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Gene Information
Gene symbol: INSR
Gene name: insulin receptor
HGNC ID: 6091
Synonyms: CD220
Related Genes
Related Sentences
| # | PMID | Sentence |
| 1 | 446930 | In conclusion, (1) the short-term adaptive response of the insulin receptor is a decrease in binding affinity whereas the long-term response is a decrease in receptor number, (2) sustained and chronic hyperinsulinemia can lead to a decrease in the number of cellular insulin receptors, (3) high carbohydrate diets lead to a general increase in insulin's ability to promote glucose removal from plasma, and (4) the paradox of enhanced insulin sensitivity in the face of decreased insulin binding can be explained if high carbohydrate diets also lead to an increase in the activity of steps in glucose metabolism distal to the insulin receptor. |
| 2 | 689305 | These facts suggest that these IgG fractions bind to or near the insulin receptor of human adipocytes, that they exhibit their insulin-like effect by binding to the insulin receptor in vitro, and, furthermore, that they are responsible for the extremely insulin-resistant diabetes. |
| 3 | 1290322 | Idiopathic insulin resistance in type 2 diabetes is additionally characterized by reduced glucose storage, the basis of which may reside in an insulin receptor defect, in the presence of insulin receptor antibodies, in a postreceptor defect or in the synthesis of abnormal insulin molecules. |
| 4 | 1301912 | Rapid and simultaneous detection of multiple mutations by pooled and multiplex single nucleotide primer extension: application to the study of insulin-responsive glucose transporter and insulin receptor mutations in non-insulin-dependent diabetes. |
| 5 | 1301912 | The usefulness of these adaptations is illustrated by their application to the simultaneous detection of three point mutations, two in the tyrosine kinase domain of the insulin receptor and one in the insulin-responsive glucose transporter (GLUT4) in a highly insulin-resistant NIDDM population. |
| 6 | 1301912 | GLUT4 Ile383 was detected in 2/42 of the highly insulin-resistant NIDDM subjects and 4/240 middle-aged blood donors. |
| 7 | 1301912 | Rapid and simultaneous detection of multiple mutations by pooled and multiplex single nucleotide primer extension: application to the study of insulin-responsive glucose transporter and insulin receptor mutations in non-insulin-dependent diabetes. |
| 8 | 1301912 | The usefulness of these adaptations is illustrated by their application to the simultaneous detection of three point mutations, two in the tyrosine kinase domain of the insulin receptor and one in the insulin-responsive glucose transporter (GLUT4) in a highly insulin-resistant NIDDM population. |
| 9 | 1301912 | GLUT4 Ile383 was detected in 2/42 of the highly insulin-resistant NIDDM subjects and 4/240 middle-aged blood donors. |
| 10 | 1307923 | Insulin-like growth factors. |
| 11 | 1307923 | The insulin-like growth factors (IGF-I and IGF-II) play important roles in the regulation of growth and metabolism. |
| 12 | 1307923 | The actions of the IGFs are mediated through their activation of specific cell surface receptors, primarily the IGF-I receptor, although some effects may be mediated through the IGF-II receptor and the insulin receptor. |
| 13 | 1309768 | Insulin stimulation of phosphatidylinositol 3-kinase activity maps to insulin receptor regions required for endogenous substrate phosphorylation. |
| 14 | 1309768 | We have studied the phosphatidylinositol 3-kinase (PtdIns 3-kinase) in insulin-stimulated Chinese hamster ovary (CHO) cells expressing normal (CHO/IR) and mutant human insulin receptors. |
| 15 | 1309768 | Insulin stimulation of CHO/IR cells results in an increase in PtdIns 3-kinase activity associated with anti-phosphotyrosine (alpha PY) immunoprecipitates, which has been previously shown to correlate with the in vivo production of PtdIns(3,4)P2, and PtdIns(3,4,5)P3 (Ruderman, N., Kapeller, R., White, M.F., and Cantley, L.C. (1990) Proc. |
| 16 | 1309768 | The PtdIns 3-kinase also associated with the insulin receptor in an insulin-stimulated manner, as approximately 50% of the total alpha PY-precipitable activity could be specifically immunoprecipitated with anti-insulin receptor antibody. |
| 17 | 1309768 | Mutant insulin receptors displayed variable ability to stimulate the PtdIns 3-kinase, but in all cases the presence of PtdIns 3-kinase in alpha PY immunoprecipitates correlated closely with the tyrosyl phosphorylation of the endogenous substrate pp185. |
| 18 | 1309768 | In CHO cells expressing a kinase-deficient mutant (IRA1018), there was no observable insulin stimulation of PtdIns 3-kinase activity in alpha PY immunoprecipitates and no tyrosyl phosphorylation of pp185. |
| 19 | 1309768 | Substitution of Tyr1146 in the insulin receptor regulatory region with phenylalanine partially impaired receptor autophosphorylation, pp185 phosphorylation, and insulin-stimulated increases in alpha PY-precipitable PtdIns 3-kinase activity. |
| 20 | 1309768 | Finally, a mutant receptor from which the C-terminal 43 amino acids had been deleted (IR delta CT) exhibited normal insulin-stimulated autophosphorylation, pp185 phosphorylation, and stimulation of the PtdIns 3-kinase activity in alpha PY immunoprecipitates. |
| 21 | 1309768 | These data suggest that the PtdIns 3-kinase is itself a substrate of the insulin receptor kinase or associates preferentially with a substrate. |
| 22 | 1309768 | A comparison of the biological activities of the mutant receptors with their activation of the PtdIns 3-kinase furthermore suggests that the PtdIns 3-kinase may be linked to insulin's ability to regulate DNA synthesis and cell growth. |
| 23 | 1309768 | Insulin stimulation of phosphatidylinositol 3-kinase activity maps to insulin receptor regions required for endogenous substrate phosphorylation. |
| 24 | 1309768 | We have studied the phosphatidylinositol 3-kinase (PtdIns 3-kinase) in insulin-stimulated Chinese hamster ovary (CHO) cells expressing normal (CHO/IR) and mutant human insulin receptors. |
| 25 | 1309768 | Insulin stimulation of CHO/IR cells results in an increase in PtdIns 3-kinase activity associated with anti-phosphotyrosine (alpha PY) immunoprecipitates, which has been previously shown to correlate with the in vivo production of PtdIns(3,4)P2, and PtdIns(3,4,5)P3 (Ruderman, N., Kapeller, R., White, M.F., and Cantley, L.C. (1990) Proc. |
| 26 | 1309768 | The PtdIns 3-kinase also associated with the insulin receptor in an insulin-stimulated manner, as approximately 50% of the total alpha PY-precipitable activity could be specifically immunoprecipitated with anti-insulin receptor antibody. |
| 27 | 1309768 | Mutant insulin receptors displayed variable ability to stimulate the PtdIns 3-kinase, but in all cases the presence of PtdIns 3-kinase in alpha PY immunoprecipitates correlated closely with the tyrosyl phosphorylation of the endogenous substrate pp185. |
| 28 | 1309768 | In CHO cells expressing a kinase-deficient mutant (IRA1018), there was no observable insulin stimulation of PtdIns 3-kinase activity in alpha PY immunoprecipitates and no tyrosyl phosphorylation of pp185. |
| 29 | 1309768 | Substitution of Tyr1146 in the insulin receptor regulatory region with phenylalanine partially impaired receptor autophosphorylation, pp185 phosphorylation, and insulin-stimulated increases in alpha PY-precipitable PtdIns 3-kinase activity. |
| 30 | 1309768 | Finally, a mutant receptor from which the C-terminal 43 amino acids had been deleted (IR delta CT) exhibited normal insulin-stimulated autophosphorylation, pp185 phosphorylation, and stimulation of the PtdIns 3-kinase activity in alpha PY immunoprecipitates. |
| 31 | 1309768 | These data suggest that the PtdIns 3-kinase is itself a substrate of the insulin receptor kinase or associates preferentially with a substrate. |
| 32 | 1309768 | A comparison of the biological activities of the mutant receptors with their activation of the PtdIns 3-kinase furthermore suggests that the PtdIns 3-kinase may be linked to insulin's ability to regulate DNA synthesis and cell growth. |
| 33 | 1309768 | Insulin stimulation of phosphatidylinositol 3-kinase activity maps to insulin receptor regions required for endogenous substrate phosphorylation. |
| 34 | 1309768 | We have studied the phosphatidylinositol 3-kinase (PtdIns 3-kinase) in insulin-stimulated Chinese hamster ovary (CHO) cells expressing normal (CHO/IR) and mutant human insulin receptors. |
| 35 | 1309768 | Insulin stimulation of CHO/IR cells results in an increase in PtdIns 3-kinase activity associated with anti-phosphotyrosine (alpha PY) immunoprecipitates, which has been previously shown to correlate with the in vivo production of PtdIns(3,4)P2, and PtdIns(3,4,5)P3 (Ruderman, N., Kapeller, R., White, M.F., and Cantley, L.C. (1990) Proc. |
| 36 | 1309768 | The PtdIns 3-kinase also associated with the insulin receptor in an insulin-stimulated manner, as approximately 50% of the total alpha PY-precipitable activity could be specifically immunoprecipitated with anti-insulin receptor antibody. |
| 37 | 1309768 | Mutant insulin receptors displayed variable ability to stimulate the PtdIns 3-kinase, but in all cases the presence of PtdIns 3-kinase in alpha PY immunoprecipitates correlated closely with the tyrosyl phosphorylation of the endogenous substrate pp185. |
| 38 | 1309768 | In CHO cells expressing a kinase-deficient mutant (IRA1018), there was no observable insulin stimulation of PtdIns 3-kinase activity in alpha PY immunoprecipitates and no tyrosyl phosphorylation of pp185. |
| 39 | 1309768 | Substitution of Tyr1146 in the insulin receptor regulatory region with phenylalanine partially impaired receptor autophosphorylation, pp185 phosphorylation, and insulin-stimulated increases in alpha PY-precipitable PtdIns 3-kinase activity. |
| 40 | 1309768 | Finally, a mutant receptor from which the C-terminal 43 amino acids had been deleted (IR delta CT) exhibited normal insulin-stimulated autophosphorylation, pp185 phosphorylation, and stimulation of the PtdIns 3-kinase activity in alpha PY immunoprecipitates. |
| 41 | 1309768 | These data suggest that the PtdIns 3-kinase is itself a substrate of the insulin receptor kinase or associates preferentially with a substrate. |
| 42 | 1309768 | A comparison of the biological activities of the mutant receptors with their activation of the PtdIns 3-kinase furthermore suggests that the PtdIns 3-kinase may be linked to insulin's ability to regulate DNA synthesis and cell growth. |
| 43 | 1309768 | Insulin stimulation of phosphatidylinositol 3-kinase activity maps to insulin receptor regions required for endogenous substrate phosphorylation. |
| 44 | 1309768 | We have studied the phosphatidylinositol 3-kinase (PtdIns 3-kinase) in insulin-stimulated Chinese hamster ovary (CHO) cells expressing normal (CHO/IR) and mutant human insulin receptors. |
| 45 | 1309768 | Insulin stimulation of CHO/IR cells results in an increase in PtdIns 3-kinase activity associated with anti-phosphotyrosine (alpha PY) immunoprecipitates, which has been previously shown to correlate with the in vivo production of PtdIns(3,4)P2, and PtdIns(3,4,5)P3 (Ruderman, N., Kapeller, R., White, M.F., and Cantley, L.C. (1990) Proc. |
| 46 | 1309768 | The PtdIns 3-kinase also associated with the insulin receptor in an insulin-stimulated manner, as approximately 50% of the total alpha PY-precipitable activity could be specifically immunoprecipitated with anti-insulin receptor antibody. |
| 47 | 1309768 | Mutant insulin receptors displayed variable ability to stimulate the PtdIns 3-kinase, but in all cases the presence of PtdIns 3-kinase in alpha PY immunoprecipitates correlated closely with the tyrosyl phosphorylation of the endogenous substrate pp185. |
| 48 | 1309768 | In CHO cells expressing a kinase-deficient mutant (IRA1018), there was no observable insulin stimulation of PtdIns 3-kinase activity in alpha PY immunoprecipitates and no tyrosyl phosphorylation of pp185. |
| 49 | 1309768 | Substitution of Tyr1146 in the insulin receptor regulatory region with phenylalanine partially impaired receptor autophosphorylation, pp185 phosphorylation, and insulin-stimulated increases in alpha PY-precipitable PtdIns 3-kinase activity. |
| 50 | 1309768 | Finally, a mutant receptor from which the C-terminal 43 amino acids had been deleted (IR delta CT) exhibited normal insulin-stimulated autophosphorylation, pp185 phosphorylation, and stimulation of the PtdIns 3-kinase activity in alpha PY immunoprecipitates. |
| 51 | 1309768 | These data suggest that the PtdIns 3-kinase is itself a substrate of the insulin receptor kinase or associates preferentially with a substrate. |
| 52 | 1309768 | A comparison of the biological activities of the mutant receptors with their activation of the PtdIns 3-kinase furthermore suggests that the PtdIns 3-kinase may be linked to insulin's ability to regulate DNA synthesis and cell growth. |
| 53 | 1310686 | Insulin increases phosphatidylinositol-3-kinase (PI-3-kinase) activity in Chinese hamster ovary cells transfected with human insulin receptor (Ruderman, N. |
| 54 | 1310858 | Cloning and characterization of the human insulin-like growth factor-I receptor gene 5'-flanking region. |
| 55 | 1310858 | The insulin-like growth factor-I receptor (IGFIR) is a membrane-bound glycoprotein that mediates the action of insulin-like growth factors. |
| 56 | 1310858 | The promoter contained binding sites for the transcription factors Sp1, AP-2, and the epidermal growth factor receptor transcription factor (ETF). |
| 57 | 1310858 | Comparison of the IGFIR promoter with that of the human insulin receptor (IR) revealed structural similarities, although the arrangement of promoter elements differed. |
| 58 | 1312492 | To study the role of membrane lipids in signal transduction by the insulin receptor, we have studied the effect of phospholipase C (Clostridium perfringens) and a phosphatidylinositol-specific phospholipase (Staphylococcus aureus) on insulin binding, a function of the alpha-subunit, and tyrosine kinase activity, a function of the beta-subunit in IM-9 lymphocytes and NIH 3T3 fibroblasts transfected with the human insulin receptor. |
| 59 | 1312492 | Treatment of the cells with phospholipase C at concentrations up to 3.4 U/ml did not affect specific insulin binding, but reduced insulin-stimulated receptor phosphorylation by 50%. |
| 60 | 1312492 | Insulin-stimulated phosphorylation of pp 185, the presumed endogenous substrate for the insulin receptor kinase, was also reduced following phospholipase C treatment, with an almost complete loss of insulin stimulation after exposure of cells to enzyme at concentrations as low as 0.6 U/ml. |
| 61 | 1312492 | In contrast to these effects of phospholipase C on intact cells, receptor autophosphorylation was not affected in insulin receptors purified on wheat germ agglutinin-agarose from phospholipase C treated cells. |
| 62 | 1312492 | Treatment of cells with the phosphatidylinositol-specific phospholipase C did not affect any of the parameters studied. |
| 63 | 1312492 | To study the role of membrane lipids in signal transduction by the insulin receptor, we have studied the effect of phospholipase C (Clostridium perfringens) and a phosphatidylinositol-specific phospholipase (Staphylococcus aureus) on insulin binding, a function of the alpha-subunit, and tyrosine kinase activity, a function of the beta-subunit in IM-9 lymphocytes and NIH 3T3 fibroblasts transfected with the human insulin receptor. |
| 64 | 1312492 | Treatment of the cells with phospholipase C at concentrations up to 3.4 U/ml did not affect specific insulin binding, but reduced insulin-stimulated receptor phosphorylation by 50%. |
| 65 | 1312492 | Insulin-stimulated phosphorylation of pp 185, the presumed endogenous substrate for the insulin receptor kinase, was also reduced following phospholipase C treatment, with an almost complete loss of insulin stimulation after exposure of cells to enzyme at concentrations as low as 0.6 U/ml. |
| 66 | 1312492 | In contrast to these effects of phospholipase C on intact cells, receptor autophosphorylation was not affected in insulin receptors purified on wheat germ agglutinin-agarose from phospholipase C treated cells. |
| 67 | 1312492 | Treatment of cells with the phosphatidylinositol-specific phospholipase C did not affect any of the parameters studied. |
| 68 | 1312712 | YMXM motifs of IRS-1 define substrate specificity of the insulin receptor kinase. |
| 69 | 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. |
| 70 | 1316988 | Growth factor receptor regulation in the Minn-1 leprechaun: defects in both insulin receptor and epidermal growth factor receptor gene expression. |
| 71 | 1316988 | Using fibroblasts from the Minn-1 leprechaun, we have now investigated the expression of three different growth factor receptor genes: the IR, the insulin-like growth factor-I receptor (IGF-IR), and the epidermal growth factor receptor (EGFR). |
| 72 | 1316988 | In contrast to the IGF-IR, when the EGFR was studied, ligand binding and mRNA content were markedly decreased. |
| 73 | 1318975 | Insulin-receptor kinase activity in diabetic KK-CAy mouse diaphragm also changed biphasically as the glucose concentration increased: an increase at 8.3 mM, but no increase at 16.7 mM or 25.0 mM glucose for 3 h-pretreatment including 1 h-insulin treatment. |
| 74 | 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. |
| 75 | 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. |
| 76 | 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. |
| 77 | 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. |
| 78 | 1321126 | Leukocyte common antigen-related phosphatase rapidly deactivates the insulin receptor kinase by preferential dephosphorylation of the receptor regulatory domain. |
| 79 | 1321126 | We evaluated the deactivation of the insulin receptor kinase by three candidate enzymes that are expressed in insulin-sensitive rat tissues, including the receptor-like PTPases LAR and LRP, and the intracellular enzyme, PTPase1B. |
| 80 | 1321126 | When related to the level of overall receptor dephosphorylation, LAR deactivated the receptor kinase 3.1 and 2.1 times more rapidly than either PTPase1B or LRP, respectively (p less than 0.03). |
| 81 | 1321126 | Relative to the rate of initial loss of 32P from receptor C-terminal sites, LAR dephosphorylated the Tris-phosphorylated Tyr-1150 domain 3.5 and 3.7 times more rapidly than either PTPase1B or LRP, respectively (p less than 0.01). |
| 82 | 1321126 | The accelerated deactivation of the insulin receptor kinase by LAR and its relative preference for regulatory phosphotyrosine residues further support a potential role for this transmembrane PTPase in the physiological regulation of insulin receptors in intact cells. |
| 83 | 1321126 | Leukocyte common antigen-related phosphatase rapidly deactivates the insulin receptor kinase by preferential dephosphorylation of the receptor regulatory domain. |
| 84 | 1321126 | We evaluated the deactivation of the insulin receptor kinase by three candidate enzymes that are expressed in insulin-sensitive rat tissues, including the receptor-like PTPases LAR and LRP, and the intracellular enzyme, PTPase1B. |
| 85 | 1321126 | When related to the level of overall receptor dephosphorylation, LAR deactivated the receptor kinase 3.1 and 2.1 times more rapidly than either PTPase1B or LRP, respectively (p less than 0.03). |
| 86 | 1321126 | Relative to the rate of initial loss of 32P from receptor C-terminal sites, LAR dephosphorylated the Tris-phosphorylated Tyr-1150 domain 3.5 and 3.7 times more rapidly than either PTPase1B or LRP, respectively (p less than 0.01). |
| 87 | 1321126 | The accelerated deactivation of the insulin receptor kinase by LAR and its relative preference for regulatory phosphotyrosine residues further support a potential role for this transmembrane PTPase in the physiological regulation of insulin receptors in intact cells. |
| 88 | 1321126 | Leukocyte common antigen-related phosphatase rapidly deactivates the insulin receptor kinase by preferential dephosphorylation of the receptor regulatory domain. |
| 89 | 1321126 | We evaluated the deactivation of the insulin receptor kinase by three candidate enzymes that are expressed in insulin-sensitive rat tissues, including the receptor-like PTPases LAR and LRP, and the intracellular enzyme, PTPase1B. |
| 90 | 1321126 | When related to the level of overall receptor dephosphorylation, LAR deactivated the receptor kinase 3.1 and 2.1 times more rapidly than either PTPase1B or LRP, respectively (p less than 0.03). |
| 91 | 1321126 | Relative to the rate of initial loss of 32P from receptor C-terminal sites, LAR dephosphorylated the Tris-phosphorylated Tyr-1150 domain 3.5 and 3.7 times more rapidly than either PTPase1B or LRP, respectively (p less than 0.01). |
| 92 | 1321126 | The accelerated deactivation of the insulin receptor kinase by LAR and its relative preference for regulatory phosphotyrosine residues further support a potential role for this transmembrane PTPase in the physiological regulation of insulin receptors in intact cells. |
| 93 | 1321840 | Hepatic PTPase activity was measured using two artificial substrates phosphorylated on tyrosine: reduced, carboxyamidomethylated, and maleylated lysozyme (P-Tyr-RCML) and myelin basic protein (P-Tyr-MBP), as well as an autophosphorylated 48-kD insulin receptor tyrosine kinase domain (P-Tyr-IRKD). |
| 94 | 1327926 | Mutated insulin receptor Val996 reduces insulin-dependent generation of inositol glycan and diacylglycerol. |
| 95 | 1327926 | We evaluated whether insulin-receptor tyrosine kinase activity is required for activation of PDH, insulin-induced hydrolysis of PIG and generation of IG and 1,2-DAG. |
| 96 | 1327926 | It is concluded that insulin-dependent PDH activation, PIG hydrolysis, and IG and DAG generation are mediated by the wild-type but not by the mutated insulin receptor of Val996. |
| 97 | 1327926 | This study suggests that tyrosine kinase activity of the insulin receptor might be a prerequisite for insulin-stimulated generation of IG and DAG. |
| 98 | 1327926 | Mutated insulin receptor Val996 reduces insulin-dependent generation of inositol glycan and diacylglycerol. |
| 99 | 1327926 | We evaluated whether insulin-receptor tyrosine kinase activity is required for activation of PDH, insulin-induced hydrolysis of PIG and generation of IG and 1,2-DAG. |
| 100 | 1327926 | It is concluded that insulin-dependent PDH activation, PIG hydrolysis, and IG and DAG generation are mediated by the wild-type but not by the mutated insulin receptor of Val996. |
| 101 | 1327926 | This study suggests that tyrosine kinase activity of the insulin receptor might be a prerequisite for insulin-stimulated generation of IG and DAG. |
| 102 | 1327926 | Mutated insulin receptor Val996 reduces insulin-dependent generation of inositol glycan and diacylglycerol. |
| 103 | 1327926 | We evaluated whether insulin-receptor tyrosine kinase activity is required for activation of PDH, insulin-induced hydrolysis of PIG and generation of IG and 1,2-DAG. |
| 104 | 1327926 | It is concluded that insulin-dependent PDH activation, PIG hydrolysis, and IG and DAG generation are mediated by the wild-type but not by the mutated insulin receptor of Val996. |
| 105 | 1327926 | This study suggests that tyrosine kinase activity of the insulin receptor might be a prerequisite for insulin-stimulated generation of IG and DAG. |
| 106 | 1327926 | Mutated insulin receptor Val996 reduces insulin-dependent generation of inositol glycan and diacylglycerol. |
| 107 | 1327926 | We evaluated whether insulin-receptor tyrosine kinase activity is required for activation of PDH, insulin-induced hydrolysis of PIG and generation of IG and 1,2-DAG. |
| 108 | 1327926 | It is concluded that insulin-dependent PDH activation, PIG hydrolysis, and IG and DAG generation are mediated by the wild-type but not by the mutated insulin receptor of Val996. |
| 109 | 1327926 | This study suggests that tyrosine kinase activity of the insulin receptor might be a prerequisite for insulin-stimulated generation of IG and DAG. |
| 110 | 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. |
| 111 | 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. |
| 112 | 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. |
| 113 | 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. |
| 114 | 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. |
| 115 | 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. |
| 116 | 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. |
| 117 | 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. |
| 118 | 1332046 | IRS-1 activates phosphatidylinositol 3'-kinase by associating with src homology 2 domains of p85. |
| 119 | 1332046 | IRS-1 is an insulin receptor substrate that undergoes tyrosine phosphorylation and associates with the phosphatidylinositol (PtdIns) 3'-kinase immediately after insulin stimulation. |
| 120 | 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. |
| 121 | 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. |
| 122 | 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. |
| 123 | 1332046 | Thus, IRS-1 likely serves to transmit the insulin signal by binding and regulating intracellular enzymes containing SH2 domains. |
| 124 | 1332046 | IRS-1 activates phosphatidylinositol 3'-kinase by associating with src homology 2 domains of p85. |
| 125 | 1332046 | IRS-1 is an insulin receptor substrate that undergoes tyrosine phosphorylation and associates with the phosphatidylinositol (PtdIns) 3'-kinase immediately after insulin stimulation. |
| 126 | 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. |
| 127 | 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. |
| 128 | 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. |
| 129 | 1332046 | Thus, IRS-1 likely serves to transmit the insulin signal by binding and regulating intracellular enzymes containing SH2 domains. |
| 130 | 1352286 | Substitution of the insulin receptor transmembrane domain with the c-neu/erbB2 transmembrane domain constitutively activates the insulin receptor kinase in vitro. |
| 131 | 1352286 | To examine the role of the transmembrane domain (TM) of the insulin receptor in insulin-induced receptor kinase activation, we prepared four mutated insulin receptors: 1) a Val938----Asp substitution (IR/TMv----D), 2) insertion of a 3-amino acid repeat (Val938-Phe939-Leu940) (IR/TM+3), or the entire TM was replaced by the corresponding domain of either the 3) platelet-derived growth factor (PDGF) receptor (IR/TMPDGFR) or 4) c-neu/erbB2 proto-oncogene product (IR/TMc-neu). |
| 132 | 1352286 | Substitution of the insulin receptor transmembrane domain with the c-neu/erbB2 transmembrane domain constitutively activates the insulin receptor kinase in vitro. |
| 133 | 1352286 | To examine the role of the transmembrane domain (TM) of the insulin receptor in insulin-induced receptor kinase activation, we prepared four mutated insulin receptors: 1) a Val938----Asp substitution (IR/TMv----D), 2) insertion of a 3-amino acid repeat (Val938-Phe939-Leu940) (IR/TM+3), or the entire TM was replaced by the corresponding domain of either the 3) platelet-derived growth factor (PDGF) receptor (IR/TMPDGFR) or 4) c-neu/erbB2 proto-oncogene product (IR/TMc-neu). |
| 134 | 1372573 | In contrast, chronic insulin exposure led to a 2.1-fold increase in GLUT1 mRNA but did not alter cellular levels of transporter protein. |
| 135 | 1372573 | Cotreatment with glucose prevented the insulin-induced rise in GLUT1 mRNA. |
| 136 | 1372573 | In conclusion, in BC3H1 myocytes 1) glucose diminished insulin sensitivity by decreasing insulin receptor binding affinity and decreased basal and maximally insulin-stimulated glucose transport rates via cellular depletion of glucose transporters and suppression of GLUT1 mRNA; 2) chronic insulin exposure exerted an independent and additive effect to reduce maximal transport activity; however, insulin increased levels of GLUT1 mRNA and did not alter the cellular content of glucose transporters; and 3) although BC3H1 cells are commonly used as a model for skeletal muscle, studies examining glucose transport should be interpreted cautiously due to the absence of GLUT4 expression. |
| 137 | 1372896 | RNAs corresponding to known insulin-responsive genes such as c-fos, c-myc, c-Ha-ras, and c-src displayed rapid and transient 2-4-fold increases between 30 and 60 min as detected by either Northern analysis or the multiple S1 nuclease protection assay. |
| 138 | 1372896 | In addition, RNA levels for the insulin receptor, Glut-4, Glut-3, and c-jun were apparently unaffected by exposure of the cells to insulin. |
| 139 | 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. |
| 140 | 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. |
| 141 | 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. |
| 142 | 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. |
| 143 | 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. |
| 144 | 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. |
| 145 | 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. |
| 146 | 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. |
| 147 | 1385403 | Expression and function of IRS-1 in insulin signal transmission. |
| 148 | 1385403 | IRS-1 is a major insulin receptor substrate which may play an important role in insulin signal transmission. |
| 149 | 1385403 | IRS-1 was phosphorylated strongly on serine residues and weakly on threonine residues before insulin stimulation. |
| 150 | 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. |
| 151 | 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. |
| 152 | 1385403 | Purified insulin receptors directly phosphorylated baculovirus-produced IRS-1 exclusively on tyrosine residues. |
| 153 | 1385403 | By immunofluorescence, IRS-1 was absent from the nucleus, but otherwise distributed uniformly before and after insulin stimulation. |
| 154 | 1385403 | Some IRS-1 associated with the insulin receptor during insulin stimulation. |
| 155 | 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. |
| 156 | 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. |
| 157 | 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. |
| 158 | 1385403 | Expression and function of IRS-1 in insulin signal transmission. |
| 159 | 1385403 | IRS-1 is a major insulin receptor substrate which may play an important role in insulin signal transmission. |
| 160 | 1385403 | IRS-1 was phosphorylated strongly on serine residues and weakly on threonine residues before insulin stimulation. |
| 161 | 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. |
| 162 | 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. |
| 163 | 1385403 | Purified insulin receptors directly phosphorylated baculovirus-produced IRS-1 exclusively on tyrosine residues. |
| 164 | 1385403 | By immunofluorescence, IRS-1 was absent from the nucleus, but otherwise distributed uniformly before and after insulin stimulation. |
| 165 | 1385403 | Some IRS-1 associated with the insulin receptor during insulin stimulation. |
| 166 | 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. |
| 167 | 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. |
| 168 | 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. |
| 169 | 1385403 | Expression and function of IRS-1 in insulin signal transmission. |
| 170 | 1385403 | IRS-1 is a major insulin receptor substrate which may play an important role in insulin signal transmission. |
| 171 | 1385403 | IRS-1 was phosphorylated strongly on serine residues and weakly on threonine residues before insulin stimulation. |
| 172 | 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. |
| 173 | 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. |
| 174 | 1385403 | Purified insulin receptors directly phosphorylated baculovirus-produced IRS-1 exclusively on tyrosine residues. |
| 175 | 1385403 | By immunofluorescence, IRS-1 was absent from the nucleus, but otherwise distributed uniformly before and after insulin stimulation. |
| 176 | 1385403 | Some IRS-1 associated with the insulin receptor during insulin stimulation. |
| 177 | 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. |
| 178 | 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. |
| 179 | 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. |
| 180 | 1385403 | Expression and function of IRS-1 in insulin signal transmission. |
| 181 | 1385403 | IRS-1 is a major insulin receptor substrate which may play an important role in insulin signal transmission. |
| 182 | 1385403 | IRS-1 was phosphorylated strongly on serine residues and weakly on threonine residues before insulin stimulation. |
| 183 | 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. |
| 184 | 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. |
| 185 | 1385403 | Purified insulin receptors directly phosphorylated baculovirus-produced IRS-1 exclusively on tyrosine residues. |
| 186 | 1385403 | By immunofluorescence, IRS-1 was absent from the nucleus, but otherwise distributed uniformly before and after insulin stimulation. |
| 187 | 1385403 | Some IRS-1 associated with the insulin receptor during insulin stimulation. |
| 188 | 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. |
| 189 | 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. |
| 190 | 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. |
| 191 | 1385403 | Expression and function of IRS-1 in insulin signal transmission. |
| 192 | 1385403 | IRS-1 is a major insulin receptor substrate which may play an important role in insulin signal transmission. |
| 193 | 1385403 | IRS-1 was phosphorylated strongly on serine residues and weakly on threonine residues before insulin stimulation. |
| 194 | 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. |
| 195 | 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. |
| 196 | 1385403 | Purified insulin receptors directly phosphorylated baculovirus-produced IRS-1 exclusively on tyrosine residues. |
| 197 | 1385403 | By immunofluorescence, IRS-1 was absent from the nucleus, but otherwise distributed uniformly before and after insulin stimulation. |
| 198 | 1385403 | Some IRS-1 associated with the insulin receptor during insulin stimulation. |
| 199 | 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. |
| 200 | 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. |
| 201 | 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. |
| 202 | 1387756 | It is possible, therefore, that insulin exerts an indirect beneficial influence through the metabolic amelioration on the decreases in bone turnover and circulating osteocalcin in diabetes mellitus, or has a direct stimulatory effect on the osteoblasts via the insulin receptor since its presence has been shown recently in osteoblastic cells. |
| 203 | 1390778 | Postbinding characterization of five naturally occurring mutations in the human insulin receptor gene: impaired insulin-stimulated c-jun expression and thymidine incorporation despite normal receptor autophosphorylation. |
| 204 | 1390778 | We previously identified five such mutations located in the extracellular domain of the insulin receptor (Asn-->Lys15, His-->Arg209, Phe-->Val382, Lys-->Glu460, and Asn-->Ser462) and studied the effects of these mutations upon posttranslational processing, insulin binding, and tyrosine autophosphorylation. |
| 205 | 1390778 | All cell lines expressing mutant receptors showed marked impairment in insulin-stimulated c-jun expression and thymidine incorporation when compared with cells expressing wild-type human insulin receptors. |
| 206 | 1390778 | These cells show a higher basal rate and much lower insulin stimulation of both c-jun expression and thymidine incorporation when compared with the cells expressing the wild-type human insulin receptors. |
| 207 | 1390778 | Postbinding characterization of five naturally occurring mutations in the human insulin receptor gene: impaired insulin-stimulated c-jun expression and thymidine incorporation despite normal receptor autophosphorylation. |
| 208 | 1390778 | We previously identified five such mutations located in the extracellular domain of the insulin receptor (Asn-->Lys15, His-->Arg209, Phe-->Val382, Lys-->Glu460, and Asn-->Ser462) and studied the effects of these mutations upon posttranslational processing, insulin binding, and tyrosine autophosphorylation. |
| 209 | 1390778 | All cell lines expressing mutant receptors showed marked impairment in insulin-stimulated c-jun expression and thymidine incorporation when compared with cells expressing wild-type human insulin receptors. |
| 210 | 1390778 | These cells show a higher basal rate and much lower insulin stimulation of both c-jun expression and thymidine incorporation when compared with the cells expressing the wild-type human insulin receptors. |
| 211 | 1397703 | Cell-free translation of size-fractionated polyadenylated RNA was used to further demonstrate that each of the major insulin-receptor mRNA size classes in rat liver contained both forms of the alternatively spliced mRNA transcripts and produced two insulin-proreceptor polypeptides. |
| 212 | 1457763 | Tyrosine phosphorylation of insulin receptor and of IRS-1 have been implicated in insulin signal transmission based on studies with insulin receptor mutants. |
| 213 | 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. |
| 214 | 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. |
| 215 | 1457763 | Tyrosine phosphorylation of insulin receptor and of IRS-1 have been implicated in insulin signal transmission based on studies with insulin receptor mutants. |
| 216 | 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. |
| 217 | 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. |
| 218 | 1457763 | Tyrosine phosphorylation of insulin receptor and of IRS-1 have been implicated in insulin signal transmission based on studies with insulin receptor mutants. |
| 219 | 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. |
| 220 | 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. |
| 221 | 1457765 | These techniques are illustrated with studies of the angiotensinogen gene and the insulin receptor gene. |
| 222 | 1499871 | The syndromes of insulin resistance are a group of clinically diverse disorders, and our understanding of their molecular pathogenesis has advanced in parallel with our understanding of the structure of the insulin receptor and the mechanism of insulin action. |
| 223 | 1499871 | The possibility that the insulin receptor and GLUT4 may be candidate genes for inherited insulin resistance in NIDDM has been addressed with the aid of genetic screening techniques such as SSCP. |
| 224 | 1499871 | The syndromes of insulin resistance are a group of clinically diverse disorders, and our understanding of their molecular pathogenesis has advanced in parallel with our understanding of the structure of the insulin receptor and the mechanism of insulin action. |
| 225 | 1499871 | The possibility that the insulin receptor and GLUT4 may be candidate genes for inherited insulin resistance in NIDDM has been addressed with the aid of genetic screening techniques such as SSCP. |
| 226 | 1500426 | These data suggest that the insulin receptor contains two tyrosine/beta-turns which contribute independently and additively to insulin-stimulated endocytosis. |
| 227 | 1521731 | Insulin receptor and insulin-responsive glucose transporter (GLUT 4) mutations and polymorphisms in a Welsh type 2 (non-insulin-dependent) diabetic population. |
| 228 | 1521731 | We have recently examined the exons encoding the insulin receptor tyrosine kinase domain and GLUT 4 in 30 subjects with Type 2 (non-insulin-dependent) diabetes mellitus using a molecular scanning approach. |
| 229 | 1521731 | The variant sequences Val-Met985 and Lys-Glu1068 of the insulin receptor and Val-Ile383 of GLUT 4 were each separately found in three different diabetic subjects. |
| 230 | 1521731 | Insulin receptor and insulin-responsive glucose transporter (GLUT 4) mutations and polymorphisms in a Welsh type 2 (non-insulin-dependent) diabetic population. |
| 231 | 1521731 | We have recently examined the exons encoding the insulin receptor tyrosine kinase domain and GLUT 4 in 30 subjects with Type 2 (non-insulin-dependent) diabetes mellitus using a molecular scanning approach. |
| 232 | 1521731 | The variant sequences Val-Met985 and Lys-Glu1068 of the insulin receptor and Val-Ile383 of GLUT 4 were each separately found in three different diabetic subjects. |
| 233 | 1521731 | Insulin receptor and insulin-responsive glucose transporter (GLUT 4) mutations and polymorphisms in a Welsh type 2 (non-insulin-dependent) diabetic population. |
| 234 | 1521731 | We have recently examined the exons encoding the insulin receptor tyrosine kinase domain and GLUT 4 in 30 subjects with Type 2 (non-insulin-dependent) diabetes mellitus using a molecular scanning approach. |
| 235 | 1521731 | The variant sequences Val-Met985 and Lys-Glu1068 of the insulin receptor and Val-Ile383 of GLUT 4 were each separately found in three different diabetic subjects. |
| 236 | 1532777 | In muscle many cellular defects in insulin action have been described including impaired insulin-receptor tyrosine kinase activity, diminished glucose transport, and reduced glycogen synthase and pyruvate dehydrogenase. |
| 237 | 1542272 | The ability to inhibit insulin binding was determined in an assay using fibroblasts that overexpress the human insulin receptor; the ability to immunoprecipitate the receptor was determined in an assay using biosynthetically labeled insulin receptors rather than insulin cross-linked receptors; and the ability to stimulate glucose oxidation was determined in isolated adipocytes. |
| 238 | 1563582 | These data demonstrate that analysis of single-stranded conformational polymorphisms is a simple and sensitive screening method for mutations and polymorphisms in the insulin receptor gene in subjects with or without insulin resistance. |
| 239 | 1563582 | Identification of a mutation in the insulin receptor gene in a patient with a moderate degree of insulin resistance associated with morbid obesity suggests that insulin receptor mutations may exist in patients with Type 2 (non-insulin-dependent) diabetes mellitus associated with a moderate degree of insulin resistance. |
| 240 | 1563582 | These data demonstrate that analysis of single-stranded conformational polymorphisms is a simple and sensitive screening method for mutations and polymorphisms in the insulin receptor gene in subjects with or without insulin resistance. |
| 241 | 1563582 | Identification of a mutation in the insulin receptor gene in a patient with a moderate degree of insulin resistance associated with morbid obesity suggests that insulin receptor mutations may exist in patients with Type 2 (non-insulin-dependent) diabetes mellitus associated with a moderate degree of insulin resistance. |
| 242 | 1576033 | The common denominator of hyperglycemic emergencies is diabetes mellitus, a group of diseases in which, either because of beta-cell destruction of the pancreas or insulin receptor-site defects, there is a relative or absolute deficiency of insulin that results in hyperglycemia. |
| 243 | 1599438 | Insulin receptor and epidermal growth factor receptor dephosphorylation by three major rat liver protein-tyrosine phosphatases expressed in a recombinant bacterial system. |
