway through activation of JNK and ERK1/2. |
| 8609 | 17242212 | Interleukin-6 impairs the insulin signaling pathway, promoting production of nitric oxide in human umbilical vein endothelial cells. |
| 8610 | 17242212 | Interleukin 6 (IL-6) is an independent predictor of type 2 diabetes and cardiovascular disease and is correlated with insulin resistance. |
| 8611 | 17242212 | Insulin stimulates nitric oxide (NO) production through the IRS-1/PI3-kinase/Akt/eNOS pathway (where IRS-1 is insulin receptor substrate 1, PI3-kinase is phosphatidylinositol 3-kinase, and eNOS is endothelial NO synthase). |
| 8612 | 17242212 | We asked if IL-6 affects insulin vasodilator action both in human umbilical vein endothelial cells (HUVEC) and in the aortas of C57BL/6J mice and whether this inhibitory effect was caused by increased Ser phosphorylation of IRS-1. |
| 8613 | 17242212 | We observed that IL-6 increased IRS-1 phosphorylation at Ser(312) and Ser(616); these effects were paralleled by increased Jun N-terminal protein kinase (JNK) and extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation and reversed by JNK and ERK1/2 inhibition. |
| 8614 | 17242212 | In addition, IL-6 treatment resulted in impaired IRS-1 phosphorylation at Tyr(612), a site essential for engaging PI3-kinase. |
| 8615 | 17242212 | Furthermore, IL-6 treatment reduced insulin-stimulated phosphorylation of eNOS at the stimulatory Ser(1177) site and impaired insulin-stimulated eNOS dephosphorylation at the inhibitory Thr(495) site. |
| 8616 | 17242212 | Insulin-stimulated eNOS activation and NO production were also inhibited by IL-6; these effects were reversed by inhibition of JNK and ERK1/2. |
| 8617 | 17242212 | Treatment of C57BL/6J mice with IL-6 resulted in impaired insulin-dependent activation of the Akt/eNOS pathway in the aorta as a result of JNK and ERK1/2 activation. |
| 8618 | 17242212 | Our data suggest that IL-6 impairs the vasodilator effects of insulin that are mediated by the IRS-1/PI3-kinase/Akt/eNOS pathway through activation of JNK and ERK1/2. |
| 8619 | 17242212 | Interleukin-6 impairs the insulin signaling pathway, promoting production of nitric oxide in human umbilical vein endothelial cells. |
| 8620 | 17242212 | Interleukin 6 (IL-6) is an independent predictor of type 2 diabetes and cardiovascular disease and is correlated with insulin resistance. |
| 8621 | 17242212 | Insulin stimulates nitric oxide (NO) production through the IRS-1/PI3-kinase/Akt/eNOS pathway (where IRS-1 is insulin receptor substrate 1, PI3-kinase is phosphatidylinositol 3-kinase, and eNOS is endothelial NO synthase). |
| 8622 | 17242212 | We asked if IL-6 affects insulin vasodilator action both in human umbilical vein endothelial cells (HUVEC) and in the aortas of C57BL/6J mice and whether this inhibitory effect was caused by increased Ser phosphorylation of IRS-1. |
| 8623 | 17242212 | We observed that IL-6 increased IRS-1 phosphorylation at Ser(312) and Ser(616); these effects were paralleled by increased Jun N-terminal protein kinase (JNK) and extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation and reversed by JNK and ERK1/2 inhibition. |
| 8624 | 17242212 | In addition, IL-6 treatment resulted in impaired IRS-1 phosphorylation at Tyr(612), a site essential for engaging PI3-kinase. |
| 8625 | 17242212 | Furthermore, IL-6 treatment reduced insulin-stimulated phosphorylation of eNOS at the stimulatory Ser(1177) site and impaired insulin-stimulated eNOS dephosphorylation at the inhibitory Thr(495) site. |
| 8626 | 17242212 | Insulin-stimulated eNOS activation and NO production were also inhibited by IL-6; these effects were reversed by inhibition of JNK and ERK1/2. |
| 8627 | 17242212 | Treatment of C57BL/6J mice with IL-6 resulted in impaired insulin-dependent activation of the Akt/eNOS pathway in the aorta as a result of JNK and ERK1/2 activation. |
| 8628 | 17242212 | Our data suggest that IL-6 impairs the vasodilator effects of insulin that are mediated by the IRS-1/PI3-kinase/Akt/eNOS pathway through activation of JNK and ERK1/2. |
| 8629 | 17259384 | Ceramide- and oxidant-induced insulin resistance involve loss of insulin-dependent Rac-activation and actin remodeling in muscle cells. |
| 8630 | 17259384 | In muscle cells, insulin elicits recruitment of the glucose transporter GLUT4 to the plasma membrane. |
| 8631 | 17259384 | This process engages sequential signaling from insulin receptor substrate (IRS)-1 to phosphatidylinositol (PI) 3-kinase and the serine/threonine kinase Akt. |
| 8632 | 17259384 | GLUT4 translocation also requires an Akt-independent but PI 3-kinase-and Rac-dependent remodeling of filamentous actin. |
| 8633 | 17259384 | Although IRS-1 phosphorylation is often reduced in insulin-resistant states in vivo, several conditions eliciting insulin resistance in cell culture spare this early step. |
| 8634 | 17259384 | Here, we show that insulin-dependent Rac activation and its consequent actin remodeling were abolished upon exposure of L6 myotubes beginning at doses of C2-ceramide or oxidant-producing glucose oxidase as low as 12.5 micromol/l and 12.5 mU/ml, respectively. |
| 8635 | 17259384 | At 25 micromol/l and 25 mU/ml, glucose oxidase and C2-ceramide markedly reduced GLUT4 translocation and glucose uptake and lowered Akt phosphorylation on Ser473 and Thr308, yet they affected neither IRS-1 tyrosine phosphorylation nor its association with p85 and PI 3-kinase activity. |
| 8636 | 17259384 | Small interfering RNA-dependent Rac1 knockdown prevented actin remodeling and GLUT4 translocation but spared Akt phosphorylation, suggesting that Rac and actin remodeling do not contribute to overall Akt activation. |
| 8637 | 17259384 | We propose that ceramide and oxidative stress can each affect two independent arms of insulin signaling to GLUT4 at distinct steps, Rac-GTP loading and Akt phosphorylation. |
| 8638 | 17259384 | Ceramide- and oxidant-induced insulin resistance involve loss of insulin-dependent Rac-activation and actin remodeling in muscle cells. |
| 8639 | 17259384 | In muscle cells, insulin elicits recruitment of the glucose transporter GLUT4 to the plasma membrane. |
| 8640 | 17259384 | This process engages sequential signaling from insulin receptor substrate (IRS)-1 to phosphatidylinositol (PI) 3-kinase and the serine/threonine kinase Akt. |
| 8641 | 17259384 | GLUT4 translocation also requires an Akt-independent but PI 3-kinase-and Rac-dependent remodeling of filamentous actin. |
| 8642 | 17259384 | Although IRS-1 phosphorylation is often reduced in insulin-resistant states in vivo, several conditions eliciting insulin resistance in cell culture spare this early step. |
| 8643 | 17259384 | Here, we show that insulin-dependent Rac activation and its consequent actin remodeling were abolished upon exposure of L6 myotubes beginning at doses of C2-ceramide or oxidant-producing glucose oxidase as low as 12.5 micromol/l and 12.5 mU/ml, respectively. |
| 8644 | 17259384 | At 25 micromol/l and 25 mU/ml, glucose oxidase and C2-ceramide markedly reduced GLUT4 translocation and glucose uptake and lowered Akt phosphorylation on Ser473 and Thr308, yet they affected neither IRS-1 tyrosine phosphorylation nor its association with p85 and PI 3-kinase activity. |
| 8645 | 17259384 | Small interfering RNA-dependent Rac1 knockdown prevented actin remodeling and GLUT4 translocation but spared Akt phosphorylation, suggesting that Rac and actin remodeling do not contribute to overall Akt activation. |
| 8646 | 17259384 | We propose that ceramide and oxidative stress can each affect two independent arms of insulin signaling to GLUT4 at distinct steps, Rac-GTP loading and Akt phosphorylation. |
| 8647 | 17259391 | Tumor necrosis factor-alpha induces intestinal insulin resistance and stimulates the overproduction of intestinal apolipoprotein B48-containing lipoproteins. |
| 8648 | 17259391 | There is growing evidence suggesting intestinal insulin resistance and overproduction of apolipoprotein (apo) B48-containing chylomicrons in insulin-resistant states. |
| 8649 | 17259391 | In the current study, we investigated the potential role of the inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) in the development of insulin resistance and aberrant lipoprotein metabolism in the small intestine in a Syrian golden hamster model. |
| 8650 | 17259391 | TNF-alpha infusion decreased whole-body insulin sensitivity, based on in vivo euglycemic clamp studies in chow-fed hamsters. |
| 8651 | 17259391 | Analysis of intestinal tissue in TNF-alpha-treated hamsters indicated impaired phosphorylation of insulin receptor-beta, insulin receptor substrate-1, Akt, and Shc and increased phosphorylation of p38, extracellular signal-related kinase-1/2, and Jun NH(2)-terminal kinase. |
| 8652 | 17259391 | TNF-alpha infusion also increased intestinal production of total apoB48, triglyceride-rich lipoprotein apoB48, and serum triglyceride levels in both fasting and postprandial (fat load) states. |
| 8653 | 17259391 | The effects of TNF-alpha on plasma apoB48 levels could be blocked by the p38 inhibitor SB203580. |
| 8654 | 17259391 | Ex vivo experiments using freshly isolated enterocytes also showed TNF-alpha-induced p38 phosphorylation and intestinal apoB48 overproduction, effects that could be blocked by SB203580. |
| 8655 | 17259391 | Interestingly, TNF-alpha increased the mRNA and protein mass of intestinal microsomal triglyceride transfer protein without altering apoB mRNA levels. |
| 8656 | 17259391 | Enterocytes were found to have detectable levels of both TNF-alpha receptor types (p55 and p75), and antibodies against either of the two TNF-alpha receptors partially blocked the stimulatory effect of TNF-alpha on apoB48 production and p38 phosphorylation. |
| 8657 | 17259391 | In summary, these data suggest that intestinal insulin resistance can be induced in hamsters by TNF-alpha infusion, and it is accompanied by intestinal overproduction of apoB48-containing lipoproteins. |
| 8658 | 17259391 | TNF-alpha-induced stimulation of intestinal lipoprotein production appears to be mediated via TNF-alpha receptors and the p38 mitogen-activated protein kinase pathway. |
| 8659 | 17259395 | These compounds trigger insulin signaling, which is characterized by rapid activation of insulin receptor substrate-1, Akt, and glycogen synthase kinase-3 independent of insulin receptor phosphorylation. |
| 8660 | 17259395 | These results demonstrate the feasibility of insulin-like regulation in the complete absence of insulin and downstream of the insulin receptor. |
| 8661 | 17279354 | C-reactive protein induces phosphorylation of insulin receptor substrate-1 on Ser307 and Ser 612 in L6 myocytes, thereby impairing the insulin signalling pathway that promotes glucose transport. |
| 8662 | 17292733 | Increased hepatic expression of ganglioside-specific sialidase, NEU3, improves insulin sensitivity and glucose tolerance in mice. |
| 8663 | 17292733 | We previously reported that mice overexpressing NEU3 mainly in muscles developed severe insulin-resistant diabetes. |
| 8664 | 17292733 | To examine the possible contributions of NEU3 to in vivo insulin sensitivity and glucose tolerance, NEU3 was expressed by using adenoviral vectors in the livers of C57BL/6 mice on standard and high-fat diets, and insulin-resistant KKAy mice on standard diets. |
| 8665 | 17292733 | Hepatic NEU3 overexpression paradoxically improved glucose tolerance and insulin sensitivity in the C57BL/6 mice fed standard diets, and glucose tolerance in the C57BL/6 mice fed high-fat diets and in KKAy mice. |
| 8666 | 17292733 | Hepatic NEU3 overexpression increased hepatic glycogen deposition and triglyceride accumulation, and enhanced the hepatic peroxisome proliferator-activated receptor gamma and fetuin expression in the C57BL/6 mice on standard and high-fat diets, and in KKAy mice. |
| 8667 | 17292733 | Basal and insulin-stimulated tyrosine phosphorylations of insulin receptor substrate 1 were significantly increased, but tyrosine phosphorylations of the insulin receptor and insulin receptor substrate 2 in the NEU3 liver were unchanged. |
| 8668 | 17292733 | Insulin-stimulated tyrosine phosphorylations of the insulin receptor were increased in adipose tissues of NEU3 mice. |
| 8669 | 17292733 | These results suggest that hepatic NEU3 overexpression improves insulin sensitivity and glucose tolerance through modification of ganglioside composition and peroxisome proliferator-activated receptor gamma signaling. |
| 8670 | 17292733 | Our findings also provide further evidence that NEU3 is an important regulator of insulin sensitivity and glucose tolerance. |
| 8671 | 17327424 | Feeding a c9,t11-CLA-enriched diet reduced fasting glucose (P < 0.05), insulin (P < 0.05), and triacylglycerol concentrations (P < 0.01) and increased adipose tissue plasma membrane GLUT4 (P < 0.05) and insulin receptor (P < 0.05) expression compared with the control linoleic acid-enriched diet. |
| 8672 | 17327424 | Interestingly, after the c9,t11-CLA diet, adipose tissue macrophage infiltration was less, with marked downregulation of several inflammatory markers in adipose tissue, including reduced tumor necrosis factor-alpha and CD68 mRNA (P < 0.05), nuclear factor-kappaB (NF-kappaB) p65 expression (P < 0.01), NF-kappaB DNA binding (P < 0.01), and NF-kappaB p65, p50, c-Rel, p52, and RelB transcriptional activity (P < 0.01). |
| 8673 | 17327424 | To define whether these observations were direct effects of the nutrient intervention, complimentary cell culture studies showed that c9,t11-CLA inhibited tumor necrosis factor-alpha-induced downregulation of insulin receptor substrate 1 and GLUT4 mRNA expression and promoted insulin-stimulated glucose transport in 3T3-L1 adipocytes compared with linoleic acid. |
| 8674 | 17340225 | Insulin-like effects of visfatin on human osteoblasts. |
| 8675 | 17340225 | Visfatin binds to and activates the insulin receptor (IR), thereby exerting insulin-mimetic effects in various cell lines. |
| 8676 | 17340225 | The expression and tyrosine phosphorylation of IR, IR substrate-1 (IRS-1), and IRS-2 were determined by immunoprecipitation and immunoblotting. |
| 8677 | 17340225 | Real-time quantitative reverse-transcription polymerase chain reaction (PCR) was used for determining alkaline phosphatase (ALP), osteocalcin, and type I collagen mRNA expression. |
| 8678 | 17340225 | Enzyme-linked immunosorbent assay and radioimmunoassay were used for measuring ALP activity, osteocalcin secretion, and type I collagen production. |
| 8679 | 17340225 | We found that visfatin induced tyrosine phosphorylation of IR, IRS-1, and IRS-2. |
| 8680 | 17340225 | Moreover, the effects of visfatin - glucose uptake, proliferation, and type I collagen enhancement of cultured human osteoblast-like cells - bore a close resemblance to those of insulin and were inhibited by hydroxy-2-naphthalenylmethylphosphonic acid tris-acetoxymethyl ester, a specific inhibitor of IR tyrosine kinase activity. |
| 8681 | 17340225 | We also unexpectedly found that visfatin downregulated osteocalcin secretion from human osteoblast-like cells. |
| 8682 | 17340225 | These data indicate that the regulation of glucose uptake, proliferation, and type I collagen production by visfatin in human osteoblasts involves IR phosphorylation, the same signal-transduction pathway used by insulin. |
| 8683 | 17340225 | Insulin-like effects of visfatin on human osteoblasts. |
| 8684 | 17340225 | Visfatin binds to and activates the insulin receptor (IR), thereby exerting insulin-mimetic effects in various cell lines. |
| 8685 | 17340225 | The expression and tyrosine phosphorylation of IR, IR substrate-1 (IRS-1), and IRS-2 were determined by immunoprecipitation and immunoblotting. |
| 8686 | 17340225 | Real-time quantitative reverse-transcription polymerase chain reaction (PCR) was used for determining alkaline phosphatase (ALP), osteocalcin, and type I collagen mRNA expression. |
| 8687 | 17340225 | Enzyme-linked immunosorbent assay and radioimmunoassay were used for measuring ALP activity, osteocalcin secretion, and type I collagen production. |
| 8688 | 17340225 | We found that visfatin induced tyrosine phosphorylation of IR, IRS-1, and IRS-2. |
| 8689 | 17340225 | Moreover, the effects of visfatin - glucose uptake, proliferation, and type I collagen enhancement of cultured human osteoblast-like cells - bore a close resemblance to those of insulin and were inhibited by hydroxy-2-naphthalenylmethylphosphonic acid tris-acetoxymethyl ester, a specific inhibitor of IR tyrosine kinase activity. |
| 8690 | 17340225 | We also unexpectedly found that visfatin downregulated osteocalcin secretion from human osteoblast-like cells. |
| 8691 | 17340225 | These data indicate that the regulation of glucose uptake, proliferation, and type I collagen production by visfatin in human osteoblasts involves IR phosphorylation, the same signal-transduction pathway used by insulin. |
| 8692 | 17363741 | Interleukin (IL)-6 is a proinflammatory cytokine shown to modify insulin sensitivity. |
| 8693 | 17363741 | Elevated plasma levels of IL-6 are observed in insulin-resistant states. |
| 8694 | 17363741 | Thus, IL-6 has also been suggested to promote insulin-mediated glucose utilization. |
| 8695 | 17363741 | A 30-min pre-exposure to IL-6 did not affect insulin-stimulated glucose transport. |
| 8696 | 17363741 | IL-6 increased phosphorylation of STAT3 (signal transducer and activator of transcription 3; P < 0.05), AMP-activated protein kinase (P = 0.063), and p38 mitogen-activated protein kinase (P < 0.05) and reduced phosphorylation of S6 ribosomal protein (P < 0.05). |
| 8697 | 17363741 | In contrast, phosphorylation of protein kinase B/Akt, AS160 (Akt substrate of 160 kDa), and GSK3alpha/beta (glycogen synthase kinase 3alpha/beta) as well as insulin receptor substrate 1-associated phosphatidylinositol 3-kinase activity remained unaltered. |
| 8698 | 17363741 | Insulin-stimulated glucose transport and insulin signaling were unchanged after IL-6 exposure. |
| 8699 | 17369524 | In skeletal muscle, Akt substrate of 160 kDa (AS160) phosphorylation, an Akt substrate implicated in the regulation of GLUT4 translocation, and its interaction with 14-3-3 was decreased (P < 0.05) only after a single exercise bout. |
| 8700 | 17369524 | Phosphorylation of insulin receptor substrate-1 and Akt were similar to changes in AS160 phosphorylation after exercise and/or insulin. |
| 8701 | 17369525 | Glucagon-like peptide-1 gene therapy in obese diabetic mice results in long-term cure of diabetes by improving insulin sensitivity and reducing hepatic gluconeogenesis. |
| 8702 | 17369525 | Glucose tolerance tests found that exogenous glucose was cleared normally. rAd-GLP-1-treated diabetic ob/ob mice showed improved beta-cell function, evidenced by glucose-responsive insulin release, and increased insulin sensitivity, evidenced by improved insulin tolerance and increased insulin-stimulated glucose uptake in adipocytes. rAd-GLP-1 treatment increased basal levels of insulin receptor substrate (IRS)-1 in the liver and activation of IRS-1 and protein kinase C by insulin in liver and muscle; increased Akt activation was only observed in muscle. rAd-GLP-1 treatment reduced hepatic glucose production and hepatic expression of phosphoenolpyruvate carboxykinase, glucose-6-phosphatase, and fatty acid synthase in ob/ob mice. |
| 8703 | 17384440 | Prolonged treatment of primary hepatocytes with oleate induces insulin resistance through p38 mitogen-activated protein kinase. |
| 8704 | 17384440 | In this study, we have investigated the role of p38 in oleate-induced hepatic insulin resistance. |
| 8705 | 17384440 | Our results show that a prolonged treatment of primary hepatocytes with oleate blunted insulin suppression of hepatic gluconeogenesis, and decreased insulin-induced phosphorylation of Akt in a p38-dependent manner. |
| 8706 | 17384440 | Reduction of the insulin-induced Akt phosphorylation by oleate correlated with activation of p38. |
| 8707 | 17384440 | In the presence of p38 inhibition, prolonged exposure of hepatocytes to oleate failed to reduce insulin-stimulated phosphorylation of Akt. |
| 8708 | 17384440 | An siRNA against p38alpha prevented oleate suppression of the insulin-induced phosphorylation of Akt. |
| 8709 | 17384440 | Furthermore, a prolonged exposure of hepatocytes to oleate decreased insulin-induced tyrosine phosphorylation of IRS1/2, while slightly increasing serine phosphorylation of IRS. |
| 8710 | 17384440 | The decrease of insulin-stimulated tyrosine phosphorylation of IRS1/2 in hepatocytes by oleate was reversed by the inhibition of p38. |
| 8711 | 17384440 | We further show that a prolonged exposure of primary hepatocytes to oleate elevated the protein level of the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) gene in a p38-dependent manner, but had no effect on the mRNA level of PTEN. |
| 8712 | 17384440 | Knocking down the PTEN gene prevented oleate to inhibit insulin activation of Akt and insulin suppression of gluconeogenesis. |
| 8713 | 17384440 | Together, results from this study demonstrate a critical role for p38 in oleate-induced hepatic insulin resistance. |
| 8714 | 17384440 | Prolonged treatment of primary hepatocytes with oleate induces insulin resistance through p38 mitogen-activated protein kinase. |
| 8715 | 17384440 | In this study, we have investigated the role of p38 in oleate-induced hepatic insulin resistance. |
| 8716 | 17384440 | Our results show that a prolonged treatment of primary hepatocytes with oleate blunted insulin suppression of hepatic gluconeogenesis, and decreased insulin-induced phosphorylation of Akt in a p38-dependent manner. |
| 8717 | 17384440 | Reduction of the insulin-induced Akt phosphorylation by oleate correlated with activation of p38. |
| 8718 | 17384440 | In the presence of p38 inhibition, prolonged exposure of hepatocytes to oleate failed to reduce insulin-stimulated phosphorylation of Akt. |
| 8719 | 17384440 | An siRNA against p38alpha prevented oleate suppression of the insulin-induced phosphorylation of Akt. |
| 8720 | 17384440 | Furthermore, a prolonged exposure of hepatocytes to oleate decreased insulin-induced tyrosine phosphorylation of IRS1/2, while slightly increasing serine phosphorylation of IRS. |
| 8721 | 17384440 | The decrease of insulin-stimulated tyrosine phosphorylation of IRS1/2 in hepatocytes by oleate was reversed by the inhibition of p38. |
| 8722 | 17384440 | We further show that a prolonged exposure of primary hepatocytes to oleate elevated the protein level of the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) gene in a p38-dependent manner, but had no effect on the mRNA level of PTEN. |
| 8723 | 17384440 | Knocking down the PTEN gene prevented oleate to inhibit insulin activation of Akt and insulin suppression of gluconeogenesis. |
| 8724 | 17384440 | Together, results from this study demonstrate a critical role for p38 in oleate-induced hepatic insulin resistance. |
| 8725 | 17400802 | After solubilization of the cells, insulin receptor kinase activity, tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1), IRS-1-associated phosphatidylinositol-3 kinase (PI3-kinase), PI3-kinase activity, Thr(308) phosphorlyation of Akt, amount of protein tyrosine phosphatase-epsilon (PTPepsilon), and glycogen synthase activity were determined. |
| 8726 | 17400802 | Incubation with PD151746 resulted in a significant reduction of insulin-stimulated glycogen synthesis compared with cells not pre-incubated with the calpain inhibitor (-PD: t(0), 4.90 +/- 1.20%; t(5), 5.90 +/- 1.02%; t(15), 5.29 +/- 0.95%; t(30), 5.60 +/- 1.10%; t(45), 5.52 +/- 0.90%; t(60), 5.67 +/- 0.97%;+PD: t(0), 4.56 +/- 1.10%; t(5), 6.16 +/- 1.05%; t(15), 7.52 +/- 1.09%; t(30), 7.68 +/- 1.10%; t(45), 8.28 +/- 0.89%; t(60), 7.69 +/- 0.98%; P < 0.05). |
| 8727 | 17400802 | These results in HepG2 cells suggest that calpains play a role in the hepatic regulation of insulin-stimulated glycogen synthesis independent of the PI3-kinase/Akt signaling pathway. |
| 8728 | 17446186 | Tumor necrosis factor-alpha induces insulin resistance in endothelial cells via a p38 mitogen-activated protein kinase-dependent pathway. |
| 8729 | 17446186 | Systemic infusion of TNF-alpha abrogates insulin's action to enhance skeletal muscle microvascular perfusion. |
| 8730 | 17446186 | In skeletal muscle TNF-alpha induces insulin resistance via the p38 MAPK pathway. |
| 8731 | 17446186 | To examine whether p38 MAPK also regulates TNF-alpha-induced vascular insulin resistance, bovine aortic endothelial cells (bAECs) were incubated+/-TNF-alpha (5 ng/ml) for 6 h in the presence or absence of SB203580 (p38 MAPK specific inhibitor, 10 microM) after serum starvation for 10 h. |
| 8732 | 17446186 | For the last 30 min, cells were treated+/-1 nM insulin, and insulin receptor substrate (IRS)-1, Akt, endothelial nitric oxide synthase (eNOS), p38 MAPK, ERK1/2, c-Jun N-terminal kinase, and AMP-activated protein kinase (AMPK) phosphorylation, and eNOS activity were measured. |
| 8733 | 17446186 | TNF-alpha increased p38 MAPK phosphorylation, potently stimulated IRS-1 serine phosphorylation, and blunted insulin-stimulated IRS-1 tyrosine and Akt phosphorylation and eNOS activity. |
| 8734 | 17446186 | TNF-alpha also potently stimulated the phosphorylation of ERK1/2 and AMPK. |
| 8735 | 17446186 | Treatment with SB203580 decreased p38 MAPK phosphorylation back to the baseline and restored insulin sensitivity of IRS-1 tyrosine and Akt phosphorylation and eNOS activity in TNF-alpha-treated bAECs without affecting TNF-alpha-induced ERK1/2 and AMPK phosphorylation. |
| 8736 | 17446186 | We conclude that in cultured bAECs, TNF-alpha induces insulin resistance in the phosphatidylinositol 3-kinase/Akt/eNOS pathway via a p38 MAPK-dependent mechanism and enhances ERK1/2 and AMPK phosphorylation independent of the p38 MAPK pathway. |
| 8737 | 17446186 | This differential modulation of TNF-alpha's actions by p38 MAPK suggests that p38 MAPK plays a key role in TNF-alpha-mediated vascular insulin resistance and may contribute to the generalized endothelial dysfunction seen in type 2 diabetes mellitus and the cardiometabolic syndrome. |
| 8738 | 17446186 | Tumor necrosis factor-alpha induces insulin resistance in endothelial cells via a p38 mitogen-activated protein kinase-dependent pathway. |
| 8739 | 17446186 | Systemic infusion of TNF-alpha abrogates insulin's action to enhance skeletal muscle microvascular perfusion. |
| 8740 | 17446186 | In skeletal muscle TNF-alpha induces insulin resistance via the p38 MAPK pathway. |
| 8741 | 17446186 | To examine whether p38 MAPK also regulates TNF-alpha-induced vascular insulin resistance, bovine aortic endothelial cells (bAECs) were incubated+/-TNF-alpha (5 ng/ml) for 6 h in the presence or absence of SB203580 (p38 MAPK specific inhibitor, 10 microM) after serum starvation for 10 h. |
| 8742 | 17446186 | For the last 30 min, cells were treated+/-1 nM insulin, and insulin receptor substrate (IRS)-1, Akt, endothelial nitric oxide synthase (eNOS), p38 MAPK, ERK1/2, c-Jun N-terminal kinase, and AMP-activated protein kinase (AMPK) phosphorylation, and eNOS activity were measured. |
| 8743 | 17446186 | TNF-alpha increased p38 MAPK phosphorylation, potently stimulated IRS-1 serine phosphorylation, and blunted insulin-stimulated IRS-1 tyrosine and Akt phosphorylation and eNOS activity. |
| 8744 | 17446186 | TNF-alpha also potently stimulated the phosphorylation of ERK1/2 and AMPK. |
| 8745 | 17446186 | Treatment with SB203580 decreased p38 MAPK phosphorylation back to the baseline and restored insulin sensitivity of IRS-1 tyrosine and Akt phosphorylation and eNOS activity in TNF-alpha-treated bAECs without affecting TNF-alpha-induced ERK1/2 and AMPK phosphorylation. |
| 8746 | 17446186 | We conclude that in cultured bAECs, TNF-alpha induces insulin resistance in the phosphatidylinositol 3-kinase/Akt/eNOS pathway via a p38 MAPK-dependent mechanism and enhances ERK1/2 and AMPK phosphorylation independent of the p38 MAPK pathway. |
| 8747 | 17446186 | This differential modulation of TNF-alpha's actions by p38 MAPK suggests that p38 MAPK plays a key role in TNF-alpha-mediated vascular insulin resistance and may contribute to the generalized endothelial dysfunction seen in type 2 diabetes mellitus and the cardiometabolic syndrome. |
| 8748 | 17462778 | The plasma membrane (PM) GLUT4 in the basal state was decreased, and the insulin-stimulated GLUT4 translocation to the PM was drastically reduced by mtDNA depletion. |
| 8749 | 17462778 | Interestingly, the expression of IRS-1 associated with insulin signaling was decreased by 90% in the depleted cells, and the insulin-stimulated phosphorylation of IRS-1 and Akt2/PKB were drastically reduced in the depleted cells. |
| 8750 | 17462778 | Taken together, our data suggest that PM GLUT4 content and insulin signal pathway intermediates are modulated by the alteration of cellular mtDNA content, and the reduction in the expression of IRS-1 and insulin-stimulated phosphorylation of IRS-1 and Akt2/PKB are associated with insulin resistance in the mtDNA-depleted L6 GLUT4myc myocytes. |
| 8751 | 17462778 | The plasma membrane (PM) GLUT4 in the basal state was decreased, and the insulin-stimulated GLUT4 translocation to the PM was drastically reduced by mtDNA depletion. |
| 8752 | 17462778 | Interestingly, the expression of IRS-1 associated with insulin signaling was decreased by 90% in the depleted cells, and the insulin-stimulated phosphorylation of IRS-1 and Akt2/PKB were drastically reduced in the depleted cells. |
| 8753 | 17462778 | Taken together, our data suggest that PM GLUT4 content and insulin signal pathway intermediates are modulated by the alteration of cellular mtDNA content, and the reduction in the expression of IRS-1 and insulin-stimulated phosphorylation of IRS-1 and Akt2/PKB are associated with insulin resistance in the mtDNA-depleted L6 GLUT4myc myocytes. |
| 8754 | 17498834 | Our recent data suggested that the improved effectiveness of insulin that occurs as a result of physical exercise is attributable, at least in part, to increases in GLUT4 protein, IRS1 and PI3-kinase protein in skeletal muscle. |
| 8755 | 17505626 | [Insulin and angiotensin II signaling pathways cross-talk: implications with the association between diabetes mellitus, arterial hypertension and cardiovascular disease]. |
| 8756 | 17505626 | Insulin (Ins) and angiotensin II (AII) play pivotal roles in the control of two vital and closely related systems: the metabolic and the circulatory, respectively. |
| 8757 | 17505626 | At an early intracellular level, AII, acting through JAK-2/IRS-1/PI3-kinase, JNK and ERK, may induce the serine phosphorylation and inhibition of key elements of the Ins-signaling pathway. |
| 8758 | 17510710 | Upregulation of myocellular DGAT1 augments triglyceride synthesis in skeletal muscle and protects against fat-induced insulin resistance. |
| 8759 | 17510710 | Transgenic overexpression of DGAT1 in mouse skeletal muscle replicated these findings and protected mice against high-fat diet-induced insulin resistance. |
| 8760 | 17510710 | Moreover, in isolated muscle, DGAT1 deficiency exacerbated insulin resistance caused by fatty acids, whereas DGAT1 overexpression mitigated the detrimental effect of fatty acids. |
| 8761 | 17510710 | The heightened insulin sensitivity in the transgenic mice was associated with attenuated fat-induced activation of DAG-responsive PKCs and the stress mediator JNK1. |
| 8762 | 17510710 | Consistent with these changes, serine phosphorylation of insulin receptor substrate 1 was reduced, and Akt activation and glucose 4 membrane translocation were increased. |
| 8763 | 17510710 | In conclusion, upregulation of DGAT1 in skeletal muscle is sufficient to recreate the athlete's paradox and illustrates a mechanism of exercise-induced enhancement of muscle insulin sensitivity. |
| 8764 | 17510710 | Thus, increasing muscle DGAT activity may offer a new approach to prevent and treat insulin resistance and type 2 diabetes mellitus. |
| 8765 | 17513702 | Effects of endurance exercise training on insulin signaling in human skeletal muscle: interactions at the level of phosphatidylinositol 3-kinase, Akt, and AS160. |
| 8766 | 17513702 | Protein content of Akt1/2 (55 +/- 17%, P < 0.05), AS160 (25 +/- 8%, P = 0.08), GLUT4 (52 +/- 19%, P < 0.001), hexokinase 2 (HK2) (197 +/- 40%, P < 0.001), and insulin-responsive aminopeptidase (65 +/- 15%, P < 0.001) increased in muscle in response to training. |
| 8767 | 17513702 | During hyperinsulinemia, activities of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase (PI3-K) (P < 0.005), Akt1 (P < 0.05), Akt2 (P < 0.005), and glycogen synthase (GS) (percent I-form, P < 0.05) increased similarly in both trained and untrained muscle, consistent with increased phosphorylation of Akt Thr(308), Akt Ser(473), AS160, glycogen synthase kinase (GSK)-3alpha Ser(21), and GSK-3beta Ser(9) and decreased phosphorylation of GS site 3a+b (all P < 0.005). |
| 8768 | 17513702 | Interestingly, training improved insulin action on thigh blood flow, and, furthermore, in both basal and insulin-stimulated muscle tissue, activities of Akt1 and GS and phosphorylation of AS160 increased with training (all P < 0.05). |
| 8769 | 17513702 | In contrast, training reduced IRS-1-associated PI3-K activity (P < 0.05) in both basal and insulin-stimulated muscle tissue. |
| 8770 | 17513706 | Activation of AMP-activated protein kinase (AMPK) in rodent muscle by exercise, metformin, 5-aminoimidazole-4-carboxamide 1-beta-d-ribofuranoside (AICAR), and adiponectin increases glucose uptake. |
| 8771 | 17513706 | The effects of AICAR and exercise on muscle AMPK activity/phosphorylation and 2DG uptake were determined. |
| 8772 | 17513706 | AMPK alpha(1) and alpha(2) activity or AMPK phosphorylation was unchanged after 20 min or 3 h of AICAR, but AMPK phosphorylation significantly increased immediately and 3 h after bicycle exercise. |
| 8773 | 17513706 | AICAR significantly increased phosphorylation of extracellular signal-regulated kinase 1/2, but phosphorylation of beta-acetyl-CoA carboxylase, glycogen synthase, and protein kinase B or insulin receptor substrate-1 level was unchanged. |
| 8774 | 17545163 | Protein-tyrosine phosphatase 1B deficiency reduces insulin resistance and the diabetic phenotype in mice with polygenic insulin resistance. |
| 8775 | 17545163 | Protein-tyrosine phosphatase 1B (PTP1B) dephosphorylates tyrosine residues in IR and possibly IRS proteins, thereby inhibiting insulin signaling. |
| 8776 | 17545163 | Mice lacking PTP1B are lean and have increased insulin sensitivity. |
| 8777 | 17545163 | To determine whether PTP1B can modify polygenic insulin resistance, we crossed PTP1B-/- mice with mice with a double heterozygous deficiency of IR and IRS-1 alleles (DHet). |
| 8778 | 17545163 | However, absence of PTP1B in DHet mice markedly improved glucose tolerance and insulin sensitivity at 10-11 weeks of age and reduced the incidence of diabetes and hyperplastic pancreatic islets at 6 months of age. |
| 8779 | 17545163 | Insulin-stimulated phosphorylation of IR, IRS proteins, Akt/protein kinase B, glycogen synthase kinase 3beta, and p70(S6K) was impaired in DHet mouse muscle and liver and was differentially improved by PTP1B deficiency. |
| 8780 | 17545163 | In summary, PTP1B deficiency reduces insulin resistance and hyperglycemia without altering body weight in a model of polygenic type 2 diabetes. |
| 8781 | 17553792 | Disruption of the insulin-like growth factor type 1 receptor in osteoblasts enhances insulin signaling and action. |
| 8782 | 17553792 | However, because insulin can cross-activate the insulin-like growth factor type 1 receptor (IGF-1R), which also functions in bone, it has been difficult to establish the direct (IGF-1-independent) actions of insulin in osteoblasts. |
| 8783 | 17553792 | To overcome this problem, we examined insulin signaling and action in primary osteoblasts engineered for conditional disruption of the IGF-1 receptor (DeltaIGF-1R). |
| 8784 | 17553792 | Disruption of IGF-1R mRNA (>90%) eliminated IGF-1R without affecting insulin receptor (IR) mRNA and protein expression and eliminated IGF-1R/IR hybrids. |
| 8785 | 17553792 | In DeltaIGF-1R osteoblasts, insulin signaling was markedly increased as evidenced by increased phosphorylation of insulin receptor substrate 1/2 and enhanced ERK/Akt activation. |
| 8786 | 17553792 | Microarray analysis of RNA samples from insulin-treated, DeltaIGF-1R osteoblasts revealed striking changes in several genes known to be downstream of ERK including Glut-1 and c-fos. |
| 8787 | 17553792 | Treatment of osteoblasts with insulin induced Glut-1 mRNA, increased 2-[1,2-(3)H]-deoxy-d-glucose uptake, and enhanced proliferation. |
| 8788 | 17553792 | Moreover, insulin treatment rescued the defective differentiation and mineralization of DeltaIGF-1R osteoblasts, suggesting that IR signaling can compensate, at least in part, for loss of IGF-1R signaling. |
| 8789 | 17553792 | We conclude that insulin exerts direct anabolic actions in osteoblasts by activation of its cognate receptor and that the strength of insulin-generated signals is tempered through interactions with the IGF-1R. |
| 8790 | 17569760 | An adipokine that could potentially mediate this effect is adiponectin, and we demonstrated that small interfering RNA-mediated knockdown of adiponectin receptor-2 in muscle cells reduced the uptake of glucose upon coculture with primary rat adipocytes. |
| 8791 | 17569760 | Coculture induced phosphorylation of AMP-activated protein kinase (T172) and interestingly also insulin receptor substrate-1 (Y612) and Akt (T308 & S473), which could be attenuated after adiponectin receptor-2-small interfering RNA treatment. |
| 8792 | 17570255 | Therefore, we assessed the functionality of proximal and distal insulin signaling elements in isolated type I (slow-twitch oxidative) soleus muscles of ZDF rats after in vitro exposure to a selective GSK-3 inhibitor (1 micromol/L CT98014, K(i) <10 nmol/L for GSK-3alpha and GSK-3beta). |
| 8793 | 17570255 | Maximally insulin-stimulated (5 mU/mL) GSK-3beta serine phosphorylation was significantly less (35%, P < .05) in soleus muscle of ZDF rats compared with insulin-sensitive lean Zucker rats, indicating GSK-3 overactivity. |
| 8794 | 17570255 | GSK-3 inhibition led to significant enhancement (28%) of insulin-stimulated glucose transport activity that was associated with significant up-regulation of tyrosine phosphorylation of IR (52%) and IRS-1 (50%), and with enhanced Akt Ser473 phosphorylation (48%) and GSK-3beta Ser9 phosphorylation (36%). |
| 8795 | 17570255 | Moreover, the selective GSK-3 inhibitor induced a significant reduction in the phosphorylation of IRS-1 Ser307 (26%) and c-jun N-terminal kinases 1 and 2 (31%), a mediator of IRS-1 Ser307 phosphorylation. |
| 8796 | 17570255 | These results indicate that selective inhibition of GSK-3 activity in type I skeletal muscle from overtly diabetic ZDF rats enhances IRS-1-dependent insulin signaling, possibly by a decrease in c-jun N-terminal kinase activation and a diminution of the deleterious effects of IRS-1 Ser307 phosphorylation. |
| 8797 | 17570255 | Therefore, we assessed the functionality of proximal and distal insulin signaling elements in isolated type I (slow-twitch oxidative) soleus muscles of ZDF rats after in vitro exposure to a selective GSK-3 inhibitor (1 micromol/L CT98014, K(i) <10 nmol/L for GSK-3alpha and GSK-3beta). |
| 8798 | 17570255 | Maximally insulin-stimulated (5 mU/mL) GSK-3beta serine phosphorylation was significantly less (35%, P < .05) in soleus muscle of ZDF rats compared with insulin-sensitive lean Zucker rats, indicating GSK-3 overactivity. |
| 8799 | 17570255 | GSK-3 inhibition led to significant enhancement (28%) of insulin-stimulated glucose transport activity that was associated with significant up-regulation of tyrosine phosphorylation of IR (52%) and IRS-1 (50%), and with enhanced Akt Ser473 phosphorylation (48%) and GSK-3beta Ser9 phosphorylation (36%). |
| 8800 | 17570255 | Moreover, the selective GSK-3 inhibitor induced a significant reduction in the phosphorylation of IRS-1 Ser307 (26%) and c-jun N-terminal kinases 1 and 2 (31%), a mediator of IRS-1 Ser307 phosphorylation. |
| 8801 | 17570255 | These results indicate that selective inhibition of GSK-3 activity in type I skeletal muscle from overtly diabetic ZDF rats enhances IRS-1-dependent insulin signaling, possibly by a decrease in c-jun N-terminal kinase activation and a diminution of the deleterious effects of IRS-1 Ser307 phosphorylation. |
| 8802 | 17570255 | Therefore, we assessed the functionality of proximal and distal insulin signaling elements in isolated type I (slow-twitch oxidative) soleus muscles of ZDF rats after in vitro exposure to a selective GSK-3 inhibitor (1 micromol/L CT98014, K(i) <10 nmol/L for GSK-3alpha and GSK-3beta). |
| 8803 | 17570255 | Maximally insulin-stimulated (5 mU/mL) GSK-3beta serine phosphorylation was significantly less (35%, P < .05) in soleus muscle of ZDF rats compared with insulin-sensitive lean Zucker rats, indicating GSK-3 overactivity. |
| 8804 | 17570255 | GSK-3 inhibition led to significant enhancement (28%) of insulin-stimulated glucose transport activity that was associated with significant up-regulation of tyrosine phosphorylation of IR (52%) and IRS-1 (50%), and with enhanced Akt Ser473 phosphorylation (48%) and GSK-3beta Ser9 phosphorylation (36%). |
| 8805 | 17570255 | Moreover, the selective GSK-3 inhibitor induced a significant reduction in the phosphorylation of IRS-1 Ser307 (26%) and c-jun N-terminal kinases 1 and 2 (31%), a mediator of IRS-1 Ser307 phosphorylation. |
| 8806 | 17570255 | These results indicate that selective inhibition of GSK-3 activity in type I skeletal muscle from overtly diabetic ZDF rats enhances IRS-1-dependent insulin signaling, possibly by a decrease in c-jun N-terminal kinase activation and a diminution of the deleterious effects of IRS-1 Ser307 phosphorylation. |
| 8807 | 17571165 | Overexpression of uncoupling protein 3 in skeletal muscle protects against fat-induced insulin resistance. |
| 8808 | 17571165 | We therefore hypothesized that overexpression of UCP3 in skeletal muscle might protect against fat-induced insulin resistance in muscle by conversion of intramyocellular fat into thermal energy. |
| 8809 | 17571165 | Insulin resistance in these tissues was associated with reduced insulin-stimulated insulin receptor substrate 1- (IRS-1-) and IRS-2-associated PI3K activity in muscle and liver, respectively. |
| 8810 | 17571165 | In contrast, UCP3-overexpressing mice were completely protected against fat-induced defects in insulin signaling and action in these tissues. |
| 8811 | 17575262 | Retinol-binding protein-4 attenuates insulin-induced phosphorylation of IRS1 and ERK1/2 in primary human adipocytes. |
| 8812 | 17575262 | Animal models and patients with type 2 diabetes exhibit elevated levels of circulating retinol-binding protein (RBP4), and RBP4 can induce insulin resistance in mice. |
| 8813 | 17575262 | However, little is known about how RBP4 affects insulin signaling. |
| 8814 | 17575262 | RBP4-treated adipocytes exhibited the same molecular defects in insulin signaling, via IRS1 to MAP kinase, as in adipocytes from patients with type 2 diabetes. |
| 8815 | 17575262 | Without affecting autophosphorylation of the insulin receptor, RBP4 blocked the insulin-stimulated phosphorylation of IRS1 at serine (307) [corresponding to serine (302) in the murine sequence] and concomitantly increased the EC50 (from 0.5 to 2 nM) for insulin stimulation of IRS1 phosphorylation at tyrosine. |
| 8816 | 17575262 | The phosphorylation of IRS1 at serine (312) [corresponding to serine (307) in the murine sequence] was not affected in cells from diabetic patients and was also not affected by RBP4. |
| 8817 | 17575262 | The EC50 for insulin stimulation of downstream phosphorylation of MAP kinase ERK1/2 was increased (from 0.2 to 0.8 nM) by RBP4. |
| 8818 | 17575262 | However, the sensitivity to insulin for downstream signaling to control of protein kinase B and glucose uptake was not affected by RBP4. |
| 8819 | 17575262 | When insulin-resistant adipocytes from patients with type 2 diabetes were incubated with antibodies against RBP4, insulin-induced phosphorylation of IRS1 at serine (307) was normalized and the EC50 for insulin stimulation of ERK1/2 phosphorylation was reduced. |
| 8820 | 17575262 | These findings indicate that RBP4 may be released from diabetic adipocytes and act locally to inhibit phosphorylation of IRS1 at serine (307), a phosphorylation site that may integrate nutrient sensing with insulin signaling. |
| 8821 | 17575262 | Retinol-binding protein-4 attenuates insulin-induced phosphorylation of IRS1 and ERK1/2 in primary human adipocytes. |
| 8822 | 17575262 | Animal models and patients with type 2 diabetes exhibit elevated levels of circulating retinol-binding protein (RBP4), and RBP4 can induce insulin resistance in mice. |
| 8823 | 17575262 | However, little is known about how RBP4 affects insulin signaling. |
| 8824 | 17575262 | RBP4-treated adipocytes exhibited the same molecular defects in insulin signaling, via IRS1 to MAP kinase, as in adipocytes from patients with type 2 diabetes. |
| 8825 | 17575262 | Without affecting autophosphorylation of the insulin receptor, RBP4 blocked the insulin-stimulated phosphorylation of IRS1 at serine (307) [corresponding to serine (302) in the murine sequence] and concomitantly increased the EC50 (from 0.5 to 2 nM) for insulin stimulation of IRS1 phosphorylation at tyrosine. |
| 8826 | 17575262 | The phosphorylation of IRS1 at serine (312) [corresponding to serine (307) in the murine sequence] was not affected in cells from diabetic patients and was also not affected by RBP4. |
| 8827 | 17575262 | The EC50 for insulin stimulation of downstream phosphorylation of MAP kinase ERK1/2 was increased (from 0.2 to 0.8 nM) by RBP4. |
| 8828 | 17575262 | However, the sensitivity to insulin for downstream signaling to control of protein kinase B and glucose uptake was not affected by RBP4. |
| 8829 | 17575262 | When insulin-resistant adipocytes from patients with type 2 diabetes were incubated with antibodies against RBP4, insulin-induced phosphorylation of IRS1 at serine (307) was normalized and the EC50 for insulin stimulation of ERK1/2 phosphorylation was reduced. |
| 8830 | 17575262 | These findings indicate that RBP4 may be released from diabetic adipocytes and act locally to inhibit phosphorylation of IRS1 at serine (307), a phosphorylation site that may integrate nutrient sensing with insulin signaling. |
| 8831 | 17575262 | Retinol-binding protein-4 attenuates insulin-induced phosphorylation of IRS1 and ERK1/2 in primary human adipocytes. |
| 8832 | 17575262 | Animal models and patients with type 2 diabetes exhibit elevated levels of circulating retinol-binding protein (RBP4), and RBP4 can induce insulin resistance in mice. |
| 8833 | 17575262 | However, little is known about how RBP4 affects insulin signaling. |
| 8834 | 17575262 | RBP4-treated adipocytes exhibited the same molecular defects in insulin signaling, via IRS1 to MAP kinase, as in adipocytes from patients with type 2 diabetes. |
| 8835 | 17575262 | Without affecting autophosphorylation of the insulin receptor, RBP4 blocked the insulin-stimulated phosphorylation of IRS1 at serine (307) [corresponding to serine (302) in the murine sequence] and concomitantly increased the EC50 (from 0.5 to 2 nM) for insulin stimulation of IRS1 phosphorylation at tyrosine. |
| 8836 | 17575262 | The phosphorylation of IRS1 at serine (312) [corresponding to serine (307) in the murine sequence] was not affected in cells from diabetic patients and was also not affected by RBP4. |
| 8837 | 17575262 | The EC50 for insulin stimulation of downstream phosphorylation of MAP kinase ERK1/2 was increased (from 0.2 to 0.8 nM) by RBP4. |
| 8838 | 17575262 | However, the sensitivity to insulin for downstream signaling to control of protein kinase B and glucose uptake was not affected by RBP4. |
| 8839 | 17575262 | When insulin-resistant adipocytes from patients with type 2 diabetes were incubated with antibodies against RBP4, insulin-induced phosphorylation of IRS1 at serine (307) was normalized and the EC50 for insulin stimulation of ERK1/2 phosphorylation was reduced. |
| 8840 | 17575262 | These findings indicate that RBP4 may be released from diabetic adipocytes and act locally to inhibit phosphorylation of IRS1 at serine (307), a phosphorylation site that may integrate nutrient sensing with insulin signaling. |
| 8841 | 17575262 | Retinol-binding protein-4 attenuates insulin-induced phosphorylation of IRS1 and ERK1/2 in primary human adipocytes. |
| 8842 | 17575262 | Animal models and patients with type 2 diabetes exhibit elevated levels of circulating retinol-binding protein (RBP4), and RBP4 can induce insulin resistance in mice. |
| 8843 | 17575262 | However, little is known about how RBP4 affects insulin signaling. |
| 8844 | 17575262 | RBP4-treated adipocytes exhibited the same molecular defects in insulin signaling, via IRS1 to MAP kinase, as in adipocytes from patients with type 2 diabetes. |
| 8845 | 17575262 | Without affecting autophosphorylation of the insulin receptor, RBP4 blocked the insulin-stimulated phosphorylation of IRS1 at serine (307) [corresponding to serine (302) in the murine sequence] and concomitantly increased the EC50 (from 0.5 to 2 nM) for insulin stimulation of IRS1 phosphorylation at tyrosine. |
| 8846 | 17575262 | The phosphorylation of IRS1 at serine (312) [corresponding to serine (307) in the murine sequence] was not affected in cells from diabetic patients and was also not affected by RBP4. |
| 8847 | 17575262 | The EC50 for insulin stimulation of downstream phosphorylation of MAP kinase ERK1/2 was increased (from 0.2 to 0.8 nM) by RBP4. |
| 8848 | 17575262 | However, the sensitivity to insulin for downstream signaling to control of protein kinase B and glucose uptake was not affected by RBP4. |
| 8849 | 17575262 | When insulin-resistant adipocytes from patients with type 2 diabetes were incubated with antibodies against RBP4, insulin-induced phosphorylation of IRS1 at serine (307) was normalized and the EC50 for insulin stimulation of ERK1/2 phosphorylation was reduced. |
| 8850 | 17575262 | These findings indicate that RBP4 may be released from diabetic adipocytes and act locally to inhibit phosphorylation of IRS1 at serine (307), a phosphorylation site that may integrate nutrient sensing with insulin signaling. |
| 8851 | 17575262 | Retinol-binding protein-4 attenuates insulin-induced phosphorylation of IRS1 and ERK1/2 in primary human adipocytes. |
| 8852 | 17575262 | Animal models and patients with type 2 diabetes exhibit elevated levels of circulating retinol-binding protein (RBP4), and RBP4 can induce insulin resistance in mice. |
| 8853 | 17575262 | However, little is known about how RBP4 affects insulin signaling. |
| 8854 | 17575262 | RBP4-treated adipocytes exhibited the same molecular defects in insulin signaling, via IRS1 to MAP kinase, as in adipocytes from patients with type 2 diabetes. |
| 8855 | 17575262 | Without affecting autophosphorylation of the insulin receptor, RBP4 blocked the insulin-stimulated phosphorylation of IRS1 at serine (307) [corresponding to serine (302) in the murine sequence] and concomitantly increased the EC50 (from 0.5 to 2 nM) for insulin stimulation of IRS1 phosphorylation at tyrosine. |
| 8856 | 17575262 | The phosphorylation of IRS1 at serine (312) [corresponding to serine (307) in the murine sequence] was not affected in cells from diabetic patients and was also not affected by RBP4. |
| 8857 | 17575262 | The EC50 for insulin stimulation of downstream phosphorylation of MAP kinase ERK1/2 was increased (from 0.2 to 0.8 nM) by RBP4. |
| 8858 | 17575262 | However, the sensitivity to insulin for downstream signaling to control of protein kinase B and glucose uptake was not affected by RBP4. |
| 8859 | 17575262 | When insulin-resistant adipocytes from patients with type 2 diabetes were incubated with antibodies against RBP4, insulin-induced phosphorylation of IRS1 at serine (307) was normalized and the EC50 for insulin stimulation of ERK1/2 phosphorylation was reduced. |
| 8860 | 17575262 | These findings indicate that RBP4 may be released from diabetic adipocytes and act locally to inhibit phosphorylation of IRS1 at serine (307), a phosphorylation site that may integrate nutrient sensing with insulin signaling. |
| 8861 | 17575262 | Retinol-binding protein-4 attenuates insulin-induced phosphorylation of IRS1 and ERK1/2 in primary human adipocytes. |
| 8862 | 17575262 | Animal models and patients with type 2 diabetes exhibit elevated levels of circulating retinol-binding protein (RBP4), and RBP4 can induce insulin resistance in mice. |
| 8863 | 17575262 | However, little is known about how RBP4 affects insulin signaling. |
| 8864 | 17575262 | RBP4-treated adipocytes exhibited the same molecular defects in insulin signaling, via IRS1 to MAP kinase, as in adipocytes from patients with type 2 diabetes. |
| 8865 | 17575262 | Without affecting autophosphorylation of the insulin receptor, RBP4 blocked the insulin-stimulated phosphorylation of IRS1 at serine (307) [corresponding to serine (302) in the murine sequence] and concomitantly increased the EC50 (from 0.5 to 2 nM) for insulin stimulation of IRS1 phosphorylation at tyrosine. |
| 8866 | 17575262 | The phosphorylation of IRS1 at serine (312) [corresponding to serine (307) in the murine sequence] was not affected in cells from diabetic patients and was also not affected by RBP4. |
| 8867 | 17575262 | The EC50 for insulin stimulation of downstream phosphorylation of MAP kinase ERK1/2 was increased (from 0.2 to 0.8 nM) by RBP4. |
| 8868 | 17575262 | However, the sensitivity to insulin for downstream signaling to control of protein kinase B and glucose uptake was not affected by RBP4. |
| 8869 | 17575262 | When insulin-resistant adipocytes from patients with type 2 diabetes were incubated with antibodies against RBP4, insulin-induced phosphorylation of IRS1 at serine (307) was normalized and the EC50 for insulin stimulation of ERK1/2 phosphorylation was reduced. |
| 8870 | 17575262 | These findings indicate that RBP4 may be released from diabetic adipocytes and act locally to inhibit phosphorylation of IRS1 at serine (307), a phosphorylation site that may integrate nutrient sensing with insulin signaling. |
| 8871 | 17596523 | Diabetic nephropathy (DN) is associated with increased oxidative stress, overexpression and activation of growth factor receptors, including those for transforming growth factor-beta1 (TGF-beta-RII), platelet-derived growth factor (PDGF-R), and insulin-like growth factor (IGF1-R). |
| 8872 | 17596523 | The early phase of diabetes was found to be associated with an increase in glomerular expression of IGF1-R, PDGF-R, and TGF-beta-RII and activation of IRS1, Erk 1/2, and Smad 2/3. |
| 8873 | 17647275 | Secretion of atherogenic risk factor apolipoprotein B-100 is increased by a potential mechanism of JNK/PKC-mediated insulin resistance in liver cells. |
| 8874 | 17647275 | Induction of insulin resistance was accompanied by a considerable rise in the production of hepatic very low density lipoprotein (VLDL) containing ApoB and triglyceride. |
| 8875 | 17647275 | Increased plasma levels of ApoB and triglyceride in VLDL are common characteristics of the dyslipidemia associated with insulin resistance and type 2 diabetes mellitus. |
| 8876 | 17647275 | Thus, we investigate whether phorbol 12-myristate-13-acetate (PMA)-induced insulin resistance affects the increase of ApoB secretion. |
| 8877 | 17647275 | PMA increased ApoB secretion and transcriptional level of microsomal triglyceride transfer protein (MTP). |
| 8878 | 17647275 | Additionally, PMA induced activation of c-jun N-terminal kinase (JNK) and protein kinase C (PKC) isoforms (alpha, betaI, delta, zeta, theta), and reduced AKT8 virus oncogene cellular homolog (AKT) activation in a time dependent manner. |
| 8879 | 17647275 | PMA-induced ApoB secretion, MTP promoter activities, and IRS1 degradation was significantly decreased by treatment of JNK and PKCs inhibitors. |
| 8880 | 17647275 | Orthovanadate, a potent tyrosine phosphatase inhibitor, increased tyrosine phosphorylation of IRS1 and decreased ApoB secretion of Chang liver cells although PMA was co-treated. |
| 8881 | 17647275 | From the results, it was concluded that PMA-induced insulin resistance, through induction of serine phosphorylation of IRS1 mediated by activated JNK and PKCs, increases ApoB secretion in Chang liver cells. |
| 8882 | 17647275 | Secretion of atherogenic risk factor apolipoprotein B-100 is increased by a potential mechanism of JNK/PKC-mediated insulin resistance in liver cells. |
| 8883 | 17647275 | Induction of insulin resistance was accompanied by a considerable rise in the production of hepatic very low density lipoprotein (VLDL) containing ApoB and triglyceride. |
| 8884 | 17647275 | Increased plasma levels of ApoB and triglyceride in VLDL are common characteristics of the dyslipidemia associated with insulin resistance and type 2 diabetes mellitus. |
| 8885 | 17647275 | Thus, we investigate whether phorbol 12-myristate-13-acetate (PMA)-induced insulin resistance affects the increase of ApoB secretion. |
| 8886 | 17647275 | PMA increased ApoB secretion and transcriptional level of microsomal triglyceride transfer protein (MTP). |
| 8887 | 17647275 | Additionally, PMA induced activation of c-jun N-terminal kinase (JNK) and protein kinase C (PKC) isoforms (alpha, betaI, delta, zeta, theta), and reduced AKT8 virus oncogene cellular homolog (AKT) activation in a time dependent manner. |
| 8888 | 17647275 | PMA-induced ApoB secretion, MTP promoter activities, and IRS1 degradation was significantly decreased by treatment of JNK and PKCs inhibitors. |
| 8889 | 17647275 | Orthovanadate, a potent tyrosine phosphatase inhibitor, increased tyrosine phosphorylation of IRS1 and decreased ApoB secretion of Chang liver cells although PMA was co-treated. |
| 8890 | 17647275 | From the results, it was concluded that PMA-induced insulin resistance, through induction of serine phosphorylation of IRS1 mediated by activated JNK and PKCs, increases ApoB secretion in Chang liver cells. |
| 8891 | 17647275 | Secretion of atherogenic risk factor apolipoprotein B-100 is increased by a potential mechanism of JNK/PKC-mediated insulin resistance in liver cells. |
| 8892 | 17647275 | Induction of insulin resistance was accompanied by a considerable rise in the production of hepatic very low density lipoprotein (VLDL) containing ApoB and triglyceride. |
| 8893 | 17647275 | Increased plasma levels of ApoB and triglyceride in VLDL are common characteristics of the dyslipidemia associated with insulin resistance and type 2 diabetes mellitus. |
| 8894 | 17647275 | Thus, we investigate whether phorbol 12-myristate-13-acetate (PMA)-induced insulin resistance affects the increase of ApoB secretion. |
| 8895 | 17647275 | PMA increased ApoB secretion and transcriptional level of microsomal triglyceride transfer protein (MTP). |
| 8896 | 17647275 | Additionally, PMA induced activation of c-jun N-terminal kinase (JNK) and protein kinase C (PKC) isoforms (alpha, betaI, delta, zeta, theta), and reduced AKT8 virus oncogene cellular homolog (AKT) activation in a time dependent manner. |
| 8897 | 17647275 | PMA-induced ApoB secretion, MTP promoter activities, and IRS1 degradation was significantly decreased by treatment of JNK and PKCs inhibitors. |
| 8898 | 17647275 | Orthovanadate, a potent tyrosine phosphatase inhibitor, increased tyrosine phosphorylation of IRS1 and decreased ApoB secretion of Chang liver cells although PMA was co-treated. |
| 8899 | 17647275 | From the results, it was concluded that PMA-induced insulin resistance, through induction of serine phosphorylation of IRS1 mediated by activated JNK and PKCs, increases ApoB secretion in Chang liver cells. |
| 8900 | 17660951 | When 3T3-L1 adipocytes were treated directly with MG, the impaired insulin signaling was also observed, indicated by decreased insulin-induced insulin-receptor substrate-1 (IRS-1) tyrosine phosphorylation and the decreased kinase activity of phosphatidylinositol (PI) 3-kinase (PI3K). |
| 8901 | 17660951 | The ability of NAC to block MG-impairment of PI3K activity and IRS-1 phosphorylation further confirmed the role of MG in the development of insulin resistance. |
| 8902 | 17660951 | When 3T3-L1 adipocytes were treated directly with MG, the impaired insulin signaling was also observed, indicated by decreased insulin-induced insulin-receptor substrate-1 (IRS-1) tyrosine phosphorylation and the decreased kinase activity of phosphatidylinositol (PI) 3-kinase (PI3K). |
| 8903 | 17660951 | The ability of NAC to block MG-impairment of PI3K activity and IRS-1 phosphorylation further confirmed the role of MG in the development of insulin resistance. |
| 8904 | 17694473 | Additionally, repeated myricetin treatments overturned the inability of insulin to increase the expression of glucose transporter subtype 4 (GLUT 4) and to increase the protein levels and phosphorylation of insulin receptor substrate-1 (IRS-1) in soleus muscle of these obese rats. |
| 8905 | 17694473 | The inability of insulin to increase expression of the p85 regulatory subunit of phosphatidylinositol 3-kinase (PI3-kinase) and to promote Akt serine phosphorylation in soleus muscle of these rats were also overturned by repeated myricetin treatments. |
| 8906 | 17694473 | These findings indicate that myricetin improves insulin sensitivity through increased post-receptor insulin signaling mediated by enhancements in IRS-1-associated PI3-kinase and GLUT 4 activity in muscles of obese Zucker rats. |
| 8907 | 17698034 | Rat hepatocytes in primary culture exhibited a rightward shift of the insulin dose-response curve for PKB phosphorylation during culture with palmitate. |
| 8908 | 17698034 | The insulin-stimulated phosphorylation of GSK-3beta, a metabolic substrate of PKB, was diminished in palmitate hepatocytes. |
| 8909 | 17698034 | Metformin treatment of the hepatocytes resulted in activation of the AMP-activated kinase, attenuation of the mTOR/S6K1 pathway, reduction of IRS-1 phosphorylation, and a leftward shift in the insulin dose-response curve for PKB activation. |
| 8910 | 17761767 | Palmitate activated the E3 ubiquitin ligases by suppressing insulin receptor substrate-1/Akt signaling in the C2C12 muscle cells, whereas adiponectin attenuated the E3 ubiquitin ligase activation by increasing both insulin receptor substrate-1 tyrosine phosphorylation and Akt Ser473 phosphorylation. |
| 8911 | 17761767 | In related experiments, adiponectin overexpression decreased TNFalpha and IL-6 expression in 3T3-L1 adipocytes, whereas exposure to free fatty acids had the opposite effect. |
| 8912 | 17761767 | We conclude that the balance between free fatty acids and adiponectin impacts muscle proteolysis in insulin-resistant conditions and suggest a role for adipose tissue-muscle cross talk in diabetes and obesity. |
| 8913 | 17761768 | TNF-alpha plays an important role in obesity-linked insulin resistance and diabetes mellitus by activating at least two serine kinases capable of promoting negative regulation of key elements of the insulin signaling pathway. |
| 8914 | 17761768 | In addition, the clinical outcomes were accompanied by improved insulin signal transduction in muscle, liver, and hypothalamus, as determined by the evaluation of insulin-induced insulin receptor, insulin receptor substrate-1, and receptor substrate-2 tyrosine phosphorylation and Akt and forkhead box protein O1 serine phosphorylation. |
| 8915 | 17761768 | Thus, pharmacological inhibition of TNF-alpha may be an attractive approach to treat severely insulin-resistant patients with type 2 diabetes mellitus. |
| 8916 | 17785466 | After observing that expression of two NR4A orphan nuclear receptors, NR4A3 and NR4A1, was altered by insulin in cDNA microarray analyses of human skeletal muscle, we studied whether these receptors could modulate insulin sensitivity. |
| 8917 | 17785466 | We found that both NR4A3 and NR4A1 were induced by insulin and by thiazolidinedione drugs (pioglitazone and troglitazone) in 3T3-L1 adipocytes. |
| 8918 | 17785466 | Furthermore, gene expression of NR4A3 and NR4A1 was reduced in skeletal muscles and adipose tissues from multiple rodent models of insulin resistance. |
| 8919 | 17785466 | To determine whether NR4A3 could modulate insulin sensitivity, 3T3-L1 adipocytes were stably transduced with NR4A3 or LacZ (control) lentiviral vectors. |
| 8920 | 17785466 | Compared with LacZ expressing cells, hyperexpression of NR4A3 increased the ability of insulin to augment glucose transport activity, and the mechanism involved increased recruitment of GLUT4 glucose transporters to the plasma membrane. |
| 8921 | 17785466 | NR4A3 hyperexpression also led to an increase in insulin-mediated tyrosine phosphorylation of insulin receptor substrate-1 as well as Akt phosphorylation. |
| 8922 | 17785466 | Suppression of NR4A3 using lentiviral short hairpin RNA constructs reduced the ability of insulin to stimulate glucose transport and phosphorylate Insulin receptor substrate-1 and Akt. |
| 8923 | 17785466 | Thus, NR4A3 and NR4A1 are attractive novel therapeutic targets for potential amelioration of insulin resistance, and treatment and prevention of type 2 diabetes and the metabolic syndrome. |
| 8924 | 17785466 | After observing that expression of two NR4A orphan nuclear receptors, NR4A3 and NR4A1, was altered by insulin in cDNA microarray analyses of human skeletal muscle, we studied whether these receptors could modulate insulin sensitivity. |
| 8925 | 17785466 | We found that both NR4A3 and NR4A1 were induced by insulin and by thiazolidinedione drugs (pioglitazone and troglitazone) in 3T3-L1 adipocytes. |
| 8926 | 17785466 | Furthermore, gene expression of NR4A3 and NR4A1 was reduced in skeletal muscles and adipose tissues from multiple rodent models of insulin resistance. |
| 8927 | 17785466 | To determine whether NR4A3 could modulate insulin sensitivity, 3T3-L1 adipocytes were stably transduced with NR4A3 or LacZ (control) lentiviral vectors. |
| 8928 | 17785466 | Compared with LacZ expressing cells, hyperexpression of NR4A3 increased the ability of insulin to augment glucose transport activity, and the mechanism involved increased recruitment of GLUT4 glucose transporters to the plasma membrane. |
| 8929 | 17785466 | NR4A3 hyperexpression also led to an increase in insulin-mediated tyrosine phosphorylation of insulin receptor substrate-1 as well as Akt phosphorylation. |
| 8930 | 17785466 | Suppression of NR4A3 using lentiviral short hairpin RNA constructs reduced the ability of insulin to stimulate glucose transport and phosphorylate Insulin receptor substrate-1 and Akt. |
| 8931 | 17785466 | Thus, NR4A3 and NR4A1 are attractive novel therapeutic targets for potential amelioration of insulin resistance, and treatment and prevention of type 2 diabetes and the metabolic syndrome. |
| 8932 | 17823251 | Des-aspartate-angiotensin I exerts hypoglycemic action via glucose transporter-4 translocation in type 2 diabetic KKAy mice and GK rats. |
| 8933 | 17823251 | The rationale was based on our earlier studies demonstrating that DAA-I acts on the angiotensin AT(1) receptor and exerts responses opposing those of angiotensin II and on recent reports that curtailment of angiotensin II formation by angiotensin converting enzyme inhibitors and blockade of the AT(1) receptor attenuate hyperglycemia in type 2 diabetics and diabetic animals. |
| 8934 | 17823251 | Animals were killed, and the levels of plasma membrane glucose transporter-4 and cytosolic tyrosine-phosphorylated insulin receptor substrate-1 in hind limb skeletal muscles were determined by Western blot in insulin-challenged and nonchallenged animals. |
| 8935 | 17823251 | At the maximal effective dose of 600 nmol/kg, insulin induced a significant increase in plasma membrane glucose transporter-4 and cytosolic tyrosine-phosphorylated insulin receptor substrate-1. |
| 8936 | 17823251 | Des-aspartate-angiotensin I exerts hypoglycemic action via glucose transporter-4 translocation in type 2 diabetic KKAy mice and GK rats. |
| 8937 | 17823251 | The rationale was based on our earlier studies demonstrating that DAA-I acts on the angiotensin AT(1) receptor and exerts responses opposing those of angiotensin II and on recent reports that curtailment of angiotensin II formation by angiotensin converting enzyme inhibitors and blockade of the AT(1) receptor attenuate hyperglycemia in type 2 diabetics and diabetic animals. |
| 8938 | 17823251 | Animals were killed, and the levels of plasma membrane glucose transporter-4 and cytosolic tyrosine-phosphorylated insulin receptor substrate-1 in hind limb skeletal muscles were determined by Western blot in insulin-challenged and nonchallenged animals. |
| 8939 | 17823251 | At the maximal effective dose of 600 nmol/kg, insulin induced a significant increase in plasma membrane glucose transporter-4 and cytosolic tyrosine-phosphorylated insulin receptor substrate-1. |
| 8940 | 17914103 | Insulin pathway related genes and risk of colorectal cancer: INSR promoter polymorphism shows a protective effect. |
| 8941 | 17914103 | We hypothesized that functional polymorphisms in the insulin pathway genes INS, INSR, IGFBPI, insulin receptor substrate 1 (IRS1), and IRS2 may be associated with CRC. |
| 8942 | 17914103 | SNPs in the INS, IGFBPI, and IRS2 genes did not affect the risk of CRC. |
| 8943 | 17924084 | In addition, LPA increased the phosphorylation of AKT-1 with no effects on IRS-1, and LPA-induced glucose uptake was abrogated by pretreatment with the PI 3-kinase inhibitor LY294002. |
| 8944 | 17963417 | Most studies involving cytochrome P450 (CYP) genes had small sample sizes (21 studies <50 subjects) and were among healthy volunteers. |
| 8945 | 17963417 | Polymorphisms in genes encoding the inwardly rectifying potassium channel Kir6.2 (KCNJ11) and the insulin receptor substrate-1 (IRS1) were reported to be associated with an increased risk of (secondary) failure to respond to sulfonylurea therapy. |
| 8946 | 17963417 | A significant decrease in fasting plasma glucose and hemoglobin A(1c) (HbA(1c)) in response to rosiglitazone was seen in subjects carrying the Pro12Ala polymorphism of the peroxisome proliferator-activated receptor-gamma (PPARG) gene. |
| 8947 | 17991427 | SH3 domain of the phosphatidylinositol 3-kinase regulatory subunit is responsible for the formation of a sequestration complex with insulin receptor substrate-1. |
| 8948 | 17991427 | Class IA phosphatidylinositol 3-kinase (PI 3-kinase), which is composed of a 110kDa catalytic subunit and a regulatory subunit, plays a key role in most insulin dependent cellular responses. |
| 8949 | 17991427 | To date, five mammalian regulatory subunit isoforms have been identified, including two 85kDa proteins (p85alpha and p85beta), two 55kDa proteins (p55gamma and p55alpha), and one 50kDa protein (p50alpha). |
| 8950 | 17991427 | Interestingly, in response to insulin, only p85alpha and p85beta redistributed to isolated foci in the cells, while both were present throughout the cytoplasm in quiescent cells. |
| 8951 | 17991427 | Immunofluorescent antibodies against endogenous IRS-1 revealed IRS-1 to be co-localized in the p85 foci in response to insulin. |
| 8952 | 17991427 | As both insulin receptors and p110alpha catalytic subunits were absent from these foci on immunofluorescence study, only p85 and IRS-1 were suggested to form a sequestration complex in response to insulin. |
| 8953 | 17991427 | To determine the domain responsible for IRS-1 complex formation, we prepared and overexpressed the SH3 domain deletion mutant of p85alpha in CHO-IR cells. |
| 8954 | 17991427 | SH3 domain of the phosphatidylinositol 3-kinase regulatory subunit is responsible for the formation of a sequestration complex with insulin receptor substrate-1. |
| 8955 | 17991427 | Class IA phosphatidylinositol 3-kinase (PI 3-kinase), which is composed of a 110kDa catalytic subunit and a regulatory subunit, plays a key role in most insulin dependent cellular responses. |
| 8956 | 17991427 | To date, five mammalian regulatory subunit isoforms have been identified, including two 85kDa proteins (p85alpha and p85beta), two 55kDa proteins (p55gamma and p55alpha), and one 50kDa protein (p50alpha). |
| 8957 | 17991427 | Interestingly, in response to insulin, only p85alpha and p85beta redistributed to isolated foci in the cells, while both were present throughout the cytoplasm in quiescent cells. |
| 8958 | 17991427 | Immunofluorescent antibodies against endogenous IRS-1 revealed IRS-1 to be co-localized in the p85 foci in response to insulin. |
| 8959 | 17991427 | As both insulin receptors and p110alpha catalytic subunits were absent from these foci on immunofluorescence study, only p85 and IRS-1 were suggested to form a sequestration complex in response to insulin. |
| 8960 | 17991427 | To determine the domain responsible for IRS-1 complex formation, we prepared and overexpressed the SH3 domain deletion mutant of p85alpha in CHO-IR cells. |
| 8961 | 17991427 | SH3 domain of the phosphatidylinositol 3-kinase regulatory subunit is responsible for the formation of a sequestration complex with insulin receptor substrate-1. |
| 8962 | 17991427 | Class IA phosphatidylinositol 3-kinase (PI 3-kinase), which is composed of a 110kDa catalytic subunit and a regulatory subunit, plays a key role in most insulin dependent cellular responses. |
| 8963 | 17991427 | To date, five mammalian regulatory subunit isoforms have been identified, including two 85kDa proteins (p85alpha and p85beta), two 55kDa proteins (p55gamma and p55alpha), and one 50kDa protein (p50alpha). |
| 8964 | 17991427 | Interestingly, in response to insulin, only p85alpha and p85beta redistributed to isolated foci in the cells, while both were present throughout the cytoplasm in quiescent cells. |
| 8965 | 17991427 | Immunofluorescent antibodies against endogenous IRS-1 revealed IRS-1 to be co-localized in the p85 foci in response to insulin. |
| 8966 | 17991427 | As both insulin receptors and p110alpha catalytic subunits were absent from these foci on immunofluorescence study, only p85 and IRS-1 were suggested to form a sequestration complex in response to insulin. |
| 8967 | 17991427 | To determine the domain responsible for IRS-1 complex formation, we prepared and overexpressed the SH3 domain deletion mutant of p85alpha in CHO-IR cells. |
| 8968 | 17991427 | SH3 domain of the phosphatidylinositol 3-kinase regulatory subunit is responsible for the formation of a sequestration complex with insulin receptor substrate-1. |
| 8969 | 17991427 | Class IA phosphatidylinositol 3-kinase (PI 3-kinase), which is composed of a 110kDa catalytic subunit and a regulatory subunit, plays a key role in most insulin dependent cellular responses. |
| 8970 | 17991427 | To date, five mammalian regulatory subunit isoforms have been identified, including two 85kDa proteins (p85alpha and p85beta), two 55kDa proteins (p55gamma and p55alpha), and one 50kDa protein (p50alpha). |
| 8971 | 17991427 | Interestingly, in response to insulin, only p85alpha and p85beta redistributed to isolated foci in the cells, while both were present throughout the cytoplasm in quiescent cells. |
| 8972 | 17991427 | Immunofluorescent antibodies against endogenous IRS-1 revealed IRS-1 to be co-localized in the p85 foci in response to insulin. |
| 8973 | 17991427 | As both insulin receptors and p110alpha catalytic subunits were absent from these foci on immunofluorescence study, only p85 and IRS-1 were suggested to form a sequestration complex in response to insulin. |
| 8974 | 17991427 | To determine the domain responsible for IRS-1 complex formation, we prepared and overexpressed the SH3 domain deletion mutant of p85alpha in CHO-IR cells. |
| 8975 | 18003719 | Activation of p38 mitogen-activated protein kinase abolishes insulin-mediated myocardial protection against ischemia-reperfusion injury. |
| 8976 | 18003719 | Ischemia-reperfusion activates p38 mitogen-activated protein kinase (MAPK), which regulates cellular apoptosis. |
| 8977 | 18003719 | To examine whether p38 MAPK affects insulin's cardioprotection against ischemia-reperfusion injury, we studied overnight-fasted adult male rats by use of an in vivo rat model of myocardial ischemia-reperfusion. |
| 8978 | 18003719 | The ischemic area showed markedly increased phosphorylation of p38 MAPK compared with the nonischemic area in saline animals. |
| 8979 | 18003719 | Acute activation of p38 MAPK with anisomycin (2 mg/kg iv 10 min before ischemia) had no effect on infarct size in saline rats. |
| 8980 | 18003719 | Activation of p38 MAPK by anisomycin was associated with marked and persistent elevation in IRS-1 serine phosphorylation. |
| 8981 | 18003719 | Treatment of animals with SB-239063, a potent and specific inhibitor of p38 MAPK, 10 min before reperfusion enabled insulin-mediated myocardial protection in InsulinAR rats. |
| 8982 | 18003719 | We conclude that insulin protects myocardium against ischemia-reperfusion injury when given prior to ischemia or reperfusion, and activation of p38 MAPK abolishes insulin's cardioprotective effect. |
| 8983 | 18048028 | Effect of GCP-02, a PPARalpha/gamma dual activator, on glucose and lipid metabolism in insulin-resistant mice. |
| 8984 | 18048028 | This paper reports on the effect of GCP-02, a dual activator of the peroxisome proliferator-activated receptors alpha/gamma (PPARalpha/gamma), on glucose and lipid metabolism in insulin-resistant obese mice induced by monosodium glutamate. |
| 8985 | 18048028 | RT-PCR revealed expression of insulin receptor substrate 1 and 2 (IRS1, IRS2) and related genes in liver. |
| 8986 | 18160431 | Hepatitis C virus core protein upregulates serine phosphorylation of insulin receptor substrate-1 and impairs the downstream akt/protein kinase B signaling pathway for insulin resistance. |
| 8987 | 18160431 | Since we and others have previously observed that HCV core protein activates c-Jun N-terminal kinase (JNK) and mitogen-activated protein kinase, we examined the contribution of these pathways to insulin resistance in hepatocytes. |
| 8988 | 18160431 | HCV core protein-mediated Ser(312) phosphorylation of IRS-1 was inhibited by JNK (SP600125) and phosphatidylinositol-3 kinase (LY294002) inhibitors. |
| 8989 | 18160431 | Taken together, our results demonstrated that HCV core protein increases IRS-1 phosphorylation at Ser(312) which may contribute in part to the mechanism of insulin resistance. |
| 8990 | 18160431 | Hepatitis C virus core protein upregulates serine phosphorylation of insulin receptor substrate-1 and impairs the downstream akt/protein kinase B signaling pathway for insulin resistance. |
| 8991 | 18160431 | Since we and others have previously observed that HCV core protein activates c-Jun N-terminal kinase (JNK) and mitogen-activated protein kinase, we examined the contribution of these pathways to insulin resistance in hepatocytes. |
| 8992 | 18160431 | HCV core protein-mediated Ser(312) phosphorylation of IRS-1 was inhibited by JNK (SP600125) and phosphatidylinositol-3 kinase (LY294002) inhibitors. |
| 8993 | 18160431 | Taken together, our results demonstrated that HCV core protein increases IRS-1 phosphorylation at Ser(312) which may contribute in part to the mechanism of insulin resistance. |
| 8994 | 18160431 | Hepatitis C virus core protein upregulates serine phosphorylation of insulin receptor substrate-1 and impairs the downstream akt/protein kinase B signaling pathway for insulin resistance. |
| 8995 | 18160431 | Since we and others have previously observed that HCV core protein activates c-Jun N-terminal kinase (JNK) and mitogen-activated protein kinase, we examined the contribution of these pathways to insulin resistance in hepatocytes. |
| 8996 | 18160431 | HCV core protein-mediated Ser(312) phosphorylation of IRS-1 was inhibited by JNK (SP600125) and phosphatidylinositol-3 kinase (LY294002) inhibitors. |
| 8997 | 18160431 | Taken together, our results demonstrated that HCV core protein increases IRS-1 phosphorylation at Ser(312) which may contribute in part to the mechanism of insulin resistance. |
| 8998 | 18187553 | Trauma and hemorrhage-induced acute hepatic insulin resistance: dominant role of tumor necrosis factor-alpha. |
| 8999 | 18187553 | With increasing extent of blood loss, there were increases in serum TNF-alpha levels, phosphorylation of liver insulin receptor substrate-1 on serine 307, and liver c-Jun N-terminal kinase activation/phosphorylation. |
| 9000 | 18187553 | Exogenous TNF-alpha infusion increased c-Jun N-terminal kinase phosphorylation and insulin receptor substrate-1 serine 307 phosphorylation, and inhibited insulin-induced signaling in liver. |
| 9001 | 18187553 | Conversely, neutralizing TNF-alpha antibody treatment reversed many of the hemorrhage-induced changes in hepatic insulin signaling. |
| 9002 | 18187553 | Trauma and hemorrhage-induced acute hepatic insulin resistance: dominant role of tumor necrosis factor-alpha. |
| 9003 | 18187553 | With increasing extent of blood loss, there were increases in serum TNF-alpha levels, phosphorylation of liver insulin receptor substrate-1 on serine 307, and liver c-Jun N-terminal kinase activation/phosphorylation. |
| 9004 | 18187553 | Exogenous TNF-alpha infusion increased c-Jun N-terminal kinase phosphorylation and insulin receptor substrate-1 serine 307 phosphorylation, and inhibited insulin-induced signaling in liver. |
| 9005 | 18187553 | Conversely, neutralizing TNF-alpha antibody treatment reversed many of the hemorrhage-induced changes in hepatic insulin signaling. |
| 9006 | 18202124 | Protein kinase C-zeta phosphorylates insulin receptor substrate-1, -3, and -4 but not -2: isoform specific determinants of specificity in insulin signaling. |
| 9007 | 18202124 | Protein kinase C-zeta, a downstream effector of phosphatidylinositol 3-kinase (PI3K), phosphorylates insulin receptor substrate (IRS)-1 on serine residues impairing activation of PI3K in response to insulin. |
| 9008 | 18202124 | Because IRS-1 is upstream from PI3K, this represents a negative feedback mechanism that may contribute to signal specificity in insulin action. |
| 9009 | 18202124 | To determine whether similar feedback pathways exist for other IRS isoforms, we evaluated IRS-2, -3, and -4 as substrates for PKC-zeta. |
| 9010 | 18202124 | In an in vitro kinase assay, purified recombinant PKC-zeta phosphorylated IRS-1, -3 and -4 but not IRS-2. |
| 9011 | 18202124 | Similar results were obtained with an immune-complex kinase assay demonstrating that wild-type, but not kinase-deficient mutant PKC-zeta, phosphorylated IRS-1, -3, and -4 but not IRS-2. |
| 9012 | 18202124 | Insulin-stimulated IRS tyrosine phosphorylation was impaired by overepxression of PKC-zeta for IRS-1, -3, and -4 but not IRS-2. |
| 9013 | 18202124 | Significant insulin-stimulated increases in PI3K activity was coimmunoprecipitated with all IRS isoforms. |
| 9014 | 18202124 | In cells overexpressing PKC-zeta there was marked inhibition of insulin-stimulated PI3K activity associated with IRS-1, -3 and -4 but not IRS-2. |
| 9015 | 18202124 | That is, PI3K activity associated with IRS-2 in response to insulin was similar in control cells and cells overexpressing PKC-zeta. |
| 9016 | 18202124 | We conclude that IRS-3 and -4 are novel substrates for PKC-zeta that may participate in a negative feedback pathway for insulin signaling similar to IRS-1. |
| 9017 | 18202124 | The inability of PKC-zeta to phosphorylate IRS-2 may help determine specific functional roles for IRS-2. |
| 9018 | 18202124 | Protein kinase C-zeta phosphorylates insulin receptor substrate-1, -3, and -4 but not -2: isoform specific determinants of specificity in insulin signaling. |
| 9019 | 18202124 | Protein kinase C-zeta, a downstream effector of phosphatidylinositol 3-kinase (PI3K), phosphorylates insulin receptor substrate (IRS)-1 on serine residues impairing activation of PI3K in response to insulin. |
| 9020 | 18202124 | Because IRS-1 is upstream from PI3K, this represents a negative feedback mechanism that may contribute to signal specificity in insulin action. |
| 9021 | 18202124 | To determine whether similar feedback pathways exist for other IRS isoforms, we evaluated IRS-2, -3, and -4 as substrates for PKC-zeta. |
| 9022 | 18202124 | In an in vitro kinase assay, purified recombinant PKC-zeta phosphorylated IRS-1, -3 and -4 but not IRS-2. |
| 9023 | 18202124 | Similar results were obtained with an immune-complex kinase assay demonstrating that wild-type, but not kinase-deficient mutant PKC-zeta, phosphorylated IRS-1, -3, and -4 but not IRS-2. |
| 9024 | 18202124 | Insulin-stimulated IRS tyrosine phosphorylation was impaired by overepxression of PKC-zeta for IRS-1, -3, and -4 but not IRS-2. |
| 9025 | 18202124 | Significant insulin-stimulated increases in PI3K activity was coimmunoprecipitated with all IRS isoforms. |
| 9026 | 18202124 | In cells overexpressing PKC-zeta there was marked inhibition of insulin-stimulated PI3K activity associated with IRS-1, -3 and -4 but not IRS-2. |
| 9027 | 18202124 | That is, PI3K activity associated with IRS-2 in response to insulin was similar in control cells and cells overexpressing PKC-zeta. |
| 9028 | 18202124 | We conclude that IRS-3 and -4 are novel substrates for PKC-zeta that may participate in a negative feedback pathway for insulin signaling similar to IRS-1. |
| 9029 | 18202124 | The inability of PKC-zeta to phosphorylate IRS-2 may help determine specific functional roles for IRS-2. |
| 9030 | 18202124 | Protein kinase C-zeta phosphorylates insulin receptor substrate-1, -3, and -4 but not -2: isoform specific determinants of specificity in insulin signaling. |
| 9031 | 18202124 | Protein kinase C-zeta, a downstream effector of phosphatidylinositol 3-kinase (PI3K), phosphorylates insulin receptor substrate (IRS)-1 on serine residues impairing activation of PI3K in response to insulin. |
| 9032 | 18202124 | Because IRS-1 is upstream from PI3K, this represents a negative feedback mechanism that may contribute to signal specificity in insulin action. |
| 9033 | 18202124 | To determine whether similar feedback pathways exist for other IRS isoforms, we evaluated IRS-2, -3, and -4 as substrates for PKC-zeta. |
| 9034 | 18202124 | In an in vitro kinase assay, purified recombinant PKC-zeta phosphorylated IRS-1, -3 and -4 but not IRS-2. |
| 9035 | 18202124 | Similar results were obtained with an immune-complex kinase assay demonstrating that wild-type, but not kinase-deficient mutant PKC-zeta, phosphorylated IRS-1, -3, and -4 but not IRS-2. |
| 9036 | 18202124 | Insulin-stimulated IRS tyrosine phosphorylation was impaired by overepxression of PKC-zeta for IRS-1, -3, and -4 but not IRS-2. |
| 9037 | 18202124 | Significant insulin-stimulated increases in PI3K activity was coimmunoprecipitated with all IRS isoforms. |
| 9038 | 18202124 | In cells overexpressing PKC-zeta there was marked inhibition of insulin-stimulated PI3K activity associated with IRS-1, -3 and -4 but not IRS-2. |
| 9039 | 18202124 | That is, PI3K activity associated with IRS-2 in response to insulin was similar in control cells and cells overexpressing PKC-zeta. |
| 9040 | 18202124 | We conclude that IRS-3 and -4 are novel substrates for PKC-zeta that may participate in a negative feedback pathway for insulin signaling similar to IRS-1. |
| 9041 | 18202124 | The inability of PKC-zeta to phosphorylate IRS-2 may help determine specific functional roles for IRS-2. |
| 9042 | 18202124 | Protein kinase C-zeta phosphorylates insulin receptor substrate-1, -3, and -4 but not -2: isoform specific determinants of specificity in insulin signaling. |
| 9043 | 18202124 | Protein kinase C-zeta, a downstream effector of phosphatidylinositol 3-kinase (PI3K), phosphorylates insulin receptor substrate (IRS)-1 on serine residues impairing activation of PI3K in response to insulin. |
| 9044 | 18202124 | Because IRS-1 is upstream from PI3K, this represents a negative feedback mechanism that may contribute to signal specificity in insulin action. |
| 9045 | 18202124 | To determine whether similar feedback pathways exist for other IRS isoforms, we evaluated IRS-2, -3, and -4 as substrates for PKC-zeta. |
| 9046 | 18202124 | In an in vitro kinase assay, purified recombinant PKC-zeta phosphorylated IRS-1, -3 and -4 but not IRS-2. |
| 9047 | 18202124 | Similar results were obtained with an immune-complex kinase assay demonstrating that wild-type, but not kinase-deficient mutant PKC-zeta, phosphorylated IRS-1, -3, and -4 but not IRS-2. |
| 9048 | 18202124 | Insulin-stimulated IRS tyrosine phosphorylation was impaired by overepxression of PKC-zeta for IRS-1, -3, and -4 but not IRS-2. |
| 9049 | 18202124 | Significant insulin-stimulated increases in PI3K activity was coimmunoprecipitated with all IRS isoforms. |
| 9050 | 18202124 | In cells overexpressing PKC-zeta there was marked inhibition of insulin-stimulated PI3K activity associated with IRS-1, -3 and -4 but not IRS-2. |
| 9051 | 18202124 | That is, PI3K activity associated with IRS-2 in response to insulin was similar in control cells and cells overexpressing PKC-zeta. |
| 9052 | 18202124 | We conclude that IRS-3 and -4 are novel substrates for PKC-zeta that may participate in a negative feedback pathway for insulin signaling similar to IRS-1. |
| 9053 | 18202124 | The inability of PKC-zeta to phosphorylate IRS-2 may help determine specific functional roles for IRS-2. |
| 9054 | 18202124 | Protein kinase C-zeta phosphorylates insulin receptor substrate-1, -3, and -4 but not -2: isoform specific determinants of specificity in insulin signaling. |
| 9055 | 18202124 | Protein kinase C-zeta, a downstream effector of phosphatidylinositol 3-kinase (PI3K), phosphorylates insulin receptor substrate (IRS)-1 on serine residues impairing activation of PI3K in response to insulin. |
| 9056 | 18202124 | Because IRS-1 is upstream from PI3K, this represents a negative feedback mechanism that may contribute to signal specificity in insulin action. |
| 9057 | 18202124 | To determine whether similar feedback pathways exist for other IRS isoforms, we evaluated IRS-2, -3, and -4 as substrates for PKC-zeta. |
| 9058 | 18202124 | In an in vitro kinase assay, purified recombinant PKC-zeta phosphorylated IRS-1, -3 and -4 but not IRS-2. |
| 9059 | 18202124 | Similar results were obtained with an immune-complex kinase assay demonstrating that wild-type, but not kinase-deficient mutant PKC-zeta, phosphorylated IRS-1, -3, and -4 but not IRS-2. |
| 9060 | 18202124 | Insulin-stimulated IRS tyrosine phosphorylation was impaired by overepxression of PKC-zeta for IRS-1, -3, and -4 but not IRS-2. |
| 9061 | 18202124 | Significant insulin-stimulated increases in PI3K activity was coimmunoprecipitated with all IRS isoforms. |
| 9062 | 18202124 | In cells overexpressing PKC-zeta there was marked inhibition of insulin-stimulated PI3K activity associated with IRS-1, -3 and -4 but not IRS-2. |
| 9063 | 18202124 | That is, PI3K activity associated with IRS-2 in response to insulin was similar in control cells and cells overexpressing PKC-zeta. |
| 9064 | 18202124 | We conclude that IRS-3 and -4 are novel substrates for PKC-zeta that may participate in a negative feedback pathway for insulin signaling similar to IRS-1. |
| 9065 | 18202124 | The inability of PKC-zeta to phosphorylate IRS-2 may help determine specific functional roles for IRS-2. |
| 9066 | 18202124 | Protein kinase C-zeta phosphorylates insulin receptor substrate-1, -3, and -4 but not -2: isoform specific determinants of specificity in insulin signaling. |
| 9067 | 18202124 | Protein kinase C-zeta, a downstream effector of phosphatidylinositol 3-kinase (PI3K), phosphorylates insulin receptor substrate (IRS)-1 on serine residues impairing activation of PI3K in response to insulin. |
| 9068 | 18202124 | Because IRS-1 is upstream from PI3K, this represents a negative feedback mechanism that may contribute to signal specificity in insulin action. |
| 9069 | 18202124 | To determine whether similar feedback pathways exist for other IRS isoforms, we evaluated IRS-2, -3, and -4 as substrates for PKC-zeta. |
| 9070 | 18202124 | In an in vitro kinase assay, purified recombinant PKC-zeta phosphorylated IRS-1, -3 and -4 but not IRS-2. |
| 9071 | 18202124 | Similar results were obtained with an immune-complex kinase assay demonstrating that wild-type, but not kinase-deficient mutant PKC-zeta, phosphorylated IRS-1, -3, and -4 but not IRS-2. |
| 9072 | 18202124 | Insulin-stimulated IRS tyrosine phosphorylation was impaired by overepxression of PKC-zeta for IRS-1, -3, and -4 but not IRS-2. |
| 9073 | 18202124 | Significant insulin-stimulated increases in PI3K activity was coimmunoprecipitated with all IRS isoforms. |
| 9074 | 18202124 | In cells overexpressing PKC-zeta there was marked inhibition of insulin-stimulated PI3K activity associated with IRS-1, -3 and -4 but not IRS-2. |
| 9075 | 18202124 | That is, PI3K activity associated with IRS-2 in response to insulin was similar in control cells and cells overexpressing PKC-zeta. |
| 9076 | 18202124 | We conclude that IRS-3 and -4 are novel substrates for PKC-zeta that may participate in a negative feedback pathway for insulin signaling similar to IRS-1. |
| 9077 | 18202124 | The inability of PKC-zeta to phosphorylate IRS-2 may help determine specific functional roles for IRS-2. |
| 9078 | 18202124 | Protein kinase C-zeta phosphorylates insulin receptor substrate-1, -3, and -4 but not -2: isoform specific determinants of specificity in insulin signaling. |
| 9079 | 18202124 | Protein kinase C-zeta, a downstream effector of phosphatidylinositol 3-kinase (PI3K), phosphorylates insulin receptor substrate (IRS)-1 on serine residues impairing activation of PI3K in response to insulin. |
| 9080 | 18202124 | Because IRS-1 is upstream from PI3K, this represents a negative feedback mechanism that may contribute to signal specificity in insulin action. |
| 9081 | 18202124 | To determine whether similar feedback pathways exist for other IRS isoforms, we evaluated IRS-2, -3, and -4 as substrates for PKC-zeta. |
| 9082 | 18202124 | In an in vitro kinase assay, purified recombinant PKC-zeta phosphorylated IRS-1, -3 and -4 but not IRS-2. |
| 9083 | 18202124 | Similar results were obtained with an immune-complex kinase assay demonstrating that wild-type, but not kinase-deficient mutant PKC-zeta, phosphorylated IRS-1, -3, and -4 but not IRS-2. |
| 9084 | 18202124 | Insulin-stimulated IRS tyrosine phosphorylation was impaired by overepxression of PKC-zeta for IRS-1, -3, and -4 but not IRS-2. |
| 9085 | 18202124 | Significant insulin-stimulated increases in PI3K activity was coimmunoprecipitated with all IRS isoforms. |
| 9086 | 18202124 | In cells overexpressing PKC-zeta there was marked inhibition of insulin-stimulated PI3K activity associated with IRS-1, -3 and -4 but not IRS-2. |
| 9087 | 18202124 | That is, PI3K activity associated with IRS-2 in response to insulin was similar in control cells and cells overexpressing PKC-zeta. |
| 9088 | 18202124 | We conclude that IRS-3 and -4 are novel substrates for PKC-zeta that may participate in a negative feedback pathway for insulin signaling similar to IRS-1. |
| 9089 | 18202124 | The inability of PKC-zeta to phosphorylate IRS-2 may help determine specific functional roles for IRS-2. |
| 9090 | 18267303 | We analyzed the genes expressed (transcriptomes) and the proteins translated (pro- teomes) in muscle tissues and activated CD4(+) and CD8(+) T-lymphocytes (T-cells) of five Type 2 diabetes (T2DM) subjects using Affymetrix microarrays and mass spectrometry, and compared them with matched non-diabetic controls. |
| 9091 | 18267303 | Gene expressions of insulin receptor (INSR), vitamin D receptor, insulin degrading enzyme, Akt, insulin receptor substrate-1 (IRS-1), IRS-2, glucose transporter 4 (GLUT4), and enzymes of the glycolytic pathway were decreased at least 50% in T2DM than in controls. |
| 9092 | 18267303 | The gene silencing for INSR or TNFalpha resulted in the inhibition or stimulation of GLUT4, respectively. |
| 9093 | 18296638 | Overexpression of the dual-specificity phosphatase MKP-4/DUSP-9 protects against stress-induced insulin resistance. |
| 9094 | 18296638 | Insulin resistance, a hallmark of type 2 diabetes and obesity, is associated with increased activity of MAP and stress-activated protein (SAP) kinases, which results in decreased insulin signaling. |
| 9095 | 18296638 | Our goal was to investigate the role of MAP kinase phosphatase-4 (MKP-4) in modulating this process. |
| 9096 | 18296638 | We found that MKP-4 expression is up-regulated during adipocyte and myocyte differentiation in vitro and up-regulated during fasting in white adipose tissue in vivo. |
| 9097 | 18296638 | Overexpression of MKP-4 in 3T3-L1 cells inhibited ERK and JNK phosphorylation and, to a lesser extent, p38MAPK phosphorylation. |
| 9098 | 18296638 | As a result, the phosphorylation of IRS-1 serine 307 induced by anisomycin was abolished, leading to a sensitization of insulin signaling with recovery of insulin-stimulated IRS-1 tyrosine phosphorylation, IRS-1 docking with phosphatidylinositol 3-kinase, and Akt phosphorylation. |
| 9099 | 18296638 | MKP-4 also reversed the effect of TNF-alpha to inhibit insulin signaling; alter IL-6, Glut1 and Glut4 expression; and inhibit insulin-stimulated glucose uptake in 3T3-L1 adipocytes. |
| 9100 | 18296638 | Overexpression of MKP-4 in the liver of ob/ob mice decreased ERK and JNK phosphorylation, leading to a reduction in fed and fasted glycemia, improved glucose intolerance, decreased expression of gluconeogenic and lipogenic genes, and reduced hepatic steatosis. |
| 9101 | 18296638 | Thus, MKP-4 has a protective effect against the development of insulin resistance through its ability to dephosphorylate and inactivate crucial mediators of stress-induced insulin resistance, such as ERK and JNK, and increasing MKP-4 activity might provide a therapy for insulin-resistant disorders. |
| 9102 | 18380932 | Telmisartan, an angiotensin II type 1 receptor blocker, inhibits advanced glycation end-product (AGE)-elicited hepatic insulin resistance via peroxisome proliferator-activated receptor-gamma activation. |
| 9103 | 18380932 | This study examined whether telmisartan, a unique angiotensin II type 1 receptor blocker (ARB) with peroxisome proliferator-activated receptor-gamma (PPAR-gamma)-modulating activity, improved insulin resistance in advanced glycation end-product (AGE)-exposed human hepatoma (Hep3B) cells. |
| 9104 | 18380932 | It also decreased tyrosine phosphorylation of IRS-1 and, subsequently, reduced the association of the p85 subunit of phosphatidylinositol 3-kinase with IRS-1 and glycogen synthesis in insulin-exposed Hep3B cells, all of which were inhibited by telmisartan. |
| 9105 | 18380932 | The insulin-sensitizing properties of telmisartan in AGE-exposed Hep3B cells were significantly blocked by GW9662, an inhibitor of PPAR-gamma. |
| 9106 | 18380932 | Our study suggests that telmisartan could improve AGE-elicited insulin resistance in Hep3B cells by inhibiting serine phosphorylation of IRS-1, at least in part, via activation of PPAR-gamma. |
| 9107 | 18380932 | Telmisartan, an angiotensin II type 1 receptor blocker, inhibits advanced glycation end-product (AGE)-elicited hepatic insulin resistance via peroxisome proliferator-activated receptor-gamma activation. |
| 9108 | 18380932 | This study examined whether telmisartan, a unique angiotensin II type 1 receptor blocker (ARB) with peroxisome proliferator-activated receptor-gamma (PPAR-gamma)-modulating activity, improved insulin resistance in advanced glycation end-product (AGE)-exposed human hepatoma (Hep3B) cells. |
| 9109 | 18380932 | It also decreased tyrosine phosphorylation of IRS-1 and, subsequently, reduced the association of the p85 subunit of phosphatidylinositol 3-kinase with IRS-1 and glycogen synthesis in insulin-exposed Hep3B cells, all of which were inhibited by telmisartan. |
| 9110 | 18380932 | The insulin-sensitizing properties of telmisartan in AGE-exposed Hep3B cells were significantly blocked by GW9662, an inhibitor of PPAR-gamma. |
| 9111 | 18380932 | Our study suggests that telmisartan could improve AGE-elicited insulin resistance in Hep3B cells by inhibiting serine phosphorylation of IRS-1, at least in part, via activation of PPAR-gamma. |
| 9112 | 18395354 | Many biological molecules, such as ROS, IRS-1, PI3K, have been identified involving in the causes of insulin resistance. |
| 9113 | 18395354 | Presently, accumulative research data showed that BVR was a strong antioxidant enzyme, which could scavenge the excess ROS, and the characteristics of kinase activity and binding with p85 could modulate the biological function of IRS-1 and PI3K. |
| 9114 | 18395354 | We hypothesize that BVR has a significant role in the progression of insulin resistance, and it will be a promising therapeutic target for treating insulin resistance. |
| 9115 | 18395354 | Many biological molecules, such as ROS, IRS-1, PI3K, have been identified involving in the causes of insulin resistance. |
| 9116 | 18395354 | Presently, accumulative research data showed that BVR was a strong antioxidant enzyme, which could scavenge the excess ROS, and the characteristics of kinase activity and binding with p85 could modulate the biological function of IRS-1 and PI3K. |
| 9117 | 18395354 | We hypothesize that BVR has a significant role in the progression of insulin resistance, and it will be a promising therapeutic target for treating insulin resistance. |
| 9118 | 18406704 | There are currently two members of the IRS family (IRS-1 and IRS-2); these IRS proteins contain elements of substantial similarity, but may also play divergent roles in mammalian physiology. |
| 9119 | 18406764 | In addition, these data confirm that isolated defects in single critical genes, including the insulin receptor, IRS-1, and glucokinase, may play a role in the development of some types of insulin resistance and NIDDM. |
| 9120 | 18430969 | Coordinated phosphorylation of insulin receptor substrate-1 by glycogen synthase kinase-3 and protein kinase C betaII in the diabetic fat tissue. |
| 9121 | 18430969 | Overexpression of PKCalpha or PKCbetaII isoforms in cells enhanced IRS-1 phosphorylation at Ser(336) and Ser(332), and in vitro kinase assays verified that these two kinases directly phosphorylated IRS-1 at Ser(336). |
| 9122 | 18430969 | Elevated levels of PKCbetaII were also associated with enhanced phosphorylation of IRS-1 at Ser(336/332) and elevated activity of GSK-3beta. |
| 9123 | 18430969 | Coordinated phosphorylation of insulin receptor substrate-1 by glycogen synthase kinase-3 and protein kinase C betaII in the diabetic fat tissue. |
| 9124 | 18430969 | Overexpression of PKCalpha or PKCbetaII isoforms in cells enhanced IRS-1 phosphorylation at Ser(336) and Ser(332), and in vitro kinase assays verified that these two kinases directly phosphorylated IRS-1 at Ser(336). |
| 9125 | 18430969 | Elevated levels of PKCbetaII were also associated with enhanced phosphorylation of IRS-1 at Ser(336/332) and elevated activity of GSK-3beta. |
| 9126 | 18430969 | Coordinated phosphorylation of insulin receptor substrate-1 by glycogen synthase kinase-3 and protein kinase C betaII in the diabetic fat tissue. |
| 9127 | 18430969 | Overexpression of PKCalpha or PKCbetaII isoforms in cells enhanced IRS-1 phosphorylation at Ser(336) and Ser(332), and in vitro kinase assays verified that these two kinases directly phosphorylated IRS-1 at Ser(336). |
| 9128 | 18430969 | Elevated levels of PKCbetaII were also associated with enhanced phosphorylation of IRS-1 at Ser(336/332) and elevated activity of GSK-3beta. |
| 9129 | 18434357 | Insulin-stimulated insulin receptor (IR) Tyr1162/Tyr1163 phosphorylation and IR substrate (IRS)-1 Tyr612 phosphorylation were increased at least twofold over basal in GLYC rats with insulin and this increase was not significantly impaired in the LIP rats. |
| 9130 | 18434357 | However, there was no insulin-stimulated protein kinase B (PKB) Ser473 or glycogen synthase kinase (GSK)-3beta Ser9 phosphorylation in the LIP rats, compared with at least a twofold increase over basal in GLYC rats for both proteins. c-Jun N-terminal kinase, inhibitor of kappa kinase beta and inhibitor of nuclear factor-kappaB phosphorylation and total protein expression, as well as Ser307-IRS-1 phosphorylation, were not altered by lipid infusion compared with GLYC infusion. |
| 9131 | 18434357 | These data indicate that acute, physiological elevation in FFA has a greater impact on insulin signalling downstream of IR and IRS-1, at the level of PKB and GSK-3beta, and that under these conditions stress signalling pathways are not significantly stimulated. |
| 9132 | 18434357 | Decreased PKB and GSK-3beta phosphorylation in RQ may therefore be primary determinants of the reduced insulin action observed in situations of acute FFA oversupply. |
| 9133 | 18445879 | Insulin receptor substrates (IRS), which is a main target molecule of insulin/IGF-1 receptor signaling, have been shown to play important roles in maintaining normal bone turn-over by skeletal analysis of IRS-1 and -2 knock-out mice. |
| 9134 | 18446001 | Molecular mechanism of moderate insulin resistance in adiponectin-knockout mice. |
| 9135 | 18446001 | Although adiponectin-knockout (adipo(-/-)) mice are known to exhibit insulin resistance, the degrees of insulin resistance and glucose intolerance are unexpectedly only moderate. |
| 9136 | 18446001 | In this study, the adipo(-/-) mice showed hepatic, but not muscle, insulin resistance. insulin-stimulated phosphorylation of IRS-1 and IRS-2 was impaired, the IRS-2 protein level was decreased, and insulin-stimulated phosphorylation of Akt was decreased in the liver of the adipo(-/-) mice. |
| 9137 | 18446001 | However, the triglyceride content in the liver was not increased in these mice, despite the decrease in the PPARalpha expression involved in lipid combustion, since the expressions of lipogenic genes such as SREBP-1 and SCD-1 were decreased in association with the increased leptin sensitivity. |
| 9138 | 18446001 | Consistent with this, the down-regulation SREBP-1 and SCD-1 observed in the adipo(-/-) mice was no longer observed, and the hepatic triglyceride content was significantly increased in the adiponectin leptin double-knockout (adipo(-/-)ob/ob) mice. |
| 9139 | 18446001 | On the other hand, the triglyceride content in the skeletal muscle was significantly decreased in the adipo(-/-) mice, probably due to up-regulated AMPK activity associated with the increased leptin sensitivity. |
| 9140 | 18446001 | In conclusion, adipo(-/-) mice showed impaired insulin signaling in the liver to cause hepatic insulin resistance, however, no increase in the triglyceride content was observed in either the liver or the skeletal muscle, presumably on account of the increased leptin sensitivity. |
| 9141 | 18453752 | Immunostaining detected a significant reduction in the insulin receptor substrate 1 (IRS1) (by 54%, P < 0.001) and IRS2 (by 55%, P < 0.001) in the beta-cells of the OLETF rats. |
| 9142 | 18469500 | Atorvastatin significantly decreased insulin-stimulated 2-deoxyglucose uptake in 3T3L1 adipocytes associated with the prevention of translocation of GLUT4 into the plasma membrane. |
| 9143 | 18469500 | The amounts of Rab4 and RhoA that required lipid modification with farnesyl or geranylgeranyl pyrophosphate, in the membrane fraction were decreased by atorvastatin. |
| 9144 | 18469500 | Insulin-induced tyrosine phosphorylation of IRS-1 and serine/threonine phosphorylation of Akt were reduced by atorvastatin. |
| 9145 | 18469500 | Inhibitors of the RhoA/Rho kinase system, C3 and Y27632, as well as atorvastatin reduced insulin-induced changes in signal transduction. |
| 9146 | 18496818 | We found that the high glucose condition causes significant increasing Ser307 phosphorylation of insulin receptor substrate-1 (IRS-1), leading to reduce insulin-stimulated phosphorylation of Akt. |
| 9147 | 18496818 | However, the treatment of EGCG improves insulin-stimulated downsignaling by reducing IRS-1 Ser307 phosphorylation. |
| 9148 | 18496818 | Together, our data suggest a putative link between high glucose and insulin resistance in HepG2 cells, and the EGCG treatment attenuates insulin signaling blockade by reducing IRS-1 Ser307 phosphorylation through the AMPK activation pathway. |
| 9149 | 18496818 | We found that the high glucose condition causes significant increasing Ser307 phosphorylation of insulin receptor substrate-1 (IRS-1), leading to reduce insulin-stimulated phosphorylation of Akt. |
| 9150 | 18496818 | However, the treatment of EGCG improves insulin-stimulated downsignaling by reducing IRS-1 Ser307 phosphorylation. |
| 9151 | 18496818 | Together, our data suggest a putative link between high glucose and insulin resistance in HepG2 cells, and the EGCG treatment attenuates insulin signaling blockade by reducing IRS-1 Ser307 phosphorylation through the AMPK activation pathway. |
| 9152 | 18496818 | We found that the high glucose condition causes significant increasing Ser307 phosphorylation of insulin receptor substrate-1 (IRS-1), leading to reduce insulin-stimulated phosphorylation of Akt. |
| 9153 | 18496818 | However, the treatment of EGCG improves insulin-stimulated downsignaling by reducing IRS-1 Ser307 phosphorylation. |
| 9154 | 18496818 | Together, our data suggest a putative link between high glucose and insulin resistance in HepG2 cells, and the EGCG treatment attenuates insulin signaling blockade by reducing IRS-1 Ser307 phosphorylation through the AMPK activation pathway. |
| 9155 | 18516099 | Impaired insulin-mediated vasorelaxation in a nonobese model of type 2 diabetes: role of endothelin-1. |
| 9156 | 18516099 | Insulin resistance involves decreased phosphorylation of insulin receptor substrate (IRS) proteins and (or) Akt. |
| 9157 | 18516099 | Diet-induced insulin resistance enhances endothelin-1(ET-1)-mediated vasoconstriction and prevents vasodilatation to insulin. |
| 9158 | 18516099 | Presently, we evaluated insulin-mediated vascular relaxation, assessed molecular markers of the insulin signaling pathway, and determined the involvement of ET-1 in response to insulin by using selective ETA- or ETB-receptor blockade in a lean model of type 2 diabetes. |
| 9159 | 18516099 | Preincubation with 1 micromol/L BQ-123 or BQ-788 for ETA- and ETB-receptor blockade, respectively, resulted in improved insulin sensitivity. |
| 9160 | 18516099 | Immunoblotting for native and phosphorylated Akt and IRS-1 revealed a decrease in Akt activation in the GK group. |
| 9161 | 18548385 | We also observed changes in transcript abundance of PPAR-gamma, PPAR-alpha, FAS, LPL, UCP2, UCP3, CPT1, RxR, ObRb, ApoAII, ApoD, and IRS1 in liver, muscle, and adipose tissue, suggesting treatment-induced effects on these genes. |
| 9162 | 18555856 | We measured basal and insulin-stimulated glucose uptake, glycogen accumulation, phosphoinositide 3 (PI-3) kinase activity, and Akt phosphorylation in primary skeletal muscle culture from subjects with type 2 diabetes mellitus incubated with or without various concentrations of PMI 5011. |
| 9163 | 18555856 | We also analyzed the abundance of insulin receptor signaling proteins, for example, IRS-1, IRS-2, and PI-3 kinase. |
| 9164 | 18555856 | PMI 5011 treatment did not appear to significantly affect protein abundance for IRS-1, IRS-2, PI-3 kinase, Akt, insulin receptor, or Glut-4. |
| 9165 | 18555856 | The cellular mechanism of action to explain the effects by which an alcoholic extract of A dracunculus L improves carbohydrate metabolism on a clinical level may be secondary to enhancing insulin receptor signaling and modulating levels of a specific protein tyrosine phosphatase, that is, PTP1B. |
| 9166 | 18555856 | We measured basal and insulin-stimulated glucose uptake, glycogen accumulation, phosphoinositide 3 (PI-3) kinase activity, and Akt phosphorylation in primary skeletal muscle culture from subjects with type 2 diabetes mellitus incubated with or without various concentrations of PMI 5011. |
| 9167 | 18555856 | We also analyzed the abundance of insulin receptor signaling proteins, for example, IRS-1, IRS-2, and PI-3 kinase. |
| 9168 | 18555856 | PMI 5011 treatment did not appear to significantly affect protein abundance for IRS-1, IRS-2, PI-3 kinase, Akt, insulin receptor, or Glut-4. |
| 9169 | 18555856 | The cellular mechanism of action to explain the effects by which an alcoholic extract of A dracunculus L improves carbohydrate metabolism on a clinical level may be secondary to enhancing insulin receptor signaling and modulating levels of a specific protein tyrosine phosphatase, that is, PTP1B. |
| 9170 | 18584041 | Acute-phase serum amyloid A as a marker of insulin resistance in mice. |
| 9171 | 18584041 | Acute-phase serum amyloid A (A-SAA) was shown recently to correlate with obesity and insulin resistance in humans. |
| 9172 | 18584041 | Plasma A-SAA elevation was due to induction of Saa1 and Saa2 expression in liver but not in adipose tissue. |
| 9173 | 18584041 | Proinflammatory genes (Ccl2, Saa3) were induced while genes critical for insulin sensitivity (Irs1, Adipoq, Glut4) were down-regulated. |
| 9174 | 18585815 | Regarding the metabolic signalling, glargine and insulin-induced comparable dose-dependent phosphorylation of insulin receptor, IRS-1, Akt, and GSK3, whereas detemir-induced kinetics were markedly lower in 3T3-L1 adipocytes and L6 myocytes. |
| 9175 | 18585815 | Concerning the mitogenic properties, glargine and insulin-induced comparable dose-dependent phosphorylation of MAP kinase (MAPK) and 5-bromo-2'-deoxyuridine (BrdU) incorporation. |
| 9176 | 18590692 | Here, we show that hepatic Irs1 and Irs2 function in a distinct manner in the regulation of glucose homeostasis. |
| 9177 | 18590692 | The PI3K activity associated with Irs2 began to increase during fasting, reached its peak immediately after refeeding, and decreased rapidly thereafter. |
| 9178 | 18590692 | By contrast, the PI3K activity associated with Irs1 began to increase a few hours after refeeding and reached its peak thereafter. |
| 9179 | 18590692 | The data indicate that Irs2 mainly functions during fasting and immediately after refeeding, and Irs1 functions primarily after refeeding. |
| 9180 | 18590692 | In fact, liver-specific Irs1-knockout mice failed to exhibit insulin resistance during fasting, but showed insulin resistance after refeeding; conversely, liver-specific Irs2-knockout mice displayed insulin resistance during fasting but not after refeeding. |
| 9181 | 18590692 | We propose the concept of the existence of a dynamic relay between Irs1 and Irs2 in hepatic insulin signaling during fasting and feeding. |
| 9182 | 18590692 | Here, we show that hepatic Irs1 and Irs2 function in a distinct manner in the regulation of glucose homeostasis. |
| 9183 | 18590692 | The PI3K activity associated with Irs2 began to increase during fasting, reached its peak immediately after refeeding, and decreased rapidly thereafter. |
| 9184 | 18590692 | By contrast, the PI3K activity associated with Irs1 began to increase a few hours after refeeding and reached its peak thereafter. |
| 9185 | 18590692 | The data indicate that Irs2 mainly functions during fasting and immediately after refeeding, and Irs1 functions primarily after refeeding. |
| 9186 | 18590692 | In fact, liver-specific Irs1-knockout mice failed to exhibit insulin resistance during fasting, but showed insulin resistance after refeeding; conversely, liver-specific Irs2-knockout mice displayed insulin resistance during fasting but not after refeeding. |
| 9187 | 18590692 | We propose the concept of the existence of a dynamic relay between Irs1 and Irs2 in hepatic insulin signaling during fasting and feeding. |
| 9188 | 18590692 | Here, we show that hepatic Irs1 and Irs2 function in a distinct manner in the regulation of glucose homeostasis. |
| 9189 | 18590692 | The PI3K activity associated with Irs2 began to increase during fasting, reached its peak immediately after refeeding, and decreased rapidly thereafter. |
| 9190 | 18590692 | By contrast, the PI3K activity associated with Irs1 began to increase a few hours after refeeding and reached its peak thereafter. |
| 9191 | 18590692 | The data indicate that Irs2 mainly functions during fasting and immediately after refeeding, and Irs1 functions primarily after refeeding. |
| 9192 | 18590692 | In fact, liver-specific Irs1-knockout mice failed to exhibit insulin resistance during fasting, but showed insulin resistance after refeeding; conversely, liver-specific Irs2-knockout mice displayed insulin resistance during fasting but not after refeeding. |
| 9193 | 18590692 | We propose the concept of the existence of a dynamic relay between Irs1 and Irs2 in hepatic insulin signaling during fasting and feeding. |
| 9194 | 18590692 | Here, we show that hepatic Irs1 and Irs2 function in a distinct manner in the regulation of glucose homeostasis. |
| 9195 | 18590692 | The PI3K activity associated with Irs2 began to increase during fasting, reached its peak immediately after refeeding, and decreased rapidly thereafter. |
| 9196 | 18590692 | By contrast, the PI3K activity associated with Irs1 began to increase a few hours after refeeding and reached its peak thereafter. |
| 9197 | 18590692 | The data indicate that Irs2 mainly functions during fasting and immediately after refeeding, and Irs1 functions primarily after refeeding. |
| 9198 | 18590692 | In fact, liver-specific Irs1-knockout mice failed to exhibit insulin resistance during fasting, but showed insulin resistance after refeeding; conversely, liver-specific Irs2-knockout mice displayed insulin resistance during fasting but not after refeeding. |
| 9199 | 18590692 | We propose the concept of the existence of a dynamic relay between Irs1 and Irs2 in hepatic insulin signaling during fasting and feeding. |
| 9200 | 18590692 | Here, we show that hepatic Irs1 and Irs2 function in a distinct manner in the regulation of glucose homeostasis. |
| 9201 | 18590692 | The PI3K activity associated with Irs2 began to increase during fasting, reached its peak immediately after refeeding, and decreased rapidly thereafter. |
| 9202 | 18590692 | By contrast, the PI3K activity associated with Irs1 began to increase a few hours after refeeding and reached its peak thereafter. |
| 9203 | 18590692 | The data indicate that Irs2 mainly functions during fasting and immediately after refeeding, and Irs1 functions primarily after refeeding. |
| 9204 | 18590692 | In fact, liver-specific Irs1-knockout mice failed to exhibit insulin resistance during fasting, but showed insulin resistance after refeeding; conversely, liver-specific Irs2-knockout mice displayed insulin resistance during fasting but not after refeeding. |
| 9205 | 18590692 | We propose the concept of the existence of a dynamic relay between Irs1 and Irs2 in hepatic insulin signaling during fasting and feeding. |
| 9206 | 18590693 | Inactivation of hepatic Foxo1 by insulin signaling is required for adaptive nutrient homeostasis and endocrine growth regulation. |
| 9207 | 18590693 | To assess the contribution of Foxo1 to metabolic dysregulation during hepatic insulin resistance, we disrupted Foxo1 expression in the liver of mice lacking hepatic Irs1 and Irs2 (DKO mice). |
| 9208 | 18590693 | DKO mice were small and developed diabetes; analysis of the DKO-liver transcriptome identified perturbed expression of growth and metabolic genes, including increased Ppargc1a and Igfbp1, and decreased glucokinase, Srebp1c, Ghr, and Igf1. |
| 9209 | 18590693 | Liver-specific deletion of Foxo1 in DKO mice resulted in significant normalization of the DKO-liver transcriptome and partial restoration of the response to fasting and feeding, near normal blood glucose and insulin concentrations, and normalization of body size. |
| 9210 | 18590693 | These results demonstrate that constitutively active Foxo1 significantly contributes to hyperglycemia during severe hepatic insulin resistance, and that the Irs1/2 --> PI3K --> Akt --> Foxo1 branch of insulin signaling is largely responsible for hepatic insulin-regulated glucose homeostasis and somatic growth. |
| 9211 | 18590693 | Inactivation of hepatic Foxo1 by insulin signaling is required for adaptive nutrient homeostasis and endocrine growth regulation. |
| 9212 | 18590693 | To assess the contribution of Foxo1 to metabolic dysregulation during hepatic insulin resistance, we disrupted Foxo1 expression in the liver of mice lacking hepatic Irs1 and Irs2 (DKO mice). |
| 9213 | 18590693 | DKO mice were small and developed diabetes; analysis of the DKO-liver transcriptome identified perturbed expression of growth and metabolic genes, including increased Ppargc1a and Igfbp1, and decreased glucokinase, Srebp1c, Ghr, and Igf1. |
| 9214 | 18590693 | Liver-specific deletion of Foxo1 in DKO mice resulted in significant normalization of the DKO-liver transcriptome and partial restoration of the response to fasting and feeding, near normal blood glucose and insulin concentrations, and normalization of body size. |
| 9215 | 18590693 | These results demonstrate that constitutively active Foxo1 significantly contributes to hyperglycemia during severe hepatic insulin resistance, and that the Irs1/2 --> PI3K --> Akt --> Foxo1 branch of insulin signaling is largely responsible for hepatic insulin-regulated glucose homeostasis and somatic growth. |
| 9216 | 18599621 | The overfed animals also had decreased insulin sensitivity in the heart, as confirmed by decreased insulin receptor (IR)-beta and IR substrate-1 (Irs1) phosphorylation, increased phosphatase, non-receptor type 1 (Ptpn1)-IR-beta association, decreased -Irs1-associated activity, and reduction in anti-phospho Akt1 phosphorylation. |
| 9217 | 18599621 | In conclusion, our findings showed that overnutrition during early life induced obesity and insulin resistance in the adult offspring, and further increased heart size and impaired cardiac insulin signaling, putatively due to an increase in Ptpn1 activity. |
| 9218 | 18618016 | Prolonged activation of p70 S6 kinase (S6K) by insulin and nutrients leads to inhibition of insulin signaling via negative feedback input to the signaling factor IRS-1. |
| 9219 | 18633112 | Muscle-specific IRS-1 Ser->Ala transgenic mice are protected from fat-induced insulin resistance in skeletal muscle. |
| 9220 | 18653708 | Cardiac muscle protein catabolism in diabetes mellitus: activation of the ubiquitin-proteasome system by insulin deficiency. |
| 9221 | 18653708 | In skeletal muscle this insulin-dependent increase in protein degradation involves activation of both caspase-3 and the ubiquitin-proteasome system. |
| 9222 | 18653708 | Expression of ubiquitin mRNA and chymotrypsin-like activity in the proteasome were increased, indicating activation of the ubiquitin-proteasome system in diabetic mouse heart. |
| 9223 | 18653708 | Insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation, and Akt phosphorylation were decreased. |
| 9224 | 18653708 | Insulin replacement prevented the decrease in IRS-1/Akt phosphorylation, the increase in proteolysis, and attenuated the increase in ubiquitin mRNA. |
| 9225 | 18653708 | We conclude that insulinopenia accelerates proteolysis in cardiac muscle by reducing IRS-1/Akt signaling, which leads to activation of the ubiquitin-proteasome proteolytic pathway. |
| 9226 | 18653708 | Cardiac muscle protein catabolism in diabetes mellitus: activation of the ubiquitin-proteasome system by insulin deficiency. |
| 9227 | 18653708 | In skeletal muscle this insulin-dependent increase in protein degradation involves activation of both caspase-3 and the ubiquitin-proteasome system. |
| 9228 | 18653708 | Expression of ubiquitin mRNA and chymotrypsin-like activity in the proteasome were increased, indicating activation of the ubiquitin-proteasome system in diabetic mouse heart. |
| 9229 | 18653708 | Insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation, and Akt phosphorylation were decreased. |
| 9230 | 18653708 | Insulin replacement prevented the decrease in IRS-1/Akt phosphorylation, the increase in proteolysis, and attenuated the increase in ubiquitin mRNA. |
| 9231 | 18653708 | We conclude that insulinopenia accelerates proteolysis in cardiac muscle by reducing IRS-1/Akt signaling, which leads to activation of the ubiquitin-proteasome proteolytic pathway. |
| 9232 | 18653708 | Cardiac muscle protein catabolism in diabetes mellitus: activation of the ubiquitin-proteasome system by insulin deficiency. |
| 9233 | 18653708 | In skeletal muscle this insulin-dependent increase in protein degradation involves activation of both caspase-3 and the ubiquitin-proteasome system. |
| 9234 | 18653708 | Expression of ubiquitin mRNA and chymotrypsin-like activity in the proteasome were increased, indicating activation of the ubiquitin-proteasome system in diabetic mouse heart. |
| 9235 | 18653708 | Insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation, and Akt phosphorylation were decreased. |
| 9236 | 18653708 | Insulin replacement prevented the decrease in IRS-1/Akt phosphorylation, the increase in proteolysis, and attenuated the increase in ubiquitin mRNA. |
| 9237 | 18653708 | We conclude that insulinopenia accelerates proteolysis in cardiac muscle by reducing IRS-1/Akt signaling, which leads to activation of the ubiquitin-proteasome proteolytic pathway. |
| 9238 | 18657616 | Although low plasma levels of E2 (days 6 and 11) increased Glut-4 plasma membrane content and subsequent improved insulin sensitivity, they could not fully reverse hyperglycaemia negative effects on p85alpha-IRS-1 association and IRS-1 content during 11 days. |
| 9239 | 18657616 | However, high plasma levels of E2 (day 16) could reverse hyperglycaemia effects not only on Glut-4 plasma membrane content but also on p85alpha-IRS-1 association and IRS-1 protein content level. |
| 9240 | 18657616 | The combined therapy had a synergic effect on insulin sensitivity when their plasma levels were low (day 6) or high (day 16), that could be associated with Glut-4 plasma membrane content modulation, p85alpha-IRS-1 association and IRS-1 amount. |
| 9241 | 18657616 | Although low plasma levels of E2 (days 6 and 11) increased Glut-4 plasma membrane content and subsequent improved insulin sensitivity, they could not fully reverse hyperglycaemia negative effects on p85alpha-IRS-1 association and IRS-1 content during 11 days. |
| 9242 | 18657616 | However, high plasma levels of E2 (day 16) could reverse hyperglycaemia effects not only on Glut-4 plasma membrane content but also on p85alpha-IRS-1 association and IRS-1 protein content level. |
| 9243 | 18657616 | The combined therapy had a synergic effect on insulin sensitivity when their plasma levels were low (day 6) or high (day 16), that could be associated with Glut-4 plasma membrane content modulation, p85alpha-IRS-1 association and IRS-1 amount. |
| 9244 | 18657616 | Although low plasma levels of E2 (days 6 and 11) increased Glut-4 plasma membrane content and subsequent improved insulin sensitivity, they could not fully reverse hyperglycaemia negative effects on p85alpha-IRS-1 association and IRS-1 content during 11 days. |
| 9245 | 18657616 | However, high plasma levels of E2 (day 16) could reverse hyperglycaemia effects not only on Glut-4 plasma membrane content but also on p85alpha-IRS-1 association and IRS-1 protein content level. |
| 9246 | 18657616 | The combined therapy had a synergic effect on insulin sensitivity when their plasma levels were low (day 6) or high (day 16), that could be associated with Glut-4 plasma membrane content modulation, p85alpha-IRS-1 association and IRS-1 amount. |
| 9247 | 18773289 | The release of serotonin, which is closely associated with the actions of insulin and leptin, was measured, by electrochemical detection following reverse-phase liquid chromatography (HPLC), in the extracellular space of the medial hypothalamus and the dorsal hippocampus in samples obtained from non-anesthetized animals, by microdialysis. |
| 9248 | 18773289 | After 1 week, there was an increased gene expression of the insulin receptor and the insulin receptor substrates IRS1 and IRS2, as measured by real-time PCR. |
| 9249 | 18779578 | Terminally ill insulin-deficient rodents with uncontrolled diabetes due to autoimmune or chemical destruction of beta-cells were made hyperleptinemic by adenoviral transfer of the leptin gene. |
| 9250 | 18779578 | Up-regulation of insulin-like growth factor 1 (IGF-1) expression and plasma levels and increasing IGF-1 receptor phosphorylation in muscle may explain the increased insulin receptor substrate 1, PI3K, and ERK phosphorylation in skeletal muscle. |
| 9251 | 18779578 | These findings suggest that leptin reverses the catabolic consequences of total lack of insulin, potentially by suppressing glucagon action on liver and enhancing the insulinomimetic actions of IGF-1 on skeletal muscle, and suggest strategies for making type 1 diabetes insulin-independent. |
| 9252 | 18780965 | In a C57BL/6 mouse model of obesity and T2DM, we characterized the histopathology, gene expression, and insulin and insulin-like growth factor (IGF)-receptor binding in temporal lobe. |
| 9253 | 18780965 | These effects were associated with significantly increased levels of tau, IGF-I receptor, insulin receptor substrate-1 (IRS-1), IRS-4, ubiquitin, glial fibrillary acidic protein, and 4-hydroxynonenol, and decreased expression of beta-actin. |
| 9254 | 18840478 | Calreticulin regulates insulin receptor expression and its downstream PI3 Kinase/Akt signalling pathway. |
| 9255 | 18840478 | Insulin signalling is initiated by the binding of insulin to its receptor and triggering cascades of events including activation of PI3kinase/Akt signalling pathway. |
| 9256 | 18840478 | Therefore, the aim of this study was to investigate the changes in the glucose uptake and insulin signalling pathway (mainly PI3 kinase/Akt) in the absence of CRT. |
| 9257 | 18840478 | This increase was accompanied by a significant increase in both insulin receptor beta expression, Insulin receptor substrate-1 phosphorylation, GLUT-1 expression and in insulin stimulated Akt phosphorylation and kinase activity in the crt-/- cells. |
| 9258 | 18840478 | Intriguingly, the increased expression of insulin receptor beta in the crt-/- was due to decreased levels of p53 protein. |
| 9259 | 18972094 | Combined thiazolidinedione-metformin treatment synergistically improves insulin signalling to insulin receptor substrate-1-dependent phosphatidylinositol 3-kinase, atypical protein kinase C and protein kinase B/Akt in human diabetic muscle. |
| 9260 | 19001411 | The phosphotyrosine interactome of the insulin receptor family and its substrates IRS-1 and IRS-2. |
| 9261 | 19001411 | We targeted and compared insulin receptor substrates 1 and 2 (IRS-1 and IRS-2) as central distributors of the insulin signal, the insulin receptor, the insulin-like growth factor 1 receptor, and the insulin receptor-related receptor. |
| 9262 | 19001411 | Our results retrieve known interactions and substantially broaden the spectrum of potential interaction partners of IRS-1 and IRS-2. |
| 9263 | 19001411 | However, several proteins involved in signaling and metabolism interact differentially with IRS-1 and IRS-2 and thus provide leads into their different physiological roles. |
| 9264 | 19001411 | Differences in interactions at the receptor level are reflected in multisite recruitment of SHP2 by the insulin-like growth factor 1 receptor and limited but exclusive interactions with the IRR. |
| 9265 | 19001411 | The phosphotyrosine interactome of the insulin receptor family and its substrates IRS-1 and IRS-2. |
| 9266 | 19001411 | We targeted and compared insulin receptor substrates 1 and 2 (IRS-1 and IRS-2) as central distributors of the insulin signal, the insulin receptor, the insulin-like growth factor 1 receptor, and the insulin receptor-related receptor. |
| 9267 | 19001411 | Our results retrieve known interactions and substantially broaden the spectrum of potential interaction partners of IRS-1 and IRS-2. |
| 9268 | 19001411 | However, several proteins involved in signaling and metabolism interact differentially with IRS-1 and IRS-2 and thus provide leads into their different physiological roles. |
| 9269 | 19001411 | Differences in interactions at the receptor level are reflected in multisite recruitment of SHP2 by the insulin-like growth factor 1 receptor and limited but exclusive interactions with the IRR. |
| 9270 | 19001411 | The phosphotyrosine interactome of the insulin receptor family and its substrates IRS-1 and IRS-2. |
| 9271 | 19001411 | We targeted and compared insulin receptor substrates 1 and 2 (IRS-1 and IRS-2) as central distributors of the insulin signal, the insulin receptor, the insulin-like growth factor 1 receptor, and the insulin receptor-related receptor. |
| 9272 | 19001411 | Our results retrieve known interactions and substantially broaden the spectrum of potential interaction partners of IRS-1 and IRS-2. |
| 9273 | 19001411 | However, several proteins involved in signaling and metabolism interact differentially with IRS-1 and IRS-2 and thus provide leads into their different physiological roles. |
| 9274 | 19001411 | Differences in interactions at the receptor level are reflected in multisite recruitment of SHP2 by the insulin-like growth factor 1 receptor and limited but exclusive interactions with the IRR. |
| 9275 | 19001411 | The phosphotyrosine interactome of the insulin receptor family and its substrates IRS-1 and IRS-2. |
| 9276 | 19001411 | We targeted and compared insulin receptor substrates 1 and 2 (IRS-1 and IRS-2) as central distributors of the insulin signal, the insulin receptor, the insulin-like growth factor 1 receptor, and the insulin receptor-related receptor. |
| 9277 | 19001411 | Our results retrieve known interactions and substantially broaden the spectrum of potential interaction partners of IRS-1 and IRS-2. |
| 9278 | 19001411 | However, several proteins involved in signaling and metabolism interact differentially with IRS-1 and IRS-2 and thus provide leads into their different physiological roles. |
| 9279 | 19001411 | Differences in interactions at the receptor level are reflected in multisite recruitment of SHP2 by the insulin-like growth factor 1 receptor and limited but exclusive interactions with the IRR. |
| 9280 | 19007436 | Studies indicate that insulin resistance can be induced by stimulating the degradation of important molecules in the insulin signaling pathway, in particular the insulin receptor substrate proteins IRS1, IRS2 and the kinase AKT1 (Akt). |
| 9281 | 19007436 | In addition, a defect in insulin secretion could occur due to UPS-mediated degradation of IRS2 in the beta-cells of the pancreas. |
| 9282 | 19011670 | Beneficial effects of an antioxidant (N-acetyl-L-cysteine, NAC) and an angiotensin I-converting enzyme (ACE) inhibitor (ramipril) were assessed in a rat model of insulin resistance induced by 10% glucose feeding for 20 weeks. |
| 9283 | 19011670 | This was associated with a higher production of superoxide anion and NADPH oxidase activity in aorta and liver and with a marked reduction in protein expression of skeletal muscle insulin receptor substrate-1 (IRS-1) in the gastrocnemius muscle. |
| 9284 | 19011670 | Although ramipril also reversed high blood pressure, it had a lesser effect on insulin resistance (including IRS-1) and blocked superoxide anion production only in aorta. |
| 9285 | 19011670 | Beneficial effects of an antioxidant (N-acetyl-L-cysteine, NAC) and an angiotensin I-converting enzyme (ACE) inhibitor (ramipril) were assessed in a rat model of insulin resistance induced by 10% glucose feeding for 20 weeks. |
| 9286 | 19011670 | This was associated with a higher production of superoxide anion and NADPH oxidase activity in aorta and liver and with a marked reduction in protein expression of skeletal muscle insulin receptor substrate-1 (IRS-1) in the gastrocnemius muscle. |
| 9287 | 19011670 | Although ramipril also reversed high blood pressure, it had a lesser effect on insulin resistance (including IRS-1) and blocked superoxide anion production only in aorta. |