| 244 | 1599438 | In order to characterize individual rat hepatic PTPases that might have specificity for autophosphorylated receptor tyrosine kinases, we isolated cDNA segments encoding three PTPases (PTPase 1B, LAR and LRP) that are expressed in insulin-sensitive liver and skeletal muscle tissue, and evaluated their catalytic activity in vitro. |
| 245 | 1599438 | The intrinsic PTPase activities of the full-length PTPase 1B protein and the cytoplasmic domains of LAR and LRP were studied by expression of recombinant cDNA constructs in the inducible bacterial vector pKK233-2 using extracts of a host strain of Escherichia coli that lacks endogenous PTPase activity. |
| 246 | 1599438 | Despite having only 30-39% sequence identity in their catalytic domains, LAR and PTPase 1B had similar relative activities between the peptide substrate and intact insulin receptors, and also displayed similar initial rates of simultaneous dephosphorylation of insulin and epidermal growth factor (EGF) receptors. |
| 247 | 1599438 | In contrast, LRP exhibited a higher rate of dephosphorylation of both intact receptors relative to the peptide substrate, and also dephosphorylated EGF receptors more rapidly than insulin receptors. |
| 248 | 1599438 | These studies indicate that three PTPases with markedly divergent structures have the catalytic potential to dephosphorylate both insulin and EGF receptors in intact cells and that redundant PTPase activity may occur in vivo. |
| 249 | 1607072 | We have shown that encapsulated insulin is able 1) to bind to insulin receptors both in rat liver plasma membranes and after solubilization from Chinese hamster ovary (CHO) cells transfected with the gene of human insulin receptor, 2) to accelerate 125I-labeled insulin dissociation from its receptor, and 3) to ensure transduction of a signal leading to stimulation of the beta-subunit phosphorylation, with parameters similar to those of native insulin. |
| 250 | 1612205 | Stimulation by proinsulin of expression of plasminogen activator inhibitor type-I in endothelial cells. |
| 251 | 1612205 | Because increased concentrations of plasminogen activator inhibitor type-1 (PAI-1) occur also, we hypothesized that proinsulin and split proinsulin may augment endothelial cell PAI-1 expression, thereby potentially attenuating endogenous fibrinolysis and accelerating atherosclerosis. |
| 252 | 1612205 | Proinsulin increased PAI-1 activity in conditioned media of endothelial cells as did split proinsulin, paralleled by increased expression of PAI-1 mRNA. |
| 253 | 1612205 | These effects of proinsulin were not dependent on its conversion to insulin nor on its interactions with the insulin receptor. |
| 254 | 1612205 | The proinsulin stimulation of PAI-1 expression was not attenuated by either anti-insulin receptor antibodies or a 100-fold excess of insulin. |
| 255 | 1612205 | Furthermore, proinsulin-mediated increases in PAI-1 expression were not inhibited by a 500-fold excess of insulinlike growth factor I. |
| 256 | 1612205 | These results indicate that proinsulin augments PAI-1 expression, potentially contributing to vasculopathy in patients with non-insulin-dependent diabetes mellitus. |
| 257 | 1612205 | Stimulation by proinsulin of expression of plasminogen activator inhibitor type-I in endothelial cells. |
| 258 | 1612205 | Because increased concentrations of plasminogen activator inhibitor type-1 (PAI-1) occur also, we hypothesized that proinsulin and split proinsulin may augment endothelial cell PAI-1 expression, thereby potentially attenuating endogenous fibrinolysis and accelerating atherosclerosis. |
| 259 | 1612205 | Proinsulin increased PAI-1 activity in conditioned media of endothelial cells as did split proinsulin, paralleled by increased expression of PAI-1 mRNA. |
| 260 | 1612205 | These effects of proinsulin were not dependent on its conversion to insulin nor on its interactions with the insulin receptor. |
| 261 | 1612205 | The proinsulin stimulation of PAI-1 expression was not attenuated by either anti-insulin receptor antibodies or a 100-fold excess of insulin. |
| 262 | 1612205 | Furthermore, proinsulin-mediated increases in PAI-1 expression were not inhibited by a 500-fold excess of insulinlike growth factor I. |
| 263 | 1612205 | These results indicate that proinsulin augments PAI-1 expression, potentially contributing to vasculopathy in patients with non-insulin-dependent diabetes mellitus. |
| 264 | 1625676 | The intrinsic tyrosyl kinase activity of the insulin receptor is regulated by a balance between insulin-induced receptor autophosphorylation, which stimulates the receptor kinase, and enzymatic dephosphorylation of the receptor, which deactivates its kinase activity. |
| 265 | 1645354 | During insulin stimulation, the wild-type and mutant insulin receptor activated the phosphatidylinositol 3-kinase. |
| 266 | 1647198 | Cytoplasmic juxtamembrane region of the insulin receptor: a critical role in ATP binding, endogenous substrate phosphorylation, and insulin-stimulated bioeffects in CHO cells. |
| 267 | 1647997 | Therefore, we examined the influence of insulin on protein tyrosine phosphatase (PTPase) activities, which may counteract the protein tyrosine kinase activity of the insulin receptor in skeletal muscle of insulin-sensitive and insulin-resistant humans. |
| 268 | 1648180 | Structure of the insulin receptor substrate IRS-1 defines a unique signal transduction protein. |
| 269 | 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. |
| 270 | 1648180 | Thus IRS-1 may link the insulin receptor kinase and enzymes regulating cellular growth and metabolism. |
| 271 | 1648180 | Structure of the insulin receptor substrate IRS-1 defines a unique signal transduction protein. |
| 272 | 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. |
| 273 | 1648180 | Thus IRS-1 may link the insulin receptor kinase and enzymes regulating cellular growth and metabolism. |
| 274 | 1648732 | Genes encoding receptors for insulin and insulin-like growth factor I are expressed in Xenopus oocytes and embryos. |
| 275 | 1648732 | Insulin and insulin-like growth factor I (IGF-I) initiate their metabolic, growth, and differentiation effects through binding to the insulin receptor and the IGF-I receptor, two members of the tyrosine kinase family of receptors. |
| 276 | 1648732 | To study the role of these peptides and receptors in early development, we used the polymerase chain reaction and embryo-derived RNA to generate partial cDNA sequences of the insulin receptor and IGF-I receptor from the amphibian Xenopus laevis. |
| 277 | 1648732 | On the basis of these similarities, the pattern of conserved amino acids, and the tetraploid nature of the Xenopus genome, we suggest that XTK 1a and XTK 1b most likely represent the product of two different nonallelic insulin receptor genes, while XTK 2 may be one of the probable two Xenopus IGF-I receptor genes. |
| 278 | 1648732 | Competition binding assays with Xenopus membrane preparations demonstrated insulin receptors and IGF-I receptors in older tadpoles. |
| 279 | 1648732 | The expression of receptors for insulin and IGF-I in early Xenopus embryos and their apparent distinct developmental regulation suggest that these molecules and their ligands may be important in early Xenopus development. |
| 280 | 1648732 | Genes encoding receptors for insulin and insulin-like growth factor I are expressed in Xenopus oocytes and embryos. |
| 281 | 1648732 | Insulin and insulin-like growth factor I (IGF-I) initiate their metabolic, growth, and differentiation effects through binding to the insulin receptor and the IGF-I receptor, two members of the tyrosine kinase family of receptors. |
| 282 | 1648732 | To study the role of these peptides and receptors in early development, we used the polymerase chain reaction and embryo-derived RNA to generate partial cDNA sequences of the insulin receptor and IGF-I receptor from the amphibian Xenopus laevis. |
| 283 | 1648732 | On the basis of these similarities, the pattern of conserved amino acids, and the tetraploid nature of the Xenopus genome, we suggest that XTK 1a and XTK 1b most likely represent the product of two different nonallelic insulin receptor genes, while XTK 2 may be one of the probable two Xenopus IGF-I receptor genes. |
| 284 | 1648732 | Competition binding assays with Xenopus membrane preparations demonstrated insulin receptors and IGF-I receptors in older tadpoles. |
| 285 | 1648732 | The expression of receptors for insulin and IGF-I in early Xenopus embryos and their apparent distinct developmental regulation suggest that these molecules and their ligands may be important in early Xenopus development. |
| 286 | 1648732 | Genes encoding receptors for insulin and insulin-like growth factor I are expressed in Xenopus oocytes and embryos. |
| 287 | 1648732 | Insulin and insulin-like growth factor I (IGF-I) initiate their metabolic, growth, and differentiation effects through binding to the insulin receptor and the IGF-I receptor, two members of the tyrosine kinase family of receptors. |
| 288 | 1648732 | To study the role of these peptides and receptors in early development, we used the polymerase chain reaction and embryo-derived RNA to generate partial cDNA sequences of the insulin receptor and IGF-I receptor from the amphibian Xenopus laevis. |
| 289 | 1648732 | On the basis of these similarities, the pattern of conserved amino acids, and the tetraploid nature of the Xenopus genome, we suggest that XTK 1a and XTK 1b most likely represent the product of two different nonallelic insulin receptor genes, while XTK 2 may be one of the probable two Xenopus IGF-I receptor genes. |
| 290 | 1648732 | Competition binding assays with Xenopus membrane preparations demonstrated insulin receptors and IGF-I receptors in older tadpoles. |
| 291 | 1648732 | The expression of receptors for insulin and IGF-I in early Xenopus embryos and their apparent distinct developmental regulation suggest that these molecules and their ligands may be important in early Xenopus development. |
| 292 | 1651107 | However, insulin-stimulated autophosphorylation of insulin receptor alpha beta heterodimers is concentration-dependent, and both autophosphorylation and kinase activity are markedly reduced following immobilization. |
| 293 | 1657668 | Prevention by protein kinase C inhibitors of glucose-induced insulin-receptor tyrosine kinase resistance in rat fat cells. |
| 294 | 1657953 | Receptors for insulin and epidermal growth factor contain cysteine-rich domains in the extracellular portion of the molecule. |
| 295 | 1657953 | His209 (insulin receptor numbering system) is 1 of 2 amino acid residues that are identically conserved in the cysteine-rich domains of insulin receptors, epidermal growth factor receptors, and other homologous receptors. |
| 296 | 1660827 | Analyses of fetal liver from the last one-third of gestation demonstrated the presence of specific mRNAs for the transforming growth factors (TGFs) TGF-alpha and TGF-beta. |
| 297 | 1660827 | TGF-alpha, a homologue of epidermal growth factor (EGF), acts through EGF receptors. |
| 298 | 1660827 | Levels of mRNA for TGF-alpha increased dramatically postnatally, whereas EGF receptor number increased just before term. |
| 299 | 1660827 | Other analyses demonstrated increases in tyrosine kinase activities of the insulin receptor, EGF receptor, and insulinlike growth factor I receptor as term approached. |
| 300 | 1660827 | TGF-beta was a potent inhibitor of fetal hepatocyte proliferation in culture, whereas insulin potentiated fetal hepatocyte growth above "mitogen-independent" levels. |
| 301 | 1661692 | Differential effects of diabetes on adipocyte and liver phosphotyrosine and phosphoserine phosphatase activities. |
| 302 | 1661692 | PTPase activity was assessed with [32P]tyrosine-phosphorylated insulin receptor (IR), whereas PSPase activity was assayed with [32P]serine-phosphorylated glycogen synthase. |
| 303 | 1661692 | Insulin therapy for 14 or 30 days restored PTPase and PSPase activities in both fractions. |
| 304 | 1661694 | Insulin receptor tyrosine kinase activity solubilized from hind limb muscle of control and streptozocin-induced diabetic (STZ-D) rats (2-3 wk) was studied with the substrates histone H2B and poly glutamic acid-tyrosine (glu-tyr) (4:1). |
| 305 | 1661694 | Under these conditions, insulin-stimulated activities of diabetic- and control-derived receptor kinase toward H2B were similar at 0.008 mg/ml H2B. |
| 306 | 1661694 | When inhibition of receptor kinase activities was prevented by allowing maximal autophosphorylation of insulin receptors before addition of H2B, kinase activity of diabetic- and control-derived receptors was similar at all H2B concentrations. |
| 307 | 1661694 | Under conditions of substrate inhibition (0.4 mg/ml H2B), insulin receptor H2B kinase activity from muscles of rats with severe diabetes (85 mg/kg STZ, 7 days) was significantly decreased, whereas the same activity from rats with moderate diabetes (50 mg/kg STZ, 7 days) was not significantly different from control rats. |
| 308 | 1661694 | Insulin receptor tyrosine kinase activity solubilized from hind limb muscle of control and streptozocin-induced diabetic (STZ-D) rats (2-3 wk) was studied with the substrates histone H2B and poly glutamic acid-tyrosine (glu-tyr) (4:1). |
| 309 | 1661694 | Under these conditions, insulin-stimulated activities of diabetic- and control-derived receptor kinase toward H2B were similar at 0.008 mg/ml H2B. |
| 310 | 1661694 | When inhibition of receptor kinase activities was prevented by allowing maximal autophosphorylation of insulin receptors before addition of H2B, kinase activity of diabetic- and control-derived receptors was similar at all H2B concentrations. |
| 311 | 1661694 | Under conditions of substrate inhibition (0.4 mg/ml H2B), insulin receptor H2B kinase activity from muscles of rats with severe diabetes (85 mg/kg STZ, 7 days) was significantly decreased, whereas the same activity from rats with moderate diabetes (50 mg/kg STZ, 7 days) was not significantly different from control rats. |
| 312 | 1691994 | Because anti-insulin-receptor antibodies immunoprecipitated a tyrosine-phosphorylated 95,000-Mr protein, this protein must be the beta-subunit of the insulin receptor; i.e., the beta-subunit of the insulin receptor and two other proteins were phosphorylated at tyrosine residues in vivo by insulin injection. |
| 313 | 1710113 | Genes for the insulin receptor and the insulin-like growth factor I receptor are expressed in the chicken embryo blastoderm and throughout organogenesis. |
| 314 | 1710113 | The early expression of insulin and insulin-like growth factor I (IGF-I) in the chicken embryo suggests that these peptides play an important role in early development. |
| 315 | 1710113 | The receptors for insulin and IGF-I, however, had not been studied at the molecular level in this model. |
| 316 | 1710113 | We report two chicken sequences that, by comparison with known tyrosine kinases, appear to correspond to the tyrosine kinase domain of the insulin receptor homologue (CTK-1) and the IGF-I receptor homologue (CTK-2). |
| 317 | 1710113 | Genes for the insulin receptor and the insulin-like growth factor I receptor are expressed in the chicken embryo blastoderm and throughout organogenesis. |
| 318 | 1710113 | The early expression of insulin and insulin-like growth factor I (IGF-I) in the chicken embryo suggests that these peptides play an important role in early development. |
| 319 | 1710113 | The receptors for insulin and IGF-I, however, had not been studied at the molecular level in this model. |
| 320 | 1710113 | We report two chicken sequences that, by comparison with known tyrosine kinases, appear to correspond to the tyrosine kinase domain of the insulin receptor homologue (CTK-1) and the IGF-I receptor homologue (CTK-2). |
| 321 | 1711209 | The human insulin receptor exists in two isoforms, HIR-A and HIR-B, which are generated by alternative splicing of a primary gene transcript and differ by a 12-amino acid insertion sequence in the alpha-subunit. |
| 322 | 1719386 | Insulin rapidly inhibits insulin-like growth factor-binding protein-1 gene expression in H4-II-E rat hepatoma cells. |
| 323 | 1719386 | The insulin-like growth factor-binding proteins (IGFBPs) are thought to determine the distribution of IGF-I and IGF-II between the blood and tissue compartments and to modulate their biological activities. |
| 324 | 1719386 | A dynamic metabolic role for one of the IGFBPs, IGFBP-1, is suggested by the fact that plasma IGFBP-1 was increased after fasting and diabetes and rapidly decreased by refeeding or insulin treatment, respectively. |
| 325 | 1719386 | IGFBP-1 mRNA also is increased in the livers of diabetic rats and decreased by insulin treatment. |
| 326 | 1719386 | To understand the molecular basis for this regulation, we have examined the effects of insulin on IGFBP-1 and IGFBP-1 mRNA in the H4-II-E cell line derived from the well differentiated H35 rat hepatoma. |
| 327 | 1719386 | Incubation of H4-II-E cells with insulin for 24 h decreased IGFBP-1 in the culture medium by approximately 50%. |
| 328 | 1719386 | Inhibition was observed at physiological concentrations of insulin (ED50, less than 0.5 nM), but not at higher concentrations of IGF-II. |
| 329 | 1719386 | These results, together with the fact that H4-II-E cells do not possess IGF-I receptors with which insulin might cross-react, suggest that insulin acts via the insulin receptor. |
| 330 | 1719386 | Insulin inhibited IGFBP-1 in the medium by 80% in the absence of glucose, suggesting that the inhibition is a direct effect of insulin; glucose exerted a smaller independent effect in the absence of insulin. |
| 331 | 1719386 | Insulin decreased IGFBP-1 mRNA in H4-II-E cells by 50% within 1 h and by 90% after 2-12 h of incubation. |
| 332 | 1719386 | Pretreatment of H4-II-E cells with dexamethasone stimulated IGFBP-1 transcription and increased steady state IGFBP-1 mRNA; stimulation was abolished by insulin treatment, indicating that inhibition by insulin was dominant over induction by dexamethasone. |
| 333 | 1719386 | Thus, insulin, acting through the insulin receptor, rapidly decreases the abundance of IGFBP-1 mRNA in H4-II-E cells. |
| 334 | 1719386 | We propose that regulation of IGFBP-1 synthesis is an important component of the regulation of IGFBP-1 by insulin in vivo. |
| 335 | 1719386 | Insulin rapidly inhibits insulin-like growth factor-binding protein-1 gene expression in H4-II-E rat hepatoma cells. |
| 336 | 1719386 | The insulin-like growth factor-binding proteins (IGFBPs) are thought to determine the distribution of IGF-I and IGF-II between the blood and tissue compartments and to modulate their biological activities. |
| 337 | 1719386 | A dynamic metabolic role for one of the IGFBPs, IGFBP-1, is suggested by the fact that plasma IGFBP-1 was increased after fasting and diabetes and rapidly decreased by refeeding or insulin treatment, respectively. |
| 338 | 1719386 | IGFBP-1 mRNA also is increased in the livers of diabetic rats and decreased by insulin treatment. |
| 339 | 1719386 | To understand the molecular basis for this regulation, we have examined the effects of insulin on IGFBP-1 and IGFBP-1 mRNA in the H4-II-E cell line derived from the well differentiated H35 rat hepatoma. |
| 340 | 1719386 | Incubation of H4-II-E cells with insulin for 24 h decreased IGFBP-1 in the culture medium by approximately 50%. |
| 341 | 1719386 | Inhibition was observed at physiological concentrations of insulin (ED50, less than 0.5 nM), but not at higher concentrations of IGF-II. |
| 342 | 1719386 | These results, together with the fact that H4-II-E cells do not possess IGF-I receptors with which insulin might cross-react, suggest that insulin acts via the insulin receptor. |
| 343 | 1719386 | Insulin inhibited IGFBP-1 in the medium by 80% in the absence of glucose, suggesting that the inhibition is a direct effect of insulin; glucose exerted a smaller independent effect in the absence of insulin. |
| 344 | 1719386 | Insulin decreased IGFBP-1 mRNA in H4-II-E cells by 50% within 1 h and by 90% after 2-12 h of incubation. |
| 345 | 1719386 | Pretreatment of H4-II-E cells with dexamethasone stimulated IGFBP-1 transcription and increased steady state IGFBP-1 mRNA; stimulation was abolished by insulin treatment, indicating that inhibition by insulin was dominant over induction by dexamethasone. |
| 346 | 1719386 | Thus, insulin, acting through the insulin receptor, rapidly decreases the abundance of IGFBP-1 mRNA in H4-II-E cells. |
| 347 | 1719386 | We propose that regulation of IGFBP-1 synthesis is an important component of the regulation of IGFBP-1 by insulin in vivo. |
| 348 | 1727740 | Furthermore, liver binding data were not due to cross-reaction of 125I-labeled insulin to the insulinlike growth factor I receptor, and treatment of liver membranes with neuraminidase did not alter the inhibitory effect of the IgGa fraction from patient I-2 on 125I-labeled insulin binding to liver. |
| 349 | 1727740 | Binding inhibition experiments performed with cells transfected with and overexpressing the -12 (human insulin receptor [HIR]-A) or the +12 (HIR-B) variant of HIR revealed that the IgGa fraction from patient I-2 inhibited 125I-labeled insulin binding to the HIR-A receptor but not to the HIR-B receptor. |
| 350 | 1764093 | The human insulin receptor gene is expressed in two variant isoforms which differ by the absence (HIR-A) or presence (HIR-B) of 12 amino acids in the COOH-terminus of the extracellular alpha-subunit as a consequence of alternative splicing of exon 11. |
| 351 | 1764093 | In this study, we have measured the levels of the two receptor variants in isolated adipocytes from 10 non-insulin-dependent diabetes mellitus (NIDDM) and 11 normal subjects using an immunological assay, based on the ability of a human anti-receptor autoantibody to discriminate between HIR-A and HIR-B. |
| 352 | 1806308 | These findings cannot completely deny the beneficial effect of the compound prescription of these drugs in the treatment of diabetes mellitus because of the following reasons: (1) The experiments were done in vitro but not in vivo and the erythrocytes from normal men but not from diabetics. (2) The drugs were not put together during exaction as in the traditional manner, but was studied separately. (3) The fact that there is no effect on insulin receptor binding cannot rule out their beneficial effect on other aspects of insulin or insulin secretion even on the amelioration of tissue insulin resistance. |
| 353 | 1816977 | To elucidate the mechanisms of decreased autophosphorylation of the insulin receptor in diabetic rats, we have investigated the effect of dephosphorylation of the insulin receptor by alkaline phosphatase on the insulin- and protein kinase-stimulating incorporation of 32P into the receptor of the liver from STZ-D rats. |
| 354 | 1816977 | Both basal and insulin-stimulated autophosphorylations of the insulin receptor from STZ-D rats were significantly impaired to those from normal rats. |
| 355 | 1816977 | Dephosphorylation of the insulin receptor by alkaline phosphatase resulted in an increase in insulin-stimulated autophosphorylation of the insulin receptor from STZ-D rats (43 +/- 13% to 66 +/- 14%, P less than 0.05), but not from normal rats (100% to 109 +/- 12%, NS). |
| 356 | 1816977 | Although maximal autophosphorylation of the dephosphorylated insulin receptor was still lower in STZ-D rats than in normal rats, the increase in insulin-stimulated autophosphorylation of the insulin receptor from STZ-D rats by dephosphorylation was higher than that from normal (159.2 +/- 27.2% vs 108.0 +/- 12.4%, p less than 0.01), supporting the idea that the residues of the insulin receptor of STZ-D rats was highly phosphorylated. |
| 357 | 1816977 | To elucidate the mechanisms of decreased autophosphorylation of the insulin receptor in diabetic rats, we have investigated the effect of dephosphorylation of the insulin receptor by alkaline phosphatase on the insulin- and protein kinase-stimulating incorporation of 32P into the receptor of the liver from STZ-D rats. |
| 358 | 1816977 | Both basal and insulin-stimulated autophosphorylations of the insulin receptor from STZ-D rats were significantly impaired to those from normal rats. |
| 359 | 1816977 | Dephosphorylation of the insulin receptor by alkaline phosphatase resulted in an increase in insulin-stimulated autophosphorylation of the insulin receptor from STZ-D rats (43 +/- 13% to 66 +/- 14%, P less than 0.05), but not from normal rats (100% to 109 +/- 12%, NS). |
| 360 | 1816977 | Although maximal autophosphorylation of the dephosphorylated insulin receptor was still lower in STZ-D rats than in normal rats, the increase in insulin-stimulated autophosphorylation of the insulin receptor from STZ-D rats by dephosphorylation was higher than that from normal (159.2 +/- 27.2% vs 108.0 +/- 12.4%, p less than 0.01), supporting the idea that the residues of the insulin receptor of STZ-D rats was highly phosphorylated. |
| 361 | 1816977 | To elucidate the mechanisms of decreased autophosphorylation of the insulin receptor in diabetic rats, we have investigated the effect of dephosphorylation of the insulin receptor by alkaline phosphatase on the insulin- and protein kinase-stimulating incorporation of 32P into the receptor of the liver from STZ-D rats. |
| 362 | 1816977 | Both basal and insulin-stimulated autophosphorylations of the insulin receptor from STZ-D rats were significantly impaired to those from normal rats. |
| 363 | 1816977 | Dephosphorylation of the insulin receptor by alkaline phosphatase resulted in an increase in insulin-stimulated autophosphorylation of the insulin receptor from STZ-D rats (43 +/- 13% to 66 +/- 14%, P less than 0.05), but not from normal rats (100% to 109 +/- 12%, NS). |
| 364 | 1816977 | Although maximal autophosphorylation of the dephosphorylated insulin receptor was still lower in STZ-D rats than in normal rats, the increase in insulin-stimulated autophosphorylation of the insulin receptor from STZ-D rats by dephosphorylation was higher than that from normal (159.2 +/- 27.2% vs 108.0 +/- 12.4%, p less than 0.01), supporting the idea that the residues of the insulin receptor of STZ-D rats was highly phosphorylated. |
| 365 | 1816977 | To elucidate the mechanisms of decreased autophosphorylation of the insulin receptor in diabetic rats, we have investigated the effect of dephosphorylation of the insulin receptor by alkaline phosphatase on the insulin- and protein kinase-stimulating incorporation of 32P into the receptor of the liver from STZ-D rats. |
| 366 | 1816977 | Both basal and insulin-stimulated autophosphorylations of the insulin receptor from STZ-D rats were significantly impaired to those from normal rats. |
| 367 | 1816977 | Dephosphorylation of the insulin receptor by alkaline phosphatase resulted in an increase in insulin-stimulated autophosphorylation of the insulin receptor from STZ-D rats (43 +/- 13% to 66 +/- 14%, P less than 0.05), but not from normal rats (100% to 109 +/- 12%, NS). |
| 368 | 1816977 | Although maximal autophosphorylation of the dephosphorylated insulin receptor was still lower in STZ-D rats than in normal rats, the increase in insulin-stimulated autophosphorylation of the insulin receptor from STZ-D rats by dephosphorylation was higher than that from normal (159.2 +/- 27.2% vs 108.0 +/- 12.4%, p less than 0.01), supporting the idea that the residues of the insulin receptor of STZ-D rats was highly phosphorylated. |
| 369 | 1846101 | Insulin receptor tyrosine kinase activity solubilized from liver of control and streptozotocin diabetic rats was studied using histone H2b and poly-Glu-Tyr (4:1) as phosphoacceptors. |
| 370 | 1846101 | When H2b was added before ATP, insulin stimulated exogenous kinase activity of diabetic-derived receptors was significantly higher (approximately 50%) than control values at low H2b concentrations, but significantly lower (approximately 50%) than control values at high H2b concentrations, suggesting a decrease in the apparent Km and maximal velocity of the diabetic receptor tyrosine kinase toward H2b. |
| 371 | 1846626 | Regulation of insulin-like growth factor I receptors in diabetic mesangial cells. |
| 372 | 1846626 | Insulin-like growth factor I (IGF-I) has been found to promote mesangial cell proliferation and regulate normal mesangial cell function in an autocrine and/or paracrine fashion. |
| 373 | 1846626 | Both IGF-I and insulin receptor mRNA levels were increased in db/db cells grown in the presence of high glucose (28 mM), whereas the receptor protein levels remained relatively constant or increased, respectively. |
| 374 | 1846626 | This increased expression of IGF-I and insulin receptors in diabetic mesangial cells may have an important role in the development of diabetic nephropathy. |
| 375 | 1846830 | This insulin-receptor-deficient fraction inhibited both basal and insulin-stimulated tyrosine kinase activity of highly purified insulin receptors. |
| 376 | 1849890 | At 1 mM CTP, GTP, ITP, TTP, and AMP were without effect in either the presence or absence of insulin; in contrast, ADP was inhibitory in the presence of insulin. |
| 377 | 1849890 | Therefore, these studies raise the possibility that, in vivo, ATP binding in the presence of insulin may induce a conformational change in the insulin receptor beta subunit which in turn signals some of the biological effects of insulin. |
| 378 | 1892473 | These include the insulin, insulin receptor, glucose transporter, amylin and glucokinase genes. |
| 379 | 1892704 | Among the candidate genes that have been reviewed herein, adipsin, calcitonin, cholecystokin, Gi alpha and Gs subunits of G proteins, insulin I and II, and lipoprotein lipase have all been mapped to specific chromosomes in mouse or rat or both. |
| 380 | 1892704 | In the case of neuropeptide Y, growth hormone, glucose transporter GLUT-4, the insulin receptor, and glyceraldehyde-3-phosphate dehydrogenase, chromosomal mapping has not yet been reported. |
| 381 | 1918382 | Analysis of the gene sequences of the insulin receptor and the insulin-sensitive glucose transporter (GLUT-4) in patients with common-type non-insulin-dependent diabetes mellitus. |
| 382 | 1918382 | Two potential candidate genes are the insulin receptor (IR) and the insulin-sensitive glucose transporter (GLUT-4). |
| 383 | 1918382 | To elucidate whether structural defects in the IR and/or GLUT-4 could be a primary cause of insulin resistance in NIDDM, we have sequenced the entire coding region of the GLUT-4 gene from DNA of six NIDDM patients. |
| 384 | 1918382 | From these studies, we conclude that the insulin resistance seen in the great majority of subjects with the common form of NIDDM is not due to genetic variation in the coding sequence of the IR beta subunit, nor to any single mutation in the GLUT-4 gene. |
| 385 | 1918382 | Analysis of the gene sequences of the insulin receptor and the insulin-sensitive glucose transporter (GLUT-4) in patients with common-type non-insulin-dependent diabetes mellitus. |
| 386 | 1918382 | Two potential candidate genes are the insulin receptor (IR) and the insulin-sensitive glucose transporter (GLUT-4). |
| 387 | 1918382 | To elucidate whether structural defects in the IR and/or GLUT-4 could be a primary cause of insulin resistance in NIDDM, we have sequenced the entire coding region of the GLUT-4 gene from DNA of six NIDDM patients. |
| 388 | 1918382 | From these studies, we conclude that the insulin resistance seen in the great majority of subjects with the common form of NIDDM is not due to genetic variation in the coding sequence of the IR beta subunit, nor to any single mutation in the GLUT-4 gene. |
| 389 | 1955101 | Recombinant human insulin-like growth factor I (rhIGF I) reduces hyperglycaemia in patients with extreme insulin resistance. |
| 390 | 1955101 | This study was undertaken to find out whether hyperglycaemia in these patients may be influenced by the administration of recombinant human insulin-like growth factor I which exerts insulin-like effects through the insulin receptor as well as the type 1 insulin-like growth factor I receptor. |
| 391 | 1955101 | Recombinant human insulin-like growth factor I was intravenously administered in two subsequent doses of 100 micrograms/kg body weight to three women with type A insulin resistance. |
| 392 | 1955101 | The results show that recombinant human insulin-like growth factor I, presumably by reacting with the type 1 insulin-like growth factor receptor, can normalize serum glucose levels in patients with severe insulin resistance at least for several hours. |
| 393 | 1955101 | We suggest that the potential or recombinant human insulin-like growth factor I to control hyperglycaemia in type A insulin resistant patients should be explored in more depth. |
| 394 | 1966886 | In contrast to the decrease in insulin binding, insulin-like growth factor-I binding was higher in cells of diabetic than control rats (20.6 +/- 5.6 vs 13.7 +/- 4.6% per mg protein). |
| 395 | 1966886 | Insulin-induced tyrosine kinase activity of partially purified insulin receptor measured using poly-glutyr as substrate was also lower in cells from diabetic rats (normal:1.4 +/- 0.6-fold; diabetic 0.5 +/- 0.3-fold above baseline; (p less than 0.05). |
| 396 | 1978826 | A cohort of 132 well-documented White Welsh non-insulin-dependent diabetic (NIDDM) subjects were genotyped for 5 restriction-fragment-length polymorphisms (RFLPs) at the insulin-receptor gene (IRG) locus and a polymorphic locus 5' to the insulin gene. |
| 397 | 2002058 | In summary, (1) we have identified a patient and her family with a genetic form of insulin resistance and diabetes due to a defect at the level of the insulin receptor; (2) the proband is a compound heterozygote displaying a missense mutation (position 981) in one allele and a nonsense mutation (position 988) in the other insulin receptor gene allele; (3) the missense mutation is in the kinase domain and encodes a receptor with impaired in vitro kinase activity; and (4) based on the in vitro and in vivo phenotype, the kinase domain mutation at position 981 is biologically significant leading to insulin resistance. |
| 398 | 2010042 | This protein, termed islet amyloid polypeptide, is related to two neuropeptides, calcitonin gene-related peptides 1 and 2, and represents a new beta-cell secretory product whose normal physiological function remains to be determined. |
| 399 | 2010042 | Characterization of the insulin-receptor gene in patients with extreme forms of insulin resistance has resulted in the identification of mutations that impair its function and lead to tissue resistance to the action of insulin. |
| 400 | 2028355 | This review discusses recent advances in understanding of the structure and function of the insulin receptor and insulin action, and how these relate to the clinical aspects of insulin resistance associated with non-insulin-dependent diabetes and other disorders. |
| 401 | 2028355 | Receptor-mediated insulin resistance may be a consequence of various factors including increased serine/threonine phosphorylation of the receptor with decreased tyrosine phosphorylation, receptor desensitization, auto-antibodies to the receptor and inherited structural defects in the insulin receptor. |
| 402 | 2028355 | Other circulating hormones, such as the newly characterised islet amyloid polypeptide (amylin), may also cause insulin resistance. |
| 403 | 2028355 | This review discusses recent advances in understanding of the structure and function of the insulin receptor and insulin action, and how these relate to the clinical aspects of insulin resistance associated with non-insulin-dependent diabetes and other disorders. |
| 404 | 2028355 | Receptor-mediated insulin resistance may be a consequence of various factors including increased serine/threonine phosphorylation of the receptor with decreased tyrosine phosphorylation, receptor desensitization, auto-antibodies to the receptor and inherited structural defects in the insulin receptor. |
| 405 | 2028355 | Other circulating hormones, such as the newly characterised islet amyloid polypeptide (amylin), may also cause insulin resistance. |
| 406 | 2040394 | To investigate the potential of the technique for screening many patients, the 5 exons that encode the tyrosine kinase domain of the insulin receptor were examined in 30 unrelated white subjects with non-insulin-dependent diabetes mellitus (NIDDM). |
| 407 | 2043221 | However, the insulin receptor tyrosine kinase, the expression of second messengers, and the action of protein kinase C may, either individually or in combination, mediate some of the insulin effects, such as translocation and activation of glucose transporter proteins. |
| 408 | 2043221 | Insulin resistance in clinical conditions such as insulin-dependent diabetes mellitus (IDDM), non-insulin-dependent diabetes mellitus (NIDDM), hypertension and obesity may be acquired to a large extent, and is thus partially reversible. |
| 409 | 2052553 | To study the role of the insulin receptor in determining adipocyte differentiation of the mouse cell line 3T3-L1, we have introduced a mutation that inactivates the insulin receptor gene by homologous recombination. |
| 410 | 2052553 | The defect in adipocyte-specific differentiation was corrected by expression of transfected human insulin receptor cDNA. |
| 411 | 2052553 | To study the role of the insulin receptor in determining adipocyte differentiation of the mouse cell line 3T3-L1, we have introduced a mutation that inactivates the insulin receptor gene by homologous recombination. |
| 412 | 2052553 | The defect in adipocyte-specific differentiation was corrected by expression of transfected human insulin receptor cDNA. |
| 413 | 2155095 | In a cell-free system, tubulin, microtubule-associated protein 2, tau, fodrin, calmodulin-dependent kinase, calmodulin, and lipocortins 1 and 2 were reported to be good substrates for insulin-receptor kinase. |
| 414 | 2157941 | In the present study, we examined in vivo insulin-mediated whole-body glucose disposal, glycogen synthesis, hepatic glucose production, and insulin secretion, as well as in vitro muscle insulin receptor tyrosine kinase activity in eight control, eight neonatal streptozotocin diabetic rats, and eight diabetic rats before and after treatment with metformin. |
| 415 | 2158467 | Autophosphorylation of the insulin receptor beta subunit was increased in liver receptors prepared from rats at the end of the glucose clamp compared to rats in the basal state both in the absence of insulin in vitro (109% increase, p less than 0.001) and after in vitro stimulation with 10(-7) mol/l insulin (clamped vs fasted; 96% increase, p less than 0.001). |
| 416 | 2161429 | Dephosphorylation of insulin and epidermal growth factor receptors in normal and alloxan diabetic rats. |
| 417 | 2161429 | Although alloxan diabetes did not affect PPTPase activity measured with artificial substrates or with epidermal growth factor receptors, a decrease in insulin receptor dephosphorylation was noted. |
| 418 | 2162754 | To identify these sites, the deduced amino acid sequence of the 3T3-L1 adipocyte insulin receptor of the mouse was determined. |
| 419 | 2162754 | Amino acid and radiochemical sequence analysis of the purified tryptic [32P]phosphopeptide revealed that pp15 is the phosphorylation product of 422(aP2) protein, a 15,000-Mr adipocyte protein whose cDNA we previously cloned and sequenced. 422(aP2) protein was found to bind fatty acids. |
| 420 | 2162754 | When exposed to a free fatty acid, notably oleic acid, 422(aP2) protein becomes an excellent substrate of the isolated insulin-receptor tyrosine kinase. |
| 421 | 2162754 | DNase I footprinting with nuclear extracts from 3T3-L1 cells revealed that a differentiation-specific nuclear factor binds to the GLUT4 promoter. |
| 422 | 2162754 | To identify these sites, the deduced amino acid sequence of the 3T3-L1 adipocyte insulin receptor of the mouse was determined. |
| 423 | 2162754 | Amino acid and radiochemical sequence analysis of the purified tryptic [32P]phosphopeptide revealed that pp15 is the phosphorylation product of 422(aP2) protein, a 15,000-Mr adipocyte protein whose cDNA we previously cloned and sequenced. 422(aP2) protein was found to bind fatty acids. |
| 424 | 2162754 | When exposed to a free fatty acid, notably oleic acid, 422(aP2) protein becomes an excellent substrate of the isolated insulin-receptor tyrosine kinase. |
| 425 | 2162754 | DNase I footprinting with nuclear extracts from 3T3-L1 cells revealed that a differentiation-specific nuclear factor binds to the GLUT4 promoter. |
| 426 | 2163202 | To investigate the relationship of insulin receptor kinase with insulin resistance in humans, we studied insulin-sensitive tyrosine kinase activity in muscle biopsies taken from 20 Pima Indians [14 nondiabetics, 6 with non-insulin-dependent mellitus (NIDDM)] during euglycemic clamps, at insulin concentrations of approximately 68 microU/ml (low dose) and approximately 1,170 microU/ml (high dose). |
| 427 | 2174332 | To clarify the role of the insulin receptor in diabetes, the hepatic insulin receptor was investigated in the spontaneously diabetic Chinese hamsters, which are the animal models for insulin-deficient diabetes. |
| 428 | 2174332 | As the phosphorylated protein of 95 kDa was immunoprecipitated by the anti-insulin receptor antibody (B-10, human) in both diabetics and controls, it was supposed that the 95 kDa protein would be the beta-subunit of insulin receptors, as in other animals. |
| 429 | 2174332 | To clarify the role of the insulin receptor in diabetes, the hepatic insulin receptor was investigated in the spontaneously diabetic Chinese hamsters, which are the animal models for insulin-deficient diabetes. |
| 430 | 2174332 | As the phosphorylated protein of 95 kDa was immunoprecipitated by the anti-insulin receptor antibody (B-10, human) in both diabetics and controls, it was supposed that the 95 kDa protein would be the beta-subunit of insulin receptors, as in other animals. |
| 431 | 2180315 | In wheat germ agglutinin purified receptors, 125I-labeled porcine insulin binding, basal and insulin-stimulated insulin receptor kinase activities for both the autophosphorylation of the beta-subunit and the phosphorylation of the artificial substrate poly (Glu-Tyr) 4:1, were found identical in diabetic and control rats, treated or not with vanadate. |
| 432 | 2180315 | Thus, in that model of non-insulin-dependent diabetes, 1) oral vanadate exerts a corrective insulin-like effect on impaired insulin action both at the level of liver and peripheral tissues, 2) impaired insulin action with no alteration of the insulin receptor tyrosine kinase is observed in the liver of untreated rats, and 3) corrective effect of vanadate on liver glucose metabolism is probably distal to the insulin receptor kinase activity. |
| 433 | 2180315 | In wheat germ agglutinin purified receptors, 125I-labeled porcine insulin binding, basal and insulin-stimulated insulin receptor kinase activities for both the autophosphorylation of the beta-subunit and the phosphorylation of the artificial substrate poly (Glu-Tyr) 4:1, were found identical in diabetic and control rats, treated or not with vanadate. |
| 434 | 2180315 | Thus, in that model of non-insulin-dependent diabetes, 1) oral vanadate exerts a corrective insulin-like effect on impaired insulin action both at the level of liver and peripheral tissues, 2) impaired insulin action with no alteration of the insulin receptor tyrosine kinase is observed in the liver of untreated rats, and 3) corrective effect of vanadate on liver glucose metabolism is probably distal to the insulin receptor kinase activity. |
| 435 | 2188117 | Structure-function studies of the insulin molecule indicate that an insulin B chain domain comprising residues 22-26 is involved both in binding to the insulin receptor (INSR) and in insulin dimer formation, suggesting that this domain might also interact with a structure resembling the insulin dimer interface in the INSR. |
| 436 | 2188117 | Expression of a mutant INSR cDNA with a deletion of the region corresponding to exon 2 of the INSR gene produces a protein devoid of insulin-binding activity, although the mutant protein is processed appropriately to alpha- and beta-subunits, suggesting that the insulin-binding domain is encoded at least in part by exon 2. |
| 437 | 2188117 | Structure-function studies of the insulin molecule indicate that an insulin B chain domain comprising residues 22-26 is involved both in binding to the insulin receptor (INSR) and in insulin dimer formation, suggesting that this domain might also interact with a structure resembling the insulin dimer interface in the INSR. |
| 438 | 2188117 | Expression of a mutant INSR cDNA with a deletion of the region corresponding to exon 2 of the INSR gene produces a protein devoid of insulin-binding activity, although the mutant protein is processed appropriately to alpha- and beta-subunits, suggesting that the insulin-binding domain is encoded at least in part by exon 2. |
| 439 | 2196279 | Previously, two classes of mutations have been identified: 1) those that impair posttranslational processing of proinsulin to insulin, and 2) those that alter the structure of the insulin molecule, thereby reducing the affinity of the molecule for the insulin receptor. |
| 440 | 2204623 | The juxtamembrane region of the insulin receptor (IR) beta-subunit contains an unphosphorylated tyrosyl residue (Tyr960) that is essential for insulin-stimulated tyrosyl phosphorylation of some endogenous substrates and certain biological responses (White, M.F., Livingston, J.N., Backer, J.M., Lauris, V., Dull, T.J., Ullrich, A., and Kahn, C.R. (1988) Cell 54, 641-649). |
| 441 | 2204623 | These data show that the juxtamembrane region of the insulin receptor contains residues essential for insulin-stimulated internalization and suggest that the sequence NPXY [corrected] may play a general role in directing the internalization of cell surface receptors. |
| 442 | 2204623 | The juxtamembrane region of the insulin receptor (IR) beta-subunit contains an unphosphorylated tyrosyl residue (Tyr960) that is essential for insulin-stimulated tyrosyl phosphorylation of some endogenous substrates and certain biological responses (White, M.F., Livingston, J.N., Backer, J.M., Lauris, V., Dull, T.J., Ullrich, A., and Kahn, C.R. (1988) Cell 54, 641-649). |
| 443 | 2204623 | These data show that the juxtamembrane region of the insulin receptor contains residues essential for insulin-stimulated internalization and suggest that the sequence NPXY [corrected] may play a general role in directing the internalization of cell surface receptors. |
| 444 | 2210055 | The sequences of the gene and oligonucleotide primers will facilitate studies of genetic variation in the hINSR gene and thereby increase our understanding of the role of this gene in the development of insulin-resistant states and glucose intolerance. |
| 445 | 2211678 | Insulin receptor-specific polyclonal antipeptide serum was generated against a synthetic pentadecapeptide (residues 657-670) of the deduced amino acid sequence of human insulin proreceptor cDNA for use in the analysis of insulin receptors in the retina. |
| 446 | 2227119 | These mutations are associated with insulin resistance and provide insight into the role of the hINSR gene in the development of diabetes mellitus. |
| 447 | 2248961 | Endogenous substrates of the EGF receptor have been described in transformed cells; however, little is known about substrates in normal tissue. |
| 448 | 2248961 | To characterize epidermal growth factor (EGF) receptor phosphorylation and search for endogenous substrates in normal rat hepatocytes, cells were labeled with [32P]orthophosphate, and phosphotyrosine-containing proteins were sought by using a high-affinity, specific anti-phosphotyrosine antibody. |
| 449 | 2248961 | The 185- and 160-kDa proteins (pp185 and pp160) were identified as the intact and proteolyzed forms of the EGF receptor by virtue of their immunoprecipitation with anti-EGF receptor antibody. |
| 450 | 2248961 | The phosphopeptide map derived from pp120 was by trypsinization and HPLC separation different from that of pp185, further indicating that pp120 is distinct from the EGF receptor. |
| 451 | 2248961 | This pp120 was also immunologically distinct from the pp120 substrate of the insulin receptor kinase and from ATP-citrate lyase. |
| 452 | 2248961 | Autophosphorylation of EGF receptor and phosphorylation of pp120 were almost maximal within 1 min of EGF stimulation. |
| 453 | 2248961 | The dose-response curves for phosphorylation of the EGF receptor and pp120 were identical (ED50 = 30 ng/mL) and were superimposable with the fractional occupancy of the EGF receptor. |
| 454 | 2248961 | These data suggest that pp120 is an endogenous substrate for the EGF receptor in hepatocytes whose phosphorylation may be closely related to EGF stimulation of cell growth. |
| 455 | 2249608 | Effect of prolonged hyperinsulinaemia on adipocyte insulin binding and action in normal man. |
| 456 | 2249608 | To examine the effects in man of such moderate hyperinsulinaemia on in vitro glucose metabolism, insulin-receptor binding, glucose transport and incorporation of glucose into lipid were determined in adipocytes isolated from paired gluteal fat biopsies, taken from six normal human volunteers before and 1 h after 20 h of exogenous hyperinsulinaemia (plasma insulin 38 +/- 3 mU/l). |
| 457 | 2249608 | In conclusion, moderate 20 h in vivo hyperinsulinaemia in normal humans induces only a small change in basal vitro adipocyte glucose transport, and no change in insulin-receptor binding or in vitro incorporation of glucose into lipid. |
| 458 | 2249608 | These data suggest that the adipocyte does not contribute to the impaired insulin action produced by in vivo moderate hyperinsulinaemia in man. |
| 459 | 2249608 | Effect of prolonged hyperinsulinaemia on adipocyte insulin binding and action in normal man. |
| 460 | 2249608 | To examine the effects in man of such moderate hyperinsulinaemia on in vitro glucose metabolism, insulin-receptor binding, glucose transport and incorporation of glucose into lipid were determined in adipocytes isolated from paired gluteal fat biopsies, taken from six normal human volunteers before and 1 h after 20 h of exogenous hyperinsulinaemia (plasma insulin 38 +/- 3 mU/l). |
| 461 | 2249608 | In conclusion, moderate 20 h in vivo hyperinsulinaemia in normal humans induces only a small change in basal vitro adipocyte glucose transport, and no change in insulin-receptor binding or in vitro incorporation of glucose into lipid. |
| 462 | 2249608 | These data suggest that the adipocyte does not contribute to the impaired insulin action produced by in vivo moderate hyperinsulinaemia in man. |
| 463 | 2332119 | We examined insulin binding, insulin-stimulated autophosphorylation, and phosphorylation of poly(Glu.Na,Tyr)4:1 by liver and skeletal muscle insulin receptor from lean, obese, and obese streptozocin-induced diabetic Zucker rats. |
| 464 | 2354998 | Increased protein kinase C activity is linked to reduced insulin receptor autophosphorylation in liver of starved rats. |
| 465 | 2354998 | Phosphorylation of the insulin receptor beta-subunit on serine/threonine residues by protein kinase C reduces both receptor kinase activity and insulin action in cultured cells. |
| 466 | 2354998 | Insulin-stimulated autophosphorylation of the partially purified hepatic insulin receptor beta-subunit was decreased by 45% in starved animals compared to fed controls. |
| 467 | 2354998 | To investigate which kinase(s) may be responsible for such increased Ser/Thr phosphorylation in vivo, protein kinase C and cAMP-dependent protein kinase A in liver were studied. |
| 468 | 2354998 | A 2-fold increase in protein kinase C activity was found in both cytosol and membrane extracts from starved rats as compared to controls, while protein kinase A activity was diminished in the cytosol of starved rats. |
| 469 | 2354998 | These findings suggest that in starved, insulin-resistant animals, an increase in hepatic protein kinase C activity is associated with increased Ser/Thr phosphorylation which in turn decreases autophosphorylation and function of the insulin receptor kinase. |
| 470 | 2354998 | Increased protein kinase C activity is linked to reduced insulin receptor autophosphorylation in liver of starved rats. |
| 471 | 2354998 | Phosphorylation of the insulin receptor beta-subunit on serine/threonine residues by protein kinase C reduces both receptor kinase activity and insulin action in cultured cells. |
| 472 | 2354998 | Insulin-stimulated autophosphorylation of the partially purified hepatic insulin receptor beta-subunit was decreased by 45% in starved animals compared to fed controls. |
| 473 | 2354998 | To investigate which kinase(s) may be responsible for such increased Ser/Thr phosphorylation in vivo, protein kinase C and cAMP-dependent protein kinase A in liver were studied. |
| 474 | 2354998 | A 2-fold increase in protein kinase C activity was found in both cytosol and membrane extracts from starved rats as compared to controls, while protein kinase A activity was diminished in the cytosol of starved rats. |
| 475 | 2354998 | These findings suggest that in starved, insulin-resistant animals, an increase in hepatic protein kinase C activity is associated with increased Ser/Thr phosphorylation which in turn decreases autophosphorylation and function of the insulin receptor kinase. |
| 476 | 2354998 | Increased protein kinase C activity is linked to reduced insulin receptor autophosphorylation in liver of starved rats. |
| 477 | 2354998 | Phosphorylation of the insulin receptor beta-subunit on serine/threonine residues by protein kinase C reduces both receptor kinase activity and insulin action in cultured cells. |
| 478 | 2354998 | Insulin-stimulated autophosphorylation of the partially purified hepatic insulin receptor beta-subunit was decreased by 45% in starved animals compared to fed controls. |
| 479 | 2354998 | To investigate which kinase(s) may be responsible for such increased Ser/Thr phosphorylation in vivo, protein kinase C and cAMP-dependent protein kinase A in liver were studied. |
| 480 | 2354998 | A 2-fold increase in protein kinase C activity was found in both cytosol and membrane extracts from starved rats as compared to controls, while protein kinase A activity was diminished in the cytosol of starved rats. |
| 481 | 2354998 | These findings suggest that in starved, insulin-resistant animals, an increase in hepatic protein kinase C activity is associated with increased Ser/Thr phosphorylation which in turn decreases autophosphorylation and function of the insulin receptor kinase. |
| 482 | 2354998 | Increased protein kinase C activity is linked to reduced insulin receptor autophosphorylation in liver of starved rats. |
| 483 | 2354998 | Phosphorylation of the insulin receptor beta-subunit on serine/threonine residues by protein kinase C reduces both receptor kinase activity and insulin action in cultured cells. |
| 484 | 2354998 | Insulin-stimulated autophosphorylation of the partially purified hepatic insulin receptor beta-subunit was decreased by 45% in starved animals compared to fed controls. |
| 485 | 2354998 | To investigate which kinase(s) may be responsible for such increased Ser/Thr phosphorylation in vivo, protein kinase C and cAMP-dependent protein kinase A in liver were studied. |
| 486 | 2354998 | A 2-fold increase in protein kinase C activity was found in both cytosol and membrane extracts from starved rats as compared to controls, while protein kinase A activity was diminished in the cytosol of starved rats. |
| 487 | 2354998 | These findings suggest that in starved, insulin-resistant animals, an increase in hepatic protein kinase C activity is associated with increased Ser/Thr phosphorylation which in turn decreases autophosphorylation and function of the insulin receptor kinase. |
| 488 | 2404717 | Linkage studies of the insulin gene, insulin-receptor gene, erythrocyte/HepG2 glucose-transporter locus, and apolipoprotein B locus have shown no association with MODY. |
| 489 | 2413420 | Insulin promotes the growth of these cells by binding, with low affinity, to the type I insulin-like growth factor (IGF) receptor, not through the high affinity insulin receptor. |
| 490 | 2413420 | Insulin acts synergistically with other factors, such as platelet-derived growth factor and epidermal growth factor, to stimulate the progression of cells through the cycle of proliferation. |
| 491 | 2430467 | By contrast, insulin-stimulated autophosphorylation of the beta-subunit of the insulin receptor was decreased in proportion to the severity of the diabetic state in the STZ rat. |
| 492 | 2449432 | We conclude that 1) autophosphorylation of the insulin receptor begins by phosphorylation of Tyr-1146 and either Tyr-1150 or Tyr-1151; 2) progression of the cascade to phosphorylation of the third tyrosyl residue fully activates the phosphotransferase during in vitro assay; 3) in vivo, the 2Tyr(P) form predominates, suggesting that progression of the autophosphorylation cascade to the 3Tyr(P) form is regulated during insulin stimulation. |
| 493 | 2454859 | We have previously identified qualitative abnormalities in insulin binding to insulin receptors from an insulin-resistant patient (Lep/Ark-1). |
| 494 | 2454859 | Several anti-receptor antibodies were impaired in their abilities to bind to the insulin receptor of Lep/Ark-1. |
| 495 | 2454859 | For example, monoclonal antibody MoAb-51 was much less effective in inhibiting binding to insulin receptors from Lep/Ark-1 (ID50 70 nM) than to those of normal subjects (ID50 8 nM). |
| 496 | 2454859 | In contrast, several site-specific antibodies against epitopes on the beta-subunit of the receptor bound to receptors from Lep/Ark-1 with normal avidity. |
| 497 | 2457028 | Thus, although lipocortins 1 and 2 are in vitro substrates of the insulin receptor kinase, only lipocortin 1 is phosphorylated in an insulin-dependent manner in intact hepatocytes, and this is only observed after dexamethasone treatment of the rats. |
| 498 | 2458910 | Dexamethasone-induced changes in phosphorylation of the insulin and epidermal growth factor receptors and their substrates in intact rat hepatocytes. |
| 499 | 2458910 | Dexamethasone-induced changes in insulin and epidermal growth factor (EGF) receptor number, autophosphorylation, and kinase activity were studied in intact rat hepatocytes. |
| 500 | 2458910 | Dexamethasone had no effect on insulin receptor number, while EGF receptor binding was slightly increased (21.3% vs. 17.2% binding/10(6) cells) after dexamethasone treatment. |
| 501 | 2458910 | Our data indicate that glucocorticoids modulate insulin and EGF receptor kinase activity, but the nature of their effect depends on other factors, including the dietary state of the animal. |
| 502 | 2463986 | Tyrosine phosphorylation of the insulin receptor during insulin-stimulated internalization in rat hepatoma cells. |
| 503 | 2470095 | The relation between insulin-stimulated autophosphorylation of the insulin receptor and internalization of the receptor was studied in Fao rat hepatoma cells. |
| 504 | 2498306 | Nonphosphorylatable substrate analogs selectively block autophosphorylation and activation of the insulin receptor, epidermal growth factor receptor, and pp60v-src kinases. |
| 505 | 2498306 | The receptors for insulin and epidermal growth factor undergo tyrosine autophosphorylation in response to ligand stimulation, while pp60v-src is an unregulated tyrosine kinase. |
| 506 | 2498306 | Both analogs inhibited insulin and epidermal growth factor receptor autophosphorylation, whereas only the Phe-substituted analog inhibited pp60v-src phosphorylation. |
| 507 | 2499587 | Insulin receptor function and glycogen synthase activity in skeletal muscle biopsies from patients with insulin-dependent diabetes mellitus: effects of physical training. |
| 508 | 2499587 | This study was designed to examine the mechanisms causing peripheral insulin resistance in patients with insulin-dependent diabetes mellitus (IDDM) by studying insulin receptor function and glycogen synthase activity in biopsies of skeletal muscle. |
| 509 | 2499587 | In addition, since physical training appears to improve insulin sensitivity, the IDDM patients were reexamined after physical training for 6 weeks. |
| 510 | 2499587 | After physical training in the diabetic patients the mean maximal oxygen uptake increased from 45.7 +/- 7.4 to 48.9 +/- 9.0 mL O2/kg.min (P less than 0.05), hemoglobin A1c decreased from 7.9 +/- 1.4% to 7.7 +/- 1.5% (P less than 0.05), and insulin requirements decreased from 43 +/- 9 to 38 +/- 8 U/day (P less than 0.05). |
| 511 | 2499587 | We conclude that insulin binding to muscle-derived insulin receptors is impaired in IDDM patients, whereas receptor kinase function appears to be normal. |
| 512 | 2499587 | Insulin receptor function and glycogen synthase activity in skeletal muscle biopsies from patients with insulin-dependent diabetes mellitus: effects of physical training. |
| 513 | 2499587 | This study was designed to examine the mechanisms causing peripheral insulin resistance in patients with insulin-dependent diabetes mellitus (IDDM) by studying insulin receptor function and glycogen synthase activity in biopsies of skeletal muscle. |
| 514 | 2499587 | In addition, since physical training appears to improve insulin sensitivity, the IDDM patients were reexamined after physical training for 6 weeks. |
| 515 | 2499587 | After physical training in the diabetic patients the mean maximal oxygen uptake increased from 45.7 +/- 7.4 to 48.9 +/- 9.0 mL O2/kg.min (P less than 0.05), hemoglobin A1c decreased from 7.9 +/- 1.4% to 7.7 +/- 1.5% (P less than 0.05), and insulin requirements decreased from 43 +/- 9 to 38 +/- 8 U/day (P less than 0.05). |
| 516 | 2499587 | We conclude that insulin binding to muscle-derived insulin receptors is impaired in IDDM patients, whereas receptor kinase function appears to be normal. |
| 517 | 2506075 | Identification of a phosphorylation site of the rat insulin receptor catalyzed by protein kinase C in an intact cell. |
| 518 | 2506075 | The synthetic peptide coding residues 1327-1343 in the C-terminal region of the rat insulin receptor was phosphorylated at the threonine residue by protein kinase C in a phosphatidylserine and oleoylacetylglycerol dependent manner. |
| 519 | 2506075 | These data suggested that Thr 1336 of the insulin receptor is the site of phosphorylation by protein kinase C in intact cells. |
| 520 | 2506075 | Identification of a phosphorylation site of the rat insulin receptor catalyzed by protein kinase C in an intact cell. |
| 521 | 2506075 | The synthetic peptide coding residues 1327-1343 in the C-terminal region of the rat insulin receptor was phosphorylated at the threonine residue by protein kinase C in a phosphatidylserine and oleoylacetylglycerol dependent manner. |
| 522 | 2506075 | These data suggested that Thr 1336 of the insulin receptor is the site of phosphorylation by protein kinase C in intact cells. |
| 523 | 2506075 | Identification of a phosphorylation site of the rat insulin receptor catalyzed by protein kinase C in an intact cell. |
| 524 | 2506075 | The synthetic peptide coding residues 1327-1343 in the C-terminal region of the rat insulin receptor was phosphorylated at the threonine residue by protein kinase C in a phosphatidylserine and oleoylacetylglycerol dependent manner. |
| 525 | 2506075 | These data suggested that Thr 1336 of the insulin receptor is the site of phosphorylation by protein kinase C in intact cells. |
| 526 | 2521209 | Characterization of induction of protooncogene c-myc and cellular growth in human vascular smooth muscle cells by insulin and IGF-I. |
| 527 | 2521209 | Insulin and insulin-like growth factor I (IGF-I) are structurally related polypeptides that stimulate DNA synthesis and cellular proliferation, probably through a common pathway. |
| 528 | 2521209 | Insulin and IGF-I both exhibited cross-reactivity to each other's receptors but with an affinity that is 100-fold less than for the homologous receptor. |
| 529 | 2521209 | To examine more closely the receptor responsible for producing the growth effects, we used the polyclonal antibody against the insulin receptor, B2, and a monoclonal antibody to the IGF-I receptor, alpha IR3. |
| 530 | 2521209 | We studied the growth effects of insulin and IGF-I as measured by stimulation of c-myc, DNA synthesis, and cellular proliferation in the presence and absence of these antibodies. |
| 531 | 2521209 | Under such blockade, insulin and IGF-I were both capable of doubling the amount of DNA synthesis and cell number in cultured human arterial smooth muscle cells. |
| 532 | 2521209 | However, in the presence of a 1:2500 dilution of the monoclonal antibody alpha IR3, which caused a 90% displacement of IGF-I bound to its receptor, both the insulin and IGF-I effects on stimulating DNA synthesis or cellular proliferation were inhibited by greater than 90%. |
| 533 | 2521209 | These findings demonstrate that the IGF-I receptor is the common pathway for the growth effects of both insulin and IGF-I. |
| 534 | 2523787 | The effects of metformin on adipocyte insulin action and metabolic control in obese subjects with type 2 diabetes. |
| 535 | 2523787 | To investigate the mechanisms of action of metformin, insulin receptor binding and the activity of several insulin-controlled metabolic pathways were measured in adipocytes taken from 10 obese Type 2 diabetic patients treated for 4 weeks with either metformin (0.5 g x 3 daily) or matching placebo using a double-blind crossover design. |
| 536 | 2523787 | Moreover, no insulin-like effects or post-binding potentiation of insulin action could be found on adipocyte glucose transport, glucose oxidation, lipogenesis, glycolysis or antilipolysis. |
| 537 | 2523787 | A complementary in vitro study using adipocytes from non-obese healthy volunteers failed to show any direct effect of metformin on adipocyte insulin binding or glucose transport and metabolism, at media drug concentrations corresponding to therapeutic plasma levels. |
| 538 | 2535823 | Results showed that significant activation of the insulin-receptor kinase occurred after exposure in vivo to mean serum insulin concentrations as low as 34 +/- 3.5 microU/ml and that maximal activation was achieved by insulin levels less than or equal to 2000 microU/ml. |
| 539 | 2535826 | The observations that calmodulin is phosphorylated by insulin-receptor kinase from all three classic target organs for insulin confirm that calmodulin is a general substrate for this kinase and suggest that Ca2+ and calmodulin may be components of the insulin-signaling mechanism. |
| 540 | 2540178 | Effect of insulin and insulin-like growth factors I and II on phosphatidylinositol and phosphatidylinositol 4,5-bisphosphate breakdown in liver from humans with and without type II diabetes. |
| 541 | 2540178 | We have characterized a plasma membrane phosphatidylinositol 4,5-bisphosphate (PIP2)-specific phospholipase C (PLC) and a cytosolic phosphatidylinositol (PI)-specific PLC in human liver. |
| 542 | 2540178 | PI-PLC stimulation was not observed by these agents. |
| 543 | 2540178 | Insulin and insulin-like growth factors (IGF-I and IGF-II) in the presence and absence of GTP gamma S did not stimulate PIP2-PLC or PI-PLC in plasma membranes and cytosol preparations nor phosphoinositide breakdown in isolated human hepatocytes. |
| 544 | 2540178 | Furthermore, the increased PIP2-PLC in diabetic liver may result in: (a) increased intracellular concentrations of IP3 and thus increased Ca2+, which has been postulated to induce insulin resistance; and (b) increased diacylglycerol and thus increased protein kinase C which phosphorylates the insulin receptor at serine residues inactivating the insulin receptor kinase. |
| 545 | 2546940 | A novel fetal insulin-like growth factor (IGF) I receptor. |
| 546 | 2546940 | Insulin and insulin-like growth factor (IGF) I receptors from fetal and adult rat skeletal muscle were compared in order to gain insight into the evolving functions of the hormones during development. |
| 547 | 2546940 | The fetal receptor is structurally more closely related to the IGF-I receptor than the insulin receptor on the basis of its precipitation with specific antibodies, binding to an IGF I affinity column, and tryptic phosphopeptide map. |
| 548 | 2546940 | The fetal receptor does not appear to bind insulin but, unlike the IGF-I receptor, its phosphorylation is stimulated by low physiological concentrations of both insulin and IGF I. |
| 549 | 2547586 | We observed the insulin-stimulated phosphorylation of a 195K protein (pp195) in extracts prepared from rat skeletal muscle and liver. pp195 copurifies with the insulin receptor on wheat germ agglutinin affinity chromatography. pp195 is not related to the insulin receptor, as assessed by lack of recognition by antinsulin receptor antibodies and by phosphopeptide mapping. |
| 550 | 2547586 | In the presence of 1 microM poly-L-lysine insulin stimulates pp195 phosphorylation in a dose-dependent manner (k0.5, approximately 5 x 10(-10) M; maximum approximately 10(-8) M insulin); pp195 phosphorylation by insulin-like growth factor-I requires about 100-fold higher doses. |
| 551 | 2551760 | Competition studies with 125I-labeled IGF-I and unlabeled IGF-I, IGF-II, and insulin showed the specificity of 125I-IGF-I binding to the IGF-I receptors in adipocytes, membranes, and partially purified detergent-solubilized extracts. |
| 552 | 2551760 | In addition, the alpha-subunit of IGF-I receptor is approximately 10,000 Mr larger than the alpha-subunit of insulin receptor, and IGF-I stimulates phosphorylation of the beta-subunit of the IGF-I receptor. |
| 553 | 2551760 | The possibility of IGF-I stimulating glucose transport by interacting predominantly with insulin receptors is suggested by data showing that 1) IGF-I competes with insulin-binding sites, 2) there is a lack of an additive effect with IGF-I and insulin in stimulating glucose transport, 3) alpha-IR3, which specifically inhibits IGF-I binding, does not inhibit IGF-I or insulin-stimulated glucose transport, 4) insulin-receptor antibody MA-10 inhibits IGF-I and insulin-stimulated glucose transport, and 5) IGF-I stimulates insulin-receptor autophosphorylation, although its effect is markedly decreased compared with insulin. |
| 554 | 2551760 | However, IGF-I stimulates glucose transport predominantly by interacting with the insulin receptor. |
| 555 | 2551760 | Competition studies with 125I-labeled IGF-I and unlabeled IGF-I, IGF-II, and insulin showed the specificity of 125I-IGF-I binding to the IGF-I receptors in adipocytes, membranes, and partially purified detergent-solubilized extracts. |
| 556 | 2551760 | In addition, the alpha-subunit of IGF-I receptor is approximately 10,000 Mr larger than the alpha-subunit of insulin receptor, and IGF-I stimulates phosphorylation of the beta-subunit of the IGF-I receptor. |
| 557 | 2551760 | The possibility of IGF-I stimulating glucose transport by interacting predominantly with insulin receptors is suggested by data showing that 1) IGF-I competes with insulin-binding sites, 2) there is a lack of an additive effect with IGF-I and insulin in stimulating glucose transport, 3) alpha-IR3, which specifically inhibits IGF-I binding, does not inhibit IGF-I or insulin-stimulated glucose transport, 4) insulin-receptor antibody MA-10 inhibits IGF-I and insulin-stimulated glucose transport, and 5) IGF-I stimulates insulin-receptor autophosphorylation, although its effect is markedly decreased compared with insulin. |
| 558 | 2551760 | However, IGF-I stimulates glucose transport predominantly by interacting with the insulin receptor. |
| 559 | 2551760 | Competition studies with 125I-labeled IGF-I and unlabeled IGF-I, IGF-II, and insulin showed the specificity of 125I-IGF-I binding to the IGF-I receptors in adipocytes, membranes, and partially purified detergent-solubilized extracts. |
| 560 | 2551760 | In addition, the alpha-subunit of IGF-I receptor is approximately 10,000 Mr larger than the alpha-subunit of insulin receptor, and IGF-I stimulates phosphorylation of the beta-subunit of the IGF-I receptor. |
| 561 | 2551760 | The possibility of IGF-I stimulating glucose transport by interacting predominantly with insulin receptors is suggested by data showing that 1) IGF-I competes with insulin-binding sites, 2) there is a lack of an additive effect with IGF-I and insulin in stimulating glucose transport, 3) alpha-IR3, which specifically inhibits IGF-I binding, does not inhibit IGF-I or insulin-stimulated glucose transport, 4) insulin-receptor antibody MA-10 inhibits IGF-I and insulin-stimulated glucose transport, and 5) IGF-I stimulates insulin-receptor autophosphorylation, although its effect is markedly decreased compared with insulin. |
| 562 | 2551760 | However, IGF-I stimulates glucose transport predominantly by interacting with the insulin receptor. |
| 563 | 2553727 | Monoclonal antibodies mimic insulin activation of ribosomal protein S6 kinase without activation of insulin receptor tyrosine kinase. |
| 564 | 2553727 | The effects of species-specific monoclonal antibodies to the human insulin receptor on ribosomal protein S6 phosphorylation were studied in rodent cell lines transfected with human insulin receptors. |
| 565 | 2553727 | Monoclonal antibodies mimic insulin activation of ribosomal protein S6 kinase without activation of insulin receptor tyrosine kinase. |
| 566 | 2553727 | The effects of species-specific monoclonal antibodies to the human insulin receptor on ribosomal protein S6 phosphorylation were studied in rodent cell lines transfected with human insulin receptors. |
| 567 | 2561992 | Following [32P]orthophosphate labelling and stimulation by insulin or IGF-I, the cells were solubilized and the phosphorylated receptors were partially purified on wheat germ agglutinin--agarose columns, and immunoprecipitated using anti-phosphotyrosine or anti-insulin receptor antibodies. |
| 568 | 2562831 | Insulin-receptor and apolipoprotein genes contribute to development of NIDDM in Chinese Americans. |
| 569 | 2562831 | The frequencies of restriction-fragment-length polymorphism (RFLP) alleles as well as RFLP haplotypes at six genetic loci responsible for carbohydrate and lipid metabolism [insulin/insulin-like growth factor II complex, insulin receptor (INSR), HepG2/erythrocyte-type glucose transporter, apolipoprotein A-II, apolipoprotein B (APOB), and the apolipoprotein A-I/C-III/A-IV cluster (APOA1/C3/A4)] were compared between nondiabetic and diabetic Chinese Americans. |
| 570 | 2562831 | The disease-association data suggest that genetic variation at the INSR, APOB, and APOA1/C3/A4 loci contributes to the development of non-insulin-dependent diabetes mellitus (NIDDM). |
| 571 | 2562831 | The APOB and APOA1/C3/A4 loci appear to contribute to the development of NIDDM in individuals who are of lean/normal weight and overweight, respectively. |
| 572 | 2562831 | Insulin-receptor and apolipoprotein genes contribute to development of NIDDM in Chinese Americans. |
| 573 | 2562831 | The frequencies of restriction-fragment-length polymorphism (RFLP) alleles as well as RFLP haplotypes at six genetic loci responsible for carbohydrate and lipid metabolism [insulin/insulin-like growth factor II complex, insulin receptor (INSR), HepG2/erythrocyte-type glucose transporter, apolipoprotein A-II, apolipoprotein B (APOB), and the apolipoprotein A-I/C-III/A-IV cluster (APOA1/C3/A4)] were compared between nondiabetic and diabetic Chinese Americans. |
| 574 | 2562831 | The disease-association data suggest that genetic variation at the INSR, APOB, and APOA1/C3/A4 loci contributes to the development of non-insulin-dependent diabetes mellitus (NIDDM). |
| 575 | 2562831 | The APOB and APOA1/C3/A4 loci appear to contribute to the development of NIDDM in individuals who are of lean/normal weight and overweight, respectively. |
| 576 | 2562831 | Insulin-receptor and apolipoprotein genes contribute to development of NIDDM in Chinese Americans. |
| 577 | 2562831 | The frequencies of restriction-fragment-length polymorphism (RFLP) alleles as well as RFLP haplotypes at six genetic loci responsible for carbohydrate and lipid metabolism [insulin/insulin-like growth factor II complex, insulin receptor (INSR), HepG2/erythrocyte-type glucose transporter, apolipoprotein A-II, apolipoprotein B (APOB), and the apolipoprotein A-I/C-III/A-IV cluster (APOA1/C3/A4)] were compared between nondiabetic and diabetic Chinese Americans. |
| 578 | 2562831 | The disease-association data suggest that genetic variation at the INSR, APOB, and APOA1/C3/A4 loci contributes to the development of non-insulin-dependent diabetes mellitus (NIDDM). |
| 579 | 2562831 | The APOB and APOA1/C3/A4 loci appear to contribute to the development of NIDDM in individuals who are of lean/normal weight and overweight, respectively. |
| 580 | 2562832 | We studied the structure of the insulin-receptor gene in normal individuals and in four unrelated patients with leprechaunism (Minn-1, Ark-1, Ark-2, Can-1) and four unrelated patients with the type A syndrome of insulin resistance, both disorders associated with genetic alterations in affinity, binding capacity, and kinase activity of the insulin receptor. |
| 581 | 2565838 | Twenty Black families in which at least two siblings had non-insulin-dependent diabetes mellitus (NIDDM) were typed for restriction-fragment-length polymorphisms at the insulin (INS), insulin-receptor (INSR), and HLA-DR beta loci. |
| 582 | 2565838 | We conclude that the INS and INSR loci can be ruled out as major susceptibility loci for NIDDM in most Black families segregating this disorder, but we recognize that defects at either of these loci may cause or contribute to NIDDM in some patients. |
| 583 | 2565838 | In addition, it is possible that variation at the INS and/or INSR loci may contribute to NIDDM susceptibility by modifying susceptibility due primarily to another major gene(s) or as part of an overall polygenic component to NIDDM. |
| 584 | 2565838 | Twenty Black families in which at least two siblings had non-insulin-dependent diabetes mellitus (NIDDM) were typed for restriction-fragment-length polymorphisms at the insulin (INS), insulin-receptor (INSR), and HLA-DR beta loci. |
| 585 | 2565838 | We conclude that the INS and INSR loci can be ruled out as major susceptibility loci for NIDDM in most Black families segregating this disorder, but we recognize that defects at either of these loci may cause or contribute to NIDDM in some patients. |
| 586 | 2565838 | In addition, it is possible that variation at the INS and/or INSR loci may contribute to NIDDM susceptibility by modifying susceptibility due primarily to another major gene(s) or as part of an overall polygenic component to NIDDM. |
| 587 | 2565838 | Twenty Black families in which at least two siblings had non-insulin-dependent diabetes mellitus (NIDDM) were typed for restriction-fragment-length polymorphisms at the insulin (INS), insulin-receptor (INSR), and HLA-DR beta loci. |
| 588 | 2565838 | We conclude that the INS and INSR loci can be ruled out as major susceptibility loci for NIDDM in most Black families segregating this disorder, but we recognize that defects at either of these loci may cause or contribute to NIDDM in some patients. |
| 589 | 2565838 | In addition, it is possible that variation at the INS and/or INSR loci may contribute to NIDDM susceptibility by modifying susceptibility due primarily to another major gene(s) or as part of an overall polygenic component to NIDDM. |
| 590 | 2569023 | To clarify the molecular basis of the insulin resistance, we investigated the insulin binding and kinase properties of the insulin receptor and the receptor gene in cultured skin fibroblasts of two patients (Ark-1 and Ark-2) with leprechaunism and in those of three of their parents. |
| 591 | 2569023 | In Ark-1, the 70% reduction in autophosphorylation correlated with the decrease in binding, whereas in Ark-2 and in the three parents included in the study, autophosphorylation of the insulin receptor was reduced below the level accounted for by a change in receptor content. |
| 592 | 2569023 | Analysis of the insulin receptor gene by hybridization with the receptor cDNA probes revealed no gross defect in either Ark-1 or Ark-2. |
| 593 | 2569023 | Thus, we have biochemically characterized a new family of leprechaunism (Ark-2) and have found insulin receptor phosphorylation defects in their phenotypically normal parents. |
| 594 | 2569023 | To clarify the molecular basis of the insulin resistance, we investigated the insulin binding and kinase properties of the insulin receptor and the receptor gene in cultured skin fibroblasts of two patients (Ark-1 and Ark-2) with leprechaunism and in those of three of their parents. |
| 595 | 2569023 | In Ark-1, the 70% reduction in autophosphorylation correlated with the decrease in binding, whereas in Ark-2 and in the three parents included in the study, autophosphorylation of the insulin receptor was reduced below the level accounted for by a change in receptor content. |
| 596 | 2569023 | Analysis of the insulin receptor gene by hybridization with the receptor cDNA probes revealed no gross defect in either Ark-1 or Ark-2. |
| 597 | 2569023 | Thus, we have biochemically characterized a new family of leprechaunism (Ark-2) and have found insulin receptor phosphorylation defects in their phenotypically normal parents. |
| 598 | 2569023 | To clarify the molecular basis of the insulin resistance, we investigated the insulin binding and kinase properties of the insulin receptor and the receptor gene in cultured skin fibroblasts of two patients (Ark-1 and Ark-2) with leprechaunism and in those of three of their parents. |
| 599 | 2569023 | In Ark-1, the 70% reduction in autophosphorylation correlated with the decrease in binding, whereas in Ark-2 and in the three parents included in the study, autophosphorylation of the insulin receptor was reduced below the level accounted for by a change in receptor content. |
| 600 | 2569023 | Analysis of the insulin receptor gene by hybridization with the receptor cDNA probes revealed no gross defect in either Ark-1 or Ark-2. |
| 601 | 2569023 | Thus, we have biochemically characterized a new family of leprechaunism (Ark-2) and have found insulin receptor phosphorylation defects in their phenotypically normal parents. |
| 602 | 2569023 | To clarify the molecular basis of the insulin resistance, we investigated the insulin binding and kinase properties of the insulin receptor and the receptor gene in cultured skin fibroblasts of two patients (Ark-1 and Ark-2) with leprechaunism and in those of three of their parents. |
| 603 | 2569023 | In Ark-1, the 70% reduction in autophosphorylation correlated with the decrease in binding, whereas in Ark-2 and in the three parents included in the study, autophosphorylation of the insulin receptor was reduced below the level accounted for by a change in receptor content. |
| 604 | 2569023 | Analysis of the insulin receptor gene by hybridization with the receptor cDNA probes revealed no gross defect in either Ark-1 or Ark-2. |
| 605 | 2569023 | Thus, we have biochemically characterized a new family of leprechaunism (Ark-2) and have found insulin receptor phosphorylation defects in their phenotypically normal parents. |
| 606 | 2574127 | Increased risk for gestational diabetes mellitus associated with insulin receptor and insulin-like growth factor II restriction fragment length polymorphisms. |
| 607 | 2574127 | Genotypes for insulin hypervariable region (HVR), insulin-like growth factor II (IGF2), insulin receptor (INSR), and glucose transporter (GLUT1) RFLPs were studied in 96 GDM and 164 control subjects, matched to GDM for race, age, and gravidity. |
| 608 | 2574127 | In Caucasian women, INSR and IGF2 alleles interact to confer additional risk for GDM. |
| 609 | 2574127 | Increased risk for gestational diabetes mellitus associated with insulin receptor and insulin-like growth factor II restriction fragment length polymorphisms. |
| 610 | 2574127 | Genotypes for insulin hypervariable region (HVR), insulin-like growth factor II (IGF2), insulin receptor (INSR), and glucose transporter (GLUT1) RFLPs were studied in 96 GDM and 164 control subjects, matched to GDM for race, age, and gravidity. |
| 611 | 2574127 | In Caucasian women, INSR and IGF2 alleles interact to confer additional risk for GDM. |
| 612 | 2574127 | Increased risk for gestational diabetes mellitus associated with insulin receptor and insulin-like growth factor II restriction fragment length polymorphisms. |
| 613 | 2574127 | Genotypes for insulin hypervariable region (HVR), insulin-like growth factor II (IGF2), insulin receptor (INSR), and glucose transporter (GLUT1) RFLPs were studied in 96 GDM and 164 control subjects, matched to GDM for race, age, and gravidity. |
| 614 | 2574127 | In Caucasian women, INSR and IGF2 alleles interact to confer additional risk for GDM. |
| 615 | 2574533 | These results support the genetic hypotheses suggested by insulin-binding studies and indicate that RFLPs can be used to identify transmission of the insulin receptor gene in families with insulin resistance. |
| 616 | 2578425 | Impaired insulin-induced RNA synthesis secondary to a genetically defective insulin receptor. |
| 617 | 2614464 | The diabetic patient, who had the typical features of the Kearns-Sayre syndrome (KSS) and deleted muscle mitochondrial DNA (mtDNA) presented a low insulin secretion rate under physiological stimuli (intravenous glucose and glucagon) whereas the insulin receptor parameters were found normal. |
| 618 | 2620783 | These data indicate that abnormalities of insulin binding and receptor function that have been previously observed in vitro with fresh and cultured cells from Pima Indians may be consequences of the diabetic milieu and/or genetic abnormalities in molecules that interact with the insulin receptor. |
| 619 | 2643342 | In control rats, intravenous insulin administration resulted in dose-dependent in vivo activation of the muscle insulin receptor kinase towards histone H2b. |
| 620 | 2644141 | Mechanisms of insulin-induced insulin-receptor downregulation. |
| 621 | 2654845 | In the period of stress the burn injury (in the first hours after the burn) leads to inhibition of insulin production in the animals, while hyperglycemia occurring in the later posttraumatic period results from inhibition of the insulin receptor interrelations and, evidently, from reduction of the postreceptor insulin action. |