| 9288 | 19013138 | Coexistences of insulin signaling-related proteins and choline acetyltransferase in neurons. |
| 9289 | 19013138 | Using immunohistochemistry, the insulin signaling-related proteins, such as insulin receptor (InsR), insulin receptor substrate-1 (IRS-1), protein kinase B (PKB, also named Akt), glycogen synthase kinase-3beta (GSK-3beta) and insulin-degrading enzyme (IDE) were analysed. |
| 9290 | 19035854 | In the present study, we stably co-expressed c-Myc and eGFP [enhanced GFP (green fluorescent protein)] dual-tagged recombinant GLUT4 with recombinant IRS1 (insulin receptor substrate 1) in HEK-293 cells (human embryonic kidney cells) (HEK-293.IRS1.GLUT4 cells). |
| 9291 | 19035854 | TRF assays confirmed insulin-stimulated GLUT4 translocation, which can be inhibited by PI3K (phosphoinositide 3-kinase) or Akt [also called PKB (protein kinase B)] inhibitors. |
| 9292 | 19035854 | Treatment with palmitate increased IRS1 serine phosphorylation and reduced insulin-stimulated Akt phosphorylation and GLUT4 translocation, indicating insulin resistance. |
| 9293 | 19035854 | Knockdown of PTEN (phosphatase and tensin homologue deleted on chromosome 10) and PTP1B (protein tyrosine phosphatase 1B) gene expression by siRNA (small interfering RNA) treatment significantly increased GLUT4 translocation only in cells treated with palmitate but not in untreated cells. |
| 9294 | 19035854 | Similar results were obtained on treatment with siRNA of JNK1 (c-Jun N-terminal kinase 1), S6K1 (ribosomal protein S6 kinase, 70 kDa, polypeptide 1) and PKC(theta) (protein kinase C theta). |
| 9295 | 19035854 | In the present study, we stably co-expressed c-Myc and eGFP [enhanced GFP (green fluorescent protein)] dual-tagged recombinant GLUT4 with recombinant IRS1 (insulin receptor substrate 1) in HEK-293 cells (human embryonic kidney cells) (HEK-293.IRS1.GLUT4 cells). |
| 9296 | 19035854 | TRF assays confirmed insulin-stimulated GLUT4 translocation, which can be inhibited by PI3K (phosphoinositide 3-kinase) or Akt [also called PKB (protein kinase B)] inhibitors. |
| 9297 | 19035854 | Treatment with palmitate increased IRS1 serine phosphorylation and reduced insulin-stimulated Akt phosphorylation and GLUT4 translocation, indicating insulin resistance. |
| 9298 | 19035854 | Knockdown of PTEN (phosphatase and tensin homologue deleted on chromosome 10) and PTP1B (protein tyrosine phosphatase 1B) gene expression by siRNA (small interfering RNA) treatment significantly increased GLUT4 translocation only in cells treated with palmitate but not in untreated cells. |
| 9299 | 19035854 | Similar results were obtained on treatment with siRNA of JNK1 (c-Jun N-terminal kinase 1), S6K1 (ribosomal protein S6 kinase, 70 kDa, polypeptide 1) and PKC(theta) (protein kinase C theta). |
| 9300 | 19043794 | As such, this study measured insulin receptor substrate-1 (IRS-1), insulin receptor substrate-2 (IRS-2), and phosphatidylinositol 3-kinase (PI3-K) P-85alpha mRNA expression levels in classical insulin-responsive sensitive tissues (liver, skeletal muscle, and abdominal fat) and peripheral leukocytes between cats and dogs by qRT-PCR. |
| 9301 | 19043794 | In addition, enzymes involved in glucose and lipid metabolism, malate dehydrogenase (MDH), glucose-6-phosphate dehydrogenase (G6PDH) and fatty acid synthase (FAS) were also assessed since glucose and lipid metabolism differs between cats and dogs. |
| 9302 | 19043794 | Overall, IRS-1, IRS-2, PI3-K, MDH, G6DPH, and FAS mRNA tissue expression profiles demonstrated different levels of expression, in various tissues for both canines and felines, which was expected. |
| 9303 | 19043794 | In addition, IRS-1, IRS-2, PI3-K, MDH, G6DPH, and FAS mRNA expression was significantly higher in canine versus feline tissues, including peripheral leukocytes. |
| 9304 | 19043794 | Remarkable differences in insulin signaling gene expression between felines and canines indicate that cats may have an underlying low insulin sensitivity level due to low IRS-1, IRS-2, and PI3-K P-85alpha mRNA expression levels which would predispose cats to develop insulin resistance. |
| 9305 | 19043794 | Moreover, differences in glucose and lipid metabolism related gene expression (MDH, G6DPH, and FAS) demonstrate that felines have an overall lower metabolic rate in various tissues which may be attributed to overall lower insulin signaling gene expression and a lack of physical activity as compared to canines. |
| 9306 | 19043794 | As such, this study measured insulin receptor substrate-1 (IRS-1), insulin receptor substrate-2 (IRS-2), and phosphatidylinositol 3-kinase (PI3-K) P-85alpha mRNA expression levels in classical insulin-responsive sensitive tissues (liver, skeletal muscle, and abdominal fat) and peripheral leukocytes between cats and dogs by qRT-PCR. |
| 9307 | 19043794 | In addition, enzymes involved in glucose and lipid metabolism, malate dehydrogenase (MDH), glucose-6-phosphate dehydrogenase (G6PDH) and fatty acid synthase (FAS) were also assessed since glucose and lipid metabolism differs between cats and dogs. |
| 9308 | 19043794 | Overall, IRS-1, IRS-2, PI3-K, MDH, G6DPH, and FAS mRNA tissue expression profiles demonstrated different levels of expression, in various tissues for both canines and felines, which was expected. |
| 9309 | 19043794 | In addition, IRS-1, IRS-2, PI3-K, MDH, G6DPH, and FAS mRNA expression was significantly higher in canine versus feline tissues, including peripheral leukocytes. |
| 9310 | 19043794 | Remarkable differences in insulin signaling gene expression between felines and canines indicate that cats may have an underlying low insulin sensitivity level due to low IRS-1, IRS-2, and PI3-K P-85alpha mRNA expression levels which would predispose cats to develop insulin resistance. |
| 9311 | 19043794 | Moreover, differences in glucose and lipid metabolism related gene expression (MDH, G6DPH, and FAS) demonstrate that felines have an overall lower metabolic rate in various tissues which may be attributed to overall lower insulin signaling gene expression and a lack of physical activity as compared to canines. |
| 9312 | 19043794 | As such, this study measured insulin receptor substrate-1 (IRS-1), insulin receptor substrate-2 (IRS-2), and phosphatidylinositol 3-kinase (PI3-K) P-85alpha mRNA expression levels in classical insulin-responsive sensitive tissues (liver, skeletal muscle, and abdominal fat) and peripheral leukocytes between cats and dogs by qRT-PCR. |
| 9313 | 19043794 | In addition, enzymes involved in glucose and lipid metabolism, malate dehydrogenase (MDH), glucose-6-phosphate dehydrogenase (G6PDH) and fatty acid synthase (FAS) were also assessed since glucose and lipid metabolism differs between cats and dogs. |
| 9314 | 19043794 | Overall, IRS-1, IRS-2, PI3-K, MDH, G6DPH, and FAS mRNA tissue expression profiles demonstrated different levels of expression, in various tissues for both canines and felines, which was expected. |
| 9315 | 19043794 | In addition, IRS-1, IRS-2, PI3-K, MDH, G6DPH, and FAS mRNA expression was significantly higher in canine versus feline tissues, including peripheral leukocytes. |
| 9316 | 19043794 | Remarkable differences in insulin signaling gene expression between felines and canines indicate that cats may have an underlying low insulin sensitivity level due to low IRS-1, IRS-2, and PI3-K P-85alpha mRNA expression levels which would predispose cats to develop insulin resistance. |
| 9317 | 19043794 | Moreover, differences in glucose and lipid metabolism related gene expression (MDH, G6DPH, and FAS) demonstrate that felines have an overall lower metabolic rate in various tissues which may be attributed to overall lower insulin signaling gene expression and a lack of physical activity as compared to canines. |
| 9318 | 19043794 | As such, this study measured insulin receptor substrate-1 (IRS-1), insulin receptor substrate-2 (IRS-2), and phosphatidylinositol 3-kinase (PI3-K) P-85alpha mRNA expression levels in classical insulin-responsive sensitive tissues (liver, skeletal muscle, and abdominal fat) and peripheral leukocytes between cats and dogs by qRT-PCR. |
| 9319 | 19043794 | In addition, enzymes involved in glucose and lipid metabolism, malate dehydrogenase (MDH), glucose-6-phosphate dehydrogenase (G6PDH) and fatty acid synthase (FAS) were also assessed since glucose and lipid metabolism differs between cats and dogs. |
| 9320 | 19043794 | Overall, IRS-1, IRS-2, PI3-K, MDH, G6DPH, and FAS mRNA tissue expression profiles demonstrated different levels of expression, in various tissues for both canines and felines, which was expected. |
| 9321 | 19043794 | In addition, IRS-1, IRS-2, PI3-K, MDH, G6DPH, and FAS mRNA expression was significantly higher in canine versus feline tissues, including peripheral leukocytes. |
| 9322 | 19043794 | Remarkable differences in insulin signaling gene expression between felines and canines indicate that cats may have an underlying low insulin sensitivity level due to low IRS-1, IRS-2, and PI3-K P-85alpha mRNA expression levels which would predispose cats to develop insulin resistance. |
| 9323 | 19043794 | Moreover, differences in glucose and lipid metabolism related gene expression (MDH, G6DPH, and FAS) demonstrate that felines have an overall lower metabolic rate in various tissues which may be attributed to overall lower insulin signaling gene expression and a lack of physical activity as compared to canines. |
| 9324 | 19057532 | Low levels of adiponectin, a fat-derived hormone, are found to be correlated with coronary heart disease, type 2 diabetes, obesity, and insulin resistance. |
| 9325 | 19057532 | Expression and phosphorylation of IRS-1, Akt, c-Jun, and c-Jun N terminal kinase (JNK) as well as markers of endoplasmic reticulum (ER) stress were evaluated using western blotting. |
| 9326 | 19057532 | Ratios between phosphorylated c-Jun and c-Jun as well as phosphorylated IRS-1 and IRS-1 were increased in db/db mice, the effect of which was attenuated by adiponectin. |
| 9327 | 19057532 | Levels of the phosphorylated ER stress makers PERK (Thr980), IRE-1, and eIF2alpha were significantly elevated in db/db mice compared with lean controls, although the effect was unaffected by adiponectin. |
| 9328 | 19057532 | Collectively, our data suggest that adiponectin improves cardiomyocyte dysfunction in db/db diabetic obese mice through a mechanism possibly related to c-Jun and IRS-1. |
| 9329 | 19057532 | Low levels of adiponectin, a fat-derived hormone, are found to be correlated with coronary heart disease, type 2 diabetes, obesity, and insulin resistance. |
| 9330 | 19057532 | Expression and phosphorylation of IRS-1, Akt, c-Jun, and c-Jun N terminal kinase (JNK) as well as markers of endoplasmic reticulum (ER) stress were evaluated using western blotting. |
| 9331 | 19057532 | Ratios between phosphorylated c-Jun and c-Jun as well as phosphorylated IRS-1 and IRS-1 were increased in db/db mice, the effect of which was attenuated by adiponectin. |
| 9332 | 19057532 | Levels of the phosphorylated ER stress makers PERK (Thr980), IRE-1, and eIF2alpha were significantly elevated in db/db mice compared with lean controls, although the effect was unaffected by adiponectin. |
| 9333 | 19057532 | Collectively, our data suggest that adiponectin improves cardiomyocyte dysfunction in db/db diabetic obese mice through a mechanism possibly related to c-Jun and IRS-1. |
| 9334 | 19057532 | Low levels of adiponectin, a fat-derived hormone, are found to be correlated with coronary heart disease, type 2 diabetes, obesity, and insulin resistance. |
| 9335 | 19057532 | Expression and phosphorylation of IRS-1, Akt, c-Jun, and c-Jun N terminal kinase (JNK) as well as markers of endoplasmic reticulum (ER) stress were evaluated using western blotting. |
| 9336 | 19057532 | Ratios between phosphorylated c-Jun and c-Jun as well as phosphorylated IRS-1 and IRS-1 were increased in db/db mice, the effect of which was attenuated by adiponectin. |
| 9337 | 19057532 | Levels of the phosphorylated ER stress makers PERK (Thr980), IRE-1, and eIF2alpha were significantly elevated in db/db mice compared with lean controls, although the effect was unaffected by adiponectin. |
| 9338 | 19057532 | Collectively, our data suggest that adiponectin improves cardiomyocyte dysfunction in db/db diabetic obese mice through a mechanism possibly related to c-Jun and IRS-1. |
| 9339 | 19083193 | The role of HSP70 on ENPP1 expression and insulin-receptor activation. |
| 9340 | 19083193 | Ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1) inhibits insulin-receptor (IR) signaling and, when over-expressed, induces insulin resistance in vitro and in vivo. |
| 9341 | 19083193 | Understanding the regulation of ENPP1 expression may, thus, unravel new molecular mechanisms of insulin resistance. |
| 9342 | 19083193 | Through this binding, HSP70 stabilizes ENPP1 mRNA and increases ENPP1 transcript and protein levels. |
| 9343 | 19083193 | This positive modulation of ENPP1 expression is paralleled by a reduced insulin-induced IR and IRS-1 phosphorylation. |
| 9344 | 19083193 | Taken together these data suggest that HSP70, by affecting ENPP1 expression, may be a novel mediator of altered insulin signaling. |
| 9345 | 19136667 | Oxidized LDL impair adipocyte response to insulin by activating serine/threonine kinases. |
| 9346 | 19136667 | Specifically, in oxLDL-treated cells insulin receptor (IR) substrate-1 (IRS-1) was highly degraded likely because of the enhanced Ser(307)phosphorylation. |
| 9347 | 19136667 | This process was largely mediated by the activation of the inhibitor of kappaB-kinase beta (IKKbeta) and the c-Jun NH(2)-terminal kinase (JNK). |
| 9348 | 19136667 | Moreover, the activation of IKKbeta positively regulated the nuclear content of nuclear factor kappaB (NF-kappaB), by inactivating the inhibitor of NF-kappaB (IkappaBalpha). |
| 9349 | 19136667 | The activated NF-kappaB further impaired per se GLUT4 functionality. |
| 9350 | 19136667 | Specific inhibitors of IKKbeta, JNK, and NF-kappaB restored insulin sensitivity in adipocytes treated with oxLDL. |
| 9351 | 19136667 | These data provide the first evidence that oxLDL, by activating serine/threonine kinases, impaired adipocyte response to insulin affecting pathways involved in the recruitment of GLUT4 to plasma membranes (PM). |
| 9352 | 19140314 | In this study, which included 105 healthy postmenopausal women and 301 female cancer patients (110 BC and 191 EC) without overt diabetes mellitus, we compared the frequency of the following genetic polymorphisms: insulin receptor substrate-1, IRS Gly972Arg; leptin receptor, LEPR Lys109Arg and Gln223Arg; mitochondrial uncoupling protein-2, UCP2_866G/A; and gene ND3 of mitochondrial DNA, mtDNA 10398A/G. |
| 9353 | 19140314 | According to data received, certain genetic markers associated with impaired glucose tolerance and/or insulin resistance (namely, leptin receptor genotypes 223 Gln/Arg and Gln/Gln) are revealed in oncological patients more often than in females without cancer. |
| 9354 | 19140314 | Other markers (like genotype UCP2 866AA and polymorphism mtDNA 10398A) appeared to be relatively more frequent in EC than in BC providing one of the interpretations for the lower insulin sensitivity and higher incidence of carbohydrate metabolism disturbances in the first of these two diseases. |
| 9355 | 19188682 | Macrophage-derived human resistin exacerbates adipose tissue inflammation and insulin resistance in mice. |
| 9356 | 19188682 | Resistin is an adipokine that contributes to insulin resistance in mice. |
| 9357 | 19188682 | We found that this resulted in increased Pkcq pathway activity, leading to increased serine phosphorylation of Irs-1 and insulin resistance. |
| 9358 | 19188682 | Thus, although the site of resistin production differs between species, human resistin exacerbates WAT inflammation and contributes to insulin resistance. |
| 9359 | 19233137 | The effects of E23K polymorphism in Kir6.2 subunit on insulin sensitivity in skeletal muscle cells by long-chain fatty acyl CoA. |
| 9360 | 19233137 | LC-CoA also reduced IRS-1 and Akt phosphorylation and glucose transport. |
| 9361 | 19237535 | This improved islet function was at least partially attributed to significant upregulation of the islet genes Irs1, SERCA, Ins1/2, and Glut2 in treated animals. |
| 9362 | 19237535 | The restoration of the Ins1/2 and Glut2 genes corresponded to a two- to threefold increase in the euchromatin marker histone H3 dimethyl-Lys4 at their respective promoters and was coincident with increased nuclear occupancy of the islet methyltransferase Set7/9. |
| 9363 | 19237535 | Consistent with this possibility, incubation of thapsigargin-treated INS-1 beta cells with the PPAR-gamma agonist resulted in the reduction of endoplasmic reticulum stress and restoration of Pdx1 protein levels and Set7/9 nuclear occupancy. |
| 9364 | 19237535 | We conclude that PPAR-gamma agonists exert a direct effect in diabetic islets to reduce endoplasmic reticulum stress and enhance Pdx1 levels, leading to favorable alterations of the islet gene chromatin architecture. |
| 9365 | 19273146 | In adrenal chromaffin cells, GSK-3 inhibition caused up-regulation of voltage-dependent Nav1.7 sodium channel, enhancing voltage-dependent calcium channel gating and catecholamine exocytosis; conversely, chronic treatment with GSK-3 inhibitors caused down-regulation of insulin receptor, IRS-1, IRS-2, and Akt1 levels. |
| 9366 | 19273146 | Comprehensive review articles about lithium (1), GSK-3 and GSK-3 inhibitors (2-4), and the inhibition of Wnt/GSK-3beta>/beta-catenin signaling pathway by therapeutic drugs (5) are useful. |
| 9367 | 19276091 | Targeted disruption of ROCK1 causes insulin resistance in vivo. |
| 9368 | 19276091 | Rho-kinase (ROCK) isoforms have been shown to participate in insulin signaling and glucose metabolism in cultured cell lines. |
| 9369 | 19276091 | To investigate the physiological role of ROCK1 in the regulation of whole body glucose homeostasis and insulin sensitivity in vivo, we studied mice with global disruption of ROCK1. |
| 9370 | 19276091 | Interestingly, ROCK1 gene ablation caused a significant increase in glucose-induced insulin secretion, leading to hyperinsulinemia. |
| 9371 | 19276091 | To determine the mechanism(s) by which deletion of ROCK1 causes insulin resistance, we measured the ability of insulin to activate phosphatidylinositol 3-kinase and multiple distal pathways in skeletal muscle. |
| 9372 | 19276091 | Insulin-stimulated phosphatidylinositol 3-kinase activity associated with IRS-1 or phospho-tyrosine was also reduced approximately 40% without any alteration in tyrosine phosphorylation of insulin receptor in skeletal muscle. |
| 9373 | 19276091 | Insulin-induced phosphorylation of Akt, AS160, S6K, and S6 was also decreased in skeletal muscle. |
| 9374 | 19276091 | These data suggest that ROCK1 deficiency causes systemic insulin resistance by impairing insulin signaling in skeletal muscle. |
| 9375 | 19276091 | Thus, our results identify ROCK1 as a novel regulator of glucose homeostasis and insulin sensitivity in vivo, which could lead to new treatment approaches for obesity and type 2 diabetes. |
| 9376 | 19283661 | EGFR kinase activity triggers numerous signaling pathways, such as the Ras/Raf/MAPK cascade, leading to the activation of various mitogen activated protein kinases, which are implicated in cell proliferation through induction of several genes, including c-fos. |
| 9377 | 19283661 | In conclusion, it seems that diabetes reduces the expression of EGFR and initiates the Ras/Raf/MAPK signal transduction pathway by enhancing activation of other signalling molecules, such as the diabetes-associated Insulin Receptor Substrate-1, leading to increased cell proliferation without c-fos involvement. |
| 9378 | 19363130 | Feed-forward signaling of TNF-alpha and NF-kappaB via IKK-beta pathway contributes to insulin resistance and coronary arteriolar dysfunction in type 2 diabetic mice. |
| 9379 | 19363130 | We hypothesized that the interaction between tumor necrosis factor-alpha (TNF-alpha)/nuclear factor-kappaB (NF-kappaB) via the activation of IKK-beta may amplify one another, resulting in the evolution of vascular disease and insulin resistance associated with diabetes. |
| 9380 | 19363130 | The NF-kappaB antagonist MG-132 or the IKK-beta inhibitor sodium salicylate (NaSal) partially restored nitric oxide-mediated endothelium-dependent coronary arteriolar dilation in Lepr(db) mice, but the responses in mLepr(db) mice were unaffected. |
| 9381 | 19363130 | The protein expression of IKK-alpha and IKK-beta were higher in Lepr(db) than in mLepr(db) mice; the expression of IKK-beta, but not the expression of IKK-alpha, was attenuated by MG-132, the antioxidant apocynin, or the genetic deletion of TNF-alpha in diabetic mice. |
| 9382 | 19363130 | The protein expression of TNF-alpha and NF-kappaB and the protein modification of phosphorylated (p)-IKK-beta and p-JNK were greater in Lepr(db) mice, but NaSal attenuated TNF-alpha, NF-kappaB, p-IKK-beta, and p-JNK in Lepr(db) mice. |
| 9383 | 19363130 | The ratio of p-insulin receptor substrate (IRS)-1 at Ser307 to IRS-1 was elevated in Lepr(db) compared with mLepr(db) mice; both NaSal and the JNK inhibitor SP-600125 reduced the p-IRS-1-to-IRS-1 ratio in Lepr(db) mice. |
| 9384 | 19363130 | In conclusion, our results indicate that the interaction between NF-kappaB and TNF-alpha signaling induces the activation of IKK-beta and amplifies oxidative stress, leading to endothelial dysfunction in type 2 diabetes. |
| 9385 | 19381127 | HCV infection promotes IR mainly through increased TNF-a and cytokine suppressor (SOCS-3) production. |
| 9386 | 19381127 | Both events inhibit insulin receptor and IRS-1 (insulin receptor substrate) tyrosine phosphorylation. |
| 9387 | 19418728 | [Effect of the Gly972Arg, SNP43 and Prol2Ala polymorphisms of the genes IRS1, CAPN10 and PPARG2 on secondary failure to sulphonylurea and metformin in patients with type 2 diabetes in Yucatán, México]. |
| 9388 | 19418728 | A possible explanation may be due to polymorphisms in the genes IRS1, CAPN10, PPARG2, which are involved in pancreatic beta cell dysfunction and a poor response to the action of insulin. |
| 9389 | 19418728 | The association of the polymorphisms Gly972Arg, SNP43, and Pro12Ala, of the genes IRS1, CAPN10, PPARG2, with the risk of failure to sulphonylurea and metformin therapies was determinated in patients with DT2 in Yucatán, México. |
| 9390 | 19418728 | [Effect of the Gly972Arg, SNP43 and Prol2Ala polymorphisms of the genes IRS1, CAPN10 and PPARG2 on secondary failure to sulphonylurea and metformin in patients with type 2 diabetes in Yucatán, México]. |
| 9391 | 19418728 | A possible explanation may be due to polymorphisms in the genes IRS1, CAPN10, PPARG2, which are involved in pancreatic beta cell dysfunction and a poor response to the action of insulin. |
| 9392 | 19418728 | The association of the polymorphisms Gly972Arg, SNP43, and Pro12Ala, of the genes IRS1, CAPN10, PPARG2, with the risk of failure to sulphonylurea and metformin therapies was determinated in patients with DT2 in Yucatán, México. |
| 9393 | 19418728 | [Effect of the Gly972Arg, SNP43 and Prol2Ala polymorphisms of the genes IRS1, CAPN10 and PPARG2 on secondary failure to sulphonylurea and metformin in patients with type 2 diabetes in Yucatán, México]. |
| 9394 | 19418728 | A possible explanation may be due to polymorphisms in the genes IRS1, CAPN10, PPARG2, which are involved in pancreatic beta cell dysfunction and a poor response to the action of insulin. |
| 9395 | 19418728 | The association of the polymorphisms Gly972Arg, SNP43, and Pro12Ala, of the genes IRS1, CAPN10, PPARG2, with the risk of failure to sulphonylurea and metformin therapies was determinated in patients with DT2 in Yucatán, México. |
| 9396 | 19509184 | Hepatic insulin resistance was evident based on reduced tyrosine phosphorylation of the insulin receptor-beta, IRS-1, and IRS-2 as well as increased protein mass of protein tyrosine phosphatase 1B. |
| 9397 | 19509184 | Interestingly, nuclear liver X receptor (LXR) target genes such as ABCA1 were upregulated on the FFC diet, and dietary supplementation with an LXR agonist (instead of dietary cholesterol) worsened dyslipidemia, glucose intolerance, and upregulation of target mRNA and proteins similar to that of dietary cholesterol. |
| 9398 | 19521344 | When 3T3-L1 adipocytes were treated with the 12/15-LO products, 12-hydroxyeicosatetranoic acid (12(S)-HETE) and 12-hydroperoxyeicosatetraenoic acid (12(S)-HPETE), expression of proinflammatory cytokine genes, including tumor necrosis factor-alpha (TNF-alpha), monocyte chemoattractant protein 1 (MCP-1), interleukin 6 (IL-6), and IL-12p40, was upregulated whereas anti-inflammatory adiponectin gene expression was downregulated. 12/15-LO products also augmented c-Jun N-terminal kinase 1 (JNK-1) phosphorylation, a known negative regulator of insulin signaling. |
| 9399 | 19521344 | Consistent with impaired insulin signaling, we found that insulin-stimulated 3T3-L1 adipocytes exhibited decreased IRS-1(Tyr) phosphorylation, increased IRS-1(Ser) phosphorylation, and impaired Akt phosphorylation when treated with 12/15-LO product. |
| 9400 | 19541746 | Dual ablation of Grb10 and Grb14 in mice reveals their combined role in regulation of insulin signaling and glucose homeostasis. |
| 9401 | 19541746 | Growth factor receptor bound (Grb)10 and Grb14 are closely related adaptor proteins that bind directly to the insulin receptor (IR) and regulate insulin-induced IR tyrosine phosphorylation and signaling to IRS-1 and Akt. |
| 9402 | 19541746 | Grb10- and Grb14-deficient mice both exhibit improved whole-body glucose homeostasis as a consequence of enhanced insulin signaling and, in the case of the former, altered body composition. |
| 9403 | 19541746 | In this study we utilize compound gene knockout mice to demonstrate that although deficiency in one adaptor can enhance insulin-induced IRS-1 phosphorylation and Akt activation, insulin signaling is not increased further upon dual ablation of Grb10 and Grb14. |
| 9404 | 19541746 | These results indicate that, in addition to their described effects on IRS-1/Akt, Grb10 and Grb14 may regulate whole-body glucose homeostasis by additional mechanisms and highlight these adaptors as potential therapeutic targets for amelioration of the insulin resistance associated with type 2 diabetes. |
| 9405 | 19541746 | Dual ablation of Grb10 and Grb14 in mice reveals their combined role in regulation of insulin signaling and glucose homeostasis. |
| 9406 | 19541746 | Growth factor receptor bound (Grb)10 and Grb14 are closely related adaptor proteins that bind directly to the insulin receptor (IR) and regulate insulin-induced IR tyrosine phosphorylation and signaling to IRS-1 and Akt. |
| 9407 | 19541746 | Grb10- and Grb14-deficient mice both exhibit improved whole-body glucose homeostasis as a consequence of enhanced insulin signaling and, in the case of the former, altered body composition. |
| 9408 | 19541746 | In this study we utilize compound gene knockout mice to demonstrate that although deficiency in one adaptor can enhance insulin-induced IRS-1 phosphorylation and Akt activation, insulin signaling is not increased further upon dual ablation of Grb10 and Grb14. |
| 9409 | 19541746 | These results indicate that, in addition to their described effects on IRS-1/Akt, Grb10 and Grb14 may regulate whole-body glucose homeostasis by additional mechanisms and highlight these adaptors as potential therapeutic targets for amelioration of the insulin resistance associated with type 2 diabetes. |
| 9410 | 19541746 | Dual ablation of Grb10 and Grb14 in mice reveals their combined role in regulation of insulin signaling and glucose homeostasis. |
| 9411 | 19541746 | Growth factor receptor bound (Grb)10 and Grb14 are closely related adaptor proteins that bind directly to the insulin receptor (IR) and regulate insulin-induced IR tyrosine phosphorylation and signaling to IRS-1 and Akt. |
| 9412 | 19541746 | Grb10- and Grb14-deficient mice both exhibit improved whole-body glucose homeostasis as a consequence of enhanced insulin signaling and, in the case of the former, altered body composition. |
| 9413 | 19541746 | In this study we utilize compound gene knockout mice to demonstrate that although deficiency in one adaptor can enhance insulin-induced IRS-1 phosphorylation and Akt activation, insulin signaling is not increased further upon dual ablation of Grb10 and Grb14. |
| 9414 | 19541746 | These results indicate that, in addition to their described effects on IRS-1/Akt, Grb10 and Grb14 may regulate whole-body glucose homeostasis by additional mechanisms and highlight these adaptors as potential therapeutic targets for amelioration of the insulin resistance associated with type 2 diabetes. |
| 9415 | 19560437 | Moreover, SIN-1 administration decreased blood glucose levels in normal mice via upregulation of IR/IRS-1 tyrosine phosphorylation. |
| 9416 | 19560437 | In contrast, SIN-1 markedly increased blood glucose levels in diabetic mice concomitant with downregulation of IR/IRS-1 tyrosine phosphorylation. |
| 9417 | 19560437 | Moreover, SIN-1 administration decreased blood glucose levels in normal mice via upregulation of IR/IRS-1 tyrosine phosphorylation. |
| 9418 | 19560437 | In contrast, SIN-1 markedly increased blood glucose levels in diabetic mice concomitant with downregulation of IR/IRS-1 tyrosine phosphorylation. |
| 9419 | 19569009 | Recently, a link between obesity and insulin resistance has been established via IKKbeta action and IRS-1 Ser (312/307) phosphorylation. |
| 9420 | 19569009 | This study measured IkappaBalpha and IRS-1 pSer (307) in mixed gastrocnemius muscle in HCR and LCR rats challenged with a 12-wk HFD. |
| 9421 | 19569009 | IkappaBalpha levels, an inverse indicator of IKKbeta activity, were lower in LCR vs. |
| 9422 | 19569009 | Recently, a link between obesity and insulin resistance has been established via IKKbeta action and IRS-1 Ser (312/307) phosphorylation. |
| 9423 | 19569009 | This study measured IkappaBalpha and IRS-1 pSer (307) in mixed gastrocnemius muscle in HCR and LCR rats challenged with a 12-wk HFD. |
| 9424 | 19569009 | IkappaBalpha levels, an inverse indicator of IKKbeta activity, were lower in LCR vs. |
| 9425 | 19587264 | The translocation and localization of glucose transporter 4 (GLUT4) to the adipocyte plasma membrane were impaired in TH mice compared to control C57BL6/J (B6) mice. |
| 9426 | 19587264 | These defects were associated with decreased GLUT4 protein, reduced phosphatidylinositol 3-kinase activity, and alterations in the phosphorylation status of insulin receptor substrate 1 (IRS1). |
| 9427 | 19587264 | Activation of c-Jun N-terminal kinase 1/2, which can phosphorylate IRS1 on Ser307, was significantly higher in TH mice compared with B6 controls. |
| 9428 | 19587264 | Immunoprecipitation with anti-ubiquitin and western blot analysis of IRS1 protein revealed increased total IRS1 ubiquitination in adipose tissue of TH mice. |
| 9429 | 19587264 | Suppressor of cytokine signaling 1, known to promote IRS1 ubiquitination and subsequent degradation, was found at significantly higher levels in TH mice compared with B6. |
| 9430 | 19587264 | Our findings suggest that increased IRS1 degradation and subsequent impaired GLUT4 mobilization play a role in the reduced glucose uptake in insulin resistant TH mice. |
| 9431 | 19587264 | The translocation and localization of glucose transporter 4 (GLUT4) to the adipocyte plasma membrane were impaired in TH mice compared to control C57BL6/J (B6) mice. |
| 9432 | 19587264 | These defects were associated with decreased GLUT4 protein, reduced phosphatidylinositol 3-kinase activity, and alterations in the phosphorylation status of insulin receptor substrate 1 (IRS1). |
| 9433 | 19587264 | Activation of c-Jun N-terminal kinase 1/2, which can phosphorylate IRS1 on Ser307, was significantly higher in TH mice compared with B6 controls. |
| 9434 | 19587264 | Immunoprecipitation with anti-ubiquitin and western blot analysis of IRS1 protein revealed increased total IRS1 ubiquitination in adipose tissue of TH mice. |
| 9435 | 19587264 | Suppressor of cytokine signaling 1, known to promote IRS1 ubiquitination and subsequent degradation, was found at significantly higher levels in TH mice compared with B6. |
| 9436 | 19587264 | Our findings suggest that increased IRS1 degradation and subsequent impaired GLUT4 mobilization play a role in the reduced glucose uptake in insulin resistant TH mice. |
| 9437 | 19587264 | The translocation and localization of glucose transporter 4 (GLUT4) to the adipocyte plasma membrane were impaired in TH mice compared to control C57BL6/J (B6) mice. |
| 9438 | 19587264 | These defects were associated with decreased GLUT4 protein, reduced phosphatidylinositol 3-kinase activity, and alterations in the phosphorylation status of insulin receptor substrate 1 (IRS1). |
| 9439 | 19587264 | Activation of c-Jun N-terminal kinase 1/2, which can phosphorylate IRS1 on Ser307, was significantly higher in TH mice compared with B6 controls. |
| 9440 | 19587264 | Immunoprecipitation with anti-ubiquitin and western blot analysis of IRS1 protein revealed increased total IRS1 ubiquitination in adipose tissue of TH mice. |
| 9441 | 19587264 | Suppressor of cytokine signaling 1, known to promote IRS1 ubiquitination and subsequent degradation, was found at significantly higher levels in TH mice compared with B6. |
| 9442 | 19587264 | Our findings suggest that increased IRS1 degradation and subsequent impaired GLUT4 mobilization play a role in the reduced glucose uptake in insulin resistant TH mice. |
| 9443 | 19587264 | The translocation and localization of glucose transporter 4 (GLUT4) to the adipocyte plasma membrane were impaired in TH mice compared to control C57BL6/J (B6) mice. |
| 9444 | 19587264 | These defects were associated with decreased GLUT4 protein, reduced phosphatidylinositol 3-kinase activity, and alterations in the phosphorylation status of insulin receptor substrate 1 (IRS1). |
| 9445 | 19587264 | Activation of c-Jun N-terminal kinase 1/2, which can phosphorylate IRS1 on Ser307, was significantly higher in TH mice compared with B6 controls. |
| 9446 | 19587264 | Immunoprecipitation with anti-ubiquitin and western blot analysis of IRS1 protein revealed increased total IRS1 ubiquitination in adipose tissue of TH mice. |
| 9447 | 19587264 | Suppressor of cytokine signaling 1, known to promote IRS1 ubiquitination and subsequent degradation, was found at significantly higher levels in TH mice compared with B6. |
| 9448 | 19587264 | Our findings suggest that increased IRS1 degradation and subsequent impaired GLUT4 mobilization play a role in the reduced glucose uptake in insulin resistant TH mice. |
| 9449 | 19587264 | The translocation and localization of glucose transporter 4 (GLUT4) to the adipocyte plasma membrane were impaired in TH mice compared to control C57BL6/J (B6) mice. |
| 9450 | 19587264 | These defects were associated with decreased GLUT4 protein, reduced phosphatidylinositol 3-kinase activity, and alterations in the phosphorylation status of insulin receptor substrate 1 (IRS1). |
| 9451 | 19587264 | Activation of c-Jun N-terminal kinase 1/2, which can phosphorylate IRS1 on Ser307, was significantly higher in TH mice compared with B6 controls. |
| 9452 | 19587264 | Immunoprecipitation with anti-ubiquitin and western blot analysis of IRS1 protein revealed increased total IRS1 ubiquitination in adipose tissue of TH mice. |
| 9453 | 19587264 | Suppressor of cytokine signaling 1, known to promote IRS1 ubiquitination and subsequent degradation, was found at significantly higher levels in TH mice compared with B6. |
| 9454 | 19587264 | Our findings suggest that increased IRS1 degradation and subsequent impaired GLUT4 mobilization play a role in the reduced glucose uptake in insulin resistant TH mice. |
| 9455 | 19593406 | Similarly to the situation in T2D subjects, in subjects on the high-calorie diet, the amount of insulin receptors was reduced and phosphorylation of IRS1 at tyrosine and at serine-307 (human sequence, corresponding to murine serine-302) were impaired. |
| 9456 | 19593406 | The amount of insulin receptor substrate protein-1 (IRS1) and the phosphorylation of IRS1 at serine-312 (human sequence, corresponding to murine serine-307) were unaffected by the diet. |
| 9457 | 19593406 | Similarly to the situation in T2D subjects, in subjects on the high-calorie diet, the amount of insulin receptors was reduced and phosphorylation of IRS1 at tyrosine and at serine-307 (human sequence, corresponding to murine serine-302) were impaired. |
| 9458 | 19593406 | The amount of insulin receptor substrate protein-1 (IRS1) and the phosphorylation of IRS1 at serine-312 (human sequence, corresponding to murine serine-307) were unaffected by the diet. |
| 9459 | 19605645 | Beta-amyloid oligomers induce phosphorylation of tau and inactivation of insulin receptor substrate via c-Jun N-terminal kinase signaling: suppression by omega-3 fatty acids and curcumin. |
| 9460 | 19605645 | Both insulin resistance (type II diabetes) and beta-amyloid (Abeta) oligomers are implicated in Alzheimer's disease (AD). |
| 9461 | 19605645 | Here, we investigate the role of Abeta oligomer-induced c-Jun N-terminal kinase (JNK) activation leading to phosphorylation and degradation of the adaptor protein insulin receptor substrate-1 (IRS-1). |
| 9462 | 19605645 | IRS-1 couples insulin and other trophic factor receptors to downstream kinases and neuroprotective signaling. |
| 9463 | 19605645 | Here, we report Abeta oligomers significantly increased active JNK and phosphorylation of IRS-1 (Ser616) and tau (Ser422) in cultured hippocampal neurons, whereas JNK inhibition blocked these responses. |
| 9464 | 19605645 | The omega-3 fatty acid docosahexaenoic acid (DHA) similarly inhibited JNK and the phosphorylation of IRS-1 and tau in cultured hippocampal neurons. |
| 9465 | 19605645 | Feeding 3xTg-AD transgenic mice a diet high in saturated and omega-6 fat increased active JNK and phosphorylated IRS-1 and tau. |
| 9466 | 19605645 | Treatment of the 3xTg-AD mice on high-fat diet with fish oil or curcumin or a combination of both for 4 months reduced phosphorylated JNK, IRS-1, and tau and prevented the degradation of total IRS-1. |
| 9467 | 19605645 | Mice fed with fish oil and curcumin for 1 month had more significant effects on Y-maze, and the combination showed more significant inhibition of JNK, IRS-1, and tau phosphorylation. |
| 9468 | 19605645 | These data indicate JNK mediates Abeta oligomer inactivation of IRS-1 and phospho-tau pathology and that dietary treatment with fish oil/DHA, curcumin, or a combination of both has the potential to improve insulin/trophic signaling and cognitive deficits in AD. |
| 9469 | 19605645 | Beta-amyloid oligomers induce phosphorylation of tau and inactivation of insulin receptor substrate via c-Jun N-terminal kinase signaling: suppression by omega-3 fatty acids and curcumin. |
| 9470 | 19605645 | Both insulin resistance (type II diabetes) and beta-amyloid (Abeta) oligomers are implicated in Alzheimer's disease (AD). |
| 9471 | 19605645 | Here, we investigate the role of Abeta oligomer-induced c-Jun N-terminal kinase (JNK) activation leading to phosphorylation and degradation of the adaptor protein insulin receptor substrate-1 (IRS-1). |
| 9472 | 19605645 | IRS-1 couples insulin and other trophic factor receptors to downstream kinases and neuroprotective signaling. |
| 9473 | 19605645 | Here, we report Abeta oligomers significantly increased active JNK and phosphorylation of IRS-1 (Ser616) and tau (Ser422) in cultured hippocampal neurons, whereas JNK inhibition blocked these responses. |
| 9474 | 19605645 | The omega-3 fatty acid docosahexaenoic acid (DHA) similarly inhibited JNK and the phosphorylation of IRS-1 and tau in cultured hippocampal neurons. |
| 9475 | 19605645 | Feeding 3xTg-AD transgenic mice a diet high in saturated and omega-6 fat increased active JNK and phosphorylated IRS-1 and tau. |
| 9476 | 19605645 | Treatment of the 3xTg-AD mice on high-fat diet with fish oil or curcumin or a combination of both for 4 months reduced phosphorylated JNK, IRS-1, and tau and prevented the degradation of total IRS-1. |
| 9477 | 19605645 | Mice fed with fish oil and curcumin for 1 month had more significant effects on Y-maze, and the combination showed more significant inhibition of JNK, IRS-1, and tau phosphorylation. |
| 9478 | 19605645 | These data indicate JNK mediates Abeta oligomer inactivation of IRS-1 and phospho-tau pathology and that dietary treatment with fish oil/DHA, curcumin, or a combination of both has the potential to improve insulin/trophic signaling and cognitive deficits in AD. |
| 9479 | 19605645 | Beta-amyloid oligomers induce phosphorylation of tau and inactivation of insulin receptor substrate via c-Jun N-terminal kinase signaling: suppression by omega-3 fatty acids and curcumin. |
| 9480 | 19605645 | Both insulin resistance (type II diabetes) and beta-amyloid (Abeta) oligomers are implicated in Alzheimer's disease (AD). |
| 9481 | 19605645 | Here, we investigate the role of Abeta oligomer-induced c-Jun N-terminal kinase (JNK) activation leading to phosphorylation and degradation of the adaptor protein insulin receptor substrate-1 (IRS-1). |
| 9482 | 19605645 | IRS-1 couples insulin and other trophic factor receptors to downstream kinases and neuroprotective signaling. |
| 9483 | 19605645 | Here, we report Abeta oligomers significantly increased active JNK and phosphorylation of IRS-1 (Ser616) and tau (Ser422) in cultured hippocampal neurons, whereas JNK inhibition blocked these responses. |
| 9484 | 19605645 | The omega-3 fatty acid docosahexaenoic acid (DHA) similarly inhibited JNK and the phosphorylation of IRS-1 and tau in cultured hippocampal neurons. |
| 9485 | 19605645 | Feeding 3xTg-AD transgenic mice a diet high in saturated and omega-6 fat increased active JNK and phosphorylated IRS-1 and tau. |
| 9486 | 19605645 | Treatment of the 3xTg-AD mice on high-fat diet with fish oil or curcumin or a combination of both for 4 months reduced phosphorylated JNK, IRS-1, and tau and prevented the degradation of total IRS-1. |
| 9487 | 19605645 | Mice fed with fish oil and curcumin for 1 month had more significant effects on Y-maze, and the combination showed more significant inhibition of JNK, IRS-1, and tau phosphorylation. |
| 9488 | 19605645 | These data indicate JNK mediates Abeta oligomer inactivation of IRS-1 and phospho-tau pathology and that dietary treatment with fish oil/DHA, curcumin, or a combination of both has the potential to improve insulin/trophic signaling and cognitive deficits in AD. |
| 9489 | 19605645 | Beta-amyloid oligomers induce phosphorylation of tau and inactivation of insulin receptor substrate via c-Jun N-terminal kinase signaling: suppression by omega-3 fatty acids and curcumin. |
| 9490 | 19605645 | Both insulin resistance (type II diabetes) and beta-amyloid (Abeta) oligomers are implicated in Alzheimer's disease (AD). |
| 9491 | 19605645 | Here, we investigate the role of Abeta oligomer-induced c-Jun N-terminal kinase (JNK) activation leading to phosphorylation and degradation of the adaptor protein insulin receptor substrate-1 (IRS-1). |
| 9492 | 19605645 | IRS-1 couples insulin and other trophic factor receptors to downstream kinases and neuroprotective signaling. |
| 9493 | 19605645 | Here, we report Abeta oligomers significantly increased active JNK and phosphorylation of IRS-1 (Ser616) and tau (Ser422) in cultured hippocampal neurons, whereas JNK inhibition blocked these responses. |
| 9494 | 19605645 | The omega-3 fatty acid docosahexaenoic acid (DHA) similarly inhibited JNK and the phosphorylation of IRS-1 and tau in cultured hippocampal neurons. |
| 9495 | 19605645 | Feeding 3xTg-AD transgenic mice a diet high in saturated and omega-6 fat increased active JNK and phosphorylated IRS-1 and tau. |
| 9496 | 19605645 | Treatment of the 3xTg-AD mice on high-fat diet with fish oil or curcumin or a combination of both for 4 months reduced phosphorylated JNK, IRS-1, and tau and prevented the degradation of total IRS-1. |
| 9497 | 19605645 | Mice fed with fish oil and curcumin for 1 month had more significant effects on Y-maze, and the combination showed more significant inhibition of JNK, IRS-1, and tau phosphorylation. |
| 9498 | 19605645 | These data indicate JNK mediates Abeta oligomer inactivation of IRS-1 and phospho-tau pathology and that dietary treatment with fish oil/DHA, curcumin, or a combination of both has the potential to improve insulin/trophic signaling and cognitive deficits in AD. |
| 9499 | 19605645 | Beta-amyloid oligomers induce phosphorylation of tau and inactivation of insulin receptor substrate via c-Jun N-terminal kinase signaling: suppression by omega-3 fatty acids and curcumin. |
| 9500 | 19605645 | Both insulin resistance (type II diabetes) and beta-amyloid (Abeta) oligomers are implicated in Alzheimer's disease (AD). |
| 9501 | 19605645 | Here, we investigate the role of Abeta oligomer-induced c-Jun N-terminal kinase (JNK) activation leading to phosphorylation and degradation of the adaptor protein insulin receptor substrate-1 (IRS-1). |
| 9502 | 19605645 | IRS-1 couples insulin and other trophic factor receptors to downstream kinases and neuroprotective signaling. |
| 9503 | 19605645 | Here, we report Abeta oligomers significantly increased active JNK and phosphorylation of IRS-1 (Ser616) and tau (Ser422) in cultured hippocampal neurons, whereas JNK inhibition blocked these responses. |
| 9504 | 19605645 | The omega-3 fatty acid docosahexaenoic acid (DHA) similarly inhibited JNK and the phosphorylation of IRS-1 and tau in cultured hippocampal neurons. |
| 9505 | 19605645 | Feeding 3xTg-AD transgenic mice a diet high in saturated and omega-6 fat increased active JNK and phosphorylated IRS-1 and tau. |
| 9506 | 19605645 | Treatment of the 3xTg-AD mice on high-fat diet with fish oil or curcumin or a combination of both for 4 months reduced phosphorylated JNK, IRS-1, and tau and prevented the degradation of total IRS-1. |
| 9507 | 19605645 | Mice fed with fish oil and curcumin for 1 month had more significant effects on Y-maze, and the combination showed more significant inhibition of JNK, IRS-1, and tau phosphorylation. |
| 9508 | 19605645 | These data indicate JNK mediates Abeta oligomer inactivation of IRS-1 and phospho-tau pathology and that dietary treatment with fish oil/DHA, curcumin, or a combination of both has the potential to improve insulin/trophic signaling and cognitive deficits in AD. |
| 9509 | 19605645 | Beta-amyloid oligomers induce phosphorylation of tau and inactivation of insulin receptor substrate via c-Jun N-terminal kinase signaling: suppression by omega-3 fatty acids and curcumin. |
| 9510 | 19605645 | Both insulin resistance (type II diabetes) and beta-amyloid (Abeta) oligomers are implicated in Alzheimer's disease (AD). |
| 9511 | 19605645 | Here, we investigate the role of Abeta oligomer-induced c-Jun N-terminal kinase (JNK) activation leading to phosphorylation and degradation of the adaptor protein insulin receptor substrate-1 (IRS-1). |
| 9512 | 19605645 | IRS-1 couples insulin and other trophic factor receptors to downstream kinases and neuroprotective signaling. |
| 9513 | 19605645 | Here, we report Abeta oligomers significantly increased active JNK and phosphorylation of IRS-1 (Ser616) and tau (Ser422) in cultured hippocampal neurons, whereas JNK inhibition blocked these responses. |
| 9514 | 19605645 | The omega-3 fatty acid docosahexaenoic acid (DHA) similarly inhibited JNK and the phosphorylation of IRS-1 and tau in cultured hippocampal neurons. |
| 9515 | 19605645 | Feeding 3xTg-AD transgenic mice a diet high in saturated and omega-6 fat increased active JNK and phosphorylated IRS-1 and tau. |
| 9516 | 19605645 | Treatment of the 3xTg-AD mice on high-fat diet with fish oil or curcumin or a combination of both for 4 months reduced phosphorylated JNK, IRS-1, and tau and prevented the degradation of total IRS-1. |
| 9517 | 19605645 | Mice fed with fish oil and curcumin for 1 month had more significant effects on Y-maze, and the combination showed more significant inhibition of JNK, IRS-1, and tau phosphorylation. |
| 9518 | 19605645 | These data indicate JNK mediates Abeta oligomer inactivation of IRS-1 and phospho-tau pathology and that dietary treatment with fish oil/DHA, curcumin, or a combination of both has the potential to improve insulin/trophic signaling and cognitive deficits in AD. |
| 9519 | 19605645 | Beta-amyloid oligomers induce phosphorylation of tau and inactivation of insulin receptor substrate via c-Jun N-terminal kinase signaling: suppression by omega-3 fatty acids and curcumin. |
| 9520 | 19605645 | Both insulin resistance (type II diabetes) and beta-amyloid (Abeta) oligomers are implicated in Alzheimer's disease (AD). |
| 9521 | 19605645 | Here, we investigate the role of Abeta oligomer-induced c-Jun N-terminal kinase (JNK) activation leading to phosphorylation and degradation of the adaptor protein insulin receptor substrate-1 (IRS-1). |
| 9522 | 19605645 | IRS-1 couples insulin and other trophic factor receptors to downstream kinases and neuroprotective signaling. |
| 9523 | 19605645 | Here, we report Abeta oligomers significantly increased active JNK and phosphorylation of IRS-1 (Ser616) and tau (Ser422) in cultured hippocampal neurons, whereas JNK inhibition blocked these responses. |
| 9524 | 19605645 | The omega-3 fatty acid docosahexaenoic acid (DHA) similarly inhibited JNK and the phosphorylation of IRS-1 and tau in cultured hippocampal neurons. |
| 9525 | 19605645 | Feeding 3xTg-AD transgenic mice a diet high in saturated and omega-6 fat increased active JNK and phosphorylated IRS-1 and tau. |
| 9526 | 19605645 | Treatment of the 3xTg-AD mice on high-fat diet with fish oil or curcumin or a combination of both for 4 months reduced phosphorylated JNK, IRS-1, and tau and prevented the degradation of total IRS-1. |
| 9527 | 19605645 | Mice fed with fish oil and curcumin for 1 month had more significant effects on Y-maze, and the combination showed more significant inhibition of JNK, IRS-1, and tau phosphorylation. |
| 9528 | 19605645 | These data indicate JNK mediates Abeta oligomer inactivation of IRS-1 and phospho-tau pathology and that dietary treatment with fish oil/DHA, curcumin, or a combination of both has the potential to improve insulin/trophic signaling and cognitive deficits in AD. |
| 9529 | 19605645 | Beta-amyloid oligomers induce phosphorylation of tau and inactivation of insulin receptor substrate via c-Jun N-terminal kinase signaling: suppression by omega-3 fatty acids and curcumin. |
| 9530 | 19605645 | Both insulin resistance (type II diabetes) and beta-amyloid (Abeta) oligomers are implicated in Alzheimer's disease (AD). |
| 9531 | 19605645 | Here, we investigate the role of Abeta oligomer-induced c-Jun N-terminal kinase (JNK) activation leading to phosphorylation and degradation of the adaptor protein insulin receptor substrate-1 (IRS-1). |
| 9532 | 19605645 | IRS-1 couples insulin and other trophic factor receptors to downstream kinases and neuroprotective signaling. |
| 9533 | 19605645 | Here, we report Abeta oligomers significantly increased active JNK and phosphorylation of IRS-1 (Ser616) and tau (Ser422) in cultured hippocampal neurons, whereas JNK inhibition blocked these responses. |
| 9534 | 19605645 | The omega-3 fatty acid docosahexaenoic acid (DHA) similarly inhibited JNK and the phosphorylation of IRS-1 and tau in cultured hippocampal neurons. |
| 9535 | 19605645 | Feeding 3xTg-AD transgenic mice a diet high in saturated and omega-6 fat increased active JNK and phosphorylated IRS-1 and tau. |
| 9536 | 19605645 | Treatment of the 3xTg-AD mice on high-fat diet with fish oil or curcumin or a combination of both for 4 months reduced phosphorylated JNK, IRS-1, and tau and prevented the degradation of total IRS-1. |
| 9537 | 19605645 | Mice fed with fish oil and curcumin for 1 month had more significant effects on Y-maze, and the combination showed more significant inhibition of JNK, IRS-1, and tau phosphorylation. |
| 9538 | 19605645 | These data indicate JNK mediates Abeta oligomer inactivation of IRS-1 and phospho-tau pathology and that dietary treatment with fish oil/DHA, curcumin, or a combination of both has the potential to improve insulin/trophic signaling and cognitive deficits in AD. |
| 9539 | 19683528 | PANDER binds to the liver cell membrane and inhibits insulin signaling in HepG2 cells. |
| 9540 | 19683528 | PANDER is a cytokine co-secreted with insulin from islet beta-cells. |
| 9541 | 19683528 | In HepG2 cells, pre-treatment with PANDER ranging from 4 pM to 4 nM for 8h resulted in a maximal inhibition of insulin-stimulated activation of insulin receptor and insulin receptor substrate 1 by 52% and 63%, respectively. |
| 9542 | 19683528 | Moreover, PANDER treatment also reduced insulin-stimulated PI3K and pAkt levels by 55% and 48%, respectively. |
| 9543 | 19683528 | In summary, we have identified the liver as a novel target for PANDER, and PANDER may be involved in the progression of diabetes by regulating hepatic insulin signaling pathways. |
| 9544 | 19699714 | Consistent with the increase in glucose uptake, Rg3 stimulated the phosphorylation of IRS-1 and Akt. |
| 9545 | 19699714 | Interestingly, Rg3 dramatically increased IRS-1 protein levels, while the protein level of Akt was not affected. |
| 9546 | 19699714 | Rg3 regulated IRS-1 expression at the transcriptional level and also increased the level of GLUT4 mRNA. |
| 9547 | 19699714 | In addition, we found that this effect of Rg3 on insulin signaling was not mediated by the AMPK pathway. |
| 9548 | 19699714 | In conclusion, these results suggest that Rg3 improves insulin signaling and glucose uptake primarily by stimulating the expression of IRS-1 and GLUT4. |
| 9549 | 19699714 | Consistent with the increase in glucose uptake, Rg3 stimulated the phosphorylation of IRS-1 and Akt. |
| 9550 | 19699714 | Interestingly, Rg3 dramatically increased IRS-1 protein levels, while the protein level of Akt was not affected. |
| 9551 | 19699714 | Rg3 regulated IRS-1 expression at the transcriptional level and also increased the level of GLUT4 mRNA. |
| 9552 | 19699714 | In addition, we found that this effect of Rg3 on insulin signaling was not mediated by the AMPK pathway. |
| 9553 | 19699714 | In conclusion, these results suggest that Rg3 improves insulin signaling and glucose uptake primarily by stimulating the expression of IRS-1 and GLUT4. |
| 9554 | 19699714 | Consistent with the increase in glucose uptake, Rg3 stimulated the phosphorylation of IRS-1 and Akt. |
| 9555 | 19699714 | Interestingly, Rg3 dramatically increased IRS-1 protein levels, while the protein level of Akt was not affected. |
| 9556 | 19699714 | Rg3 regulated IRS-1 expression at the transcriptional level and also increased the level of GLUT4 mRNA. |
| 9557 | 19699714 | In addition, we found that this effect of Rg3 on insulin signaling was not mediated by the AMPK pathway. |
| 9558 | 19699714 | In conclusion, these results suggest that Rg3 improves insulin signaling and glucose uptake primarily by stimulating the expression of IRS-1 and GLUT4. |
| 9559 | 19699714 | Consistent with the increase in glucose uptake, Rg3 stimulated the phosphorylation of IRS-1 and Akt. |
| 9560 | 19699714 | Interestingly, Rg3 dramatically increased IRS-1 protein levels, while the protein level of Akt was not affected. |
| 9561 | 19699714 | Rg3 regulated IRS-1 expression at the transcriptional level and also increased the level of GLUT4 mRNA. |
| 9562 | 19699714 | In addition, we found that this effect of Rg3 on insulin signaling was not mediated by the AMPK pathway. |
| 9563 | 19699714 | In conclusion, these results suggest that Rg3 improves insulin signaling and glucose uptake primarily by stimulating the expression of IRS-1 and GLUT4. |
| 9564 | 19706599 | A novel pathway of insulin sensitivity in chromogranin A null mice: a crucial role for pancreastatin in glucose homeostasis. |
| 9565 | 19706599 | Thus, PST action may be mediated by suppressing IRS1/2-phosphatidylinositol 3-kinase-Akt-FOXO-1 signaling and insulin-induced maturation of SREBP1c by PKC and a high level of NO. |
| 9566 | 19716569 | Diverse single nucleotide polymorphisms (SNPs) of the IRS1 gene have been associated with insulin resistance and T2D risk. |
| 9567 | 19730809 | Aspirin attenuates insulin resistance in muscle of diet-induced obese rats by inhibiting inducible nitric oxide synthase production and S-nitrosylation of IRbeta/IRS-1 and Akt. |
| 9568 | 19759515 | These responses were related to increased association of PI3K with the glucocorticoid receptor (GR). |
| 9569 | 19759515 | Fluorescence resonance energy transfer and an in vitro competition assay revealed that activated GRs competed for PI3K, reducing its association with IRS-1. |
| 9570 | 19764108 | No significant alterations were found in cellular content of key proteins in the insulin signaling cascade (insulin receptor substrate-1 and -2, and glucose transporter 4) that could explain the impaired insulin-stimulated glucose transport in control adipocytes incubated with serum from type 2 diabetic donors. |
| 9571 | 19775880 | Daidzein and the daidzein metabolite, equol, enhance adipocyte differentiation and PPARgamma transcriptional activity. |
| 9572 | 19775880 | Since the insulin-sensitizing effects of thiazolidinediones, antidiabetic drugs, are mediated through activation of peroxisome proliferators-activated receptor gamma (PPARgamma), we examined the effects of daidzein and the daidzein metabolite, equol, on adipocyte differentiation and PPARgamma activation. |
| 9573 | 19775880 | In 3T3-L1 cells, daidzein enhanced adipocyte differentiation and PPARgamma expression in a dose-dependent manner. |
| 9574 | 19775880 | Daidzein also dose-dependently increased insulin-stimulated glucose uptake and the relative abundance of insulin-responsive glucose transporter 4 (GLUT4) and insulin receptor substrate 1 (IRS-1) mRNA. |
| 9575 | 19775880 | In C3H10T1/2 cells, both daidzein and equol at 1 micromol/L and higher significantly increased adipocyte differentiation and insulin-stimulated glucose uptake. |
| 9576 | 19775880 | Furthermore, daidzein and equol up-regulated PPARgamma-mediated transcriptional activity, and daidzein restored the PPARgamma antagonist-induced inhibition of aP2 and GLUT4 mRNA levels. |
| 9577 | 19775880 | Our results indicate that daidzein enhances insulin-stimulated glucose uptake in adipocytes by increasing the expression of GLUT4 and IRS-1 via the activation of PPARgamma. |
| 9578 | 19775880 | Daidzein and the daidzein metabolite, equol, enhance adipocyte differentiation and PPARgamma transcriptional activity. |
| 9579 | 19775880 | Since the insulin-sensitizing effects of thiazolidinediones, antidiabetic drugs, are mediated through activation of peroxisome proliferators-activated receptor gamma (PPARgamma), we examined the effects of daidzein and the daidzein metabolite, equol, on adipocyte differentiation and PPARgamma activation. |
| 9580 | 19775880 | In 3T3-L1 cells, daidzein enhanced adipocyte differentiation and PPARgamma expression in a dose-dependent manner. |
| 9581 | 19775880 | Daidzein also dose-dependently increased insulin-stimulated glucose uptake and the relative abundance of insulin-responsive glucose transporter 4 (GLUT4) and insulin receptor substrate 1 (IRS-1) mRNA. |
| 9582 | 19775880 | In C3H10T1/2 cells, both daidzein and equol at 1 micromol/L and higher significantly increased adipocyte differentiation and insulin-stimulated glucose uptake. |
| 9583 | 19775880 | Furthermore, daidzein and equol up-regulated PPARgamma-mediated transcriptional activity, and daidzein restored the PPARgamma antagonist-induced inhibition of aP2 and GLUT4 mRNA levels. |
| 9584 | 19775880 | Our results indicate that daidzein enhances insulin-stimulated glucose uptake in adipocytes by increasing the expression of GLUT4 and IRS-1 via the activation of PPARgamma. |
| 9585 | 19800638 | Glimepiride induces proliferation and differentiation of rat osteoblasts via the PI3-kinase/Akt pathway. |
| 9586 | 19800638 | In addition to the stimulatory effects on pancreatic insulin secretion, glimepiride has also been reported to have extrapancreatic functions including activation of PI3 kinase (PI3K) and Akt in rat adipocytes and skeletal muscle. |
| 9587 | 19800638 | PI3-kinase and Akt are important signaling molecules in the regulation of proliferation and differentiation in various cells. |
| 9588 | 19800638 | This study investigated the actions of glimepiride in rat osteoblasts and the role of PI3K/Akt pathway. |
| 9589 | 19800638 | Western blot analysis was used for determining collagen I, insulin receptor substrate-1/2, PI3K/Akt, and endothelial nitric oxide synthase expression. |
| 9590 | 19800638 | We found that glimepiride significantly enhanced proliferation and differentiation of osteoblasts and led to activation of several key signaling molecules including insulin receptor substrate-1/2, PI3K/Akt, and endothelial nitric oxide synthase. |
| 9591 | 19800638 | Taken together, these observations provide concrete evidence that glimepiride activates the PI3K/Akt pathway; and this activation is likely required for glimepiride to stimulate proliferation and differentiation of rat osteoblasts. |
| 9592 | 19800638 | Glimepiride induces proliferation and differentiation of rat osteoblasts via the PI3-kinase/Akt pathway. |
| 9593 | 19800638 | In addition to the stimulatory effects on pancreatic insulin secretion, glimepiride has also been reported to have extrapancreatic functions including activation of PI3 kinase (PI3K) and Akt in rat adipocytes and skeletal muscle. |
| 9594 | 19800638 | PI3-kinase and Akt are important signaling molecules in the regulation of proliferation and differentiation in various cells. |
| 9595 | 19800638 | This study investigated the actions of glimepiride in rat osteoblasts and the role of PI3K/Akt pathway. |
| 9596 | 19800638 | Western blot analysis was used for determining collagen I, insulin receptor substrate-1/2, PI3K/Akt, and endothelial nitric oxide synthase expression. |
| 9597 | 19800638 | We found that glimepiride significantly enhanced proliferation and differentiation of osteoblasts and led to activation of several key signaling molecules including insulin receptor substrate-1/2, PI3K/Akt, and endothelial nitric oxide synthase. |
| 9598 | 19800638 | Taken together, these observations provide concrete evidence that glimepiride activates the PI3K/Akt pathway; and this activation is likely required for glimepiride to stimulate proliferation and differentiation of rat osteoblasts. |
| 9599 | 19815546 | Moreover, LPC did not affect IRS-1 and AKT2 phosphorylations, and LPC-induced glucose uptake was not influenced by pretreatment with the PI 3-kinase inhibitor LY294002. |
| 9600 | 19838201 | Foxo1 integrates insulin signaling with mitochondrial function in the liver. |
| 9601 | 19838201 | Here we used previously generated mice with hepatic insulin resistance owing to the deletion of the genes encoding insulin receptor substrate-1 (Irs-1) and Irs-2 (referred to here as double-knockout (DKO) mice) to establish the molecular link between dysregulated insulin action and mitochondrial function. |
| 9602 | 19838201 | The expression of several forkhead box O1 (Foxo1) target genes increased in the DKO liver, including heme oxygenase-1 (Hmox1), which disrupts complex III and IV of the respiratory chain and lowers the NAD(+)/NADH ratio and ATP production. |
| 9603 | 19838201 | Although peroxisome proliferator-activated receptor-gamma coactivator-1alpha (Ppargc-1alpha) was also upregulated in DKO liver, it was acetylated and failed to promote compensatory mitochondrial biogenesis or function. |
| 9604 | 19838201 | Deletion of hepatic Foxo1 in DKO liver normalized the expression of Hmox1 and the NAD(+)/NADH ratio, reduced Ppargc-1alpha acetylation and restored mitochondrial oxidative metabolism and biogenesis. |
| 9605 | 19838201 | Thus, Foxo1 integrates insulin signaling with mitochondrial function, and inhibition of Foxo1 can improve hepatic metabolism during insulin resistance and the metabolic syndrome. |
| 9606 | 19913855 | In the present study, the influence of leucine supplementation on metabolic parameters, insulin secretion to glucose and to amino acids, as well as the levels of proteins that participate in the phosphatidylinositol 3-phosphate kinase (PI3K) pathway was investigated in malnourished rats. |
| 9607 | 19913855 | Both NPL and LPL rats had higher circulating insulin levels than controls. |
| 9608 | 19913855 | The LPL rats also showed increased insulin secretion by pancreatic islets in response to glucose or arginine compared with those observed in islets from LP animals. |
| 9609 | 19913855 | Western blotting analysis demonstrated increased PI3K and mammalian target protein of rapamycin protein contents in LPL compared with LP islets. |
| 9610 | 19913855 | A significant increase in insulin-induced insulin receptor substrate 1-associated PI3K activation was also observed in LPL compared with LP islets. |
| 9611 | 19924153 | In this Review, we discuss the role of relatively infrequent polymorphisms of genes that regulate insulin signaling (including the K121Q polymorphism of ENPP1, the G972R polymorphism of IRS1 and the Q84R polymorphism of TRIB3) in T2DM and other conditions related to insulin resistance. |
| 9612 | 19955252 | This study demonstrated altered mRNA expression of insulin receptor substrate (IRS)-1, IRS-2, glucose transporter (GLUT)-1, GLUT-4 and glycogen synthase kinase (GSK)-3 isoforms genes in adipose tissue in GDM women in comparison to NGT pregnant controls. |
| 9613 | 19955252 | In skeletal muscle, insulin-controlled GDM was associated with decreased IRS-1, phosphatidylinositol-3-kinase (PI3-K) p85alpha, GLUT-1 and -4, GSK-3 isoforms and phosphoinositide-dependent kinase-1. |
| 9614 | 19955252 | Both adipose tissue and skeletal muscle from women with GDM displayed decreased IRS-1 and GLUT-4 and increased PI3-K p85alpha protein expression. |
| 9615 | 19955252 | Both skeletal muscle and adipose tissue from obese women demonstrated lower GLUT-1 and -4 mRNA expression and diminished GLUT-4 protein expression in skeletal muscle only. |
| 9616 | 19955252 | This study demonstrated altered mRNA expression of insulin receptor substrate (IRS)-1, IRS-2, glucose transporter (GLUT)-1, GLUT-4 and glycogen synthase kinase (GSK)-3 isoforms genes in adipose tissue in GDM women in comparison to NGT pregnant controls. |
| 9617 | 19955252 | In skeletal muscle, insulin-controlled GDM was associated with decreased IRS-1, phosphatidylinositol-3-kinase (PI3-K) p85alpha, GLUT-1 and -4, GSK-3 isoforms and phosphoinositide-dependent kinase-1. |
| 9618 | 19955252 | Both adipose tissue and skeletal muscle from women with GDM displayed decreased IRS-1 and GLUT-4 and increased PI3-K p85alpha protein expression. |
| 9619 | 19955252 | Both skeletal muscle and adipose tissue from obese women demonstrated lower GLUT-1 and -4 mRNA expression and diminished GLUT-4 protein expression in skeletal muscle only. |
| 9620 | 19956100 | No association of the IRS1 and PAX4 genes with type I diabetes. |
| 9621 | 19956100 | To reassess earlier suggested type I diabetes (T1D) associations of the insulin receptor substrate 1 (IRS1) and the paired domain 4 gene (PAX4) genes, the Type I Diabetes Genetics Consortium (T1DGC) evaluated single-nucleotide polymorphisms (SNPs) covering the two genomic regions. |
| 9622 | 19956100 | Sixteen SNPs were evaluated for IRS1 and 10 for PAX4. |
| 9623 | 19956100 | In conclusion, the earlier suggested associations of IRS1 and PAX4 to T1D were not supported, suggesting that they may have been false positive results. |
| 9624 | 19956100 | No association of the IRS1 and PAX4 genes with type I diabetes. |
| 9625 | 19956100 | To reassess earlier suggested type I diabetes (T1D) associations of the insulin receptor substrate 1 (IRS1) and the paired domain 4 gene (PAX4) genes, the Type I Diabetes Genetics Consortium (T1DGC) evaluated single-nucleotide polymorphisms (SNPs) covering the two genomic regions. |