| 622 | 2655470 | To clarify the mechanism(s) responsible for the insulin resistance in streptozotocin (STZ)-treated diabetic rats, we studied insulin-induced glucose disposal by using the glucose clamp technique and measured insulin receptor and glucose transporter of muscles. |
| 623 | 2659912 | Increased autophosphorylation of insulin-like growth factor-I and insulin receptors in placentas of diabetic women. |
| 624 | 2659912 | Autophosphorylation of insulin and insulin-like growth factor (IGF)-I receptors were measured in lectin purified receptor preparations from placentas of normal and diabetic patients. |
| 625 | 2659912 | The basal and insulin or IGF-I stimulated phosphorylation of the approximately 94 kD protein, corresponding to beta-subunit of the insulin and IGF-I receptors, were approximately 2 times greater (p less than 0.05) in placentas from diabetic patients with poor glycemic control (as judged by their serum HbA1c level) compared to the normals. |
| 626 | 2659912 | The magnitude of IGF-I or insulin stimulation of the phosphorylation of the 94 kD protein was comparable in placentas from both diabetic and normal patients. |
| 627 | 2659912 | Immunoprecipitation and immunodepletion of IGF-I receptor by alpha-IR3, a monoclonal antibody to IGF-I receptor, revealed the increased basal phosphorylation of the approximately 94 kD protein in placentas of diabetic patients to be associated with IGF-I and insulin receptors. |
| 628 | 2659912 | The magnitude of IGF-I and insulin stimulated phosphorylation of the immunoprecipitated and immunodepleted IGF-I receptor, respectively, was the same in both normal and diabetic patients. |
| 629 | 2659912 | These results suggested that the increased basal phosphorylation of the 94 kD protein in placentas from diabetic patients may be intrinsic to IGF-I and insulin receptor, however, the regulatory mechanisms effecting the increase may not be dependent on IGF-I or insulin. |
| 630 | 2668084 | In competitive insulin binding to intact cells, [LeuA3]-, [LeuB24]-, [SerB24]-insulin, and mini-proinsulin ([ B(1-29)-Ala-Ala-Lys-A(1-21)]-insulin) had the same relative binding activity in both the patient's and the control cells, but proinsulin and IGF-I were markedly less able to displace 125I-insulin in the patient's cells. |
| 631 | 2668084 | In contrast to the study in intact cells, proinsulin and IGF-I as well as other insulin analogues had the same relative binding activity to bind to the partially lectin-purified insulin receptor preparations from both the patient's and the control cells. |
| 632 | 2684714 | We investigated intracellular processing of the insulin-receptor complex in monocytes from 12 healthy control subjects, 11 obese nondiabetic subjects, and 13 obese patients with non-insulin-dependent diabetes mellitus (NIDDM) by measuring receptor internalization, recovery of cell-surface insulin binding after receptor internalization, and the release of intracellular intact insulin (insulin retroendocytosis). |
| 633 | 2689121 | Linkage studies of the insulin gene, the insulin receptor gene, the erythrocyte/Hep G2 glucose transporter locus, and the apolipoprotein B locus have shown no association with MODY. |
| 634 | 2691120 | However, glucocorticoid receptor binding characteristics did not correlate with insulin receptor binding characteristics or with HbA1c. |
| 635 | 2722845 | The insulin receptor purified from skeletal muscle of patients with non-insulin-dependent diabetes mellitus (NIDDM) displayed a 25-55% reduction in insulin-stimulated autophosphorylation and tyrosyl-specific phosphotransferase activity relative to controls. |
| 636 | 2722845 | Therefore, the reduced formation of the tris-phosphorylated regulatory region in the diabetic receptors suggests that a defective autophosphorylation cascade leading to tris-phosphorylation of the regulatory region may cause, in part, the reduced insulin-stimulated kinase activity of the insulin receptor in muscle of NIDDM patients. |
| 637 | 2722845 | The insulin receptor purified from skeletal muscle of patients with non-insulin-dependent diabetes mellitus (NIDDM) displayed a 25-55% reduction in insulin-stimulated autophosphorylation and tyrosyl-specific phosphotransferase activity relative to controls. |
| 638 | 2722845 | Therefore, the reduced formation of the tris-phosphorylated regulatory region in the diabetic receptors suggests that a defective autophosphorylation cascade leading to tris-phosphorylation of the regulatory region may cause, in part, the reduced insulin-stimulated kinase activity of the insulin receptor in muscle of NIDDM patients. |
| 639 | 2732294 | Uniformly labeled [32P]antisense RNA probes complementary to insulin receptor mRNA were prepared by an SP6 or T7 RNA polymerase transcription reaction. |
| 640 | 2736256 | By using poly(Glu: Tyr, 4:1) as an exogenous substrate, the characteristics of insulin receptor associated protein tyrosine kinase (PTK) from rabbit skeletal muscle has been compared with a growth factor-independent non-receptor PTK partially purified from rat lung particulate fraction. |
| 641 | 2736256 | The two PTKs phosphorylated poly(Glu: Tyr; 4:1) very effectively with apparent Km values of 0.3 mg/ml for insulin receptor PTK and 0.8 mg/ml for lung PTK. |
| 642 | 2736256 | Furthermore, the lung PTK appears to be immunologically distinct from both insulin receptor and pp60Src, since it was not immunoprecipitated by antibodies to either pp60Src or insulin receptor. |
| 643 | 2736256 | By using poly(Glu: Tyr, 4:1) as an exogenous substrate, the characteristics of insulin receptor associated protein tyrosine kinase (PTK) from rabbit skeletal muscle has been compared with a growth factor-independent non-receptor PTK partially purified from rat lung particulate fraction. |
| 644 | 2736256 | The two PTKs phosphorylated poly(Glu: Tyr; 4:1) very effectively with apparent Km values of 0.3 mg/ml for insulin receptor PTK and 0.8 mg/ml for lung PTK. |
| 645 | 2736256 | Furthermore, the lung PTK appears to be immunologically distinct from both insulin receptor and pp60Src, since it was not immunoprecipitated by antibodies to either pp60Src or insulin receptor. |
| 646 | 2736256 | By using poly(Glu: Tyr, 4:1) as an exogenous substrate, the characteristics of insulin receptor associated protein tyrosine kinase (PTK) from rabbit skeletal muscle has been compared with a growth factor-independent non-receptor PTK partially purified from rat lung particulate fraction. |
| 647 | 2736256 | The two PTKs phosphorylated poly(Glu: Tyr; 4:1) very effectively with apparent Km values of 0.3 mg/ml for insulin receptor PTK and 0.8 mg/ml for lung PTK. |
| 648 | 2736256 | Furthermore, the lung PTK appears to be immunologically distinct from both insulin receptor and pp60Src, since it was not immunoprecipitated by antibodies to either pp60Src or insulin receptor. |
| 649 | 2767337 | The fractions were tested for their ability to inhibit 125I-labeled insulin binding to human placental membranes, immunoprecipitate solubilized insulin receptor cross-linked with 125I-insulin, and mimic or inhibit the action of insulin in rat adipocytes. |
| 650 | 2779582 | Although the functional significance of alternative splicing of the insulin receptor mRNA is unknown, differential expression of these two receptor mRNAs may provide a structural basis for previously observed tissue-specific differences in insulin binding and action. |
| 651 | 2806053 | A radioimmunoassay developed with the antiserum and synthetic peptide HIRP(957-980) enabled us to separate, in combination with gel filtration, two insulin-binding components in solubilized human placental membranes which conceivably correspond to the alpha 2 beta 2 and alpha beta structures of the placental insulin receptor. |
| 652 | 2806057 | These results suggest that sera from nine of these 104 diabetics contained a new type of anti-insulin receptor antibodies (AIRA) which bound to a locus different from the insulin binding site, and that only one of the 104 diabetic sera contained a low titer of conventional AIRA which could cause a clinical condition not distinguishable from ordinary non-insulin-dependent diabetes. |
| 653 | 2808704 | Maximal epidermal growth factor (EGF) binding was reduced in fibroblasts from three unrelated patients with leprechaunism (Ark-1, Can-1, and Minn-1) compared with control (0.8-2.2%/mg protein vs. 5.5%/mg protein). |
| 654 | 2808704 | Sphingosine (40 microM), a protein kinase C inhibitor, increased EGF receptor affinity twofold in control cells and six- to nine-fold in cells of leprechaunism. |
| 655 | 2808704 | These data indicate that in patients with leprechaunism, there are functional abnormalities of the EGF receptor, as well as of the insulin receptor, that may contribute to the severity of the syndrome. |
| 656 | 2808704 | These data also suggest a role for the insulin receptor in maintaining normal EGF receptor function in these cells. |
| 657 | 2808704 | Maximal epidermal growth factor (EGF) binding was reduced in fibroblasts from three unrelated patients with leprechaunism (Ark-1, Can-1, and Minn-1) compared with control (0.8-2.2%/mg protein vs. 5.5%/mg protein). |
| 658 | 2808704 | Sphingosine (40 microM), a protein kinase C inhibitor, increased EGF receptor affinity twofold in control cells and six- to nine-fold in cells of leprechaunism. |
| 659 | 2808704 | These data indicate that in patients with leprechaunism, there are functional abnormalities of the EGF receptor, as well as of the insulin receptor, that may contribute to the severity of the syndrome. |
| 660 | 2808704 | These data also suggest a role for the insulin receptor in maintaining normal EGF receptor function in these cells. |
| 661 | 2821993 | Beside the insulin-stimulated phosphorylation of the 95 kDa beta-subunit of the insulin receptor, an insulin-stimulated phosphorylation of a 180 kDa protein was found. |
| 662 | 2833110 | Decreased autophosphorylation of EGF receptor in insulin-deficient diabetic rats. |
| 663 | 2833110 | We have previously reported that despite an increase in receptor concentration, there is a decrease in autophosphorylation and tyrosine kinase activity of the insulin receptor in insulin-deficient diabetic rats. |
| 664 | 2833110 | To determine if other tyrosine kinases might be altered, we have studied the epidermal growth factor (EGF) receptor kinase in wheat germ agglutinin-purified, Triton X-100-solubilized liver membranes from streptozotocin (STZ)-induced diabetic rats and the insulin-deficient BB rat. |
| 665 | 2833110 | We find that autophosphorylation of EGF receptor is decreased in proportion to the severity of the diabetic state in STZ rats with a maximal decrease of 67% (P less than 0.01). |
| 666 | 2833110 | A parallel decrease in EGF receptor phosphorylation was also found by immunoblotting with an anti-phosphotyrosine antibody. |
| 667 | 2833110 | EGF receptor concentration, determined by Scatchard analysis of 125I-labeled EGF binding, was decreased by 39% in the STZ rat (P less than 0.05) and 27% in the diabetic BB rat (not significant). |
| 668 | 2833110 | Thus autophosphorylation of EGF receptor, like that of the insulin receptor, is decreased in insulin-deficient rat liver. |
| 669 | 2833110 | In the case of EGF receptor, this is due in part to a decrease in receptor number and in part to a decrease in the specific activity of the kinase. |
| 670 | 2833110 | Decreased autophosphorylation of EGF receptor in insulin-deficient diabetic rats. |
| 671 | 2833110 | We have previously reported that despite an increase in receptor concentration, there is a decrease in autophosphorylation and tyrosine kinase activity of the insulin receptor in insulin-deficient diabetic rats. |
| 672 | 2833110 | To determine if other tyrosine kinases might be altered, we have studied the epidermal growth factor (EGF) receptor kinase in wheat germ agglutinin-purified, Triton X-100-solubilized liver membranes from streptozotocin (STZ)-induced diabetic rats and the insulin-deficient BB rat. |
| 673 | 2833110 | We find that autophosphorylation of EGF receptor is decreased in proportion to the severity of the diabetic state in STZ rats with a maximal decrease of 67% (P less than 0.01). |
| 674 | 2833110 | A parallel decrease in EGF receptor phosphorylation was also found by immunoblotting with an anti-phosphotyrosine antibody. |
| 675 | 2833110 | EGF receptor concentration, determined by Scatchard analysis of 125I-labeled EGF binding, was decreased by 39% in the STZ rat (P less than 0.05) and 27% in the diabetic BB rat (not significant). |
| 676 | 2833110 | Thus autophosphorylation of EGF receptor, like that of the insulin receptor, is decreased in insulin-deficient rat liver. |
| 677 | 2833110 | In the case of EGF receptor, this is due in part to a decrease in receptor number and in part to a decrease in the specific activity of the kinase. |
| 678 | 2837175 | We have thus studied the properties of liver insulin receptor in that model. 125I-porcine insulin binding was found normal both in isolated plasma membranes and in solubilized, wheat germ agglutinin purified receptors prepared from livers of rats with non-insulin-dependent diabetes, when compared to controls. |
| 679 | 2837175 | Basal and insulin-stimulated insulin receptor kinase activities were also found normal for both the autophosphorylation of the beta subunit of the insulin receptor and the phosphorylation of the artificial substrate poly (Glu-Tyr) 4:1. |
| 680 | 2837175 | We have thus studied the properties of liver insulin receptor in that model. 125I-porcine insulin binding was found normal both in isolated plasma membranes and in solubilized, wheat germ agglutinin purified receptors prepared from livers of rats with non-insulin-dependent diabetes, when compared to controls. |
| 681 | 2837175 | Basal and insulin-stimulated insulin receptor kinase activities were also found normal for both the autophosphorylation of the beta subunit of the insulin receptor and the phosphorylation of the artificial substrate poly (Glu-Tyr) 4:1. |
| 682 | 2838354 | We conclude that high doses of insulin lead to insulin-receptor internalization and recycling through a pathway that is functionally distinct from the pathway taken by receptors internalized by low (physiologic) concentrations of insulin. |
| 683 | 2839227 | Phosphorylation of insulin-like growth factor I receptor by insulin receptor tyrosine kinase in intact cultured skeletal muscle cells. |
| 684 | 2839227 | The interaction between insulin and insulin-like growth factor I (IGF I) receptors was examined by determining the ability of each receptor type to phosphorylate tyrosine residues on the other receptor in intact L6 skeletal muscle cells. |
| 685 | 2842060 | Mutation of the beta-subunit of the insulin receptor by substitution of tyrosyl residue 960 with phenylalanine had no effect on insulin-stimulated autophosphorylation or phosphotransferase activity of the purified receptor. |
| 686 | 2842060 | Therefore, beta-subunit autophosphorylation was not sufficient for the insulin response, and a region of the insulin receptor around Tyr-960 may facilitate phosphorylation of cellular substrates required for transmission of the insulin signal. |
| 687 | 2842060 | Mutation of the beta-subunit of the insulin receptor by substitution of tyrosyl residue 960 with phenylalanine had no effect on insulin-stimulated autophosphorylation or phosphotransferase activity of the purified receptor. |
| 688 | 2842060 | Therefore, beta-subunit autophosphorylation was not sufficient for the insulin response, and a region of the insulin receptor around Tyr-960 may facilitate phosphorylation of cellular substrates required for transmission of the insulin signal. |
| 689 | 2843408 | In adipocyte experiments, HF feeding led to a 65% decrease in the maximal response stimulated by insulin in a 2-deoxyglucose uptake study. |
| 690 | 2843408 | Insulin-stimulated phosphorylation of the beta-subunit of the insulin receptor was decreased to almost 50% throughout the entire dose-response curve. |
| 691 | 2853680 | Characterisation of insulin-like growth factor I receptor in skeletal muscles of normal and insulin resistant subjects. |
| 692 | 2853680 | The insulin-like growth factor I receptor and the activity of its associated tyrosine kinase activity were characterised in wheat germ agglutinin extracts from skeletal muscle biopsies from nine control and ten obese Type 2 (non-insulin-dependent) diabetic subjects, who had marked peripheral in vivo insulin resistance for glucose disposal and hyperinsulinaemia. |
| 693 | 2853680 | In parallel studies, the concentration of the insulin receptor and its tyrosine kinase activity were examined in the biopsy extracts and compared to the findings for the insulin-like growth factor I receptor system. |
| 694 | 2853680 | Specific binding sites for insulin-like growth factor I were detected. |
| 695 | 2853680 | The receptor binding of insulin-like growth factor I was not changed in the obese diabetic subjects as compared to binding activity in the biopsies from the control subjects. |
| 696 | 2853680 | The molecular weight of the insulin-like growth factor I receptor alpha subunit was similar in both groups (135 kDa). |
| 697 | 2853680 | The insulin-like growth factor I stimulated tyrosine kinase activity was also similar for the two groups. |
| 698 | 2853680 | Thus, specific insulin-like growth factor I receptors are present in human skeletal muscle. |
| 699 | 2867167 | To investigate the possibility that metformin (dimethylbiguanide) modifies insulin-mediated glucose metabolism by an effect that is independent of insulin receptor binding, glycogenesis and insulin binding were measured in soleus muscles isolated from streptozocin diabetic mice after treatment with 60 mg kg-1 metformin daily for 10 weeks. |
| 700 | 2867847 | Somatostatin release from freshly isolated and cultured rat islets in response to rat insulin and to anti-insulin serum. |
| 701 | 2867847 | This study deals with the influence insulin exerts upon pancreatic somatostatin release. |
| 702 | 2867847 | No change in somatostatin release was caused by insulin (25 U/l) during perifusion of freshly isolated islets at 8.3 mmol/l glucose, whereas AIS showed an inhibitory effect. |
| 703 | 2867847 | During a 42 hr culture period, somatostatin content of culture medium remained low in the presence of insulin but was elevated when AIS has been added. |
| 704 | 2867847 | Precultivated islets responded to exogenous insulin with a decrease in somatostatin release in static incubations and in perifusion experiments. |
| 705 | 2867847 | The inhibition of somatostatin release from freshly isolated islets observed during perifusion with AIS may be caused by anti-insulin receptor antibodies probably present in the anti-insulin serum. |
| 706 | 2894928 | Serological and/or DNA markers for genes that confer susceptibility to the insulin-dependent form of the disorder (IDDM; type 1) have been identified in the HLA-D region of chromosome 6 and near the insulin gene on chromosome 11. |
| 707 | 2894928 | Patients with non-insulin-dependent diabetes mellitus (NIDDM; type 2) make up a more heterogeneous group than those with IDDM and it is likely that in these patients similar clinical phenotypes may be produced by different genetic defects. |
| 708 | 2894928 | The synthesis of either an abnormal insulin/proinsulin molecule or an abnormal insulin receptor can confer susceptibility to NIDDM. |
| 709 | 2894928 | In addition, studies of restriction fragment length polymorphism and disease associations suggest that two other genes may contribute to the development of NIDDM on chromosome 11, one near the insulin gene on the short arm of this chromosome and the other near the apolipoprotein A-I gene on the long arm. |
| 710 | 2903867 | To determine the role of genetic defects in the insulin receptor in the insulin resistance of lipoatrophic diabetes mellitus, we studied insulin binding, insulin receptor autophosphorylation, and insulin receptor mRNA levels and performed Southern blot analysis of genomic DNA in four siblings, all of whom have some degree of insulin resistance and three of whom have lipoatrophy. |
| 711 | 2906902 | Genotypes identified by two restriction fragment length polymorphisms (RFLPs) of the insulin receptor gene (IRG) with the restriction endonuclease Sst-1 were determined in a Japanese group comprising 51 patients with non-insulin-dependent diabetes mellitus (NIDDM) and 50 control subjects. |
| 712 | 2910904 | Binding studies of insulin and insulin-like growth factor I (IGF-I) showed that cells from diabetic rats had 50% decrease of insulin receptor binding (nondiabetic: 4.6 +/- 0.7; diabetic: 2.6 +/- 0.4% per milligram protein, P less than 0.01), which was caused by a 50% decrease in the number of binding sites per milligram protein, whereas IGF-I binding was not changed. |
| 713 | 2910904 | Insulin stimulation of 2-deoxy-glucose uptake and alpha-aminoisobutyric acid uptake were also severely impaired with a 80-90% decrease in maximal stimulation, in parallel with a 62% decrease in insulin-stimulated autophosphorylation (P less than 0.05). 125I-insulin cross-linking revealed an 140-kD alpha subunit of the insulin receptor similar to that in cells from nondiabetic rats, although bands at greater than 200 kD were also detected. |
| 714 | 2910904 | Binding studies of insulin and insulin-like growth factor I (IGF-I) showed that cells from diabetic rats had 50% decrease of insulin receptor binding (nondiabetic: 4.6 +/- 0.7; diabetic: 2.6 +/- 0.4% per milligram protein, P less than 0.01), which was caused by a 50% decrease in the number of binding sites per milligram protein, whereas IGF-I binding was not changed. |
| 715 | 2910904 | Insulin stimulation of 2-deoxy-glucose uptake and alpha-aminoisobutyric acid uptake were also severely impaired with a 80-90% decrease in maximal stimulation, in parallel with a 62% decrease in insulin-stimulated autophosphorylation (P less than 0.05). 125I-insulin cross-linking revealed an 140-kD alpha subunit of the insulin receptor similar to that in cells from nondiabetic rats, although bands at greater than 200 kD were also detected. |
| 716 | 2958492 | Studies of acute effects of insulin-like growth factors I and II in human fat cells. |
| 717 | 2958492 | The acute metabolic effects and receptor binding of insulin-like growth factors (IGFs) I and II were studied in human adipose tissue. |
| 718 | 2958492 | The IGFs inhibited fat cell glycerol release and stimulated adipocyte 3-O-methylglucose transport and adipose tissue glucose oxidation as effectively as did insulin, but the biological potencies of the IGFs, on a molar basis, were 600-1000 times less than that of insulin. |
| 719 | 2958492 | The insulin dose-response curve for antilipolysis gradually shifted to the left in the presence of submaximally and maximally effective IGF-I concentrations, whereas no additive response was found when fat cells were incubated with maximally effective concentrations of insulin and the IGFs. |
| 720 | 2958492 | In contrast, IGF-I inhibited [125I]insulin binding with a molar potency 1600 times lower than that of native insulin. |
| 721 | 2958492 | In adipose tissue segments obtained from patients with untreated noninsulin-dependent diabetes mellitus, IGF-I and insulin inhibited glycerol release in a normal way. |
| 722 | 2958492 | Conversely, neither insulin nor IGF-I increased the rate of glucose oxidation significantly above the nonhormone-stimulated level. |
| 723 | 2958492 | However, the IGFs definitely produce acute insulin-like effects in the human adipocyte, which seems to be mediated via the insulin receptor. |
| 724 | 2968369 | We conclude (a) that sera from 9/104 diabetics (five insulin-dependent and four noninsulin-dependent) contained a newly identified species of IgG antiinsulin receptor autoantibodies (AIRA), which bound to the insulin receptor at a locus different from the insulin binding site and did not inhibit insulin binding; and (b) that only 1/104 diabetic sera contained low-titer "conventional" antiinsulin receptor autoantibodies that bound to the insulin receptor at or near the insulin binding site, inhibited insulin binding and caused a clinical condition, which was difficult to distinguish from typical NIDDM. |
| 725 | 2969796 | That insulin may be involved in the pathogenesis of these growth-related abnormalities despite resistance to its metabolic effects mediated through the insulin receptor is suggested by the known ability of high concentrations of insulin to stimulate DNA synthesis and cell proliferation in vitro through the insulin-like growth factor I (IGF-I) receptor. |
| 726 | 2969796 | Cultured, transformed T-lymphocytes from an infant with leprechaunism fail to augment basal-colony formation in response to physiologic insulin concentrations in vitro (compared to a doubling seen in normal subjects), but respond normally to supraphysiologic insulin concentrations, the effect of which is competitively inhibited by a monoclonal antibody to the IGF-I receptor. |
| 727 | 2969796 | Thus, insulin action mediated through the IGF-I receptor may initiate growth-promoting tissue effects in the face of limited insulin effect on glucose metabolism. |
| 728 | 2972576 | Clarification of signaling pathways mediated by insulin and insulin-like growth factor I receptors in fibroblasts from patients with specific defect in insulin receptor. |
| 729 | 2972576 | Receptor binding and biological action of insulin and insulin-like growth factor I (IGF-I) were studied in fibroblasts from a patient with leprechaunism and a patient with type A syndrome of insulin resistance. |
| 730 | 2972576 | In competitive binding studies, IGF-I had 0.2% of the ability of insulin to compete with 125I-labeled insulin binding, and insulin had 0.1% of the ability of IGF-I to compete with 125I-labeled IGF-I binding in control subjects and patient fibroblasts. |
| 731 | 2972576 | These results indicate that 1) the defect is specific to the insulin-receptor binding in these patients, 2) insulin and IGF-I activate glucose incorporation and alpha-aminoisobutyric acid uptake mainly through their own specific receptors, but 3) the IGF-I receptor appears to have a more important role in stimulating thymidine incorporation than the insulin receptor in physiological condition or, alternatively, an unknown postreceptor process with cascade signal transmission may overcome the decreased insulin-receptor binding to produce a normal dose-response curve. |
| 732 | 2972576 | Clarification of signaling pathways mediated by insulin and insulin-like growth factor I receptors in fibroblasts from patients with specific defect in insulin receptor. |
| 733 | 2972576 | Receptor binding and biological action of insulin and insulin-like growth factor I (IGF-I) were studied in fibroblasts from a patient with leprechaunism and a patient with type A syndrome of insulin resistance. |
| 734 | 2972576 | In competitive binding studies, IGF-I had 0.2% of the ability of insulin to compete with 125I-labeled insulin binding, and insulin had 0.1% of the ability of IGF-I to compete with 125I-labeled IGF-I binding in control subjects and patient fibroblasts. |
| 735 | 2972576 | These results indicate that 1) the defect is specific to the insulin-receptor binding in these patients, 2) insulin and IGF-I activate glucose incorporation and alpha-aminoisobutyric acid uptake mainly through their own specific receptors, but 3) the IGF-I receptor appears to have a more important role in stimulating thymidine incorporation than the insulin receptor in physiological condition or, alternatively, an unknown postreceptor process with cascade signal transmission may overcome the decreased insulin-receptor binding to produce a normal dose-response curve. |
| 736 | 2990869 | Characterization of the receptors for insulin and the insulin-like growth factors on micro- and macrovascular tissues. |
| 737 | 2990869 | Insulin and insulin-like growth factors (IGFs) have been implicated in the pathogenesis of diabetic retinopathy and peripheral vascular complications. |
| 738 | 2990869 | In contrast, vascular supporting cells from both retinal capillaries (i.e. pericytes) and aorta (i.e. smooth muscle cells) responded equally to insulin, IGF-I, and IGF-II. |
| 739 | 2990869 | Labeling of this band was inhibited by 10(-9) M insulin, antiinsulin receptor antibodies, and 10(-8) M IGF-I, but not by multiplication-stimulating activity (IGF-II). |
| 740 | 2990869 | Covalent cross-linking of IGF-I to its receptor revealed a mol wt of 145,000, similar to that of insulin receptor, except that IGF-I was 100-fold more potent than insulin in competing with [125I]IGF-I for binding. [125I]IGF-II in all cells was cross-linked to receptor with mol wt of 260,000 and 230,000 under reduced and nonreduced conditions, respectively. |
| 741 | 2990869 | IGF-I competed weakly with [125I]IGF-II, whereas insulin was ineffective. [125I]IGF-II also bound to the band with alpha mol wt of 135,000, which was inhibited by insulin, IGF-I, and IGF-II. |
| 742 | 2990869 | In summary, receptors for insulin, IGF-I, and IGF-II on cells from micro- and macrovessels are biochemically similar to those in other cells. |
| 743 | 2990869 | Interestingly, the finding of large numbers of IGF-I and IGF-II receptors on endothelial cells suggests that these growth factors play a physiological role and are involved in vascular complications associated with diabetes. |
| 744 | 3047118 | To further delineate the mechanisms of insulin receptor regulation, we have measured insulin receptor mRNA levels in hydrocortisone-treated and insulin-treated IM-9 lymphocytes. |
| 745 | 3049675 | Insulin receptor function was examined in cultured skin fibroblasts from three patients with leprechaunism (Ark-1, Minn-1, and Can-1), a rare syndrome of severe insulin resistance and neonatal growth retardation. |
| 746 | 3049675 | When normalized to insulin binding, insulin receptor autophosphorylation was normal in cells from Can-1, but reduced in those of Ark-1 and Minn-1. |
| 747 | 3049675 | Insulin receptor function was examined in cultured skin fibroblasts from three patients with leprechaunism (Ark-1, Minn-1, and Can-1), a rare syndrome of severe insulin resistance and neonatal growth retardation. |
| 748 | 3049675 | When normalized to insulin binding, insulin receptor autophosphorylation was normal in cells from Can-1, but reduced in those of Ark-1 and Minn-1. |
| 749 | 3066742 | Chromosome assignment of mouse insulin, colony stimulating factor 1, and low-density lipoprotein receptors. |
| 750 | 3066742 | Receptors for insulin, low-density lipoprotein, and colony stimulating factor 1 are associated with diabetes, atherosclerosis, and cancer in man. |
| 751 | 3066742 | Complementary DNA clones for Insr, Ldlr, and Csfmr were used to chromosomally assign the three genes in mouse. |
| 752 | 3066742 | In contrast to their close linkage on the short arm of human Chromosome 19, Insr and Ldlr are asyntenic, residing on mouse Chromosomes 8 and 9, respectively. |
| 753 | 3066742 | The genes for CSF1R, CSF1, CSF2, IL-3, and IL-5 form a cluster on the long arm of human Chromosome 5. |
| 754 | 3066742 | Chromosome assignment of mouse insulin, colony stimulating factor 1, and low-density lipoprotein receptors. |
| 755 | 3066742 | Receptors for insulin, low-density lipoprotein, and colony stimulating factor 1 are associated with diabetes, atherosclerosis, and cancer in man. |
| 756 | 3066742 | Complementary DNA clones for Insr, Ldlr, and Csfmr were used to chromosomally assign the three genes in mouse. |
| 757 | 3066742 | In contrast to their close linkage on the short arm of human Chromosome 19, Insr and Ldlr are asyntenic, residing on mouse Chromosomes 8 and 9, respectively. |
| 758 | 3066742 | The genes for CSF1R, CSF1, CSF2, IL-3, and IL-5 form a cluster on the long arm of human Chromosome 5. |
| 759 | 3082700 | Insulin receptor antiserum blocked the suppression of GH by 7 nM insulin, but had no effect on the suppression of GH by IGF-I (3.25 nM). |
| 760 | 3082700 | Insulin (7 nM) prevented the stimulation of GH induced by up to 1 nM GRF (P less than 0.01) and this suppression was also selectively blocked by insulin receptor antiserum. |
| 761 | 3082700 | The inhibition of GRF-stimulated GH required a lag period of 48 h and the dose of insulin required for 50% inhibition of GRF stimulation was 3.5 nM. |
| 762 | 3082700 | Fibroblast growth factor, epidermal growth factor, and insulin A-chain at similar doses did not alter basal or GRF-stimulated GH secretion. |
| 763 | 3082700 | Insulin receptor antiserum blocked the suppression of GH by 7 nM insulin, but had no effect on the suppression of GH by IGF-I (3.25 nM). |
| 764 | 3082700 | Insulin (7 nM) prevented the stimulation of GH induced by up to 1 nM GRF (P less than 0.01) and this suppression was also selectively blocked by insulin receptor antiserum. |
| 765 | 3082700 | The inhibition of GRF-stimulated GH required a lag period of 48 h and the dose of insulin required for 50% inhibition of GRF stimulation was 3.5 nM. |
| 766 | 3082700 | Fibroblast growth factor, epidermal growth factor, and insulin A-chain at similar doses did not alter basal or GRF-stimulated GH secretion. |
| 767 | 3125181 | Incubation of the insulin receptor purified from TPA-treated cells with alkaline phosphatase decreased the phosphate content of the beta-subunit to the control level and reversed the inhibition, suggesting that the serine phosphorylation of the beta-subunit was responsible for the decreased tyrosine kinase activity. |
| 768 | 3125181 | Our results support the notion that the insulin receptor is a substrate for protein kinase C in the Fao cell and that the increase in serine phosphorylation of the beta-subunit of the receptor produced by TPA treatment inhibited tyrosine kinase activity in vivo and in vitro. |
| 769 | 3125181 | These data suggest that protein kinase C may regulate the function of the insulin receptor. |
| 770 | 3125181 | Incubation of the insulin receptor purified from TPA-treated cells with alkaline phosphatase decreased the phosphate content of the beta-subunit to the control level and reversed the inhibition, suggesting that the serine phosphorylation of the beta-subunit was responsible for the decreased tyrosine kinase activity. |
| 771 | 3125181 | Our results support the notion that the insulin receptor is a substrate for protein kinase C in the Fao cell and that the increase in serine phosphorylation of the beta-subunit of the receptor produced by TPA treatment inhibited tyrosine kinase activity in vivo and in vitro. |
| 772 | 3125181 | These data suggest that protein kinase C may regulate the function of the insulin receptor. |
| 773 | 3125181 | Incubation of the insulin receptor purified from TPA-treated cells with alkaline phosphatase decreased the phosphate content of the beta-subunit to the control level and reversed the inhibition, suggesting that the serine phosphorylation of the beta-subunit was responsible for the decreased tyrosine kinase activity. |
| 774 | 3125181 | Our results support the notion that the insulin receptor is a substrate for protein kinase C in the Fao cell and that the increase in serine phosphorylation of the beta-subunit of the receptor produced by TPA treatment inhibited tyrosine kinase activity in vivo and in vitro. |
| 775 | 3125181 | These data suggest that protein kinase C may regulate the function of the insulin receptor. |
| 776 | 3139671 | Pertussis toxin activity itself was uninfluenced by insulin, as ribosylation of tubulin or heat-treated bovine serum albumin was unaltered. |
| 777 | 3139671 | Because both protein kinase C and purified insulin receptor phosphorylate purified Gi in vitro, we examined Gi as a substrate for the insulin receptor tyrosine kinase in vivo. |
| 778 | 3149924 | The role of calcium in mediating phorbol ester- and insulin-stimulated adipocyte lipogenesis. |
| 779 | 3149924 | The roles of protein kinase C, calcium and calmodulin in mediating insulin-stimulated lipogenesis by rat adipocytes were investigated using the protein kinase C activator, phorbol myristate acetate (PMA); the protein kinase C inhibitors, H7 and polymixin B; the calcium ionophore, A23187; the calcium channel blocker, verapamil; and the calmodulin inhibitor, calmidazolium. |
| 780 | 3149924 | These data indicate that insulin receptor-lipogenesis coupling in rat adipocytes is mediated by protein kinase C-elicited calcium influx and activation of calmodulin. |
| 781 | 3170749 | Reversibility of defective adipocyte insulin receptor kinase activity in non-insulin-dependent diabetes mellitus. |
| 782 | 3277631 | Reversal of insulin-induced negative cooperativity by monoclonal antibodies that stabilize the slowly dissociating ("Ksuper") state of the insulin receptor. |
| 783 | 3279808 | Receptors for and effects of insulin and IGF-I in rat glomerular mesangial cells. |
| 784 | 3279808 | Receptors for and biological effects of insulin and insulin-like growth factor I (IGF-I) were studied in cultured rat renal mesangial cells. |
| 785 | 3279808 | For 125I-IGF-I, 50% inhibition required 1.8 x 10(-9) M unlabeled IGF-I. 125I-IGF-I was also displaced by IGF-II and insulin but at 10-and 100-fold lower potencies, respectively, than IGF-I. |
| 786 | 3279808 | Cross-linking of 125I-insulin and 125I-IGF-I to their receptors, using disuccinimidyl suberate (DSS), and identification of the receptor with sodium dodecyl sulfate-polyacrylamide gel electrophoresis and autoradiography showed a band with a molecular mass of 135 kDa, probably corresponding to the alpha-subunit of the insulin receptor and a major band with a molecular mass of 145 kDa for the alpha-subunit of the IGF-I receptor. |
| 787 | 3279808 | Both insulin and IGF-I stimulated the incorporation of [3H]thymidine into DNA. |
| 788 | 3279808 | A half-maximal effect was obtained at 1.6 x 10(-8) M for insulin and 1.2 x 10(-9) M for IGF-I. |
| 789 | 3279808 | Insulin at 8 x 10(-10) M increased the accumulation of [14C]glucose in mesangial cells, whereas IGF-I was 10-fold less potent. |
| 790 | 3280181 | Sera from 80 subjects with IDDM and NIDDM, together with sera from 20 patients with miscellaneous autoimmune conditions and 20 healthy adult subjects were tested for insulin receptor antibodies by (1) inhibition of 125I-insulin binding to EBV-transformed lymphoid cells, and by (2) immunoprecipitation of solubilized insulin receptors in the presence of an excess of mono-specific anti-human IgG or IgM; this test allowed the assessment of the class of antibody activity. |
| 791 | 3280181 | Anti-insulin receptor antibodies were found in 13 of 33 subjects with IDDM and six of 47 with NIDDM. |
| 792 | 3280181 | Insulin antibodies were found in seven of 33 subjects with IDDM and six of 12 with NIDDM, all of whom were on insulin treatment. |
| 793 | 3280181 | Sera from 80 subjects with IDDM and NIDDM, together with sera from 20 patients with miscellaneous autoimmune conditions and 20 healthy adult subjects were tested for insulin receptor antibodies by (1) inhibition of 125I-insulin binding to EBV-transformed lymphoid cells, and by (2) immunoprecipitation of solubilized insulin receptors in the presence of an excess of mono-specific anti-human IgG or IgM; this test allowed the assessment of the class of antibody activity. |
| 794 | 3280181 | Anti-insulin receptor antibodies were found in 13 of 33 subjects with IDDM and six of 47 with NIDDM. |
| 795 | 3280181 | Insulin antibodies were found in seven of 33 subjects with IDDM and six of 12 with NIDDM, all of whom were on insulin treatment. |
| 796 | 3282940 | Protein kinase C (PKC) has been suggested as a mediator of insulin's effect on glucose transport, and PKC-mediated modulation of tyrosine kinase activity in the insulin receptor has been implicated in regulating the insulin sensitivity of tissues. |
| 797 | 3286332 | Anti-insulin-receptor antibodies were not detected in any of 33 patients with Graves' disease, and cytoplasmic islet cell antibodies were not detected in sera from seven patients with Graves' disease who had insulin-binding antibodies. |
| 798 | 3291523 | We have compared metabolic parameters, insulin sensitivity and insulin receptor status in 12 patients with insulin-dependent diabetes after 6 months treatment with insulin injection therapy and continuous subcutaneous insulin infusion therapy (CSII) in random order. |
| 799 | 3291523 | Peripheral insulin sensitivity as assessed by the euglycemic clamp, basal hepatic glucose output, glucose carbon recycling, adipocyte insulin binding, adipocyte insulin sensitivity and lipogenesis were all similar after the two treatments. |
| 800 | 3308586 | The relative differences in insulin-mediated biological functions in fetal and adult rat livers as reported previously are due to alterations in a step(s) distal to activation of insulin-receptor kinase. |
| 801 | 3317776 | Assuming that the serum-to-saliva transfer of insulin reflects internalization and re-cycling of the hormone in the membrane-located binding sites of salivary epithelial cells and that these cells have in obesity a'marked decrease in insulin receptor content, it has been postulated that insulin resistance in infantile obesity can be detected by the changes in the salivary immunoreactive insulin during the oral glucose tolerance test (OGTT). |
| 802 | 3391339 | Intact adipocyte insulin-receptor phosphorylation and in vitro tyrosine kinase activity in animal models of insulin resistance. |
| 803 | 3391339 | We evaluated the possibility that impaired insulin-receptor kinase activity contributes to insulin resistance by examining in vitro receptor tyrosine kinase activity and in situ receptor phosphorylation in four models of insulin resistance. |
| 804 | 3391339 | Intact adipocyte insulin-receptor phosphorylation and in vitro tyrosine kinase activity in animal models of insulin resistance. |
| 805 | 3391339 | We evaluated the possibility that impaired insulin-receptor kinase activity contributes to insulin resistance by examining in vitro receptor tyrosine kinase activity and in situ receptor phosphorylation in four models of insulin resistance. |
| 806 | 3511099 | Insulin-binding antibodies were absent from serum, erythrocyte insulin receptor binding was normal, and greater than 90% of circulating immunoreactive insulin coeluted with 125I-labeled insulin on gel filtration. |
| 807 | 3514067 | In Type 1 diabetic patients before insulin pump treatment we found decreased adipocyte insulin binding (p less than 0.01), normal insulin binding to monocytes and erythrocytes, impaired insulin sensitivity of the adipocyte glucose transport (p = 0.02) and reduced basal and maximally insulin-stimulated rates of adipocyte glucose oxidation and lipogenesis (all p less than 0.05). |
| 808 | 3514067 | After pump therapy for 6 months we found a further reduction of basal and maximal adipocyte glucose oxidation and lipogenesis (all p less than or equal to 0.05), whereas we found no significant changes of insulin receptor binding or insulin sensitivity of adipocyte glucose utilization. |
| 809 | 3522628 | However, insulin-stimulated insulin receptor kinase activity was decreased in diabetics. |
| 810 | 3522682 | Because effects of ketone infusion on net fluxes of fatty acids, acetoacetate, and beta-hydroxybutyrate were similar in normal and diabetic, insulin-treated sheep but were diminished or totally absent in diabetic, untreated animals, the mechanism of autoregulation of ketogenesis may be mediated at the insulin receptor or at the site of hepatic fatty acid uptake. |