| 9626 | 19956100 | Sixteen SNPs were evaluated for IRS1 and 10 for PAX4. |
| 9627 | 19956100 | In conclusion, the earlier suggested associations of IRS1 and PAX4 to T1D were not supported, suggesting that they may have been false positive results. |
| 9628 | 19956100 | No association of the IRS1 and PAX4 genes with type I diabetes. |
| 9629 | 19956100 | To reassess earlier suggested type I diabetes (T1D) associations of the insulin receptor substrate 1 (IRS1) and the paired domain 4 gene (PAX4) genes, the Type I Diabetes Genetics Consortium (T1DGC) evaluated single-nucleotide polymorphisms (SNPs) covering the two genomic regions. |
| 9630 | 19956100 | Sixteen SNPs were evaluated for IRS1 and 10 for PAX4. |
| 9631 | 19956100 | In conclusion, the earlier suggested associations of IRS1 and PAX4 to T1D were not supported, suggesting that they may have been false positive results. |
| 9632 | 19956100 | No association of the IRS1 and PAX4 genes with type I diabetes. |
| 9633 | 19956100 | To reassess earlier suggested type I diabetes (T1D) associations of the insulin receptor substrate 1 (IRS1) and the paired domain 4 gene (PAX4) genes, the Type I Diabetes Genetics Consortium (T1DGC) evaluated single-nucleotide polymorphisms (SNPs) covering the two genomic regions. |
| 9634 | 19956100 | Sixteen SNPs were evaluated for IRS1 and 10 for PAX4. |
| 9635 | 19956100 | In conclusion, the earlier suggested associations of IRS1 and PAX4 to T1D were not supported, suggesting that they may have been false positive results. |
| 9636 | 19966184 | Inhibition of thrombin action ameliorates insulin resistance in type 2 diabetic db/db mice. |
| 9637 | 19966184 | The binding of thrombin to its receptor stimulates inflammatory cytokines including IL-6 and monocyte chemoattractant protein-1 (MCP-1); both are associated with the development of insulin resistance. |
| 9638 | 19966184 | Because increased adiposity enhanced the expression of coagulation factor VII that stimulates the coagulation pathway in adipose tissue, we tested whether the inhibition of thrombin action ameliorates insulin resistance in obese diabetic (Lpr(-/-):db/db) mice. |
| 9639 | 19966184 | The 4-wk administration of argatroban, a selective thrombin inhibitor, reduced fasting plasma glucose and ameliorated insulin resistance in these mice. |
| 9640 | 19966184 | The aberrant gene expression of MCP-1, IL-6, adiponectin, and factor VII and suppressed insulin receptor substrate-1-Akt signaling in adipose tissue of db/db mice were reversed by argatroban treatment. |
| 9641 | 19966184 | These results demonstrate that increased adiposity enhances the production of thrombin in adipose tissue by stimulating factor VII expression and suggest that increased thrombin activity in adipose tissue plays an important role in the development of insulin resistance via enhancing MCP-1 production, leading to macrophage infiltration and insulin receptor substrate-1-Akt pathway inactivation. |
| 9642 | 19966184 | Inhibition of thrombin action ameliorates insulin resistance in type 2 diabetic db/db mice. |
| 9643 | 19966184 | The binding of thrombin to its receptor stimulates inflammatory cytokines including IL-6 and monocyte chemoattractant protein-1 (MCP-1); both are associated with the development of insulin resistance. |
| 9644 | 19966184 | Because increased adiposity enhanced the expression of coagulation factor VII that stimulates the coagulation pathway in adipose tissue, we tested whether the inhibition of thrombin action ameliorates insulin resistance in obese diabetic (Lpr(-/-):db/db) mice. |
| 9645 | 19966184 | The 4-wk administration of argatroban, a selective thrombin inhibitor, reduced fasting plasma glucose and ameliorated insulin resistance in these mice. |
| 9646 | 19966184 | The aberrant gene expression of MCP-1, IL-6, adiponectin, and factor VII and suppressed insulin receptor substrate-1-Akt signaling in adipose tissue of db/db mice were reversed by argatroban treatment. |
| 9647 | 19966184 | These results demonstrate that increased adiposity enhances the production of thrombin in adipose tissue by stimulating factor VII expression and suggest that increased thrombin activity in adipose tissue plays an important role in the development of insulin resistance via enhancing MCP-1 production, leading to macrophage infiltration and insulin receptor substrate-1-Akt pathway inactivation. |
| 9648 | 19966489 | This study researched the effects of chicken meat extract on blood glucose and insulin level, membrane glucose transporter-4 (GLUT4), and tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) in type 2 diabetic KKAy mice and GK rats. |
| 9649 | 19966489 | In the BEC-treated diabetic animals, insulin induced a significant increase in plasma membrane GLUT4 and cytosolic tyrosine-phosphorylated IRS-1, indicating that it attenuates insulin resistance. |
| 9650 | 19966489 | This study researched the effects of chicken meat extract on blood glucose and insulin level, membrane glucose transporter-4 (GLUT4), and tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) in type 2 diabetic KKAy mice and GK rats. |
| 9651 | 19966489 | In the BEC-treated diabetic animals, insulin induced a significant increase in plasma membrane GLUT4 and cytosolic tyrosine-phosphorylated IRS-1, indicating that it attenuates insulin resistance. |
| 9652 | 19996382 | Mammalian Tribbles homolog 3 impairs insulin action in skeletal muscle: role in glucose-induced insulin resistance. |
| 9653 | 19996382 | Tribbles homolog 3 (TRIB3) was found to inhibit insulin-stimulated Akt phosphorylation and modulate gluconeogenesis in rodent liver. |
| 9654 | 19996382 | Currently, we examined a role for TRIB3 in skeletal muscle insulin resistance. |
| 9655 | 19996382 | Finally, L6 muscle cells were used to examine regulation of TRIB3 by glucose, and stable cell lines hyperexpressing TRIB3 were generated to identify mechanisms underlying TRIB3-induced insulin resistance. |
| 9656 | 19996382 | We found that 1) skeletal muscle TRIB3 protein levels are significantly elevated in T2DM patients; 2) muscle TRIB3 protein content is inversely correlated with glucose disposal rates and positively correlated with fasting glucose; 3) skeletal muscle TRIB3 protein levels are increased in STZ-diabetic rats, db/db mice, and Zucker fatty rats; 4) stable TRIB3 hyperexpression in muscle cells blocks insulin-stimulated glucose transport and glucose transporter 4 (GLUT4) translocation and impairs phosphorylation of Akt, ERK, and insulin receptor substrate-1 in insulin signal transduction; and 5) TRIB3 mRNA and protein levels are increased by high glucose concentrations, as well as by glucose deprivation in muscle cells. |
| 9657 | 19996382 | These data identify TRIB3 induction as a novel molecular mechanism in human insulin resistance and diabetes. |
| 9658 | 19996382 | TRIB3 acts as a nutrient sensor and could mediate the component of insulin resistance attributable to hyperglycemia (i.e., glucose toxicity) in diabetes. |
| 9659 | 19996384 | Exercise maintains euglycemia in association with decreased activation of c-Jun NH2-terminal kinase and serine phosphorylation of IRS-1 in the liver of ZDF rats. |
| 9660 | 19996384 | Ten weeks of exercise also decreased whole body markers of inflammation and oxidative stress in plasma and liver, including lowered circulating IL-6, haptoglobin, and malondialdehyde levels, hepatic protein oxidation, and phosphorylated JNK, the latter indicating decreased JNK activity. |
| 9661 | 19996384 | In summary, we show that, in a rodent model of T2DM, voluntary exercise decreases circulating markers of inflammation and oxidative stress and lowers hepatic JNK activation and Ser(307)-phosphorylated insulin receptor substrate-1. |
| 9662 | 19996384 | Exercise maintains euglycemia in association with decreased activation of c-Jun NH2-terminal kinase and serine phosphorylation of IRS-1 in the liver of ZDF rats. |
| 9663 | 19996384 | Ten weeks of exercise also decreased whole body markers of inflammation and oxidative stress in plasma and liver, including lowered circulating IL-6, haptoglobin, and malondialdehyde levels, hepatic protein oxidation, and phosphorylated JNK, the latter indicating decreased JNK activity. |
| 9664 | 19996384 | In summary, we show that, in a rodent model of T2DM, voluntary exercise decreases circulating markers of inflammation and oxidative stress and lowers hepatic JNK activation and Ser(307)-phosphorylated insulin receptor substrate-1. |
| 9665 | 20028942 | Inhibition of PTP1B restores IRS1-mediated hepatic insulin signaling in IRS2-deficient mice. |
| 9666 | 20038265 | Metformin also blocked the induction of ER stress proteins (GRP78, Chop, Cleaved ATF-6, p-eIF2 alpha and XBP-1) and regulated serine phosphorylation of IRS-1. |
| 9667 | 20064934 | Using a gain-of-function model of endothelial nitric-oxide synthase (eNOS)-transfected COS-7 cells, we have shown a critical role of NO in insulin responsiveness, as evidenced by an NO-dependent increase of tyrosine phosphorylation levels of the insulin receptor and its downstream effectors insulin receptor substrate-1 and PKB/AKT. |
| 9668 | 20064934 | We hypothesized that NO-induced inactivation of endogenous protein-tyrosine phosphatases (PTPs) would enhance insulin receptor-mediated signaling. |
| 9669 | 20064934 | Our data suggest that phosphatases SHP-1, SHP-2, and PTP1B, but not TC-PTP, are likely S-nitrosylated at the active site cysteine residue concomitantly with a burst of NO production in signaling response to insulin stimulation. |
| 9670 | 20064934 | We investigated further the role of NO as a regulator of insulin signaling by RNA interference that ablates endogenous eNOS expression in endothelial MS-1 cells. |
| 9671 | 20064934 | We have shown that eNOS-dependent NO production is essential for the activation of insulin signaling. |
| 9672 | 20087248 | In the last decade new genetic defects have been described in all the levels of the growth hormone-releasing hormone (GH-RH)-GH-IGF (insulin-like growth factor) axis. |
| 9673 | 20087248 | Genetic defects in the GHRH and in various parts of the Insulin-like growth factor system have been demonstrated. |
| 9674 | 20087248 | In animal models and in humans the importance of the transcription factors HESX1, PROP1, POU1F1, LHX3, LHX4, TBX19, SOX2 and SOX3 has been extensively studied. |
| 9675 | 20087248 | A group of signalling proteins are involved in prenatal (SGA) growth retardation: IRS-1, PDK1, AKT1, and S6K1. |
| 9676 | 20097161 | Transcription factor AP-2beta: a negative regulator of IRS-1 gene expression. |
| 9677 | 20097161 | However, few studies have investigated the transcriptional regulation of IRS-1 in the pathogenesis of insulin resistance. |
| 9678 | 20097161 | Overexpression of AP-2beta leads to adipocyte hypertrophy, directly inhibits adiponectin expression, and enhanced the expression of inflammatory adipokines such as IL-6 and MCP-1. |
| 9679 | 20097161 | In this study, we found that overexpression of AP-2beta in 3T3-L1 adipocytes impaired the promoter activity of IRS-1, and subsequently decreased mRNA and protein expression. |
| 9680 | 20097161 | Electrophoretic mobility shift assays showed that AP-2beta bound specifically to the IRS-1 promoter region. |
| 9681 | 20097161 | Furthermore, site-directed mutagenesis of the AP-2 binding site located at -362 to -351, relative to the transcription start site, markedly decreased AP-2-induced suppression of IRS-1 promoter activity, whereas other putative AP-2 binding sites did not. |
| 9682 | 20097161 | Our results clearly showed that AP-2beta directly decreased IRS-1 expression by binding to its promoter. |
| 9683 | 20097161 | Based on these findings, we speculate that the AP-2beta transcriptional factor is a unique regulator of IRS-1 and a candidate gene for insulin resistance. |
| 9684 | 20097161 | Transcription factor AP-2beta: a negative regulator of IRS-1 gene expression. |
| 9685 | 20097161 | However, few studies have investigated the transcriptional regulation of IRS-1 in the pathogenesis of insulin resistance. |
| 9686 | 20097161 | Overexpression of AP-2beta leads to adipocyte hypertrophy, directly inhibits adiponectin expression, and enhanced the expression of inflammatory adipokines such as IL-6 and MCP-1. |
| 9687 | 20097161 | In this study, we found that overexpression of AP-2beta in 3T3-L1 adipocytes impaired the promoter activity of IRS-1, and subsequently decreased mRNA and protein expression. |
| 9688 | 20097161 | Electrophoretic mobility shift assays showed that AP-2beta bound specifically to the IRS-1 promoter region. |
| 9689 | 20097161 | Furthermore, site-directed mutagenesis of the AP-2 binding site located at -362 to -351, relative to the transcription start site, markedly decreased AP-2-induced suppression of IRS-1 promoter activity, whereas other putative AP-2 binding sites did not. |
| 9690 | 20097161 | Our results clearly showed that AP-2beta directly decreased IRS-1 expression by binding to its promoter. |
| 9691 | 20097161 | Based on these findings, we speculate that the AP-2beta transcriptional factor is a unique regulator of IRS-1 and a candidate gene for insulin resistance. |
| 9692 | 20097161 | Transcription factor AP-2beta: a negative regulator of IRS-1 gene expression. |
| 9693 | 20097161 | However, few studies have investigated the transcriptional regulation of IRS-1 in the pathogenesis of insulin resistance. |
| 9694 | 20097161 | Overexpression of AP-2beta leads to adipocyte hypertrophy, directly inhibits adiponectin expression, and enhanced the expression of inflammatory adipokines such as IL-6 and MCP-1. |
| 9695 | 20097161 | In this study, we found that overexpression of AP-2beta in 3T3-L1 adipocytes impaired the promoter activity of IRS-1, and subsequently decreased mRNA and protein expression. |
| 9696 | 20097161 | Electrophoretic mobility shift assays showed that AP-2beta bound specifically to the IRS-1 promoter region. |
| 9697 | 20097161 | Furthermore, site-directed mutagenesis of the AP-2 binding site located at -362 to -351, relative to the transcription start site, markedly decreased AP-2-induced suppression of IRS-1 promoter activity, whereas other putative AP-2 binding sites did not. |
| 9698 | 20097161 | Our results clearly showed that AP-2beta directly decreased IRS-1 expression by binding to its promoter. |
| 9699 | 20097161 | Based on these findings, we speculate that the AP-2beta transcriptional factor is a unique regulator of IRS-1 and a candidate gene for insulin resistance. |
| 9700 | 20097161 | Transcription factor AP-2beta: a negative regulator of IRS-1 gene expression. |
| 9701 | 20097161 | However, few studies have investigated the transcriptional regulation of IRS-1 in the pathogenesis of insulin resistance. |
| 9702 | 20097161 | Overexpression of AP-2beta leads to adipocyte hypertrophy, directly inhibits adiponectin expression, and enhanced the expression of inflammatory adipokines such as IL-6 and MCP-1. |
| 9703 | 20097161 | In this study, we found that overexpression of AP-2beta in 3T3-L1 adipocytes impaired the promoter activity of IRS-1, and subsequently decreased mRNA and protein expression. |
| 9704 | 20097161 | Electrophoretic mobility shift assays showed that AP-2beta bound specifically to the IRS-1 promoter region. |
| 9705 | 20097161 | Furthermore, site-directed mutagenesis of the AP-2 binding site located at -362 to -351, relative to the transcription start site, markedly decreased AP-2-induced suppression of IRS-1 promoter activity, whereas other putative AP-2 binding sites did not. |
| 9706 | 20097161 | Our results clearly showed that AP-2beta directly decreased IRS-1 expression by binding to its promoter. |
| 9707 | 20097161 | Based on these findings, we speculate that the AP-2beta transcriptional factor is a unique regulator of IRS-1 and a candidate gene for insulin resistance. |
| 9708 | 20097161 | Transcription factor AP-2beta: a negative regulator of IRS-1 gene expression. |
| 9709 | 20097161 | However, few studies have investigated the transcriptional regulation of IRS-1 in the pathogenesis of insulin resistance. |
| 9710 | 20097161 | Overexpression of AP-2beta leads to adipocyte hypertrophy, directly inhibits adiponectin expression, and enhanced the expression of inflammatory adipokines such as IL-6 and MCP-1. |
| 9711 | 20097161 | In this study, we found that overexpression of AP-2beta in 3T3-L1 adipocytes impaired the promoter activity of IRS-1, and subsequently decreased mRNA and protein expression. |
| 9712 | 20097161 | Electrophoretic mobility shift assays showed that AP-2beta bound specifically to the IRS-1 promoter region. |
| 9713 | 20097161 | Furthermore, site-directed mutagenesis of the AP-2 binding site located at -362 to -351, relative to the transcription start site, markedly decreased AP-2-induced suppression of IRS-1 promoter activity, whereas other putative AP-2 binding sites did not. |
| 9714 | 20097161 | Our results clearly showed that AP-2beta directly decreased IRS-1 expression by binding to its promoter. |
| 9715 | 20097161 | Based on these findings, we speculate that the AP-2beta transcriptional factor is a unique regulator of IRS-1 and a candidate gene for insulin resistance. |
| 9716 | 20097161 | Transcription factor AP-2beta: a negative regulator of IRS-1 gene expression. |
| 9717 | 20097161 | However, few studies have investigated the transcriptional regulation of IRS-1 in the pathogenesis of insulin resistance. |
| 9718 | 20097161 | Overexpression of AP-2beta leads to adipocyte hypertrophy, directly inhibits adiponectin expression, and enhanced the expression of inflammatory adipokines such as IL-6 and MCP-1. |
| 9719 | 20097161 | In this study, we found that overexpression of AP-2beta in 3T3-L1 adipocytes impaired the promoter activity of IRS-1, and subsequently decreased mRNA and protein expression. |
| 9720 | 20097161 | Electrophoretic mobility shift assays showed that AP-2beta bound specifically to the IRS-1 promoter region. |
| 9721 | 20097161 | Furthermore, site-directed mutagenesis of the AP-2 binding site located at -362 to -351, relative to the transcription start site, markedly decreased AP-2-induced suppression of IRS-1 promoter activity, whereas other putative AP-2 binding sites did not. |
| 9722 | 20097161 | Our results clearly showed that AP-2beta directly decreased IRS-1 expression by binding to its promoter. |
| 9723 | 20097161 | Based on these findings, we speculate that the AP-2beta transcriptional factor is a unique regulator of IRS-1 and a candidate gene for insulin resistance. |
| 9724 | 20097161 | Transcription factor AP-2beta: a negative regulator of IRS-1 gene expression. |
| 9725 | 20097161 | However, few studies have investigated the transcriptional regulation of IRS-1 in the pathogenesis of insulin resistance. |
| 9726 | 20097161 | Overexpression of AP-2beta leads to adipocyte hypertrophy, directly inhibits adiponectin expression, and enhanced the expression of inflammatory adipokines such as IL-6 and MCP-1. |
| 9727 | 20097161 | In this study, we found that overexpression of AP-2beta in 3T3-L1 adipocytes impaired the promoter activity of IRS-1, and subsequently decreased mRNA and protein expression. |
| 9728 | 20097161 | Electrophoretic mobility shift assays showed that AP-2beta bound specifically to the IRS-1 promoter region. |
| 9729 | 20097161 | Furthermore, site-directed mutagenesis of the AP-2 binding site located at -362 to -351, relative to the transcription start site, markedly decreased AP-2-induced suppression of IRS-1 promoter activity, whereas other putative AP-2 binding sites did not. |
| 9730 | 20097161 | Our results clearly showed that AP-2beta directly decreased IRS-1 expression by binding to its promoter. |
| 9731 | 20097161 | Based on these findings, we speculate that the AP-2beta transcriptional factor is a unique regulator of IRS-1 and a candidate gene for insulin resistance. |
| 9732 | 20142634 | This study was performed to establish whether only 2 sessions per week of combined aerobic and resistance exercise are enough to reduce glycated hemoglobin (HbA(1c)) and to induce changes in skeletal muscle gene expression in Type 2 diabetes mellitus (DM2) subjects with metabolic syndrome. |
| 9733 | 20142634 | There was a significant increase of mRNA of peroxisome proliferator- activated receptor (PPAR)-gamma after 6 months of train - ing (p=0.024); PPARalpha mRNA levels were significantly increased at 6 (p=0.035) and 12 months (p=0.044). |
| 9734 | 20142634 | The mRNA quantification of other genes measured [mitochondrially encoded cytochrome c oxidase subunit II (MTCO2), cytochrome c oxidase subunit Vb (COX5b), PPARgamma coactivator 1alpha (PGC- 1alpha), glucose transporter 4 (GLUT 4), forkhead transcription factor BOX O1 (FOXO-1), carnitine palmitoyltransferase 1 (CPT-1), lipoprotein lipase (LPL), and insulin receptor substrate 1 (IRS-1)] did not show significant changes at 6 and 12 months. |
| 9735 | 20142634 | This study suggests that a twice-per-week frequency of exercise is sufficient to improve glucose control and the expression of skeletal muscle PPARgamma and PPARalpha in DM2 subjects with metabolic syndrome. |
| 9736 | 20158940 | GLUT4 and insulin receptor substrate (IRS)-1), (b) serine phosphorylation of IRS-1 blocking its tyrosine phosphorylation in response to insulin and (c) induction of cytokine signalling molecules that sterically hinder insulin signalling by blocking coupling of the insulin receptor to IRS-1. |
| 9737 | 20158940 | Long-chain (LC) n-3 PUFA regulate gene expression (a) through transcription factors such as PPAR and NF-kappaB and (b) via eicosanoid production, reducing pro-inflammatory cytokine production from many different cells including the macrophage. |
| 9738 | 20177806 | Protein tyrosine phosphatase-1B (PTP-1B) knockdown improves palmitate-induced insulin resistance in C2C12 skeletal muscle cells. |
| 9739 | 20177806 | During the development of insulin resistance a lipid accumulation is accompanied by increased PTP-1B expression in the muscle. |
| 9740 | 20177806 | The aim of this study was to examine the effects of PTP-1B knockdown on insulin signaling and insulin resistance in the presence or absence of palmitate in C2C12 skeletal muscle cells. |
| 9741 | 20177806 | Analysis of PTP-1B protein expression and phosphorylation and protein levels of IRS-1 and Akt were detected by western blot. |
| 9742 | 20177806 | The stable C2C12 cell line harboring the PTP-1B shRNA showed 62% decrease in the PTP-1B protein levels. 0.5 mM palmitate significantly induced insulin resistance in both control (26%) and PTP-1B knockdown cells (16.5%) compared to the untreated cells. |
| 9743 | 20177806 | Under treatment with palmitate, insulin stimulated phosphorylation of IRS-1 (Tyr632) and Akt (Ser473) in knockdown cells was significantly 1.55- and 1.86-fold, respectively, greater than the controls. |
| 9744 | 20177806 | In the presence of palmitate, insulin dependent glucose uptake was significantly about 3-fold higher in PTP-1B knockdown stable C2C12 cells compared to the control cells. |
| 9745 | 20177806 | Our data showed that decreasing the PTP-1B protein level by shRNA can enhance the activity of important elements of insulin signaling. |
| 9746 | 20177806 | Protein tyrosine phosphatase-1B (PTP-1B) knockdown improves palmitate-induced insulin resistance in C2C12 skeletal muscle cells. |
| 9747 | 20177806 | During the development of insulin resistance a lipid accumulation is accompanied by increased PTP-1B expression in the muscle. |
| 9748 | 20177806 | The aim of this study was to examine the effects of PTP-1B knockdown on insulin signaling and insulin resistance in the presence or absence of palmitate in C2C12 skeletal muscle cells. |
| 9749 | 20177806 | Analysis of PTP-1B protein expression and phosphorylation and protein levels of IRS-1 and Akt were detected by western blot. |
| 9750 | 20177806 | The stable C2C12 cell line harboring the PTP-1B shRNA showed 62% decrease in the PTP-1B protein levels. 0.5 mM palmitate significantly induced insulin resistance in both control (26%) and PTP-1B knockdown cells (16.5%) compared to the untreated cells. |
| 9751 | 20177806 | Under treatment with palmitate, insulin stimulated phosphorylation of IRS-1 (Tyr632) and Akt (Ser473) in knockdown cells was significantly 1.55- and 1.86-fold, respectively, greater than the controls. |
| 9752 | 20177806 | In the presence of palmitate, insulin dependent glucose uptake was significantly about 3-fold higher in PTP-1B knockdown stable C2C12 cells compared to the control cells. |
| 9753 | 20177806 | Our data showed that decreasing the PTP-1B protein level by shRNA can enhance the activity of important elements of insulin signaling. |
| 9754 | 20208423 | S-Adenosyl-L-methionine ameliorates TNFalpha-induced insulin resistance in 3T3-L1 adipocytes. |
| 9755 | 20208423 | The IkappaB kinase-beta (IKK-beta)/ nuclear factor-kappaB (NF-kappaB) pathway is a molecular mediator of insulin resistance. |
| 9756 | 20208423 | We investigated the effects of SAM on the glucose transport and insulin signaling impaired by the tumor necrosis factor alpha (TNFalpha) in 3T3-L1 adipocytes. |
| 9757 | 20208423 | SAM partially reversed the basal and insulin stimulated glucose transport, which was impaired by TNFalpha. |
| 9758 | 20208423 | The TNFalpha-induced suppression of the tyrosine phosphorylation of the insulin receptor substrate-1 (IRS-1) and Akt in 3T3-L1 adipocytes was also reversed by SAM. |
| 9759 | 20208423 | In addition, SAM significantly attenuated the TNFalpha-induced degradation of IkappaB-alpha and NF-kappaB activation. |
| 9760 | 20208423 | These results suggest that SAM can alleviate TNFalpha mediated-insulin resistance by inhibiting the IKK-beta/NF-kappaB pathway and thus can have a beneficial role in the treatment of type 2 diabetes mellitus. |
| 9761 | 20306473 | Chromium dinicocysteinate supplementation can lower blood glucose, CRP, MCP-1, ICAM-1, creatinine, apparently mediated by elevated blood vitamin C and adiponectin and inhibition of NFkappaB, Akt, and Glut-2 in livers of zucker diabetic fatty rats. |
| 9762 | 20306473 | D rats showed elevated levels of fasting blood glucose, HbA(1), CRP, MCP-1, ICAM-1 and oxidative stress (lipid peroxidation) and lower adiponectin and vitamin C, when compared with baseline rats. |
| 9763 | 20306473 | In comparison to D group, CDNC group had significantly lower blood glucose, HbA(1), CRP, MCP-1, ICAM-1 and lipid peroxidation and increased vitamin C and adiponectin levels. |
| 9764 | 20306473 | While CDN and CP had no effect, activation of NFkappaB, Akt and glucose transporter-2 levels were decreased, insulin receptor substrate 1 (IRS-1) activation increased in livers of CDNC-rats. |
| 9765 | 20306473 | CDNC effect on glycemia, NFkappaB, Akt and IRS-1 in liver was significantly greater compared with LC. |
| 9766 | 20306473 | CDNC is a potent hypoglycemic compound with anti-inflammatory activity apparently mediated by elevated blood vitamin C and adiponectin and inhibition of NFkappaB, Akt, and Glut-2 and increased IRS-1 activation in livers of type 2 diabetic rats. |
| 9767 | 20306473 | Chromium dinicocysteinate supplementation can lower blood glucose, CRP, MCP-1, ICAM-1, creatinine, apparently mediated by elevated blood vitamin C and adiponectin and inhibition of NFkappaB, Akt, and Glut-2 in livers of zucker diabetic fatty rats. |
| 9768 | 20306473 | D rats showed elevated levels of fasting blood glucose, HbA(1), CRP, MCP-1, ICAM-1 and oxidative stress (lipid peroxidation) and lower adiponectin and vitamin C, when compared with baseline rats. |
| 9769 | 20306473 | In comparison to D group, CDNC group had significantly lower blood glucose, HbA(1), CRP, MCP-1, ICAM-1 and lipid peroxidation and increased vitamin C and adiponectin levels. |
| 9770 | 20306473 | While CDN and CP had no effect, activation of NFkappaB, Akt and glucose transporter-2 levels were decreased, insulin receptor substrate 1 (IRS-1) activation increased in livers of CDNC-rats. |
| 9771 | 20306473 | CDNC effect on glycemia, NFkappaB, Akt and IRS-1 in liver was significantly greater compared with LC. |
| 9772 | 20306473 | CDNC is a potent hypoglycemic compound with anti-inflammatory activity apparently mediated by elevated blood vitamin C and adiponectin and inhibition of NFkappaB, Akt, and Glut-2 and increased IRS-1 activation in livers of type 2 diabetic rats. |
| 9773 | 20306473 | Chromium dinicocysteinate supplementation can lower blood glucose, CRP, MCP-1, ICAM-1, creatinine, apparently mediated by elevated blood vitamin C and adiponectin and inhibition of NFkappaB, Akt, and Glut-2 in livers of zucker diabetic fatty rats. |
| 9774 | 20306473 | D rats showed elevated levels of fasting blood glucose, HbA(1), CRP, MCP-1, ICAM-1 and oxidative stress (lipid peroxidation) and lower adiponectin and vitamin C, when compared with baseline rats. |
| 9775 | 20306473 | In comparison to D group, CDNC group had significantly lower blood glucose, HbA(1), CRP, MCP-1, ICAM-1 and lipid peroxidation and increased vitamin C and adiponectin levels. |
| 9776 | 20306473 | While CDN and CP had no effect, activation of NFkappaB, Akt and glucose transporter-2 levels were decreased, insulin receptor substrate 1 (IRS-1) activation increased in livers of CDNC-rats. |
| 9777 | 20306473 | CDNC effect on glycemia, NFkappaB, Akt and IRS-1 in liver was significantly greater compared with LC. |
| 9778 | 20306473 | CDNC is a potent hypoglycemic compound with anti-inflammatory activity apparently mediated by elevated blood vitamin C and adiponectin and inhibition of NFkappaB, Akt, and Glut-2 and increased IRS-1 activation in livers of type 2 diabetic rats. |
| 9779 | 20371624 | FOXO3a mediates signaling crosstalk that coordinates ubiquitin and atrogin-1/MAFbx expression during glucocorticoid-induced skeletal muscle atrophy. |
| 9780 | 20371624 | Muscle atrophy is a consequence of chronic diseases (e.g., diabetes) and glucocorticoid-induced insulin resistance that results from enhanced activity of the ubiquitin-proteasome pathway. |
| 9781 | 20371624 | The PI3K/Akt pathway inhibits the FOXO-mediated transcription of the muscle-specific E3 ligase atrogin-1/MAFbx (AT-1), whereas the MEK/ERK pathway increases Sp1 activity and ubiquitin (UbC) expression. |
| 9782 | 20371624 | We tested a signaling model in which FOXO3a mediates crosstalk between the PI3K/Akt and MEK/ERK pathways to coordinate AT-1 and UbC expression. |
| 9783 | 20371624 | In rat L6 myotubes, dexamethasone (> or = 24 h) reduced insulin receptor substrate (IRS)-1 protein and PI3K/Akt signaling and increased AT-1 mRNA. |
| 9784 | 20371624 | IRS-2 protein, MEK/ERK signaling, Sp1 phosphorylation, and UbC transcription were simultaneously increased. |
| 9785 | 20371624 | Knockdown of IRS-1 using small interfering RNA or adenovirus-mediated expression of constitutively activated FOXO3a increased IRS-2 protein, MEK/ERK signaling, and UbC expression. |
| 9786 | 20371624 | Changes in PI3K/Akt and MEK/ERK signaling were recapitulated in rat muscles undergoing atrophy due to streptozotocin-induced insulin deficiency and concurrently elevated glucocorticoid production. |
| 9787 | 20371624 | IRS-1 and Akt phosphorylation were decreased, whereas MEK/ERK signaling and expression of IRS-2, UbC and AT-1 were increased. |
| 9788 | 20371624 | We conclude that FOXO3a mediates a reciprocal communication between the IRS-1/PI3K/Akt and IRS-2/MEK/ERK pathways that coordinates AT-1 and ubiquitin expression during muscle atrophy. |
| 9789 | 20371624 | FOXO3a mediates signaling crosstalk that coordinates ubiquitin and atrogin-1/MAFbx expression during glucocorticoid-induced skeletal muscle atrophy. |
| 9790 | 20371624 | Muscle atrophy is a consequence of chronic diseases (e.g., diabetes) and glucocorticoid-induced insulin resistance that results from enhanced activity of the ubiquitin-proteasome pathway. |
| 9791 | 20371624 | The PI3K/Akt pathway inhibits the FOXO-mediated transcription of the muscle-specific E3 ligase atrogin-1/MAFbx (AT-1), whereas the MEK/ERK pathway increases Sp1 activity and ubiquitin (UbC) expression. |
| 9792 | 20371624 | We tested a signaling model in which FOXO3a mediates crosstalk between the PI3K/Akt and MEK/ERK pathways to coordinate AT-1 and UbC expression. |
| 9793 | 20371624 | In rat L6 myotubes, dexamethasone (> or = 24 h) reduced insulin receptor substrate (IRS)-1 protein and PI3K/Akt signaling and increased AT-1 mRNA. |
| 9794 | 20371624 | IRS-2 protein, MEK/ERK signaling, Sp1 phosphorylation, and UbC transcription were simultaneously increased. |
| 9795 | 20371624 | Knockdown of IRS-1 using small interfering RNA or adenovirus-mediated expression of constitutively activated FOXO3a increased IRS-2 protein, MEK/ERK signaling, and UbC expression. |
| 9796 | 20371624 | Changes in PI3K/Akt and MEK/ERK signaling were recapitulated in rat muscles undergoing atrophy due to streptozotocin-induced insulin deficiency and concurrently elevated glucocorticoid production. |
| 9797 | 20371624 | IRS-1 and Akt phosphorylation were decreased, whereas MEK/ERK signaling and expression of IRS-2, UbC and AT-1 were increased. |
| 9798 | 20371624 | We conclude that FOXO3a mediates a reciprocal communication between the IRS-1/PI3K/Akt and IRS-2/MEK/ERK pathways that coordinates AT-1 and ubiquitin expression during muscle atrophy. |
| 9799 | 20371624 | FOXO3a mediates signaling crosstalk that coordinates ubiquitin and atrogin-1/MAFbx expression during glucocorticoid-induced skeletal muscle atrophy. |
| 9800 | 20371624 | Muscle atrophy is a consequence of chronic diseases (e.g., diabetes) and glucocorticoid-induced insulin resistance that results from enhanced activity of the ubiquitin-proteasome pathway. |
| 9801 | 20371624 | The PI3K/Akt pathway inhibits the FOXO-mediated transcription of the muscle-specific E3 ligase atrogin-1/MAFbx (AT-1), whereas the MEK/ERK pathway increases Sp1 activity and ubiquitin (UbC) expression. |
| 9802 | 20371624 | We tested a signaling model in which FOXO3a mediates crosstalk between the PI3K/Akt and MEK/ERK pathways to coordinate AT-1 and UbC expression. |
| 9803 | 20371624 | In rat L6 myotubes, dexamethasone (> or = 24 h) reduced insulin receptor substrate (IRS)-1 protein and PI3K/Akt signaling and increased AT-1 mRNA. |
| 9804 | 20371624 | IRS-2 protein, MEK/ERK signaling, Sp1 phosphorylation, and UbC transcription were simultaneously increased. |
| 9805 | 20371624 | Knockdown of IRS-1 using small interfering RNA or adenovirus-mediated expression of constitutively activated FOXO3a increased IRS-2 protein, MEK/ERK signaling, and UbC expression. |
| 9806 | 20371624 | Changes in PI3K/Akt and MEK/ERK signaling were recapitulated in rat muscles undergoing atrophy due to streptozotocin-induced insulin deficiency and concurrently elevated glucocorticoid production. |
| 9807 | 20371624 | IRS-1 and Akt phosphorylation were decreased, whereas MEK/ERK signaling and expression of IRS-2, UbC and AT-1 were increased. |
| 9808 | 20371624 | We conclude that FOXO3a mediates a reciprocal communication between the IRS-1/PI3K/Akt and IRS-2/MEK/ERK pathways that coordinates AT-1 and ubiquitin expression during muscle atrophy. |
| 9809 | 20383279 | Angiotensin II inhibits insulin-stimulated GLUT4 translocation and Akt activation through tyrosine nitration-dependent mechanisms. |
| 9810 | 20383279 | Angiotensin II (Ang II) plays a major role in the pathogenesis of insulin resistance and diabetes by inhibiting insulin's metabolic and potentiating its trophic effects. |
| 9811 | 20383279 | We found Ang II to block insulin-dependent GLUT4 translocation in L6 myotubes in an NO- and O(2)(*-)-dependent fashion suggesting the involvement of peroxynitrite. |
| 9812 | 20383279 | This hypothesis was confirmed by the ability of Ang II to induce tyrosine nitration of the MAP kinases ERK1/2 and of protein kinase B/Akt (Akt). |
| 9813 | 20383279 | Tyrosine nitration of ERK1/2 was required for their phosphorylation on Thr and Tyr and their subsequent activation, whereas it completely inhibited Akt phosphorylation on Ser(473) and Thr(308) as well as its activity. |
| 9814 | 20383279 | The inhibitory effect of nitration on Akt activity was confirmed by the ability of SIN-1 to completely block GSK3alpha phosphorylation in vitro. |
| 9815 | 20383279 | Inhibition of nitric oxide synthase and NAD(P)Hoxidase and scavenging of free radicals with myricetin restored insulin-stimulated Akt phosphorylation and GLUT4 translocation in the presence of Ang II. |
| 9816 | 20383279 | Similar restoration was obtained by inhibiting the ERK activating kinase MEK, indicating that these kinases regulate Akt activation. |
| 9817 | 20383279 | Taken together, our data show that Ang II inhibits insulin-mediated GLUT4 translocation in this skeletal muscle model through at least two pathways: first through the transient activation of ERK1/2 which inhibit IRS-1/2 and second through a direct inhibitory nitration of Akt. |
| 9818 | 20383279 | They underline the role of protein nitration as a major mechanism in the regulation of Ang II and insulin signaling pathways and more particularly as a key regulator of protein kinase activity. |
| 9819 | 20384568 | Direct inhibition by angiotensin II of insulin-dependent glucose transport activity in mammalian skeletal muscle involves a ROS-dependent mechanism. |
| 9820 | 20384568 | No previous study has investigated how the vaso-constrictive peptide Ang II impacts insulin action in isolated mammalian skeletal muscle. |
| 9821 | 20384568 | We investigated the molecular actions of Ang II on insulin signalling and glucose transport in skeletal muscle from lean Zucker rats. |
| 9822 | 20384568 | Soleus strips were incubated with insulin (5 mU/ml) and/or Ang II (500 nM) for 2 hours. |
| 9823 | 20384568 | Ang II caused significant (p < 0.05) inhibition of insulin-stimulated glucose transport (39%) and decreased phosphorylation of Akt Ser(473) (37%) and glycogen synthase kinase-3beta Ser(9) (42%) without affecting phosphorylation of IRS-1 Ser(307) or p38 MAPK. |
| 9824 | 20384568 | We used the superoxide dismutase mimetic, tempol (1 mM), to determine if reactive oxygen species (ROS) contribute to Ang II-mediated insulin resistance. |
| 9825 | 20384568 | Tempol partially reversed (42%) Ang II-induced inhibition of insulin-stimulated glucose transport. |
| 9826 | 20384568 | These results indicate that Ang II inhibits distal insulin signalling and insulin-stimulated glucose transport in isolated mammalian skeletal muscle, and that this effect is partially mediated by ROS. |
| 9827 | 20386866 | Conversely, mitochondrial dysfunction attenuated insulin activation of mTORC1, enhanced autophagy and attenuated feedback to IRS1. |
| 9828 | 20393162 | Lipid-induced insulin resistance is prevented in lean and obese myotubes by AICAR treatment. |
| 9829 | 20393162 | Additionally, given that AMPK-activating drugs are widely prescribed for their insulin-sensitizing effects, we sought to determine whether 5-aminoimidazole-4-carboxamide 1-beta-D-ribofuranoside (AICAR)-stimulated AMPK activation could prevent or reverse the deleterious effects of lipid on insulin signaling. |
| 9830 | 20393162 | We found that a 1-h palmitate incubation in lean myotubes reduced (P < 0.05) insulin-stimulated phosphoprotein kinase B (Akt), Akt substrate 160 (AS160), and inhibitory factor kappaBalpha (IkappaBalpha) mass, all of which were prevented with AICAR inclusion. |
| 9831 | 20393162 | With a longer incubation, we observed that myotubes from morbidly obese individuals appear to be largely resistant to the detrimental effects of 16 h lipid exposure as was evident, in contrast to the lean, by the absence of a reduction in insulin-stimulated insulin receptor substrate (IRS)-1 Tyr phosphorylation, phospho-Akt, and phospho-AS160 (P < 0.05). |
| 9832 | 20393162 | Furthermore, 16 h lipid exposure significantly reduced IkappaBalpha levels and increased phosphorylation of c-Jun NH(2)-terminal kinase (JNK) and IRS1-Ser(312) in lean myotubes only (P < 0.05). |
| 9833 | 20393162 | Despite a divergent response to lipid between lean and obese myotubes, AICAR inclusion improved insulin signaling in all myotubes. |
| 9834 | 20407209 | In contrast, cardiac insulin signaling was upregulated by chronic pressure overload because of mechanical stretch-induced activation of cardiomyocyte insulin receptors and upregulation of insulin receptor and Irs1 expression. |
| 9835 | 20430894 | Acute oxidative stress can reverse insulin resistance by inactivation of cytoplasmic JNK. |
| 9836 | 20430894 | Activation of the JNK signaling pathway can mediate many of the effects of stress on insulin resistance through inhibitory phosphorylation of insulin receptor substrate 1. |
| 9837 | 20430894 | To elucidate the mechanism underlying the contrasting effects of acute versus chronic oxidative stress on insulin sensitivity, we used a cellular model of insulin-resistant muscle to induce either chronic or acute oxidative stress and investigate their effects on insulin and JNK signaling. |
| 9838 | 20430894 | Chronic oxidative stress resulted in increased levels of phosphorylated (activated) JNK in the cytoplasm, whereas acute oxidative stress led to redistribution of JNK-specific phosphatase MKP7 from the nucleus into the cytoplasm, reduction in cytoplasmic phospho-JNK, and a concurrent accumulation of phospho-JNK in the nucleus. |
| 9839 | 20430894 | Acute oxidative stress restored normal insulin sensitivity and glucose uptake in insulin-resistant muscle cells, and this effect was dependent on MKP7. |
| 9840 | 20430894 | We propose that the contrasting effects of acute and chronic stress on insulin sensitivity are driven by changes in subcellular distribution of MKP7 and activated JNK. |
| 9841 | 20466847 | Glycogen synthase kinase 3 beta mediates high glucose-induced ubiquitination and proteasome degradation of insulin receptor substrate 1. |
| 9842 | 20466847 | Genetic and biological studies have shown that reductions in IRS1 and/or IRS2 protein levels are associated with insulin resistance. |
| 9843 | 20466847 | In this study we have shown that proteasome degradation of IRS1, but not of IRS2, is involved in HG-induced insulin resistance in Chinese hamster ovary (CHO) cells as well as in primary hepatocytes. |
| 9844 | 20466847 | To further investigate the molecular mechanism by which HG induces insulin resistance, we examined various molecular candidates with respect to their involvement in the reduction in IRS1 protein levels. |
| 9845 | 20466847 | In contrast to the insulin-induced degradation of IRS1, HG-induced degradation of IRS1 did not require IR signaling or phosphatidylinositol 3-kinase/Akt activity. |
| 9846 | 20466847 | We have identified glycogen synthase kinase 3beta (GSK3 beta or GSK3B as listed in the MGI Database) as a kinase required for HG-induced serine(332) phosphorylation, ubiquitination, and degradation of IRS1. |
| 9847 | 20466847 | Our data reveal the molecular mechanism of HG-induced insulin resistance, and support the notion that activation of GSK3 beta contributes to the induction of insulin resistance via phosphorylation of IRS1, triggering the ubiquitination and degradation of IRS1. |
| 9848 | 20466847 | Glycogen synthase kinase 3 beta mediates high glucose-induced ubiquitination and proteasome degradation of insulin receptor substrate 1. |
| 9849 | 20466847 | Genetic and biological studies have shown that reductions in IRS1 and/or IRS2 protein levels are associated with insulin resistance. |
| 9850 | 20466847 | In this study we have shown that proteasome degradation of IRS1, but not of IRS2, is involved in HG-induced insulin resistance in Chinese hamster ovary (CHO) cells as well as in primary hepatocytes. |
| 9851 | 20466847 | To further investigate the molecular mechanism by which HG induces insulin resistance, we examined various molecular candidates with respect to their involvement in the reduction in IRS1 protein levels. |
| 9852 | 20466847 | In contrast to the insulin-induced degradation of IRS1, HG-induced degradation of IRS1 did not require IR signaling or phosphatidylinositol 3-kinase/Akt activity. |
| 9853 | 20466847 | We have identified glycogen synthase kinase 3beta (GSK3 beta or GSK3B as listed in the MGI Database) as a kinase required for HG-induced serine(332) phosphorylation, ubiquitination, and degradation of IRS1. |
| 9854 | 20466847 | Our data reveal the molecular mechanism of HG-induced insulin resistance, and support the notion that activation of GSK3 beta contributes to the induction of insulin resistance via phosphorylation of IRS1, triggering the ubiquitination and degradation of IRS1. |
| 9855 | 20466847 | Glycogen synthase kinase 3 beta mediates high glucose-induced ubiquitination and proteasome degradation of insulin receptor substrate 1. |
| 9856 | 20466847 | Genetic and biological studies have shown that reductions in IRS1 and/or IRS2 protein levels are associated with insulin resistance. |
| 9857 | 20466847 | In this study we have shown that proteasome degradation of IRS1, but not of IRS2, is involved in HG-induced insulin resistance in Chinese hamster ovary (CHO) cells as well as in primary hepatocytes. |
| 9858 | 20466847 | To further investigate the molecular mechanism by which HG induces insulin resistance, we examined various molecular candidates with respect to their involvement in the reduction in IRS1 protein levels. |
| 9859 | 20466847 | In contrast to the insulin-induced degradation of IRS1, HG-induced degradation of IRS1 did not require IR signaling or phosphatidylinositol 3-kinase/Akt activity. |
| 9860 | 20466847 | We have identified glycogen synthase kinase 3beta (GSK3 beta or GSK3B as listed in the MGI Database) as a kinase required for HG-induced serine(332) phosphorylation, ubiquitination, and degradation of IRS1. |
| 9861 | 20466847 | Our data reveal the molecular mechanism of HG-induced insulin resistance, and support the notion that activation of GSK3 beta contributes to the induction of insulin resistance via phosphorylation of IRS1, triggering the ubiquitination and degradation of IRS1. |
| 9862 | 20466847 | Glycogen synthase kinase 3 beta mediates high glucose-induced ubiquitination and proteasome degradation of insulin receptor substrate 1. |
| 9863 | 20466847 | Genetic and biological studies have shown that reductions in IRS1 and/or IRS2 protein levels are associated with insulin resistance. |
| 9864 | 20466847 | In this study we have shown that proteasome degradation of IRS1, but not of IRS2, is involved in HG-induced insulin resistance in Chinese hamster ovary (CHO) cells as well as in primary hepatocytes. |
| 9865 | 20466847 | To further investigate the molecular mechanism by which HG induces insulin resistance, we examined various molecular candidates with respect to their involvement in the reduction in IRS1 protein levels. |
| 9866 | 20466847 | In contrast to the insulin-induced degradation of IRS1, HG-induced degradation of IRS1 did not require IR signaling or phosphatidylinositol 3-kinase/Akt activity. |
| 9867 | 20466847 | We have identified glycogen synthase kinase 3beta (GSK3 beta or GSK3B as listed in the MGI Database) as a kinase required for HG-induced serine(332) phosphorylation, ubiquitination, and degradation of IRS1. |
| 9868 | 20466847 | Our data reveal the molecular mechanism of HG-induced insulin resistance, and support the notion that activation of GSK3 beta contributes to the induction of insulin resistance via phosphorylation of IRS1, triggering the ubiquitination and degradation of IRS1. |
| 9869 | 20466847 | Glycogen synthase kinase 3 beta mediates high glucose-induced ubiquitination and proteasome degradation of insulin receptor substrate 1. |
| 9870 | 20466847 | Genetic and biological studies have shown that reductions in IRS1 and/or IRS2 protein levels are associated with insulin resistance. |
| 9871 | 20466847 | In this study we have shown that proteasome degradation of IRS1, but not of IRS2, is involved in HG-induced insulin resistance in Chinese hamster ovary (CHO) cells as well as in primary hepatocytes. |
| 9872 | 20466847 | To further investigate the molecular mechanism by which HG induces insulin resistance, we examined various molecular candidates with respect to their involvement in the reduction in IRS1 protein levels. |
| 9873 | 20466847 | In contrast to the insulin-induced degradation of IRS1, HG-induced degradation of IRS1 did not require IR signaling or phosphatidylinositol 3-kinase/Akt activity. |
| 9874 | 20466847 | We have identified glycogen synthase kinase 3beta (GSK3 beta or GSK3B as listed in the MGI Database) as a kinase required for HG-induced serine(332) phosphorylation, ubiquitination, and degradation of IRS1. |
| 9875 | 20466847 | Our data reveal the molecular mechanism of HG-induced insulin resistance, and support the notion that activation of GSK3 beta contributes to the induction of insulin resistance via phosphorylation of IRS1, triggering the ubiquitination and degradation of IRS1. |
| 9876 | 20466847 | Glycogen synthase kinase 3 beta mediates high glucose-induced ubiquitination and proteasome degradation of insulin receptor substrate 1. |
| 9877 | 20466847 | Genetic and biological studies have shown that reductions in IRS1 and/or IRS2 protein levels are associated with insulin resistance. |
| 9878 | 20466847 | In this study we have shown that proteasome degradation of IRS1, but not of IRS2, is involved in HG-induced insulin resistance in Chinese hamster ovary (CHO) cells as well as in primary hepatocytes. |
| 9879 | 20466847 | To further investigate the molecular mechanism by which HG induces insulin resistance, we examined various molecular candidates with respect to their involvement in the reduction in IRS1 protein levels. |
| 9880 | 20466847 | In contrast to the insulin-induced degradation of IRS1, HG-induced degradation of IRS1 did not require IR signaling or phosphatidylinositol 3-kinase/Akt activity. |
| 9881 | 20466847 | We have identified glycogen synthase kinase 3beta (GSK3 beta or GSK3B as listed in the MGI Database) as a kinase required for HG-induced serine(332) phosphorylation, ubiquitination, and degradation of IRS1. |
| 9882 | 20466847 | Our data reveal the molecular mechanism of HG-induced insulin resistance, and support the notion that activation of GSK3 beta contributes to the induction of insulin resistance via phosphorylation of IRS1, triggering the ubiquitination and degradation of IRS1. |
| 9883 | 20466847 | Glycogen synthase kinase 3 beta mediates high glucose-induced ubiquitination and proteasome degradation of insulin receptor substrate 1. |
| 9884 | 20466847 | Genetic and biological studies have shown that reductions in IRS1 and/or IRS2 protein levels are associated with insulin resistance. |
| 9885 | 20466847 | In this study we have shown that proteasome degradation of IRS1, but not of IRS2, is involved in HG-induced insulin resistance in Chinese hamster ovary (CHO) cells as well as in primary hepatocytes. |
| 9886 | 20466847 | To further investigate the molecular mechanism by which HG induces insulin resistance, we examined various molecular candidates with respect to their involvement in the reduction in IRS1 protein levels. |
| 9887 | 20466847 | In contrast to the insulin-induced degradation of IRS1, HG-induced degradation of IRS1 did not require IR signaling or phosphatidylinositol 3-kinase/Akt activity. |
| 9888 | 20466847 | We have identified glycogen synthase kinase 3beta (GSK3 beta or GSK3B as listed in the MGI Database) as a kinase required for HG-induced serine(332) phosphorylation, ubiquitination, and degradation of IRS1. |
| 9889 | 20466847 | Our data reveal the molecular mechanism of HG-induced insulin resistance, and support the notion that activation of GSK3 beta contributes to the induction of insulin resistance via phosphorylation of IRS1, triggering the ubiquitination and degradation of IRS1. |
| 9890 | 20560104 | It was shown previously in hepatocytes that the UPR activates c-jun N-terminal kinase (JNK), which phosphorylates insulin receptor substrate (IRS) proteins on serine residues thereby inhibiting insulin signal transduction. |
| 9891 | 20560104 | Concomitantly, insulin-induced activation of Akt/PKB and of ERK1/2 was strongly inhibited. |
| 9892 | 20560104 | Ectopic expression of IRS1 or IRS2 strongly counteracted the inhibitory effect of ER stress on insulin signaling while pharmacological inhibition of JNK with SP600125 resulted only in a mild improvement. |
| 9893 | 20560104 | ER stress decreased the secretion of the adipokines adiponectin and leptin, but strongly increased secretion of IL-6. |
| 9894 | 20573722 | Glucagon secretion, insulin and IGF-IR autophosphorylation, and insulin receptor substrate (IRS)-1, IRS-2, phosphatidylinositol kinase (PI3K) (p85 alpha), and serine-threonine protein kinase (Akt) phosphorylated (active) forms were measured. |
| 9895 | 20573722 | Because MAPK can regulate Pax6, a transcription factor that controls glucagon expression, paired box gene 6 (Pax6) and glucagon gene and protein expression were also measured. |
| 9896 | 20573722 | Insulin-stimulated insulin receptor phosphorylation was greatly reduced by exposure to palmitate. |
| 9897 | 20573722 | Similar results were observed with IRS-1-P, PI3K (p85 alpha), and Akt-P. |
| 9898 | 20573722 | In these cells cultured, specifics MAPKs inhibitors were able to reduce both Pax6 and glucagon gene and protein expression. |
| 9899 | 20573722 | These results indicate that alpha-cells exposed to palmitate show insulin resistance of the IRS-1/PI3K/Akt pathway that likely controls glucagon secretion. |
| 9900 | 20573722 | In contrast, the IRS-2/MAPKs pathway is stimulated, through an activation of the IGF-IR, leading to increased Pax6 and glucagon expression. |
| 9901 | 20584981 | Both insulin and bone morphogenetic protein (BMP) signaling systems are important for adipocyte differentiation. |
| 9902 | 20584981 | Analysis of gene expression in BMP7-treated fibroblasts revealed a coordinated change in insulin signaling components by BMP7. |
| 9903 | 20584981 | To further investigate the cross talk between insulin and BMP signaling systems in brown adipogenesis, we examined the effect of BMP7 in insulin receptor substrate 1 (IRS-1)-deficient brown preadipocytes, which exhibit a severe defect in differentiation. |
| 9904 | 20584981 | The high level of adipogenic inhibitor preadipocyte factor 1 (Pref-1) in IRS-1-null cells was markedly reduced by 3 days of BMP7 treatment, and analysis of the 1.3-kb pref-1 promoter revealed 9 putative Smad binding elements (SBEs), suggesting that BMP7 could directly suppress Pref-1 expression, thereby allowing the initiation of the adipogenic program. |
| 9905 | 20584981 | Together, these data suggest cross talk between the insulin and BMP signaling systems by which BMP7 can rescue brown adipogenesis in cells with insulin resistance. |
| 9906 | 20601126 | Molecular mechanism of angiotensin II-induced insulin resistance in aortic vascular smooth muscle cells: roles of Protein Tyrosine Phosphatase-1B. |
| 9907 | 20601126 | Recent evidence suggests that crosstalk between angiotensin II (Ang II) and the insulin signaling in vascular smooth muscle cell (VSMC) may contribute to cellular insulin resistance. |
| 9908 | 20601126 | We hypothesized that Ang II inhibits the anti-mitogenic pathways while enhancing the mitogenic pathways stimulated by insulin via activation of Protein Tyrosine Phosphatase-1B (PTP-1B) in VSMC. |
| 9909 | 20601126 | We found that Ang II significantly inhibited insulin-induced phosphorylation of tyrosine 608 of IRS-1 and serine 473 of Akt, a downstream member of anti-mitogenic pathway of insulin. |
| 9910 | 20601126 | In contrast, Ang II increased the serine phosphorylation of IRS-1 which was not affected by the presence of insulin. |
| 9911 | 20601126 | Activation of p42/p44 MAPK (a mitogenic pathway) induced by insulin was further enhanced by Ang II. |
| 9912 | 20601126 | Transfection of VSMC with PTP-1B antisense oligonucleotide markedly reduced the effects of Ang II on insulin signaling. |
| 9913 | 20601126 | Furthermore, an increase in VSMC growth was attenuated by PTP-1B antisense only in the presence of both Ang II and insulin. |
| 9914 | 20601126 | Finally, we also showed that Ang II-induced activation of PTP-1B in VSMC was PKA/JAK2 dependent. |
| 9915 | 20601126 | We conclude that Ang II modulates both anti-mitogenic and mitogenic pathways of insulin via the activation of PTP-1B. |
| 9916 | 20601126 | Molecular mechanism of angiotensin II-induced insulin resistance in aortic vascular smooth muscle cells: roles of Protein Tyrosine Phosphatase-1B. |
| 9917 | 20601126 | Recent evidence suggests that crosstalk between angiotensin II (Ang II) and the insulin signaling in vascular smooth muscle cell (VSMC) may contribute to cellular insulin resistance. |
| 9918 | 20601126 | We hypothesized that Ang II inhibits the anti-mitogenic pathways while enhancing the mitogenic pathways stimulated by insulin via activation of Protein Tyrosine Phosphatase-1B (PTP-1B) in VSMC. |
| 9919 | 20601126 | We found that Ang II significantly inhibited insulin-induced phosphorylation of tyrosine 608 of IRS-1 and serine 473 of Akt, a downstream member of anti-mitogenic pathway of insulin. |
| 9920 | 20601126 | In contrast, Ang II increased the serine phosphorylation of IRS-1 which was not affected by the presence of insulin. |
| 9921 | 20601126 | Activation of p42/p44 MAPK (a mitogenic pathway) induced by insulin was further enhanced by Ang II. |
| 9922 | 20601126 | Transfection of VSMC with PTP-1B antisense oligonucleotide markedly reduced the effects of Ang II on insulin signaling. |
| 9923 | 20601126 | Furthermore, an increase in VSMC growth was attenuated by PTP-1B antisense only in the presence of both Ang II and insulin. |
| 9924 | 20601126 | Finally, we also showed that Ang II-induced activation of PTP-1B in VSMC was PKA/JAK2 dependent. |
| 9925 | 20601126 | We conclude that Ang II modulates both anti-mitogenic and mitogenic pathways of insulin via the activation of PTP-1B. |
| 9926 | 20624962 | We found that p66 deficiency exerts a modest but significant protective effect on fat accumulation and premature death in lepOb/Ob mice, an established genetic model of obesity and insulin resistance; strikingly, however, p66 inactivation improved glucose tolerance in these animals, without affecting (hyper)insulinaemia and independent of body weight. |
| 9927 | 20624962 | Biochemical studies revealed that p66shc promotes the signal-inhibitory phosphorylation of the major insulin transducer IRS-1, by bridging IRS-1 and the mTOR effector p70S6 kinase, a molecule previously linked to obesity-induced insulin resistance. |
| 9928 | 20624962 | Importantly, IRS-1 was strongly up-regulated in the adipose tissue of p66KO lepOb/Ob mice, confirming that effects of p66 on tissue responsiveness to insulin are largely mediated by this molecule. |
| 9929 | 20624962 | Taken together, these findings identify p66shc as a major mediator of insulin resistance by excess nutrients, and by extension, as a potential molecular target against the spreading epidemic of obesity and type II diabetes. |
| 9930 | 20624962 | We found that p66 deficiency exerts a modest but significant protective effect on fat accumulation and premature death in lepOb/Ob mice, an established genetic model of obesity and insulin resistance; strikingly, however, p66 inactivation improved glucose tolerance in these animals, without affecting (hyper)insulinaemia and independent of body weight. |
| 9931 | 20624962 | Biochemical studies revealed that p66shc promotes the signal-inhibitory phosphorylation of the major insulin transducer IRS-1, by bridging IRS-1 and the mTOR effector p70S6 kinase, a molecule previously linked to obesity-induced insulin resistance. |
| 9932 | 20624962 | Importantly, IRS-1 was strongly up-regulated in the adipose tissue of p66KO lepOb/Ob mice, confirming that effects of p66 on tissue responsiveness to insulin are largely mediated by this molecule. |
| 9933 | 20624962 | Taken together, these findings identify p66shc as a major mediator of insulin resistance by excess nutrients, and by extension, as a potential molecular target against the spreading epidemic of obesity and type II diabetes. |
| 9934 | 20640583 | Although the canonical NF-κB cascade was not activated, STZ induced a decrease in insulin pathway proteins including insulin receptor (IR) and substrate (IRS-1) content and phosphorylation compared to control animals. |
| 9935 | 20683642 | SOCS3 inhibits insulin signaling in porcine primary adipocytes. |
| 9936 | 20683642 | SOCS3 plays an important role in the development of insulin resistance. |
| 9937 | 20683642 | To investigate the role of SOCS3 in porcine adipocyte insulin signaling, we first detected the effect of insulin on SOCS3 mRNA and protein expression in porcine primary adipocytes by real-time RT-PCR and Western blotting. |
| 9938 | 20683642 | The results showed that 100 nM insulin could induce SOCS3 mRNA expression but not protein expression, and overexpression of SOCS3 decreased IRS1 protein level, insulin-stimulated IRS1 tyrosine phosphorylation, PI3K activation, and Akt phosphorylation, but increased IRS1 serine phosphorylation in porcine primary adipocytes. |
| 9939 | 20683642 | These results indicate that SOCS3 is an important negative regulator of insulin signaling in porcine adipocytes. |
| 9940 | 20683642 | Thus, SOCS3 may be a novel therapeutic target for the prevention or treatment of insulin resistance and type II diabetes. |
| 9941 | 20693650 | Quantitative RT-PCR analysis revealed significant alterations in expression of several genes needed for insulin and IGF-I signaling, and multiplex ELISAs demonstrated inhibition of signaling through the insulin or IGF-1 receptors, IRS-1, and Akt in both liver and brain. |
| 9942 | 20714323 | Vitamin D inhibits CEACAM1 to promote insulin/IGF-I receptor signaling without compromising anti-proliferative action. |
| 9943 | 20714323 | The insulin/IGF-I receptor represents a signaling target of the carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) that is implicated in both diabetes and cancer, therefore we hypothesized that VD actions may be mediated through this adhesion molecule. |
| 9944 | 20714323 | Insulin/IGF-I-mediated IRS-1 and Akt activation were enhanced by VD treatment. |
| 9945 | 20714323 | Similarly, CEACAM1 downregulation significantly upregulated the insulin and IGF-I receptors and mimicked the effect of VD-mediated enhanced insulin/IGF-I receptor signaling. |
| 9946 | 20714323 | Despite improved insulin/IGF-I signaling, the anti-proliferative actions of VD were preserved in the absence or presence of forced CEACAM1 expression. |
| 9947 | 20798864 | Metformin Improves Insulin Signaling in Obese Rats via Reduced IKKbeta Action in a Fiber-Type Specific Manner. |
| 9948 | 20798864 | The aim of this study was to (1) determine the ability of metformin to attenuate IKKbeta action, (2) determine whether changes in AMPK activity are associated with changes in IKKbeta action in skeletal muscle, and (3) examine whether changes in AMPK and IKKbeta function are consistent with improved insulin signaling. |
| 9949 | 20798864 | Further, metformin increased IkappaBalpha levels in both WG (150%) and RG (67%) of obese rats, indicative of reduced IKKbeta activity (P < .05), and was associated with reduced IRS1-pSer(307) (30%) in the WG of obese rats (P < .02). |
| 9950 | 20798864 | From these data we conclude that metformin treatment appears to exert an inhibitory influence on skeletal muscle IKKbeta activity, as evidenced by elevated IkappaBalpha levels and reduced IRS1-Ser(307) phosphorylation in a fiber-type specific manner. |
| 9951 | 20798864 | Metformin Improves Insulin Signaling in Obese Rats via Reduced IKKbeta Action in a Fiber-Type Specific Manner. |
| 9952 | 20798864 | The aim of this study was to (1) determine the ability of metformin to attenuate IKKbeta action, (2) determine whether changes in AMPK activity are associated with changes in IKKbeta action in skeletal muscle, and (3) examine whether changes in AMPK and IKKbeta function are consistent with improved insulin signaling. |
| 9953 | 20798864 | Further, metformin increased IkappaBalpha levels in both WG (150%) and RG (67%) of obese rats, indicative of reduced IKKbeta activity (P < .05), and was associated with reduced IRS1-pSer(307) (30%) in the WG of obese rats (P < .02). |
| 9954 | 20798864 | From these data we conclude that metformin treatment appears to exert an inhibitory influence on skeletal muscle IKKbeta activity, as evidenced by elevated IkappaBalpha levels and reduced IRS1-Ser(307) phosphorylation in a fiber-type specific manner. |
| 9955 | 20813836 | In this report, we show that phenylmethimazole (C10) blocks basal IL6 and leptin production as well as basal Socs-3 expression in fully differentiated 3T3L1 cells (3T3L1 adipocytes) without affecting insulin-stimulated AKT signaling. |
| 9956 | 20813836 | In addition, C10 inhibits palmitate-induced IL6 and iNos up-regulation in both 3T3L1 adipocytes and RAW 264.7 macrophages, LPS-induced NF-κB and IFN-β activation in 3T3L1 cells, and LPS-induced iNos, Ifn-β, Il1β, Cxcl10, and Il6 expression in RAW 264.7 macrophages. |
| 9957 | 20813836 | C10 also blocks palmitate-induced Socs-3 up-regulation and insulin receptor substrate-1 (IRS-1) serine 307 phosphorylation in 3T3L1 adipocytes. |
| 9958 | 20813836 | Additionally, we show for the first time that although palmitate increases IRS-1 serine 307 phosphorylation in 3T3L1 adipocytes, AKT serine 473 phosphorylation is enhanced, not reduced, by palmitate. |
| 9959 | 20813836 | In this report, we show that phenylmethimazole (C10) blocks basal IL6 and leptin production as well as basal Socs-3 expression in fully differentiated 3T3L1 cells (3T3L1 adipocytes) without affecting insulin-stimulated AKT signaling. |
| 9960 | 20813836 | In addition, C10 inhibits palmitate-induced IL6 and iNos up-regulation in both 3T3L1 adipocytes and RAW 264.7 macrophages, LPS-induced NF-κB and IFN-β activation in 3T3L1 cells, and LPS-induced iNos, Ifn-β, Il1β, Cxcl10, and Il6 expression in RAW 264.7 macrophages. |
| 9961 | 20813836 | C10 also blocks palmitate-induced Socs-3 up-regulation and insulin receptor substrate-1 (IRS-1) serine 307 phosphorylation in 3T3L1 adipocytes. |
| 9962 | 20813836 | Additionally, we show for the first time that although palmitate increases IRS-1 serine 307 phosphorylation in 3T3L1 adipocytes, AKT serine 473 phosphorylation is enhanced, not reduced, by palmitate. |
| 9963 | 20855122 | Taurine prevents free fatty acid-induced hepatic insulin resistance in association with inhibiting JNK1 activation and improving insulin signaling in vivo. |
| 9964 | 20855122 | Co-infusion of taurine was designed for the purpose of studying the effects of taurine on insulin sensitivity, oxidative stress, c-Jun NH-terminal kinase (JNK)1 activity and insulin signaling in livers of prolonged IH-infused rats. |
| 9965 | 20855122 | IH also increased JNK1 activity and insulin receptor substrate 1/2 (IRS-1/2) serine phosphorylation, reduced insulin-stimulated IRS-1/2 tyrosine phosphorylation and Akt serine 473 phosphorylation, and induced hepatic insulin resistance. |
| 9966 | 20855122 | Taurine co-infusion with IH prevented the rise in 8-isoprostaglandin and MDA, inhibited the activation of JNK1, and improved insulin signaling and insulin resistance in liver. |
| 9967 | 20855122 | And this effect may be associated with the inhibition of JNK1 activation and the improvement of insulin signaling. |
| 9968 | 20947509 | Genetic analysis of type-1 insulin-like growth factor receptor signaling through insulin receptor substrate-1 and -2 in pancreatic beta cells. |
| 9969 | 20947509 | Inactivation of insulin receptor (InsR), IGF1 receptor (Igf1r), or Irs1 in β cells impairs insulin secretion. |
| 9970 | 20947509 | To examine genetically the involvement of Irs1 and Irs2 in Igf1r signaling, we generated double mutant mice lacking Igf1r specifically in pancreatic β cells in an Irs1- or Irs2-null background. |
| 9971 | 20947509 | We show that Igf1r/Irs1 double mutants do not differ phenotypically from Irs1 single mutants and exhibit hyperinsulinemia, while maintaining normal β cell mass and glucose tolerance. |
| 9972 | 20947509 | In contrast, lack of Igf1r function in β cells aggravates the consequences of Irs2 ablation in double mutants and results in lethal diabetes by 6 weeks of age. |
| 9973 | 20947509 | This additivity of phenotypic manifestations indicates that Irs2 serves a pathway that is largely independent of Igf1r signaling. |
| 9974 | 20947509 | Consistent with the view that the latter is the InsR pathway, we show that combined β cell-specific knock-out of both Insr and Igf1r results in a phenocopy of double mutants lacking Igf1r and Irs2. |
| 9975 | 20947509 | We conclude that Igf1r signals primarily through Irs1 and affects insulin secretion, whereas β cell proliferation is mainly regulated by InsR using Irs2 as a downstream signaling effector. |
| 9976 | 20947509 | Genetic analysis of type-1 insulin-like growth factor receptor signaling through insulin receptor substrate-1 and -2 in pancreatic beta cells. |
| 9977 | 20947509 | Inactivation of insulin receptor (InsR), IGF1 receptor (Igf1r), or Irs1 in β cells impairs insulin secretion. |
| 9978 | 20947509 | To examine genetically the involvement of Irs1 and Irs2 in Igf1r signaling, we generated double mutant mice lacking Igf1r specifically in pancreatic β cells in an Irs1- or Irs2-null background. |
| 9979 | 20947509 | We show that Igf1r/Irs1 double mutants do not differ phenotypically from Irs1 single mutants and exhibit hyperinsulinemia, while maintaining normal β cell mass and glucose tolerance. |
| 9980 | 20947509 | In contrast, lack of Igf1r function in β cells aggravates the consequences of Irs2 ablation in double mutants and results in lethal diabetes by 6 weeks of age. |
| 9981 | 20947509 | This additivity of phenotypic manifestations indicates that Irs2 serves a pathway that is largely independent of Igf1r signaling. |
| 9982 | 20947509 | Consistent with the view that the latter is the InsR pathway, we show that combined β cell-specific knock-out of both Insr and Igf1r results in a phenocopy of double mutants lacking Igf1r and Irs2. |
| 9983 | 20947509 | We conclude that Igf1r signals primarily through Irs1 and affects insulin secretion, whereas β cell proliferation is mainly regulated by InsR using Irs2 as a downstream signaling effector. |
| 9984 | 20947509 | Genetic analysis of type-1 insulin-like growth factor receptor signaling through insulin receptor substrate-1 and -2 in pancreatic beta cells. |
| 9985 | 20947509 | Inactivation of insulin receptor (InsR), IGF1 receptor (Igf1r), or Irs1 in β cells impairs insulin secretion. |
| 9986 | 20947509 | To examine genetically the involvement of Irs1 and Irs2 in Igf1r signaling, we generated double mutant mice lacking Igf1r specifically in pancreatic β cells in an Irs1- or Irs2-null background. |
| 9987 | 20947509 | We show that Igf1r/Irs1 double mutants do not differ phenotypically from Irs1 single mutants and exhibit hyperinsulinemia, while maintaining normal β cell mass and glucose tolerance. |
| 9988 | 20947509 | In contrast, lack of Igf1r function in β cells aggravates the consequences of Irs2 ablation in double mutants and results in lethal diabetes by 6 weeks of age. |
| 9989 | 20947509 | This additivity of phenotypic manifestations indicates that Irs2 serves a pathway that is largely independent of Igf1r signaling. |
| 9990 | 20947509 | Consistent with the view that the latter is the InsR pathway, we show that combined β cell-specific knock-out of both Insr and Igf1r results in a phenocopy of double mutants lacking Igf1r and Irs2. |
| 9991 | 20947509 | We conclude that Igf1r signals primarily through Irs1 and affects insulin secretion, whereas β cell proliferation is mainly regulated by InsR using Irs2 as a downstream signaling effector. |
| 9992 | 20947509 | Genetic analysis of type-1 insulin-like growth factor receptor signaling through insulin receptor substrate-1 and -2 in pancreatic beta cells. |
| 9993 | 20947509 | Inactivation of insulin receptor (InsR), IGF1 receptor (Igf1r), or Irs1 in β cells impairs insulin secretion. |
| 9994 | 20947509 | To examine genetically the involvement of Irs1 and Irs2 in Igf1r signaling, we generated double mutant mice lacking Igf1r specifically in pancreatic β cells in an Irs1- or Irs2-null background. |
| 9995 | 20947509 | We show that Igf1r/Irs1 double mutants do not differ phenotypically from Irs1 single mutants and exhibit hyperinsulinemia, while maintaining normal β cell mass and glucose tolerance. |
| 9996 | 20947509 | In contrast, lack of Igf1r function in β cells aggravates the consequences of Irs2 ablation in double mutants and results in lethal diabetes by 6 weeks of age. |
| 9997 | 20947509 | This additivity of phenotypic manifestations indicates that Irs2 serves a pathway that is largely independent of Igf1r signaling. |
| 9998 | 20947509 | Consistent with the view that the latter is the InsR pathway, we show that combined β cell-specific knock-out of both Insr and Igf1r results in a phenocopy of double mutants lacking Igf1r and Irs2. |
| 9999 | 20947509 | We conclude that Igf1r signals primarily through Irs1 and affects insulin secretion, whereas β cell proliferation is mainly regulated by InsR using Irs2 as a downstream signaling effector. |
| 10000 | 20947509 | Genetic analysis of type-1 insulin-like growth factor receptor signaling through insulin receptor substrate-1 and -2 in pancreatic beta cells. |
| 10001 | 20947509 | Inactivation of insulin receptor (InsR), IGF1 receptor (Igf1r), or Irs1 in β cells impairs insulin secretion. |
| 10002 | 20947509 | To examine genetically the involvement of Irs1 and Irs2 in Igf1r signaling, we generated double mutant mice lacking Igf1r specifically in pancreatic β cells in an Irs1- or Irs2-null background. |
| 10003 | 20947509 | We show that Igf1r/Irs1 double mutants do not differ phenotypically from Irs1 single mutants and exhibit hyperinsulinemia, while maintaining normal β cell mass and glucose tolerance. |
| 10004 | 20947509 | In contrast, lack of Igf1r function in β cells aggravates the consequences of Irs2 ablation in double mutants and results in lethal diabetes by 6 weeks of age. |
| 10005 | 20947509 | This additivity of phenotypic manifestations indicates that Irs2 serves a pathway that is largely independent of Igf1r signaling. |
| 10006 | 20947509 | Consistent with the view that the latter is the InsR pathway, we show that combined β cell-specific knock-out of both Insr and Igf1r results in a phenocopy of double mutants lacking Igf1r and Irs2. |
| 10007 | 20947509 | We conclude that Igf1r signals primarily through Irs1 and affects insulin secretion, whereas β cell proliferation is mainly regulated by InsR using Irs2 as a downstream signaling effector. |
| 10008 | 20979575 | Compared with the subcutaneous arterioles of lean subjects, obesity activated the endothelium, enhanced the accumulation of collagen within vascular wall and increased the sensitivity of adrenergic response; obesity also diminished eNOS (endothelial NO synthase) protein expression, NO production, and endothelium-dependent and insulin-induced vasodilatation, as well as the protein expression of both IRS (insulin receptor substrates)-1 and IRS-2 and of the downstream molecules in the insulin signalling pathway, such as PI3K (phosphoinositide 3-kinase), phospho-Akt and Akt. |
| 10009 | 20979575 | In conclusion, obesity alone or obesity associated with Type 2 diabetes alters human periumbilical adipose tissue arterioles in terms of structure, function and biochemsitry, including diminished eNOS expression and reduced levels of IRS-1, IRS-2, PI3K and Akt in the insulin signalling pathway. |
| 10010 | 21072680 | Over-expression of LYRM1 inhibits glucose transport in rat skeletal muscles via attenuated phosphorylation of PI3K (p85) and Akt. |
| 10011 | 21072680 | Western blotting was performed to assess the translocation of insulin-sensitive glucose transporter 4 (GLUT4). |
| 10012 | 21072680 | It was also used to measure the phosphorylation and total protein contents of insulin-signaling proteins, such as the insulin receptor (IR), insulin receptor substrate (IRS)-1, phosphatidylinositol-3-kinase (PI3K) p85, Akt, ERK1/2, P38, and JNK. |
| 10013 | 21072680 | LYRM1 over-expression in L6 myotubes reduced insulin-stimulated glucose uptake and impaired insulin-stimulated GLUT4 translocation. |
| 10014 | 21072680 | It also diminished insulin-stimulated tyrosine phosphorylation of IRS-1, PI3K (p85), and serine phosphorylation of Akt without affecting the phosphorylation of IR, ERK1/2, P38, and JNK. |
| 10015 | 21072680 | LYRM1 regulates the function of IRS-1, PI3K, and Akt, and decreases GLUT4 translocation and glucose uptake in response to insulin. |
| 10016 | 21072680 | Over-expression of LYRM1 inhibits glucose transport in rat skeletal muscles via attenuated phosphorylation of PI3K (p85) and Akt. |
| 10017 | 21072680 | Western blotting was performed to assess the translocation of insulin-sensitive glucose transporter 4 (GLUT4). |
| 10018 | 21072680 | It was also used to measure the phosphorylation and total protein contents of insulin-signaling proteins, such as the insulin receptor (IR), insulin receptor substrate (IRS)-1, phosphatidylinositol-3-kinase (PI3K) p85, Akt, ERK1/2, P38, and JNK. |
| 10019 | 21072680 | LYRM1 over-expression in L6 myotubes reduced insulin-stimulated glucose uptake and impaired insulin-stimulated GLUT4 translocation. |
| 10020 | 21072680 | It also diminished insulin-stimulated tyrosine phosphorylation of IRS-1, PI3K (p85), and serine phosphorylation of Akt without affecting the phosphorylation of IR, ERK1/2, P38, and JNK. |
| 10021 | 21072680 | LYRM1 regulates the function of IRS-1, PI3K, and Akt, and decreases GLUT4 translocation and glucose uptake in response to insulin. |
| 10022 | 21088934 | To investigate insulin sensitivity within the liver, serine phosphorylation of IRS-1 (Ser307) and Akt (Ser473) and expression of gluconeogenic genes, PEPCK and G6Pase, were tested. |
| 10023 | 21088934 | In the diabetic (DM) group, IRS-1 phosphorylation was increased (P < 0.05), Akt phosphorylation was reduced (P < 0.05), expression of PEPCK and G6Pase was elevated (P < 0.05), and ER stress markers were up-regulated (P < 0.05) relative to the non-diabetic rats. |
| 10024 | 21088934 | In addition, c-Jun N-terminal kinase (JNK) activity and SREBP-1 expression were decreased (P < 0.05). |
| 10025 | 21088934 | To investigate insulin sensitivity within the liver, serine phosphorylation of IRS-1 (Ser307) and Akt (Ser473) and expression of gluconeogenic genes, PEPCK and G6Pase, were tested. |
| 10026 | 21088934 | In the diabetic (DM) group, IRS-1 phosphorylation was increased (P < 0.05), Akt phosphorylation was reduced (P < 0.05), expression of PEPCK and G6Pase was elevated (P < 0.05), and ER stress markers were up-regulated (P < 0.05) relative to the non-diabetic rats. |
| 10027 | 21088934 | In addition, c-Jun N-terminal kinase (JNK) activity and SREBP-1 expression were decreased (P < 0.05). |
| 10028 | 21119640 | Disruption of TBP-2 ameliorates insulin sensitivity and secretion without affecting obesity. |
| 10029 | 21119640 | In this study, we show that disruption of thioredoxin binding protein-2 (TBP-2, also called Txnip) in obese mice (ob/ob) dramatically improves hyperglycaemia and glucose intolerance, without affecting obesity or adipocytokine concentrations. |
| 10030 | 21119640 | TBP-2-deficient ob/ob mice exhibited enhanced insulin sensitivity with activated insulin receptor substrate-1/Akt signalling in skeletal muscle and GSIS in islets compared with ob/ob mice. |
| 10031 | 21119640 | The elevation of uncoupling protein-2 (UCP-2) expression in ob/ob islets was downregulated by TBP-2 deficiency. |
| 10032 | 21119640 | In β-cells, TBP-2 enhanced the expression level and transcriptional activity of UCP-2 by recruitment of peroxisome proliferator-activated receptor-γ co-activator-1α to the UCP-2 promoter. |
| 10033 | 21119640 | Thus, TBP-2 is a key regulatory molecule of both insulin sensitivity and GSIS in diabetes, raising the possibility that inhibition of TBP-2 may be a novel therapeutic approach for T2DM. |
| 10034 | 21123564 | Leptin rapidly improves glucose homeostasis in obese mice by increasing hypothalamic insulin sensitivity. |
| 10035 | 21123564 | Obesity is associated with resistance to the actions of both leptin and insulin via mechanisms that remain incompletely understood. |
| 10036 | 21123564 | To investigate whether leptin resistance per se contributes to insulin resistance and impaired glucose homeostasis, we investigated the effect of acute leptin administration on glucose homeostasis in normal as well as leptin- or leptin receptor-deficient mice. |
| 10037 | 21123564 | In hyperglycemic, leptin-deficient Lep(ob/ob) mice, leptin acutely and potently improved glucose metabolism, before any change of body fat mass, via a mechanism involving the p110α and β isoforms of phosphatidylinositol-3-kinase (PI3K). |
| 10038 | 21123564 | Unlike insulin, however, the anti-diabetic effect of leptin occurred independently of phospho-AKT, a major downstream target of PI3K, and instead involved enhanced sensitivity of the hypothalamus to insulin action upstream of PI3K, through modulation of IRS1 (insulin receptor substrate 1) phosphorylation. |
| 10039 | 21123564 | These data suggest that leptin resistance, as occurs in obesity, reduces the hypothalamic response to insulin and thereby impairs peripheral glucose homeostasis, contributing to the development of type 2 diabetes. |
| 10040 | 21136963 | Mediators of insulin resistance operate through activation of various protein kinase C isoforms, IκB kinase β (IKKβ), and/or c-Jun N-terminal kinase, and subsequent inhibition of the proximal insulin signaling pathway via the insulin receptor substrate 1 and Akt. |
| 10041 | 21136963 | Of interest, the increase in protein kinase C signaling responses with phorbol esters was associated with activation of the lipid phosphatase PTEN and a 27 kDa HSP. |
| 10042 | 21153603 | ANG II type I receptor antagonism improved nitric oxide production and enhanced eNOS and PKB/Akt expression in hearts from a rat model of insulin resistance. |
| 10043 | 21153603 | Exogenous insulin therapy improves endothelial function in insulin resistant patients, indirectly indicating that nitric oxide synthase activity and NO production may be impaired. |
| 10044 | 21153603 | Insulin stimulates production of NO by activating a signaling pathway including insulin receptor substrate-1, phosphatidylinositol-3-kinase and protein kinase B (PKB/Akt). |
| 10045 | 21153603 | Angiotensin II type I (AT1) receptor-evoked oxidative stress is implicated in the inactivation of NO, impairing endothelium-dependent vasodilatation. |
| 10046 | 21153603 | Blocking the actions of Angiotensin II with an AT1 receptor antagonist (Losartan), has beneficial effects in patients with insulin resistance or type 2 diabetes mellitus. |
| 10047 | 21153603 | This study investigated whether elevated Angiotensin II influences myocardial insulin resistance, insulin signaling and NO production in a rat model of diet-induced obesity (DIO) by antagonizing the actions of the AT1 receptor with Losartan. |
| 10048 | 21153603 | Results showed that hearts from DIO rats are insulin resistant (higher serine phosphorylation of IRS-1, lower insulin-stimulated phosphorylation of PKB/Akt and eNOS, lower NO production) and had poorer functional recovery and larger infarct development after ischaemia/reperfusion. |
| 10049 | 21153603 | Data obtained from Losartan treatment also revealed that Angiotensin II signaling modulates myocardial PKB/Akt expression. |
| 10050 | 21153603 | We conclude that Angiotensin II signaling exacerbates inhibition of NO production in insulin resistance and that this can be improved by AT1 antagonism. |
| 10051 | 21153603 | ANG II type I receptor antagonism improved nitric oxide production and enhanced eNOS and PKB/Akt expression in hearts from a rat model of insulin resistance. |
| 10052 | 21153603 | Exogenous insulin therapy improves endothelial function in insulin resistant patients, indirectly indicating that nitric oxide synthase activity and NO production may be impaired. |
| 10053 | 21153603 | Insulin stimulates production of NO by activating a signaling pathway including insulin receptor substrate-1, phosphatidylinositol-3-kinase and protein kinase B (PKB/Akt). |
| 10054 | 21153603 | Angiotensin II type I (AT1) receptor-evoked oxidative stress is implicated in the inactivation of NO, impairing endothelium-dependent vasodilatation. |
| 10055 | 21153603 | Blocking the actions of Angiotensin II with an AT1 receptor antagonist (Losartan), has beneficial effects in patients with insulin resistance or type 2 diabetes mellitus. |
| 10056 | 21153603 | This study investigated whether elevated Angiotensin II influences myocardial insulin resistance, insulin signaling and NO production in a rat model of diet-induced obesity (DIO) by antagonizing the actions of the AT1 receptor with Losartan. |
| 10057 | 21153603 | Results showed that hearts from DIO rats are insulin resistant (higher serine phosphorylation of IRS-1, lower insulin-stimulated phosphorylation of PKB/Akt and eNOS, lower NO production) and had poorer functional recovery and larger infarct development after ischaemia/reperfusion. |
| 10058 | 21153603 | Data obtained from Losartan treatment also revealed that Angiotensin II signaling modulates myocardial PKB/Akt expression. |
| 10059 | 21153603 | We conclude that Angiotensin II signaling exacerbates inhibition of NO production in insulin resistance and that this can be improved by AT1 antagonism. |
| 10060 | 21189360 | In vivo activation of ROCK1 by insulin is impaired in skeletal muscle of humans with type 2 diabetes. |
| 10061 | 21189360 | To determine whether serine/threonine ROCK1 is activated by insulin in vivo in humans and whether impaired activation of ROCK1 could play a role in the pathogenesis of insulin resistance, we measured the activity of ROCK1 and the protein content of the Rho family in vastus lateralis muscle of lean, obese nondiabetic, and obese type 2 diabetic subjects. |
| 10062 | 21189360 | Insulin-stimulated IRS-1 tyrosine phosphorylation is impaired 41-48% in diabetic subjects compared with lean or obese subjects. |
| 10063 | 21189360 | Insulin increased ROCK1 activity 2.1-fold in lean and 1.7-fold in obese nondiabetic subjects in muscle. |
| 10064 | 21189360 | However, ROCK1 activity did not increase in response to insulin in muscle of obese type 2 diabetic subjects without change in ROCK1 protein levels. |
| 10065 | 21189360 | Importantly, insulin-stimulated ROCK1 activity was positively correlated with insulin-mediated GDR in lean subjects (P < 0.01) but not in obese or type 2 diabetic subjects. |
| 10066 | 21189360 | Moreover, RhoE GTPase that inhibits the catalytic activity of ROCK1 by binding to the kinase domain of the enzyme is notably increased in obese type 2 diabetic subjects, accounting for defective ROCK1 activity. |
| 10067 | 21189360 | Thus, these data suggest that ROCK1 may play an important role in the pathogenesis of resistance to insulin action on glucose disposal in muscle of obese type 2 diabetic subjects. |
| 10068 | 21228767 | Glomerular-specific protein kinase C-β-induced insulin receptor substrate-1 dysfunction and insulin resistance in rat models of diabetes and obesity. |
| 10069 | 21228767 | Compared with nondiabetic and Zucker lean rats, the insulin-induced phosphorylation of insulin receptor substrate-1 (IRS1), Akt, endothelial nitric oxide synthase, and glycogen synthase kinase 3α were selectively inhibited in the glomeruli but not in the renal tubules of both respective models. |
| 10070 | 21228767 | Treatment with the protein kinase C-β inhibitor, ruboxistaurin, enhanced insulin actions and elevated IRS1 expression. |
| 10071 | 21228767 | In glomerular endothelial cells, high glucose inhibited the phosphorylation of Akt, endothelial nitric oxide synthase, and glycogen synthase kinase 3α; decreased IRS1 protein expression and increased its association with ubiquitin. |
| 10072 | 21228767 | Thus, loss of insulin's effect on endothelial nitric oxide synthase and glycogen synthase kinase 3α activation may contribute to the glomerulopathy observed in diabetes and obesity. |
| 10073 | 21228767 | Glomerular-specific protein kinase C-β-induced insulin receptor substrate-1 dysfunction and insulin resistance in rat models of diabetes and obesity. |
| 10074 | 21228767 | Compared with nondiabetic and Zucker lean rats, the insulin-induced phosphorylation of insulin receptor substrate-1 (IRS1), Akt, endothelial nitric oxide synthase, and glycogen synthase kinase 3α were selectively inhibited in the glomeruli but not in the renal tubules of both respective models. |
| 10075 | 21228767 | Treatment with the protein kinase C-β inhibitor, ruboxistaurin, enhanced insulin actions and elevated IRS1 expression. |
| 10076 | 21228767 | In glomerular endothelial cells, high glucose inhibited the phosphorylation of Akt, endothelial nitric oxide synthase, and glycogen synthase kinase 3α; decreased IRS1 protein expression and increased its association with ubiquitin. |
| 10077 | 21228767 | Thus, loss of insulin's effect on endothelial nitric oxide synthase and glycogen synthase kinase 3α activation may contribute to the glomerulopathy observed in diabetes and obesity. |
| 10078 | 21228767 | Glomerular-specific protein kinase C-β-induced insulin receptor substrate-1 dysfunction and insulin resistance in rat models of diabetes and obesity. |
| 10079 | 21228767 | Compared with nondiabetic and Zucker lean rats, the insulin-induced phosphorylation of insulin receptor substrate-1 (IRS1), Akt, endothelial nitric oxide synthase, and glycogen synthase kinase 3α were selectively inhibited in the glomeruli but not in the renal tubules of both respective models. |
| 10080 | 21228767 | Treatment with the protein kinase C-β inhibitor, ruboxistaurin, enhanced insulin actions and elevated IRS1 expression. |
| 10081 | 21228767 | In glomerular endothelial cells, high glucose inhibited the phosphorylation of Akt, endothelial nitric oxide synthase, and glycogen synthase kinase 3α; decreased IRS1 protein expression and increased its association with ubiquitin. |
| 10082 | 21228767 | Thus, loss of insulin's effect on endothelial nitric oxide synthase and glycogen synthase kinase 3α activation may contribute to the glomerulopathy observed in diabetes and obesity. |
| 10083 | 21228767 | Glomerular-specific protein kinase C-β-induced insulin receptor substrate-1 dysfunction and insulin resistance in rat models of diabetes and obesity. |
| 10084 | 21228767 | Compared with nondiabetic and Zucker lean rats, the insulin-induced phosphorylation of insulin receptor substrate-1 (IRS1), Akt, endothelial nitric oxide synthase, and glycogen synthase kinase 3α were selectively inhibited in the glomeruli but not in the renal tubules of both respective models. |
| 10085 | 21228767 | Treatment with the protein kinase C-β inhibitor, ruboxistaurin, enhanced insulin actions and elevated IRS1 expression. |
| 10086 | 21228767 | In glomerular endothelial cells, high glucose inhibited the phosphorylation of Akt, endothelial nitric oxide synthase, and glycogen synthase kinase 3α; decreased IRS1 protein expression and increased its association with ubiquitin. |
| 10087 | 21228767 | Thus, loss of insulin's effect on endothelial nitric oxide synthase and glycogen synthase kinase 3α activation may contribute to the glomerulopathy observed in diabetes and obesity. |
| 10088 | 21266508 | At the whole-body level, IR reverted after the 10-d treatment; however, tissue-specific indications of IR were observed, such as down-regulation of adipose glucose transporter 4, hepatic peroxisome proliferative activated receptor-γ1 and -2, and muscle insulin receptor substrate-1. |
| 10089 | 21266508 | In adipose tissue, increased hormone-sensitive lipase activity led to reduced adipocyte size, concomitant with increased plasma and hepatic triglyceride content and decreased total and high-density lipoprotein cholesterol levels. |
| 10090 | 21296137 | Modified Si-Miao-San extract inhibits inflammatory response and modulates insulin sensitivity in hepatocytes through an IKKβ/IRS-1/Akt-dependent pathway. |
| 10091 | 21305025 | The signaling mechanisms involved several proteins that include 7 major functional proteins such as INS, INSR, IRS1, IRS2, PIK3CA, Akt2, and GLUT4. |
| 10092 | 21321112 | An early response transcription factor, Egr-1, enhances insulin resistance in type 2 diabetes with chronic hyperinsulinism. |
| 10093 | 21321112 | An elevation in Egr-1 augmented Erk1/2 activation via geranylgeranyl diphosphate synthase (GGPPS). |
| 10094 | 21321112 | Egr-1-promoted GGPPS transcription increased Ras prenylation and caused Erk1/2 activation. |
| 10095 | 21321112 | The sustained activation of Erk1/2 resulted in the phosphorylation of insulin receptor substrate-1 at Serine 612. |
| 10096 | 21321112 | The loss of Egr-1 function, knockdown of GGPPS, or inhibition of Erk1/2 activity in insulin-resistant adipocytes restored insulin receptor substrate-1 tyrosine phosphorylation and increased insulin sensitivity. |
| 10097 | 21321112 | Our results suggest a new mechanism by which the Egr-1/GGPPS/Erk1/2 pathway is responsible for insulin resistance during hyperinsulinism. |
| 10098 | 21321112 | This pathway provides a new therapeutic target for increasing insulin sensitivity: inhibiting the function of Egr-1. |
| 10099 | 21321112 | An early response transcription factor, Egr-1, enhances insulin resistance in type 2 diabetes with chronic hyperinsulinism. |
| 10100 | 21321112 | An elevation in Egr-1 augmented Erk1/2 activation via geranylgeranyl diphosphate synthase (GGPPS). |
| 10101 | 21321112 | Egr-1-promoted GGPPS transcription increased Ras prenylation and caused Erk1/2 activation. |
| 10102 | 21321112 | The sustained activation of Erk1/2 resulted in the phosphorylation of insulin receptor substrate-1 at Serine 612. |
| 10103 | 21321112 | The loss of Egr-1 function, knockdown of GGPPS, or inhibition of Erk1/2 activity in insulin-resistant adipocytes restored insulin receptor substrate-1 tyrosine phosphorylation and increased insulin sensitivity. |
| 10104 | 21321112 | Our results suggest a new mechanism by which the Egr-1/GGPPS/Erk1/2 pathway is responsible for insulin resistance during hyperinsulinism. |
| 10105 | 21321112 | This pathway provides a new therapeutic target for increasing insulin sensitivity: inhibiting the function of Egr-1. |
| 10106 | 21354306 | Insulin receptor substrate-1 and -2 mediate resistance to glucose-induced caspase-3 activation in human neuroblastoma cells. |
| 10107 | 21354306 | Insulin and insulin-like growth factor-1 (IGF-1) receptor signaling inhibits glucose-induced caspase-3 activation and apoptotic cell death. |
| 10108 | 21354306 | Even though all IRS proteins have similar function and structure, recent data suggest different actions of IRS-1 and IRS-2 in mediating their anti-apoptotic effects in glucose neurotoxicity. |
| 10109 | 21354306 | We therefore investigated the role of IRS-1/-2 in glucose-induced caspase-3 activation using human neuroblastoma cells. |
| 10110 | 21354306 | Overexpression of IRS-1 or IRS-2 caused complete resistance to glucose-induced caspase-3 cleavage. |
| 10111 | 21354306 | Inhibition of PI3-kinase reversed this protective effect of IRS-1 or IRS-2. |
| 10112 | 21354306 | IRS overexpression increased MnSOD abundance as well as BAD phosphorylation while Bim and BAX levels remained unchanged. |
| 10113 | 21354306 | Since Akt promotes cell survival at least partially via phosphorylation and inhibition of downstream forkhead box-O (FoxO) transcription factors, we generated neuroblastoma cells stably overexpressing a dominant negative mutant of FoxO1 mimicking activation of the insulin/IGF-1 pathway on FoxO-mediated transcription. |
| 10114 | 21354306 | Using these cells we showed that FoxO1 is not involved in neuronal protection mediated by increased IRS-1/-2 expression. |
| 10115 | 21354306 | Thus, overexpression of both IRS-1 and IRS-2 induces complete resistance to glucose-induced caspase-3 activation via PI3-kinase mediated BAD phosphorylation and MnSOD expression independent of FoxO1. |
| 10116 | 21354306 | Insulin receptor substrate-1 and -2 mediate resistance to glucose-induced caspase-3 activation in human neuroblastoma cells. |
| 10117 | 21354306 | Insulin and insulin-like growth factor-1 (IGF-1) receptor signaling inhibits glucose-induced caspase-3 activation and apoptotic cell death. |
| 10118 | 21354306 | Even though all IRS proteins have similar function and structure, recent data suggest different actions of IRS-1 and IRS-2 in mediating their anti-apoptotic effects in glucose neurotoxicity. |
| 10119 | 21354306 | We therefore investigated the role of IRS-1/-2 in glucose-induced caspase-3 activation using human neuroblastoma cells. |
| 10120 | 21354306 | Overexpression of IRS-1 or IRS-2 caused complete resistance to glucose-induced caspase-3 cleavage. |
| 10121 | 21354306 | Inhibition of PI3-kinase reversed this protective effect of IRS-1 or IRS-2. |
| 10122 | 21354306 | IRS overexpression increased MnSOD abundance as well as BAD phosphorylation while Bim and BAX levels remained unchanged. |
| 10123 | 21354306 | Since Akt promotes cell survival at least partially via phosphorylation and inhibition of downstream forkhead box-O (FoxO) transcription factors, we generated neuroblastoma cells stably overexpressing a dominant negative mutant of FoxO1 mimicking activation of the insulin/IGF-1 pathway on FoxO-mediated transcription. |
| 10124 | 21354306 | Using these cells we showed that FoxO1 is not involved in neuronal protection mediated by increased IRS-1/-2 expression. |
| 10125 | 21354306 | Thus, overexpression of both IRS-1 and IRS-2 induces complete resistance to glucose-induced caspase-3 activation via PI3-kinase mediated BAD phosphorylation and MnSOD expression independent of FoxO1. |
| 10126 | 21354306 | Insulin receptor substrate-1 and -2 mediate resistance to glucose-induced caspase-3 activation in human neuroblastoma cells. |
| 10127 | 21354306 | Insulin and insulin-like growth factor-1 (IGF-1) receptor signaling inhibits glucose-induced caspase-3 activation and apoptotic cell death. |
| 10128 | 21354306 | Even though all IRS proteins have similar function and structure, recent data suggest different actions of IRS-1 and IRS-2 in mediating their anti-apoptotic effects in glucose neurotoxicity. |
| 10129 | 21354306 | We therefore investigated the role of IRS-1/-2 in glucose-induced caspase-3 activation using human neuroblastoma cells. |
| 10130 | 21354306 | Overexpression of IRS-1 or IRS-2 caused complete resistance to glucose-induced caspase-3 cleavage. |
| 10131 | 21354306 | Inhibition of PI3-kinase reversed this protective effect of IRS-1 or IRS-2. |
| 10132 | 21354306 | IRS overexpression increased MnSOD abundance as well as BAD phosphorylation while Bim and BAX levels remained unchanged. |
| 10133 | 21354306 | Since Akt promotes cell survival at least partially via phosphorylation and inhibition of downstream forkhead box-O (FoxO) transcription factors, we generated neuroblastoma cells stably overexpressing a dominant negative mutant of FoxO1 mimicking activation of the insulin/IGF-1 pathway on FoxO-mediated transcription. |
| 10134 | 21354306 | Using these cells we showed that FoxO1 is not involved in neuronal protection mediated by increased IRS-1/-2 expression. |
| 10135 | 21354306 | Thus, overexpression of both IRS-1 and IRS-2 induces complete resistance to glucose-induced caspase-3 activation via PI3-kinase mediated BAD phosphorylation and MnSOD expression independent of FoxO1. |
| 10136 | 21354306 | Insulin receptor substrate-1 and -2 mediate resistance to glucose-induced caspase-3 activation in human neuroblastoma cells. |
| 10137 | 21354306 | Insulin and insulin-like growth factor-1 (IGF-1) receptor signaling inhibits glucose-induced caspase-3 activation and apoptotic cell death. |
| 10138 | 21354306 | Even though all IRS proteins have similar function and structure, recent data suggest different actions of IRS-1 and IRS-2 in mediating their anti-apoptotic effects in glucose neurotoxicity. |
| 10139 | 21354306 | We therefore investigated the role of IRS-1/-2 in glucose-induced caspase-3 activation using human neuroblastoma cells. |
| 10140 | 21354306 | Overexpression of IRS-1 or IRS-2 caused complete resistance to glucose-induced caspase-3 cleavage. |
| 10141 | 21354306 | Inhibition of PI3-kinase reversed this protective effect of IRS-1 or IRS-2. |
| 10142 | 21354306 | IRS overexpression increased MnSOD abundance as well as BAD phosphorylation while Bim and BAX levels remained unchanged. |
| 10143 | 21354306 | Since Akt promotes cell survival at least partially via phosphorylation and inhibition of downstream forkhead box-O (FoxO) transcription factors, we generated neuroblastoma cells stably overexpressing a dominant negative mutant of FoxO1 mimicking activation of the insulin/IGF-1 pathway on FoxO-mediated transcription. |
| 10144 | 21354306 | Using these cells we showed that FoxO1 is not involved in neuronal protection mediated by increased IRS-1/-2 expression. |
| 10145 | 21354306 | Thus, overexpression of both IRS-1 and IRS-2 induces complete resistance to glucose-induced caspase-3 activation via PI3-kinase mediated BAD phosphorylation and MnSOD expression independent of FoxO1. |
| 10146 | 21354306 | Insulin receptor substrate-1 and -2 mediate resistance to glucose-induced caspase-3 activation in human neuroblastoma cells. |
| 10147 | 21354306 | Insulin and insulin-like growth factor-1 (IGF-1) receptor signaling inhibits glucose-induced caspase-3 activation and apoptotic cell death. |
| 10148 | 21354306 | Even though all IRS proteins have similar function and structure, recent data suggest different actions of IRS-1 and IRS-2 in mediating their anti-apoptotic effects in glucose neurotoxicity. |
| 10149 | 21354306 | We therefore investigated the role of IRS-1/-2 in glucose-induced caspase-3 activation using human neuroblastoma cells. |
| 10150 | 21354306 | Overexpression of IRS-1 or IRS-2 caused complete resistance to glucose-induced caspase-3 cleavage. |
| 10151 | 21354306 | Inhibition of PI3-kinase reversed this protective effect of IRS-1 or IRS-2. |
| 10152 | 21354306 | IRS overexpression increased MnSOD abundance as well as BAD phosphorylation while Bim and BAX levels remained unchanged. |
| 10153 | 21354306 | Since Akt promotes cell survival at least partially via phosphorylation and inhibition of downstream forkhead box-O (FoxO) transcription factors, we generated neuroblastoma cells stably overexpressing a dominant negative mutant of FoxO1 mimicking activation of the insulin/IGF-1 pathway on FoxO-mediated transcription. |
| 10154 | 21354306 | Using these cells we showed that FoxO1 is not involved in neuronal protection mediated by increased IRS-1/-2 expression. |
| 10155 | 21354306 | Thus, overexpression of both IRS-1 and IRS-2 induces complete resistance to glucose-induced caspase-3 activation via PI3-kinase mediated BAD phosphorylation and MnSOD expression independent of FoxO1. |
| 10156 | 21354306 | Insulin receptor substrate-1 and -2 mediate resistance to glucose-induced caspase-3 activation in human neuroblastoma cells. |
| 10157 | 21354306 | Insulin and insulin-like growth factor-1 (IGF-1) receptor signaling inhibits glucose-induced caspase-3 activation and apoptotic cell death. |
| 10158 | 21354306 | Even though all IRS proteins have similar function and structure, recent data suggest different actions of IRS-1 and IRS-2 in mediating their anti-apoptotic effects in glucose neurotoxicity. |
| 10159 | 21354306 | We therefore investigated the role of IRS-1/-2 in glucose-induced caspase-3 activation using human neuroblastoma cells. |
| 10160 | 21354306 | Overexpression of IRS-1 or IRS-2 caused complete resistance to glucose-induced caspase-3 cleavage. |
| 10161 | 21354306 | Inhibition of PI3-kinase reversed this protective effect of IRS-1 or IRS-2. |
| 10162 | 21354306 | IRS overexpression increased MnSOD abundance as well as BAD phosphorylation while Bim and BAX levels remained unchanged. |
| 10163 | 21354306 | Since Akt promotes cell survival at least partially via phosphorylation and inhibition of downstream forkhead box-O (FoxO) transcription factors, we generated neuroblastoma cells stably overexpressing a dominant negative mutant of FoxO1 mimicking activation of the insulin/IGF-1 pathway on FoxO-mediated transcription. |
| 10164 | 21354306 | Using these cells we showed that FoxO1 is not involved in neuronal protection mediated by increased IRS-1/-2 expression. |
| 10165 | 21354306 | Thus, overexpression of both IRS-1 and IRS-2 induces complete resistance to glucose-induced caspase-3 activation via PI3-kinase mediated BAD phosphorylation and MnSOD expression independent of FoxO1. |
| 10166 | 21354306 | Insulin receptor substrate-1 and -2 mediate resistance to glucose-induced caspase-3 activation in human neuroblastoma cells. |
| 10167 | 21354306 | Insulin and insulin-like growth factor-1 (IGF-1) receptor signaling inhibits glucose-induced caspase-3 activation and apoptotic cell death. |
| 10168 | 21354306 | Even though all IRS proteins have similar function and structure, recent data suggest different actions of IRS-1 and IRS-2 in mediating their anti-apoptotic effects in glucose neurotoxicity. |
| 10169 | 21354306 | We therefore investigated the role of IRS-1/-2 in glucose-induced caspase-3 activation using human neuroblastoma cells. |
| 10170 | 21354306 | Overexpression of IRS-1 or IRS-2 caused complete resistance to glucose-induced caspase-3 cleavage. |
| 10171 | 21354306 | Inhibition of PI3-kinase reversed this protective effect of IRS-1 or IRS-2. |
| 10172 | 21354306 | IRS overexpression increased MnSOD abundance as well as BAD phosphorylation while Bim and BAX levels remained unchanged. |
| 10173 | 21354306 | Since Akt promotes cell survival at least partially via phosphorylation and inhibition of downstream forkhead box-O (FoxO) transcription factors, we generated neuroblastoma cells stably overexpressing a dominant negative mutant of FoxO1 mimicking activation of the insulin/IGF-1 pathway on FoxO-mediated transcription. |
| 10174 | 21354306 | Using these cells we showed that FoxO1 is not involved in neuronal protection mediated by increased IRS-1/-2 expression. |
| 10175 | 21354306 | Thus, overexpression of both IRS-1 and IRS-2 induces complete resistance to glucose-induced caspase-3 activation via PI3-kinase mediated BAD phosphorylation and MnSOD expression independent of FoxO1. |
| 10176 | 21400856 | These inflammatory mediators inhibit insulin signaling with several mechanisms, such as serine-phosphorylation of IRS-1, the induction of SOCS3 and the activation of JNK or NFkappaB signaling in insulin-target tissues. |
| 10177 | 21472564 | Label-free proteomic identification of endogenous, insulin-stimulated interaction partners of insulin receptor substrate-1. |
| 10178 | 21472564 | Here, we report an application of a straightforward, label-free CO-IP-MS/MS method, without the use of protein overexpression or protein tags, to the investigation of changes in the abundance of endogenous proteins associated with a bait protein, which is in this case insulin receptor substrate-1 (IRS-1), under basal and insulin stimulated conditions. |
| 10179 | 21472564 | IRS-1 plays a central role in the insulin signaling cascade. |
| 10180 | 21472564 | Defects in the protein-protein interactions involving IRS-1 may lead to the development of insulin resistance and type 2 diabetes. |
| 10181 | 21472564 | HPLC-ESI-MS/MS analyses identified eleven novel endogenous insulin-stimulated IRS-1 interaction partners in L6 myotubes reproducibly, including proteins play an important role in protein dephosphorylation [protein phosphatase 1 regulatory subunit 12A, (PPP1R12A)], muscle contraction and actin cytoskeleton rearrangement, endoplasmic reticulum stress, and protein folding, as well as protein synthesis. |
| 10182 | 21472564 | Label-free proteomic identification of endogenous, insulin-stimulated interaction partners of insulin receptor substrate-1. |
| 10183 | 21472564 | Here, we report an application of a straightforward, label-free CO-IP-MS/MS method, without the use of protein overexpression or protein tags, to the investigation of changes in the abundance of endogenous proteins associated with a bait protein, which is in this case insulin receptor substrate-1 (IRS-1), under basal and insulin stimulated conditions. |
| 10184 | 21472564 | IRS-1 plays a central role in the insulin signaling cascade. |
| 10185 | 21472564 | Defects in the protein-protein interactions involving IRS-1 may lead to the development of insulin resistance and type 2 diabetes. |
| 10186 | 21472564 | HPLC-ESI-MS/MS analyses identified eleven novel endogenous insulin-stimulated IRS-1 interaction partners in L6 myotubes reproducibly, including proteins play an important role in protein dephosphorylation [protein phosphatase 1 regulatory subunit 12A, (PPP1R12A)], muscle contraction and actin cytoskeleton rearrangement, endoplasmic reticulum stress, and protein folding, as well as protein synthesis. |
| 10187 | 21472564 | Label-free proteomic identification of endogenous, insulin-stimulated interaction partners of insulin receptor substrate-1. |
| 10188 | 21472564 | Here, we report an application of a straightforward, label-free CO-IP-MS/MS method, without the use of protein overexpression or protein tags, to the investigation of changes in the abundance of endogenous proteins associated with a bait protein, which is in this case insulin receptor substrate-1 (IRS-1), under basal and insulin stimulated conditions. |
| 10189 | 21472564 | IRS-1 plays a central role in the insulin signaling cascade. |
| 10190 | 21472564 | Defects in the protein-protein interactions involving IRS-1 may lead to the development of insulin resistance and type 2 diabetes. |
| 10191 | 21472564 | HPLC-ESI-MS/MS analyses identified eleven novel endogenous insulin-stimulated IRS-1 interaction partners in L6 myotubes reproducibly, including proteins play an important role in protein dephosphorylation [protein phosphatase 1 regulatory subunit 12A, (PPP1R12A)], muscle contraction and actin cytoskeleton rearrangement, endoplasmic reticulum stress, and protein folding, as well as protein synthesis. |
| 10192 | 21472564 | Label-free proteomic identification of endogenous, insulin-stimulated interaction partners of insulin receptor substrate-1. |
| 10193 | 21472564 | Here, we report an application of a straightforward, label-free CO-IP-MS/MS method, without the use of protein overexpression or protein tags, to the investigation of changes in the abundance of endogenous proteins associated with a bait protein, which is in this case insulin receptor substrate-1 (IRS-1), under basal and insulin stimulated conditions. |
| 10194 | 21472564 | IRS-1 plays a central role in the insulin signaling cascade. |
| 10195 | 21472564 | Defects in the protein-protein interactions involving IRS-1 may lead to the development of insulin resistance and type 2 diabetes. |
| 10196 | 21472564 | HPLC-ESI-MS/MS analyses identified eleven novel endogenous insulin-stimulated IRS-1 interaction partners in L6 myotubes reproducibly, including proteins play an important role in protein dephosphorylation [protein phosphatase 1 regulatory subunit 12A, (PPP1R12A)], muscle contraction and actin cytoskeleton rearrangement, endoplasmic reticulum stress, and protein folding, as well as protein synthesis. |
| 10197 | 21472564 | Label-free proteomic identification of endogenous, insulin-stimulated interaction partners of insulin receptor substrate-1. |
| 10198 | 21472564 | Here, we report an application of a straightforward, label-free CO-IP-MS/MS method, without the use of protein overexpression or protein tags, to the investigation of changes in the abundance of endogenous proteins associated with a bait protein, which is in this case insulin receptor substrate-1 (IRS-1), under basal and insulin stimulated conditions. |
| 10199 | 21472564 | IRS-1 plays a central role in the insulin signaling cascade. |
| 10200 | 21472564 | Defects in the protein-protein interactions involving IRS-1 may lead to the development of insulin resistance and type 2 diabetes. |
| 10201 | 21472564 | HPLC-ESI-MS/MS analyses identified eleven novel endogenous insulin-stimulated IRS-1 interaction partners in L6 myotubes reproducibly, including proteins play an important role in protein dephosphorylation [protein phosphatase 1 regulatory subunit 12A, (PPP1R12A)], muscle contraction and actin cytoskeleton rearrangement, endoplasmic reticulum stress, and protein folding, as well as protein synthesis. |
| 10202 | 21478152 | Resistin promotes cardiac hypertrophy via the AMP-activated protein kinase/mammalian target of rapamycin (AMPK/mTOR) and c-Jun N-terminal kinase/insulin receptor substrate 1 (JNK/IRS1) pathways. |
| 10203 | 21478152 | Resistin has been suggested to be involved in the development of diabetes and insulin resistance. |
| 10204 | 21478152 | Therefore, we wanted to elucidate the mechanisms associated with resistin-induced cardiac hypertrophy and myocardial insulin resistance. |
| 10205 | 21478152 | Overexpression of resistin using adenoviral vector in neonatal rat ventricular myocytes was associated with inhibition of AMP-activated protein kinase (AMPK) activity, activation of tuberous sclerosis complex 2/mammalian target of rapamycin (mTOR) pathway, and increased cell size, [(3)H]leucine incorporation (i.e. protein synthesis) and mRNA expression of the hypertrophic marker genes, atrial natriuretic factor, brain natriuretic peptide, and β-myosin heavy chain. |
| 10206 | 21478152 | Activation of AMPK with 5-aminoimidazole-4-carbozamide-1-β-D-ribifuranoside or inhibition of mTOR with rapamycin or mTOR siRNA attenuated these resistin-induced changes. |
| 10207 | 21478152 | Furthermore, resistin increased serine phosphorylation of insulin receptor substrate (IRS1) through the activation of the apoptosis signal-regulating kinase 1/c-Jun N-terminal Kinase (JNK) pathway, a module known to stimulate insulin resistance. |
| 10208 | 21478152 | Inhibition of JNK (with JNK inhibitor SP600125 or using dominant-negative JNK) reduced serine 307 phosphorylation of IRS1. |
| 10209 | 21478152 | Resistin also stimulated the activation of p70(S6K), a downstream kinase target of mTOR, and increased phosphorylation of the IRS1 serine 636/639 residues, whereas treatment with rapamycin reduced the phosphorylation of these residues. |
| 10210 | 21478152 | These data demonstrate that resistin induces cardiac hypertrophy and myocardial insulin resistance, possibly via the AMPK/mTOR/p70(S6K) and apoptosis signal-regulating kinase 1/JNK/IRS1 pathways. |
| 10211 | 21478152 | Resistin promotes cardiac hypertrophy via the AMP-activated protein kinase/mammalian target of rapamycin (AMPK/mTOR) and c-Jun N-terminal kinase/insulin receptor substrate 1 (JNK/IRS1) pathways. |
| 10212 | 21478152 | Resistin has been suggested to be involved in the development of diabetes and insulin resistance. |
| 10213 | 21478152 | Therefore, we wanted to elucidate the mechanisms associated with resistin-induced cardiac hypertrophy and myocardial insulin resistance. |
| 10214 | 21478152 | Overexpression of resistin using adenoviral vector in neonatal rat ventricular myocytes was associated with inhibition of AMP-activated protein kinase (AMPK) activity, activation of tuberous sclerosis complex 2/mammalian target of rapamycin (mTOR) pathway, and increased cell size, [(3)H]leucine incorporation (i.e. protein synthesis) and mRNA expression of the hypertrophic marker genes, atrial natriuretic factor, brain natriuretic peptide, and β-myosin heavy chain. |
| 10215 | 21478152 | Activation of AMPK with 5-aminoimidazole-4-carbozamide-1-β-D-ribifuranoside or inhibition of mTOR with rapamycin or mTOR siRNA attenuated these resistin-induced changes. |
| 10216 | 21478152 | Furthermore, resistin increased serine phosphorylation of insulin receptor substrate (IRS1) through the activation of the apoptosis signal-regulating kinase 1/c-Jun N-terminal Kinase (JNK) pathway, a module known to stimulate insulin resistance. |
| 10217 | 21478152 | Inhibition of JNK (with JNK inhibitor SP600125 or using dominant-negative JNK) reduced serine 307 phosphorylation of IRS1. |
| 10218 | 21478152 | Resistin also stimulated the activation of p70(S6K), a downstream kinase target of mTOR, and increased phosphorylation of the IRS1 serine 636/639 residues, whereas treatment with rapamycin reduced the phosphorylation of these residues. |
| 10219 | 21478152 | These data demonstrate that resistin induces cardiac hypertrophy and myocardial insulin resistance, possibly via the AMPK/mTOR/p70(S6K) and apoptosis signal-regulating kinase 1/JNK/IRS1 pathways. |
| 10220 | 21478152 | Resistin promotes cardiac hypertrophy via the AMP-activated protein kinase/mammalian target of rapamycin (AMPK/mTOR) and c-Jun N-terminal kinase/insulin receptor substrate 1 (JNK/IRS1) pathways. |
| 10221 | 21478152 | Resistin has been suggested to be involved in the development of diabetes and insulin resistance. |
| 10222 | 21478152 | Therefore, we wanted to elucidate the mechanisms associated with resistin-induced cardiac hypertrophy and myocardial insulin resistance. |
| 10223 | 21478152 | Overexpression of resistin using adenoviral vector in neonatal rat ventricular myocytes was associated with inhibition of AMP-activated protein kinase (AMPK) activity, activation of tuberous sclerosis complex 2/mammalian target of rapamycin (mTOR) pathway, and increased cell size, [(3)H]leucine incorporation (i.e. protein synthesis) and mRNA expression of the hypertrophic marker genes, atrial natriuretic factor, brain natriuretic peptide, and β-myosin heavy chain. |
| 10224 | 21478152 | Activation of AMPK with 5-aminoimidazole-4-carbozamide-1-β-D-ribifuranoside or inhibition of mTOR with rapamycin or mTOR siRNA attenuated these resistin-induced changes. |
| 10225 | 21478152 | Furthermore, resistin increased serine phosphorylation of insulin receptor substrate (IRS1) through the activation of the apoptosis signal-regulating kinase 1/c-Jun N-terminal Kinase (JNK) pathway, a module known to stimulate insulin resistance. |
| 10226 | 21478152 | Inhibition of JNK (with JNK inhibitor SP600125 or using dominant-negative JNK) reduced serine 307 phosphorylation of IRS1. |
| 10227 | 21478152 | Resistin also stimulated the activation of p70(S6K), a downstream kinase target of mTOR, and increased phosphorylation of the IRS1 serine 636/639 residues, whereas treatment with rapamycin reduced the phosphorylation of these residues. |
| 10228 | 21478152 | These data demonstrate that resistin induces cardiac hypertrophy and myocardial insulin resistance, possibly via the AMPK/mTOR/p70(S6K) and apoptosis signal-regulating kinase 1/JNK/IRS1 pathways. |
| 10229 | 21478152 | Resistin promotes cardiac hypertrophy via the AMP-activated protein kinase/mammalian target of rapamycin (AMPK/mTOR) and c-Jun N-terminal kinase/insulin receptor substrate 1 (JNK/IRS1) pathways. |
| 10230 | 21478152 | Resistin has been suggested to be involved in the development of diabetes and insulin resistance. |
| 10231 | 21478152 | Therefore, we wanted to elucidate the mechanisms associated with resistin-induced cardiac hypertrophy and myocardial insulin resistance. |
| 10232 | 21478152 | Overexpression of resistin using adenoviral vector in neonatal rat ventricular myocytes was associated with inhibition of AMP-activated protein kinase (AMPK) activity, activation of tuberous sclerosis complex 2/mammalian target of rapamycin (mTOR) pathway, and increased cell size, [(3)H]leucine incorporation (i.e. protein synthesis) and mRNA expression of the hypertrophic marker genes, atrial natriuretic factor, brain natriuretic peptide, and β-myosin heavy chain. |
| 10233 | 21478152 | Activation of AMPK with 5-aminoimidazole-4-carbozamide-1-β-D-ribifuranoside or inhibition of mTOR with rapamycin or mTOR siRNA attenuated these resistin-induced changes. |
| 10234 | 21478152 | Furthermore, resistin increased serine phosphorylation of insulin receptor substrate (IRS1) through the activation of the apoptosis signal-regulating kinase 1/c-Jun N-terminal Kinase (JNK) pathway, a module known to stimulate insulin resistance. |
| 10235 | 21478152 | Inhibition of JNK (with JNK inhibitor SP600125 or using dominant-negative JNK) reduced serine 307 phosphorylation of IRS1. |
| 10236 | 21478152 | Resistin also stimulated the activation of p70(S6K), a downstream kinase target of mTOR, and increased phosphorylation of the IRS1 serine 636/639 residues, whereas treatment with rapamycin reduced the phosphorylation of these residues. |
| 10237 | 21478152 | These data demonstrate that resistin induces cardiac hypertrophy and myocardial insulin resistance, possibly via the AMPK/mTOR/p70(S6K) and apoptosis signal-regulating kinase 1/JNK/IRS1 pathways. |
| 10238 | 21478152 | Resistin promotes cardiac hypertrophy via the AMP-activated protein kinase/mammalian target of rapamycin (AMPK/mTOR) and c-Jun N-terminal kinase/insulin receptor substrate 1 (JNK/IRS1) pathways. |
| 10239 | 21478152 | Resistin has been suggested to be involved in the development of diabetes and insulin resistance. |
| 10240 | 21478152 | Therefore, we wanted to elucidate the mechanisms associated with resistin-induced cardiac hypertrophy and myocardial insulin resistance. |
| 10241 | 21478152 | Overexpression of resistin using adenoviral vector in neonatal rat ventricular myocytes was associated with inhibition of AMP-activated protein kinase (AMPK) activity, activation of tuberous sclerosis complex 2/mammalian target of rapamycin (mTOR) pathway, and increased cell size, [(3)H]leucine incorporation (i.e. protein synthesis) and mRNA expression of the hypertrophic marker genes, atrial natriuretic factor, brain natriuretic peptide, and β-myosin heavy chain. |
| 10242 | 21478152 | Activation of AMPK with 5-aminoimidazole-4-carbozamide-1-β-D-ribifuranoside or inhibition of mTOR with rapamycin or mTOR siRNA attenuated these resistin-induced changes. |
| 10243 | 21478152 | Furthermore, resistin increased serine phosphorylation of insulin receptor substrate (IRS1) through the activation of the apoptosis signal-regulating kinase 1/c-Jun N-terminal Kinase (JNK) pathway, a module known to stimulate insulin resistance. |
| 10244 | 21478152 | Inhibition of JNK (with JNK inhibitor SP600125 or using dominant-negative JNK) reduced serine 307 phosphorylation of IRS1. |
| 10245 | 21478152 | Resistin also stimulated the activation of p70(S6K), a downstream kinase target of mTOR, and increased phosphorylation of the IRS1 serine 636/639 residues, whereas treatment with rapamycin reduced the phosphorylation of these residues. |
| 10246 | 21478152 | These data demonstrate that resistin induces cardiac hypertrophy and myocardial insulin resistance, possibly via the AMPK/mTOR/p70(S6K) and apoptosis signal-regulating kinase 1/JNK/IRS1 pathways. |
| 10247 | 21483233 | Rosiglitazone attenuates tumor necrosis factor-α-induced protein-tyrosine phosphatase-1B production in HepG2 cells. |
| 10248 | 21483233 | Tumor necrosis factor (TNF)-α impairs insulin signaling and plays an important role in the development of insulin resistance. |
| 10249 | 21483233 | TNF-α up-regulates PTP- 1B expression in a dose-dependent manner and decreases insulin-stimulated phosphorylation of IR and insulin receptor substrate-1 in HepG2 cells. |
| 10250 | 21503913 | The HCV core protein has been shown to be sufficient to impair insulin signaling in vitro through several post-receptorial mechanisms, mostly via the activation of suppressor of cytokine signaling (SOCS) family members and the consequent decrease of insulin receptor substrate-1 (IRS-1). |
| 10251 | 21503913 | The levels of IRS-1 and SOCS were investigated upon expression of the core protein of HCV genotypes 1-4. |
| 10252 | 21503913 | Furthermore, the core protein sequences were analyzed to identify the amino acid residues responsible for IRS-1 decrease, with particular regard to SOCS mRNA deregulation. |
| 10253 | 21503913 | The HCV core protein has been shown to be sufficient to impair insulin signaling in vitro through several post-receptorial mechanisms, mostly via the activation of suppressor of cytokine signaling (SOCS) family members and the consequent decrease of insulin receptor substrate-1 (IRS-1). |
| 10254 | 21503913 | The levels of IRS-1 and SOCS were investigated upon expression of the core protein of HCV genotypes 1-4. |
| 10255 | 21503913 | Furthermore, the core protein sequences were analyzed to identify the amino acid residues responsible for IRS-1 decrease, with particular regard to SOCS mRNA deregulation. |
| 10256 | 21503913 | The HCV core protein has been shown to be sufficient to impair insulin signaling in vitro through several post-receptorial mechanisms, mostly via the activation of suppressor of cytokine signaling (SOCS) family members and the consequent decrease of insulin receptor substrate-1 (IRS-1). |
| 10257 | 21503913 | The levels of IRS-1 and SOCS were investigated upon expression of the core protein of HCV genotypes 1-4. |
| 10258 | 21503913 | Furthermore, the core protein sequences were analyzed to identify the amino acid residues responsible for IRS-1 decrease, with particular regard to SOCS mRNA deregulation. |
| 10259 | 21506723 | Accordingly, cell lines derived from insulin target tissues such as brown adipose tissue, liver and beta islets lacking insulin receptors or sensitive candidate genes such as IRS-1, IRS-2, IRS-3, IR and PTP1B were developed. |
| 10260 | 21514684 | Epigallocatechin-3-O-gallate (EGCG) attenuates FFAs-induced peripheral insulin resistance through AMPK pathway and insulin signaling pathway in vivo. |
| 10261 | 21514684 | Co-injection with EGCG significantly prevented FFAs-induced peripheral insulin resistance, decreased plasma markers of oxidative stress: malondialdehyde (MDA) and 8-isoprostaglandin, and increased antioxidant enzymes: superoxide dismutases (SOD) and Glutathione peroxidase (GPx). |
| 10262 | 21514684 | Furthermore, EGCG treatment reversed IH-induced: (1) decrease in Thr172 phosphorylation of AMP activated protein kinase (AMPK); (2) increase in protein kinase Cθ(PKCθ) membrane translocation and Ser307 phosphorylation of insulin receptor substrate-1 (IRS-1); (3) decrease in Ser473 phosphorylation of Akt and Glucose transporter 4 (GLUT4) translocation in skeletal muscle and adipose tissue. |
| 10263 | 21514684 | Our data suggest that EGCG treatment ameliorated FFAs-induced peripheral insulin resistance in vivo, and this might be through decreasing oxidative stress and PKCθ membrane translocation, activating the AMPK pathway and improving insulin signaling pathway in vivo. |
| 10264 | 21520470 | It was further confirmed in a series of experiments that ginsenosides Rg3 and Re stimulated the mRNA expression of insulin receptor substrate (IRS-1) and the expression of phosphatidylinositol 3-kinase (PI3K)-110α protein, which is involved in downstream events in the insulin signaling pathway. |
| 10265 | 21520470 | These findings demonstrate that ginsenosides Rg3 and Re may stimulate glucose uptake via the PI3K pathways involving IRS-1. |
| 10266 | 21520470 | It was further confirmed in a series of experiments that ginsenosides Rg3 and Re stimulated the mRNA expression of insulin receptor substrate (IRS-1) and the expression of phosphatidylinositol 3-kinase (PI3K)-110α protein, which is involved in downstream events in the insulin signaling pathway. |
| 10267 | 21520470 | These findings demonstrate that ginsenosides Rg3 and Re may stimulate glucose uptake via the PI3K pathways involving IRS-1. |
| 10268 | 21530660 | Moreover, footpads expressed mRNAs of the downstream insulin transduction molecules, IRS-1 and IRS-2. |
| 10269 | 21602124 | [Adiponectin decreases insulin receptor substrate-1 phosphorylation in the liver of OLETF rats possibly through nuclear factor-κB signaling pathway]. |
| 10270 | 21643948 | To replicating the associations of type 2 diabetes (T2D) and six novel reported variants in Han Chinese lean individuals of first episode T2D, a total of six high risk single nucleotide polymorphisms (SNPs) from the BCL11A, DUSP9, IRS1, CENTD2, ADRA2A, and CDKAL1 genes were examined. |
| 10271 | 21647634 | Monoclonal antibody to six transmembrane epithelial antigen of prostate-4 influences insulin sensitivity by attenuating phosphorylation of P13K (P85) and Akt: possible mitochondrial mechanism. |
| 10272 | 21647634 | We examined the effects of anti-six-transmembrane epithelial antigen of the prostate-4 (STEAP4) antibodies on glucose transport in mature adipocytes and determined the mechanism of insulin resistance in obesity. |
| 10273 | 21647634 | Western blotting was performed to determine STEAP4 expression, to assess translocation of insulin-sensitive glucose transporter 4 (GLUT4), and to measure phosphorylation and total protein content of insulin-signaling proteins. |
| 10274 | 21647634 | After the application of anti-STEAP4 antibodies at 0.002 mg/mL, adipocytes exhibited reduced insulin-stimulated glucose transport by attenuating the phosphorylation of IRS-1, PI3K (p85), and Akt. |
| 10275 | 21647634 | In conclusion, (i) STEAP4 regulates the function of IRS-1, PI3K, and Akt and decreases insulin-induced GLUT4 translocation and glucose uptake; (ii) ROS-related mitochondrial dysfunction may be related to a reduced IRS-1 correlation with the PI3K signaling pathway, leading to insulin resistance. |
| 10276 | 21647634 | These observations highlight the potential role of STEAP4 in glucose homeostasis and possibly in the pathophysiology of type 2 diabetes related to obesity and may provide new insights into the mechanisms of insulin resistance in obesity. |
| 10277 | 21647634 | Monoclonal antibody to six transmembrane epithelial antigen of prostate-4 influences insulin sensitivity by attenuating phosphorylation of P13K (P85) and Akt: possible mitochondrial mechanism. |
| 10278 | 21647634 | We examined the effects of anti-six-transmembrane epithelial antigen of the prostate-4 (STEAP4) antibodies on glucose transport in mature adipocytes and determined the mechanism of insulin resistance in obesity. |
| 10279 | 21647634 | Western blotting was performed to determine STEAP4 expression, to assess translocation of insulin-sensitive glucose transporter 4 (GLUT4), and to measure phosphorylation and total protein content of insulin-signaling proteins. |
| 10280 | 21647634 | After the application of anti-STEAP4 antibodies at 0.002 mg/mL, adipocytes exhibited reduced insulin-stimulated glucose transport by attenuating the phosphorylation of IRS-1, PI3K (p85), and Akt. |
| 10281 | 21647634 | In conclusion, (i) STEAP4 regulates the function of IRS-1, PI3K, and Akt and decreases insulin-induced GLUT4 translocation and glucose uptake; (ii) ROS-related mitochondrial dysfunction may be related to a reduced IRS-1 correlation with the PI3K signaling pathway, leading to insulin resistance. |
| 10282 | 21647634 | These observations highlight the potential role of STEAP4 in glucose homeostasis and possibly in the pathophysiology of type 2 diabetes related to obesity and may provide new insights into the mechanisms of insulin resistance in obesity. |
| 10283 | 21650468 | Glucose utilization rates and the expression of insulin signaling-associated proteins, including Akt, insulin receptor substrate-1, and glucose transporter 4, were determined. |
| 10284 | 21680774 | Role of inhibitory κB kinase and c-Jun NH2-terminal kinase in the development of hepatic insulin resistance in critical illness diabetes. |
| 10285 | 21680774 | In the present studies, the roles of serine kinases, inhibitory κB kinase (IKK) and c-Jun NH(2)-terminal kinase (JNK), in the acute development of hepatic insulin resistance were investigated. |
| 10286 | 21680774 | In our animal model of critical illness diabetes, activation of hepatic IKK and JNK was observed as early as 15 min, concomitant with the rapid impairment of hepatic insulin signaling and increased serine phosphorylation of insulin receptor substrate 1. |
| 10287 | 21680774 | Similarly, inhibition of JNK1 kinase by expression of dominant-negative JNK1 also resulted in improved hepatic insulin signaling, indicating that IKK and JNK1 kinases contribute to critical illness-induced insulin resistance in liver. |
| 10288 | 21706003 | We confirmed a previously established adiposity locus in FTO (P = 3 × 10(-26)) and identified two new loci associated with body fat percentage, one near IRS1 (P = 4 × 10(-11)) and one near SPRY2 (P = 3 × 10(-8)). |
| 10289 | 21706003 | Notably, the body-fat-decreasing allele near IRS1 is associated with decreased IRS1 expression and with an impaired metabolic profile, including an increased visceral to subcutaneous fat ratio, insulin resistance, dyslipidemia, risk of diabetes and coronary artery disease and decreased adiponectin levels. |
| 10290 | 21706003 | We confirmed a previously established adiposity locus in FTO (P = 3 × 10(-26)) and identified two new loci associated with body fat percentage, one near IRS1 (P = 4 × 10(-11)) and one near SPRY2 (P = 3 × 10(-8)). |
| 10291 | 21706003 | Notably, the body-fat-decreasing allele near IRS1 is associated with decreased IRS1 expression and with an impaired metabolic profile, including an increased visceral to subcutaneous fat ratio, insulin resistance, dyslipidemia, risk of diabetes and coronary artery disease and decreased adiponectin levels. |
| 10292 | 21707534 | IGF-I is structurally related to proinsulin and when administered to human subjects it enhances insulin sensitivity. |
| 10293 | 21707534 | Under normoglycemic conditions vascular smooth muscle and endothelial cells are cystostatic and stimulation of the IGF-I receptor activates the adaptor protein IRS-1 which leads to PI-3 kinase pathway activation. |
| 10294 | 21731668 | After 8 weeks on HFD, mice developed obesity, fatty liver, inflammatory changes in adipose tissue and insulin resistance at the level of IRS-1 phosphorylation, as well as alterations in metabolomic profile of amino acid metabolites, TCA cycle intermediates, glucose and cholesterol metabolites, and fatty acids in liver, muscle, fat and serum. |
| 10295 | 21754917 | Both IRS1 and IRS2 are expressed in DRG; however, IRS2 appears to be the prevalent isoform and is expressed by many DRG neuronal subtypes. |
| 10296 | 21754917 | Additionally, Akt activation and neurite outgrowth in response to insulin were significantly decreased in DRG cultures from diabetic ob/ob mice. |
| 10297 | 21785636 | Miq on IRS-1, Akt and Glut-4 in Fat-Fed C57BL/6J Type 2 Diabetes Mouse Model. |
| 10298 | 21785636 | Immunoblot analysis of IRS-1, Akt and Glut-4 protein expressions in muscles of extract-supplemented animals revealed that glucoregulation was mediated through the insulin-signaling pathway. |
| 10299 | 21785636 | Miq on IRS-1, Akt and Glut-4 in Fat-Fed C57BL/6J Type 2 Diabetes Mouse Model. |
| 10300 | 21785636 | Immunoblot analysis of IRS-1, Akt and Glut-4 protein expressions in muscles of extract-supplemented animals revealed that glucoregulation was mediated through the insulin-signaling pathway. |
| 10301 | 21786209 | The possible mechanism may function by inhibiting the expression of the insulin receptor, glucose transporter-4, fatty acid synthase, and the lipid droplet proteins perilipin and adipophilin. |
| 10302 | 21786209 | In addition, betel nut extract and arecoline increased the basal level of IRS-1 serine(307) phosphorylation and decreased insulin-stimulated IRS-1 tyrosine, Akt, and PI3 kinase phosphorylation. |
| 10303 | 21799686 | Expression of insulin signaling proteins (IRS1, AKT2) in atropine-exposed rats before and after EA was measured by western blot. |
| 10304 | 21799686 | EA stimulated the expression of IRS1 and AKT2 and atropine treatment blocked the EA-induced expression of those insulin signaling proteins. |
| 10305 | 21799686 | Expression of insulin signaling proteins (IRS1, AKT2) in atropine-exposed rats before and after EA was measured by western blot. |