| 811 | 3530852 | Insulin-receptor number was decreased by 60-70% in obese mice, when expressed per milligram of plasma membrane protein or per microgram of glycoprotein, whereas only a 30-40% diminution was observed in skeletal muscle, indicating that insulin receptors from brown adipose tissue are greatly affected by the downregulation process. |
| 812 | 3530852 | Insulin-stimulated autophosphorylation of the insulin-receptor beta-subunit was decreased by 60-70% in preparations of obese mice compared with lean mice in direct proportion to the diminished level of insulin-receptor number. |
| 813 | 3530852 | Insulin-receptor number was decreased by 60-70% in obese mice, when expressed per milligram of plasma membrane protein or per microgram of glycoprotein, whereas only a 30-40% diminution was observed in skeletal muscle, indicating that insulin receptors from brown adipose tissue are greatly affected by the downregulation process. |
| 814 | 3530852 | Insulin-stimulated autophosphorylation of the insulin-receptor beta-subunit was decreased by 60-70% in preparations of obese mice compared with lean mice in direct proportion to the diminished level of insulin-receptor number. |
| 815 | 3532666 | In a serial study of insulin receptor binding to monocytes from normal pregnant women, a significant increase in insulin binding in mid pregnancy followed by a significant decrease in late pregnancy at tracer insulin concentration was found. |
| 816 | 3533683 | The ability of diacylglycerol to mimic the effects of TPA on the insulin receptor supports the concept of diacylglycerols as endogenous phorbol diester analogues even though the sole role of protein kinase C in our system is doubtful. |
| 817 | 3533684 | Basally and 1 h after cessation of a 20-h infusion of insulin (0.5 mU X kg-1 X min-1, aimed at elevating plasma insulin levels to approximately 30 mU/L) or normal saline, subjects were assessed for glucose turnover with 3-[3H]glucose; insulin sensitivity, as measured by either the euglycemic glucose-clamp technique or the intravenous glucose tolerance test (IVGTT) minimal model method of Bergman; and monocyte insulin-receptor binding. |
| 818 | 3540010 | The tyrosine kinase activity of the insulin receptor was examined with partially-purified insulin receptors from adipocytes obtained from 13 lean nondiabetics, 14 obese nondiabetics, and 13 obese subjects with non-insulin-dependent diabetes (NIDDM). |
| 819 | 3543053 | The insulin receptor contains an alpha subunit with insulin binding properties and a beta subunit with insulin-stimulated tyrosine kinase function. |
| 820 | 3543053 | Preparations containing insulin and insulinlike growth factor I (IGF-I) receptors were obtained from solubilized human red cell membranes by affinity chromatography. |
| 821 | 3549760 | Using high performance liquid chromatography six intracellular forms of radioactivity derived from A14-[125I] insulin were identified; 10-20% of intracellular radioactivity had approximately 300,000 mol wt and was identified as radioactivity bound to the insulin receptor, and the remaining intracellular radioactivity included intact A14-[125I]insulin, [125I]iodide, or [125I]tyrosine, and three intermediate compounds. |
| 822 | 3603112 | Altered mental status, acanthosis nigricans, immune complex glomerulonephritis with nephrotic syndrome, fasting hypoglycemia, and postprandial hyperglycemia associated with anti-insulin receptor antibodies (type B insulin resistance) developed in a 43-year-old black woman who initially was treated for diabetes mellitus. |
| 823 | 3653562 | Previously we have described an insulin resistant patient (leprechaun/Ark-1) with qualitative abnormalities in insulin binding suggestive of a structural defect in her insulin receptors. |
| 824 | 3653562 | In studies of insulin receptors from leprechaun/Ark-1, we observed that both the magnitude and the dose-dependency of insulin's effect to stimulate the tyrosine kinase activity were normal. |
| 825 | 3653562 | In the course of these studies, we noted that an anti-receptor antiserum (B-d) had a markedly decreased ability to immunoprecipitate insulin receptors from leprechaun/Ark-1. |
| 826 | 3653562 | This observation further supports our previous conclusion that the insulin receptor from leprechaun/Ark-1 is abnormal in structure. |
| 827 | 3817302 | Insulin and insulin-receptor autoantibodies in children with newly diagnosed IDDM before insulin therapy. |
| 828 | 3817302 | Twenty-nine children, aged 1-15 yr, with newly diagnosed insulin-dependent diabetes mellitus (IDDM) had sera taken before insulin therapy to be examined for the presence of insulin-receptor antibodies by measuring the inhibition of binding of radiolabeled insulin to IM-9 lymphocytes in both whole serum and purified IgG fractions. |
| 829 | 3817302 | Insulin-receptor antibodies and insulin autoantibodies may play a currently undefined pathophysiologic role in the development of IDDM. |
| 830 | 3817302 | Insulin and insulin-receptor autoantibodies in children with newly diagnosed IDDM before insulin therapy. |
| 831 | 3817302 | Twenty-nine children, aged 1-15 yr, with newly diagnosed insulin-dependent diabetes mellitus (IDDM) had sera taken before insulin therapy to be examined for the presence of insulin-receptor antibodies by measuring the inhibition of binding of radiolabeled insulin to IM-9 lymphocytes in both whole serum and purified IgG fractions. |
| 832 | 3817302 | Insulin-receptor antibodies and insulin autoantibodies may play a currently undefined pathophysiologic role in the development of IDDM. |
| 833 | 3817302 | Insulin and insulin-receptor autoantibodies in children with newly diagnosed IDDM before insulin therapy. |
| 834 | 3817302 | Twenty-nine children, aged 1-15 yr, with newly diagnosed insulin-dependent diabetes mellitus (IDDM) had sera taken before insulin therapy to be examined for the presence of insulin-receptor antibodies by measuring the inhibition of binding of radiolabeled insulin to IM-9 lymphocytes in both whole serum and purified IgG fractions. |
| 835 | 3817302 | Insulin-receptor antibodies and insulin autoantibodies may play a currently undefined pathophysiologic role in the development of IDDM. |
| 836 | 3884963 | Binding of insulin to IgG, IgM, and IgE was not increased, insulin binding to monocytes and erythrocytes was not sufficiently abnormal to account for the the insulin resistance, and insulin receptor increased insulin clearance or accelerated degradation of insulin by tissues. |
| 837 | 3890451 | The insulin receptor is not the site for the stimulatory effect of copper on glucose incorporation into total lipids by adipose tissue; prewashing of adipose tissue of rats fed a stock diet in an insulin-free medium increases the glucose incorporation into total lipids in the presence of 0.1 unit insulin from 220 above control to 430% in the nondiabetic and from 154 to 230% in the streptozotocin-diabetic rat. |
| 838 | 3890451 | On the other hand, mild trypsin digestion of adipocytes decreases the glucose incorporation in the presence of 28.5 mU insulin, from 201 to 126% - whereas the effect of copper on glucose incorporation is the same in the trypsin-treated or untreated adipocyte. |
| 839 | 3890451 | In order to obtain maximal copper effect the adipocyte has to be preconditioned by insulin; preincubation of diabetic adipose tissue first for one hour with 0.1 unit insulin, and another hour with 100 micrograms CuCl2 X 2H2O added to the medium, results in greater glucose incorporation (230% above control) than when incubated alone with either CuCl2 X 2H2O (125%) or insulin (154%) for two hours. |
| 840 | 3890853 | To determine if the postbinding hepatic insulin resistance of nonketotic diabetes mellitus could reside in an inability of insulin to stimulate insulin receptor autophosphorylation, we evaluated the ability of insulin to stimulate 32P incorporation into the beta subunit of lectin-purified rat liver plasma membrane insulin receptors. |
| 841 | 3890853 | We conclude, therefore, that the hepatic insulin resistance of nonketotic diabetes mellitus resides distal to insulin receptor binding and autophosphorylation and is reflected in metabolic events at or near the plasma membrane which may include the generation or release of the putative mediator of insulin action. |
| 842 | 3890853 | To determine if the postbinding hepatic insulin resistance of nonketotic diabetes mellitus could reside in an inability of insulin to stimulate insulin receptor autophosphorylation, we evaluated the ability of insulin to stimulate 32P incorporation into the beta subunit of lectin-purified rat liver plasma membrane insulin receptors. |
| 843 | 3890853 | We conclude, therefore, that the hepatic insulin resistance of nonketotic diabetes mellitus resides distal to insulin receptor binding and autophosphorylation and is reflected in metabolic events at or near the plasma membrane which may include the generation or release of the putative mediator of insulin action. |
| 844 | 3894119 | We studied the effect of aerobic training and detraining on insulin-stimulated glucose disposal and on erythrocyte insulin receptor binding. |
| 845 | 3894560 | Cortisol implants in normal and diabetic rats reduced body weight, adiposity, insulin receptor concentration and both basal and insulin-stimulated rates of lipogenesis in isolated adipocytes, whilst insulin sensitivity was unchanged. |
| 846 | 3894560 | In contrast, progesterone implants in normal and diabetic rats increased body weight gain, adiposity, insulin receptor concentration and both basal and insulin-stimulated rates of lipogenesis in adipose tissue, again without affecting insulin sensitivity. |
| 847 | 3894560 | The results suggest that cortisol inhibits lipogenesis in adipose tissue without affecting insulin sensitivity, cortisol reduces insulin binding in adipose tissue without a requirement for hyperinsulinaemia, which might itself indirectly lead to down-regulation of the insulin receptor, and in diabetic rats progesterone stimulates lipogenesis in adipose tissue without any increase in food intake or serum insulin concentrations suggesting that progesterone may have a direct anabolic role in adipose tissue. |
| 848 | 3894560 | Cortisol implants in normal and diabetic rats reduced body weight, adiposity, insulin receptor concentration and both basal and insulin-stimulated rates of lipogenesis in isolated adipocytes, whilst insulin sensitivity was unchanged. |
| 849 | 3894560 | In contrast, progesterone implants in normal and diabetic rats increased body weight gain, adiposity, insulin receptor concentration and both basal and insulin-stimulated rates of lipogenesis in adipose tissue, again without affecting insulin sensitivity. |
| 850 | 3894560 | The results suggest that cortisol inhibits lipogenesis in adipose tissue without affecting insulin sensitivity, cortisol reduces insulin binding in adipose tissue without a requirement for hyperinsulinaemia, which might itself indirectly lead to down-regulation of the insulin receptor, and in diabetic rats progesterone stimulates lipogenesis in adipose tissue without any increase in food intake or serum insulin concentrations suggesting that progesterone may have a direct anabolic role in adipose tissue. |
| 851 | 3894560 | Cortisol implants in normal and diabetic rats reduced body weight, adiposity, insulin receptor concentration and both basal and insulin-stimulated rates of lipogenesis in isolated adipocytes, whilst insulin sensitivity was unchanged. |
| 852 | 3894560 | In contrast, progesterone implants in normal and diabetic rats increased body weight gain, adiposity, insulin receptor concentration and both basal and insulin-stimulated rates of lipogenesis in adipose tissue, again without affecting insulin sensitivity. |
| 853 | 3894560 | The results suggest that cortisol inhibits lipogenesis in adipose tissue without affecting insulin sensitivity, cortisol reduces insulin binding in adipose tissue without a requirement for hyperinsulinaemia, which might itself indirectly lead to down-regulation of the insulin receptor, and in diabetic rats progesterone stimulates lipogenesis in adipose tissue without any increase in food intake or serum insulin concentrations suggesting that progesterone may have a direct anabolic role in adipose tissue. |
| 854 | 3915257 | Characterization of an insulin degrading enzyme from cultured human lymphocytes. |
| 855 | 3915257 | An insulin degrading enzyme from cultured human lymphocytes, IM-9 cells, has been purified and characterized. |
| 856 | 3915257 | Furthermore, this insulin degrading enzyme was found to have no effect on the structure of the insulin receptor nor to be linked to the insulin receptor either on the plasma membrane of cells or when they are shed into the media. |
| 857 | 3915270 | Provided the monocyte insulin receptor reflects insulin receptors of more determinant tissues for insulin action, our data indicate that an increased insulin receptor binding is not involved in the improved insulin effectiveness of gestational diabetics after hypoenergetic dieting. |
| 858 | 3918399 | Before treatment, the adipocyte insulin receptor binding and the sensitivity to insulin stimulation of adipose tissue glucose oxidation were normal and did not change after treatment. |
| 859 | 4077982 | Although the cells of patient A-7 have a normal number of insulin receptors, we have detected subtle abnormalities in the posttranslational processing of the insulin receptor precursor, which may be a biochemical marker for a postbinding defect that causes insulin resistance in this patient. |
| 860 | 6096045 | Both insulin and the related peptides, the insulin-like growth factors/somatomedins, may function as anabolic factors in the regulation of fetal body size. |
| 861 | 6096045 | Insulin-like growth factors I (IGFI) and II are present in the circulation of the newborn infant and animal fetus and correlate positively with birth size. |
| 862 | 6096045 | The fetal tissues are biologically responsive to IGFs in vitro and are rich in specific cell membrane receptors, those predominantly recognizing IGFI being structurally and functionally similar to the insulin receptor. |
| 863 | 6096045 | Fetal IGF production may be influenced by placental lactogen, especially IGFII which rapidly declines in the circulation following parturition in the rat and sheep. |
| 864 | 6096045 | Similarly the infant born with transient diabetes mellitus has low cord blood levels of insulin and IGFI. |
| 865 | 6293791 | Increased insulin receptor binding to monocytes from insulin-dependent diabetic patients after a low-fat, high-starch, high-fiber diet. |
| 866 | 6295857 | Insulin-induced loss of insulin-like growth factor-I receptors on IM-9 lymphocytes. |
| 867 | 6295857 | Preexposure of IM-9 lymphocytes to the somatomedin peptide insulin-like growth factor-I (IGF-I) results in a time- and concentration-dependent reduction in specific receptors for IGF-I. |
| 868 | 6295857 | Since insulin and proinsulin are structurally homologous to IGF-I, we investigated the ability of insulin analogues to compete for occupancy and to directly modulate IGF-I receptor concentrations. |
| 869 | 6295857 | IGF-I binds rapidly and reversibly to IM-9 cells at 15 degrees C, with half-maximal displacement of 125I-I-IGF-I at IGF-I concentrations of 3.6 X 10(-9) M and insulin concentrations of 5 x 10(-7) M. |
| 870 | 6295857 | Preexposure of cells at 37 degrees C to either IGF-I or insulin produced a concentration-dependent reduction in binding of 125I-IGF-I. |
| 871 | 6295857 | A 50% decrease in binding was observed following preincubation of cells with IGF-I at 2.5 x 10(-9) M and insulin at 2 x 10(-7) M. |
| 872 | 6295857 | Bovine proinsulin and guinea pig insulin competed less potently than porcine insulin for the IGF-I receptor, and produced receptor loss in proportion to their ability to occupy the IGF-I receptor. |
| 873 | 6295857 | Scatchard analysis indicated that at all insulin concentrations, the decrease in binding was secondary to loss of available IGF-I receptors, with no change in affinity. |
| 874 | 6295857 | Similarly, IGF-I and IGF-II competed for occupancy of the IM-9 insulin receptor, with 50% displacement of 125I-insulin occurring at peptide concentrations of 3.5 x 10(-9) M (insulin), 3.5 x 10(-8) M (IGF-II), and 3 x 10(-7) M (IGF-I). |
| 875 | 6295857 | Preexposure of cells to these peptides at 37 degrees C for 20 h resulted in a concentration-dependent reduction in binding of 125I-insulin, with the order of analogue effectiveness being insulin greater than IGF-II greater than IGF-I. |
| 876 | 6295857 | These data emphasize the structural and functional homology of insulin and the somatomedin peptides, IGF-I and II, as well as their respective receptors. |
| 877 | 6307791 | We conclude that on the cell surface of the adipocyte, there is one molecular-weight form of insulin receptor of 380 kDa composed of one 130-kDa, one 90-kDa, one 85-kDa, and two 40-kDa subunits. |
| 878 | 6337485 | Direct addition of insulin, concanavalin A or anti-insulin receptor antibody to this system resulted in the production of a mediator substance from the plasma membrane that caused dephosphorylation of the alpha subunit of pyruvate dehydrogenase in the mitochondria with concomitant activation of the enzyme. |
| 879 | 6337485 | The mediator activated pyruvate dehydrogenase by activating the pyruvate dehydrogenase phosphatase and not by inhibiting the pyruvate dehydrogenase kinase. |
| 880 | 6337485 | The insulin-sensitive mediator material from the adipocyte plasma membrane was acid-stable with a molecular weight of 1,000 to 1,500. |
| 881 | 6337485 | We have shown the mediator to mimic insulin action on the low Km cyclic adenosine monophosphate (AMP) phosphodiesterase and the (calcium++-magnesium++)-adenosine triphosphatase (Ca++-Mg++)-ATPase of adipocyte plasma membranes in addition to pyruvate dehydrogenase. |
| 882 | 6337893 | Insulin receptor affinity was significantly higher in subcutaneous than in omental fat cells, but there was no difference in receptor number (about 300,000 sites/cell). 125I-insulin dissociated more rapidly from omental than from subcutaneous adipocytes in both the absence and the presence of excess native insulin. |
| 883 | 6338670 | These findings suggest that the increased insulin sensitivity characteristic for adrenocortical insufficiency is not an effect of an increased insulin receptor concentration and that hypocortisolaemia is associated with a down-regulation of the insulin receptors. |
| 884 | 6343099 | Insulin receptor binding and insulin-mediated glucose uptake in type-II-diabetics. |
| 885 | 6346102 | Autoantibodies to the insulin receptor in juvenile onset insulin-dependent diabetes. |
| 886 | 6346102 | Insulin-dependent diabetes mellitus (IDDM) usually begins in childhood or early adulthood, and its aetiology is thought to involve autoimmune damage to the islet cells that secrete insulin. |
| 887 | 6346102 | To investigate an additional target of autoimmunity in IDDM we examined sera for antibodies to insulin receptors. |
| 888 | 6346102 | We now report the occurrence of anti-insulin receptor antibodies of the IgM class in the sera of 10 of 22 IDDM patients obtained before their treatment with exogenous insulin. |
| 889 | 6346102 | Furthermore, two of five IDDM patients who were initially negative developed anti-insulin receptor antibodies during treatment with human or pork insulin. |
| 890 | 6346102 | These findings suggest that autoimmunity to the insulin receptor may contribute to the pathophysiology of IDDM. |
| 891 | 6346102 | Autoantibodies to the insulin receptor in juvenile onset insulin-dependent diabetes. |
| 892 | 6346102 | Insulin-dependent diabetes mellitus (IDDM) usually begins in childhood or early adulthood, and its aetiology is thought to involve autoimmune damage to the islet cells that secrete insulin. |
| 893 | 6346102 | To investigate an additional target of autoimmunity in IDDM we examined sera for antibodies to insulin receptors. |
| 894 | 6346102 | We now report the occurrence of anti-insulin receptor antibodies of the IgM class in the sera of 10 of 22 IDDM patients obtained before their treatment with exogenous insulin. |
| 895 | 6346102 | Furthermore, two of five IDDM patients who were initially negative developed anti-insulin receptor antibodies during treatment with human or pork insulin. |
| 896 | 6346102 | These findings suggest that autoimmunity to the insulin receptor may contribute to the pathophysiology of IDDM. |
| 897 | 6346102 | Autoantibodies to the insulin receptor in juvenile onset insulin-dependent diabetes. |
| 898 | 6346102 | Insulin-dependent diabetes mellitus (IDDM) usually begins in childhood or early adulthood, and its aetiology is thought to involve autoimmune damage to the islet cells that secrete insulin. |
| 899 | 6346102 | To investigate an additional target of autoimmunity in IDDM we examined sera for antibodies to insulin receptors. |
| 900 | 6346102 | We now report the occurrence of anti-insulin receptor antibodies of the IgM class in the sera of 10 of 22 IDDM patients obtained before their treatment with exogenous insulin. |
| 901 | 6346102 | Furthermore, two of five IDDM patients who were initially negative developed anti-insulin receptor antibodies during treatment with human or pork insulin. |
| 902 | 6346102 | These findings suggest that autoimmunity to the insulin receptor may contribute to the pathophysiology of IDDM. |
| 903 | 6346102 | Autoantibodies to the insulin receptor in juvenile onset insulin-dependent diabetes. |
| 904 | 6346102 | Insulin-dependent diabetes mellitus (IDDM) usually begins in childhood or early adulthood, and its aetiology is thought to involve autoimmune damage to the islet cells that secrete insulin. |
| 905 | 6346102 | To investigate an additional target of autoimmunity in IDDM we examined sera for antibodies to insulin receptors. |
| 906 | 6346102 | We now report the occurrence of anti-insulin receptor antibodies of the IgM class in the sera of 10 of 22 IDDM patients obtained before their treatment with exogenous insulin. |
| 907 | 6346102 | Furthermore, two of five IDDM patients who were initially negative developed anti-insulin receptor antibodies during treatment with human or pork insulin. |
| 908 | 6346102 | These findings suggest that autoimmunity to the insulin receptor may contribute to the pathophysiology of IDDM. |
| 909 | 6347782 | These results show that insulin receptor binding is diminished in Type 1 diabetes, perhaps as a consequence of higher peripheral blood insulin levels and that metformin can improve binding, and so reduce the amount of insulin needed to reach euglycaemia. |
| 910 | 6352381 | Age was significantly and negatively correlated with insulin receptor number (r = -0.81), basal production of 14CO2 (r = -0.73) and maximum level of insulin-induced glucose oxidation (r =- -0.68). |
| 911 | 6354791 | The data showed that ciglitazone increased the basal rate of glucose metabolism, lipogenesis, insulin receptor number, and post-receptor responses in the C57BL/6J-ob/ob mice; it increased the basal rate of glucose metabolism and lipogenesis but not insulin sensitivity in the lean mice. |
| 912 | 6360764 | Insulin-induced internalization of the insulin receptor in the isolated rat adipose cell. |
| 913 | 6369968 | Among its other qualities, it has been shown (1) to stimulate insulin action through extrapancreatic effects that affect insulin-receptor binding and enhance tissue responsiveness to insulin; (2) to favorably influence the principal pathophysiologic abnormalities, defective secretory dynamics, and target-cell resistance to insulin observed in noninsulin-dependent diabetes; (3) to improve control of blood glucose, and when used in conjunction with insulin, to achieve glycemic control with reductions in insulin dosage; (4) to lower the level of plasma glucose and to maintain this effect despite a short half-life; (5) to stimulate insulin secretion following its oral administration; (6) to be more effective than tolbutamide in elderly patients with long-standing diabetes; and (7) to be well tolerated with few side effects. |
| 914 | 6376034 | To determine whether long-term sulfonylurea therapy ameliorates glucose homeostasis in patients with NIDDM predominantly by improving insulin secretion or by improving insulin action, we evaluated changes in fasting plasma glucose concentrations, intravenous glucose tolerance, glucose-stimulated insulin secretion, facilitation of glucose disposal by exogenous insulin, and erythrocyte insulin receptor binding before and after prolonged (congruent to 4 mo) administration of tolazamide to 18 patients with NIDDM. |
| 915 | 6376034 | The insulin-resistant patients had fasting hyperinsulinemia (19 +/- 4 vs 11 +/- 1 microU/ml in nondiabetic subjects, P less than 0.05), decreased erythrocyte insulin receptor binding (4.8 +/- 0.4 vs 5.8 +/- 0.3%/1.6 X 10(9) cells in nondiabetic subjects, P less than 0.05), and impairment in both insulin-induced suppression of glucose production (Km 97 +/- 31 vs 21 +/- 7 microU/ml in nondiabetic subjects, P less than 0.05), and insulin-induced stimulation of glucose utilization (Km and Vmax 176 +/- 29 microU/ml and 5.8 +/- 0.7 mg/kg/min vs 50 +/- 2 microU/ml and 9.1 +/- 0.6 mg/kg/min in nondiabetic subjects, both P less than 0.05). |
| 916 | 6376034 | To determine whether long-term sulfonylurea therapy ameliorates glucose homeostasis in patients with NIDDM predominantly by improving insulin secretion or by improving insulin action, we evaluated changes in fasting plasma glucose concentrations, intravenous glucose tolerance, glucose-stimulated insulin secretion, facilitation of glucose disposal by exogenous insulin, and erythrocyte insulin receptor binding before and after prolonged (congruent to 4 mo) administration of tolazamide to 18 patients with NIDDM. |
| 917 | 6376034 | The insulin-resistant patients had fasting hyperinsulinemia (19 +/- 4 vs 11 +/- 1 microU/ml in nondiabetic subjects, P less than 0.05), decreased erythrocyte insulin receptor binding (4.8 +/- 0.4 vs 5.8 +/- 0.3%/1.6 X 10(9) cells in nondiabetic subjects, P less than 0.05), and impairment in both insulin-induced suppression of glucose production (Km 97 +/- 31 vs 21 +/- 7 microU/ml in nondiabetic subjects, P less than 0.05), and insulin-induced stimulation of glucose utilization (Km and Vmax 176 +/- 29 microU/ml and 5.8 +/- 0.7 mg/kg/min vs 50 +/- 2 microU/ml and 9.1 +/- 0.6 mg/kg/min in nondiabetic subjects, both P less than 0.05). |
| 918 | 6378598 | Binding of [125I]insulin to retinal microvessels, followed by covalent cross-linking of the bound ligand to the alpha-subunit of the insulin receptor with the bifunctional reagent disuccinimidyl suberate, yielded a prominent specific [125I]insulin-labeled band when analyzed by sodium dodecyl sulfate-gel electrophoresis followed by autoradiography, and this band had a mobility identical to that of the corresponding complex obtained with rat liver plasma membranes (mol wt, 125,000). |
| 919 | 6378700 | After covalent cross-linking of 125I-insulin to the insulin receptor on cultured human lymphocytes (IM-9 cells) using disuccinimidyl suberate, we inquired whether the insulin-receptor complex could be immunoprecipitated with anti-insulin antibodies. |
| 920 | 6378702 | Maximum binding at 37 degrees C occurred at 90 min, and was 3.8%/mg protein and, at 15 degrees C, 7%/mg protein at 4 h. 125I-insulin was crosslinked to its receptor using disuccinimidyl suberate (DSS), and the structure of the receptor complex was identified by SDS-polyacrylamide gel electrophoresis and autoradiography; a major band with Mr = 145,000 was identified, which corresponds to the alpha-subunit of the insulin receptor reported in other tissues. |
| 921 | 6385424 | It is suggested that in insulin-induced regulation of insulin receptor number the relationship between intracellular membrane receptors and receptors in the plasma membrane and nuclear envelope is the same. |
| 922 | 6389099 | In this study, results from Scatchard analysis for insulin receptor on hepatocytes of streptozotocin (STZ)-induced diabetic rats were compared with those from association and dissociation studies and those from Scatchard analysis using hepatocyte membrane which does not internalize insulin. |
| 923 | 6389544 | Insulin-stimulated (10(-7) M) phosphorylation of the beta subunit of the insulin receptor was decreased by 40% in diabetic rats when equal quantities of insulin binding capacity were compared. |
| 924 | 6392291 | These data suggest that the insulin resistance in this syndrome is due to a genetic abnormality which impairs insulin receptor phosphorylation and kinase activity and further support the possible role of receptor phosphorylation and kinase activity in insulin action. |
| 925 | 6397418 | The method for detecting antibodies to the insulin receptor was interfered by the presences of serum insulin with a relatively high levels and anti-insulin antibodies in the direct incubation method in which serum and radioinsulin were incubated simultaneously, but the interference by anti-insulin antibody was avoided in the indirect incubation method in which the receptor incubated with serum was washed before incubation with radioinsulin. |
| 926 | 6397418 | In the first case with hypoglycemia due to extrapancreatic tumor, a low insulin immunoreactivity and a high insulin-like activity (ILA) measured with receptor assay were observed. |
| 927 | 6397418 | In considering the ILA in her serum, the presence of immunoinactive insulin-like substance with hypoglycemic action was speculated. |
| 928 | 6432611 | To directly examine the relationship between insulin receptors and insulin action in fetal tissue, we compared insulin receptor characteristics and insulin-mediated 14C-glucose incorporation into glycogen, as well as glycogen synthase activity, in freshly isolated hepatocytes from 21-day fetal (F) and adult (A) rats. |
| 929 | 6642085 | Red blood cell age, pyruvate kinase activity, and insulin receptors. |
| 930 | 6642085 | Data emerging from insulin receptor studies performed on red blood cells (RBCs) and monocytes from the same subject are not always in agreement; dichotomy might occur since variations in mean RBC age are not taken into account or because insulin receptors on the two cell types behave differently. |
| 931 | 6642085 | Insulin binding varied significantly depending upon the RBC population tested and was closely correlated to the activity of pyruvate kinase (r2 = 0.86), a well-known marker of RBC age. |
| 932 | 6642085 | To confirm this hypothesis, RBCs from 10 normal male subjects and 13 male patients with hemolytic anemia were studied; insulin binding was correlated to pyruvate kinase activity. |
| 933 | 6642085 | By adjusting insulin binding to 2 X 10(9) RBCs/ml the range of data was abnormally high, but it became acceptable after adjusting insulin binding to pyruvate kinase activity (0.75 U/2 X 10(9) RBCs). |
| 934 | 6642085 | The overall data indicated that insulin binding was highly correlated to pyruvate kinase activity (r2 = 0.82) but only slightly to reticulocyte number (r2 = 0.56) since not only reticulocytes but also erythrocytes lose receptors during maturation. |
| 935 | 6694560 | Perfusion with POCA selectively inhibited the activity of carnitine palmitoyltransferase 1, but had no influence on the activities of carnitine palmitoyltransferase 2, pyruvate dehydrogenase, and triglyceride lipase. |
| 936 | 6694560 | Whereas the disturbances of glucose oxidation are mediated by the excessive metabolism of endogenous triglycerides, the reason for the disturbed glycogen synthesis remains unclear. (2) Since in vitro perfusion with POCA partially restored the insulin sensitivity of the diabetic hearts, insulin-receptor defects should be of minor importance for the insulin resistance of diabetic hearts. (3) Since POCA inhibited carnitine palmitoyltransferase 1 and reduced the rate of lipolysis but had no effect on triglyceride lipase activity, we assume that product inhibition plays an important role in the regulation of myocardial lipolysis. |
| 937 | 6694560 | In summary, inhibition of carnitine palmitoyltransferase 1 by POCA is suggested to be a useful approach for restoring insulin sensitivity depressed by an excessive metabolism of lipids. |
| 938 | 6759222 | Sulfonylureas alone are ineffective in the therapy of insulin-independent diabetes mellitus (IDDM). |
| 939 | 6759222 | We studied 11 patients with IDDM to determine whether chlorpropamide acts directly on the insulin receptor and whether it could augment the effect of insulin on glycemic control. |
| 940 | 6759222 | We conclude that short-term use of chlorpropamide in addition to insulin in IDDM does not alter insulin binding to circulating monocytes or erythrocytes. |
| 941 | 6759222 | In addition, we were unable to show that this agent is a clinically useful adjunct to insulin in IDDM. |
| 942 | 6761209 | Insulin receptor binding to fat and blood cells and insulin action in fat cells from insulin-dependent diabetics. |
| 943 | 6765518 | Specific cell binding of human proinsulin was significantly lower compared with the human insulin receptor binding with an approximately 100-fold lower average affinity (3.71 mol-1 X 10(8) for human insulin versus 0.042 mol-1 X 10(8) for human proinsulin). |
| 944 | 6765518 | Native human proinsulin at low concentrations had no significant effect on specific human insulin receptor binding. |
| 945 | 6765518 | Only at high hormone concentrations human proinsulin could displace human insulin from the insulin receptor. |
| 946 | 6765518 | Specific cell binding of human proinsulin was significantly lower compared with the human insulin receptor binding with an approximately 100-fold lower average affinity (3.71 mol-1 X 10(8) for human insulin versus 0.042 mol-1 X 10(8) for human proinsulin). |
| 947 | 6765518 | Native human proinsulin at low concentrations had no significant effect on specific human insulin receptor binding. |
| 948 | 6765518 | Only at high hormone concentrations human proinsulin could displace human insulin from the insulin receptor. |
| 949 | 6765518 | Specific cell binding of human proinsulin was significantly lower compared with the human insulin receptor binding with an approximately 100-fold lower average affinity (3.71 mol-1 X 10(8) for human insulin versus 0.042 mol-1 X 10(8) for human proinsulin). |
| 950 | 6765518 | Native human proinsulin at low concentrations had no significant effect on specific human insulin receptor binding. |
| 951 | 6765518 | Only at high hormone concentrations human proinsulin could displace human insulin from the insulin receptor. |
| 952 | 6997311 | These results indicate that in comparison with fibroblastic cultures from nondiabetic animals, those from diabetic animals expressed differences in insulin receptor numbers which are maintained in culture over many generations and are accompanied by diminished insulin responses. |
| 953 | 7015070 | The insulin receptor in insulin-dependent diabetes mellitus: an in vivo and in vitro study. |
| 954 | 7021273 | Characterization of insulin-induced receptor loss and evidence for internalization of the insulin receptor. |
| 955 | 7046470 | Resistance to the action of insulin can result from a variety of causes, including the formation of abnormal insulin or proinsulin molecules, the presence of circulating antagonists to insulin or the insulin receptor, or defects in insulin action at the target tissue level. |
| 956 | 7050215 | Newer terminology identifies those uncommon patients with true insulin deficiency as having insulin-dependent diabetes (IDDM), while the majority of patients with diabetes have some residual insulin secretion but may have a disorder of insulin receptor number or affinity. |
| 957 | 7149890 | [Adrenoleukodystrophy and diabetes mellitus caused by insulin receptor deficiency]. |
| 958 | 7350438 | Plasma proinsulin, glucagon, growth hormone, and cortisol levels were normal; insulin antibodies and insulin-receptor antibodies were not detected. |
| 959 | 7429030 | Three forms of disulfide-linked insulin receptor complexes are labeled by covalent cross-linking to receptor-bound 125I-insulin in native adipocyte or liver membranes. |
| 960 | 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. |
| 961 | 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. |
| 962 | 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. |
| 963 | 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. |
| 964 | 7486683 | Moreover, PDGF, but not insulin, caused tyrosine phosphorylation of phospholipase C gamma in HIR 3.5 cells. |
| 965 | 7486683 | Thus, the insulin signal differs from that of PDGF by the insertion of a cytosolic, nonreceptor SH2 domain docking protein (IRS-1). |
| 966 | 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. |
| 967 | 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. |
| 968 | 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. |
| 969 | 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. |
| 970 | 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. |
| 971 | 7486683 | Moreover, PDGF, but not insulin, caused tyrosine phosphorylation of phospholipase C gamma in HIR 3.5 cells. |
| 972 | 7486683 | Thus, the insulin signal differs from that of PDGF by the insertion of a cytosolic, nonreceptor SH2 domain docking protein (IRS-1). |
| 973 | 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. |
| 974 | 7487920 | Two compounds, (naphth-2-yl) difluoromethylphosphonic acid (12) and (napthy-1-yl) difluoromethylphosphonic acid (13) have been found to inhibit dephosphorylation of [32P]insulin receptors by PTP-1B, a protein tyrosine phosphatase (PTPase), with IC50 values of 40-50 microM. |
| 975 | 7487920 | Compound 12 competitively inhibited insulin-receptor dephosphorylation by PTP-1B. |
| 976 | 7487920 | Nine out of the 15 compounds potently inhibited serine/threonine phosphatase PP-2A activity without any effect on serine/threonine phosphatase PP-1 when tested at a concentration as high as 675 microM. |
| 977 | 7487920 | These PP-2A inhibitors could be useful tools for studying serine/threonine-phosphatase-mediated signal transduction. |
| 978 | 7487920 | Two compounds, 12 and 13, inhibited both tyrosine phosphatase PTP-1B and serine/threonine phosphatase PP-2A with similar potency; IC50 values being 40-50 microM in both cases. |
| 979 | 7497000 | The insulin-like growth factor I (IGF-I) receptor mediates most of the biological effects of IGF-I and -II. |
| 980 | 7497000 | Despite its structural similarity to the insulin receptor, the IGF-I receptor is mainly involved in the transduction of growth and differentiation types of signals. |
| 981 | 7497000 | Transcription factor Sp1 is a strong activator of IGF-I receptor gene expression, whereas tumor suppressor WT1 represses its activity. |
| 982 | 7504175 | Pleiotropic insulin signals are engaged by multisite phosphorylation of IRS-1. |
| 983 | 7504175 | Tyrosine-phosphorylated IRS-1 binds specifically to various cellular proteins containing Src homology 2 (SH2) domains (SH2 proteins). |
| 984 | 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. |
| 985 | 7504175 | These results extend the notion that IRS-1 is a multisite docking protein that engages various downstream regulatory elements during insulin signal transmission. |
| 986 | 7505243 | Expression under the control of the mouse transferrin promoter of a transgene encoding a soluble secreted derivative of the ectodomain of the human insulin receptor in transgenic mice results in the accumulation of this high-affinity insulin-binding protein in the plasma. |
| 987 | 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. |
| 988 | 7505252 | Thus, the insulin receptor, IRS-1 and PI-3 kinase represent three of the earliest steps in insulin action at the cellular level. |
| 989 | 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. |
| 990 | 7508873 | Vanadate augments insulin-stimulated insulin receptor kinase activity and prolongs insulin action in rat adipocytes. |
| 991 | 7508873 | However, insulin-stimulated IRK activity was markedly augmented by vanadate to 319 +/- 19% of insulin alone, associated with a similar augmentation of phosphotyrosine incorporation into the insulin receptor beta-subunit determined by Western blotting with antiphosphotyrosine antibodies. |
| 992 | 7508873 | Vanadate augments insulin-stimulated insulin receptor kinase activity and prolongs insulin action in rat adipocytes. |
| 993 | 7508873 | However, insulin-stimulated IRK activity was markedly augmented by vanadate to 319 +/- 19% of insulin alone, associated with a similar augmentation of phosphotyrosine incorporation into the insulin receptor beta-subunit determined by Western blotting with antiphosphotyrosine antibodies. |
| 994 | 7508875 | Acute hyperglycemia (25 mM glucose) induced a significant inhibition of the insulin receptor kinase (IRK) activity within 30 min (inhibition to 30 +/- 12.5% of maximal insulin-stimulated beta-subunit phosphorylation, n = 9, P < 0.01). |
| 995 | 7520127 | Regulation of insulin receptor, insulin receptor substrate-1 and phosphatidylinositol 3-kinase in 3T3-F442A adipocytes. |
| 996 | 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). |
| 997 | 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. |
| 998 | 7520127 | The expression of insulin receptor mRNA was unchanged, but the expression of IRS-1 mRNA was decreased by approximately 75% after dexamethasone. |
| 999 | 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. |
| 1000 | 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. |
| 1001 | 7520127 | The expression of insulin receptor and IRS-1 mRNA was unchanged during chronic insulin treatment. |
| 1002 | 7520127 | Regulation of insulin receptor, insulin receptor substrate-1 and phosphatidylinositol 3-kinase in 3T3-F442A adipocytes. |
| 1003 | 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). |
| 1004 | 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. |
| 1005 | 7520127 | The expression of insulin receptor mRNA was unchanged, but the expression of IRS-1 mRNA was decreased by approximately 75% after dexamethasone. |
| 1006 | 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. |
| 1007 | 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. |
| 1008 | 7520127 | The expression of insulin receptor and IRS-1 mRNA was unchanged during chronic insulin treatment. |
| 1009 | 7520127 | Regulation of insulin receptor, insulin receptor substrate-1 and phosphatidylinositol 3-kinase in 3T3-F442A adipocytes. |
| 1010 | 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). |
| 1011 | 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. |
| 1012 | 7520127 | The expression of insulin receptor mRNA was unchanged, but the expression of IRS-1 mRNA was decreased by approximately 75% after dexamethasone. |
| 1013 | 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. |
| 1014 | 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. |
| 1015 | 7520127 | The expression of insulin receptor and IRS-1 mRNA was unchanged during chronic insulin treatment. |
| 1016 | 7520127 | Regulation of insulin receptor, insulin receptor substrate-1 and phosphatidylinositol 3-kinase in 3T3-F442A adipocytes. |
| 1017 | 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). |
| 1018 | 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. |
| 1019 | 7520127 | The expression of insulin receptor mRNA was unchanged, but the expression of IRS-1 mRNA was decreased by approximately 75% after dexamethasone. |