| 10306 | 21799686 | EA stimulated the expression of IRS1 and AKT2 and atropine treatment blocked the EA-induced expression of those insulin signaling proteins. |
| 10307 | 21803028 | Des-aspartate-angiotensin-I and angiotensin IV improve glucose tolerance and insulin signalling in diet-induced hyperglycaemic mice. |
| 10308 | 21803028 | Insulin-induced activation of IR, IRS-1, IRS-1-PI3K coupling, phosphorylation of Akt, and GLUT4 translocation were attenuated in skeletal muscles of HFD animals. |
| 10309 | 21803028 | In corresponding Ang-IV treated animals, insulin induced IRAP and PI3K interaction, activation of pAkt and GLUT4 translocation, but no corresponding activation of IR, IRS-1 and IRS-1-PI3K coupling were observed. |
| 10310 | 21803028 | DAA-I acts via the angiotensin AT(1) receptor and activates the insulin pathway. |
| 10311 | 21803028 | Ang-IV acts via IRAP, which couples PI3K and activates the later part of the insulin pathway. |
| 10312 | 21803028 | Des-aspartate-angiotensin-I and angiotensin IV improve glucose tolerance and insulin signalling in diet-induced hyperglycaemic mice. |
| 10313 | 21803028 | Insulin-induced activation of IR, IRS-1, IRS-1-PI3K coupling, phosphorylation of Akt, and GLUT4 translocation were attenuated in skeletal muscles of HFD animals. |
| 10314 | 21803028 | In corresponding Ang-IV treated animals, insulin induced IRAP and PI3K interaction, activation of pAkt and GLUT4 translocation, but no corresponding activation of IR, IRS-1 and IRS-1-PI3K coupling were observed. |
| 10315 | 21803028 | DAA-I acts via the angiotensin AT(1) receptor and activates the insulin pathway. |
| 10316 | 21803028 | Ang-IV acts via IRAP, which couples PI3K and activates the later part of the insulin pathway. |
| 10317 | 21810481 | Basic fibroblast growth factor regulates glucose metabolism through glucose transporter 1 induced by hypoxia-inducible factor-1α in adipocytes. |
| 10318 | 21810481 | Hypoxia-inducible factor-1α (HIF-1α), which is a transcription factor that enhances glycolysis in cells in response to hypoxia, is induced in hypertrophied adipocytes in obesity. |
| 10319 | 21810481 | Since basic fibroblast growth factor (bFGF), an angiogenic factor, is concentrated in expanding adipose tissue, the possible effects of bFGF on regulation of HIF-1α in adipocytes were investigated. |
| 10320 | 21810481 | Concomitantly, glucose transporter 1 (GLUT1), which is a target gene of HIF-1α, was induced at both mRNA and protein levels and was translocated to the plasma membrane. |
| 10321 | 21810481 | A chromatin immunoprecipitation assay and an RNA interference study indicated that bFGF-induced HIF-1α directly upregulates GLUT1. |
| 10322 | 21810481 | Intraperitoneal injection of bFGF into mice upregulated HIF-1α and GLUT1 in adipose tissues, suggesting that bFGF regulates the metabolism of adipocytes via HIF-1α-GLUT1 regulation in vivo. |
| 10323 | 21810481 | We also found that bFGF inhibits insulin-induced phosphorylation of insulin receptor substrate-1 and Akt, suggesting that bFGF attenuates the insulin signal in adipocytes. |
| 10324 | 21829658 | MicroRNA 144 impairs insulin signaling by inhibiting the expression of insulin receptor substrate 1 in type 2 diabetes mellitus. |
| 10325 | 21850156 | Increased tumor necrosis factor-α, cleaved caspase 3 levels and insulin receptor substrate-1 phosphorylation in the β₁-adrenergic receptor knockout mouse. |
| 10326 | 21850561 | Global IRS-1 phosphorylation analysis in insulin resistance. |
| 10327 | 21869538 | In contrast, expression of the A1028V receptor was much lower than that of WT INSR, and impairment of insulin binding and autophosphorylation were nearly commensurate with the decrease in expression detected. |
| 10328 | 21869538 | Reductions in the phosphorylation of IRS-1, Akt, and Erk1/2 (60%, 40%, and 50% of WT, respectively) indicate that the A1028V receptor contributes to impaired signal transduction. |
| 10329 | 21873205 | Sirtuin-3 (Sirt3) regulates skeletal muscle metabolism and insulin signaling via altered mitochondrial oxidation and reactive oxygen species production. |
| 10330 | 21873205 | Sirt3 knockout mice exhibit decreased oxygen consumption and develop oxidative stress in skeletal muscle, leading to JNK activation and impaired insulin signaling. |
| 10331 | 21873205 | This effect is mimicked by knockdown of Sirt3 in cultured myoblasts, which exhibit reduced mitochondrial oxidation, increased reactive oxygen species, activation of JNK, increased serine and decreased tyrosine phosphorylation of IRS-1, and decreased insulin signaling. |
| 10332 | 21873205 | Thus, Sirt3 plays an important role in diabetes through regulation of mitochondrial oxidation, reactive oxygen species production, and insulin resistance in skeletal muscle. |
| 10333 | 21896669 | Obesity and type 2 diabetes are characterized by insulin resistance, and the common basis of these events is a chronic and systemic inflammatory process marked by the activation of the c-Jun N-terminal kinase (JNK) and inhibitor-κB kinase (IKKβ)/nuclear factor-κB (NFκB) pathways, up-regulated cytokine synthesis, and endoplasmic reticulum dysfunction. |
| 10334 | 21896669 | Western blotting was used to quantify the expression and phosphorylation of insulin receptor, insulin receptor substrate 1, and Akt and of inflammatory mediators that modulate insulin signaling in a negative manner (IKKβ, JNK, and inducible nitric oxide synthase). |
| 10335 | 21896669 | We show here, for the first time, that the administration of diacerhein in DIO mice improved endoplasmic reticulum stress, reduced JNK and IKKβ phosphorylation, and resulted in a marked improvement in fasting glucose, a decrease in macrophage infiltration in adipose tissue, and a reduced expression and activity of proinflammatory mediators accompanied by an improvement in the insulin signaling mainly in the liver and adipose tissue. |
| 10336 | 21953448 | Hydrogen sulfide and L-cysteine increase phosphatidylinositol 3,4,5-trisphosphate (PIP3) and glucose utilization by inhibiting phosphatase and tensin homolog (PTEN) protein and activating phosphoinositide 3-kinase (PI3K)/serine/threonine protein kinase (AKT)/protein kinase Cζ/λ (PKCζ/λ) in 3T3l1 adipocytes. |
| 10337 | 21953448 | H(2)S and LC caused phosphatidylinositol 3-kinase activation and PTEN inhibition. |
| 10338 | 21953448 | Treatment with LC, H(2)S, or PIP3 increased the phosphorylation of IRS1, AKT, and PKCζ/λ as well as GLUT4 activation and glucose utilization in HG-treated cells. |
| 10339 | 21953448 | The PIP3 increase is mediated by PI3K activation and inhibition of PTEN but not of SHIP2. |
| 10340 | 21959757 | Genetic and biochemical evidence also implicates protein-tyrosine phosphatases in several disease processes, including negative regulation of insulin receptor signaling at the level of the insulin receptor and perhaps in signaling at the IRS-1 level. |
| 10341 | 21959757 | The expression of protein tyrosine phosphatase-1B (PTP1B) is elevated in muscle and adipose tissue in insulin-resistant states both in man and rodents suggesting that PTP1B may play a role in the insulin-resistant state associated with diabetes and obesity. |
| 10342 | 21977024 | In conditions of over-nutrition, increased insulin (INS) and angiotensin II (Ang II) activate mammalian target for rapamycin (mTOR)/p70 S6 kinase (S6K1) signaling, whereas chronic alcohol consumption inhibits mTOR/S6K1 activation in cardiac tissue. |
| 10343 | 21977024 | Although excessive activation of mTOR/S6K1 induces cardiac INS resistance via serine phosphorylation of INS receptor substrates (IRS-1/2), it also renders cardioprotection via increased Ang II receptor 2 (AT2R) upregulation and adaptive hypertrophy. |
| 10344 | 21977024 | Conversely, alcohol-mediated inhibition of mTOR/S6K1, down-regulation of INS receptor and growth-inhibitory mir-200 family, and upregulation of mir-212 that promotes fetal gene program may exacerbate CRS-related cardiomyopathy. |
| 10345 | 22001674 | Insulin receptor substrate 1 (IRS-1) and insulin receptor substrate 2 (IRS-2) content, the main subtypes of IRSs, were measured in skeletal muscle, adipose tissue and liver using western immunoblot analyses on postoperative day 28. |
| 10346 | 22001674 | These findings suggest that improvements in glucose tolerance and insulin resistance following RYGB surgery are associated with upregulation of IRS-1. |
| 10347 | 22001674 | Insulin receptor substrate 1 (IRS-1) and insulin receptor substrate 2 (IRS-2) content, the main subtypes of IRSs, were measured in skeletal muscle, adipose tissue and liver using western immunoblot analyses on postoperative day 28. |
| 10348 | 22001674 | These findings suggest that improvements in glucose tolerance and insulin resistance following RYGB surgery are associated with upregulation of IRS-1. |
| 10349 | 22009727 | Role of substance P in the regulation of glucose metabolism via insulin signaling-associated pathways. |
| 10350 | 22009727 | Substance P (SP), encoded by the tachykinin 1 (Tac1) gene, is the most potent tachykinin ligand for the high-affinity neurokinin-1 receptor (NK-1R). |
| 10351 | 22009727 | We previously reported that NK-1R-deficient mice show less weight gain and reduced circulating levels of leptin and insulin in response to a high-fat diet (HFD) and demonstrated the presence of functional NK-1R in isolated human preadipocytes. |
| 10352 | 22009727 | We show that although weight accumulation in response to HFD was similar between Tac1(-/-) mice and wild-type littermates, Tac1(-/-) mice demonstrated lower glucose and leptin and increased adiponectin blood levels and showed improved responses to insulin challenge after HFD. |
| 10353 | 22009727 | SP stimulated phosphorylation of c-Jun N-terminal kinase, protein kinase C, mammalian target of rapamycin, and inhibitory serine insulin receptor substrate-1 phosphorylation in human preadipocytes in vitro. |
| 10354 | 22009727 | Preincubation of human mesenteric preadipocytes with the protein kinase C pseudosubstrate inhibitor reduced insulin receptor substrate 1 phosphorylation in response to SP. |
| 10355 | 22009727 | These novel SP effects on molecules that enhance insulin resistance at the adipocyte level may reflect an important role for this peptide in the pathophysiology of type 2 diabetes. |
| 10356 | 22009727 | Role of substance P in the regulation of glucose metabolism via insulin signaling-associated pathways. |
| 10357 | 22009727 | Substance P (SP), encoded by the tachykinin 1 (Tac1) gene, is the most potent tachykinin ligand for the high-affinity neurokinin-1 receptor (NK-1R). |
| 10358 | 22009727 | We previously reported that NK-1R-deficient mice show less weight gain and reduced circulating levels of leptin and insulin in response to a high-fat diet (HFD) and demonstrated the presence of functional NK-1R in isolated human preadipocytes. |
| 10359 | 22009727 | We show that although weight accumulation in response to HFD was similar between Tac1(-/-) mice and wild-type littermates, Tac1(-/-) mice demonstrated lower glucose and leptin and increased adiponectin blood levels and showed improved responses to insulin challenge after HFD. |
| 10360 | 22009727 | SP stimulated phosphorylation of c-Jun N-terminal kinase, protein kinase C, mammalian target of rapamycin, and inhibitory serine insulin receptor substrate-1 phosphorylation in human preadipocytes in vitro. |
| 10361 | 22009727 | Preincubation of human mesenteric preadipocytes with the protein kinase C pseudosubstrate inhibitor reduced insulin receptor substrate 1 phosphorylation in response to SP. |
| 10362 | 22009727 | These novel SP effects on molecules that enhance insulin resistance at the adipocyte level may reflect an important role for this peptide in the pathophysiology of type 2 diabetes. |
| 10363 | 22028412 | Activation of mTOR/p70S6 kinase by ANG II inhibits insulin-stimulated endothelial nitric oxide synthase and vasodilation. |
| 10364 | 22028412 | Elevated tissue levels of angiotensin II (ANG II) are associated with impairment of insulin actions in metabolic and cardiovascular tissues. |
| 10365 | 22028412 | ANG II-stimulated activation of mammalian target of rapamycin (mTOR)/p70 S6 kinase (p70S6K) in cardiovascular tissues is implicated in cardiac hypertrophy and vascular remodeling. |
| 10366 | 22028412 | ANG II increased phosphorylation of insulin receptor substrate-1 (IRS-1) at Ser(636/639) and inhibited the insulin-stimulated phosphorylation of endothelial nitric oxide synthase (eNOS). |
| 10367 | 22028412 | An inhibitor of mTOR, rapamycin, attenuated the ANG II-stimulated phosphorylation of p70S6K and phosphorylation of IRS-1 (Ser(636/639)) and blocked the ability of ANG II to impair insulin-stimulated phosphorylation of eNOS, nitric oxide production, and mesenteric-arteriole vasodilation. |
| 10368 | 22028412 | Moreover, point mutations of IRS-1 at Ser(636/639) to Ala prevented the ANG II-mediated inhibition of insulin signaling. |
| 10369 | 22028412 | From these results, we conclude that activation of mTOR/p70S6K by ANG II in vascular endothelium may contribute to impairment of insulin-stimulated vasodilation through phosphorylation of IRS-1 at Ser(636/639). |
| 10370 | 22028412 | This ANG II-mediated impairment of vascular actions of insulin may help explain the role of ANG II as a link between insulin resistance and hypertension. |
| 10371 | 22028412 | Activation of mTOR/p70S6 kinase by ANG II inhibits insulin-stimulated endothelial nitric oxide synthase and vasodilation. |
| 10372 | 22028412 | Elevated tissue levels of angiotensin II (ANG II) are associated with impairment of insulin actions in metabolic and cardiovascular tissues. |
| 10373 | 22028412 | ANG II-stimulated activation of mammalian target of rapamycin (mTOR)/p70 S6 kinase (p70S6K) in cardiovascular tissues is implicated in cardiac hypertrophy and vascular remodeling. |
| 10374 | 22028412 | ANG II increased phosphorylation of insulin receptor substrate-1 (IRS-1) at Ser(636/639) and inhibited the insulin-stimulated phosphorylation of endothelial nitric oxide synthase (eNOS). |
| 10375 | 22028412 | An inhibitor of mTOR, rapamycin, attenuated the ANG II-stimulated phosphorylation of p70S6K and phosphorylation of IRS-1 (Ser(636/639)) and blocked the ability of ANG II to impair insulin-stimulated phosphorylation of eNOS, nitric oxide production, and mesenteric-arteriole vasodilation. |
| 10376 | 22028412 | Moreover, point mutations of IRS-1 at Ser(636/639) to Ala prevented the ANG II-mediated inhibition of insulin signaling. |
| 10377 | 22028412 | From these results, we conclude that activation of mTOR/p70S6K by ANG II in vascular endothelium may contribute to impairment of insulin-stimulated vasodilation through phosphorylation of IRS-1 at Ser(636/639). |
| 10378 | 22028412 | This ANG II-mediated impairment of vascular actions of insulin may help explain the role of ANG II as a link between insulin resistance and hypertension. |
| 10379 | 22028412 | Activation of mTOR/p70S6 kinase by ANG II inhibits insulin-stimulated endothelial nitric oxide synthase and vasodilation. |
| 10380 | 22028412 | Elevated tissue levels of angiotensin II (ANG II) are associated with impairment of insulin actions in metabolic and cardiovascular tissues. |
| 10381 | 22028412 | ANG II-stimulated activation of mammalian target of rapamycin (mTOR)/p70 S6 kinase (p70S6K) in cardiovascular tissues is implicated in cardiac hypertrophy and vascular remodeling. |
| 10382 | 22028412 | ANG II increased phosphorylation of insulin receptor substrate-1 (IRS-1) at Ser(636/639) and inhibited the insulin-stimulated phosphorylation of endothelial nitric oxide synthase (eNOS). |
| 10383 | 22028412 | An inhibitor of mTOR, rapamycin, attenuated the ANG II-stimulated phosphorylation of p70S6K and phosphorylation of IRS-1 (Ser(636/639)) and blocked the ability of ANG II to impair insulin-stimulated phosphorylation of eNOS, nitric oxide production, and mesenteric-arteriole vasodilation. |
| 10384 | 22028412 | Moreover, point mutations of IRS-1 at Ser(636/639) to Ala prevented the ANG II-mediated inhibition of insulin signaling. |
| 10385 | 22028412 | From these results, we conclude that activation of mTOR/p70S6K by ANG II in vascular endothelium may contribute to impairment of insulin-stimulated vasodilation through phosphorylation of IRS-1 at Ser(636/639). |
| 10386 | 22028412 | This ANG II-mediated impairment of vascular actions of insulin may help explain the role of ANG II as a link between insulin resistance and hypertension. |
| 10387 | 22028412 | Activation of mTOR/p70S6 kinase by ANG II inhibits insulin-stimulated endothelial nitric oxide synthase and vasodilation. |
| 10388 | 22028412 | Elevated tissue levels of angiotensin II (ANG II) are associated with impairment of insulin actions in metabolic and cardiovascular tissues. |
| 10389 | 22028412 | ANG II-stimulated activation of mammalian target of rapamycin (mTOR)/p70 S6 kinase (p70S6K) in cardiovascular tissues is implicated in cardiac hypertrophy and vascular remodeling. |
| 10390 | 22028412 | ANG II increased phosphorylation of insulin receptor substrate-1 (IRS-1) at Ser(636/639) and inhibited the insulin-stimulated phosphorylation of endothelial nitric oxide synthase (eNOS). |
| 10391 | 22028412 | An inhibitor of mTOR, rapamycin, attenuated the ANG II-stimulated phosphorylation of p70S6K and phosphorylation of IRS-1 (Ser(636/639)) and blocked the ability of ANG II to impair insulin-stimulated phosphorylation of eNOS, nitric oxide production, and mesenteric-arteriole vasodilation. |
| 10392 | 22028412 | Moreover, point mutations of IRS-1 at Ser(636/639) to Ala prevented the ANG II-mediated inhibition of insulin signaling. |
| 10393 | 22028412 | From these results, we conclude that activation of mTOR/p70S6K by ANG II in vascular endothelium may contribute to impairment of insulin-stimulated vasodilation through phosphorylation of IRS-1 at Ser(636/639). |
| 10394 | 22028412 | This ANG II-mediated impairment of vascular actions of insulin may help explain the role of ANG II as a link between insulin resistance and hypertension. |
| 10395 | 22028447 | Heparin-binding EGF-like growth factor (HB-EGF) mediates 5-HT-induced insulin resistance through activation of EGF receptor-ERK1/2-mTOR pathway. |
| 10396 | 22028447 | Although an inverse correlation between insulin sensitivity and the level of Gq/11-coupled receptor agonists, such as endothelin-1, thrombin, and 5-hydroxytryptamine (5-HT), has been reported, its precise mechanism remains unclear. |
| 10397 | 22028447 | In this report, we provide evidence that 5-HT induced production of heparin-binding epidermal growth factor-like growth factor (HB-EGF) and caused insulin resistance in 3T3-L1 adipocytes, primary adipocytes, and C2C12 myotubes. |
| 10398 | 22028447 | In 3T3-L1 adipocytes, 5-HT stimulated HB-EGF production by promoting metalloproteinase-dependent shedding of transmembrane protein pro-HB-EGF. |
| 10399 | 22028447 | HB-EGF then bound and tyrosine-phosphorylated EGF receptors, which activated the mammalian target of rapamycin pathway through ERK1/2 phosphorylation. |
| 10400 | 22028447 | Mammalian target of rapamycin activation caused serine phosphorylation of insulin receptor substrate-1, which attenuated insulin-stimulated tyrosine phosphorylation of insulin receptor substrate-1 and glucose uptake. |
| 10401 | 22028447 | Pharmacological inhibition of either Gq/11-coupled receptors or metalloproteinases, as well as either inhibition or knockdown of HB-EGF or Gαq/11, restored insulin signal transduction impaired by 5-HT. |
| 10402 | 22028447 | Inhibition of metalloproteinase activity also abolished HB-EGF production and subsequent EGF receptor activation by other Gq/11-coupled receptor agonists known to cause insulin resistance, such as endothelin-1 and thrombin. |
| 10403 | 22028447 | These results suggest that transactivation of the EGF receptor through HB-EGF processing plays a pivotal role in 5-HT-induced insulin resistance. |
| 10404 | 22036866 | Inflammation impairs insulin signaling through the functional inhibition of IRS-1 and PPARγ. |
| 10405 | 22128025 | Adenoviral vectors were used to deliver the DNA repair enzyme human 8-oxoguanine DNA glycosylase/(apurinic/apyrimidinic) lyase (hOGG1) to mitochondria in L6 myotubes. |
| 10406 | 22128025 | Protection of mtDNA from palmitate-induced damage by overexpression of hOGG1 targeted to mitochondria significantly diminished palmitate-induced mitochondrial superoxide production, restored the decline in ATP levels, reduced activation of c-Jun N-terminal kinase (JNK) kinase, prevented cells from entering apoptosis, increased insulin-stimulated phosphorylation of serine-threonine kinase (Akt) (Ser473) and tyrosine phosphorylation of insulin receptor substrate-1, and thereby enhanced glucose transporter 4 translocation to plasma membrane, and restored insulin signaling. |
| 10407 | 22128025 | Addition of a specific inhibitor of JNK mimicked the effect of mitochondrial overexpression of hOGG1 and partially restored insulin sensitivity, thus confirming the involvement of mtDNA damage and subsequent increase of oxidative stress and JNK activation in insulin signaling in L6 myotubes. |
| 10408 | 22138235 | Moreover, it increased oxidative stress (decreased antioxidant enzyme activities and GSH/GSSG ratio, increased xanthine oxidase enzyme activity, lipid peroxidation, protein carbonylation and ROS generation) and enhanced the proinflammatory cytokines levels, activity of myeloperoxidase and nuclear translocation of NFκB in the cardiac tissue of the experimental animals. |
| 10409 | 22138235 | In addition, taurine increased GLUT 4 translocation to the cardiac membrane by enhanced phosphorylation of IR and IRS1 at tyrosine and Akt at serine residue in the heart. |
| 10410 | 22138235 | Results also suggest that taurine could protect cardiac tissue from ALX induced apoptosis via the regulation of Bcl2 family and caspase 9/3 proteins. |
| 10411 | 22158866 | Inhibition of insulin signaling in endothelial cells by protein kinase C-induced phosphorylation of p85 subunit of phosphatidylinositol 3-kinase (PI3K). |
| 10412 | 22158866 | Protein kinase C (PKC) activation has been reported to inhibit insulin signaling selectively in endothelial cells via the insulin receptor substrate/PI3K/Akt pathway to reduce the activation of endothelial nitric-oxide synthase (eNOS). |
| 10413 | 22158866 | In this study, it was observed that PKC activation differentially inhibited insulin receptor substrate 1/2 (IRS1/2) signaling of insulin's activation of PI3K/eNOS by decreasing only tyrosine phosphorylation of IRS2. |
| 10414 | 22158866 | In addition, PKC activation, by general activator and specifically by angiotensin II, increased the phosphorylation of p85/PI3K, which decreases its association with IRS1 and activation. |
| 10415 | 22158866 | Thr-86 of p85/PI3K was identified to be phosphorylated by PKC activation and confirmed to affect IRS1-mediated activation of Akt/eNOS by insulin and VEGF using a deletion mutant of the Thr-86 region of p85/PI3K. |
| 10416 | 22158866 | Thus, PKC and angiotensin-induced phosphorylation of Thr-86 of p85/PI3K may partially inhibit the activation of PI3K/eNOS by multiple cytokines and contribute to endothelial dysfunction in metabolic disorders. |
| 10417 | 22158866 | Inhibition of insulin signaling in endothelial cells by protein kinase C-induced phosphorylation of p85 subunit of phosphatidylinositol 3-kinase (PI3K). |
| 10418 | 22158866 | Protein kinase C (PKC) activation has been reported to inhibit insulin signaling selectively in endothelial cells via the insulin receptor substrate/PI3K/Akt pathway to reduce the activation of endothelial nitric-oxide synthase (eNOS). |
| 10419 | 22158866 | In this study, it was observed that PKC activation differentially inhibited insulin receptor substrate 1/2 (IRS1/2) signaling of insulin's activation of PI3K/eNOS by decreasing only tyrosine phosphorylation of IRS2. |
| 10420 | 22158866 | In addition, PKC activation, by general activator and specifically by angiotensin II, increased the phosphorylation of p85/PI3K, which decreases its association with IRS1 and activation. |
| 10421 | 22158866 | Thr-86 of p85/PI3K was identified to be phosphorylated by PKC activation and confirmed to affect IRS1-mediated activation of Akt/eNOS by insulin and VEGF using a deletion mutant of the Thr-86 region of p85/PI3K. |
| 10422 | 22158866 | Thus, PKC and angiotensin-induced phosphorylation of Thr-86 of p85/PI3K may partially inhibit the activation of PI3K/eNOS by multiple cytokines and contribute to endothelial dysfunction in metabolic disorders. |
| 10423 | 22158866 | Inhibition of insulin signaling in endothelial cells by protein kinase C-induced phosphorylation of p85 subunit of phosphatidylinositol 3-kinase (PI3K). |
| 10424 | 22158866 | Protein kinase C (PKC) activation has been reported to inhibit insulin signaling selectively in endothelial cells via the insulin receptor substrate/PI3K/Akt pathway to reduce the activation of endothelial nitric-oxide synthase (eNOS). |
| 10425 | 22158866 | In this study, it was observed that PKC activation differentially inhibited insulin receptor substrate 1/2 (IRS1/2) signaling of insulin's activation of PI3K/eNOS by decreasing only tyrosine phosphorylation of IRS2. |
| 10426 | 22158866 | In addition, PKC activation, by general activator and specifically by angiotensin II, increased the phosphorylation of p85/PI3K, which decreases its association with IRS1 and activation. |
| 10427 | 22158866 | Thr-86 of p85/PI3K was identified to be phosphorylated by PKC activation and confirmed to affect IRS1-mediated activation of Akt/eNOS by insulin and VEGF using a deletion mutant of the Thr-86 region of p85/PI3K. |
| 10428 | 22158866 | Thus, PKC and angiotensin-induced phosphorylation of Thr-86 of p85/PI3K may partially inhibit the activation of PI3K/eNOS by multiple cytokines and contribute to endothelial dysfunction in metabolic disorders. |
| 10429 | 22198320 | We have examined the ability of HI and HF, purified from SJW, to modulate adipocyte development and insulin action in mature adipocytes. |
| 10430 | 22198320 | Our novel studies indicate that the profound effects of SJW on adipogenesis, IRS-1 activation, and insulin-stimulated glucose uptake are not mediated by HI and/or HF. |
| 10431 | 22198320 | Nonetheless, we propose that extracts of SJW may contribute to adipocyte related diseases by limiting differentiation of preadipocytes and significantly inducing insulin resistance in mature fat cells. |
| 10432 | 22210743 | Differential insulin receptor substrate-1 (IRS1)-related modulation of neuropeptide Y and proopiomelanocortin expression in nondiabetic and diabetic IRS2-/- mice. |
| 10433 | 22210743 | Insulin resistance and type 2 diabetes correlate with impaired leptin and insulin signaling. |
| 10434 | 22210743 | Our aim was to analyze how leptin and insulin signaling may differentially affect the expression of hypothalamic neuropeptides regulating food intake and hypothalamic inflammation in diabetic (D) and nondiabetic (ND) IRS2(-/-) mice. |
| 10435 | 22210743 | We analyzed the activation of leptin and insulin targets by Western blotting and their association by immunoprecipitation, as well as the mRNA levels of neuropeptide Y (NPY), proopiomelanocortin, and inflammatory markers by real-time PCR and colocalization of forkhead box protein O1 (FOXO1) and NPY by double immunohistochemistry in the hypothalamus. |
| 10436 | 22210743 | Serum leptin and insulin levels and hypothalamic Janus kinase 2 and signal transducer and activator of transcription factor 3 activation were increased in ND IRS2(-/-) mice. |
| 10437 | 22210743 | IRS1 levels and its association with Janus kinase 2 and p85 and protein kinase B activation were increased in ND IRS2(-/-). |
| 10438 | 22210743 | Increased FOXO1 positively correlated with NPY mRNA levels in D IRS2(-/-) mice, with FOXO1 showing mainly nuclear localization in D IRS2(-/-) and cytoplasmic in ND IRS2(-/-) mice. |
| 10439 | 22210743 | In conclusion, differential activation of these pathways and changes in the expression of NPY and inflammation may exert a protective effect against hypothalamic deregulation of appetite, suggesting that manipulation of these targets could be of interest in the treatment of insulin resistance and type 2 diabetes. |
| 10440 | 22210743 | Differential insulin receptor substrate-1 (IRS1)-related modulation of neuropeptide Y and proopiomelanocortin expression in nondiabetic and diabetic IRS2-/- mice. |
| 10441 | 22210743 | Insulin resistance and type 2 diabetes correlate with impaired leptin and insulin signaling. |
| 10442 | 22210743 | Our aim was to analyze how leptin and insulin signaling may differentially affect the expression of hypothalamic neuropeptides regulating food intake and hypothalamic inflammation in diabetic (D) and nondiabetic (ND) IRS2(-/-) mice. |
| 10443 | 22210743 | We analyzed the activation of leptin and insulin targets by Western blotting and their association by immunoprecipitation, as well as the mRNA levels of neuropeptide Y (NPY), proopiomelanocortin, and inflammatory markers by real-time PCR and colocalization of forkhead box protein O1 (FOXO1) and NPY by double immunohistochemistry in the hypothalamus. |
| 10444 | 22210743 | Serum leptin and insulin levels and hypothalamic Janus kinase 2 and signal transducer and activator of transcription factor 3 activation were increased in ND IRS2(-/-) mice. |
| 10445 | 22210743 | IRS1 levels and its association with Janus kinase 2 and p85 and protein kinase B activation were increased in ND IRS2(-/-). |
| 10446 | 22210743 | Increased FOXO1 positively correlated with NPY mRNA levels in D IRS2(-/-) mice, with FOXO1 showing mainly nuclear localization in D IRS2(-/-) and cytoplasmic in ND IRS2(-/-) mice. |
| 10447 | 22210743 | In conclusion, differential activation of these pathways and changes in the expression of NPY and inflammation may exert a protective effect against hypothalamic deregulation of appetite, suggesting that manipulation of these targets could be of interest in the treatment of insulin resistance and type 2 diabetes. |
| 10448 | 22215652 | Insulin-stimulated PI3K activity in skeletal muscle and adipose tissue of DIO mice was significantly reduced ∼50-65%, but this was restored completely by INT131 therapy. |
| 10449 | 22215652 | The INT131 effects on PI3K activity are most likely due to increased IRS-1 tyrosine phosphorylation. |
| 10450 | 22215652 | Concurrently, insulin-mediated Akt phosphorylation also increased after INT131 treatment in DIO mice. |
| 10451 | 22215652 | These data suggest that a newly developed insulin-sensitizing agent, INT131, normalizes obesity-related defects in insulin action on PI3K signaling in insulin target tissues by a mechanism involved in glycemic control. |
| 10452 | 22266116 | TNFα and SOCS3 regulate IRS-1 to increase retinal endothelial cell apoptosis. |
| 10453 | 22266116 | Cell lysates were processed for Western blotting and ELISA analyses to verify TNFα and SOCS3 knockdown, as well as key pro- and anti-apoptotic factors, IRS-1, and Akt. |
| 10454 | 22266116 | Knockdown of TNFα leads to decreased phosphorylation of IRS-1(Ser307), which would promote normal insulin signaling. |
| 10455 | 22266116 | Knockdown of SOCS3 increased total IRS-1 levels, as well as decreased IR(Tyr960), both of which would inhibit retinal endothelial cell apoptosis through increased insulin signaling. |
| 10456 | 22266116 | Taken together, our findings suggest that increased TNFα inhibits insulin signaling in 2 ways: 1) increased phosphorylation of IRS-1(Ser307), 2) increased SOCS3 levels to decrease total IRS-1 and increase IR(Tyr960), both of which block normal insulin signal transduction. |
| 10457 | 22266116 | TNFα and SOCS3 regulate IRS-1 to increase retinal endothelial cell apoptosis. |
| 10458 | 22266116 | Cell lysates were processed for Western blotting and ELISA analyses to verify TNFα and SOCS3 knockdown, as well as key pro- and anti-apoptotic factors, IRS-1, and Akt. |
| 10459 | 22266116 | Knockdown of TNFα leads to decreased phosphorylation of IRS-1(Ser307), which would promote normal insulin signaling. |
| 10460 | 22266116 | Knockdown of SOCS3 increased total IRS-1 levels, as well as decreased IR(Tyr960), both of which would inhibit retinal endothelial cell apoptosis through increased insulin signaling. |
| 10461 | 22266116 | Taken together, our findings suggest that increased TNFα inhibits insulin signaling in 2 ways: 1) increased phosphorylation of IRS-1(Ser307), 2) increased SOCS3 levels to decrease total IRS-1 and increase IR(Tyr960), both of which block normal insulin signal transduction. |
| 10462 | 22266116 | TNFα and SOCS3 regulate IRS-1 to increase retinal endothelial cell apoptosis. |
| 10463 | 22266116 | Cell lysates were processed for Western blotting and ELISA analyses to verify TNFα and SOCS3 knockdown, as well as key pro- and anti-apoptotic factors, IRS-1, and Akt. |
| 10464 | 22266116 | Knockdown of TNFα leads to decreased phosphorylation of IRS-1(Ser307), which would promote normal insulin signaling. |
| 10465 | 22266116 | Knockdown of SOCS3 increased total IRS-1 levels, as well as decreased IR(Tyr960), both of which would inhibit retinal endothelial cell apoptosis through increased insulin signaling. |
| 10466 | 22266116 | Taken together, our findings suggest that increased TNFα inhibits insulin signaling in 2 ways: 1) increased phosphorylation of IRS-1(Ser307), 2) increased SOCS3 levels to decrease total IRS-1 and increase IR(Tyr960), both of which block normal insulin signal transduction. |
| 10467 | 22266116 | TNFα and SOCS3 regulate IRS-1 to increase retinal endothelial cell apoptosis. |
| 10468 | 22266116 | Cell lysates were processed for Western blotting and ELISA analyses to verify TNFα and SOCS3 knockdown, as well as key pro- and anti-apoptotic factors, IRS-1, and Akt. |
| 10469 | 22266116 | Knockdown of TNFα leads to decreased phosphorylation of IRS-1(Ser307), which would promote normal insulin signaling. |
| 10470 | 22266116 | Knockdown of SOCS3 increased total IRS-1 levels, as well as decreased IR(Tyr960), both of which would inhibit retinal endothelial cell apoptosis through increased insulin signaling. |
| 10471 | 22266116 | Taken together, our findings suggest that increased TNFα inhibits insulin signaling in 2 ways: 1) increased phosphorylation of IRS-1(Ser307), 2) increased SOCS3 levels to decrease total IRS-1 and increase IR(Tyr960), both of which block normal insulin signal transduction. |
| 10472 | 22266116 | TNFα and SOCS3 regulate IRS-1 to increase retinal endothelial cell apoptosis. |
| 10473 | 22266116 | Cell lysates were processed for Western blotting and ELISA analyses to verify TNFα and SOCS3 knockdown, as well as key pro- and anti-apoptotic factors, IRS-1, and Akt. |
| 10474 | 22266116 | Knockdown of TNFα leads to decreased phosphorylation of IRS-1(Ser307), which would promote normal insulin signaling. |
| 10475 | 22266116 | Knockdown of SOCS3 increased total IRS-1 levels, as well as decreased IR(Tyr960), both of which would inhibit retinal endothelial cell apoptosis through increased insulin signaling. |
| 10476 | 22266116 | Taken together, our findings suggest that increased TNFα inhibits insulin signaling in 2 ways: 1) increased phosphorylation of IRS-1(Ser307), 2) increased SOCS3 levels to decrease total IRS-1 and increase IR(Tyr960), both of which block normal insulin signal transduction. |
| 10477 | 22278080 | Subsequently, skeletal muscle was isolated for assessment in terms of levels of gene and protein IR, IRS1, Akt and glucose transporter 4 (GLUT4). |
| 10478 | 22278080 | Consistent with these effects, aglycin restored insulin signaling transduction by maintaining IR and IRS1 expression at both the mRNA and protein levels, as well as elevating the expression of p-IR, p-IRS1, p-Akt and membrane GLUT4 protein. |
| 10479 | 22278080 | Subsequently, skeletal muscle was isolated for assessment in terms of levels of gene and protein IR, IRS1, Akt and glucose transporter 4 (GLUT4). |
| 10480 | 22278080 | Consistent with these effects, aglycin restored insulin signaling transduction by maintaining IR and IRS1 expression at both the mRNA and protein levels, as well as elevating the expression of p-IR, p-IRS1, p-Akt and membrane GLUT4 protein. |
| 10481 | 22285432 | In this study, we attempt to reveal how sodium arsenite (iAs) could induce stress mediated impaired insulin signaling in mice and if an isolated active fraction of ginger, [6]-gingerol could attenuate the iAs intoxicated hyperglycemic condition of mice and bring about improvement in their impaired insulin signaling. [6]-Gingerol treatment reduced elevated blood glucose level and oxidative stress by enhancing activity of super oxide dismutase (SOD), catalase, glutathione peroxidase (GPx) and GSH. [6]-Gingerol also helped in increasing plasma insulin level, brought down after iAs exposure. iAs treatment to primary cell culture of β-cells and hepatocytes in vitro produced cyto-degenerative effect and accumulated reactive oxygen species (ROS) in pancreatic β-cells and hepatocytes of mice. [6]-Gingerol appeared to inhibit/intervene iAs induced cyto-degeneration of pancreatic β-cells and hepatocytes, helped in scavenging the free radicals. |
| 10482 | 22285432 | The over-expression of TNFα and IL6 in iAs intoxicated mice was down-regulated by [6]-gingerol treatment. iAs intoxication reduced expression levels of GLUT4, IRS-1, IRS-2, PI3K, AKT, PPARγ signaling molecules; [6]-gingerol mediated its action through enhancing the expressions of these signaling molecules, both at protein and mRNA levels. |
| 10483 | 22307069 | Nominally significant genotype-by-intervention interactions were detected for 1-year change in waist circumference with JAZF1, MTNR1B, and IRS1, and BMI with JAZF1. |
| 10484 | 22326951 | Furthermore, we found that FoxO1-dependent downregulation of IRS1 resulted in blunted Akt signaling and insulin resistance. |
| 10485 | 22362362 | An indolent non-healing wound and insulin and/or insulin-like growth factor (IGF1) resistance are cardinal features of diabetes, inflammation and hypercortisolemia. |
| 10486 | 22362362 | Do the various triggers that induce insulin and/or IGF1 resistance and retard wound healing act through a common mechanism? |
| 10487 | 22362362 | In normal fibroblasts, IGF1 initiated a strong degree of phosphorylation of insulin receptor substrate 1 (IRS1) (Tyr612) and Akt (Ser473), concomitantly with increased PI3K activity. |
| 10488 | 22362362 | The above-mentioned defects were reflected functionally by attenuation in IGF1-dependent stimulation of key fibroblast functions, including collagen synthesis and cell proliferation, migration and contraction. |
| 10489 | 22362362 | The ROS suppressors EUK-134 and α-lipoic acid, or small interfering RNA (siRNA)-mediated silencing of JNK expression, restored IGF1 sensitivity both in vitro and in vivo, and also ameliorated the impairment in IGF1-mediated wound responses during diabetes, inflammation and hypercortisolemia. |
| 10490 | 22374967 | Adiponectin and fructosamine levels were completely recovered by melatonin, whereas neither plasma insulin level nor insulin secretion capacity was improved in diabetic animals. |
| 10491 | 22374967 | Melatonin treatment improved the responsiveness of adipocytes to insulin in diabetic animals measured by tests of glucose uptake (sc, EP, and RP), glucose oxidation, and incorporation of glucose into lipids (EP and RP), an effect that seems partially related to an increased expression of insulin receptor substrate 1, acetyl-coenzyme A carboxylase and fatty acid synthase. |
| 10492 | 22387882 | Alterations in insulin signaling in primary mammalian adipocytes were determined by the phosphorylation of Akt, a critical insulin signaling intermediate. |
| 10493 | 22387882 | Treatment of primary murine adipose tissue in vitro with 100nM TF for 48h markedly attenuated acute insulin-stimulated Akt phosphorylation in a strain- and species-independent fashion. |
| 10494 | 22387882 | A similar TF-induced reduction in insulin-stimulated Akt phosphorylation was observed in primary human subcutaneous adipose tissue. |
| 10495 | 22387882 | In contrast, insulin receptor-β, phosphatidylinositol 3-kinase, and Akt expression were unchanged, indicating a specific abrogation of insulin signaling. |
| 10496 | 22387882 | Additionally, TF-treated adipocytes exhibited altered endocrine function with a reduction in both basal and insulin-stimulated leptin secretion. |
| 10497 | 22387882 | These studies demonstrate that TF induces cellular insulin resistance in primary murine and human adipocytes through a reduction of IRS-1 expression and protein stability, raising concern about the potential for this fungicide to disrupt metabolism and thereby contribute to the pathogenesis of diabetes. |
| 10498 | 22396205 | Stress augments insulin resistance and prothrombotic state: role of visceral adipose-derived monocyte chemoattractant protein-1. |
| 10499 | 22396205 | Expression of plasma lipids, monocyte/macrophage markers (CD11b, CD68, and F4/80), proinflammatory cytokines (monocyte chemoattractant protein-1 [MCP-1], tumor necrosis factor-α, and interleukin-6), adiponectin, heat shock protein 70.1 (HSP70.1), and coagulation factors (plasminogen activation inhibitor-1 [PAI-1] and tissue factor [TF]) in blood and inguinal white adipose tissue (WAT) was determined using immunohistochemistry, enzyme-linked immunosorbent assay, and RT-PCR, respectively. |
| 10500 | 22396205 | Glucose metabolism was assessed by glucose tolerance tests (GTTs) and insulin tolerance tests, and expression of insulin receptor substrate-1 (IRS-1) and glucose transporter 4 (GLUT4) in WAT. |
| 10501 | 22396205 | Stress increased monocyte accumulation, free fatty acids, proinflammatory cytokine, and HSP70.1 and reduced adiponectin. |
| 10502 | 22396205 | Without any changes in GTT, stress worsened insulin sensitivity and decreased IRS-1 and GLUT4 in WAT. |
| 10503 | 22396205 | Stress evoked adipose inflammation to increase coagulation factors and impair insulin sensitivity through adipose-derived MCP-1. |
| 10504 | 22396205 | Stress augments insulin resistance and prothrombotic state: role of visceral adipose-derived monocyte chemoattractant protein-1. |
| 10505 | 22396205 | Expression of plasma lipids, monocyte/macrophage markers (CD11b, CD68, and F4/80), proinflammatory cytokines (monocyte chemoattractant protein-1 [MCP-1], tumor necrosis factor-α, and interleukin-6), adiponectin, heat shock protein 70.1 (HSP70.1), and coagulation factors (plasminogen activation inhibitor-1 [PAI-1] and tissue factor [TF]) in blood and inguinal white adipose tissue (WAT) was determined using immunohistochemistry, enzyme-linked immunosorbent assay, and RT-PCR, respectively. |
| 10506 | 22396205 | Glucose metabolism was assessed by glucose tolerance tests (GTTs) and insulin tolerance tests, and expression of insulin receptor substrate-1 (IRS-1) and glucose transporter 4 (GLUT4) in WAT. |
| 10507 | 22396205 | Stress increased monocyte accumulation, free fatty acids, proinflammatory cytokine, and HSP70.1 and reduced adiponectin. |
| 10508 | 22396205 | Without any changes in GTT, stress worsened insulin sensitivity and decreased IRS-1 and GLUT4 in WAT. |
| 10509 | 22396205 | Stress evoked adipose inflammation to increase coagulation factors and impair insulin sensitivity through adipose-derived MCP-1. |
| 10510 | 22396207 | Loss of AMP-activated protein kinase-α2 impairs the insulin-sensitizing effect of calorie restriction in skeletal muscle. |
| 10511 | 22396207 | Whether the well-known metabolic switch AMP-activated protein kinase (AMPK) is involved in the insulin-sensitizing effect of calorie restriction (CR) is unclear. |
| 10512 | 22396207 | In this study, we investigated the role of AMPK in the insulin-sensitizing effect of CR in skeletal muscle. |
| 10513 | 22396207 | Furthermore, CR-induced activation of Akt-TBC1D1/TBC1D4 signaling, inhibition of mammalian target of rapamycin-S6K1-insulin receptor substrate-1 pathway, and induction of nicotinamide phosphoribosyltransferase-NAD(+)-sirtuin-1 cascade were remarkably impaired in AMPK-α2(-/-) mice. |
| 10514 | 22396207 | CR serum increased stability of AMPK-α2 protein via inhibiting the X chromosome-linked ubiquitin-specific protease 9-mediated ubiquitylation of AMPK-α2. |
| 10515 | 22396207 | Our results suggest that AMPK may be modulated by CR in a ubiquitylation-dependent manner and acts as a chief dictator for the insulin-sensitizing effects of CR in skeletal muscle. |
| 10516 | 22412912 | GLUT 4 translocation, phosphorylation of AMPK and Akt, AMPK activity, and association of IRS-1 and PI3K were investigated in the presence of CGA. |
| 10517 | 22412912 | Consistent with these results, CGA was found to phosphorylate AMPK and ACC, consistent with the result of increased AMPK activities. |
| 10518 | 22412912 | CGA did not appear to enhance association of IRS-1 with p85. |
| 10519 | 22412912 | GLUT 4 translocation, phosphorylation of AMPK and Akt, AMPK activity, and association of IRS-1 and PI3K were investigated in the presence of CGA. |
| 10520 | 22412912 | Consistent with these results, CGA was found to phosphorylate AMPK and ACC, consistent with the result of increased AMPK activities. |
| 10521 | 22412912 | CGA did not appear to enhance association of IRS-1 with p85. |
| 10522 | 22442749 | Dairy proteins and meat stimulate insulin/insulin-like growth factor 1 signaling and provide high amounts of leucine, a primary and independent stimulator for mTORC1 activation. |
| 10523 | 22442749 | The downstream target of mTORC1, the kinase S6K1, induces insulin resistance by phosphorylation of insulin receptor substrate-1, thereby increasing the metabolic burden of β-cells. |
| 10524 | 22442749 | Disturbances of β-cell mass regulation with increased β-cell proliferation and apoptosis as well as insulin resistance are hallmarks of T2D, which are all associated with hyperactivation of mTORC1. |
| 10525 | 22457223 | Induction of heat shock proteins (Hsp) 72 and 27 can improve insulin signalling in obesity and type 2 diabetes via inhibition of key stress kinases. |
| 10526 | 22457223 | This study specifically investigated insulin-stimulated glucose metabolism in monocytes and examined the impact of HSP induction on insulin signalling. |
| 10527 | 22457223 | Glucose transporter (GLUT)4 expression on monocytes, phosphorylated JNK, IKK-β and IRS-1, as well as Hsp27 and Hsp72, were measured in monocytes under fasting conditions. |
| 10528 | 22457223 | HSP induction as well as JNK, IKK-β activation and IRS-1 serine phosphorylation was investigated following heat stress. |
| 10529 | 22457223 | Obese patients showed lower GLUT4 levels on monocytes during the OGTT. pJNK, pIKK-β and pIRS-1 levels were increased in OG with pJNK and pIKK-β levels positively correlated with serine pIRS-1 and negatively with GLUT4 supporting their role in insulin resistance. |
| 10530 | 22457223 | Induction of heat shock proteins (Hsp) 72 and 27 can improve insulin signalling in obesity and type 2 diabetes via inhibition of key stress kinases. |
| 10531 | 22457223 | This study specifically investigated insulin-stimulated glucose metabolism in monocytes and examined the impact of HSP induction on insulin signalling. |
| 10532 | 22457223 | Glucose transporter (GLUT)4 expression on monocytes, phosphorylated JNK, IKK-β and IRS-1, as well as Hsp27 and Hsp72, were measured in monocytes under fasting conditions. |
| 10533 | 22457223 | HSP induction as well as JNK, IKK-β activation and IRS-1 serine phosphorylation was investigated following heat stress. |
| 10534 | 22457223 | Obese patients showed lower GLUT4 levels on monocytes during the OGTT. pJNK, pIKK-β and pIRS-1 levels were increased in OG with pJNK and pIKK-β levels positively correlated with serine pIRS-1 and negatively with GLUT4 supporting their role in insulin resistance. |
| 10535 | 22457523 | Hepatitis C virus activates the mTOR/S6K1 signaling pathway in inhibiting IRS-1 function for insulin resistance. |
| 10536 | 22457523 | We have previously shown that HCV infection modulates phosphorylation of Akt, a downstream target of IRS-1. |
| 10537 | 22457523 | In this study, we further examined the status of total IRS-1 and the downstream regulation of the Akt pathway in understanding mTOR/S6K1 signaling using HCV genotype 2a (clone JFH1)-infected hepatocytes. |
| 10538 | 22457523 | The status of the tuberous sclerosis complex (TSC-1/TSC-2) was significantly decreased after HCV infection of human hepatocytes, showing a modulation of the downstream Akt pathway. |
| 10539 | 22457523 | Subsequent study indicated an increased level of Rheb and mTOR expression in HCV-infected hepatocytes. |
| 10540 | 22457523 | Ectopic expression of TSC-1/TSC-2 significantly recovered the IRS-1 protein expression level in HCV-infected hepatocytes. |
| 10541 | 22457523 | Further analyses indicated that HCV core protein plays a significant role in modulating the mTOR/S6K1 signaling pathway. |
| 10542 | 22457523 | Proteasome inhibitor MG 132 recovered IRS-1 and TSC1/2 expression, suggesting that degradation occurred via the ubiquitin proteasome pathway. |
| 10543 | 22457523 | A functional consequence of IRS-1 inhibition was reflected in a decrease in GLUT4 protein expression and upregulation of the gluconeogenic enzyme PCK2 in HCV-infected hepatocytes. |
| 10544 | 22457523 | Together, these observations suggested that HCV infection activates the mTOR/S6K1 pathway in inhibiting IRS-1 function and perturbs glucose metabolism via downregulation of GLUT4 and upregulation of PCK2 for insulin resistance. |
| 10545 | 22457523 | Hepatitis C virus activates the mTOR/S6K1 signaling pathway in inhibiting IRS-1 function for insulin resistance. |
| 10546 | 22457523 | We have previously shown that HCV infection modulates phosphorylation of Akt, a downstream target of IRS-1. |
| 10547 | 22457523 | In this study, we further examined the status of total IRS-1 and the downstream regulation of the Akt pathway in understanding mTOR/S6K1 signaling using HCV genotype 2a (clone JFH1)-infected hepatocytes. |
| 10548 | 22457523 | The status of the tuberous sclerosis complex (TSC-1/TSC-2) was significantly decreased after HCV infection of human hepatocytes, showing a modulation of the downstream Akt pathway. |
| 10549 | 22457523 | Subsequent study indicated an increased level of Rheb and mTOR expression in HCV-infected hepatocytes. |
| 10550 | 22457523 | Ectopic expression of TSC-1/TSC-2 significantly recovered the IRS-1 protein expression level in HCV-infected hepatocytes. |
| 10551 | 22457523 | Further analyses indicated that HCV core protein plays a significant role in modulating the mTOR/S6K1 signaling pathway. |
| 10552 | 22457523 | Proteasome inhibitor MG 132 recovered IRS-1 and TSC1/2 expression, suggesting that degradation occurred via the ubiquitin proteasome pathway. |
| 10553 | 22457523 | A functional consequence of IRS-1 inhibition was reflected in a decrease in GLUT4 protein expression and upregulation of the gluconeogenic enzyme PCK2 in HCV-infected hepatocytes. |
| 10554 | 22457523 | Together, these observations suggested that HCV infection activates the mTOR/S6K1 pathway in inhibiting IRS-1 function and perturbs glucose metabolism via downregulation of GLUT4 and upregulation of PCK2 for insulin resistance. |
| 10555 | 22457523 | Hepatitis C virus activates the mTOR/S6K1 signaling pathway in inhibiting IRS-1 function for insulin resistance. |
| 10556 | 22457523 | We have previously shown that HCV infection modulates phosphorylation of Akt, a downstream target of IRS-1. |
| 10557 | 22457523 | In this study, we further examined the status of total IRS-1 and the downstream regulation of the Akt pathway in understanding mTOR/S6K1 signaling using HCV genotype 2a (clone JFH1)-infected hepatocytes. |
| 10558 | 22457523 | The status of the tuberous sclerosis complex (TSC-1/TSC-2) was significantly decreased after HCV infection of human hepatocytes, showing a modulation of the downstream Akt pathway. |
| 10559 | 22457523 | Subsequent study indicated an increased level of Rheb and mTOR expression in HCV-infected hepatocytes. |
| 10560 | 22457523 | Ectopic expression of TSC-1/TSC-2 significantly recovered the IRS-1 protein expression level in HCV-infected hepatocytes. |
| 10561 | 22457523 | Further analyses indicated that HCV core protein plays a significant role in modulating the mTOR/S6K1 signaling pathway. |
| 10562 | 22457523 | Proteasome inhibitor MG 132 recovered IRS-1 and TSC1/2 expression, suggesting that degradation occurred via the ubiquitin proteasome pathway. |
| 10563 | 22457523 | A functional consequence of IRS-1 inhibition was reflected in a decrease in GLUT4 protein expression and upregulation of the gluconeogenic enzyme PCK2 in HCV-infected hepatocytes. |
| 10564 | 22457523 | Together, these observations suggested that HCV infection activates the mTOR/S6K1 pathway in inhibiting IRS-1 function and perturbs glucose metabolism via downregulation of GLUT4 and upregulation of PCK2 for insulin resistance. |
| 10565 | 22457523 | Hepatitis C virus activates the mTOR/S6K1 signaling pathway in inhibiting IRS-1 function for insulin resistance. |
| 10566 | 22457523 | We have previously shown that HCV infection modulates phosphorylation of Akt, a downstream target of IRS-1. |
| 10567 | 22457523 | In this study, we further examined the status of total IRS-1 and the downstream regulation of the Akt pathway in understanding mTOR/S6K1 signaling using HCV genotype 2a (clone JFH1)-infected hepatocytes. |
| 10568 | 22457523 | The status of the tuberous sclerosis complex (TSC-1/TSC-2) was significantly decreased after HCV infection of human hepatocytes, showing a modulation of the downstream Akt pathway. |
| 10569 | 22457523 | Subsequent study indicated an increased level of Rheb and mTOR expression in HCV-infected hepatocytes. |
| 10570 | 22457523 | Ectopic expression of TSC-1/TSC-2 significantly recovered the IRS-1 protein expression level in HCV-infected hepatocytes. |
| 10571 | 22457523 | Further analyses indicated that HCV core protein plays a significant role in modulating the mTOR/S6K1 signaling pathway. |
| 10572 | 22457523 | Proteasome inhibitor MG 132 recovered IRS-1 and TSC1/2 expression, suggesting that degradation occurred via the ubiquitin proteasome pathway. |
| 10573 | 22457523 | A functional consequence of IRS-1 inhibition was reflected in a decrease in GLUT4 protein expression and upregulation of the gluconeogenic enzyme PCK2 in HCV-infected hepatocytes. |
| 10574 | 22457523 | Together, these observations suggested that HCV infection activates the mTOR/S6K1 pathway in inhibiting IRS-1 function and perturbs glucose metabolism via downregulation of GLUT4 and upregulation of PCK2 for insulin resistance. |
| 10575 | 22457523 | Hepatitis C virus activates the mTOR/S6K1 signaling pathway in inhibiting IRS-1 function for insulin resistance. |
| 10576 | 22457523 | We have previously shown that HCV infection modulates phosphorylation of Akt, a downstream target of IRS-1. |
| 10577 | 22457523 | In this study, we further examined the status of total IRS-1 and the downstream regulation of the Akt pathway in understanding mTOR/S6K1 signaling using HCV genotype 2a (clone JFH1)-infected hepatocytes. |
| 10578 | 22457523 | The status of the tuberous sclerosis complex (TSC-1/TSC-2) was significantly decreased after HCV infection of human hepatocytes, showing a modulation of the downstream Akt pathway. |
| 10579 | 22457523 | Subsequent study indicated an increased level of Rheb and mTOR expression in HCV-infected hepatocytes. |
| 10580 | 22457523 | Ectopic expression of TSC-1/TSC-2 significantly recovered the IRS-1 protein expression level in HCV-infected hepatocytes. |
| 10581 | 22457523 | Further analyses indicated that HCV core protein plays a significant role in modulating the mTOR/S6K1 signaling pathway. |
| 10582 | 22457523 | Proteasome inhibitor MG 132 recovered IRS-1 and TSC1/2 expression, suggesting that degradation occurred via the ubiquitin proteasome pathway. |
| 10583 | 22457523 | A functional consequence of IRS-1 inhibition was reflected in a decrease in GLUT4 protein expression and upregulation of the gluconeogenic enzyme PCK2 in HCV-infected hepatocytes. |
| 10584 | 22457523 | Together, these observations suggested that HCV infection activates the mTOR/S6K1 pathway in inhibiting IRS-1 function and perturbs glucose metabolism via downregulation of GLUT4 and upregulation of PCK2 for insulin resistance. |
| 10585 | 22457523 | Hepatitis C virus activates the mTOR/S6K1 signaling pathway in inhibiting IRS-1 function for insulin resistance. |
| 10586 | 22457523 | We have previously shown that HCV infection modulates phosphorylation of Akt, a downstream target of IRS-1. |
| 10587 | 22457523 | In this study, we further examined the status of total IRS-1 and the downstream regulation of the Akt pathway in understanding mTOR/S6K1 signaling using HCV genotype 2a (clone JFH1)-infected hepatocytes. |
| 10588 | 22457523 | The status of the tuberous sclerosis complex (TSC-1/TSC-2) was significantly decreased after HCV infection of human hepatocytes, showing a modulation of the downstream Akt pathway. |
| 10589 | 22457523 | Subsequent study indicated an increased level of Rheb and mTOR expression in HCV-infected hepatocytes. |
| 10590 | 22457523 | Ectopic expression of TSC-1/TSC-2 significantly recovered the IRS-1 protein expression level in HCV-infected hepatocytes. |
| 10591 | 22457523 | Further analyses indicated that HCV core protein plays a significant role in modulating the mTOR/S6K1 signaling pathway. |
| 10592 | 22457523 | Proteasome inhibitor MG 132 recovered IRS-1 and TSC1/2 expression, suggesting that degradation occurred via the ubiquitin proteasome pathway. |
| 10593 | 22457523 | A functional consequence of IRS-1 inhibition was reflected in a decrease in GLUT4 protein expression and upregulation of the gluconeogenic enzyme PCK2 in HCV-infected hepatocytes. |
| 10594 | 22457523 | Together, these observations suggested that HCV infection activates the mTOR/S6K1 pathway in inhibiting IRS-1 function and perturbs glucose metabolism via downregulation of GLUT4 and upregulation of PCK2 for insulin resistance. |
| 10595 | 22457523 | Hepatitis C virus activates the mTOR/S6K1 signaling pathway in inhibiting IRS-1 function for insulin resistance. |
| 10596 | 22457523 | We have previously shown that HCV infection modulates phosphorylation of Akt, a downstream target of IRS-1. |
| 10597 | 22457523 | In this study, we further examined the status of total IRS-1 and the downstream regulation of the Akt pathway in understanding mTOR/S6K1 signaling using HCV genotype 2a (clone JFH1)-infected hepatocytes. |
| 10598 | 22457523 | The status of the tuberous sclerosis complex (TSC-1/TSC-2) was significantly decreased after HCV infection of human hepatocytes, showing a modulation of the downstream Akt pathway. |
| 10599 | 22457523 | Subsequent study indicated an increased level of Rheb and mTOR expression in HCV-infected hepatocytes. |
| 10600 | 22457523 | Ectopic expression of TSC-1/TSC-2 significantly recovered the IRS-1 protein expression level in HCV-infected hepatocytes. |
| 10601 | 22457523 | Further analyses indicated that HCV core protein plays a significant role in modulating the mTOR/S6K1 signaling pathway. |
| 10602 | 22457523 | Proteasome inhibitor MG 132 recovered IRS-1 and TSC1/2 expression, suggesting that degradation occurred via the ubiquitin proteasome pathway. |
| 10603 | 22457523 | A functional consequence of IRS-1 inhibition was reflected in a decrease in GLUT4 protein expression and upregulation of the gluconeogenic enzyme PCK2 in HCV-infected hepatocytes. |
| 10604 | 22457523 | Together, these observations suggested that HCV infection activates the mTOR/S6K1 pathway in inhibiting IRS-1 function and perturbs glucose metabolism via downregulation of GLUT4 and upregulation of PCK2 for insulin resistance. |
| 10605 | 22470480 | Although evidence points to consider exposure to BPA as a risk factor for insulin resistance, its actions on whole body metabolism and on insulin-sensitive tissues are still unclear. |
| 10606 | 22470480 | The aim of the present work was to study the effects of low doses of BPA in insulin-sensitive peripheral tissues and whole body metabolism in adult mice. |
| 10607 | 22470480 | Mice treated with BPA were insulin resistant and had increased glucose-stimulated insulin release. |
| 10608 | 22470480 | In skeletal muscle, insulin-stimulated tyrosine phosphorylation of the insulin receptor β subunit was impaired in BPA-treated mice. |
| 10609 | 22470480 | This impairment was associated with a reduced insulin-stimulated Akt phosphorylation in the Thr(308) residue. |
| 10610 | 22470480 | Both skeletal muscle and liver displayed an upregulation of IRS-1 protein by BPA. |
| 10611 | 22470480 | In the liver, BPA effects were of lesser intensity with decreased insulin-stimulated tyrosine phosphorylation of the insulin receptor β subunit.In conclusion, short-term treatment with low doses of BPA slows down whole body energy metabolism and disrupts insulin signaling in peripheral tissues. |
| 10612 | 22476617 | Adipose tissue secretes numerous pro-inflammatory cytokines, such as interleukin (IL)-6 and tumor necrosis factor (TNF)-α that can lead to insulin resistance (IR). |
| 10613 | 22476617 | In the liver, both IL-6 and TNF-α induce IR by inhibiting phosphorylation or ubiquitination of IRS1. |
| 10614 | 22476617 | We measured intracellular Fe levels and the relative expression of hepcidin, NF-κB, IL-6, TNF-α, hypoxia inducible factor 1α (HIF-1α), and mitofusin 2 (Mfn-2) mRNA using qRT-PCR. |
| 10615 | 22476617 | HepG2 cells incubated with 40 μM Fe alone or Fe/glucose and challenged with IL-6 and/or CoCl(2) showed increased IL-6, NF-κB, and TNF-α mRNA expression and decreased mRNA expression of Mfn-2 in all experimental conditions. 3T3-L1 cells incubated with 40 μM Fe alone or Fe/glucose and challenged with IL-6 showed increased NF-κB mRNA expression and decreased Mfn-2 expression in all experimental conditions. |
| 10616 | 22521887 | There was a reduction in insulin-induced phosphorylation of IR, IRS-1, Akt and GSK-3β. |
| 10617 | 22617042 | The Gly(972)Arg variant of human IRS1 gene is associated with variation in glomerular filtration rate likely through impaired insulin receptor signaling. |
| 10618 | 22617042 | Expression of IRS1 mutant Arg972 in human mesangial cells significantly reduced the insulin-stimulated phosphorylation of IRS1 and Akt kinase. |
| 10619 | 22617042 | Taken together, the data provide the first evidence that genetic variation in IRS1 may influence variation in GFR probably through impaired insulin receptor signaling. |
| 10620 | 22617042 | The Gly(972)Arg variant of human IRS1 gene is associated with variation in glomerular filtration rate likely through impaired insulin receptor signaling. |
| 10621 | 22617042 | Expression of IRS1 mutant Arg972 in human mesangial cells significantly reduced the insulin-stimulated phosphorylation of IRS1 and Akt kinase. |
| 10622 | 22617042 | Taken together, the data provide the first evidence that genetic variation in IRS1 may influence variation in GFR probably through impaired insulin receptor signaling. |
| 10623 | 22617042 | The Gly(972)Arg variant of human IRS1 gene is associated with variation in glomerular filtration rate likely through impaired insulin receptor signaling. |
| 10624 | 22617042 | Expression of IRS1 mutant Arg972 in human mesangial cells significantly reduced the insulin-stimulated phosphorylation of IRS1 and Akt kinase. |
| 10625 | 22617042 | Taken together, the data provide the first evidence that genetic variation in IRS1 may influence variation in GFR probably through impaired insulin receptor signaling. |
| 10626 | 22618776 | Infusion of MSCs resulted in an increase of GLUT4 expression and an elevation of phosphorylated insulin receptor substrate 1 (IRS-1) and Akt (protein kinase B) in insulin target tissues. |
| 10627 | 22638648 | Basal phosphorylation of PKB/Akt was elevated but IRS-1 and SERCA-2 expression severely downregulated. |
| 10628 | 22688332 | Nesfatin-1 action in the brain increases insulin sensitivity through Akt/AMPK/TORC2 pathway in diet-induced insulin resistance. |
| 10629 | 22688332 | In addition, central nesfatin-1 increased insulin receptor (InsR)/insulin receptor substrate-1 (IRS-1)/AMP-dependent protein kinase (AMPK)/Akt kinase (Akt)/target of rapamycin complex (TORC) 2 phosphorylation and resulted in an increase in Fos immunoreactivity in the hypothalamic nuclei that mediate glucose homeostasis. |
| 10630 | 22688332 | Taken together, these results reveal what we believe to be a novel site of action of nesfatin-1 on HGP and the PEPCK/InsR/IRS-1/AMPK/Akt/TORC2 pathway and suggest that hypothalamic nesfatin-1 action through a neural-mediated pathway can contribute to increased peripheral and hepatic insulin sensitivity by decreasing gluconeogenesis and promoting peripheral glucose uptake in vivo. |
| 10631 | 22688332 | Nesfatin-1 action in the brain increases insulin sensitivity through Akt/AMPK/TORC2 pathway in diet-induced insulin resistance. |
| 10632 | 22688332 | In addition, central nesfatin-1 increased insulin receptor (InsR)/insulin receptor substrate-1 (IRS-1)/AMP-dependent protein kinase (AMPK)/Akt kinase (Akt)/target of rapamycin complex (TORC) 2 phosphorylation and resulted in an increase in Fos immunoreactivity in the hypothalamic nuclei that mediate glucose homeostasis. |
| 10633 | 22688332 | Taken together, these results reveal what we believe to be a novel site of action of nesfatin-1 on HGP and the PEPCK/InsR/IRS-1/AMPK/Akt/TORC2 pathway and suggest that hypothalamic nesfatin-1 action through a neural-mediated pathway can contribute to increased peripheral and hepatic insulin sensitivity by decreasing gluconeogenesis and promoting peripheral glucose uptake in vivo. |
| 10634 | 22700871 | Using adipose tissue explants from perigonadal depots of aging female C57BL/6J mice (Animalia, Chordata, Mus musculus) as a model of age-associated adipose inflammation, we report that LXA4 (1 nM) attenuates adipose inflammation, decreasing IL-6 and increasing IL-10 expression (P<0.05). |
| 10635 | 22700871 | The altered cytokine milieu correlated with increased GLUT-4 and IRS-1 expression, suggesting improved insulin sensitivity. |
| 10636 | 22728334 | Protein phosphatase 1 regulatory subunit 12A and catalytic subunit δ, new members in the phosphatidylinositide 3 kinase insulin-signaling pathway. |
| 10637 | 22728334 | Numerous studies have focused on kinases in IRS1 phosphorylation and insulin resistance; however, the mechanism for serine/threonine phosphatase action in insulin signaling is largely unknown. |
| 10638 | 22728334 | Recently, we identified protein phosphatase 1 (PP1) regulatory subunit 12A (PPP1R12A) as a novel endogenous insulin-stimulated interaction partner of IRS1 in L6 myotubes. |
| 10639 | 22728334 | Insulin stimulation promoted an interaction between the IRS1/p85 complex and PPP1R12A; however, p85 and PPP1R12A did not interact independent of IRS1. |
| 10640 | 22728334 | Moreover, kinase inhibition experiments indicated that insulin-induced interaction between IRS1 and PPP1R12A was reduced by treatment with inhibitors of phosphatidylinositide 3 kinase, PDK1, Akt, and mTOR/raptor but not MAPK. |
| 10641 | 22728334 | Furthermore, a novel insulin-stimulated IRS1 interaction partner, PP1 catalytic subunit (PP1cδ), was identified, and its interaction with IRS1 was also disrupted by inhibitors of Akt and mTOR/raptor. |
| 10642 | 22728334 | These results indicate that PPP1R12A and PP1cδ are new members of the insulin-stimulated IRS1 signaling complex, and the interaction of PPP1R12A and PP1cδ with IRS1 is dependent on Akt and mTOR/raptor activation. |
| 10643 | 22728334 | These findings provide evidence for the involvement of a particular PP1 complex, PPP1R12A/PP1cδ, in insulin signaling and may lead to a better understanding of dysregulated IRS1 phosphorylation in insulin resistance and T2D. |
| 10644 | 22728334 | Protein phosphatase 1 regulatory subunit 12A and catalytic subunit δ, new members in the phosphatidylinositide 3 kinase insulin-signaling pathway. |
| 10645 | 22728334 | Numerous studies have focused on kinases in IRS1 phosphorylation and insulin resistance; however, the mechanism for serine/threonine phosphatase action in insulin signaling is largely unknown. |
| 10646 | 22728334 | Recently, we identified protein phosphatase 1 (PP1) regulatory subunit 12A (PPP1R12A) as a novel endogenous insulin-stimulated interaction partner of IRS1 in L6 myotubes. |
| 10647 | 22728334 | Insulin stimulation promoted an interaction between the IRS1/p85 complex and PPP1R12A; however, p85 and PPP1R12A did not interact independent of IRS1. |
| 10648 | 22728334 | Moreover, kinase inhibition experiments indicated that insulin-induced interaction between IRS1 and PPP1R12A was reduced by treatment with inhibitors of phosphatidylinositide 3 kinase, PDK1, Akt, and mTOR/raptor but not MAPK. |
| 10649 | 22728334 | Furthermore, a novel insulin-stimulated IRS1 interaction partner, PP1 catalytic subunit (PP1cδ), was identified, and its interaction with IRS1 was also disrupted by inhibitors of Akt and mTOR/raptor. |
| 10650 | 22728334 | These results indicate that PPP1R12A and PP1cδ are new members of the insulin-stimulated IRS1 signaling complex, and the interaction of PPP1R12A and PP1cδ with IRS1 is dependent on Akt and mTOR/raptor activation. |
| 10651 | 22728334 | These findings provide evidence for the involvement of a particular PP1 complex, PPP1R12A/PP1cδ, in insulin signaling and may lead to a better understanding of dysregulated IRS1 phosphorylation in insulin resistance and T2D. |
| 10652 | 22728334 | Protein phosphatase 1 regulatory subunit 12A and catalytic subunit δ, new members in the phosphatidylinositide 3 kinase insulin-signaling pathway. |
| 10653 | 22728334 | Numerous studies have focused on kinases in IRS1 phosphorylation and insulin resistance; however, the mechanism for serine/threonine phosphatase action in insulin signaling is largely unknown. |
| 10654 | 22728334 | Recently, we identified protein phosphatase 1 (PP1) regulatory subunit 12A (PPP1R12A) as a novel endogenous insulin-stimulated interaction partner of IRS1 in L6 myotubes. |
| 10655 | 22728334 | Insulin stimulation promoted an interaction between the IRS1/p85 complex and PPP1R12A; however, p85 and PPP1R12A did not interact independent of IRS1. |
| 10656 | 22728334 | Moreover, kinase inhibition experiments indicated that insulin-induced interaction between IRS1 and PPP1R12A was reduced by treatment with inhibitors of phosphatidylinositide 3 kinase, PDK1, Akt, and mTOR/raptor but not MAPK. |
| 10657 | 22728334 | Furthermore, a novel insulin-stimulated IRS1 interaction partner, PP1 catalytic subunit (PP1cδ), was identified, and its interaction with IRS1 was also disrupted by inhibitors of Akt and mTOR/raptor. |
| 10658 | 22728334 | These results indicate that PPP1R12A and PP1cδ are new members of the insulin-stimulated IRS1 signaling complex, and the interaction of PPP1R12A and PP1cδ with IRS1 is dependent on Akt and mTOR/raptor activation. |
| 10659 | 22728334 | These findings provide evidence for the involvement of a particular PP1 complex, PPP1R12A/PP1cδ, in insulin signaling and may lead to a better understanding of dysregulated IRS1 phosphorylation in insulin resistance and T2D. |
| 10660 | 22728334 | Protein phosphatase 1 regulatory subunit 12A and catalytic subunit δ, new members in the phosphatidylinositide 3 kinase insulin-signaling pathway. |
| 10661 | 22728334 | Numerous studies have focused on kinases in IRS1 phosphorylation and insulin resistance; however, the mechanism for serine/threonine phosphatase action in insulin signaling is largely unknown. |
| 10662 | 22728334 | Recently, we identified protein phosphatase 1 (PP1) regulatory subunit 12A (PPP1R12A) as a novel endogenous insulin-stimulated interaction partner of IRS1 in L6 myotubes. |
| 10663 | 22728334 | Insulin stimulation promoted an interaction between the IRS1/p85 complex and PPP1R12A; however, p85 and PPP1R12A did not interact independent of IRS1. |
| 10664 | 22728334 | Moreover, kinase inhibition experiments indicated that insulin-induced interaction between IRS1 and PPP1R12A was reduced by treatment with inhibitors of phosphatidylinositide 3 kinase, PDK1, Akt, and mTOR/raptor but not MAPK. |
| 10665 | 22728334 | Furthermore, a novel insulin-stimulated IRS1 interaction partner, PP1 catalytic subunit (PP1cδ), was identified, and its interaction with IRS1 was also disrupted by inhibitors of Akt and mTOR/raptor. |
| 10666 | 22728334 | These results indicate that PPP1R12A and PP1cδ are new members of the insulin-stimulated IRS1 signaling complex, and the interaction of PPP1R12A and PP1cδ with IRS1 is dependent on Akt and mTOR/raptor activation. |
| 10667 | 22728334 | These findings provide evidence for the involvement of a particular PP1 complex, PPP1R12A/PP1cδ, in insulin signaling and may lead to a better understanding of dysregulated IRS1 phosphorylation in insulin resistance and T2D. |
| 10668 | 22728334 | Protein phosphatase 1 regulatory subunit 12A and catalytic subunit δ, new members in the phosphatidylinositide 3 kinase insulin-signaling pathway. |
| 10669 | 22728334 | Numerous studies have focused on kinases in IRS1 phosphorylation and insulin resistance; however, the mechanism for serine/threonine phosphatase action in insulin signaling is largely unknown. |
| 10670 | 22728334 | Recently, we identified protein phosphatase 1 (PP1) regulatory subunit 12A (PPP1R12A) as a novel endogenous insulin-stimulated interaction partner of IRS1 in L6 myotubes. |
| 10671 | 22728334 | Insulin stimulation promoted an interaction between the IRS1/p85 complex and PPP1R12A; however, p85 and PPP1R12A did not interact independent of IRS1. |
| 10672 | 22728334 | Moreover, kinase inhibition experiments indicated that insulin-induced interaction between IRS1 and PPP1R12A was reduced by treatment with inhibitors of phosphatidylinositide 3 kinase, PDK1, Akt, and mTOR/raptor but not MAPK. |
| 10673 | 22728334 | Furthermore, a novel insulin-stimulated IRS1 interaction partner, PP1 catalytic subunit (PP1cδ), was identified, and its interaction with IRS1 was also disrupted by inhibitors of Akt and mTOR/raptor. |
| 10674 | 22728334 | These results indicate that PPP1R12A and PP1cδ are new members of the insulin-stimulated IRS1 signaling complex, and the interaction of PPP1R12A and PP1cδ with IRS1 is dependent on Akt and mTOR/raptor activation. |
| 10675 | 22728334 | These findings provide evidence for the involvement of a particular PP1 complex, PPP1R12A/PP1cδ, in insulin signaling and may lead to a better understanding of dysregulated IRS1 phosphorylation in insulin resistance and T2D. |
| 10676 | 22728334 | Protein phosphatase 1 regulatory subunit 12A and catalytic subunit δ, new members in the phosphatidylinositide 3 kinase insulin-signaling pathway. |
| 10677 | 22728334 | Numerous studies have focused on kinases in IRS1 phosphorylation and insulin resistance; however, the mechanism for serine/threonine phosphatase action in insulin signaling is largely unknown. |
| 10678 | 22728334 | Recently, we identified protein phosphatase 1 (PP1) regulatory subunit 12A (PPP1R12A) as a novel endogenous insulin-stimulated interaction partner of IRS1 in L6 myotubes. |
| 10679 | 22728334 | Insulin stimulation promoted an interaction between the IRS1/p85 complex and PPP1R12A; however, p85 and PPP1R12A did not interact independent of IRS1. |
| 10680 | 22728334 | Moreover, kinase inhibition experiments indicated that insulin-induced interaction between IRS1 and PPP1R12A was reduced by treatment with inhibitors of phosphatidylinositide 3 kinase, PDK1, Akt, and mTOR/raptor but not MAPK. |
| 10681 | 22728334 | Furthermore, a novel insulin-stimulated IRS1 interaction partner, PP1 catalytic subunit (PP1cδ), was identified, and its interaction with IRS1 was also disrupted by inhibitors of Akt and mTOR/raptor. |
| 10682 | 22728334 | These results indicate that PPP1R12A and PP1cδ are new members of the insulin-stimulated IRS1 signaling complex, and the interaction of PPP1R12A and PP1cδ with IRS1 is dependent on Akt and mTOR/raptor activation. |
| 10683 | 22728334 | These findings provide evidence for the involvement of a particular PP1 complex, PPP1R12A/PP1cδ, in insulin signaling and may lead to a better understanding of dysregulated IRS1 phosphorylation in insulin resistance and T2D. |
| 10684 | 22728334 | Protein phosphatase 1 regulatory subunit 12A and catalytic subunit δ, new members in the phosphatidylinositide 3 kinase insulin-signaling pathway. |
| 10685 | 22728334 | Numerous studies have focused on kinases in IRS1 phosphorylation and insulin resistance; however, the mechanism for serine/threonine phosphatase action in insulin signaling is largely unknown. |
| 10686 | 22728334 | Recently, we identified protein phosphatase 1 (PP1) regulatory subunit 12A (PPP1R12A) as a novel endogenous insulin-stimulated interaction partner of IRS1 in L6 myotubes. |
| 10687 | 22728334 | Insulin stimulation promoted an interaction between the IRS1/p85 complex and PPP1R12A; however, p85 and PPP1R12A did not interact independent of IRS1. |
| 10688 | 22728334 | Moreover, kinase inhibition experiments indicated that insulin-induced interaction between IRS1 and PPP1R12A was reduced by treatment with inhibitors of phosphatidylinositide 3 kinase, PDK1, Akt, and mTOR/raptor but not MAPK. |
| 10689 | 22728334 | Furthermore, a novel insulin-stimulated IRS1 interaction partner, PP1 catalytic subunit (PP1cδ), was identified, and its interaction with IRS1 was also disrupted by inhibitors of Akt and mTOR/raptor. |
| 10690 | 22728334 | These results indicate that PPP1R12A and PP1cδ are new members of the insulin-stimulated IRS1 signaling complex, and the interaction of PPP1R12A and PP1cδ with IRS1 is dependent on Akt and mTOR/raptor activation. |
| 10691 | 22728334 | These findings provide evidence for the involvement of a particular PP1 complex, PPP1R12A/PP1cδ, in insulin signaling and may lead to a better understanding of dysregulated IRS1 phosphorylation in insulin resistance and T2D. |
| 10692 | 22733364 | Co-location of HDAC2 and insulin signaling components in the adult mouse hippocampus. |
| 10693 | 22733364 | However, the recent studies indicated that HDAC2, a member of HDACs family, played a role in insulin signaling pathway and synaptic plasticity. |
| 10694 | 22733364 | Here, we are concerned about whether HDAC2 was co-located with insulin signaling components in postsynaptic glutamatergic neurons (PSGNs) of the adult mouse hippocampus using double immunofluorescence staining. |
| 10695 | 22733364 | The results displayed that HDAC2 was present in PSGNs marked by N-methyl-D-aspartate receptor subunit 2B, in which major components of insulin signaling pathway such as insulin receptor alpha and beta and insulin receptor substrate-1 were also involved. |
| 10696 | 22733364 | Accordingly, we speculate that the interaction of HDAC2 and insulin signaling system in PSGNs observed in the present study may serve as a potential mechanism in memory formation. |
| 10697 | 22733364 | We hope this could provide a valuable basis for understanding the roles of HDAC2 and insulin on cognitive impairment of diabetes mellitus, involved Alzheimer's disease, which is also called type 3 diabetes recently. |
| 10698 | 22761437 | Sequestosome 1/p62, a scaffolding protein, is a newly identified partner of IRS-1 protein. |
| 10699 | 22761437 | Previous studies have shown that deletion of the mouse sequestosome 1/p62 gene results in mature-onset obesity that progresses to insulin and leptin resistance and, ultimately, type 2 diabetes. |
| 10700 | 22761437 | Mapping studies demonstrated that the SH(2) domain at the amino terminus of sequestosome 1/p62 interacts with IRS-1 upon insulin stimulation. |
| 10701 | 22761437 | Further, IRS-1 interacts with p62 through its YMXM motifs at Tyr-608, Tyr-628, and/or Tyr-658 in a manner similar to its interaction with p85 of phosphoinositol 3-kinase. |
| 10702 | 22761437 | Overexpression of p62 increased phosphorylation of Akt, GLUT4 translocation, and glucose uptake, providing evidence that p62 participates in the insulin-signaling pathway through its interactions with IRS-1. |
| 10703 | 22761437 | Sequestosome 1/p62, a scaffolding protein, is a newly identified partner of IRS-1 protein. |
| 10704 | 22761437 | Previous studies have shown that deletion of the mouse sequestosome 1/p62 gene results in mature-onset obesity that progresses to insulin and leptin resistance and, ultimately, type 2 diabetes. |
| 10705 | 22761437 | Mapping studies demonstrated that the SH(2) domain at the amino terminus of sequestosome 1/p62 interacts with IRS-1 upon insulin stimulation. |
| 10706 | 22761437 | Further, IRS-1 interacts with p62 through its YMXM motifs at Tyr-608, Tyr-628, and/or Tyr-658 in a manner similar to its interaction with p85 of phosphoinositol 3-kinase. |
| 10707 | 22761437 | Overexpression of p62 increased phosphorylation of Akt, GLUT4 translocation, and glucose uptake, providing evidence that p62 participates in the insulin-signaling pathway through its interactions with IRS-1. |
| 10708 | 22761437 | Sequestosome 1/p62, a scaffolding protein, is a newly identified partner of IRS-1 protein. |
| 10709 | 22761437 | Previous studies have shown that deletion of the mouse sequestosome 1/p62 gene results in mature-onset obesity that progresses to insulin and leptin resistance and, ultimately, type 2 diabetes. |
| 10710 | 22761437 | Mapping studies demonstrated that the SH(2) domain at the amino terminus of sequestosome 1/p62 interacts with IRS-1 upon insulin stimulation. |
| 10711 | 22761437 | Further, IRS-1 interacts with p62 through its YMXM motifs at Tyr-608, Tyr-628, and/or Tyr-658 in a manner similar to its interaction with p85 of phosphoinositol 3-kinase. |
| 10712 | 22761437 | Overexpression of p62 increased phosphorylation of Akt, GLUT4 translocation, and glucose uptake, providing evidence that p62 participates in the insulin-signaling pathway through its interactions with IRS-1. |
| 10713 | 22761437 | Sequestosome 1/p62, a scaffolding protein, is a newly identified partner of IRS-1 protein. |
| 10714 | 22761437 | Previous studies have shown that deletion of the mouse sequestosome 1/p62 gene results in mature-onset obesity that progresses to insulin and leptin resistance and, ultimately, type 2 diabetes. |
| 10715 | 22761437 | Mapping studies demonstrated that the SH(2) domain at the amino terminus of sequestosome 1/p62 interacts with IRS-1 upon insulin stimulation. |
| 10716 | 22761437 | Further, IRS-1 interacts with p62 through its YMXM motifs at Tyr-608, Tyr-628, and/or Tyr-658 in a manner similar to its interaction with p85 of phosphoinositol 3-kinase. |
| 10717 | 22761437 | Overexpression of p62 increased phosphorylation of Akt, GLUT4 translocation, and glucose uptake, providing evidence that p62 participates in the insulin-signaling pathway through its interactions with IRS-1. |
| 10718 | 22791750 | We replicated SNPs in or near SC4MOL and TCERG1L in West Africans. |
| 10719 | 22791750 | The meta-analysis of 1497 African Americans and West Africans yielded genome-wide significant associations for SNPs in the SC4MOL gene: rs17046216 (P = 1.7 × 10(-8) and 2.9 × 10(-8) for FI and IR, respectively); and near the TCERG1L gene with rs7077836 as the top scoring (P = 7.5 × 10(-9) and 4.9 × 10(-10) for FI and IR, respectively). |
| 10720 | 22791750 | In addition, we replicated previous GWAS findings for IR and FI in Europeans for GCKR, and for variants in four T2D loci (FTO, IRS1, KLF14 and PPARG) which exert their action via IR. |
| 10721 | 22791750 | In summary, variants in/near SC4MOL, and TCERG1L were associated with FI and IR in this cohort of African Americans and were replicated in West Africans. |
| 10722 | 22791750 | TCERG1L is associated with plasma adiponectin, a key modulator of obesity, inflammation, IR and diabetes. |
| 10723 | 22819562 | In liver, postnatal EO programmed for lower catalase (-42%), superoxide dismutase (-45%) and glutathione peroxidase (-65%) activities. |
| 10724 | 22819562 | Regarding insulin signaling pathway in liver, SL offspring showed lower IRβ (-66%), IRS1 (-50%), phospho-IRS1 (-73%), PI3-K (-30%) and Akt1 (-58%). |
| 10725 | 22820932 | Bone insulin signaling is known to support bone metabolism; therefore, we also tested the hypothesis that OVX DMII rats (DOVX) would exhibit greater reductions in the expression of proteins important in insulin signaling, including IRS-1, IRS-2, and IGF-1. |
| 10726 | 22820932 | While IRS-1 and IRS-2 decreased in most groups in all tissues examined, the expression patterns differed in both a group- and tissue-dependent fashion. |
| 10727 | 22820932 | Bone insulin signaling is known to support bone metabolism; therefore, we also tested the hypothesis that OVX DMII rats (DOVX) would exhibit greater reductions in the expression of proteins important in insulin signaling, including IRS-1, IRS-2, and IGF-1. |
| 10728 | 22820932 | While IRS-1 and IRS-2 decreased in most groups in all tissues examined, the expression patterns differed in both a group- and tissue-dependent fashion. |
| 10729 | 22824914 | Intrahepatic triglyceride contents and expression of inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and monocyte chemo-attractant protein-1 (MCP-1) and also, PPAR-γ coactivator (PGC)-1α gene were evaluated in liver tissues of OLETF rats and HepG2 cells after GW0742 treatment. |
| 10730 | 22824914 | In liver tissues, mRNA expressions of TNF-α, MCP-1, and PGC-1α were significantly decreased in diabetic rats treated with GW0742 compared to diabetic control rats. |
| 10731 | 22824914 | The expression level of Akt and IRS-1 was significantly increased by treatment with GW0742. |
| 10732 | 22824914 | The PPAR-δ agonist may attenuate hepatic fat accumulation through anti-inflammatory mechanism, reducing hepatic PGC-1α gene expression, and improvement of insulin signaling. |
| 10733 | 22859932 | The transcriptional coactivators p/CIP and SRC-1 control insulin resistance through IRS1 in obesity models. |
| 10734 | 22859932 | Three p160 family members, p/CIP, SRC1, and TIF2, have been identified as transcriptional coactivators for nuclear hormone receptors and other transcription factors in vitro. |
| 10735 | 22859932 | In a previous study, we reported initial characterization of the obesity-resistant phenotypes of p/CIP and SRC-1 double knockout (DKO) mice, which exhibit increased energy expenditure, and suggested that nuclear hormone receptor target genes were involved in these phenotypes. |
| 10736 | 22859932 | In this study, we demonstrate that p/CIP and SRC1 control insulin signaling in a cell-autonomous manner both in vitro and in vivo. |
| 10737 | 22859932 | Genetic deletion of p/CIP and SRC-1 increases glucose uptake and enhances insulin sensitivity in both regular chow- and high fat diet-fed DKO mice despite increased food intake. |
| 10738 | 22859932 | Interestingly, we discover that loss of p/CIP and SRC-1 results in resistance to age-related obesity and glucose intolerance. |
| 10739 | 22859932 | We show that expression levels of a key insulin signaling component, insulin receptor substrate 1 (IRS1), are significantly increased in two cell lines representing fat and muscle lineages with p/CIP and SRC-1 deletions and in white adipose tissue and skeletal muscle of DKO mice; this may account for increased glucose metabolism and insulin sensitivity. |
| 10740 | 22859932 | This is the first evidence that the p160 coactivators control insulin signaling and glucose metabolism through IRS1. |
| 10741 | 22859932 | Therefore, our studies indicate that p/CIP and SRC-1 are potential therapeutic targets not only for obesity but also for diabetes. |
| 10742 | 22859932 | The transcriptional coactivators p/CIP and SRC-1 control insulin resistance through IRS1 in obesity models. |
| 10743 | 22859932 | Three p160 family members, p/CIP, SRC1, and TIF2, have been identified as transcriptional coactivators for nuclear hormone receptors and other transcription factors in vitro. |
| 10744 | 22859932 | In a previous study, we reported initial characterization of the obesity-resistant phenotypes of p/CIP and SRC-1 double knockout (DKO) mice, which exhibit increased energy expenditure, and suggested that nuclear hormone receptor target genes were involved in these phenotypes. |
| 10745 | 22859932 | In this study, we demonstrate that p/CIP and SRC1 control insulin signaling in a cell-autonomous manner both in vitro and in vivo. |
| 10746 | 22859932 | Genetic deletion of p/CIP and SRC-1 increases glucose uptake and enhances insulin sensitivity in both regular chow- and high fat diet-fed DKO mice despite increased food intake. |
| 10747 | 22859932 | Interestingly, we discover that loss of p/CIP and SRC-1 results in resistance to age-related obesity and glucose intolerance. |
| 10748 | 22859932 | We show that expression levels of a key insulin signaling component, insulin receptor substrate 1 (IRS1), are significantly increased in two cell lines representing fat and muscle lineages with p/CIP and SRC-1 deletions and in white adipose tissue and skeletal muscle of DKO mice; this may account for increased glucose metabolism and insulin sensitivity. |
| 10749 | 22859932 | This is the first evidence that the p160 coactivators control insulin signaling and glucose metabolism through IRS1. |
| 10750 | 22859932 | Therefore, our studies indicate that p/CIP and SRC-1 are potential therapeutic targets not only for obesity but also for diabetes. |
| 10751 | 22859932 | The transcriptional coactivators p/CIP and SRC-1 control insulin resistance through IRS1 in obesity models. |
| 10752 | 22859932 | Three p160 family members, p/CIP, SRC1, and TIF2, have been identified as transcriptional coactivators for nuclear hormone receptors and other transcription factors in vitro. |
| 10753 | 22859932 | In a previous study, we reported initial characterization of the obesity-resistant phenotypes of p/CIP and SRC-1 double knockout (DKO) mice, which exhibit increased energy expenditure, and suggested that nuclear hormone receptor target genes were involved in these phenotypes. |
| 10754 | 22859932 | In this study, we demonstrate that p/CIP and SRC1 control insulin signaling in a cell-autonomous manner both in vitro and in vivo. |
| 10755 | 22859932 | Genetic deletion of p/CIP and SRC-1 increases glucose uptake and enhances insulin sensitivity in both regular chow- and high fat diet-fed DKO mice despite increased food intake. |
| 10756 | 22859932 | Interestingly, we discover that loss of p/CIP and SRC-1 results in resistance to age-related obesity and glucose intolerance. |
| 10757 | 22859932 | We show that expression levels of a key insulin signaling component, insulin receptor substrate 1 (IRS1), are significantly increased in two cell lines representing fat and muscle lineages with p/CIP and SRC-1 deletions and in white adipose tissue and skeletal muscle of DKO mice; this may account for increased glucose metabolism and insulin sensitivity. |
| 10758 | 22859932 | This is the first evidence that the p160 coactivators control insulin signaling and glucose metabolism through IRS1. |
| 10759 | 22859932 | Therefore, our studies indicate that p/CIP and SRC-1 are potential therapeutic targets not only for obesity but also for diabetes. |
| 10760 | 22869320 | Regulation of insulin sensitivity by serine/threonine phosphorylation of insulin receptor substrate proteins IRS1 and IRS2. |
| 10761 | 22869320 | The insulin receptor substrate proteins IRS1 and IRS2 are key targets of the insulin receptor tyrosine kinase and are required for hormonal control of metabolism. |
| 10762 | 22869320 | However, IRS1 and IRS2 are regulated through a complex mechanism involving phosphorylation of >50 serine/threonine residues (S/T) within their long, unstructured tail regions. |
| 10763 | 22869320 | In cultured cells, insulin-stimulated kinases (including atypical PKC, AKT, SIK2, mTOR, S6K1, ERK1/2 and ROCK1) mediate feedback (autologous) S/T phosphorylation of IRS, with both positive and negative effects on insulin sensitivity. |
| 10764 | 22869320 | Additionally, insulin-independent (heterologous) kinases can phosphorylate IRS1/2 under basal conditions (AMPK, GSK3) or in response to sympathetic activation and lipid/inflammatory mediators, which are present at elevated levels in metabolic disease (GRK2, novel and conventional PKCs, JNK, IKKβ, mPLK). |
| 10765 | 22869320 | Regulation of insulin sensitivity by serine/threonine phosphorylation of insulin receptor substrate proteins IRS1 and IRS2. |
| 10766 | 22869320 | The insulin receptor substrate proteins IRS1 and IRS2 are key targets of the insulin receptor tyrosine kinase and are required for hormonal control of metabolism. |
| 10767 | 22869320 | However, IRS1 and IRS2 are regulated through a complex mechanism involving phosphorylation of >50 serine/threonine residues (S/T) within their long, unstructured tail regions. |
| 10768 | 22869320 | In cultured cells, insulin-stimulated kinases (including atypical PKC, AKT, SIK2, mTOR, S6K1, ERK1/2 and ROCK1) mediate feedback (autologous) S/T phosphorylation of IRS, with both positive and negative effects on insulin sensitivity. |
| 10769 | 22869320 | Additionally, insulin-independent (heterologous) kinases can phosphorylate IRS1/2 under basal conditions (AMPK, GSK3) or in response to sympathetic activation and lipid/inflammatory mediators, which are present at elevated levels in metabolic disease (GRK2, novel and conventional PKCs, JNK, IKKβ, mPLK). |
| 10770 | 22869320 | Regulation of insulin sensitivity by serine/threonine phosphorylation of insulin receptor substrate proteins IRS1 and IRS2. |
| 10771 | 22869320 | The insulin receptor substrate proteins IRS1 and IRS2 are key targets of the insulin receptor tyrosine kinase and are required for hormonal control of metabolism. |
| 10772 | 22869320 | However, IRS1 and IRS2 are regulated through a complex mechanism involving phosphorylation of >50 serine/threonine residues (S/T) within their long, unstructured tail regions. |
| 10773 | 22869320 | In cultured cells, insulin-stimulated kinases (including atypical PKC, AKT, SIK2, mTOR, S6K1, ERK1/2 and ROCK1) mediate feedback (autologous) S/T phosphorylation of IRS, with both positive and negative effects on insulin sensitivity. |
| 10774 | 22869320 | Additionally, insulin-independent (heterologous) kinases can phosphorylate IRS1/2 under basal conditions (AMPK, GSK3) or in response to sympathetic activation and lipid/inflammatory mediators, which are present at elevated levels in metabolic disease (GRK2, novel and conventional PKCs, JNK, IKKβ, mPLK). |
| 10775 | 22869320 | Regulation of insulin sensitivity by serine/threonine phosphorylation of insulin receptor substrate proteins IRS1 and IRS2. |
| 10776 | 22869320 | The insulin receptor substrate proteins IRS1 and IRS2 are key targets of the insulin receptor tyrosine kinase and are required for hormonal control of metabolism. |
| 10777 | 22869320 | However, IRS1 and IRS2 are regulated through a complex mechanism involving phosphorylation of >50 serine/threonine residues (S/T) within their long, unstructured tail regions. |
| 10778 | 22869320 | In cultured cells, insulin-stimulated kinases (including atypical PKC, AKT, SIK2, mTOR, S6K1, ERK1/2 and ROCK1) mediate feedback (autologous) S/T phosphorylation of IRS, with both positive and negative effects on insulin sensitivity. |
| 10779 | 22869320 | Additionally, insulin-independent (heterologous) kinases can phosphorylate IRS1/2 under basal conditions (AMPK, GSK3) or in response to sympathetic activation and lipid/inflammatory mediators, which are present at elevated levels in metabolic disease (GRK2, novel and conventional PKCs, JNK, IKKβ, mPLK). |
| 10780 | 22908267 | Oral advanced glycation endproducts (AGEs) promote insulin resistance and diabetes by depleting the antioxidant defenses AGE receptor-1 and sirtuin 1. |
| 10781 | 22908267 | Impaired 2-deoxy-glucose uptake was associated with marked changes in insulin receptor (InsR), IRS-1, IRS-2, Akt activation, and a macrophage and adipocyte shift to a pro-OS/inflammatory (M1) phenotype. |
| 10782 | 22908267 | MG stimulation of 3T3-L1 adipocytes led to suppressed AGER1 and SIRT1, and altered InsR, IRS-1, IRS-2 phosphorylation, and nuclear factor kappa-light chain enhancer of activated B cells (Nf-κB) p65 acetylation. |
| 10783 | 22908267 | Oral advanced glycation endproducts (AGEs) promote insulin resistance and diabetes by depleting the antioxidant defenses AGE receptor-1 and sirtuin 1. |
| 10784 | 22908267 | Impaired 2-deoxy-glucose uptake was associated with marked changes in insulin receptor (InsR), IRS-1, IRS-2, Akt activation, and a macrophage and adipocyte shift to a pro-OS/inflammatory (M1) phenotype. |
| 10785 | 22908267 | MG stimulation of 3T3-L1 adipocytes led to suppressed AGER1 and SIRT1, and altered InsR, IRS-1, IRS-2 phosphorylation, and nuclear factor kappa-light chain enhancer of activated B cells (Nf-κB) p65 acetylation. |
| 10786 | 22961082 | Central resistin overexposure induces insulin resistance through Toll-like receptor 4. |
| 10787 | 22961082 | Resistin promotes both inflammation and insulin resistance associated with energy homeostasis impairment. |
| 10788 | 22961082 | However, the resistin receptor and the molecular mechanisms mediating its effects in the hypothalamus, crucial for energy homeostasis control, and key insulin-sensitive tissues are still unknown. |
| 10789 | 22961082 | In the current study, we report that chronic resistin infusion in the lateral cerebral ventricle of normal rats markedly affects both hypothalamic and peripheral insulin responsiveness. |
| 10790 | 22961082 | Central resistin treatment inhibited insulin-dependent phosphorylation of insulin receptor (IR), AKT, and extracellular signal-related kinase 1/2 associated with reduced IR expression and with upregulation of suppressor of cytokine signaling-3 and phosphotyrosine phosphatase 1B, two negative regulators of insulin signaling. |
| 10791 | 22961082 | Additionally, central resistin promotes the activation of the serine kinases Jun NH(2)-terminal kinase and p38 mitogen-activated protein kinase, enhances the serine phosphorylation of insulin receptor substrate-1, and increases the expression of the proinflammatory cytokine interleukin-6 in the hypothalamus and key peripheral insulin-sensitive tissues. |
| 10792 | 22961082 | Taken together, our findings clearly identify TLR4 as the binding site for resistin in the hypothalamus and bring new insight into the molecular mechanisms involved in resistin-induced inflammation and insulin resistance in the whole animal. |
| 10793 | 22961088 | Deletion of skeletal muscle SOCS3 prevents insulin resistance in obesity. |
| 10794 | 22961088 | Suppressor of cytokine signaling (SOCS)-3 expression is increased in skeletal muscle of obese humans. |
| 10795 | 22961088 | SOCS3 inhibits leptin signaling in the hypothalamus and insulin signal transduction in adipose tissue and the liver. |
| 10796 | 22961088 | Skeletal muscle is an important tissue for controlling energy expenditure and whole-body insulin sensitivity; however, the physiological importance of SOCS3 in this tissue has not been examined. |
| 10797 | 22961088 | Therefore, we generated mice that had SOCS3 specifically deleted in skeletal muscle (SOCS MKO). |
| 10798 | 22961088 | Despite similar degrees of obesity when fed a high-fat diet, SOCS3 MKO mice were protected against the development of hyperinsulinemia and insulin resistance because of enhanced skeletal muscle insulin receptor substrate 1 (IRS1) and Akt phosphorylation that resulted in increased skeletal muscle glucose uptake. |
| 10799 | 22961088 | These data indicate that skeletal muscle SOCS3 does not play a critical role in regulating muscle development or energy expenditure, but it is an important contributing factor for inhibiting insulin sensitivity in obesity. |
| 10800 | 22961088 | Therapies aimed at inhibiting SOCS3 in skeletal muscle may be effective in reversing obesity-related glucose intolerance and insulin resistance. |
| 10801 | 22966072 | Improvements in insulin sensitivity after smoking cessation occurred with normalization of IRS-1(ser636) phosphorylation. |
| 10802 | 22966072 | In muscle cell culture, nicotine exposure significantly increased IRS-1(ser636) phosphorylation and decreased insulin sensitivity, recapitulating the phenotype of smoking-induced insulin resistance in humans. |
| 10803 | 22966072 | The two pathways known to stimulate IRS-1(ser636) phosphorylation (p44/42 mitogen-activated protein kinase [MAPK] and mammalian target of rapamycin [mTOR]) were both stimulated by nicotine in culture. |
| 10804 | 22966072 | Inhibition of mTOR, but not p44/42 MAPK, during nicotine exposure prevented IRS-1(ser636) phosphorylation and normalized insulin sensitivity. |
| 10805 | 22966072 | Improvements in insulin sensitivity after smoking cessation occurred with normalization of IRS-1(ser636) phosphorylation. |
| 10806 | 22966072 | In muscle cell culture, nicotine exposure significantly increased IRS-1(ser636) phosphorylation and decreased insulin sensitivity, recapitulating the phenotype of smoking-induced insulin resistance in humans. |
| 10807 | 22966072 | The two pathways known to stimulate IRS-1(ser636) phosphorylation (p44/42 mitogen-activated protein kinase [MAPK] and mammalian target of rapamycin [mTOR]) were both stimulated by nicotine in culture. |
| 10808 | 22966072 | Inhibition of mTOR, but not p44/42 MAPK, during nicotine exposure prevented IRS-1(ser636) phosphorylation and normalized insulin sensitivity. |
| 10809 | 22966072 | Improvements in insulin sensitivity after smoking cessation occurred with normalization of IRS-1(ser636) phosphorylation. |
| 10810 | 22966072 | In muscle cell culture, nicotine exposure significantly increased IRS-1(ser636) phosphorylation and decreased insulin sensitivity, recapitulating the phenotype of smoking-induced insulin resistance in humans. |
| 10811 | 22966072 | The two pathways known to stimulate IRS-1(ser636) phosphorylation (p44/42 mitogen-activated protein kinase [MAPK] and mammalian target of rapamycin [mTOR]) were both stimulated by nicotine in culture. |
| 10812 | 22966072 | Inhibition of mTOR, but not p44/42 MAPK, during nicotine exposure prevented IRS-1(ser636) phosphorylation and normalized insulin sensitivity. |
| 10813 | 22966072 | Improvements in insulin sensitivity after smoking cessation occurred with normalization of IRS-1(ser636) phosphorylation. |
| 10814 | 22966072 | In muscle cell culture, nicotine exposure significantly increased IRS-1(ser636) phosphorylation and decreased insulin sensitivity, recapitulating the phenotype of smoking-induced insulin resistance in humans. |
| 10815 | 22966072 | The two pathways known to stimulate IRS-1(ser636) phosphorylation (p44/42 mitogen-activated protein kinase [MAPK] and mammalian target of rapamycin [mTOR]) were both stimulated by nicotine in culture. |
| 10816 | 22966072 | Inhibition of mTOR, but not p44/42 MAPK, during nicotine exposure prevented IRS-1(ser636) phosphorylation and normalized insulin sensitivity. |
| 10817 | 22969776 | The insulin receptor substrate 1/phosphatidylinositol 3-kinase association and the activation of protein kinase B were decreased in ERαKO mice, whereas immunostaining for 3-nitrotyrosine was increased. |
| 10818 | 22975078 | Activation of Akt through 5-HT2A receptor ameliorates serotonin-induced degradation of insulin receptor substrate-1 in adipocytes. |
| 10819 | 22975078 | In this study, we investigate the mechanism of insulin desensitization caused by 5-HT. |
| 10820 | 22975078 | In 3T3-L1 adipocytes, 5-HT treatment induced the translocation of insulin receptor substrate-1 (IRS-1) from low density microsome (LDM), the important intracellular compartment for its functions, to cytosol, inducing IRS-1 ubiquitination and degradation. |
| 10821 | 22975078 | Moreover, inhibition of 5-HT-stimulated Akt activation by either ketanserin (a specific 5-HT2A receptor antagonist) or knocking-down the expression of 5-HT2A receptor promoted 5-HT-stimulated IRS-1 dissociation from 14-3-3β in LDM, leading to drastic ubiquitination. |
| 10822 | 22975078 | Interestingly, sarpogrelate, another antagonist of 5-HT2A receptor, protected IRS-1 from degradation through activation of Akt. |
| 10823 | 22975078 | This implicates the importance of Akt activation in extending IRS-1 life span through maintaining their optimal sub-location into adipocytes. |
| 10824 | 22975078 | Taken together, this study suggest that activation of Akt may be able to compensate the adverse effects of 5-HT by stabilizing IRS-1 in LDM. |
| 10825 | 22975078 | Activation of Akt through 5-HT2A receptor ameliorates serotonin-induced degradation of insulin receptor substrate-1 in adipocytes. |
| 10826 | 22975078 | In this study, we investigate the mechanism of insulin desensitization caused by 5-HT. |
| 10827 | 22975078 | In 3T3-L1 adipocytes, 5-HT treatment induced the translocation of insulin receptor substrate-1 (IRS-1) from low density microsome (LDM), the important intracellular compartment for its functions, to cytosol, inducing IRS-1 ubiquitination and degradation. |
| 10828 | 22975078 | Moreover, inhibition of 5-HT-stimulated Akt activation by either ketanserin (a specific 5-HT2A receptor antagonist) or knocking-down the expression of 5-HT2A receptor promoted 5-HT-stimulated IRS-1 dissociation from 14-3-3β in LDM, leading to drastic ubiquitination. |
| 10829 | 22975078 | Interestingly, sarpogrelate, another antagonist of 5-HT2A receptor, protected IRS-1 from degradation through activation of Akt. |
| 10830 | 22975078 | This implicates the importance of Akt activation in extending IRS-1 life span through maintaining their optimal sub-location into adipocytes. |
| 10831 | 22975078 | Taken together, this study suggest that activation of Akt may be able to compensate the adverse effects of 5-HT by stabilizing IRS-1 in LDM. |
| 10832 | 22975078 | Activation of Akt through 5-HT2A receptor ameliorates serotonin-induced degradation of insulin receptor substrate-1 in adipocytes. |
| 10833 | 22975078 | In this study, we investigate the mechanism of insulin desensitization caused by 5-HT. |
| 10834 | 22975078 | In 3T3-L1 adipocytes, 5-HT treatment induced the translocation of insulin receptor substrate-1 (IRS-1) from low density microsome (LDM), the important intracellular compartment for its functions, to cytosol, inducing IRS-1 ubiquitination and degradation. |
| 10835 | 22975078 | Moreover, inhibition of 5-HT-stimulated Akt activation by either ketanserin (a specific 5-HT2A receptor antagonist) or knocking-down the expression of 5-HT2A receptor promoted 5-HT-stimulated IRS-1 dissociation from 14-3-3β in LDM, leading to drastic ubiquitination. |
| 10836 | 22975078 | Interestingly, sarpogrelate, another antagonist of 5-HT2A receptor, protected IRS-1 from degradation through activation of Akt. |
| 10837 | 22975078 | This implicates the importance of Akt activation in extending IRS-1 life span through maintaining their optimal sub-location into adipocytes. |
| 10838 | 22975078 | Taken together, this study suggest that activation of Akt may be able to compensate the adverse effects of 5-HT by stabilizing IRS-1 in LDM. |
| 10839 | 22975078 | Activation of Akt through 5-HT2A receptor ameliorates serotonin-induced degradation of insulin receptor substrate-1 in adipocytes. |
| 10840 | 22975078 | In this study, we investigate the mechanism of insulin desensitization caused by 5-HT. |
| 10841 | 22975078 | In 3T3-L1 adipocytes, 5-HT treatment induced the translocation of insulin receptor substrate-1 (IRS-1) from low density microsome (LDM), the important intracellular compartment for its functions, to cytosol, inducing IRS-1 ubiquitination and degradation. |
| 10842 | 22975078 | Moreover, inhibition of 5-HT-stimulated Akt activation by either ketanserin (a specific 5-HT2A receptor antagonist) or knocking-down the expression of 5-HT2A receptor promoted 5-HT-stimulated IRS-1 dissociation from 14-3-3β in LDM, leading to drastic ubiquitination. |
| 10843 | 22975078 | Interestingly, sarpogrelate, another antagonist of 5-HT2A receptor, protected IRS-1 from degradation through activation of Akt. |
| 10844 | 22975078 | This implicates the importance of Akt activation in extending IRS-1 life span through maintaining their optimal sub-location into adipocytes. |
| 10845 | 22975078 | Taken together, this study suggest that activation of Akt may be able to compensate the adverse effects of 5-HT by stabilizing IRS-1 in LDM. |
| 10846 | 22975078 | Activation of Akt through 5-HT2A receptor ameliorates serotonin-induced degradation of insulin receptor substrate-1 in adipocytes. |
| 10847 | 22975078 | In this study, we investigate the mechanism of insulin desensitization caused by 5-HT. |
| 10848 | 22975078 | In 3T3-L1 adipocytes, 5-HT treatment induced the translocation of insulin receptor substrate-1 (IRS-1) from low density microsome (LDM), the important intracellular compartment for its functions, to cytosol, inducing IRS-1 ubiquitination and degradation. |
| 10849 | 22975078 | Moreover, inhibition of 5-HT-stimulated Akt activation by either ketanserin (a specific 5-HT2A receptor antagonist) or knocking-down the expression of 5-HT2A receptor promoted 5-HT-stimulated IRS-1 dissociation from 14-3-3β in LDM, leading to drastic ubiquitination. |
| 10850 | 22975078 | Interestingly, sarpogrelate, another antagonist of 5-HT2A receptor, protected IRS-1 from degradation through activation of Akt. |
| 10851 | 22975078 | This implicates the importance of Akt activation in extending IRS-1 life span through maintaining their optimal sub-location into adipocytes. |
| 10852 | 22975078 | Taken together, this study suggest that activation of Akt may be able to compensate the adverse effects of 5-HT by stabilizing IRS-1 in LDM. |
| 10853 | 22975078 | Activation of Akt through 5-HT2A receptor ameliorates serotonin-induced degradation of insulin receptor substrate-1 in adipocytes. |
| 10854 | 22975078 | In this study, we investigate the mechanism of insulin desensitization caused by 5-HT. |
| 10855 | 22975078 | In 3T3-L1 adipocytes, 5-HT treatment induced the translocation of insulin receptor substrate-1 (IRS-1) from low density microsome (LDM), the important intracellular compartment for its functions, to cytosol, inducing IRS-1 ubiquitination and degradation. |
| 10856 | 22975078 | Moreover, inhibition of 5-HT-stimulated Akt activation by either ketanserin (a specific 5-HT2A receptor antagonist) or knocking-down the expression of 5-HT2A receptor promoted 5-HT-stimulated IRS-1 dissociation from 14-3-3β in LDM, leading to drastic ubiquitination. |
| 10857 | 22975078 | Interestingly, sarpogrelate, another antagonist of 5-HT2A receptor, protected IRS-1 from degradation through activation of Akt. |
| 10858 | 22975078 | This implicates the importance of Akt activation in extending IRS-1 life span through maintaining their optimal sub-location into adipocytes. |
| 10859 | 22975078 | Taken together, this study suggest that activation of Akt may be able to compensate the adverse effects of 5-HT by stabilizing IRS-1 in LDM. |
| 10860 | 22983684 | Effects of selenium and exendin-4 on glucagon-like peptide-1 receptor, IRS-1, and Raf-1 in the liver of diabetic rats. |
| 10861 | 22983684 | Herein, we investigated their effects on the expression of glucagon-like peptide-1 receptor (GLP-1R), insulin receptor substrate-1 (IRS-1), and Raf-1 in the livers of rats with streptozotocin-induced diabetes. |
| 10862 | 22983684 | Induction of diabetes mellitus resulted in decreased level of GLP-1R and increased levels of IRS-1 and Raf-1 in the liver. |
| 10863 | 22983684 | Treatment of diabetic rats with selenium or exendin-4 resulted in increased level of GLP-1R and decreased levels of IRS-1 and Raf-1 in the liver, compared with the levels in diabetic rats. |
| 10864 | 22983684 | Therefore, the antidiabetic actions of selenium and exendin-4 involve their effects on GLP-1R, IRS-1, and Raf-1 levels in the liver. |
| 10865 | 22983684 | Effects of selenium and exendin-4 on glucagon-like peptide-1 receptor, IRS-1, and Raf-1 in the liver of diabetic rats. |
| 10866 | 22983684 | Herein, we investigated their effects on the expression of glucagon-like peptide-1 receptor (GLP-1R), insulin receptor substrate-1 (IRS-1), and Raf-1 in the livers of rats with streptozotocin-induced diabetes. |
| 10867 | 22983684 | Induction of diabetes mellitus resulted in decreased level of GLP-1R and increased levels of IRS-1 and Raf-1 in the liver. |
| 10868 | 22983684 | Treatment of diabetic rats with selenium or exendin-4 resulted in increased level of GLP-1R and decreased levels of IRS-1 and Raf-1 in the liver, compared with the levels in diabetic rats. |
| 10869 | 22983684 | Therefore, the antidiabetic actions of selenium and exendin-4 involve their effects on GLP-1R, IRS-1, and Raf-1 levels in the liver. |
| 10870 | 22983684 | Effects of selenium and exendin-4 on glucagon-like peptide-1 receptor, IRS-1, and Raf-1 in the liver of diabetic rats. |
| 10871 | 22983684 | Herein, we investigated their effects on the expression of glucagon-like peptide-1 receptor (GLP-1R), insulin receptor substrate-1 (IRS-1), and Raf-1 in the livers of rats with streptozotocin-induced diabetes. |
| 10872 | 22983684 | Induction of diabetes mellitus resulted in decreased level of GLP-1R and increased levels of IRS-1 and Raf-1 in the liver. |
| 10873 | 22983684 | Treatment of diabetic rats with selenium or exendin-4 resulted in increased level of GLP-1R and decreased levels of IRS-1 and Raf-1 in the liver, compared with the levels in diabetic rats. |
| 10874 | 22983684 | Therefore, the antidiabetic actions of selenium and exendin-4 involve their effects on GLP-1R, IRS-1, and Raf-1 levels in the liver. |
| 10875 | 22983684 | Effects of selenium and exendin-4 on glucagon-like peptide-1 receptor, IRS-1, and Raf-1 in the liver of diabetic rats. |
| 10876 | 22983684 | Herein, we investigated their effects on the expression of glucagon-like peptide-1 receptor (GLP-1R), insulin receptor substrate-1 (IRS-1), and Raf-1 in the livers of rats with streptozotocin-induced diabetes. |
| 10877 | 22983684 | Induction of diabetes mellitus resulted in decreased level of GLP-1R and increased levels of IRS-1 and Raf-1 in the liver. |
| 10878 | 22983684 | Treatment of diabetic rats with selenium or exendin-4 resulted in increased level of GLP-1R and decreased levels of IRS-1 and Raf-1 in the liver, compared with the levels in diabetic rats. |
| 10879 | 22983684 | Therefore, the antidiabetic actions of selenium and exendin-4 involve their effects on GLP-1R, IRS-1, and Raf-1 levels in the liver. |
| 10880 | 22983684 | Effects of selenium and exendin-4 on glucagon-like peptide-1 receptor, IRS-1, and Raf-1 in the liver of diabetic rats. |
| 10881 | 22983684 | Herein, we investigated their effects on the expression of glucagon-like peptide-1 receptor (GLP-1R), insulin receptor substrate-1 (IRS-1), and Raf-1 in the livers of rats with streptozotocin-induced diabetes. |
| 10882 | 22983684 | Induction of diabetes mellitus resulted in decreased level of GLP-1R and increased levels of IRS-1 and Raf-1 in the liver. |
| 10883 | 22983684 | Treatment of diabetic rats with selenium or exendin-4 resulted in increased level of GLP-1R and decreased levels of IRS-1 and Raf-1 in the liver, compared with the levels in diabetic rats. |
| 10884 | 22983684 | Therefore, the antidiabetic actions of selenium and exendin-4 involve their effects on GLP-1R, IRS-1, and Raf-1 levels in the liver. |
| 10885 | 22984506 | We genotyped previously reported polymorphisms (or their proxies) in/near G6PC2, MTNR1B, GCK, DGKB, GCKR, ADCY5, MADD, CRY2, ADRA2A, FADS1, PROX1, SLC2A2, GLIS3, C2CD4B, IGF1, and IRS1 in 3,548 Diabetes Prevention Program participants. |
| 10886 | 23007523 | Aldosterone treatment impaired the rate of glucose uptake, oxidation, and insulin signal transduction in the gastrocnemius muscle through defective expression of IR, IRS-1, Akt, AS160, and GLUT4 genes. |
| 10887 | 23007523 | Phosphorylation of IRS-1, β-arrestin-2, and Akt was also reduced in a dose-dependent manner. |
| 10888 | 23007523 | Aldosterone treatment impaired the rate of glucose uptake, oxidation, and insulin signal transduction in the gastrocnemius muscle through defective expression of IR, IRS-1, Akt, AS160, and GLUT4 genes. |
| 10889 | 23007523 | Phosphorylation of IRS-1, β-arrestin-2, and Akt was also reduced in a dose-dependent manner. |
| 10890 | 23011592 | This is accompanied by decreased mRNA expression of the anti-inflammatory marker adiponectin in WAT and an increase of the proinflammatory monocyte chemoattractant protein-1 (MCP-1). |
| 10891 | 23011592 | In vitro, activated Y1-deficient intraperitoneal macrophages display an increased inflammatory response, with exacerbated secretion of MCP-1 and tumor necrosis factor, whereas addition of neuropeptide Y to wild-type macrophages attenuates the release of these cytokines, this effect being blocked by Y1 but not Y2 receptor antagonism. |
| 10892 | 23011592 | Importantly, treatment of adipocytes with the supernatant of activated Y1-deficient macrophages causes insulin resistance, as demonstrated by decreased insulin-induced phosphorylation of the insulin receptor and Akt as well as decreased expression of insulin receptor substrate 1. |
| 10893 | 23011726 | Liraglutide, a novel glucagon-like peptide 1 (GLP-1) analogue that facilitates insulin signalling, is currently approved for use in type 2 diabetes mellitus. |
| 10894 | 23011726 | In the present study, we show that distinctive alterations in the localisation and distribution of the IR and increased levels of insulin receptor substrate (IRS)-1 phosphorylated at serine 616 (IRS-1 pS(616)), a key marker of insulin resistance, are associated with amyloid-β plaque pathology in the frontal cortex of a mouse model of AD, APPSWE/PS1dE9. |
| 10895 | 23011726 | We show that liraglutide treatment for 8 weeks at 25 nmol/kg body weight i.p. once daily in 7-month-old mice significantly decreases IR aberrations in conjunction with a concomitant decrease in amyloid plaque load and levels of IRS-1 pS(616). |
| 10896 | 23011726 | The amelioration of IR aberrations and attenuation of IRS-1 pS(616) upregulation, plaque and glial activation in APPSWE/PS1dE9 mice treated with liraglutide support the investigation of the therapeutic potential of liraglutide and long-lasting GLP-1 agonists in patients with AD. |
| 10897 | 23011726 | Liraglutide, a novel glucagon-like peptide 1 (GLP-1) analogue that facilitates insulin signalling, is currently approved for use in type 2 diabetes mellitus. |
| 10898 | 23011726 | In the present study, we show that distinctive alterations in the localisation and distribution of the IR and increased levels of insulin receptor substrate (IRS)-1 phosphorylated at serine 616 (IRS-1 pS(616)), a key marker of insulin resistance, are associated with amyloid-β plaque pathology in the frontal cortex of a mouse model of AD, APPSWE/PS1dE9. |
| 10899 | 23011726 | We show that liraglutide treatment for 8 weeks at 25 nmol/kg body weight i.p. once daily in 7-month-old mice significantly decreases IR aberrations in conjunction with a concomitant decrease in amyloid plaque load and levels of IRS-1 pS(616). |
| 10900 | 23011726 | The amelioration of IR aberrations and attenuation of IRS-1 pS(616) upregulation, plaque and glial activation in APPSWE/PS1dE9 mice treated with liraglutide support the investigation of the therapeutic potential of liraglutide and long-lasting GLP-1 agonists in patients with AD. |
| 10901 | 23011726 | Liraglutide, a novel glucagon-like peptide 1 (GLP-1) analogue that facilitates insulin signalling, is currently approved for use in type 2 diabetes mellitus. |
| 10902 | 23011726 | In the present study, we show that distinctive alterations in the localisation and distribution of the IR and increased levels of insulin receptor substrate (IRS)-1 phosphorylated at serine 616 (IRS-1 pS(616)), a key marker of insulin resistance, are associated with amyloid-β plaque pathology in the frontal cortex of a mouse model of AD, APPSWE/PS1dE9. |
| 10903 | 23011726 | We show that liraglutide treatment for 8 weeks at 25 nmol/kg body weight i.p. once daily in 7-month-old mice significantly decreases IR aberrations in conjunction with a concomitant decrease in amyloid plaque load and levels of IRS-1 pS(616). |
| 10904 | 23011726 | The amelioration of IR aberrations and attenuation of IRS-1 pS(616) upregulation, plaque and glial activation in APPSWE/PS1dE9 mice treated with liraglutide support the investigation of the therapeutic potential of liraglutide and long-lasting GLP-1 agonists in patients with AD. |
| 10905 | 23018631 | These genes belong to three major classes: genes involved in drug metabolism and transporters that influence pharmacokinetics (including the cytochrome P450 [CYP] superfamily, the organic anion transporting polypeptide [OATP] family, and the polyspecific organic cation transporter [OCT] family); genes encoding drug targets and receptors (including peroxisome proliferator-activated receptor gamma [PPARG], the adenosine triphosphate [ATP]-sensitive potassium channel [K(ATP)], and incretin receptors); and genes involved in the causal pathway of T2DM that are able to modify the effects of drugs (including adipokines, transcription factor 7-like 2 (T cell specific, HMG-box) [TCF7L2], insulin receptor substrate 1 [IRS1], nitric oxide synthase 1 (neuronal) adaptor protein [NOS1AP], and solute carrier family 30 (zinc transporter), member 8 [SLC30A8]). |
| 10906 | 23018631 | In addition to these three major classes, we also review the available evidence on novel genes (CDK5 regulatory subunit associated protein 1-like 1 [CDKAL1], insulin-like growth factor 2 mRNA binding protein 2 [IGF2BP2], potassium voltage-gated channel, KQT-like subfamily, member 1 [KCNQ1], paired box 4 [PAX4] and neuronal differentiation 1 [NEUROD1] transcription factors, ataxia telangiectasia mutated [ATM], and serine racemase [SRR]) that have recently been proposed as possible modulators of therapeutic response in subjects with T2DM. |
| 10907 | 23045529 | Identification of the degradation determinants of insulin receptor substrate 1 for signaling cullin-RING E3 ubiquitin ligase 7-mediated ubiquitination. |
| 10908 | 23052710 | The recombinant peptide, DBAYL, a promising therapeutic peptide for type 2 diabetes, is a new, potent, and highly selective agonist for VPAC2 generated through site-directed mutagenesis based on sequence alignments of pituitary adenylate cyclase-activating peptide (PACAP), vasoactive intestinal peptide (VIP), and related analogs. |
| 10909 | 23052710 | DBAYL enhances the cAMP accumulation in CHO cells expressing human VPAC2 with a half-maximal stimulatory concentration (EC(50)) of 0.68 nM, whereas the receptor potency of DBAYL at human VPAC1 (EC(50) of 737 nM) was only 1/1083 of that at human VPAC2, and DBAYL had no activity toward human PAC1 receptor. |
| 10910 | 23052710 | Western blot analysis of the key proteins of insulin receptor signaling pathway: insulin receptor substrate 1 (IRS-1) and glucose transporter 4 (GLUT4) indicated that the DBAYL could significantly induce the insulin-stimulated IRS-1 and GLUT4 expression more efficiently than BAY55-9837 and VIP in adipocytes. |
| 10911 | 23065822 | There is a post-binding defect in receptor signaling likely due to increased receptor and insulin receptor substrate-1 serine phosphorylation that selectively affects metabolic but not mitogenic pathways in classic insulin target tissues and in the ovary. |
| 10912 | 23086038 | Phosphoinositide 3-kinase (PI3K) mediates insulin actions by relaying signals from insulin receptors (IRs) to downstream targets. |
| 10913 | 23086038 | The p110α catalytic subunit of class IA PI3K is the primary insulin-responsive PI3K implicated in insulin signaling. |
| 10914 | 23086038 | We demonstrate here a new mode of spatial regulation for the p110α subunit of PI3K by PAQR3 that is exclusively localized in the Golgi apparatus. |
| 10915 | 23086038 | Insulin-stimulated PI3K activity and phosphoinositide (3,4,5)-triphosphate production are enhanced by Paqr3 deletion and reduced by PAQR3 overexpression in hepatocytes. |
| 10916 | 23086038 | Deletion of Paqr3 enhances insulin-stimulated phosphorylation of AKT and glycogen synthase kinase 3β, but not phosphorylation of IR and IR substrate-1 (IRS-1), in hepatocytes, mouse liver, and skeletal muscle. |
| 10917 | 23086038 | Insulin-stimulated GLUT4 translocation to the plasma membrane and glucose uptake are enhanced by Paqr3 ablation. |
| 10918 | 23086038 | Furthermore, PAQR3 interacts with the domain of p110α involved in its binding with p85, the regulatory subunit of PI3K. |
| 10919 | 23086038 | Thus, PAQR3 negatively regulates insulin signaling by shunting cytosolic p110α to the Golgi apparatus while competing with p85 subunit in forming a PI3K complex with p110α. |
| 10920 | 23144758 | NADPH oxidase 4 mediates insulin-stimulated HIF-1α and VEGF expression, and angiogenesis in vitro. |
| 10921 | 23144758 | Acute intensive insulin therapy causes a transient worsening of diabetic retinopathy in type 1 diabetes patients and is related to VEGF expression. |
| 10922 | 23144758 | Reactive oxygen species (ROS) have been shown to be involved in HIF-1α and VEGF expression induced by insulin, but the role of specific ROS sources has not been fully elucidated. |
| 10923 | 23144758 | In this study we examined the role of NADPH oxidase subunit 4 (Nox4) in insulin-stimulated HIF-1α and VEGF expression, and angiogenic responses in human microvascular endothelial cells (HMVECs). |
| 10924 | 23144758 | Here we demonstrate that knockdown of Nox4 by siRNA reduced insulin-stimulated ROS generation, the tyrosine phosphorylation of IR-β and IRS-1, but did not change the serine phosphorylation of IRS-1. |
| 10925 | 23144758 | Nox4 gene silencing had a much greater inhibitory effect on insulin-induced AKT activation than ERK1/2 activation, whereas it had little effect on the expression of the phosphatases such as MKP-1 and SHIP. |
| 10926 | 23144758 | Inhibition of Nox4 expression inhibited the transcriptional activity of VEGF through HIF-1. |
| 10927 | 23144758 | Overexpression of wild-type Nox4 was sufficient to increase VEGF transcriptional activity, and further enhanced insulin-stimulated the activation of VEGF. |
| 10928 | 23144758 | Downregulation of Nox4 expression decreased insulin-stimulated mRNA and protein expression of HIF-1α, but did not change the rate of HIF-1α degradation. |
| 10929 | 23144758 | Inhibition of Nox4 impaired insulin-stimulated VEGF expression, cell migration, cell proliferation, and tube formation in HMVECs. |
| 10930 | 23144758 | Our data indicate that Nox4-derived ROS are essential for HIF-1α-dependent VEGF expression, and angiogenesis in vitro induced by insulin. |
| 10931 | 23144758 | Nox4 may be an attractive therapeutic target for diabetic retinopathy caused by intensive insulin treatment. |
| 10932 | 23179947 | Choline supplementation promotes hepatic insulin resistance in phosphatidylethanolamine N-methyltransferase-deficient mice via increased glucagon action. |
| 10933 | 23179947 | Glucose and insulin intolerance occurred in Pemt(-/-) mice fed the HFHC diet, but not in their Pemt(-/-) littermates fed the HF diet. |
| 10934 | 23179947 | Plasma glucagon was elevated in Pemt(-/-) mice fed the HFHC diet compared with Pemt(-/-) mice fed the HF diet, concomitant with increased hepatic expression of glucagon receptor, phosphorylated AMP-activated protein kinase (AMPK), and phosphorylated insulin receptor substrate 1 at serine 307 (IRS1-s307). |
| 10935 | 23179947 | A glucagon receptor antagonist (2-aminobenzimidazole) attenuated choline-induced hyperglycemia and insulin intolerance and blunted up-regulation of phosphorylated AMPK and IRS1-s307. |
| 10936 | 23179947 | Choline induces glucose and insulin intolerance in Pemt(-/-) mice through modulating plasma glucagon and its action in liver. |
| 10937 | 23197113 | Improvement of insulin sensitivity promotes extravillous trophoblast cell migration stimulated by insulin-like growth factor-I. |
| 10938 | 23197113 | Insulin-like growth factor-I (IGF-I) has been shown to stimulate extravillous trophoblast (EVT) cell migration and invasion, and to play a crucial role in placental function, thereby, influencing placental development and fetal growth. |
| 10939 | 23197113 | Insulin-resistant conditions such as polycystic ovary syndrome (PCOS) and gestational diabetes mellitus (GDM) have also been associated with abortion and PIH. |
| 10940 | 23197113 | However, the effects of IGF-I on EVT cells under insulin-resistant conditions have not been elucidated yet. |
| 10941 | 23197113 | The current study was undertaken to analyze the effects of IGF-I under insulin-resistant conditions and to determine whether improvement in insulin sensitivity alters IGF signaling and cell migration in the EVT. |
| 10942 | 23197113 | Long-term exposure to insulin reduced phosphorylation of the IGF-I receptor, insulin receptor substrate-1 (IRS-1), and Akt, and also reduced EVT cell migration. |
| 10943 | 23226034 | The insulin gene (INS), insulin receptor gene (INSR), and insulin receptor substrate 1 gene (IRS1), identified by polymerase chain reaction and digestion with selected restriction enzymes PstI, NsiI, and BstnI, have been proposed as T2DM candidate genes. |
| 10944 | 23226034 | Results showed that the NsiI polymorphism in INSR and BstnI polymorphism of IRS1 were significantly associated with T2DM only among the Berber group. |
| 10945 | 23226034 | The insulin gene (INS), insulin receptor gene (INSR), and insulin receptor substrate 1 gene (IRS1), identified by polymerase chain reaction and digestion with selected restriction enzymes PstI, NsiI, and BstnI, have been proposed as T2DM candidate genes. |
| 10946 | 23226034 | Results showed that the NsiI polymorphism in INSR and BstnI polymorphism of IRS1 were significantly associated with T2DM only among the Berber group. |
| 10947 | 23292283 | These changes may be partially related to impaired insulin and insulin-like growth factor 1 (IGF-1) signaling. |
| 10948 | 23292283 | Weak gene expression of insulin receptor (IR), IGF-1, insulin-like growth factor 1 receptor (IGF-1R), and insulin receptor substrate-1 (IRS-1) was observed in the diabetic BMSCs compared with normal BMSCs, together with decreased protein level of IGF-1, IGF-1R, IRS-1 and phosphorylated extracellular signal-regulated kinase. |
| 10949 | 23292283 | Therefore, impaired proliferation and osteogenic potential of BMSCs may be responsible for bone complications related to T1DM, mediated partially by impaired insulin and IGF-1 signaling. |
| 10950 | 23326455 | The levels of fasting blood glucose, serum insulin and glucose tolerance were measured and the relative levels of insulin-related phosphatidylinositol 3-kinase (PI3K)/Akt, insulin receptor (IR) and IR substrate 1 (IRS1) phosphorylation were determined. |
| 10951 | 23326455 | The levels of phosphoenolpyruvate carboxykinase (PEPCK), glucose-6- phosphatase (G6Pase), toll like receptor 4 (TLR4), tumor necrosis factor (TNF)-α and IL-6 expression and nuclear factor-κB (NF-κB) and c-Jun N-terminal kinase (JNK), extracellular-signal-regulated kinase (ERK) and p38 MAPK activation in the liver were examined. |
| 10952 | 23326455 | EPO treatment significantly reduced the body weights and the levels of fasting blood glucose and serum insulin and improved the HFD-induced glucose intolerance in mice. |
| 10953 | 23326455 | EPO treatment significantly enhanced the levels of Akt, but not IR and IRS1, phosphorylation, accompanied by inhibiting the PEPCK and G6Pase expression in the liver. |
| 10954 | 23326455 | Furthermore, EPO treatment mitigated the HFD-induced inflammatory TNF-α and IL-6 production, TLR4 expression, NF-κB and JNK, but not ERK and p38 MAPK, phosphorylation in the liver. |
| 10955 | 23326455 | The levels of fasting blood glucose, serum insulin and glucose tolerance were measured and the relative levels of insulin-related phosphatidylinositol 3-kinase (PI3K)/Akt, insulin receptor (IR) and IR substrate 1 (IRS1) phosphorylation were determined. |
| 10956 | 23326455 | The levels of phosphoenolpyruvate carboxykinase (PEPCK), glucose-6- phosphatase (G6Pase), toll like receptor 4 (TLR4), tumor necrosis factor (TNF)-α and IL-6 expression and nuclear factor-κB (NF-κB) and c-Jun N-terminal kinase (JNK), extracellular-signal-regulated kinase (ERK) and p38 MAPK activation in the liver were examined. |
| 10957 | 23326455 | EPO treatment significantly reduced the body weights and the levels of fasting blood glucose and serum insulin and improved the HFD-induced glucose intolerance in mice. |
| 10958 | 23326455 | EPO treatment significantly enhanced the levels of Akt, but not IR and IRS1, phosphorylation, accompanied by inhibiting the PEPCK and G6Pase expression in the liver. |
| 10959 | 23326455 | Furthermore, EPO treatment mitigated the HFD-induced inflammatory TNF-α and IL-6 production, TLR4 expression, NF-κB and JNK, but not ERK and p38 MAPK, phosphorylation in the liver. |
| 10960 | 23340252 | The endocrine disrupting chemical tolylfluanid alters adipocyte metabolism via glucocorticoid receptor activation. |
| 10961 | 23340252 | Previous studies have shown that the phenylsulfamide fungicide tolylfluanid (TF) augments glucocorticoid receptor (GR)-dependent luciferase expression in 3T3-L1 preadipocytes while modulating insulin action in primary murine and human adipocytes. |
| 10962 | 23340252 | The augmentation of insulin-stimulated lipogenesis was mediated through a specific enhancement of Akt phosphorylation at T308. |
| 10963 | 23340252 | These findings support modulation of IRS-1 levels as a mechanism for glucocorticoid-mediated changes in insulin action in primary adipocytes. |
| 10964 | 23354051 | Central role of E3 ubiquitin ligase MG53 in insulin resistance and metabolic disorders. |
| 10965 | 23354051 | Here we show in mice that muscle-specific mitsugumin 53 (MG53; also called TRIM72) mediates the degradation of the insulin receptor and insulin receptor substrate 1 (IRS1), and when upregulated, causes metabolic syndrome featuring insulin resistance, obesity, hypertension and dyslipidaemia. |
| 10966 | 23354051 | Conversely, ablation of MG53 prevents diet-induced metabolic syndrome by preserving the insulin receptor, IRS1 and insulin signalling integrity. |
| 10967 | 23354051 | Mechanistically, MG53 acts as an E3 ligase targeting the insulin receptor and IRS1 for ubiquitin-dependent degradation, comprising a central mechanism controlling insulin signal strength in skeletal muscle. |
| 10968 | 23354051 | Central role of E3 ubiquitin ligase MG53 in insulin resistance and metabolic disorders. |
| 10969 | 23354051 | Here we show in mice that muscle-specific mitsugumin 53 (MG53; also called TRIM72) mediates the degradation of the insulin receptor and insulin receptor substrate 1 (IRS1), and when upregulated, causes metabolic syndrome featuring insulin resistance, obesity, hypertension and dyslipidaemia. |
| 10970 | 23354051 | Conversely, ablation of MG53 prevents diet-induced metabolic syndrome by preserving the insulin receptor, IRS1 and insulin signalling integrity. |
| 10971 | 23354051 | Mechanistically, MG53 acts as an E3 ligase targeting the insulin receptor and IRS1 for ubiquitin-dependent degradation, comprising a central mechanism controlling insulin signal strength in skeletal muscle. |
| 10972 | 23354051 | Central role of E3 ubiquitin ligase MG53 in insulin resistance and metabolic disorders. |
| 10973 | 23354051 | Here we show in mice that muscle-specific mitsugumin 53 (MG53; also called TRIM72) mediates the degradation of the insulin receptor and insulin receptor substrate 1 (IRS1), and when upregulated, causes metabolic syndrome featuring insulin resistance, obesity, hypertension and dyslipidaemia. |
| 10974 | 23354051 | Conversely, ablation of MG53 prevents diet-induced metabolic syndrome by preserving the insulin receptor, IRS1 and insulin signalling integrity. |