| 1020 | 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. |
| 1021 | 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. |
| 1022 | 7520127 | The expression of insulin receptor and IRS-1 mRNA was unchanged during chronic insulin treatment. |
| 1023 | 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. |
| 1024 | 7523453 | However, the mechanism by which TNF-alpha interferes with insulin action is not known. |
| 1025 | 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. |
| 1026 | 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. |
| 1027 | 7523453 | In contrast, no significant changes were observed in insulin-stimulated tyrosine phosphorylations of IR and IRS-1 in liver. |
| 1028 | 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. |
| 1029 | 7524845 | There is a common epitope in the beta-chain of insulin and LDL and VLDL apoprotein B. |
| 1030 | 7524845 | The existence of the common epitope leads to competition of insulin and apoprotein B for an insulin receptor and reduces tissue glucose uptake. |
| 1031 | 7526222 | Alternative pathway of insulin signalling in mice with targeted disruption of the IRS-1 gene. |
| 1032 | 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). |
| 1033 | 7526222 | To elucidate the role of IRS-1 in insulin/IGF-1 action, we created IRS-1-deficient mice by targeted gene mutation. |
| 1034 | 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. |
| 1035 | 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. |
| 1036 | 7537758 | Insulin receptor phosphorylation, insulin receptor substrate-1 phosphorylation, and phosphatidylinositol 3-kinase activity are decreased in intact skeletal muscle strips from obese subjects. |
| 1037 | 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. |
| 1038 | 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. |
| 1039 | 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). |
| 1040 | 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). |
| 1041 | 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). |
| 1042 | 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. |
| 1043 | 7537758 | Insulin receptor phosphorylation, insulin receptor substrate-1 phosphorylation, and phosphatidylinositol 3-kinase activity are decreased in intact skeletal muscle strips from obese subjects. |
| 1044 | 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. |
| 1045 | 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. |
| 1046 | 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). |
| 1047 | 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). |
| 1048 | 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). |
| 1049 | 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. |
| 1050 | 7537758 | Insulin receptor phosphorylation, insulin receptor substrate-1 phosphorylation, and phosphatidylinositol 3-kinase activity are decreased in intact skeletal muscle strips from obese subjects. |
| 1051 | 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. |
| 1052 | 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. |
| 1053 | 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). |
| 1054 | 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). |
| 1055 | 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). |
| 1056 | 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. |
| 1057 | 7540574 | Glucose-induced insulin receptor tyrosine phosphorylation in insulin-secreting beta-cells. |
| 1058 | 7540574 | In the beta TC3 insulin-secreting beta-cell line, glucose rapidly induces the tyrosine phosphorylation of the 97-kDa insulin receptor beta-subunit. |
| 1059 | 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. |
| 1060 | 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. |
| 1061 | 7540574 | Glucose-induced insulin receptor tyrosine phosphorylation in insulin-secreting beta-cells. |
| 1062 | 7540574 | In the beta TC3 insulin-secreting beta-cell line, glucose rapidly induces the tyrosine phosphorylation of the 97-kDa insulin receptor beta-subunit. |
| 1063 | 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. |
| 1064 | 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. |
| 1065 | 7540574 | Glucose-induced insulin receptor tyrosine phosphorylation in insulin-secreting beta-cells. |
| 1066 | 7540574 | In the beta TC3 insulin-secreting beta-cell line, glucose rapidly induces the tyrosine phosphorylation of the 97-kDa insulin receptor beta-subunit. |
| 1067 | 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. |
| 1068 | 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. |
| 1069 | 7544790 | Osmotic loading of neutralizing antibodies demonstrates a role for protein-tyrosine phosphatase 1B in negative regulation of the insulin action pathway. |
| 1070 | 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. |
| 1071 | 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). |
| 1072 | 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. |
| 1073 | 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. |
| 1074 | 7553082 | IGF-I and insulin receptors in bovine skeletal muscle: comparisons of different developmental ages, two different genotypes and various individual muscles. |
| 1075 | 7553082 | To investigate the regulation of the IGF-I and the insulin receptor in bovine skeletal muscle, we determined their concentrations and their affinity constants in animals of different age, muscle type and breed. |
| 1076 | 7553082 | In order to compare different muscle types, seven muscles, which represent large differences in fibre type composition and growth impetus, were selected from 6 month old female Jersey calves and were assayed for IGF-I and insulin receptors. |
| 1077 | 7553082 | We observed significant differences of the IGF-I as well as the insulin receptor concentrations between distinct muscles. |
| 1078 | 7553082 | In muscle of two cattle breeds, differing markedly with regard to muscle growth intensity, the Jersey and the German Fleckvieh breed, we observed no divergence in IGF-I nor insulin receptor concentrations. |
| 1079 | 7553082 | We found no differences in IGF-I and in insulin receptor affinities in any of the adult animals. |
| 1080 | 7553082 | IGF-I and insulin receptors in bovine skeletal muscle: comparisons of different developmental ages, two different genotypes and various individual muscles. |
| 1081 | 7553082 | To investigate the regulation of the IGF-I and the insulin receptor in bovine skeletal muscle, we determined their concentrations and their affinity constants in animals of different age, muscle type and breed. |
| 1082 | 7553082 | In order to compare different muscle types, seven muscles, which represent large differences in fibre type composition and growth impetus, were selected from 6 month old female Jersey calves and were assayed for IGF-I and insulin receptors. |
| 1083 | 7553082 | We observed significant differences of the IGF-I as well as the insulin receptor concentrations between distinct muscles. |
| 1084 | 7553082 | In muscle of two cattle breeds, differing markedly with regard to muscle growth intensity, the Jersey and the German Fleckvieh breed, we observed no divergence in IGF-I nor insulin receptor concentrations. |
| 1085 | 7553082 | We found no differences in IGF-I and in insulin receptor affinities in any of the adult animals. |
| 1086 | 7553082 | IGF-I and insulin receptors in bovine skeletal muscle: comparisons of different developmental ages, two different genotypes and various individual muscles. |
| 1087 | 7553082 | To investigate the regulation of the IGF-I and the insulin receptor in bovine skeletal muscle, we determined their concentrations and their affinity constants in animals of different age, muscle type and breed. |
| 1088 | 7553082 | In order to compare different muscle types, seven muscles, which represent large differences in fibre type composition and growth impetus, were selected from 6 month old female Jersey calves and were assayed for IGF-I and insulin receptors. |
| 1089 | 7553082 | We observed significant differences of the IGF-I as well as the insulin receptor concentrations between distinct muscles. |
| 1090 | 7553082 | In muscle of two cattle breeds, differing markedly with regard to muscle growth intensity, the Jersey and the German Fleckvieh breed, we observed no divergence in IGF-I nor insulin receptor concentrations. |
| 1091 | 7553082 | We found no differences in IGF-I and in insulin receptor affinities in any of the adult animals. |
| 1092 | 7553082 | IGF-I and insulin receptors in bovine skeletal muscle: comparisons of different developmental ages, two different genotypes and various individual muscles. |
| 1093 | 7553082 | To investigate the regulation of the IGF-I and the insulin receptor in bovine skeletal muscle, we determined their concentrations and their affinity constants in animals of different age, muscle type and breed. |
| 1094 | 7553082 | In order to compare different muscle types, seven muscles, which represent large differences in fibre type composition and growth impetus, were selected from 6 month old female Jersey calves and were assayed for IGF-I and insulin receptors. |
| 1095 | 7553082 | We observed significant differences of the IGF-I as well as the insulin receptor concentrations between distinct muscles. |
| 1096 | 7553082 | In muscle of two cattle breeds, differing markedly with regard to muscle growth intensity, the Jersey and the German Fleckvieh breed, we observed no divergence in IGF-I nor insulin receptor concentrations. |
| 1097 | 7553082 | We found no differences in IGF-I and in insulin receptor affinities in any of the adult animals. |
| 1098 | 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. |
| 1099 | 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. |
| 1100 | 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. |
| 1101 | 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. |
| 1102 | 7562114 | It is suggested that the PUFA-mediated suppression of insulin-dependent gene expression of lipogenic enzymes can be ascribed to a decrease in insulin receptor binding primarily and also to receptor phosphorylation. |
| 1103 | 7584573 | [Correlative study of erythrocyte membrane insulin receptor with blood lipids and albumin in non-obese noninsulin-dependent diabetics (NIDDM) patients before and after exercise]. |
| 1104 | 7584573 | To understand the effects of the levels of blood lipids and albumin on insulin receptor binding before and after acute exercise, we measured insulin binding to erythrocyt membrane before and after 30 minutes moderate exercise in thirty-eight non-obese noninsulin-dependent diabetics (NIDDM) and thirty-seven normal subjects. |
| 1105 | 7584573 | The correlations between parameters of insulin receptor and blood lipids and albumin were also studied. |
| 1106 | 7584573 | After acute exercise, no significant correlations between the parameters of insulin receptor, blood lipids and albumin were found. |
| 1107 | 7584573 | These suggest that blood lipids and albumin are important influential factors for affinities of insulin receptor. |
| 1108 | 7584573 | [Correlative study of erythrocyte membrane insulin receptor with blood lipids and albumin in non-obese noninsulin-dependent diabetics (NIDDM) patients before and after exercise]. |
| 1109 | 7584573 | To understand the effects of the levels of blood lipids and albumin on insulin receptor binding before and after acute exercise, we measured insulin binding to erythrocyt membrane before and after 30 minutes moderate exercise in thirty-eight non-obese noninsulin-dependent diabetics (NIDDM) and thirty-seven normal subjects. |
| 1110 | 7584573 | The correlations between parameters of insulin receptor and blood lipids and albumin were also studied. |
| 1111 | 7584573 | After acute exercise, no significant correlations between the parameters of insulin receptor, blood lipids and albumin were found. |
| 1112 | 7584573 | These suggest that blood lipids and albumin are important influential factors for affinities of insulin receptor. |
| 1113 | 7584573 | [Correlative study of erythrocyte membrane insulin receptor with blood lipids and albumin in non-obese noninsulin-dependent diabetics (NIDDM) patients before and after exercise]. |
| 1114 | 7584573 | To understand the effects of the levels of blood lipids and albumin on insulin receptor binding before and after acute exercise, we measured insulin binding to erythrocyt membrane before and after 30 minutes moderate exercise in thirty-eight non-obese noninsulin-dependent diabetics (NIDDM) and thirty-seven normal subjects. |
| 1115 | 7584573 | The correlations between parameters of insulin receptor and blood lipids and albumin were also studied. |
| 1116 | 7584573 | After acute exercise, no significant correlations between the parameters of insulin receptor, blood lipids and albumin were found. |
| 1117 | 7584573 | These suggest that blood lipids and albumin are important influential factors for affinities of insulin receptor. |
| 1118 | 7584573 | [Correlative study of erythrocyte membrane insulin receptor with blood lipids and albumin in non-obese noninsulin-dependent diabetics (NIDDM) patients before and after exercise]. |
| 1119 | 7584573 | To understand the effects of the levels of blood lipids and albumin on insulin receptor binding before and after acute exercise, we measured insulin binding to erythrocyt membrane before and after 30 minutes moderate exercise in thirty-eight non-obese noninsulin-dependent diabetics (NIDDM) and thirty-seven normal subjects. |
| 1120 | 7584573 | The correlations between parameters of insulin receptor and blood lipids and albumin were also studied. |
| 1121 | 7584573 | After acute exercise, no significant correlations between the parameters of insulin receptor, blood lipids and albumin were found. |
| 1122 | 7584573 | These suggest that blood lipids and albumin are important influential factors for affinities of insulin receptor. |
| 1123 | 7584573 | [Correlative study of erythrocyte membrane insulin receptor with blood lipids and albumin in non-obese noninsulin-dependent diabetics (NIDDM) patients before and after exercise]. |
| 1124 | 7584573 | To understand the effects of the levels of blood lipids and albumin on insulin receptor binding before and after acute exercise, we measured insulin binding to erythrocyt membrane before and after 30 minutes moderate exercise in thirty-eight non-obese noninsulin-dependent diabetics (NIDDM) and thirty-seven normal subjects. |
| 1125 | 7584573 | The correlations between parameters of insulin receptor and blood lipids and albumin were also studied. |
| 1126 | 7584573 | After acute exercise, no significant correlations between the parameters of insulin receptor, blood lipids and albumin were found. |
| 1127 | 7584573 | These suggest that blood lipids and albumin are important influential factors for affinities of insulin receptor. |
| 1128 | 7622001 | To examine the kinetic steps in insulin's in vivo action, we have assessed the temporal relationship between arterial insulin, interstitial insulin, glucose disposal rate (GDR), and insulin receptor kinase (IRK) activity in muscle and between portal insulin, hepatic glucose production (HGP), and IRK activity in liver. |
| 1129 | 7626603 | Insulin-stimulated phosphorylation of recombinant pp120/HA4, an endogenous substrate of the insulin receptor tyrosine kinase. |
| 1130 | 7626603 | Since pp120/HA4 is believed to be associated with a Ca2+/Mg(2+)-dependent ecto-ATPase activity, we determined the effects of insulin-induced phosphorylation on this enzymatic activity. |
| 1131 | 7626603 | In NIH 3T3 cells co-expressing the insulin receptor and pp120/HA4, insulin caused a 2-fold increase in ecto-ATPase activity. |
| 1132 | 7626603 | Moreover, elimination of the phosphorylation sites of pp120/HA4 impaired the ability of insulin to stimulate the ecto-ATPase activity. |
| 1133 | 7626603 | Insulin-stimulated phosphorylation of recombinant pp120/HA4, an endogenous substrate of the insulin receptor tyrosine kinase. |
| 1134 | 7626603 | Since pp120/HA4 is believed to be associated with a Ca2+/Mg(2+)-dependent ecto-ATPase activity, we determined the effects of insulin-induced phosphorylation on this enzymatic activity. |
| 1135 | 7626603 | In NIH 3T3 cells co-expressing the insulin receptor and pp120/HA4, insulin caused a 2-fold increase in ecto-ATPase activity. |
| 1136 | 7626603 | Moreover, elimination of the phosphorylation sites of pp120/HA4 impaired the ability of insulin to stimulate the ecto-ATPase activity. |
| 1137 | 7635975 | The factor responsible for excessive serine phosphorylation appeared to be extrinsic to the receptor since no insulin receptor gene mutations were identified, immunoprecipitation before autophosphorylation corrected the phosphorylation defect and control insulin receptors mixed with lectin eluates from affected PCOS fibroblasts displayed increased serine phosphorylation. |
| 1138 | 7677175 | Human islet amyloid polypeptide expression in COS-1 cells. |
| 1139 | 7677175 | Non-insulin-dependent diabetes mellitus is characterized by concurrent loss of beta-cells and deposition of islet amyloid derived from islet amyloid polypeptide (IAPP). |
| 1140 | 7677175 | We have previously demonstrated that IAPP-derived amyloid forms intracellularly in humans with chronic excess insulin expression (eg, insulinoma and insulin receptor antibody-induced insulin resistance). |
| 1141 | 7677175 | Thus, overexpression of human IAPP can result in intracellular amyloid formation that is associated with cell death, suggesting that intracellular amyloid may play a role in beta-cell loss in non-insulin-dependent diabetes mellitus. |
| 1142 | 7681983 | To assess whether the abnormal expression of the structurally distinct human insulin receptor isoforms, HIR-A and HIR-B, which has been found in skeletal muscle of NIDDM patients, is a feature of a prediabetic state, skeletal muscle biopsies from nondiabetic individuals ranging from high insulin sensitivity to insulin resistance were examined. |
| 1143 | 7681983 | Polymerase chain reaction analysis of mRNA from muscle biopsies detected exclusive or predominant expression of HIR-A in 13 patients with normal insulin sensitivity. |
| 1144 | 7683695 | Glucocorticoid regulation of insulin receptor and substrate IRS-1 tyrosine phosphorylation in rat skeletal muscle in vivo. |
| 1145 | 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. |
| 1146 | 7683695 | Insulin receptors and substrate IRS-1 were identified and quantified with specific antibodies. |
| 1147 | 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. |
| 1148 | 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. |
| 1149 | 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. |
| 1150 | 7683695 | Glucocorticoid regulation of insulin receptor and substrate IRS-1 tyrosine phosphorylation in rat skeletal muscle in vivo. |
| 1151 | 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. |
| 1152 | 7683695 | Insulin receptors and substrate IRS-1 were identified and quantified with specific antibodies. |
| 1153 | 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. |
| 1154 | 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. |
| 1155 | 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. |
| 1156 | 7686165 | Paradoxical biological effects of overexpressed insulin-like growth factor-1 receptors in Chinese hamster ovary cells. |
| 1157 | 7686165 | Studies of this type with insulin and insulin-like growth factor-I (IGF-I) receptors often use Chinese hamster ovary (CHO) cells. |
| 1158 | 7686165 | Overexpression of IGF-I receptors in NIH-3T3 cells resulted in increased sensitivity and maximal responsiveness of thymidine incorporation, 2-deoxyglucose uptake, and phosphatidylinositol-3 (PI3) kinase activation to IGF-I stimulation. |
| 1159 | 7686165 | In CHO cells, on the other hand, overexpression of either IGF-I or insulin receptors increased the sensitivity of thymidine incorporation to ligand, but maximal responsiveness was unchanged or decreased. |
| 1160 | 7686165 | Overexpression of the insulin receptor increased sensitivity of glucose uptake and the maximal response of PI3 kinase activation to insulin. |
| 1161 | 7686165 | Overexpression of the IGF-I receptor did not affect sensitivity or maximal responsiveness of glucose uptake or PI3 kinase activation to IGF-I. |
| 1162 | 7686165 | These data suggest that IGF-I and insulin signal pathways may differ in CHO cells, and that there may even be divergent IGF-I signaling pathways for short vs. long-term effects. |
| 1163 | 7686917 | The fibroblast insulin receptor content was within the normal range, but both basal and insulin-stimulated tyrosine kinase activity in fibroblast extracts were markedly decreased compared to those in extracts of fibroblasts from nondiabetic subjects. |
| 1164 | 7688476 | Substitution of the erbB-2 oncoprotein transmembrane domain activates the insulin receptor and modulates the action of insulin and insulin-receptor substrate 1. |
| 1165 | 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. |
| 1166 | 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. |
| 1167 | 7688476 | Substitution of the erbB-2 oncoprotein transmembrane domain activates the insulin receptor and modulates the action of insulin and insulin-receptor substrate 1. |
| 1168 | 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. |
| 1169 | 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. |
| 1170 | 7688476 | Substitution of the erbB-2 oncoprotein transmembrane domain activates the insulin receptor and modulates the action of insulin and insulin-receptor substrate 1. |
| 1171 | 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. |
| 1172 | 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. |
| 1173 | 7688706 | The consequences of type I diabetes on cellular endocytosis were investigated by comparing [125I]insulin, [125I]alpha 2-macroglobulin, and Lucifer yellow uptake in hepatocytes freshly isolated from control and STZ-induced diabetic rats. |
| 1174 | 7688706 | In addition to the previously described reversible inhibition of ligand-induced internalization of the insulin receptor, we report a decrease in the constitutive receptor-mediated endocytosis of alpha 2-macroglobulin and a near abolition of fluid-phase endocytosis of Lucifer yellow in cells from diabetic animals. |
| 1175 | 7691892 | Modulation of insulin receptor, insulin receptor substrate-1, and phosphatidylinositol 3-kinase in liver and muscle of dexamethasone-treated rats. |
| 1176 | 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. |
| 1177 | 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. |
| 1178 | 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). |
| 1179 | 7691892 | IRS-1 phosphorylation showed no significant change in muscle, but insulin-stimulated IRS-1 associated PI 3-kinase was decreased by 41%. |
| 1180 | 7744813 | During insulin stimulation, IRS-1 delta PH is poorly tyrosine-phosphorylated in CHO cells, but undergoes serine/threonine phosphorylation. |
| 1181 | 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. |
| 1182 | 7744813 | Overexpression of the insulin receptor in 32DIR cells, however, restores tyrosine phosphorylation of IRS-1 delta PH and rescues insulin responses including mitogenesis. |
| 1183 | 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. |
| 1184 | 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. |
| 1185 | 7762655 | Insulin increased tyrosine phosphorylation of the insulin receptor and IRS-1, whereas contraction alone had no effect. |
| 1186 | 7762655 | Contraction before insulin injection decreased the insulin effect on receptor and IRS-1 phosphorylation by 20-25%. |
| 1187 | 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. |
| 1188 | 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. |
| 1189 | 7762655 | Insulin increased tyrosine phosphorylation of the insulin receptor and IRS-1, whereas contraction alone had no effect. |
| 1190 | 7762655 | Contraction before insulin injection decreased the insulin effect on receptor and IRS-1 phosphorylation by 20-25%. |
| 1191 | 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. |
| 1192 | 7775636 | We have used a new technique of denaturing gradient gel blotting to determine the prevalence of alterations in the intracellular domain of the insulin receptor in normal individuals and subjects with non-insulin-dependent diabetes mellitus (NIDDM). |
| 1193 | 7783364 | Specific phenotypes have also led to the discovery of the insulin gene mutations in patients with high insulin or proinsulin levels, to the insulin receptor mutations in patients with marked insulin resistance, and to the mutations in mitochondrial DNA associated with deafness and maternal inheritance. |
| 1194 | 7783364 | Genetic diagnosis provides clear definite diagnosis and specific therapies, such as IGF-1 for the insulin receptor mutations and coenzyme Q10 for the mitochondrial gene mutations. |
| 1195 | 7783364 | Specific phenotypes have also led to the discovery of the insulin gene mutations in patients with high insulin or proinsulin levels, to the insulin receptor mutations in patients with marked insulin resistance, and to the mutations in mitochondrial DNA associated with deafness and maternal inheritance. |
| 1196 | 7783364 | Genetic diagnosis provides clear definite diagnosis and specific therapies, such as IGF-1 for the insulin receptor mutations and coenzyme Q10 for the mitochondrial gene mutations. |
| 1197 | 7789629 | Acute hyperglycemia provides an insulin-independent inducer for GLUT4 translocation in C2C12 myotubes and rat skeletal muscle. |
| 1198 | 7789629 | GLUT4 translocation and activation of glucose uptake in skeletal muscle can be induced by both physiological (i.e., insulin, nerve stimulation, or exercise) and pharmacological (i.e., phorbol ester) means. |
| 1199 | 7789629 | Recently, we demonstrated that high glucose levels may mimic the effects of phorbol esters on protein kinase C (PKC) and insulin receptor function (J Biol Chem 269:3381-3386, 1994). |
| 1200 | 7789629 | We found that stimulation of C2C12 myotubes with both insulin (10(-7) mol/l, 5 min) and glucose (25 mmol/l, 10 min) induces a comparable increase of the GLUT4 content in the plasma membrane. |
| 1201 | 7796985 | The insulin receptor exists in two isoforms differing by the absence (HIR-A) or presence (HIR-B) of 12 amino acids in the COOH-terminus of the alpha-subunit as a consequence of alternative splicing of exon 11. |
| 1202 | 7814014 | Failure to detect Glut4-Ile383 and IR-Gln1152 variants in NIDDM (non-insulin dependent diabetes mellitus) and control subjects in an Italian population. |
| 1203 | 7814014 | Insulin receptor (IR) and insulin-responsive glucose transporter (Glut4) represent two candidate genes involved in the development of non-insulin dependent diabetes mellitus (NIDDM); detection of molecular alterations in these genes might explain their possible contribution to NIDDM. |
| 1204 | 7815442 | Homozygosity for a new mutation (Ile119-->Met) in the insulin receptor gene in five sibs with familial insulin resistance. |
| 1205 | 7815442 | There are a total of nine children in the family, five of whom are homozygous for the Ile119-->Met mutation in the insulin receptor gene, and are clinically affected with varying degrees of severity. |
| 1206 | 7815442 | Homozygosity for a new mutation (Ile119-->Met) in the insulin receptor gene in five sibs with familial insulin resistance. |
| 1207 | 7815442 | There are a total of nine children in the family, five of whom are homozygous for the Ile119-->Met mutation in the insulin receptor gene, and are clinically affected with varying degrees of severity. |
| 1208 | 7815975 | Recent studies indicate that oxyanions, such as vanadate (V) or vanadyl (IV), cause insulin-like effects on rats by stimulating the insulin receptor tyrosine kinase. |
| 1209 | 7821727 | These studies allowed us to propose the following ordered sequence of events: 1) insulin binds to receptors preferentially associated with microvilli on the cell surface; 2) insulin triggers receptor kinase activation and autophosphorylation which not only results in initiation of the various biological signals leading to insulin action but also in redistribution of the hormone-receptor complex in the plane of the membrane; 3) on the non-villous domain of the cell surface, insulin receptors anchor to clathrin-coated pits through specific "internalization sequences" present in their cytoplasmic juxtamembrane domain; 4) insulin-receptor complexes are internalized together with other receptors present in the same clathrin-coated pits through the formation of clathrin-coated vesicles; 5) the complexes are delivered to endosomes, the acidic pH of which induces the dissociation of insulin molecules from insulin receptors and their sorting in different directions; 6) insulin molecules are targetted to late endosomes and lysosomes where they are degraded; 7) receptors are recycled back to the cell surface in order to be reused. |
| 1210 | 7821728 | Signalling through the insulin receptor and the insulin-like growth factor-I receptor. |
| 1211 | 7821728 | The insulin receptor and the insulin-like growth factor I receptor belong to the family of tyrosine kinase receptors. |
| 1212 | 7821728 | Signalling through the insulin receptor and the insulin-like growth factor-I receptor. |
| 1213 | 7821728 | The insulin receptor and the insulin-like growth factor I receptor belong to the family of tyrosine kinase receptors. |
| 1214 | 7821730 | The insulin receptor is expressed in two different isoforms (HIR-A and HIR-B). |
| 1215 | 7821730 | This appears to be mediated through activation of certain protein kinase C isoforms which form stable complexes with the insulin receptor and modulate the tyrosine kinase activity of the insulin receptor through serine phosphorylation of the receptor beta subunit. |
| 1216 | 7821730 | The insulin receptor is expressed in two different isoforms (HIR-A and HIR-B). |
| 1217 | 7821730 | This appears to be mediated through activation of certain protein kinase C isoforms which form stable complexes with the insulin receptor and modulate the tyrosine kinase activity of the insulin receptor through serine phosphorylation of the receptor beta subunit. |
| 1218 | 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. |
| 1219 | 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. |
| 1220 | 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. |
| 1221 | 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. |
| 1222 | 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. |
| 1223 | 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. |
| 1224 | 7859597 | About 20 cases of primary receptor mutations (type A syndrome of insulin resistance, leprechaunism and Rabson-Mendenhall syndrome) and 16 cases of autoantibodies against insulin receptor (type B syndrome of insulin resistance) are described in Japan. |
| 1225 | 7869584 | In this study, this method was used to determine the mutations of the LDL receptor or insulin receptor. |
| 1226 | 7869584 | We found new mutations in Exon 14 of the LDL receptor, and a patient had a new missense mutation in which Asn461 was substituted for Thr461 in the alpha-subunit of the insulin receptor. |
| 1227 | 7869584 | In this study, this method was used to determine the mutations of the LDL receptor or insulin receptor. |
| 1228 | 7869584 | We found new mutations in Exon 14 of the LDL receptor, and a patient had a new missense mutation in which Asn461 was substituted for Thr461 in the alpha-subunit of the insulin receptor. |
| 1229 | 7883115 | Using quantitative trait linkage analyses, we excluded tight linkage between this gene affecting 2-h insulin levels and three candidate loci for insulin levels: the insulin receptor gene, the low-density lipoprotein receptor gene, and the glucokinase gene. |
| 1230 | 7885272 | Insulin-stimulated receptor autophosphorylation reflects an early physiologic step in transmission of the insulin signal, and for that reason, changes in autophosphorylation activity of the insulin receptor were used as a marker to determine the functionality of the insulin receptor. |
| 1231 | 7885272 | Receptor activity was monitored by measuring insulin-stimulated [gamma-32P]adenosine triphosphate (ATP) receptor autophosphorylation. |
| 1232 | 7895667 | Insulin and dexamethasone regulate insulin receptors, insulin receptor substrate-1, and phosphatidylinositol 3-kinase in Fao hepatoma cells. |
| 1233 | 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. |
| 1234 | 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. |
| 1235 | 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. |
| 1236 | 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. |
| 1237 | 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. |
| 1238 | 7895667 | Insulin and dexamethasone regulate insulin receptors, insulin receptor substrate-1, and phosphatidylinositol 3-kinase in Fao hepatoma cells. |
| 1239 | 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. |
| 1240 | 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. |
| 1241 | 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. |
| 1242 | 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. |
| 1243 | 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. |
| 1244 | 7895667 | Insulin and dexamethasone regulate insulin receptors, insulin receptor substrate-1, and phosphatidylinositol 3-kinase in Fao hepatoma cells. |
| 1245 | 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. |
| 1246 | 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. |
| 1247 | 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. |
| 1248 | 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. |
| 1249 | 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. |
| 1250 | 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. |
| 1251 | 7895862 | The regulation of IRS-1 has been analyzed in animal models of insulin resistance, and its mechanism has been studied in culture cells. |
| 1252 | 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. |
| 1253 | 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. |
| 1254 | 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. |
| 1255 | 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. |
| 1256 | 7895862 | The regulation of IRS-1 has been analyzed in animal models of insulin resistance, and its mechanism has been studied in culture cells. |
| 1257 | 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. |
| 1258 | 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. |
| 1259 | 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. |
| 1260 | 7901717 | Insulin receptor substrate (IRS-1) gene polymorphisms in French NIDDM families. |
| 1261 | 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). |
| 1262 | 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. |
| 1263 | 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. |
| 1264 | 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. |
| 1265 | 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). |
| 1266 | 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. |
| 1267 | 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. |
| 1268 | 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. |
| 1269 | 7944536 | Long-term follow up in type A insulin resistant syndrome treated by insulin-like growth factor I. |
| 1270 | 7944536 | Insulin-like growth factor I (IGF-I) is a useful therapeutic agent in insulin resistant diabetes mellitus due to insulin receptor disease because of its hypoglycaemic effects through the IGF-I receptor. |
| 1271 | 7944536 | A girl with typical type A insulin resistant syndrome was treated with IGF-I for two years and the treatment was effective in ameliorating hyperglycaemia. |
| 1272 | 7961833 | Insulin receptor substrate-1 mediates phosphatidylinositol 3'-kinase and p70S6k signaling during insulin, insulin-like growth factor-1, and interleukin-4 stimulation. |
| 1273 | 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). |
| 1274 | 7961833 | The 32D myeloid progenitor cell line contains few insulin receptors and no detectable IRS-1. |
| 1275 | 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. |
| 1276 | 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. |
| 1277 | 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. |
| 1278 | 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. |
| 1279 | 7961833 | Insulin receptor substrate-1 mediates phosphatidylinositol 3'-kinase and p70S6k signaling during insulin, insulin-like growth factor-1, and interleukin-4 stimulation. |
| 1280 | 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). |
| 1281 | 7961833 | The 32D myeloid progenitor cell line contains few insulin receptors and no detectable IRS-1. |
| 1282 | 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. |
| 1283 | 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. |
| 1284 | 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. |
| 1285 | 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. |
| 1286 | 7961833 | Insulin receptor substrate-1 mediates phosphatidylinositol 3'-kinase and p70S6k signaling during insulin, insulin-like growth factor-1, and interleukin-4 stimulation. |
| 1287 | 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). |
| 1288 | 7961833 | The 32D myeloid progenitor cell line contains few insulin receptors and no detectable IRS-1. |
| 1289 | 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. |
| 1290 | 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. |
| 1291 | 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. |
| 1292 | 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. |
| 1293 | 7965046 | Insulin receptor substrate 1 (IRS-1) is the primary cytosolic substrate of the insulin and insulin-like growth factor-I (IGF-I) receptors. |
| 1294 | 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. |
| 1295 | 7965046 | Immunoprecipitation and Western blotting experiments demonstrate the presence of substantial amounts of IRS-1, insulin receptor, and PI-3 kinase in the brain. |
| 1296 | 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. |
| 1297 | 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. |
| 1298 | 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. |
| 1299 | 7965046 | Insulin receptor substrate 1 (IRS-1) is the primary cytosolic substrate of the insulin and insulin-like growth factor-I (IGF-I) receptors. |
| 1300 | 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. |
| 1301 | 7965046 | Immunoprecipitation and Western blotting experiments demonstrate the presence of substantial amounts of IRS-1, insulin receptor, and PI-3 kinase in the brain. |
| 1302 | 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. |
| 1303 | 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. |
| 1304 | 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. |
| 1305 | 7983004 | Insulin-inducible changes in insulin receptor mRNA splice variants. |
| 1306 | 7983060 | Demonstration that the p85 subunit binds directly to the COOH terminus of the insulin receptor in intact cells. |
| 1307 | 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. |
| 1308 | 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. |
| 1309 | 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. |
| 1310 | 7983060 | Subsequent to insulin-stimulated phosphorylation of the insulin receptor, a complex is formed that contains the insulin receptor and PI 3-kinase. |
| 1311 | 7983060 | This complex can be immunoprecipitated by antibodies directed against either the insulin receptor or the p85 subunit of PI 3-kinase. |
| 1312 | 7983060 | The delta 43 mutant insulin receptor that lacks 43 amino acids at the COOH terminus does not bind p85. |
| 1313 | 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. |
| 1314 | 7983060 | Demonstration that the p85 subunit binds directly to the COOH terminus of the insulin receptor in intact cells. |
| 1315 | 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. |
| 1316 | 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. |
| 1317 | 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. |
| 1318 | 7983060 | Subsequent to insulin-stimulated phosphorylation of the insulin receptor, a complex is formed that contains the insulin receptor and PI 3-kinase. |
| 1319 | 7983060 | This complex can be immunoprecipitated by antibodies directed against either the insulin receptor or the p85 subunit of PI 3-kinase. |
| 1320 | 7983060 | The delta 43 mutant insulin receptor that lacks 43 amino acids at the COOH terminus does not bind p85. |
| 1321 | 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. |
| 1322 | 7983060 | Demonstration that the p85 subunit binds directly to the COOH terminus of the insulin receptor in intact cells. |
| 1323 | 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. |
| 1324 | 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. |
| 1325 | 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. |
| 1326 | 7983060 | Subsequent to insulin-stimulated phosphorylation of the insulin receptor, a complex is formed that contains the insulin receptor and PI 3-kinase. |
| 1327 | 7983060 | This complex can be immunoprecipitated by antibodies directed against either the insulin receptor or the p85 subunit of PI 3-kinase. |
| 1328 | 7983060 | The delta 43 mutant insulin receptor that lacks 43 amino acids at the COOH terminus does not bind p85. |
| 1329 | 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. |
| 1330 | 7983060 | Demonstration that the p85 subunit binds directly to the COOH terminus of the insulin receptor in intact cells. |
| 1331 | 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. |
| 1332 | 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. |
| 1333 | 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. |
| 1334 | 7983060 | Subsequent to insulin-stimulated phosphorylation of the insulin receptor, a complex is formed that contains the insulin receptor and PI 3-kinase. |
| 1335 | 7983060 | This complex can be immunoprecipitated by antibodies directed against either the insulin receptor or the p85 subunit of PI 3-kinase. |
| 1336 | 7983060 | The delta 43 mutant insulin receptor that lacks 43 amino acids at the COOH terminus does not bind p85. |
| 1337 | 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. |
| 1338 | 7983060 | Demonstration that the p85 subunit binds directly to the COOH terminus of the insulin receptor in intact cells. |
| 1339 | 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. |
| 1340 | 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. |
| 1341 | 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. |
| 1342 | 7983060 | Subsequent to insulin-stimulated phosphorylation of the insulin receptor, a complex is formed that contains the insulin receptor and PI 3-kinase. |
| 1343 | 7983060 | This complex can be immunoprecipitated by antibodies directed against either the insulin receptor or the p85 subunit of PI 3-kinase. |
| 1344 | 7983060 | The delta 43 mutant insulin receptor that lacks 43 amino acids at the COOH terminus does not bind p85. |
| 1345 | 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. |
| 1346 | 7983060 | Demonstration that the p85 subunit binds directly to the COOH terminus of the insulin receptor in intact cells. |
| 1347 | 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. |
| 1348 | 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. |
| 1349 | 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. |
| 1350 | 7983060 | Subsequent to insulin-stimulated phosphorylation of the insulin receptor, a complex is formed that contains the insulin receptor and PI 3-kinase. |
| 1351 | 7983060 | This complex can be immunoprecipitated by antibodies directed against either the insulin receptor or the p85 subunit of PI 3-kinase. |
| 1352 | 7983060 | The delta 43 mutant insulin receptor that lacks 43 amino acids at the COOH terminus does not bind p85. |
| 1353 | 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. |
| 1354 | 7983791 | Recent reports provide evidence that mutations in the insulin-receptor gene are, at least in pant, the cause of this syndrome, and that recombinant IGF-I (insulin-like growth factor-1) reduces hyperglycemia in patients of this syndrome. |
| 1355 | 8013752 | Proximal enhancer of the human insulin receptor gene binds the transcription factor Sp1. |
| 1356 | 8039433 | No specific abnormalities of the insulin receptor kinase activity were revealed in insulin-dependent diabetes (IDDM) or in common NIDDM. |
| 1357 | 8039433 | Recently, insulin was shown to stimulate a cascade of phosphorylation-dependent kinases which ultimately activate a glycogen-bound subunit of a phosphatase (G-subunit of phosphatase-1) which promotes dephosphorylation GS by the catalytic subunit. |
| 1358 | 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. |
| 1359 | 8048169 | IRS-1 undergoes multisite tyrosine phosphorylation and mediates downstream signals by 'docking' various proteins that contain Src homology 2 domains. |
| 1360 | 8048502 | Phenylarsine oxide inhibits insulin-stimulated protein phosphatase 1 activity and GLUT-4 translocation. |
| 1361 | 8048502 | Phenylarsine oxide (PAO) has previously been shown to inhibit insulin-stimulated glucose transport without affecting insulin binding and tyrosine kinase activity of insulin receptor (S. |
| 1362 | 8048502 | This study examines the effect of PAO on insulin's ability to activate adipocyte protein phosphatase 1 (PP-1) and dephosphorylate GLUT-4, the insulin-sensitive glucose transporter. |
| 1363 | 8048502 | In particulate fractions, insulin stimulated PP-1 activity (40% increase over basal with phosphorylase a) in a time- and dose-dependent manner (half-maximal effect of 0.89 nM in 1 min). |
| 1364 | 8048502 | Insulin did not alter cytosolic PP-1 activity. |
| 1365 | 8048502 | With GLUT-4 as a substrate, insulin caused more than twofold stimulation of particulate PP-1 activity. |
| 1366 | 8048502 | Addition of PAO (5 microM) before or after insulin treatment abolished insulin's effect on PP-1 activation. |
| 1367 | 8048502 | In addition, PAO significantly increased GLUT-4 phosphorylation, blocked insulin-stimulated dephosphorylation, and partially diminished insulin-stimulated translocation of GLUT-4. |
| 1368 | 8048502 | We conclude that PAO may interfere with the components of insulin signal transduction pathways that lead to the activation of PP-1 and this may be responsible for the observed inhibition in insulin action. |
| 1369 | 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. |
| 1370 | 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. |
| 1371 | 8058065 | The level of insulin receptor tyrosine kinase activity modulates the activities of phosphatidylinositol 3-kinase, microtubule-associated protein, and S6 kinases. |
| 1372 | 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). |
| 1373 | 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. |
| 1374 | 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. |
| 1375 | 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. |
| 1376 | 8058065 | The level of insulin receptor tyrosine kinase activity modulates the activities of phosphatidylinositol 3-kinase, microtubule-associated protein, and S6 kinases. |
| 1377 | 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). |
| 1378 | 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. |
| 1379 | 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. |
| 1380 | 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. |
| 1381 | 8068015 | Staurosporine inhibits phorbol 12-myristate 13-acetate- and insulin-stimulated translocation of GLUT1 and GLUT4 glucose transporters in rat adipose cells. |
| 1382 | 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. |
| 1383 | 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. |
| 1384 | 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. |
| 1385 | 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. |
| 1386 | 8070609 | The precise nature of the insulin-binding site of the insulin receptor (IR) has not been determined, although the importance of several regions of the alpha-subunit in insulin binding has been demonstrated. |
| 1387 | 8071374 | Expression of a cDNA encoding the human insulin receptor-related receptor. |
| 1388 | 8071374 | The insulin receptor-related receptor (IRR) gene encodes a protein that is homologous to the receptors for insulin and insulin-like growth factor-I (IGF-I). |
| 1389 | 8071374 | Like receptors for insulin and IGF-I, the IRR was synthesized as a single polypeptide precursor that underwent proteolytic cleavage and glycosylation to yield an alpha subunit and a beta subunit. |
| 1390 | 8071374 | However, both subunits of the IRR had smaller apparent molecular mass than the homologous subunits of the insulin receptor (108,000 versus 135,000 for the alpha subunits and 66,000 versus 95,000 for the beta subunits). |
| 1391 | 8071374 | IRR tyrosine phosphorylation could be stimulated by vanadate plus H2O2, which have been demonstrated previously to increase the phosphotyrosine content of the insulin receptor tyrosine kinase. |
| 1392 | 8071374 | However, proinsulin, insulin, IGF-I, and IGF-II did not stimulate tyrosine phosphorylation of the IRR. |
| 1393 | 8071374 | Expression of a cDNA encoding the human insulin receptor-related receptor. |
| 1394 | 8071374 | The insulin receptor-related receptor (IRR) gene encodes a protein that is homologous to the receptors for insulin and insulin-like growth factor-I (IGF-I). |
| 1395 | 8071374 | Like receptors for insulin and IGF-I, the IRR was synthesized as a single polypeptide precursor that underwent proteolytic cleavage and glycosylation to yield an alpha subunit and a beta subunit. |
| 1396 | 8071374 | However, both subunits of the IRR had smaller apparent molecular mass than the homologous subunits of the insulin receptor (108,000 versus 135,000 for the alpha subunits and 66,000 versus 95,000 for the beta subunits). |
| 1397 | 8071374 | IRR tyrosine phosphorylation could be stimulated by vanadate plus H2O2, which have been demonstrated previously to increase the phosphotyrosine content of the insulin receptor tyrosine kinase. |
| 1398 | 8071374 | However, proinsulin, insulin, IGF-I, and IGF-II did not stimulate tyrosine phosphorylation of the IRR. |
| 1399 | 8071374 | Expression of a cDNA encoding the human insulin receptor-related receptor. |
| 1400 | 8071374 | The insulin receptor-related receptor (IRR) gene encodes a protein that is homologous to the receptors for insulin and insulin-like growth factor-I (IGF-I). |
| 1401 | 8071374 | Like receptors for insulin and IGF-I, the IRR was synthesized as a single polypeptide precursor that underwent proteolytic cleavage and glycosylation to yield an alpha subunit and a beta subunit. |
| 1402 | 8071374 | However, both subunits of the IRR had smaller apparent molecular mass than the homologous subunits of the insulin receptor (108,000 versus 135,000 for the alpha subunits and 66,000 versus 95,000 for the beta subunits). |
| 1403 | 8071374 | IRR tyrosine phosphorylation could be stimulated by vanadate plus H2O2, which have been demonstrated previously to increase the phosphotyrosine content of the insulin receptor tyrosine kinase. |
| 1404 | 8071374 | However, proinsulin, insulin, IGF-I, and IGF-II did not stimulate tyrosine phosphorylation of the IRR. |
| 1405 | 8071374 | Expression of a cDNA encoding the human insulin receptor-related receptor. |
| 1406 | 8071374 | The insulin receptor-related receptor (IRR) gene encodes a protein that is homologous to the receptors for insulin and insulin-like growth factor-I (IGF-I). |
| 1407 | 8071374 | Like receptors for insulin and IGF-I, the IRR was synthesized as a single polypeptide precursor that underwent proteolytic cleavage and glycosylation to yield an alpha subunit and a beta subunit. |
| 1408 | 8071374 | However, both subunits of the IRR had smaller apparent molecular mass than the homologous subunits of the insulin receptor (108,000 versus 135,000 for the alpha subunits and 66,000 versus 95,000 for the beta subunits). |
| 1409 | 8071374 | IRR tyrosine phosphorylation could be stimulated by vanadate plus H2O2, which have been demonstrated previously to increase the phosphotyrosine content of the insulin receptor tyrosine kinase. |
| 1410 | 8071374 | However, proinsulin, insulin, IGF-I, and IGF-II did not stimulate tyrosine phosphorylation of the IRR. |
| 1411 | 8083198 | A synthetic tris-sulfotyrosyl dodecapeptide (TRDIY(S)ETDY(S)Y(S)RK-amide), whose primary sequence is identical to the 1142-1153 sequence of the insulin proreceptor, inhibited insulin receptor dephosphorylation in solubilized membranes, and digitonin-permeabilized cells derived from Chinese hamster ovary (CHO) cells expressing high levels of human insulin receptors (CHO/HIRc). |
| 1412 | 8083198 | The peptide displayed specificity toward tyrosine-class phosphatases only, as it had no effect on the activities of the serine/threonine phosphatases PP-1 and PP-2A, or alkaline phosphatase. |
| 1413 | 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. |
| 1414 | 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. |
| 1415 | 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. |
| 1416 | 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. |
| 1417 | 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. |
| 1418 | 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. |
| 1419 | 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. |
| 1420 | 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. |
| 1421 | 8088708 | How does the mitogenic insulin-like growth factor I receptor differ from the metabolic insulin receptor? |
| 1422 | 8088708 | The insulin-like growth factors (IGF-I and IGF-II), on the other hand, are primarily involved in the regulation of growth and development of the whole organism and interact with IGF receptors expressed by most, if not all, tissues of the body. |
| 1423 | 8088708 | As the insulin and IGF-I receptors are both structurally and functionally similar, one of the fundamental questions in this area of research has been the basis for the distinct pathways of hormone action elicited by insulin and the IGFs. |
| 1424 | 8088708 | Finally, structural differences in the beta-subunits of the insulin and IGF-I receptors may result in divergence of the signal pathways. |
| 1425 | 8088709 | The insulin receptor is expressed in two different isoforms (HIR-A and HIR-B). |
| 1426 | 8088709 | This effect appears to be mediated through activation of certain protein kinase C isoforms, which are able to form stable complexes with the insulin receptor and modulate its tyrosine kinase activity through serine phosphorylation of the receptor beta-subunit. |
| 1427 | 8088709 | The insulin receptor is expressed in two different isoforms (HIR-A and HIR-B). |
| 1428 | 8088709 | This effect appears to be mediated through activation of certain protein kinase C isoforms, which are able to form stable complexes with the insulin receptor and modulate its tyrosine kinase activity through serine phosphorylation of the receptor beta-subunit. |
| 1429 | 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. |
| 1430 | 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. |
| 1431 | 8104271 | Both aminoacid substitutions were located close to tyrosine phosphorylation motifs that are putative recognition sites for insulin and IGF1 signal transmission proteins. |
| 1432 | 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. |
| 1433 | 8135754 | We observed a significant (approximately 30%) (P < 0.001, n = 18) elevation of cytosolic protein tyrosine phosphatase (PTP) activity directed against the beta subunit of the insulin receptor in livers of old rats. |
| 1434 | 8137907 | We have previously reported that a mutation substituting Val for Phe382 in the alpha-subunit of the insulin receptor impairs intracellular processing and insulin-induced autophosphorylation of the mutant receptor. |
| 1435 | 8138059 | Palmitate has been shown to stimulate glucose transport, translocation of GLUT4 and insulin receptor autophosphorylation in isolated rat adipocytes (Biochem Biophys Res Commun 177:343-49, 1991). |
| 1436 | 8141246 | This has allowed the synthesis of many insulin derivatives, and we review our recent exploitation of one such derivative to understand the biochemistry of the interaction of this ligand with the receptor and to dissect the complicated steps of ligand-induced insulin receptor autophosphorylation. |
| 1437 | 8145651 | Genetic studies have attempted to link (bipolar) affective disorder to the short arm of chromosome 11 (where the loci for insulin, insulin growth factor (IGF), tyrosine hydroxylase (TH) and h-ras-oncogene are located) but these have failed. |
| 1438 | 8145651 | Since TH and the insulin receptor require phosphorylation by protein kinases, then a defect of the h-ras-oncogene or its products (p21) could disorder both these systems and compromise catecholaminergic transmission in neurones and energy flow in glial cells. |
| 1439 | 8175972 | Furthermore, the existence of apparently asymptomatic carriers of mutations in the insulin receptor gene, such as the father in the present study, suggests that the prevalence of mutations in the insulin receptor gene may be higher than would be predicted on the basis of the observed prevalence of patients with extreme insulin resistance. |
| 1440 | 8184737 | Molecular cloning of pp120/ECTO-ATPase, an endogenous substrate of the insulin receptor kinase. |
| 1441 | 8193539 | IRS-1 is a principal substrate of the insulin receptor tyrosine kinase. |
| 1442 | 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. |
| 1443 | 8195122 | In order to study how alpha beta half-receptors interact to form the insulin-binding site, we cotransfected NIH-3T3 cells with two insulin receptor cDNA constructs: a truncated insulin receptor lacking the C-terminal 43 amino acids (delta 43) and the full-length Leu323 mutant receptor. |
| 1444 | 8195122 | Both beta and beta delta-subunits of the Leu323-delta 43 hybrid receptor are phosphorylated in vivo and in vitro in an insulin-dependent manner, suggesting an intramolecular transphosphorylation mechanism and that the presence of the Leu323 mutant receptor that lacks an intrinsic high affinity binding site does not prevent the associated beta-subunit from functioning either as a tyrosine kinase or as a phosphate acceptor in the hybrid insulin receptor molecule (alpha alpha mut beta delta beta). |
| 1445 | 8195122 | In order to study how alpha beta half-receptors interact to form the insulin-binding site, we cotransfected NIH-3T3 cells with two insulin receptor cDNA constructs: a truncated insulin receptor lacking the C-terminal 43 amino acids (delta 43) and the full-length Leu323 mutant receptor. |
| 1446 | 8195122 | Both beta and beta delta-subunits of the Leu323-delta 43 hybrid receptor are phosphorylated in vivo and in vitro in an insulin-dependent manner, suggesting an intramolecular transphosphorylation mechanism and that the presence of the Leu323 mutant receptor that lacks an intrinsic high affinity binding site does not prevent the associated beta-subunit from functioning either as a tyrosine kinase or as a phosphate acceptor in the hybrid insulin receptor molecule (alpha alpha mut beta delta beta). |
| 1447 | 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. |
| 1448 | 8196603 | During insulin stimulation, GRB-2 binds to the phosphorylated Y895VNI motif of IRS-1. |
| 1449 | 8196603 | The myeloid progenitor cell line, 32-D, is insensitive to insulin because it contains few insulin receptors and no IRS-1. |
| 1450 | 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. |
| 1451 | 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. |
| 1452 | 8196603 | Interestingly, IRS-1, but not IRS-1F-895, enhanced the stimulation of MAP kinase by insulin in 32-D cells expressing insulin receptors. |
| 1453 | 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. |
| 1454 | 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. |
| 1455 | 8197147 | Tumor necrosis factor alpha inhibits signaling from the insulin receptor. |
| 1456 | 8197147 | We have recently shown that tumor necrosis factor (TNF) alpha is a key mediator of insulin resistance in animal models of non-insulin-dependent diabetes mellitus. |
| 1457 | 8197147 | Here, we investigate how TNF-alpha interferes with insulin action. |
| 1458 | 8197147 | Chronic exposure of adipocytes to low concentrations of TNF-alpha strongly inhibits insulin-stimulated glucose uptake. |
| 1459 | 8197147 | Concurrently, TNF-alpha treatment causes a moderate decrease in the insulin-stimulated autophosphorylation of the insulin receptor (IR) and a dramatic decrease in the phosphorylation of IR substrate 1, the major substrate of the IR in vivo. |
| 1460 | 8197147 | These results show that TNF-alpha directly interferes with the signaling of insulin through its receptor and consequently blocks biological actions of insulin. |
| 1461 | 8197147 | Tumor necrosis factor alpha inhibits signaling from the insulin receptor. |
| 1462 | 8197147 | We have recently shown that tumor necrosis factor (TNF) alpha is a key mediator of insulin resistance in animal models of non-insulin-dependent diabetes mellitus. |
| 1463 | 8197147 | Here, we investigate how TNF-alpha interferes with insulin action. |
| 1464 | 8197147 | Chronic exposure of adipocytes to low concentrations of TNF-alpha strongly inhibits insulin-stimulated glucose uptake. |
| 1465 | 8197147 | Concurrently, TNF-alpha treatment causes a moderate decrease in the insulin-stimulated autophosphorylation of the insulin receptor (IR) and a dramatic decrease in the phosphorylation of IR substrate 1, the major substrate of the IR in vivo. |
| 1466 | 8197147 | These results show that TNF-alpha directly interferes with the signaling of insulin through its receptor and consequently blocks biological actions of insulin. |
| 1467 | 8200291 | Insulin-stimulated 32P-incorporation into the insulin receptor beta-subunit was increased by 133% in the LGA group versus the control, whereas incorporation in the AGA group was equivalent to the control. |
| 1468 | 8200291 | Insulin-stimulated tyrosine kinase activity of the receptor preparation for histone H2B phosphorylation was also significantly increased in the LGA group compared to the control. 32P-incorporation into beta-subunit IGF-1 receptor and IGF-1-stimulated tyrosine kinase activity did not show any significant differences among the three groups. |
| 1469 | 8200911 | We conclude that the novel pathway of insulin signaling involving the regulatory Gi proteins via biochemical mechanisms not directly involving the tyrosine kinase of the insulin receptor is altered in obese type II diabetes and offers a new target for the search of the mechanism(s) of insulin resistance. |
| 1470 | 8202531 | Tyrosine kinase-deficient mutant human insulin receptors (Met1153-->Ile) overexpressed in transfected rat adipose cells fail to mediate translocation of epitope-tagged GLUT4. |
| 1471 | 8202531 | Insulin stimulates a 4.3-fold recruitment of transfected epitope-tagged GLUT4 to the cell surface. |
| 1472 | 8202531 | Cells cotransfected with the reporter gene and the human insulin receptor gene show an increase in cell surface GLUT4 in the basal state (no insulin) to levels comparable to those seen with maximal insulin stimulation of cells transfected with the reporter gene alone. |
| 1473 | 8202531 | In contrast, cells overexpressing a naturally occurring tyrosine kinase-deficient mutant insulin receptor (Met1153-->Ile) show no increase in the basal cell surface GLUT4 and no shift in the insulin dose-response curve relative to cells transfected with the reporter gene alone. |
| 1474 | 8202531 | These results demonstrate that insulin receptor tyrosine kinase activity is essential in insulin-stimulated glucose transport in adipose cells. |
| 1475 | 8202531 | Tyrosine kinase-deficient mutant human insulin receptors (Met1153-->Ile) overexpressed in transfected rat adipose cells fail to mediate translocation of epitope-tagged GLUT4. |
| 1476 | 8202531 | Insulin stimulates a 4.3-fold recruitment of transfected epitope-tagged GLUT4 to the cell surface. |
| 1477 | 8202531 | Cells cotransfected with the reporter gene and the human insulin receptor gene show an increase in cell surface GLUT4 in the basal state (no insulin) to levels comparable to those seen with maximal insulin stimulation of cells transfected with the reporter gene alone. |
| 1478 | 8202531 | In contrast, cells overexpressing a naturally occurring tyrosine kinase-deficient mutant insulin receptor (Met1153-->Ile) show no increase in the basal cell surface GLUT4 and no shift in the insulin dose-response curve relative to cells transfected with the reporter gene alone. |
| 1479 | 8202531 | These results demonstrate that insulin receptor tyrosine kinase activity is essential in insulin-stimulated glucose transport in adipose cells. |
| 1480 | 8202531 | Tyrosine kinase-deficient mutant human insulin receptors (Met1153-->Ile) overexpressed in transfected rat adipose cells fail to mediate translocation of epitope-tagged GLUT4. |
| 1481 | 8202531 | Insulin stimulates a 4.3-fold recruitment of transfected epitope-tagged GLUT4 to the cell surface. |
| 1482 | 8202531 | Cells cotransfected with the reporter gene and the human insulin receptor gene show an increase in cell surface GLUT4 in the basal state (no insulin) to levels comparable to those seen with maximal insulin stimulation of cells transfected with the reporter gene alone. |
| 1483 | 8202531 | In contrast, cells overexpressing a naturally occurring tyrosine kinase-deficient mutant insulin receptor (Met1153-->Ile) show no increase in the basal cell surface GLUT4 and no shift in the insulin dose-response curve relative to cells transfected with the reporter gene alone. |
| 1484 | 8202531 | These results demonstrate that insulin receptor tyrosine kinase activity is essential in insulin-stimulated glucose transport in adipose cells. |
| 1485 | 8227156 | The insulin receptor substrate protein 1 (IRS-1) could not be detected in the nucleus by immunoblotting. |
| 1486 | 8243830 | We identified a heterozygous missense mutation that substituted aspartic acid (GAC) for alanine (GCC) at codon 1048 of the insulin receptor gene in a patient who displayed typical symptoms of Type A syndrome of insulin resistance. |
| 1487 | 8243830 | Insulin-stimulated phosphorylation of exogenous substrate by partially purified insulin receptors prepared from COS 7 cells that were cotransfected with wild-type and mutant insulin receptor cDNAs was markedly impaired, whereas autophosphorylation was decreased by approximately 50% of wild-type receptors. |
| 1488 | 8243830 | We identified a heterozygous missense mutation that substituted aspartic acid (GAC) for alanine (GCC) at codon 1048 of the insulin receptor gene in a patient who displayed typical symptoms of Type A syndrome of insulin resistance. |
| 1489 | 8243830 | Insulin-stimulated phosphorylation of exogenous substrate by partially purified insulin receptors prepared from COS 7 cells that were cotransfected with wild-type and mutant insulin receptor cDNAs was markedly impaired, whereas autophosphorylation was decreased by approximately 50% of wild-type receptors. |
| 1490 | 8243832 | Immunoprecipitation of GLUT4 from 32Pi- and [35S]methionine-labeled adipocytes revealed that the insulin resistance of GLUT4 translocation is accompanied by increased (three- to fourfold) phosphorylation of GLUT4 in both low-density microsomes and plasma membranes. |
| 1491 | 8243832 | Short-term treatment of desensitized adipocytes with glimepiride or insulin reduced GLUT4 phosphorylation by approximately 70 and 25%, respectively, in both fractions. |
| 1492 | 8243832 | We conclude that glimepiride activates glucose transport by stimulation of GLUT1 and GLUT4 translocation in rat adipocytes via interference at a site downstream of the putative molecular defect in the signaling cascade between the insulin receptor and the glucose transport system induced by high concentrations of glucose and insulin. |
| 1493 | 8262308 | To determine whether this delay was related to transcapillary transport of insulin, we determined increments in serum insulin levels, glucose disposal rates (GDR), and insulin receptor (IR) kinase activity measured during continuous infusions of insulin (40 and 120 mU.m-2.min-1) administered to 8 nondiabetic males; similar studies were done at 1,200.m-2.min-1 in 2 of the subjects. |
| 1494 | 8268238 | Furthermore, insulin-stimulated autophosphorylation of the mutant insulin receptor is impaired. |
| 1495 | 8349045 | Insulin receptor number, activation of the insulin receptor tyrosine kinase in situ and after solubilization, and the total pool of glucose transporters (GLUT4) were unaffected, and glycogen synthase was activated by glucosamine pretreatment. |
| 1496 | 8349045 | In HIR-cells, which express GLUT1 and not GLUT4, basal and insulin-stimulated glucose transport were unaffected by glucosamine, but glycogen synthesis was markedly inhibited. |
| 1497 | 8349045 | Insulin-stimulated activation of protein kinases (MAP and S6) was unaffected, and the fractional velocity and apparent total activity of glycogen synthase was increased in glucosamine-treated HIR-cells. |
| 1498 | 8349045 | Glucosamine-induced insulin resistance of glucose transport appears to be restricted to GLUT4-expressing cells, i.e., skeletal muscle and adipocytes; it may reflect impaired translocation of GLUT4 to the plasmalemma. |
| 1499 | 8359580 | The human insulin receptor exists in two isoforms (HIR-A alpha-subunit 719 amino acids and HIR-B alpha-subunit 731 amino acids) which are generated by alternative splicing of a small exon and display distinct patterns of tissue-specific expression. |
| 1500 | 8359580 | Using the polymerase chain reaction we have recently shown that skeletal muscle of non-diabetic individuals contains predominantly mRNA encoding HIR-A while in skeletal muscle derived from subjects with Type 2 (non-insulin-dependent) diabetes mellitus similar amounts of each mRNA are expressed. |
| 1501 | 8363571 | Peptides representing two putative G-protein-binding motifs (GPBP1 and GPBP2) derived from insulin-receptor sequences were tested for their ability to stimulate guanosine 5'-[gamma-thio]-triphosphate (GTP[S]; 'GTP gamma S') binding to a preparation containing the 41 and 67 kDa G-proteins that are associated with the insulin receptor [Jo, Cha, Davis and McDonald (1992) Endocrinology (Baltimore) 131, 2855-2861]. |
| 1502 | 8376587 | Identification of unique nuclear regulatory proteins for the insulin receptor gene, which appear during myocyte and adipocyte differentiation. |
| 1503 | 8376587 | Gel retardation assays, combined with DNase I footprinting, showed that the increased insulin receptor gene transcription occurring during differentiation was directly correlated with the appearance of DNA binding proteins that specifically interacted with two AT-rich sequences of the regulatory region of the insulin receptor gene. |
| 1504 | 8376587 | Identification of unique nuclear regulatory proteins for the insulin receptor gene, which appear during myocyte and adipocyte differentiation. |
| 1505 | 8376587 | Gel retardation assays, combined with DNase I footprinting, showed that the increased insulin receptor gene transcription occurring during differentiation was directly correlated with the appearance of DNA binding proteins that specifically interacted with two AT-rich sequences of the regulatory region of the insulin receptor gene. |
| 1506 | 8380406 | pp120/ecto-ATPase, an endogenous substrate of the insulin receptor tyrosine kinase, is expressed as two variably spliced isoforms. |
| 1507 | 8380406 | The insulin receptor possesses tyrosine kinase activity which is thought to mediate the biological effects of insulin upon target cells. pp120 is a liver-specific glycoprotein of apparent molecular size of 120 kDa that is phosphorylated on tyrosine residues by the receptors for insulin, insulin-like growth factor-I, and epidermal growth factor. |
| 1508 | 8380406 | pp120/ecto-ATPase, an endogenous substrate of the insulin receptor tyrosine kinase, is expressed as two variably spliced isoforms. |
| 1509 | 8380406 | The insulin receptor possesses tyrosine kinase activity which is thought to mediate the biological effects of insulin upon target cells. pp120 is a liver-specific glycoprotein of apparent molecular size of 120 kDa that is phosphorylated on tyrosine residues by the receptors for insulin, insulin-like growth factor-I, and epidermal growth factor. |
| 1510 | 8380564 | However, in both HepG2 and MCF-7 cells, a protein was identified that specifically binds to this important insulin-receptor promoter region, but does not bind to the Sp1 consensus element. |
| 1511 | 8380564 | We conclude that activation of insulin-receptor gene transcription occurs in a 40 bp region 578 bp upstream from the translational initiation site, and that Sp1 and another nuclear factor other than Sp1 may be important in regulating transcription in HepG2 cells. |
| 1512 | 8380564 | However, in both HepG2 and MCF-7 cells, a protein was identified that specifically binds to this important insulin-receptor promoter region, but does not bind to the Sp1 consensus element. |
| 1513 | 8380564 | We conclude that activation of insulin-receptor gene transcription occurs in a 40 bp region 578 bp upstream from the translational initiation site, and that Sp1 and another nuclear factor other than Sp1 may be important in regulating transcription in HepG2 cells. |
| 1514 | 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. |
| 1515 | 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. |
| 1516 | 8384986 | IRS-1 is a common element in insulin and insulin-like growth factor-I signaling to the phosphatidylinositol 3'-kinase. |
| 1517 | 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). |
| 1518 | 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. |
| 1519 | 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. |
| 1520 | 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. |
| 1521 | 8384986 | These data demonstrate that IRS-1 is a common element for signal transmission by the IGF-I and insulin receptors. |
| 1522 | 8385139 | Association of IRS-1 with the insulin receptor and the phosphatidylinositol 3'-kinase. |
| 1523 | 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. |
| 1524 | 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. |
| 1525 | 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. |
| 1526 | 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. |
| 1527 | 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. |
| 1528 | 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. |
| 1529 | 8385139 | Association of IRS-1 with the insulin receptor and the phosphatidylinositol 3'-kinase. |
| 1530 | 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. |
| 1531 | 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. |
| 1532 | 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. |
| 1533 | 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. |
| 1534 | 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. |
| 1535 | 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. |
| 1536 | 8385139 | Association of IRS-1 with the insulin receptor and the phosphatidylinositol 3'-kinase. |
| 1537 | 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. |
| 1538 | 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. |
| 1539 | 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. |
| 1540 | 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. |
| 1541 | 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. |
| 1542 | 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. |
| 1543 | 8385139 | Association of IRS-1 with the insulin receptor and the phosphatidylinositol 3'-kinase. |
| 1544 | 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. |
| 1545 | 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. |
| 1546 | 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. |
| 1547 | 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. |
| 1548 | 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. |
| 1549 | 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. |
| 1550 | 8385139 | Association of IRS-1 with the insulin receptor and the phosphatidylinositol 3'-kinase. |
| 1551 | 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. |
| 1552 | 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. |
| 1553 | 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. |
| 1554 | 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. |
| 1555 | 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. |
| 1556 | 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. |
| 1557 | 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. |
| 1558 | 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. |
| 1559 | 8387037 | We suspect that insulin signals are enabled when the activated insulin receptor kinase phosphorylates specific tyrosine residues in IRS-1. |
| 1560 | 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. |
| 1561 | 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. |
| 1562 | 8387037 | We suspect that insulin signals are enabled when the activated insulin receptor kinase phosphorylates specific tyrosine residues in IRS-1. |
| 1563 | 8390949 | The maximal insulin-stimulated autophosphorylation of the insulin receptor from the patient's transformed lymphocytes was decreased to 45% of that from the control subjects. |
| 1564 | 8390949 | On examination, the biological activities of insulin and insulin-like growth factor I in the patient's cultured fibroblasts, insulin sensitivity of amino isobutyric acid uptake and thymidine incorporation was decreased, but insulin-like growth factor I action was normal. |
| 1565 | 8398110 | Phylogeny of the insulin-like growth factors (IGFs) and receptors: a molecular approach. |
| 1566 | 8398110 | The IGFs (IGF-I and IGF-II) are essential for normal mammalian growth and development. |
| 1567 | 8398110 | The ligands and the IGF-I receptor are structurally related to insulin and to the insulin receptor, respectively. |
| 1568 | 8398110 | The sequences of the exons encoding the mature insulin and IGF peptides are highly conserved among vertebrate species, and IGF-I-like molecules are found in species whose origins extend back as much as 550 million years. |
| 1569 | 8398110 | The insulin receptor is also highly conserved in vertebrate species, and an insulin-receptor-like molecule has been characterized in Drosophila. |
| 1570 | 8398110 | Phylogeny of the insulin-like growth factors (IGFs) and receptors: a molecular approach. |
| 1571 | 8398110 | The IGFs (IGF-I and IGF-II) are essential for normal mammalian growth and development. |
| 1572 | 8398110 | The ligands and the IGF-I receptor are structurally related to insulin and to the insulin receptor, respectively. |
| 1573 | 8398110 | The sequences of the exons encoding the mature insulin and IGF peptides are highly conserved among vertebrate species, and IGF-I-like molecules are found in species whose origins extend back as much as 550 million years. |
| 1574 | 8398110 | The insulin receptor is also highly conserved in vertebrate species, and an insulin-receptor-like molecule has been characterized in Drosophila. |
| 1575 | 8419148 | Using a novel immunoenzymatic assay with intact insulin-like growth factor-I (IGF-I) and insulin receptors as substrates, we show that phosphotyrosine-protein phosphatases (PTP-ases) from normal rat tissues induce a decrease in tyrosine phosphorylation of both receptors. |
| 1576 | 8419148 | In general, the dephosphorylation of IGF-I receptor follows a pattern similar to that of insulin receptor except in red skeletal muscle in which it is not modified. |
| 1577 | 8419148 | Pregnancy also induces alterations of liver PTP-ases similar to those elicited by diabetes with a 50% reduction of insulin and IGF-I receptor dephosphorylation. |
| 1578 | 8425625 | Tyrosine kinase activity of insulin-like growth factor I and insulin receptors in human endometrium during the menstrual cycle: cyclic variation of insulin receptor expression. |
| 1579 | 8425673 | In this study, we sought to determine whether insulin stimulates the production and secretion of ET-1 as a possible basis for the association of hyperinsulinemia and vascular disease. |
| 1580 | 8425673 | We demonstrated that insulin significantly stimulates the gene expression and secretion of ET-1 from cultured BAEC, and that insulin increases ET-1 mRNA expressed in BBCEC. |
| 1581 | 8425673 | Insulin caused a maximal twofold inducement above control ET-1 mRNA expression in a dose-related fashion in BAEC. |
| 1582 | 8425673 | Increased ET-1 mRNA was seen after 4 h of incubation with insulin: the peak occurred at 6-8 h and persisted for 24 h. |
| 1583 | 8425673 | Insulin caused as much as a fourfold stimulation of ET-1 secretion from BAEC in a dose-related fashion, including a twofold increase at a physiological concentration (10(-9) M): The increase began at 1 h of incubation and continued for the entire 24-h incubation period. |
| 1584 | 8425673 | The insulin-induced increases in both ET-1 mRNA and ET-1 protein secretion were significantly attenuated by genistein, a tyrosine kinase inhibitor. |
| 1585 | 8425673 | This stimulation probably occurred through the insulin receptor, because IGF-1 had no effect on ET-1 gene expression or secretion from these cells. |
| 1586 | 8432414 | INSR gene mutations have been described in multiple individuals with extreme insulin resistance, but the INSR gene has not been implicated in familial NIDDM. |
| 1587 | 8458533 | The insulin receptor related insulin-like growth factor I receptor also showed no functional changes. |
| 1588 | 8458533 | These findings demonstrate that the primary genetic lesion in Seip-Berardinelli's lipodystrophy is outside the insulin receptor gene and that an involvement of the insulin-like growth factor I receptor is also unlikely. |
| 1589 | 8458533 | The insulin receptor related insulin-like growth factor I receptor also showed no functional changes. |
| 1590 | 8458533 | These findings demonstrate that the primary genetic lesion in Seip-Berardinelli's lipodystrophy is outside the insulin receptor gene and that an involvement of the insulin-like growth factor I receptor is also unlikely. |
| 1591 | 8477820 | Taking the insulin receptor as an exemplary protein involved in insulin action we review molecular mechanisms regulating insulin receptor activity, gene expression, and the role of natural occurring insulin receptor gene mutations in patients with insulin resistant diabetes mellitus. |
| 1592 | 8496180 | Insulin-stimulated autophosphorylation of the cytoplasmic juxtamembrane region of the human insulin receptor was examined by Tricine/SDS-PAGE. |
| 1593 | 8513978 | Q-397 and Q-418 mutant insulin receptors had insulin-binding characteristics similar to the wild-type human insulin receptor, whereas no insulin-binding activity could be detected above the control level in cells transfected with Q-D. |
| 1594 | 8513978 | Finally, pulse-chase experiments with [35S]Met were able to detect 190,000-M(r) proreceptors and the alpha-subunits for Q-397, Q-418, and wild-type human insulin receptors. |
| 1595 | 8518461 | Insulin-receptor substrate 1 may be central to phosphorylation reactions through a role in serine and threonine kinase activity. |
| 1596 | 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. |
| 1597 | 8518461 | Insulin-receptor substrate 1 may be central to phosphorylation reactions through a role in serine and threonine kinase activity. |
| 1598 | 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. |
| 1599 | 8529511 | Activation of protein kinase C probably leads to phosphorylation of the beta-subunit of the insulin receptor at serine residues. |
| 1600 | 8529511 | The hyperglycaemic effect can be antagonized in the isolated cell system both by protein kinase C inhibitors and so-called insulin sensitizers such as thiazolidindiones. |
| 1601 | 8529511 | As TNF alpha is probably increasingly expressed in obesity, the modulation of receptor kinase activity by TNF alpha could be an important factor for insulin resistance in obesity. |
| 1602 | 8529763 | There was no change in erythrocyte insulin receptor binding associated with metformin treatment, but both basal and insulin-stimulated insulin receptor tyrosine kinase activities of solubilized erythrocyte insulin receptors were significantly higher after 10 weeks of metformin treatment. |
| 1603 | 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. |
| 1604 | 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). |
| 1605 | 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. |
| 1606 | 8530404 | When insulin is added, p85 is released from phosphorylated PDGF receptors and binds to phosphorylated insulin receptors and insulin receptor substrate-1. |
| 1607 | 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. |
| 1608 | 8530404 | In contrast, insulin activation does not displace PDGF receptors from binding sites on Ras GTPase-activating protein. |
| 1609 | 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. |
| 1610 | 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. |
| 1611 | 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). |
| 1612 | 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. |
| 1613 | 8530404 | When insulin is added, p85 is released from phosphorylated PDGF receptors and binds to phosphorylated insulin receptors and insulin receptor substrate-1. |
| 1614 | 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. |
| 1615 | 8530404 | In contrast, insulin activation does not displace PDGF receptors from binding sites on Ras GTPase-activating protein. |
| 1616 | 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. |
| 1617 | 8530617 | Insulin resistance associated with substitution of histidine for arginine 252 in the alpha-subunit of the human insulin receptor: trial of insulin-like growth factor I injection therapy to enhance insulin sensitivity. |
| 1618 | 8530617 | A homozygous point mutation that results in the substitution of histidine for arginine 252 in the insulin receptor alpha-subunit has now been identified by polymerase chain reaction and single stranded conformational polymorphism analysis in a 20-yr-old Japanese woman with type A syndrome and severe insulin resistance. |
| 1619 | 8530617 | The chronic sc administration of insulin-like growth factor I (IGF-I) improved the patient's hyperglycemia and corrected certain metabolic abnormalities over a 9-month period, even though the binding of 125I-labeled IGF-I to her cultured fibroblasts was decreased by 40% relative to that to cells from healthy controls. |
| 1620 | 8530617 | Studies of the binding of 125I-labeled insulin to the proband's cultured fibroblasts, to COS-I cells transfected with complementary DNA encoding the mutant insulin receptor, and to partially purified mutant receptors revealed that the Arg252-->His mutation decreased both cell surface expression and the affinity for insulin for the receptor. |