| 10975 | 23354051 | Mechanistically, MG53 acts as an E3 ligase targeting the insulin receptor and IRS1 for ubiquitin-dependent degradation, comprising a central mechanism controlling insulin signal strength in skeletal muscle. |
| 10976 | 23363253 | Insulin receptor, IRS1, IRS2, INSIG1, INSIG2, RRAD, and BAIAP2 gene expressions in glioma U87 cells with ERN1 loss of function: effect of hypoxia and glutamine or glucose deprivation. |
| 10977 | 23396401 | Further, LKB1 deletion markedly reduced the levels of insulin receptor substrate 1 (IRS1), peroxisome proliferator-activated receptor γ, CCAAT/enhancer-binding protein α, and phosphorylated AMP-activated protein kinase (AMPK). |
| 10978 | 23396401 | Consistent with these results, overexpression of constitutively active AMPK partially ablated IRS1 degradation in LKB1-deficient cells. |
| 10979 | 23396401 | LKB1 deletion increased the levels of F-box/WD repeat-containing protein (Fbw) 8, the IRS1 ubiquitination E3 ligase. |
| 10980 | 23396401 | Silencing of Fbw8 increased IRS1 levels. |
| 10981 | 23396401 | Taken together, these data indicate that LKB1 controls IRS1-dependent adipogenesis via AMPK in WAT. |
| 10982 | 23396401 | Further, LKB1 deletion markedly reduced the levels of insulin receptor substrate 1 (IRS1), peroxisome proliferator-activated receptor γ, CCAAT/enhancer-binding protein α, and phosphorylated AMP-activated protein kinase (AMPK). |
| 10983 | 23396401 | Consistent with these results, overexpression of constitutively active AMPK partially ablated IRS1 degradation in LKB1-deficient cells. |
| 10984 | 23396401 | LKB1 deletion increased the levels of F-box/WD repeat-containing protein (Fbw) 8, the IRS1 ubiquitination E3 ligase. |
| 10985 | 23396401 | Silencing of Fbw8 increased IRS1 levels. |
| 10986 | 23396401 | Taken together, these data indicate that LKB1 controls IRS1-dependent adipogenesis via AMPK in WAT. |
| 10987 | 23396401 | Further, LKB1 deletion markedly reduced the levels of insulin receptor substrate 1 (IRS1), peroxisome proliferator-activated receptor γ, CCAAT/enhancer-binding protein α, and phosphorylated AMP-activated protein kinase (AMPK). |
| 10988 | 23396401 | Consistent with these results, overexpression of constitutively active AMPK partially ablated IRS1 degradation in LKB1-deficient cells. |
| 10989 | 23396401 | LKB1 deletion increased the levels of F-box/WD repeat-containing protein (Fbw) 8, the IRS1 ubiquitination E3 ligase. |
| 10990 | 23396401 | Silencing of Fbw8 increased IRS1 levels. |
| 10991 | 23396401 | Taken together, these data indicate that LKB1 controls IRS1-dependent adipogenesis via AMPK in WAT. |
| 10992 | 23396401 | Further, LKB1 deletion markedly reduced the levels of insulin receptor substrate 1 (IRS1), peroxisome proliferator-activated receptor γ, CCAAT/enhancer-binding protein α, and phosphorylated AMP-activated protein kinase (AMPK). |
| 10993 | 23396401 | Consistent with these results, overexpression of constitutively active AMPK partially ablated IRS1 degradation in LKB1-deficient cells. |
| 10994 | 23396401 | LKB1 deletion increased the levels of F-box/WD repeat-containing protein (Fbw) 8, the IRS1 ubiquitination E3 ligase. |
| 10995 | 23396401 | Silencing of Fbw8 increased IRS1 levels. |
| 10996 | 23396401 | Taken together, these data indicate that LKB1 controls IRS1-dependent adipogenesis via AMPK in WAT. |
| 10997 | 23396401 | Further, LKB1 deletion markedly reduced the levels of insulin receptor substrate 1 (IRS1), peroxisome proliferator-activated receptor γ, CCAAT/enhancer-binding protein α, and phosphorylated AMP-activated protein kinase (AMPK). |
| 10998 | 23396401 | Consistent with these results, overexpression of constitutively active AMPK partially ablated IRS1 degradation in LKB1-deficient cells. |
| 10999 | 23396401 | LKB1 deletion increased the levels of F-box/WD repeat-containing protein (Fbw) 8, the IRS1 ubiquitination E3 ligase. |
| 11000 | 23396401 | Silencing of Fbw8 increased IRS1 levels. |
| 11001 | 23396401 | Taken together, these data indicate that LKB1 controls IRS1-dependent adipogenesis via AMPK in WAT. |
| 11002 | 23400783 | The model structure and parameters are identical in the normal and diabetic states of the model, except for three parameters that change in diabetes: (i) reduced concentration of insulin receptor, (ii) reduced concentration of insulin-regulated glucose transporter GLUT4, and (iii) changed feedback from mammalian target of rapamycin in complex with raptor (mTORC1). |
| 11003 | 23400783 | Modeling reveals that at the core of insulin resistance in human adipocytes is attenuation of a positive feedback from mTORC1 to the insulin receptor substrate-1, which explains reduced sensitivity and signal strength throughout the signaling network. |
| 11004 | 23442249 | In ZDFs, hemin administration increased HO activity; normalized glycemia; potentiated insulin signaling by enhancing insulin receptor substrate 1(IRS-1), phosphatidylinositol-3-kinase (PI3K), and protein kinase B (PKB)/Akt; suppressed pericardial adiposity, cardiac hypertrophy, and left ventricular longitudinal muscle fiber thickness, a pathophysiological feature of cardiomyocyte hypertrophy; and correspondingly reduced systolic blood pressure, total peripheral resistance, and pro-inflammatory/oxidative mediators, including nuclear factor κB (NF-κB), cJNK, c-Jun-N-terminal kinase (cJNK), endothelin (ET-1), tumor necrosis factor α (TNF-α), interleukin (IL)-6, IL-1β, activating protein 1 (AP-1), and 8-isoprostane, whereas the HO inhibitor, stannous mesoporphyrin, nullified the effects. |
| 11005 | 23442249 | Because NF-κB activates TNFα, IL-6, and IL-1β and TNF-α, cJNK, and AP-1 impair insulin signaling, the high levels of these cytokines in obesity/diabetes would create a vicious cycle that, together with 8-isoprostane and ET-1, exacerbates cardiac injury, compromising cardiac function. |
| 11006 | 23442249 | Therefore, the concomitant reduction of pro-inflammatory cytokines and macrophage infiltration coupled to increased expressions of IRS-1, PI3K, and PKB may account for enhanced glucose metabolism and amelioration of cardiac injury and function in diabetic cardiomyopathy. |
| 11007 | 23442249 | In ZDFs, hemin administration increased HO activity; normalized glycemia; potentiated insulin signaling by enhancing insulin receptor substrate 1(IRS-1), phosphatidylinositol-3-kinase (PI3K), and protein kinase B (PKB)/Akt; suppressed pericardial adiposity, cardiac hypertrophy, and left ventricular longitudinal muscle fiber thickness, a pathophysiological feature of cardiomyocyte hypertrophy; and correspondingly reduced systolic blood pressure, total peripheral resistance, and pro-inflammatory/oxidative mediators, including nuclear factor κB (NF-κB), cJNK, c-Jun-N-terminal kinase (cJNK), endothelin (ET-1), tumor necrosis factor α (TNF-α), interleukin (IL)-6, IL-1β, activating protein 1 (AP-1), and 8-isoprostane, whereas the HO inhibitor, stannous mesoporphyrin, nullified the effects. |
| 11008 | 23442249 | Because NF-κB activates TNFα, IL-6, and IL-1β and TNF-α, cJNK, and AP-1 impair insulin signaling, the high levels of these cytokines in obesity/diabetes would create a vicious cycle that, together with 8-isoprostane and ET-1, exacerbates cardiac injury, compromising cardiac function. |
| 11009 | 23442249 | Therefore, the concomitant reduction of pro-inflammatory cytokines and macrophage infiltration coupled to increased expressions of IRS-1, PI3K, and PKB may account for enhanced glucose metabolism and amelioration of cardiac injury and function in diabetic cardiomyopathy. |
| 11010 | 23444388 | Furthermore, mice with IES exposure and behavioral escape failure exhibited impaired hepatic insulin signaling via the insulin-induced insulin receptor/insulin receptor substrate 1/Akt pathway, without affecting similar pathways in skeletal muscle, adipose tissue, and brain. |
| 11011 | 23460019 | Knockdown of PRAS40 inhibits insulin action via proteasome-mediated degradation of IRS1 in primary human skeletal muscle cells. |
| 11012 | 23463119 | HCV core protein was shown to stimulate suppressor of cytokine signaling, resulting in ubiquitination and degradation of tyrosine kinase phosphorylated insulin receptor substrates (IRS1/2) in proteasomes. |
| 11013 | 23463119 | HCV-nonstructural protein could increase protein phosphatase 2A which has been shown to inactivate the key enzyme Akt by dephosphorylating it. |
| 11014 | 23463119 | Insulin signaling defects in hepatic IRS-1 tyrosine phosphorylation and PI3-kinase association/activation may contribute to IR, which leads to the development of T2D in patients with HCV infection. |
| 11015 | 23463119 | PPARα upregulates glycerol-3-phosphate dehydrogenase, glycerol kinase, and glycerol transport proteins, which allows for glucose synthesis during fasting states. |
| 11016 | 23463119 | It is speculated that TNF-alpha plays a major role in the pathogenesis of IR through lowering IRS1/2. |
| 11017 | 23463119 | Furthermore, HCV infection- triggered ER stress could lead to the activation of PP2A, which inhibits both Akt and the AMP-activated kinase, the regulators of gluconeogenesis. |
| 11018 | 23463119 | HCV core protein was shown to stimulate suppressor of cytokine signaling, resulting in ubiquitination and degradation of tyrosine kinase phosphorylated insulin receptor substrates (IRS1/2) in proteasomes. |
| 11019 | 23463119 | HCV-nonstructural protein could increase protein phosphatase 2A which has been shown to inactivate the key enzyme Akt by dephosphorylating it. |
| 11020 | 23463119 | Insulin signaling defects in hepatic IRS-1 tyrosine phosphorylation and PI3-kinase association/activation may contribute to IR, which leads to the development of T2D in patients with HCV infection. |
| 11021 | 23463119 | PPARα upregulates glycerol-3-phosphate dehydrogenase, glycerol kinase, and glycerol transport proteins, which allows for glucose synthesis during fasting states. |
| 11022 | 23463119 | It is speculated that TNF-alpha plays a major role in the pathogenesis of IR through lowering IRS1/2. |
| 11023 | 23463119 | Furthermore, HCV infection- triggered ER stress could lead to the activation of PP2A, which inhibits both Akt and the AMP-activated kinase, the regulators of gluconeogenesis. |
| 11024 | 23463119 | HCV core protein was shown to stimulate suppressor of cytokine signaling, resulting in ubiquitination and degradation of tyrosine kinase phosphorylated insulin receptor substrates (IRS1/2) in proteasomes. |
| 11025 | 23463119 | HCV-nonstructural protein could increase protein phosphatase 2A which has been shown to inactivate the key enzyme Akt by dephosphorylating it. |
| 11026 | 23463119 | Insulin signaling defects in hepatic IRS-1 tyrosine phosphorylation and PI3-kinase association/activation may contribute to IR, which leads to the development of T2D in patients with HCV infection. |
| 11027 | 23463119 | PPARα upregulates glycerol-3-phosphate dehydrogenase, glycerol kinase, and glycerol transport proteins, which allows for glucose synthesis during fasting states. |
| 11028 | 23463119 | It is speculated that TNF-alpha plays a major role in the pathogenesis of IR through lowering IRS1/2. |
| 11029 | 23463119 | Furthermore, HCV infection- triggered ER stress could lead to the activation of PP2A, which inhibits both Akt and the AMP-activated kinase, the regulators of gluconeogenesis. |
| 11030 | 23468892 | Obesity-induced insulin resistance in human skeletal muscle is characterised by defective activation of p42/p44 MAP kinase. |
| 11031 | 23468892 | Although IR is closely associated with obesity, the identity of the molecular defect(s) underlying obesity-induced IR in skeletal muscle remains controversial; reduced post-receptor signalling of the insulin receptor substrate 1 (IRS1) adaptor protein and downstream effectors such as protein kinase B (PKB) have previously been implicated. |
| 11032 | 23468892 | The most striking abnormality was significantly reduced insulin-induced activation of p42/44 MAP kinase, measured by specific assay, in the volunteers with poor insulin sensitivity. |
| 11033 | 23468892 | However, there was no relationship between individuals' BMI or M-value and protein expression/phosphorylation of IRS1, PKB, or p42/44 MAP kinase protein, under basal or hyperinsulinaemic conditions. |
| 11034 | 23468892 | In the few individuals with poor insulin sensitivity but preserved p42/44 MAP kinase activation, other signalling defects were evident. |
| 11035 | 23468892 | These findings implicate defective p42/44 MAP kinase signalling as a potential contributor to obesity-related IR in a non-diabetic population, although clearly multiple signalling defects underlie obesity associated IR. |
| 11036 | 23468892 | Obesity-induced insulin resistance in human skeletal muscle is characterised by defective activation of p42/p44 MAP kinase. |
| 11037 | 23468892 | Although IR is closely associated with obesity, the identity of the molecular defect(s) underlying obesity-induced IR in skeletal muscle remains controversial; reduced post-receptor signalling of the insulin receptor substrate 1 (IRS1) adaptor protein and downstream effectors such as protein kinase B (PKB) have previously been implicated. |
| 11038 | 23468892 | The most striking abnormality was significantly reduced insulin-induced activation of p42/44 MAP kinase, measured by specific assay, in the volunteers with poor insulin sensitivity. |
| 11039 | 23468892 | However, there was no relationship between individuals' BMI or M-value and protein expression/phosphorylation of IRS1, PKB, or p42/44 MAP kinase protein, under basal or hyperinsulinaemic conditions. |
| 11040 | 23468892 | In the few individuals with poor insulin sensitivity but preserved p42/44 MAP kinase activation, other signalling defects were evident. |
| 11041 | 23468892 | These findings implicate defective p42/44 MAP kinase signalling as a potential contributor to obesity-related IR in a non-diabetic population, although clearly multiple signalling defects underlie obesity associated IR. |
| 11042 | 23469261 | Protein kinase Cε modulates insulin receptor localization and trafficking in mouse embryonic fibroblasts. |
| 11043 | 23469261 | PKCε(-/-) MEFs exhibited reduced insulin uptake which was associated with decreased insulin receptor phosphorylation, while downstream signalling through IRS-1 and Akt was unaffected. |
| 11044 | 23469261 | Cellular fractionation demonstrated that PKCε deletion changed the localization of the insulin receptor, a greater proportion of which co-fractionated with flotillin-1, a marker of membrane microdomains. |
| 11045 | 23469261 | These alterations in insulin receptor trafficking were associated with reduced expression of CEACAM1, a receptor substrate previously shown to modulate insulin clearance. |
| 11046 | 23469261 | Virally-mediated reconstitution of PKCε in MEFs increased CEACAM1 expression and partly restored the sensitivity of the receptor to insulin-stimulated redistribution. |
| 11047 | 23469261 | These data indicate that PKCε can affect insulin uptake in MEFs through promotion of receptor-mediated endocytosis, and that this may be mediated by regulation of CEACAM1 expression. |
| 11048 | 23482058 | With these activations, an impairment of the insulin signaling is observed, with decreased phosphorylation of the insulin receptor, insulin receptor substrate (IRS) and Akt, as well as increased inhibitory serine phosphorylation of IRS-1. |
| 11049 | 23493568 | X-box binding protein 1 is essential for insulin regulation of pancreatic α-cell function. |
| 11050 | 23493568 | X-box binding protein 1 (XBP1) is a transcription factor that plays a crucial role in the unfolded protein response (UPR), and its deficiency in β-cells has been reported to impair insulin secretion, leading to glucose intolerance. |
| 11051 | 23493568 | The αXBPKO mice exhibited glucose intolerance, mild insulin resistance, and an inability to suppress glucagon secretion after glucose stimulation. αXBPKD cells exhibited activation of inositol-requiring enzyme 1, an upstream activator of XBP1, leading to phosphorylation of Jun NH2-terminal kinase. |
| 11052 | 23493568 | Interestingly, insulin treatment of αXBPKD cells reduced tyrosine phosphorylation of insulin receptor substrate 1 (IRS1) (pY(896)) and phosphorylation of Akt while enhancing serine phosphorylation (pS(307)) of IRS1. |
| 11053 | 23493568 | Together, these data indicate that XBP1 deficiency in pancreatic α-cells induces altered insulin signaling and dysfunctional glucagon secretion. |
| 11054 | 23500900 | Role of GALNT2 in the modulation of ENPP1 expression, and insulin signaling and action: GALNT2: a novel modulator of insulin signaling. |
| 11055 | 23500900 | Ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1) inhibits insulin signaling and action. |
| 11056 | 23500900 | Understanding the mechanisms underlying ENPP1 expression may help unravel molecular mechanisms of insulin resistance. |
| 11057 | 23500900 | Recent data suggest a role of ENPP1-3'untraslated region (UTR), in controlling ENPP1 expression. |
| 11058 | 23500900 | Among these, in silico analysis of genome wide association studies and expression profile datasets pointed to N-acetylgalactosaminyltransferase 2 gene (GALNT2) for subsequent investigations. |
| 11059 | 23500900 | Protein expression levels, IRS-1 and Akt phosphorylation were evaluated by Western blot. |
| 11060 | 23500900 | GALNT2 down-regulation increased while GALNT2 over-expression reduced ENPP1 expression levels. |
| 11061 | 23500900 | In addition, GALNT2 down-regulation reduced insulin stimulation of IR, IRS-1 and Akt phosphorylation and insulin inhibition of phosphoenolpyruvate carboxykinase (PEPCK) expression, a key neoglucogenetic enzyme. |
| 11062 | 23500900 | Our data point to GALNT2 as a novel factor involved in the modulation of ENPP1 expression as well as insulin signaling and action in human liver HepG2 cells. |
| 11063 | 23500900 | Role of GALNT2 in the modulation of ENPP1 expression, and insulin signaling and action: GALNT2: a novel modulator of insulin signaling. |
| 11064 | 23500900 | Ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1) inhibits insulin signaling and action. |
| 11065 | 23500900 | Understanding the mechanisms underlying ENPP1 expression may help unravel molecular mechanisms of insulin resistance. |
| 11066 | 23500900 | Recent data suggest a role of ENPP1-3'untraslated region (UTR), in controlling ENPP1 expression. |
| 11067 | 23500900 | Among these, in silico analysis of genome wide association studies and expression profile datasets pointed to N-acetylgalactosaminyltransferase 2 gene (GALNT2) for subsequent investigations. |
| 11068 | 23500900 | Protein expression levels, IRS-1 and Akt phosphorylation were evaluated by Western blot. |
| 11069 | 23500900 | GALNT2 down-regulation increased while GALNT2 over-expression reduced ENPP1 expression levels. |
| 11070 | 23500900 | In addition, GALNT2 down-regulation reduced insulin stimulation of IR, IRS-1 and Akt phosphorylation and insulin inhibition of phosphoenolpyruvate carboxykinase (PEPCK) expression, a key neoglucogenetic enzyme. |
| 11071 | 23500900 | Our data point to GALNT2 as a novel factor involved in the modulation of ENPP1 expression as well as insulin signaling and action in human liver HepG2 cells. |
| 11072 | 23507573 | Minireview: nuclear insulin and insulin-like growth factor-1 receptors: a novel paradigm in signal transduction. |
| 11073 | 23507573 | The specificity of the insulin receptor (InsR) and insulin-like growth factor-1 receptor (IGF1R) signaling pathways has been the focus of significant debate over the past few years. |
| 11074 | 23507573 | Recent evidence showing nuclear import and a direct transcriptional role for both InsR and IGF1R adds a new layer of complexity to this dialog. |
| 11075 | 23507573 | Hence, in addition to the classical roles associated with cell-surface receptors (eg, ligand binding, autophosphorylation of the tyrosine kinase domain, activation of insulin receptor substrate 1 (IRS-1) and additional substrates, protein-protein interactions with membrane and cytoplasm components), new data are consistent with nuclear (genomic) role(s) for both InsR and IGF1R. |
| 11076 | 23507573 | The present review provides a brief overview of the physical and functional similarities and differences between InsR and IGF1R and describes data from a number of laboratories providing evidence for a new layer of signaling regulation (ie, the ability of InsR and IGF1R to translocate to the cell nucleus and to elicit genomic activities usually associated with transcription factors). |
| 11077 | 23507573 | The ability of InsR and IGF1R to function as transcription factors, although poorly understood, constitutes a new paradigm in signal transduction. |
| 11078 | 23507573 | Although research on the role of nuclear InsR/IGF1R is still in its infancy, we believe that this rapidly developing area may have a major basic and translational impact on the fields of metabolism, diabetes, and cancer. |
| 11079 | 23528355 | Cilostazol ameliorates systemic insulin resistance in diabetic db/db mice by suppressing chronic inflammation in adipose tissue via modulation of both adipocyte and macrophage functions. |
| 11080 | 23528355 | Cilostazol reduced the adipocyte size and suppressed mRNA expressions of monocyte chemoattractant protein 1, CD11c, and tumor necrosis factor α (TNFα) in the epididymal fat tissue of db/db mice. |
| 11081 | 23528355 | Cilostazol also effectively ameliorated the TNFα-induced decrease of insulin-stimulated Akt phosphorylation and [(3)H]2-deoxyglucose uptake by suppressing c-Jun N terminal kinase-mediated serine phosphorylation of insulin receptor substrate 1 in 3T3-L1 adipocytes. |
| 11082 | 23528355 | Importantly, the improvement of impaired insulin signaling was blunted by pretreatment with KT5720, a protein kinase A inhibitor, but not with GW9662, a peroxisome proliferator-activated receptor γ. |
| 11083 | 23565163 | Phosphorylation of IRS1 at serine 307 in response to insulin in human adipocytes is not likely to be catalyzed by p70 ribosomal S6 kinase. |
| 11084 | 23565163 | The insulin receptor substrate-1 (IRS1) is phosphorylated on serine 307 (human sequence, corresponding to murine serine 302) in response to insulin as part of a feedback loop that controls IRS1 phosphorylation on tyrosine residues by the insulin receptor. |
| 11085 | 23565163 | The mTORC1-downstream p70 ribosomal protein S6 kinase (S6K1), which is activated by insulin, can phosphorylate IRS1 at serine 307 in vitro and is considered the physiological protein kinase. |
| 11086 | 23565163 | Because the IRS1 serine 307-kinase catalyzes a critical step in the control of insulin signaling and constitutes a potential target for treatment of insulin resistance, it is important to know whether S6K1 is the physiological serine 307-kinase or not. |
| 11087 | 23565163 | We report that, by several criteria, S6K1 does not phosphorylate IRS1 at serine 307 in response to insulin in intact human primary adipocytes: (i) The time-courses for phosphorylation of S6K1 and its phosphorylation of S6 are not compatible with the phosphorylation of IRS1 at serine 307; (ii) A dominant-negative construct of S6K1 inhibits the phosphorylation of S6, without effect on the phosphorylation of IRS1 at serine 307; (iii) The specific inhibitor of S6K1 PF-4708671 inhibits the phosphorylation of S6, without effect on phosphorylation of IRS1 at serine 307. mTOR-immunoprecipitates from insulin-stimulated adipocytes contains an unidentified protein kinase specific for phosphorylation of IRS1 at serine 307, but it is not mTOR or S6K1. |
| 11088 | 23565163 | Phosphorylation of IRS1 at serine 307 in response to insulin in human adipocytes is not likely to be catalyzed by p70 ribosomal S6 kinase. |
| 11089 | 23565163 | The insulin receptor substrate-1 (IRS1) is phosphorylated on serine 307 (human sequence, corresponding to murine serine 302) in response to insulin as part of a feedback loop that controls IRS1 phosphorylation on tyrosine residues by the insulin receptor. |
| 11090 | 23565163 | The mTORC1-downstream p70 ribosomal protein S6 kinase (S6K1), which is activated by insulin, can phosphorylate IRS1 at serine 307 in vitro and is considered the physiological protein kinase. |
| 11091 | 23565163 | Because the IRS1 serine 307-kinase catalyzes a critical step in the control of insulin signaling and constitutes a potential target for treatment of insulin resistance, it is important to know whether S6K1 is the physiological serine 307-kinase or not. |
| 11092 | 23565163 | We report that, by several criteria, S6K1 does not phosphorylate IRS1 at serine 307 in response to insulin in intact human primary adipocytes: (i) The time-courses for phosphorylation of S6K1 and its phosphorylation of S6 are not compatible with the phosphorylation of IRS1 at serine 307; (ii) A dominant-negative construct of S6K1 inhibits the phosphorylation of S6, without effect on the phosphorylation of IRS1 at serine 307; (iii) The specific inhibitor of S6K1 PF-4708671 inhibits the phosphorylation of S6, without effect on phosphorylation of IRS1 at serine 307. mTOR-immunoprecipitates from insulin-stimulated adipocytes contains an unidentified protein kinase specific for phosphorylation of IRS1 at serine 307, but it is not mTOR or S6K1. |
| 11093 | 23565163 | Phosphorylation of IRS1 at serine 307 in response to insulin in human adipocytes is not likely to be catalyzed by p70 ribosomal S6 kinase. |
| 11094 | 23565163 | The insulin receptor substrate-1 (IRS1) is phosphorylated on serine 307 (human sequence, corresponding to murine serine 302) in response to insulin as part of a feedback loop that controls IRS1 phosphorylation on tyrosine residues by the insulin receptor. |
| 11095 | 23565163 | The mTORC1-downstream p70 ribosomal protein S6 kinase (S6K1), which is activated by insulin, can phosphorylate IRS1 at serine 307 in vitro and is considered the physiological protein kinase. |
| 11096 | 23565163 | Because the IRS1 serine 307-kinase catalyzes a critical step in the control of insulin signaling and constitutes a potential target for treatment of insulin resistance, it is important to know whether S6K1 is the physiological serine 307-kinase or not. |
| 11097 | 23565163 | We report that, by several criteria, S6K1 does not phosphorylate IRS1 at serine 307 in response to insulin in intact human primary adipocytes: (i) The time-courses for phosphorylation of S6K1 and its phosphorylation of S6 are not compatible with the phosphorylation of IRS1 at serine 307; (ii) A dominant-negative construct of S6K1 inhibits the phosphorylation of S6, without effect on the phosphorylation of IRS1 at serine 307; (iii) The specific inhibitor of S6K1 PF-4708671 inhibits the phosphorylation of S6, without effect on phosphorylation of IRS1 at serine 307. mTOR-immunoprecipitates from insulin-stimulated adipocytes contains an unidentified protein kinase specific for phosphorylation of IRS1 at serine 307, but it is not mTOR or S6K1. |
| 11098 | 23565163 | Phosphorylation of IRS1 at serine 307 in response to insulin in human adipocytes is not likely to be catalyzed by p70 ribosomal S6 kinase. |
| 11099 | 23565163 | The insulin receptor substrate-1 (IRS1) is phosphorylated on serine 307 (human sequence, corresponding to murine serine 302) in response to insulin as part of a feedback loop that controls IRS1 phosphorylation on tyrosine residues by the insulin receptor. |
| 11100 | 23565163 | The mTORC1-downstream p70 ribosomal protein S6 kinase (S6K1), which is activated by insulin, can phosphorylate IRS1 at serine 307 in vitro and is considered the physiological protein kinase. |
| 11101 | 23565163 | Because the IRS1 serine 307-kinase catalyzes a critical step in the control of insulin signaling and constitutes a potential target for treatment of insulin resistance, it is important to know whether S6K1 is the physiological serine 307-kinase or not. |
| 11102 | 23565163 | We report that, by several criteria, S6K1 does not phosphorylate IRS1 at serine 307 in response to insulin in intact human primary adipocytes: (i) The time-courses for phosphorylation of S6K1 and its phosphorylation of S6 are not compatible with the phosphorylation of IRS1 at serine 307; (ii) A dominant-negative construct of S6K1 inhibits the phosphorylation of S6, without effect on the phosphorylation of IRS1 at serine 307; (iii) The specific inhibitor of S6K1 PF-4708671 inhibits the phosphorylation of S6, without effect on phosphorylation of IRS1 at serine 307. mTOR-immunoprecipitates from insulin-stimulated adipocytes contains an unidentified protein kinase specific for phosphorylation of IRS1 at serine 307, but it is not mTOR or S6K1. |
| 11103 | 23565163 | Phosphorylation of IRS1 at serine 307 in response to insulin in human adipocytes is not likely to be catalyzed by p70 ribosomal S6 kinase. |
| 11104 | 23565163 | The insulin receptor substrate-1 (IRS1) is phosphorylated on serine 307 (human sequence, corresponding to murine serine 302) in response to insulin as part of a feedback loop that controls IRS1 phosphorylation on tyrosine residues by the insulin receptor. |
| 11105 | 23565163 | The mTORC1-downstream p70 ribosomal protein S6 kinase (S6K1), which is activated by insulin, can phosphorylate IRS1 at serine 307 in vitro and is considered the physiological protein kinase. |
| 11106 | 23565163 | Because the IRS1 serine 307-kinase catalyzes a critical step in the control of insulin signaling and constitutes a potential target for treatment of insulin resistance, it is important to know whether S6K1 is the physiological serine 307-kinase or not. |
| 11107 | 23565163 | We report that, by several criteria, S6K1 does not phosphorylate IRS1 at serine 307 in response to insulin in intact human primary adipocytes: (i) The time-courses for phosphorylation of S6K1 and its phosphorylation of S6 are not compatible with the phosphorylation of IRS1 at serine 307; (ii) A dominant-negative construct of S6K1 inhibits the phosphorylation of S6, without effect on the phosphorylation of IRS1 at serine 307; (iii) The specific inhibitor of S6K1 PF-4708671 inhibits the phosphorylation of S6, without effect on phosphorylation of IRS1 at serine 307. mTOR-immunoprecipitates from insulin-stimulated adipocytes contains an unidentified protein kinase specific for phosphorylation of IRS1 at serine 307, but it is not mTOR or S6K1. |
| 11108 | 23579487 | Cellular insulin resistance disrupts leptin-mediated control of neuronal signaling and transcription. |
| 11109 | 23579487 | Central resistance to the actions of insulin and leptin is associated with the onset of obesity and type 2 diabetes mellitus, whereas leptin and insulin signaling is essential for both glucose and energy homeostasis. |
| 11110 | 23579487 | Although it is known that leptin resistance can lead to attenuated insulin signaling, whether insulin resistance can lead to or exacerbate leptin resistance is unknown. |
| 11111 | 23579487 | Prolonged insulin exposure was used to induce cellular insulin resistance, and thereafter leptin-mediated regulation of signal transduction and gene expression was assessed. |
| 11112 | 23579487 | Leptin directly repressed agouti-related peptide mRNA levels but induced urocortin-2, insulin receptor substrate (IRS)-1, IRS2, and IR transcription, through leptin-mediated phosphatidylinositol 3-kinase/Akt activation. |
| 11113 | 23579487 | Neuronal insulin resistance, as assessed by attenuated Akt phosphorylation, blocked leptin-mediated signal transduction and agouti-related peptide, urocortin-2, IRS1, IRS2, and insulin receptor synthesis. |
| 11114 | 23579487 | Insulin resistance caused a substantial decrease in insulin receptor protein levels, forkhead box protein 1 phosphorylation, and an increase in suppressor of cytokine signaling 3 protein levels. |
| 11115 | 23579487 | Cellular insulin resistance may cause or exacerbate neuronal leptin resistance and, by extension, obesity. |
| 11116 | 23579487 | This study provides improved understanding of the complex cellular crosstalk between insulin-leptin signal transduction that is disrupted during neuronal insulin resistance. |
| 11117 | 23582850 | The balance between mitogenic and metabolic actions of insulin can be modulated by various mechanisms, including the way the ligand binds to its receptor or to the closely related insulin-like growth factor-1 (IGF-1) receptor. |
| 11118 | 23582850 | Cross-talks with other signaling pathways implicated in cell proliferation have also been described, like the Wnt/β catenin pathway, and involve the activation of common downstream effectors such as insulin receptor substrate-1 (IRS-1). |
| 11119 | 23582850 | As an example, the molecular adaptor Grb14, which is a specific inhibitor of insulin receptor catalytic activity, also controls insulin-induced metabolic and mitogenic signaling pathways through post-receptor mechanisms that remain to be fully elucidated. |
| 11120 | 23584706 | Our immunohistochemistry approach has shown that the insulin receptor, insulin receptor substrate 1 (IRS1), protein kinase B (PKB) and insulin-sensitive glucose transporter (GLUT4) are expressed in the sensory epithelium of the human saccule, which also exhibits expression of a calcium-sensitive cAMP/cGMP phosphodiesterase 1C (PDE1C) and the vasopressin type 2 receptor. |
| 11121 | 23584706 | IRS1 and PDE1C are selectively expressed in sensory epithelial hair cells, whereas the other components are expressed in sensory epithelial supporting cells or in both cell types, as judged from co-expression or non-co-expression with glial fibrillary acidic protein, a marker for supporting cells. |
| 11122 | 23584706 | Furthermore, IRS1 appears to be localized in association with sensory nerves, whereas GLUT4 is expressed in the peri-nuclear area of stromal cells, as is the case for aquaporin 2. |
| 11123 | 23584706 | Our immunohistochemistry approach has shown that the insulin receptor, insulin receptor substrate 1 (IRS1), protein kinase B (PKB) and insulin-sensitive glucose transporter (GLUT4) are expressed in the sensory epithelium of the human saccule, which also exhibits expression of a calcium-sensitive cAMP/cGMP phosphodiesterase 1C (PDE1C) and the vasopressin type 2 receptor. |
| 11124 | 23584706 | IRS1 and PDE1C are selectively expressed in sensory epithelial hair cells, whereas the other components are expressed in sensory epithelial supporting cells or in both cell types, as judged from co-expression or non-co-expression with glial fibrillary acidic protein, a marker for supporting cells. |
| 11125 | 23584706 | Furthermore, IRS1 appears to be localized in association with sensory nerves, whereas GLUT4 is expressed in the peri-nuclear area of stromal cells, as is the case for aquaporin 2. |
| 11126 | 23584706 | Our immunohistochemistry approach has shown that the insulin receptor, insulin receptor substrate 1 (IRS1), protein kinase B (PKB) and insulin-sensitive glucose transporter (GLUT4) are expressed in the sensory epithelium of the human saccule, which also exhibits expression of a calcium-sensitive cAMP/cGMP phosphodiesterase 1C (PDE1C) and the vasopressin type 2 receptor. |
| 11127 | 23584706 | IRS1 and PDE1C are selectively expressed in sensory epithelial hair cells, whereas the other components are expressed in sensory epithelial supporting cells or in both cell types, as judged from co-expression or non-co-expression with glial fibrillary acidic protein, a marker for supporting cells. |
| 11128 | 23584706 | Furthermore, IRS1 appears to be localized in association with sensory nerves, whereas GLUT4 is expressed in the peri-nuclear area of stromal cells, as is the case for aquaporin 2. |
| 11129 | 23603037 | Various biomarkers like pyruvate-kinase and glucokinase, ATP/ADP ratio, mitochondrial membrane potential, cytosolic release of mitochondrial cytochrome c, cell membrane potential and calcium-ion level were studied and analyzed to ascertain the status of mitochondrial functioning in all experimental and control sets of L6 cells. |
| 11130 | 23603037 | Expression of signalling cascades like GLUT4, IRS1, IRS2, UCP2, PI3, and p38 was critically analyzed. |
| 11131 | 23615306 | In this study, insulin receptor substrate 1 and 2 (Irs-1, Irs-2) were selected as target genes. |
| 11132 | 23615306 | Based on the results of siRNAs, shRNA expression vectors against Irs-1 and Irs-2 were constructed, respectively. |
| 11133 | 23615306 | After 24 h, the liver, pancreas, and muscle were isolated, and the expression levels of Irs-1 and Irs-2 were analyzed by quantitative RT-PCR. |
| 11134 | 23615306 | In the liver, Irs-2 was effectively knocked down to 60% of the control level, but Irs-1 was not influenced even under the same conditions. |
| 11135 | 23615306 | In this study, insulin receptor substrate 1 and 2 (Irs-1, Irs-2) were selected as target genes. |
| 11136 | 23615306 | Based on the results of siRNAs, shRNA expression vectors against Irs-1 and Irs-2 were constructed, respectively. |
| 11137 | 23615306 | After 24 h, the liver, pancreas, and muscle were isolated, and the expression levels of Irs-1 and Irs-2 were analyzed by quantitative RT-PCR. |
| 11138 | 23615306 | In the liver, Irs-2 was effectively knocked down to 60% of the control level, but Irs-1 was not influenced even under the same conditions. |
| 11139 | 23615306 | In this study, insulin receptor substrate 1 and 2 (Irs-1, Irs-2) were selected as target genes. |
| 11140 | 23615306 | Based on the results of siRNAs, shRNA expression vectors against Irs-1 and Irs-2 were constructed, respectively. |
| 11141 | 23615306 | After 24 h, the liver, pancreas, and muscle were isolated, and the expression levels of Irs-1 and Irs-2 were analyzed by quantitative RT-PCR. |
| 11142 | 23615306 | In the liver, Irs-2 was effectively knocked down to 60% of the control level, but Irs-1 was not influenced even under the same conditions. |
| 11143 | 23615306 | In this study, insulin receptor substrate 1 and 2 (Irs-1, Irs-2) were selected as target genes. |
| 11144 | 23615306 | Based on the results of siRNAs, shRNA expression vectors against Irs-1 and Irs-2 were constructed, respectively. |
| 11145 | 23615306 | After 24 h, the liver, pancreas, and muscle were isolated, and the expression levels of Irs-1 and Irs-2 were analyzed by quantitative RT-PCR. |
| 11146 | 23615306 | In the liver, Irs-2 was effectively knocked down to 60% of the control level, but Irs-1 was not influenced even under the same conditions. |
| 11147 | 23639858 | Paraoxonase1 (PON1) reduces insulin resistance in mice fed a high-fat diet, and promotes GLUT4 overexpression in myocytes, via the IRS-1/Akt pathway. |
| 11148 | 23662615 | Second, the signaling proteins IRS-1 and GLUT-4 collected from the muscle were detected. |
| 11149 | 23662615 | However, atropine injection made CM-induced hypoglycemia or elevation of IRS-1 and GLUT-4 not significant. |
| 11150 | 23662615 | Second, the signaling proteins IRS-1 and GLUT-4 collected from the muscle were detected. |
| 11151 | 23662615 | However, atropine injection made CM-induced hypoglycemia or elevation of IRS-1 and GLUT-4 not significant. |
| 11152 | 23665494 | Reduced testosterone and LH (luteinizing hormone) levels in serum were significant in association with a decrease in the levels of mRNA and steroidogenic acute regulatory protein (StAR), insulin receptor substrate (IRS-1), activated IκBβ and ER stress chaperone C/EBP homologous protein (CHOP) in the diabetic testis and sperm count, motility and sexual behaviors were reduced in vivo. |
| 11153 | 23665494 | Additionally, Leydig cells cultured with high glucose showed upregulated IκBβ, ER stress sensor PERK (PKR-like ER kinase) and p-Akt/Akt in vitro. |
| 11154 | 23698110 | Inhibition of the TNF-α-induced serine phosphorylation of IRS-1 at 636/639 by AICAR. |
| 11155 | 23698110 | AMP-activated protein kinase (AMPK) contributes to the acceleration of insulin signaling. |
| 11156 | 23698110 | However, the mechanism by which AMPK regulates insulin signaling remains unclear. |
| 11157 | 23698110 | Here we investigated the role of AMPK in serine phosphorylation of IRS-1 at 636/639 and 307, which is induced by tumor necrosis factor (TNF)-α in 3T3L1 adipocytes. |
| 11158 | 23698110 | We demonstrated that the AMPK activator 5-aminoimidazole-4-carboxamide-1-d-ribofuranoside (AICAR) significantly inhibited the TNF-α-induced serine phosphorylation of IRS-1 at 636/639 and 307 by suppression of extracellular signal-regulated kinase (ERK) phosphorylation but not c-Jun-NH2-terminal kinase (JNK) phosphorylation. |
| 11159 | 23698110 | In addition, AICAR stimulation resulted in enhanced interaction between ERK and MAP kinase phosphatase-4 (DUSP9/MKP-4) without affecting DUSP9/MPK4 mRNA synthesis. |
| 11160 | 23698110 | Moreover, intraperitoneal administration (0.25 g/kg) of AICAR to db/db mice improved blood glucose levels and inhibited the phosphorylation of ERK in adipose tissue. |
| 11161 | 23698110 | In conclusion, we propose a new mechanism in which AICAR suppresses TNF-α-induced serine phosphorylation of IRS-1 at 636/639 and 307 by enhancing the interaction between ERK and DUSP9/MKP-4. |
| 11162 | 23698110 | Inhibition of the TNF-α-induced serine phosphorylation of IRS-1 at 636/639 by AICAR. |
| 11163 | 23698110 | AMP-activated protein kinase (AMPK) contributes to the acceleration of insulin signaling. |
| 11164 | 23698110 | However, the mechanism by which AMPK regulates insulin signaling remains unclear. |
| 11165 | 23698110 | Here we investigated the role of AMPK in serine phosphorylation of IRS-1 at 636/639 and 307, which is induced by tumor necrosis factor (TNF)-α in 3T3L1 adipocytes. |
| 11166 | 23698110 | We demonstrated that the AMPK activator 5-aminoimidazole-4-carboxamide-1-d-ribofuranoside (AICAR) significantly inhibited the TNF-α-induced serine phosphorylation of IRS-1 at 636/639 and 307 by suppression of extracellular signal-regulated kinase (ERK) phosphorylation but not c-Jun-NH2-terminal kinase (JNK) phosphorylation. |
| 11167 | 23698110 | In addition, AICAR stimulation resulted in enhanced interaction between ERK and MAP kinase phosphatase-4 (DUSP9/MKP-4) without affecting DUSP9/MPK4 mRNA synthesis. |
| 11168 | 23698110 | Moreover, intraperitoneal administration (0.25 g/kg) of AICAR to db/db mice improved blood glucose levels and inhibited the phosphorylation of ERK in adipose tissue. |
| 11169 | 23698110 | In conclusion, we propose a new mechanism in which AICAR suppresses TNF-α-induced serine phosphorylation of IRS-1 at 636/639 and 307 by enhancing the interaction between ERK and DUSP9/MKP-4. |
| 11170 | 23698110 | Inhibition of the TNF-α-induced serine phosphorylation of IRS-1 at 636/639 by AICAR. |
| 11171 | 23698110 | AMP-activated protein kinase (AMPK) contributes to the acceleration of insulin signaling. |
| 11172 | 23698110 | However, the mechanism by which AMPK regulates insulin signaling remains unclear. |
| 11173 | 23698110 | Here we investigated the role of AMPK in serine phosphorylation of IRS-1 at 636/639 and 307, which is induced by tumor necrosis factor (TNF)-α in 3T3L1 adipocytes. |
| 11174 | 23698110 | We demonstrated that the AMPK activator 5-aminoimidazole-4-carboxamide-1-d-ribofuranoside (AICAR) significantly inhibited the TNF-α-induced serine phosphorylation of IRS-1 at 636/639 and 307 by suppression of extracellular signal-regulated kinase (ERK) phosphorylation but not c-Jun-NH2-terminal kinase (JNK) phosphorylation. |
| 11175 | 23698110 | In addition, AICAR stimulation resulted in enhanced interaction between ERK and MAP kinase phosphatase-4 (DUSP9/MKP-4) without affecting DUSP9/MPK4 mRNA synthesis. |
| 11176 | 23698110 | Moreover, intraperitoneal administration (0.25 g/kg) of AICAR to db/db mice improved blood glucose levels and inhibited the phosphorylation of ERK in adipose tissue. |
| 11177 | 23698110 | In conclusion, we propose a new mechanism in which AICAR suppresses TNF-α-induced serine phosphorylation of IRS-1 at 636/639 and 307 by enhancing the interaction between ERK and DUSP9/MKP-4. |
| 11178 | 23698110 | Inhibition of the TNF-α-induced serine phosphorylation of IRS-1 at 636/639 by AICAR. |
| 11179 | 23698110 | AMP-activated protein kinase (AMPK) contributes to the acceleration of insulin signaling. |
| 11180 | 23698110 | However, the mechanism by which AMPK regulates insulin signaling remains unclear. |
| 11181 | 23698110 | Here we investigated the role of AMPK in serine phosphorylation of IRS-1 at 636/639 and 307, which is induced by tumor necrosis factor (TNF)-α in 3T3L1 adipocytes. |
| 11182 | 23698110 | We demonstrated that the AMPK activator 5-aminoimidazole-4-carboxamide-1-d-ribofuranoside (AICAR) significantly inhibited the TNF-α-induced serine phosphorylation of IRS-1 at 636/639 and 307 by suppression of extracellular signal-regulated kinase (ERK) phosphorylation but not c-Jun-NH2-terminal kinase (JNK) phosphorylation. |
| 11183 | 23698110 | In addition, AICAR stimulation resulted in enhanced interaction between ERK and MAP kinase phosphatase-4 (DUSP9/MKP-4) without affecting DUSP9/MPK4 mRNA synthesis. |
| 11184 | 23698110 | Moreover, intraperitoneal administration (0.25 g/kg) of AICAR to db/db mice improved blood glucose levels and inhibited the phosphorylation of ERK in adipose tissue. |
| 11185 | 23698110 | In conclusion, we propose a new mechanism in which AICAR suppresses TNF-α-induced serine phosphorylation of IRS-1 at 636/639 and 307 by enhancing the interaction between ERK and DUSP9/MKP-4. |
| 11186 | 23702602 | The association of adipose-derived dimethylarginine dimethylaminohydrolase-2 with insulin sensitivity in experimental type 2 diabetes mellitus. |
| 11187 | 23702602 | Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase (NOS), which can be hydrolyzed by dimethylarginine-dimethylaminohydrolase (DDAH). |
| 11188 | 23702602 | In the present study, we examined the effects of adipocyte-derived DDAH/ADMA on insulin sensitivity using animal and cell models. |
| 11189 | 23702602 | Results showed that in adipose tissue of high fat diet-fed diabetic rats, as well as in high glucose (25 mM) plus insulin (100 nM)-treated 3T3-L1 adipocytes, expression levels of insulin receptor substance-1 (IRS-1), glucose transporter-4 (GLUT-4), and DDAH isoform-2 (DDAH-2) were down-regulated compared with control, although DDAH-1 expression showed no significant changes. |
| 11190 | 23702602 | We also observed that nitric oxide bioavailability, DDAH and NOS activities were subsequently decreased, while the local ADMA content was elevated in diabetic adipose tissue. |
| 11191 | 23702602 | Transfection of human DDAH-2 gene into high glucose- and insulin-treated 3T3-L1 adipocytes significantly ameliorated DDAH activity, reduced ADMA contents, and up-regulated the mRNA expression levels of IRS-1 and GLUT-4. |
| 11192 | 23702602 | These findings suggested that in the development of type 2 diabetes mellitus, local DDAH-2 in adipocytes might play an important role in regulating insulin sensitivity. |
| 11193 | 23702602 | The association of adipose-derived dimethylarginine dimethylaminohydrolase-2 with insulin sensitivity in experimental type 2 diabetes mellitus. |
| 11194 | 23702602 | Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase (NOS), which can be hydrolyzed by dimethylarginine-dimethylaminohydrolase (DDAH). |
| 11195 | 23702602 | In the present study, we examined the effects of adipocyte-derived DDAH/ADMA on insulin sensitivity using animal and cell models. |
| 11196 | 23702602 | Results showed that in adipose tissue of high fat diet-fed diabetic rats, as well as in high glucose (25 mM) plus insulin (100 nM)-treated 3T3-L1 adipocytes, expression levels of insulin receptor substance-1 (IRS-1), glucose transporter-4 (GLUT-4), and DDAH isoform-2 (DDAH-2) were down-regulated compared with control, although DDAH-1 expression showed no significant changes. |
| 11197 | 23702602 | We also observed that nitric oxide bioavailability, DDAH and NOS activities were subsequently decreased, while the local ADMA content was elevated in diabetic adipose tissue. |
| 11198 | 23702602 | Transfection of human DDAH-2 gene into high glucose- and insulin-treated 3T3-L1 adipocytes significantly ameliorated DDAH activity, reduced ADMA contents, and up-regulated the mRNA expression levels of IRS-1 and GLUT-4. |
| 11199 | 23702602 | These findings suggested that in the development of type 2 diabetes mellitus, local DDAH-2 in adipocytes might play an important role in regulating insulin sensitivity. |
| 11200 | 23704966 | Plasma LPS (r = -0.46, P = 0.005) and LBP (r = -0.49, P = 0.005) concentrations negatively correlated with muscle insulin sensitivity (M). |
| 11201 | 23704966 | In human myotubes, LPS increased JNK phosphorylation and MCP-1 and IL-6 gene expression. |
| 11202 | 23704966 | This inflammatory response led to reduced insulin-stimulated IRS-1, Akt and AS160 phosphorylation and impaired glucose transport. |
| 11203 | 23704966 | Both pharmacologic blockade of TLR4 with TAK-242, and TLR4 gene silencing, suppressed the inflammatory response and insulin resistance caused by LPS in human muscle cells. |
| 11204 | 23704966 | Taken together, these findings suggest that elevations in plasma LPS concentration found in obese and T2DM subjects could play a role in the pathogenesis of insulin resistance and that antagonists of TLR4 may improve insulin action in these individuals. |
| 11205 | 23715867 | We examined the effect of astaxanthin on insulin-stimulated glucose transporter 4 (GLUT4) translocation, glucose uptake, and insulin signaling in cultured rat L6 muscle cells using plasma membrane lawn assay, 2-deoxyglucose uptake, and Western blot analysis. |
| 11206 | 23715867 | We observed astaxanthin enhanced insulin-stimulated GLUT4 translocation and glucose uptake, which was associated with an increase in insulin receptor substrate-1 tyrosine and Akt phosphorylation and a decrease in c-Jun N-terminal kinase (JNK) and insulin receptor substrate-1 serine 307 phosphorylation. |
| 11207 | 23715867 | Furthermore, astaxanthin restored TNFα- and palmitate-induced decreases in insulin-stimulated GLUT4 translocation or glucose uptake with a concomitant decrease in reactive oxygen species generation. α-Lipoic acid enhanced Akt phosphorylation and decreased ERK and JNK phosphorylation, whereas α-tocopherol enhanced ERK and JNK phosphorylation but had little effect on Akt phosphorylation. |
| 11208 | 23719722 | This phenomenon is accompanied by attenuated receptor expression of insulin and insulin-like growth factor, enhanced serine phosphorylation of insulin receptor substrate-1, and impaired transport of insulin across the blood-brain barrier. |
| 11209 | 23719722 | These results, in conjunction with the finding that insulin mitigates hippocampal synapse vulnerability to beta amyloid, a peptide thought to be causative in the development of AD, provide a strong rationale for hypothesizing that pharmacological strategies bolstering brain insulin signaling, such as intranasal administration of insulin, could have significant potential in the treatment and prevention of AD. |
| 11210 | 23729590 | We found that exposure to maternal obesity resulted in increased hepatic miR-29b (P<0.05), miR-103 (P<0.01), and miR-107 (P<0.05) expression, a decrease in IR (P<0.05), phopsho-Akt (P<0.01), and phospho-FoxO1 (P<0.01) abundance, and a paradoxical decrease in 11βHSD1 (P<0.05), PEPCK-C (P<0.01), and PEPCK-M (P<0.05) expression in lambs. |
| 11211 | 23729590 | Maternal dietary restriction alone also resulted in decreased abundance of a separate subset of hepatic insulin-signaling molecules, namely, IRS1 (P<0.05), PDK1 (P<0.01), phospho-PDK1 (P<0.05), and aPKCζ (P<0.05) and in decreased PEPCK-C (P<0.01) and G6Pase (P<0.01) expression in the lamb. |
| 11212 | 23741292 | Insulin receptor substrate (IRS) proteins are key mediators of insulin and insulin-like growth factor (IGF) signalling. |
| 11213 | 23741292 | In mice, deletion of Irs1 is associated with profound growth retardation and increased longevity whereas Irs2-deficiency causes diabetes and female infertility. |
| 11214 | 23741292 | Expression of Irs1, Irs3, and Irs4 was comparable between experimental groups. |
| 11215 | 23741292 | Collectively, our results demonstrate that IRS2 plays a critical role in testicular development, potentially by mediating IGF1 signalling during embryonic and early postnatal development. |
| 11216 | 23741292 | Insulin receptor substrate (IRS) proteins are key mediators of insulin and insulin-like growth factor (IGF) signalling. |
| 11217 | 23741292 | In mice, deletion of Irs1 is associated with profound growth retardation and increased longevity whereas Irs2-deficiency causes diabetes and female infertility. |
| 11218 | 23741292 | Expression of Irs1, Irs3, and Irs4 was comparable between experimental groups. |
| 11219 | 23741292 | Collectively, our results demonstrate that IRS2 plays a critical role in testicular development, potentially by mediating IGF1 signalling during embryonic and early postnatal development. |
| 11220 | 23762123 | Upon the intragastric administration in obese insulin-resistant diabetic KKAy mice for 28 days, TLSP, LSP1, and LSP2 all caused a remarkable decrease of fasting blood glucose and significant improvement of insulin resistance and serum lipid metabolism in diabetic mice. |
| 11221 | 23762123 | In addition, liver histological analysis showed that TLSP, LSP1, and LSP2 significantly ameliorated the hepatocyte hypertrophy and decreased the lipid accumulation in the mice liver. |
| 11222 | 23762123 | Further experiments suggested that TLSP, LSP1, and LSP2 effectively inhibited hepatic gluconeogenesis and increased hepatic glycolysis and hepatic glycogen content. |
| 11223 | 23762123 | Furthermore, the mechanistic analysis showed the increased expression of insulin-receptor α subunit, insulin-receptor substrate-1, phosphatidylinositol 3-kinase, and peroxisome proliferators-activated receptors γ . |
| 11224 | 23762123 | These results suggested that TLSP, LSP1, and LSP2 manifest strong antidiabetic activity, therefore hold a great promise for therapeutic application in diabetic therapy and other related metabolic disorders. |
| 11225 | 23800881 | SG, IT, and SGIT surgeries resulted in increased tissue expression and plasma concentrations of the lower gut hormones glucagon-like peptide-1 and peptide YY and decreased plasma glucose-dependent insulinotropic peptide, insulin, and leptin concentrations. |
| 11226 | 23800881 | In support of glycemic improvements, the protein abundance of key markers of glucose metabolism (e.g., GLUT4, PKA, IRS-1) in muscle and adipose tissue were increased, whereas the expression of key gluconeogenic enzyme in liver (G-6-Pase) were decreased following the surgeries. |
| 11227 | 23800882 | Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) promotes hepatic insulin clearance and endothelial survival. |
| 11228 | 23800882 | Mice lacking Ceacam1 (Cc1-/-) exhibit hyperinsulinemia, which causes insulin resistance and fatty liver. |
| 11229 | 23800882 | Basal aortic eNOS protein and NO content were reduced, in parallel with reduced Akt/eNOS and Akt/Foxo1 phosphorylation. |
| 11230 | 23800882 | Increased NADPH oxidase activity and plasma 8-isoprostane levels revealed oxidative stress and lipid peroxidation in Cc1-/- aortae. siRNA-mediated CEACAM1 knockdown in bovine aortic endothelial cells adversely affected insulin's stimulation of IRS-1/PI 3-kinase/Akt/eNOS activation by increasing IRS-1 binding to SHP2 phosphatase. |
| 11231 | 23800882 | Cc1-/- mice provide a first in vivo demonstration of distinct CEACAM1-dependent hepatic insulin clearance linking hepatic to macrovascular abnormalities. |
| 11232 | 23810379 | This mutation led to impaired interaction between p85α and IRS-1 and reduced AKT-mediated insulin signaling in fibroblasts from affected subjects and in reconstituted Pik3r1-knockout preadipocytes. |
| 11233 | 23810379 | Normal PI3K activity is critical for adipose differentiation and insulin signaling; the mutated PIK3R1 therefore provides a unique link among lipodystrophy, growth, and insulin signaling. |
| 11234 | 23831466 | Pinusolide improves high glucose-induced insulin resistance via activation of AMP-activated protein kinase. |
| 11235 | 23831466 | In this study, we found that pinusolide stimulated AMPK phosphorylation and glucose uptake and these effects were significantly reduced by siRNA LKB1 or compound C, suggesting that enhanced glucose uptake by pinusolide is predominantly accomplished via an LKB1-mediated AMPK activation pathway. |
| 11236 | 23831466 | An insulin resistance state was induced by exposing cells to 30mM glucose, as indicated by reduced insulin-stimulated tyrosine phosphorylation of IRS-1 and glucose uptake. |
| 11237 | 23831466 | Under these conditions, the phosphorylation of AMPK and ACC were decreased. |
| 11238 | 23831466 | Surprisingly, disrupted insulin signaling and decreased AMPK activity by high glucose concentrations were prevented by pinusolide. |
| 11239 | 23831466 | Moreover, this treatment increased insulin-stimulated glucose uptake via AMPK activation. |
| 11240 | 23831466 | Taken together, our findings suggest a link between high glucose and insulin resistance in muscle cells, and provide further evidence that pinusolide attenuates blockade of insulin signaling by enhancing IRS-1 tyrosine phosphorylation by the activating the AMPK pathway. |
| 11241 | 23831466 | In addition, this study indicates the targeting of AMPK represents a new therapeutic strategy for hyperglycemia-induced insulin resistance and type 2 diabetes. |
| 11242 | 23831466 | Pinusolide improves high glucose-induced insulin resistance via activation of AMP-activated protein kinase. |
| 11243 | 23831466 | In this study, we found that pinusolide stimulated AMPK phosphorylation and glucose uptake and these effects were significantly reduced by siRNA LKB1 or compound C, suggesting that enhanced glucose uptake by pinusolide is predominantly accomplished via an LKB1-mediated AMPK activation pathway. |
| 11244 | 23831466 | An insulin resistance state was induced by exposing cells to 30mM glucose, as indicated by reduced insulin-stimulated tyrosine phosphorylation of IRS-1 and glucose uptake. |
| 11245 | 23831466 | Under these conditions, the phosphorylation of AMPK and ACC were decreased. |
| 11246 | 23831466 | Surprisingly, disrupted insulin signaling and decreased AMPK activity by high glucose concentrations were prevented by pinusolide. |
| 11247 | 23831466 | Moreover, this treatment increased insulin-stimulated glucose uptake via AMPK activation. |
| 11248 | 23831466 | Taken together, our findings suggest a link between high glucose and insulin resistance in muscle cells, and provide further evidence that pinusolide attenuates blockade of insulin signaling by enhancing IRS-1 tyrosine phosphorylation by the activating the AMPK pathway. |
| 11249 | 23831466 | In addition, this study indicates the targeting of AMPK represents a new therapeutic strategy for hyperglycemia-induced insulin resistance and type 2 diabetes. |
| 11250 | 23840461 | Tectorigenin Attenuates Palmitate-Induced Endothelial Insulin Resistance via Targeting ROS-Associated Inflammation and IRS-1 Pathway. |
| 11251 | 23840461 | Palmitic acid (PA) was chosen as a stimulant to induce ROS production in endothelial cells and successfully established insulin resistance evidenced by the specific impairment of insulin PI3K signaling. |
| 11252 | 23840461 | Moreover, tectorigenin presented strong inhibition effect on ROS-associated inflammation, as TNF-α and IL-6 production in endothelial cells was greatly reduced with suppression of IKKβ/NF-κB phosphorylation and JNK activation. |
| 11253 | 23840461 | Tectorigenin also can inhibit inflammation-stimulated IRS-1 serine phosphorylation and restore the impaired insulin PI3K signaling, leading to a decreased NO production. |
| 11254 | 23840461 | Meanwhile, tectorigenin down-regulated endothelin-1 and vascular cell adhesion molecule-1 overexpression, and restored the loss of insulin-mediated vasodilation in rat aorta. |
| 11255 | 23840461 | These findings suggested that tectorigenin could inhibit ROS-associated inflammation and ameliorated endothelial dysfunction implicated in insulin resistance through regulating IRS-1 function. |
| 11256 | 23840461 | Tectorigenin Attenuates Palmitate-Induced Endothelial Insulin Resistance via Targeting ROS-Associated Inflammation and IRS-1 Pathway. |
| 11257 | 23840461 | Palmitic acid (PA) was chosen as a stimulant to induce ROS production in endothelial cells and successfully established insulin resistance evidenced by the specific impairment of insulin PI3K signaling. |
| 11258 | 23840461 | Moreover, tectorigenin presented strong inhibition effect on ROS-associated inflammation, as TNF-α and IL-6 production in endothelial cells was greatly reduced with suppression of IKKβ/NF-κB phosphorylation and JNK activation. |
| 11259 | 23840461 | Tectorigenin also can inhibit inflammation-stimulated IRS-1 serine phosphorylation and restore the impaired insulin PI3K signaling, leading to a decreased NO production. |
| 11260 | 23840461 | Meanwhile, tectorigenin down-regulated endothelin-1 and vascular cell adhesion molecule-1 overexpression, and restored the loss of insulin-mediated vasodilation in rat aorta. |
| 11261 | 23840461 | These findings suggested that tectorigenin could inhibit ROS-associated inflammation and ameliorated endothelial dysfunction implicated in insulin resistance through regulating IRS-1 function. |
| 11262 | 23840461 | Tectorigenin Attenuates Palmitate-Induced Endothelial Insulin Resistance via Targeting ROS-Associated Inflammation and IRS-1 Pathway. |
| 11263 | 23840461 | Palmitic acid (PA) was chosen as a stimulant to induce ROS production in endothelial cells and successfully established insulin resistance evidenced by the specific impairment of insulin PI3K signaling. |
| 11264 | 23840461 | Moreover, tectorigenin presented strong inhibition effect on ROS-associated inflammation, as TNF-α and IL-6 production in endothelial cells was greatly reduced with suppression of IKKβ/NF-κB phosphorylation and JNK activation. |
| 11265 | 23840461 | Tectorigenin also can inhibit inflammation-stimulated IRS-1 serine phosphorylation and restore the impaired insulin PI3K signaling, leading to a decreased NO production. |
| 11266 | 23840461 | Meanwhile, tectorigenin down-regulated endothelin-1 and vascular cell adhesion molecule-1 overexpression, and restored the loss of insulin-mediated vasodilation in rat aorta. |
| 11267 | 23840461 | These findings suggested that tectorigenin could inhibit ROS-associated inflammation and ameliorated endothelial dysfunction implicated in insulin resistance through regulating IRS-1 function. |
| 11268 | 23894818 | [Effects of retinol binding protein 4 knockdown on the PI3K/Akt pathways in porcine adipocytes]. |
| 11269 | 23894818 | Retinol-binding protein 4 (RBP4) is adipocyte-derived secreted adipokines and elevated RBP4 expression level was closely related to insulin resistance and type II diabetes mellitus. |
| 11270 | 23894818 | RBP4 interference efficiency and the gene expression of each treatment groups in PI3K/Akt pathways were examined by QRT-PCR and Western blotting. |
| 11271 | 23894818 | Furthermore, no matter under insulin stimulation or insulin resistance, RBP4 knockdown significantly increased the mRNA expressions of AKT2, PI3K, GLUT4 and IRS1 compared with the control. |
| 11272 | 23894818 | The protein phosphorylate levels of AKT2, PI3K, IRS1 arised, meanwhile enhanced the AKT2, PI3K, GLUT4 total protein expressions. |
| 11273 | 23894818 | Collectively, knockdown of RBP4 increased the insulin sensitivity through upregulated PI3K/Akt pathways related factors' expression and phosphorylation in porcine adipocytes. |
| 11274 | 23894818 | [Effects of retinol binding protein 4 knockdown on the PI3K/Akt pathways in porcine adipocytes]. |
| 11275 | 23894818 | Retinol-binding protein 4 (RBP4) is adipocyte-derived secreted adipokines and elevated RBP4 expression level was closely related to insulin resistance and type II diabetes mellitus. |
| 11276 | 23894818 | RBP4 interference efficiency and the gene expression of each treatment groups in PI3K/Akt pathways were examined by QRT-PCR and Western blotting. |
| 11277 | 23894818 | Furthermore, no matter under insulin stimulation or insulin resistance, RBP4 knockdown significantly increased the mRNA expressions of AKT2, PI3K, GLUT4 and IRS1 compared with the control. |
| 11278 | 23894818 | The protein phosphorylate levels of AKT2, PI3K, IRS1 arised, meanwhile enhanced the AKT2, PI3K, GLUT4 total protein expressions. |
| 11279 | 23894818 | Collectively, knockdown of RBP4 increased the insulin sensitivity through upregulated PI3K/Akt pathways related factors' expression and phosphorylation in porcine adipocytes. |
| 11280 | 23912035 | HSu rats displayed a poorer performance in hippocampal-dependent short- and long-term spatial memory performance, assessed with the modified Y-maze and Morris water maze tasks, respectively; this was accompanied by a reduction of insulin receptor-β density with normal levels of insulin receptor substrate-1 pSer636/639, and decreased hippocampal glucocorticoid receptor levels without changes of the plasma corticosterone levels. |
| 11281 | 23927877 | Meanwhile, intrapancreatic protein levels of insulin receptor substrate-1 (IRS-1) and insulin-like growth factor-1 (IGF-1) were up-regulated, respectively. |
| 11282 | 23940800 | Genetic inactivation of pyruvate dehydrogenase kinases improves hepatic insulin resistance induced diabetes. |
| 11283 | 23940800 | Pyruvate dehydrogenase kinases (PDK1-4) play a critical role in the inhibition of the mitochondrial pyruvate dehydrogenase complex especially when blood glucose levels are low and pyruvate can be conserved for gluconeogenesis. |
| 11284 | 23940800 | To address this question, we crossed Pdk2 or Pdk4 null mice with a diabetic model that is deficient in hepatic insulin receptor substrates 1 and 2 (Irs1/2). |
| 11285 | 23940800 | Metabolic analyses reveal that deletion of the Pdk4 gene had better improvement in hyperglycemia and glucose tolerance than knockout of the Pdk2 gene whereas the Pdk2 gene deletion showed better insulin tolerance as compared to the Pdk4 gene inactivation on the Irs1/2 knockout genetic background. |
| 11286 | 23940800 | To examine the specific hepatic effects of Pdks on diabetes, we also knocked down the Pdk2 or Pdk4 gene using specific shRNAs. |
| 11287 | 23940800 | The data also indicate that the Pdk4 gene knockdown led to better glucose tolerance than the Pdk2 gene knockdown. |
| 11288 | 23940800 | Genetic inactivation of pyruvate dehydrogenase kinases improves hepatic insulin resistance induced diabetes. |
| 11289 | 23940800 | Pyruvate dehydrogenase kinases (PDK1-4) play a critical role in the inhibition of the mitochondrial pyruvate dehydrogenase complex especially when blood glucose levels are low and pyruvate can be conserved for gluconeogenesis. |
| 11290 | 23940800 | To address this question, we crossed Pdk2 or Pdk4 null mice with a diabetic model that is deficient in hepatic insulin receptor substrates 1 and 2 (Irs1/2). |
| 11291 | 23940800 | Metabolic analyses reveal that deletion of the Pdk4 gene had better improvement in hyperglycemia and glucose tolerance than knockout of the Pdk2 gene whereas the Pdk2 gene deletion showed better insulin tolerance as compared to the Pdk4 gene inactivation on the Irs1/2 knockout genetic background. |
| 11292 | 23940800 | To examine the specific hepatic effects of Pdks on diabetes, we also knocked down the Pdk2 or Pdk4 gene using specific shRNAs. |
| 11293 | 23940800 | The data also indicate that the Pdk4 gene knockdown led to better glucose tolerance than the Pdk2 gene knockdown. |
| 11294 | 23946430 | Pioglitazone (PIO) is a member of the thiazolidinediones - a group of insulin-sensitizing drugs that are selective agonists of peroxisome proliferator-activated receptor gamma (PPARγ). |
| 11295 | 23946430 | In the liver, PIO decreased the phosphorylation of insulin receptor substrate-1 (IRS1) at a serine residue (Ser(307)-pS-IRS1), which inhibits insulin action, and had a tendency to increase tyrosine phosphorylation of IRS2 (Tyr-pY-IRS2) only in N mice but did not affect either of these parameters in Tg mice. |