| 1621 | 8530617 | Insulin resistance associated with substitution of histidine for arginine 252 in the alpha-subunit of the human insulin receptor: trial of insulin-like growth factor I injection therapy to enhance insulin sensitivity. |
| 1622 | 8530617 | A homozygous point mutation that results in the substitution of histidine for arginine 252 in the insulin receptor alpha-subunit has now been identified by polymerase chain reaction and single stranded conformational polymorphism analysis in a 20-yr-old Japanese woman with type A syndrome and severe insulin resistance. |
| 1623 | 8530617 | The chronic sc administration of insulin-like growth factor I (IGF-I) improved the patient's hyperglycemia and corrected certain metabolic abnormalities over a 9-month period, even though the binding of 125I-labeled IGF-I to her cultured fibroblasts was decreased by 40% relative to that to cells from healthy controls. |
| 1624 | 8530617 | Studies of the binding of 125I-labeled insulin to the proband's cultured fibroblasts, to COS-I cells transfected with complementary DNA encoding the mutant insulin receptor, and to partially purified mutant receptors revealed that the Arg252-->His mutation decreased both cell surface expression and the affinity for insulin for the receptor. |
| 1625 | 8530617 | Insulin resistance associated with substitution of histidine for arginine 252 in the alpha-subunit of the human insulin receptor: trial of insulin-like growth factor I injection therapy to enhance insulin sensitivity. |
| 1626 | 8530617 | A homozygous point mutation that results in the substitution of histidine for arginine 252 in the insulin receptor alpha-subunit has now been identified by polymerase chain reaction and single stranded conformational polymorphism analysis in a 20-yr-old Japanese woman with type A syndrome and severe insulin resistance. |
| 1627 | 8530617 | The chronic sc administration of insulin-like growth factor I (IGF-I) improved the patient's hyperglycemia and corrected certain metabolic abnormalities over a 9-month period, even though the binding of 125I-labeled IGF-I to her cultured fibroblasts was decreased by 40% relative to that to cells from healthy controls. |
| 1628 | 8530617 | Studies of the binding of 125I-labeled insulin to the proband's cultured fibroblasts, to COS-I cells transfected with complementary DNA encoding the mutant insulin receptor, and to partially purified mutant receptors revealed that the Arg252-->His mutation decreased both cell surface expression and the affinity for insulin for the receptor. |
| 1629 | 8543058 | TNF-alpha inhibits glucose-induced insulin secretion in a pancreatic beta-cell line (INS-1). |
| 1630 | 8543058 | Recent studies suggest that TNF-alpha affects various biochemical and physiological processes which may be linked to the etiology of non-insulin-dependent diabetes mellitus (NIDDM). |
| 1631 | 8543058 | For example, TNF-alpha interferes with the signaling of the insulin receptor and the metabolism of glucose transporters. |
| 1632 | 8543058 | The possibility that TNF-alpha might directly reduce glucose-stimulated insulin secretion in pancreatic beta-cells was examined by using an established pancreatic beta-cell line (INS-1). |
| 1633 | 8543058 | TNF-alpha did not affect glucose-induced acute insulin secretion (30 min). |
| 1634 | 8543058 | However, over a longer time period (24 h), TNF-alpha decreased glucose-induced insulin secretion without affecting the total amount of insulin in the cell. |
| 1635 | 8543058 | In the presence of TNF-alpha levels of 0, 10, 100 and 1000 U/ml, the respective 20 mM glucose-induced insulin secretion was 1.736 +/- 0.166, 1.750 +/- 0.302, 1.550 +/- 0.200, and 1.400 +/- 0.112 mU/ml per 3 x 10(5) cells in 24 h. |
| 1636 | 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. |
| 1637 | 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. |
| 1638 | 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. |
| 1639 | 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. |
| 1640 | 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. |
| 1641 | 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. |
| 1642 | 8571133 | IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-induced insulin resistance. |
| 1643 | 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). |
| 1644 | 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. |
| 1645 | 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. |
| 1646 | 8571133 | These results indicate that TNF-alpha induces insulin resistance through an unexpected action of IRS-1 to attenuate insulin receptor signaling. |
| 1647 | 8571133 | IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-induced insulin resistance. |
| 1648 | 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). |
| 1649 | 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. |
| 1650 | 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. |
| 1651 | 8571133 | These results indicate that TNF-alpha induces insulin resistance through an unexpected action of IRS-1 to attenuate insulin receptor signaling. |
| 1652 | 8571133 | IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-induced insulin resistance. |
| 1653 | 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). |
| 1654 | 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. |
| 1655 | 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. |
| 1656 | 8571133 | These results indicate that TNF-alpha induces insulin resistance through an unexpected action of IRS-1 to attenuate insulin receptor signaling. |
| 1657 | 8581776 | The genes resistant to insulin include glucokinase gene and phosphoenolpyruvate carboxykinase gene. |
| 1658 | 8581776 | In contrast, L-type pyruvate kinase gene responds to insulin normally, raising the possibility that the signaling pathway from the insulin receptor to the insulin-resistant genes, but not to the insulin-sensitive genes, is defective at a point beyond the receptor kinase in the fatty rats. |
| 1659 | 8587610 | G ialpha2 deficiency increases protein-tyrosine phosphatase activity and attenuates insulin-stimulated tyrosine phosphorylation of IRS (insulin-receptor substrate 1) in vivo. |
| 1660 | 8593783 | Tumorigenic and mitogenic capacities are reduced in transfected fibroblasts expressing mutant insulin-like growth factor (IGF)-I receptors. |
| 1661 | 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. |
| 1662 | 8593783 | The yyFH mutation results in an IGF-I receptor with the amino acids found in the homologous position of the human insulin receptor. |
| 1663 | 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. |
| 1664 | 8593937 | Regulation of glycogen synthase and protein phosphatase-1 by hexosamines. |
| 1665 | 8593937 | Here we examine the effects of glucose and glucosamine on insulin-stimulated GS activity and on protein phosphatase-1 (PP1) activity. |
| 1666 | 8593937 | Cells overexpressing the normal human insulin receptor (HIRc-B) were used to facilitate analysis of insulin-stimulated PP1 activity. |
| 1667 | 8593937 | Stimulation with 1.7 mmol/l insulin led to a 37.6 +/- 9.9% increase in PP1 activity in HIRc-B cells cultured in 1 mmol/l glucose, while cells cultured in 5 mmol/l glucosamine or 20 mmol/l glucose demonstrated only 3.79 +/- 0.60 or 1.6 +/- 0.75% increases, respectively. |
| 1668 | 8593937 | We conclude that both basal and insulin- stimulable GS and PP1 activity are downregulated by high glucose in fibroblasts and this regulation is mediated by products of the hexosamine biosynthesis pathway. |
| 1669 | 8597496 | The cloning of the insulin receptor not only established the primary structure of this membrane-bound glycoprotein but also offered the material necessary for the study of the molecular functions of this tyrosine-kinase receptor using molecular biology tools. |
| 1670 | 8620937 | Low molecular weight acid phosphatase encoded by the highly polymorphic locus ACP1 is a member of the protein-tyrosin phosphatase family (PTPases) which plays an essential role in the control of receptor signalling through phosphotyrosine pathways. |
| 1671 | 8620937 | Recent experiments have shown that purified rat liver ACP, corresponding to human ACP1, is able to hydrolyze a phosphotyrosine-containing synthetic peptide corresponding to the 1146-1158 sequence of the human insulin receptor, and shows a high affinity for it. |
| 1672 | 8620937 | This prompted us to analyze the degree of glycemic control in relation to ACP1 genetic variability in a sample of 214 diabetic pregnant women including IDDM, NIDDM and gestational diabetes. |
| 1673 | 8620937 | The data suggest that quantitative variations of ACP1 may influence the clinical manifestations of diabetic disorders, and call for further studies on the role of this enzyme in the modulation of insulin-receptor phosphotyrosine pathways. |
| 1674 | 8620937 | Low molecular weight acid phosphatase encoded by the highly polymorphic locus ACP1 is a member of the protein-tyrosin phosphatase family (PTPases) which plays an essential role in the control of receptor signalling through phosphotyrosine pathways. |
| 1675 | 8620937 | Recent experiments have shown that purified rat liver ACP, corresponding to human ACP1, is able to hydrolyze a phosphotyrosine-containing synthetic peptide corresponding to the 1146-1158 sequence of the human insulin receptor, and shows a high affinity for it. |
| 1676 | 8620937 | This prompted us to analyze the degree of glycemic control in relation to ACP1 genetic variability in a sample of 214 diabetic pregnant women including IDDM, NIDDM and gestational diabetes. |
| 1677 | 8620937 | The data suggest that quantitative variations of ACP1 may influence the clinical manifestations of diabetic disorders, and call for further studies on the role of this enzyme in the modulation of insulin-receptor phosphotyrosine pathways. |
| 1678 | 8621012 | We assessed the protein expression of GLUT4 and glycogen synthase, as well as insulin-induced translocation of GLUT4 to the plasma membrane, in soleus skeletal muscle from control rats, OVX rats, and OVX rats treated for 8 weeks with testosterone (OVX + T). |
| 1679 | 8621012 | Insulin induced a 3.7-fold increase (P < 0.05) in the plasma membrane content of GLUT4 in soleus muscle from control rats, whereas plasma membrane content of GLUT4 in soleus muscle from OVX or OVX + T rats was unaltered in response to insulin. |
| 1680 | 8621012 | Insulin receptor and tyrosine kinase activities in the basal and insulin-stimulated states did not differ between the OVX and OVX + T rats. |
| 1681 | 8621012 | In conclusion, the absence of female sex hormones appears to decrease insulin-mediated whole-body glucose uptake via an impaired insulin-stimulated translocation of GLUT4 to the plasma membrane and by decreased protein expression of glycogen synthase. |
| 1682 | 8621530 | Interaction between the Grb10 SH2 domain and the insulin receptor carboxyl terminus. |
| 1683 | 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. |
| 1684 | 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. |
| 1685 | 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. |
| 1686 | 8621530 | Co-precipitation experiments revealed the association of cellular Grb10 with hormone-stimulated insulin receptors in cell extracts. |
| 1687 | 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. |
| 1688 | 8621530 | Unlike p85 and Syp, which also bind to Tyr(P)-1322, Grb10 was not found to associate with insulin receptor substrate-1. |
| 1689 | 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. |
| 1690 | 8621530 | Interaction between the Grb10 SH2 domain and the insulin receptor carboxyl terminus. |
| 1691 | 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. |
| 1692 | 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. |
| 1693 | 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. |
| 1694 | 8621530 | Co-precipitation experiments revealed the association of cellular Grb10 with hormone-stimulated insulin receptors in cell extracts. |
| 1695 | 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. |
| 1696 | 8621530 | Unlike p85 and Syp, which also bind to Tyr(P)-1322, Grb10 was not found to associate with insulin receptor substrate-1. |
| 1697 | 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. |
| 1698 | 8621530 | Interaction between the Grb10 SH2 domain and the insulin receptor carboxyl terminus. |
| 1699 | 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. |
| 1700 | 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. |
| 1701 | 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. |
| 1702 | 8621530 | Co-precipitation experiments revealed the association of cellular Grb10 with hormone-stimulated insulin receptors in cell extracts. |
| 1703 | 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. |
| 1704 | 8621530 | Unlike p85 and Syp, which also bind to Tyr(P)-1322, Grb10 was not found to associate with insulin receptor substrate-1. |
| 1705 | 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. |
| 1706 | 8621530 | Interaction between the Grb10 SH2 domain and the insulin receptor carboxyl terminus. |
| 1707 | 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. |
| 1708 | 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. |
| 1709 | 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. |
| 1710 | 8621530 | Co-precipitation experiments revealed the association of cellular Grb10 with hormone-stimulated insulin receptors in cell extracts. |
| 1711 | 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. |
| 1712 | 8621530 | Unlike p85 and Syp, which also bind to Tyr(P)-1322, Grb10 was not found to associate with insulin receptor substrate-1. |
| 1713 | 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. |
| 1714 | 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. |
| 1715 | 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. |
| 1716 | 8628319 | However, both receptors required IRS-1 to mediate insulin-stimulated mitogenesis. |
| 1717 | 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. |
| 1718 | 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. |
| 1719 | 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. |
| 1720 | 8628319 | However, both receptors required IRS-1 to mediate insulin-stimulated mitogenesis. |
| 1721 | 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. |
| 1722 | 8631859 | The Fyn tyrosine kinase binds Irs-1 and forms a distinct signaling complex during insulin stimulation. |
| 1723 | 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). |
| 1724 | 8631859 | Mutation of p59fyn at the COOH-terminal tyrosine phosphorylation site (Tyr531) enhanced its binding to Irs-1 during insulin stimulation. |
| 1725 | 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. |
| 1726 | 8631859 | By comparison with the insulin receptor, p59fyn kinase phosphorylated a unique cohort of tyrosine residues in Irs-1. |
| 1727 | 8635675 | Alternative splicing of the 36-base pair exon 11 of the human insulin receptor gene results in the synthesis of two insulin receptor isoforms with distinct functional characteristics (the isoform containing exon 11 has lower insulin binding affinity and lower internalization rate). |
| 1728 | 8635675 | In order to address this issue in patients with pure non-genetically determined hyperinsulinaemia, we examined the alternative splicing of insulin receptor mRNAs in skeletal muscle of eight patients with surgically confirmed insulinoma and insulin resistance and in eight healthy subjects, using the reverse transcriptase-polymerase chain reaction technique. |
| 1729 | 8635675 | The insulinoma patients displayed a significant increase in the expression of the insulin receptor isoform containing exon 11 (75.7 +/- 2.3%) when compared with normal subjects (57.9 +/- 1.5%); furthermore, this increase was positively correlated with plasma insulin concentration and negatively correlated with in vivo insulin sensitivity (glucose clamp). |
| 1730 | 8635675 | Alternative splicing of the 36-base pair exon 11 of the human insulin receptor gene results in the synthesis of two insulin receptor isoforms with distinct functional characteristics (the isoform containing exon 11 has lower insulin binding affinity and lower internalization rate). |
| 1731 | 8635675 | In order to address this issue in patients with pure non-genetically determined hyperinsulinaemia, we examined the alternative splicing of insulin receptor mRNAs in skeletal muscle of eight patients with surgically confirmed insulinoma and insulin resistance and in eight healthy subjects, using the reverse transcriptase-polymerase chain reaction technique. |
| 1732 | 8635675 | The insulinoma patients displayed a significant increase in the expression of the insulin receptor isoform containing exon 11 (75.7 +/- 2.3%) when compared with normal subjects (57.9 +/- 1.5%); furthermore, this increase was positively correlated with plasma insulin concentration and negatively correlated with in vivo insulin sensitivity (glucose clamp). |
| 1733 | 8635675 | Alternative splicing of the 36-base pair exon 11 of the human insulin receptor gene results in the synthesis of two insulin receptor isoforms with distinct functional characteristics (the isoform containing exon 11 has lower insulin binding affinity and lower internalization rate). |
| 1734 | 8635675 | In order to address this issue in patients with pure non-genetically determined hyperinsulinaemia, we examined the alternative splicing of insulin receptor mRNAs in skeletal muscle of eight patients with surgically confirmed insulinoma and insulin resistance and in eight healthy subjects, using the reverse transcriptase-polymerase chain reaction technique. |
| 1735 | 8635675 | The insulinoma patients displayed a significant increase in the expression of the insulin receptor isoform containing exon 11 (75.7 +/- 2.3%) when compared with normal subjects (57.9 +/- 1.5%); furthermore, this increase was positively correlated with plasma insulin concentration and negatively correlated with in vivo insulin sensitivity (glucose clamp). |
| 1736 | 8635677 | The bpV(pic) inhibited the lipolytic effect of isoprenaline to the same extent as insulin; however, when the cGMP-inhibitable low-K(m) phosphodiesterase (cGI-PDE) was blocked with the specific inhibitor OPC 3911, the antilipolytic effect of insulin, but not that of bpV(pic), was completely prevented. |
| 1737 | 8635677 | These findings indicate that bpV(pic) exerts its antilipolytic effect not only through cGI-PDE activation, similar to the effect of insulin, but also by means of other mechanisms. |
| 1738 | 8635677 | In contrast, in situ tyrosine phosphorylation of the insulin receptor beta-subunit as well as that of several other proteins was clearly increased in cells which were treated with bpV(pic), whereas vanadate only amplified insulin-stimulated tyrosine phosphorylation. |
| 1739 | 8636261 | RNA from the proto-oncogenes c-Ha-ras, c-myc, and c-src transiently increased 2- to 4-fold within 30 min of insulin infusion. |
| 1740 | 8636261 | In addition, the RNA abundance of myf-5, a muscle specific differentiation factor, increased 3-fold with a time course similar to that of c-Ha-ras, c-myc, and c-src. |
| 1741 | 8636261 | In insulin-resistant individuals, the RNA levels of c-Ha-ras and myf-5 did not increase, whereas c-src RNA did increase within 30 min of insulin infusion. |
| 1742 | 8636261 | RNA encoding c-myc transiently increased in both groups; however, this response was lower in insulin-resistant individuals than in insulin-sensitive individuals in a pattern similar to c-Ha-ras and myf-5. |
| 1743 | 8636261 | PPP1A RNA levels slightly increased in insulin-resistant individuals. |
| 1744 | 8636261 | In both insulin-sensitive and insulin-resistant persons, RNA quantities of GLUT4, c-jun, c-fos, and the insulin receptor did not change over the period of insulin infusion. |
| 1745 | 8636261 | However, overall RNA levels of the insulin receptor and c-jun were lower in insulin-resistant individuals. |
| 1746 | 8636261 | RNA from the proto-oncogenes c-Ha-ras, c-myc, and c-src transiently increased 2- to 4-fold within 30 min of insulin infusion. |
| 1747 | 8636261 | In addition, the RNA abundance of myf-5, a muscle specific differentiation factor, increased 3-fold with a time course similar to that of c-Ha-ras, c-myc, and c-src. |
| 1748 | 8636261 | In insulin-resistant individuals, the RNA levels of c-Ha-ras and myf-5 did not increase, whereas c-src RNA did increase within 30 min of insulin infusion. |
| 1749 | 8636261 | RNA encoding c-myc transiently increased in both groups; however, this response was lower in insulin-resistant individuals than in insulin-sensitive individuals in a pattern similar to c-Ha-ras and myf-5. |
| 1750 | 8636261 | PPP1A RNA levels slightly increased in insulin-resistant individuals. |
| 1751 | 8636261 | In both insulin-sensitive and insulin-resistant persons, RNA quantities of GLUT4, c-jun, c-fos, and the insulin receptor did not change over the period of insulin infusion. |
| 1752 | 8636261 | However, overall RNA levels of the insulin receptor and c-jun were lower in insulin-resistant individuals. |
| 1753 | 8641192 | We conclude that 1) severe defects in muscle insulin receptor function result in impaired insulin-stimulated glucose uptake and metabolism in this tissue; 2) muscle-specific insulin resistance can contribute to the development of obesity; and 3) a "pure" defect in insulin-mediated muscle glucose disposal is sufficient to result in impaired glucose tolerance and other features of the insulin resistance syndrome, including hyperinsulinemia and dyslipidemia. |
| 1754 | 8641194 | Increased amounts of a high molecular weight insulin-like growth factor II (IGF-II) peptide and IGF-II messenger ribonucleic acid in pancreatic islets of diabetic Goto-Kakizaki rats. |
| 1755 | 8641194 | Insulin-like growth factor II (IGF-II), a member of the insulin family, regulates cell growth and differentiation. |
| 1756 | 8641194 | The IGF-II gene is localized close to the insulin gene in man and rat. |
| 1757 | 8641194 | IGF-II peptide binds weakly to the insulin receptor and exerts insulin-like effects on the blood glucose level. |
| 1758 | 8647950 | Insulin receptor substrates-1 (IRS-1) is the major cytoplasmic substrate of the insulin and IGF-1 receptors. |
| 1759 | 8647950 | Recent studies have identified multiple sequence variants of IRS-1, especially in patients with non-insulin-dependent diabetes mellitus. |
| 1760 | 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. |
| 1761 | 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). |
| 1762 | 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. |
| 1763 | 8647950 | The changes occurred with no change in insulin receptor or IRS-1 tyrosine phosphorylation. |
| 1764 | 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. |
| 1765 | 8647950 | Insulin receptor substrates-1 (IRS-1) is the major cytoplasmic substrate of the insulin and IGF-1 receptors. |
| 1766 | 8647950 | Recent studies have identified multiple sequence variants of IRS-1, especially in patients with non-insulin-dependent diabetes mellitus. |
| 1767 | 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. |
| 1768 | 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). |
| 1769 | 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. |
| 1770 | 8647950 | The changes occurred with no change in insulin receptor or IRS-1 tyrosine phosphorylation. |
| 1771 | 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. |
| 1772 | 8647950 | Insulin receptor substrates-1 (IRS-1) is the major cytoplasmic substrate of the insulin and IGF-1 receptors. |
| 1773 | 8647950 | Recent studies have identified multiple sequence variants of IRS-1, especially in patients with non-insulin-dependent diabetes mellitus. |
| 1774 | 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. |
| 1775 | 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). |
| 1776 | 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. |
| 1777 | 8647950 | The changes occurred with no change in insulin receptor or IRS-1 tyrosine phosphorylation. |
| 1778 | 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. |
| 1779 | 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. |
| 1780 | 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). |
| 1781 | 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. |
| 1782 | 8662948 | In contrast, ligand-stimulated EGF receptor phosphorylation in CHO/EGF-R cells was not affected by the presence of stearyl 3S-peptide-I. |
| 1783 | 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. |
| 1784 | 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. |
| 1785 | 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. |
| 1786 | 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). |
| 1787 | 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. |
| 1788 | 8662948 | In contrast, ligand-stimulated EGF receptor phosphorylation in CHO/EGF-R cells was not affected by the presence of stearyl 3S-peptide-I. |
| 1789 | 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. |
| 1790 | 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. |
| 1791 | 8666152 | The inhibition of the insulin receptor by the receptor protein PC-1 is not specific and results from the hydrolysis of ATP. |
| 1792 | 8666152 | The membrane protein plasma cell differentiation antigen 1 (PC-1) has been purified as an inhibitor of insulin receptor tyrosine kinase activity and has been implicated in the pathogenesis of NIDDM. |
| 1793 | 8666152 | However, we show here that PC-1 is a general protein kinase inhibitor in vitro and that this inhibition results from the hydrolysis of ATP by the intrinsic nucleotide pyrophosphatase activity of PC-1. |
| 1794 | 8666152 | When care was taken to avoid ATP depletion, PC-1 did not affect the insulin sensitivity of insulin receptor autophosphorylation. |
| 1795 | 8666152 | We conclude that the reported inhibition of insulin signaling by PC-1 does not result from a direct inhibition of the insulin receptor kinase activity. |
| 1796 | 8666152 | The inhibition of the insulin receptor by the receptor protein PC-1 is not specific and results from the hydrolysis of ATP. |
| 1797 | 8666152 | The membrane protein plasma cell differentiation antigen 1 (PC-1) has been purified as an inhibitor of insulin receptor tyrosine kinase activity and has been implicated in the pathogenesis of NIDDM. |
| 1798 | 8666152 | However, we show here that PC-1 is a general protein kinase inhibitor in vitro and that this inhibition results from the hydrolysis of ATP by the intrinsic nucleotide pyrophosphatase activity of PC-1. |
| 1799 | 8666152 | When care was taken to avoid ATP depletion, PC-1 did not affect the insulin sensitivity of insulin receptor autophosphorylation. |
| 1800 | 8666152 | We conclude that the reported inhibition of insulin signaling by PC-1 does not result from a direct inhibition of the insulin receptor kinase activity. |
| 1801 | 8666152 | The inhibition of the insulin receptor by the receptor protein PC-1 is not specific and results from the hydrolysis of ATP. |
| 1802 | 8666152 | The membrane protein plasma cell differentiation antigen 1 (PC-1) has been purified as an inhibitor of insulin receptor tyrosine kinase activity and has been implicated in the pathogenesis of NIDDM. |
| 1803 | 8666152 | However, we show here that PC-1 is a general protein kinase inhibitor in vitro and that this inhibition results from the hydrolysis of ATP by the intrinsic nucleotide pyrophosphatase activity of PC-1. |
| 1804 | 8666152 | When care was taken to avoid ATP depletion, PC-1 did not affect the insulin sensitivity of insulin receptor autophosphorylation. |
| 1805 | 8666152 | We conclude that the reported inhibition of insulin signaling by PC-1 does not result from a direct inhibition of the insulin receptor kinase activity. |
| 1806 | 8666152 | The inhibition of the insulin receptor by the receptor protein PC-1 is not specific and results from the hydrolysis of ATP. |
| 1807 | 8666152 | The membrane protein plasma cell differentiation antigen 1 (PC-1) has been purified as an inhibitor of insulin receptor tyrosine kinase activity and has been implicated in the pathogenesis of NIDDM. |
| 1808 | 8666152 | However, we show here that PC-1 is a general protein kinase inhibitor in vitro and that this inhibition results from the hydrolysis of ATP by the intrinsic nucleotide pyrophosphatase activity of PC-1. |
| 1809 | 8666152 | When care was taken to avoid ATP depletion, PC-1 did not affect the insulin sensitivity of insulin receptor autophosphorylation. |
| 1810 | 8666152 | We conclude that the reported inhibition of insulin signaling by PC-1 does not result from a direct inhibition of the insulin receptor kinase activity. |
| 1811 | 8674895 | We further demonstrated the detection of the gene transcripts of CNP and atrial natriuretic peptide (ANP) B receptor, a specific receptor for CNP, in human blood vessels. |
| 1812 | 8674895 | To clarify the significance of vascular NPS in proliferative vascular complications associated with diabetes, hypertension, or atherosclerosis, in the present study we examined the effect of insulin on CNP secretion from cultured ECs. |
| 1813 | 8674895 | Insulin at a concentration in the physiological range (10(-10)-10(-7) mol/l) potently suppressed CNP secretion, whereas insulin at the same concentration did not suppress endothelin (ET) secretion from EC. |
| 1814 | 8674895 | IGF-I had no significant effect on CNP secretion. |
| 1815 | 8674895 | Insulin, therefore, can be a potent inhibitor of CNP secretion through the activation of insulin receptor. |
| 1816 | 8679660 | Cryptic receptors for insulin-like growth factor II in the plasma membrane of rat adipocytes--a possible link to cellular insulin resistance. |
| 1817 | 8679660 | To further elucidate the mechanisms for short-term regulation of the receptor for insulin-like growth factor II (IGF-II), we investigated effects of insulin, cAMP and phosphatase inhibitors on cell surface 125I-IGF-II binding in rat adipocytes. |
| 1818 | 8679660 | Preincubation with the serine/threonine phosphatase inhibitor okadaic acid (OA, 1 microM) or the non-hydrolysable cAMP analogue N6-mbcAMP (4 mM) markedly impaired insulin-stimulated 125I-IGF-II binding. |
| 1819 | 8679660 | Phospholipase C (PLC), which cleaves phospholipids at the cell surface, markedly enhanced cell surface 125I-IGF-II binding in a concentration-dependent manner. |
| 1820 | 8679660 | Scatchard analysis demonstrated that the effect of PLC was due to an increased number of binding sites suggesting that "cryptic' IGF-II receptors are associated with the plasma membrane (PM). |
| 1821 | 8679660 | PLC (5 U/ml) also reversed the N6-mbcAMP-induced decrease of 125I-IGF-II binding at a low insulin concentration (10 microU/ml). |
| 1822 | 8679660 | Taken together, these data indicate that cAMP, similar to its effects on the glucose transporter GLUT 4 and the insulin receptor, may increase the proportion of functionally cryptic IGF-II receptors in the PM through mechanisms involving serine phosphorylation, possibly of a docking or coupling protein. |
| 1823 | 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). |
| 1824 | 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. |
| 1825 | 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). |
| 1826 | 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. |
| 1827 | 8750566 | Insulin leads to a parallel translocation of PI-3-kinase and protein kinase C zeta. |
| 1828 | 8750566 | In the present study we used rat-1 fibroblasts stably over-expressing human insulin receptor to investigate whether insulin can activate PKC-zeta and whether such an effect might be related to insulin's effect on PI-3-kinase. |
| 1829 | 8750566 | After stimulation of the cells with insulin (10(-7) mol/l) for one to ten minutes, a rapid translocation of PKC-zeta to the plasma membrane was detectable, as determined by immunoblotting of plasma membrane proteins with antibodies against PKC-zeta. |
| 1830 | 8750566 | In parallel immunoblots applying antibodies against the regulatory subunit of PI-3-kinase (p85), an insulin-induced translocation of p85 was detectable within one minute after stimulation. |
| 1831 | 8750566 | The data show that insulin stimulates translocation of PKC-zeta in rat-1 fibroblasts. |
| 1832 | 8750566 | The parallel kinetics of PI-3-kinase translocation/activation and PKC-zeta translocation are compatible with the idea that the insulin effect on PKC-zeta is transduced through PI-3-kinase activation. |
| 1833 | 8798502 | Rad is a Ras-like GTPase that was isolated by subtraction cloning of human muscle and shown to have increased expression in some individuals with Type II diabetes. |
| 1834 | 8798502 | To ascertain the potential role of Rad in insulin-mediated signaling, we have overexpressed Rad in myocyte and adipocyte cell lines. |
| 1835 | 8798502 | This occurred despite unaltered levels of glucose transporter expression, with no detectable change in Glut4 translocation and with no alteration in insulin receptor or substrate phosphorylation or phosphatidylinositol 3-kinase activity. |
| 1836 | 8798677 | The pleckstrin homology domain is the principal link between the insulin receptor and IRS-1. |
| 1837 | 8798677 | Interaction domains located in the NH2 terminus of IRS-1 mediate its recognition by the insulin receptor. |
| 1838 | 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. |
| 1839 | 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. |
| 1840 | 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. |
| 1841 | 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. |
| 1842 | 8798677 | Overexpression of the insulin receptor in 32DIR cells increased IRS-1 tyrosine phosphorylation and mediated insulin-stimulated DNA synthesis. |
| 1843 | 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. |
| 1844 | 8798677 | The pleckstrin homology domain is the principal link between the insulin receptor and IRS-1. |
| 1845 | 8798677 | Interaction domains located in the NH2 terminus of IRS-1 mediate its recognition by the insulin receptor. |
| 1846 | 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. |
| 1847 | 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. |
| 1848 | 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. |
| 1849 | 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. |
| 1850 | 8798677 | Overexpression of the insulin receptor in 32DIR cells increased IRS-1 tyrosine phosphorylation and mediated insulin-stimulated DNA synthesis. |
| 1851 | 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. |
| 1852 | 8798677 | The pleckstrin homology domain is the principal link between the insulin receptor and IRS-1. |
| 1853 | 8798677 | Interaction domains located in the NH2 terminus of IRS-1 mediate its recognition by the insulin receptor. |
| 1854 | 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. |
| 1855 | 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. |
| 1856 | 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. |
| 1857 | 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. |
| 1858 | 8798677 | Overexpression of the insulin receptor in 32DIR cells increased IRS-1 tyrosine phosphorylation and mediated insulin-stimulated DNA synthesis. |
| 1859 | 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. |
| 1860 | 8798677 | The pleckstrin homology domain is the principal link between the insulin receptor and IRS-1. |
| 1861 | 8798677 | Interaction domains located in the NH2 terminus of IRS-1 mediate its recognition by the insulin receptor. |
| 1862 | 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. |
| 1863 | 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. |
| 1864 | 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. |
| 1865 | 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. |
| 1866 | 8798677 | Overexpression of the insulin receptor in 32DIR cells increased IRS-1 tyrosine phosphorylation and mediated insulin-stimulated DNA synthesis. |
| 1867 | 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. |
| 1868 | 8798677 | The pleckstrin homology domain is the principal link between the insulin receptor and IRS-1. |
| 1869 | 8798677 | Interaction domains located in the NH2 terminus of IRS-1 mediate its recognition by the insulin receptor. |
| 1870 | 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. |
| 1871 | 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. |
| 1872 | 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. |
| 1873 | 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. |
| 1874 | 8798677 | Overexpression of the insulin receptor in 32DIR cells increased IRS-1 tyrosine phosphorylation and mediated insulin-stimulated DNA synthesis. |
| 1875 | 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. |
| 1876 | 8826966 | Membrane glycoprotein PC-1, an inhibitor of insulin signaling, produces insulin resistance when overexpressed in cells transfected with PC-1 cDNA. |
| 1877 | 8826966 | In the present study, we determined whether PC-1 plays a role in the insulin resistance of skeletal muscle in obesity. |
| 1878 | 8826966 | Insulin-stimulated glucose transport was measured in incubated muscle strips, and PC-1 content, enzymatic activity, and insulin receptor content were measured in solubilized muscle extracts. |
| 1879 | 8826966 | Increasing BMI correlated with both an increase in the content of PC-1 in muscle (r = 0.55, P < 0.001) and a decrease in insulin stimulation of muscle glucose transport (r = -0.58, P = 0.008). |
| 1880 | 8826966 | Insulin stimulation of muscle glucose transport was negatively related to muscle PC-1 content (r = -0.68, P = 0.001) and positively related to insulin receptor content (r = 0.60, P = 0.005). |
| 1881 | 8826966 | Multivariate analysis indicated that both skeletal muscle PC-1 content and insulin receptor content, but not BMI, were independent predictors of insulin-stimulated glucose transport. |
| 1882 | 8826966 | Muscle PC-1 content accounted for 42% and insulin receptor content for 17% of the variance in glucose transport values. |
| 1883 | 8826966 | These studies raise the possibility that increased expression of PC-1 and a decreased insulin receptor content in skeletal muscle may be involved in the insulin resistance of obesity. |
| 1884 | 8826966 | Membrane glycoprotein PC-1, an inhibitor of insulin signaling, produces insulin resistance when overexpressed in cells transfected with PC-1 cDNA. |
| 1885 | 8826966 | In the present study, we determined whether PC-1 plays a role in the insulin resistance of skeletal muscle in obesity. |
| 1886 | 8826966 | Insulin-stimulated glucose transport was measured in incubated muscle strips, and PC-1 content, enzymatic activity, and insulin receptor content were measured in solubilized muscle extracts. |
| 1887 | 8826966 | Increasing BMI correlated with both an increase in the content of PC-1 in muscle (r = 0.55, P < 0.001) and a decrease in insulin stimulation of muscle glucose transport (r = -0.58, P = 0.008). |
| 1888 | 8826966 | Insulin stimulation of muscle glucose transport was negatively related to muscle PC-1 content (r = -0.68, P = 0.001) and positively related to insulin receptor content (r = 0.60, P = 0.005). |
| 1889 | 8826966 | Multivariate analysis indicated that both skeletal muscle PC-1 content and insulin receptor content, but not BMI, were independent predictors of insulin-stimulated glucose transport. |
| 1890 | 8826966 | Muscle PC-1 content accounted for 42% and insulin receptor content for 17% of the variance in glucose transport values. |
| 1891 | 8826966 | These studies raise the possibility that increased expression of PC-1 and a decreased insulin receptor content in skeletal muscle may be involved in the insulin resistance of obesity. |
| 1892 | 8826966 | Membrane glycoprotein PC-1, an inhibitor of insulin signaling, produces insulin resistance when overexpressed in cells transfected with PC-1 cDNA. |
| 1893 | 8826966 | In the present study, we determined whether PC-1 plays a role in the insulin resistance of skeletal muscle in obesity. |
| 1894 | 8826966 | Insulin-stimulated glucose transport was measured in incubated muscle strips, and PC-1 content, enzymatic activity, and insulin receptor content were measured in solubilized muscle extracts. |
| 1895 | 8826966 | Increasing BMI correlated with both an increase in the content of PC-1 in muscle (r = 0.55, P < 0.001) and a decrease in insulin stimulation of muscle glucose transport (r = -0.58, P = 0.008). |
| 1896 | 8826966 | Insulin stimulation of muscle glucose transport was negatively related to muscle PC-1 content (r = -0.68, P = 0.001) and positively related to insulin receptor content (r = 0.60, P = 0.005). |
| 1897 | 8826966 | Multivariate analysis indicated that both skeletal muscle PC-1 content and insulin receptor content, but not BMI, were independent predictors of insulin-stimulated glucose transport. |
| 1898 | 8826966 | Muscle PC-1 content accounted for 42% and insulin receptor content for 17% of the variance in glucose transport values. |
| 1899 | 8826966 | These studies raise the possibility that increased expression of PC-1 and a decreased insulin receptor content in skeletal muscle may be involved in the insulin resistance of obesity. |
| 1900 | 8826966 | Membrane glycoprotein PC-1, an inhibitor of insulin signaling, produces insulin resistance when overexpressed in cells transfected with PC-1 cDNA. |
| 1901 | 8826966 | In the present study, we determined whether PC-1 plays a role in the insulin resistance of skeletal muscle in obesity. |
| 1902 | 8826966 | Insulin-stimulated glucose transport was measured in incubated muscle strips, and PC-1 content, enzymatic activity, and insulin receptor content were measured in solubilized muscle extracts. |
| 1903 | 8826966 | Increasing BMI correlated with both an increase in the content of PC-1 in muscle (r = 0.55, P < 0.001) and a decrease in insulin stimulation of muscle glucose transport (r = -0.58, P = 0.008). |
| 1904 | 8826966 | Insulin stimulation of muscle glucose transport was negatively related to muscle PC-1 content (r = -0.68, P = 0.001) and positively related to insulin receptor content (r = 0.60, P = 0.005). |
| 1905 | 8826966 | Multivariate analysis indicated that both skeletal muscle PC-1 content and insulin receptor content, but not BMI, were independent predictors of insulin-stimulated glucose transport. |
| 1906 | 8826966 | Muscle PC-1 content accounted for 42% and insulin receptor content for 17% of the variance in glucose transport values. |
| 1907 | 8826966 | These studies raise the possibility that increased expression of PC-1 and a decreased insulin receptor content in skeletal muscle may be involved in the insulin resistance of obesity. |
| 1908 | 8826966 | Membrane glycoprotein PC-1, an inhibitor of insulin signaling, produces insulin resistance when overexpressed in cells transfected with PC-1 cDNA. |
| 1909 | 8826966 | In the present study, we determined whether PC-1 plays a role in the insulin resistance of skeletal muscle in obesity. |
| 1910 | 8826966 | Insulin-stimulated glucose transport was measured in incubated muscle strips, and PC-1 content, enzymatic activity, and insulin receptor content were measured in solubilized muscle extracts. |
| 1911 | 8826966 | Increasing BMI correlated with both an increase in the content of PC-1 in muscle (r = 0.55, P < 0.001) and a decrease in insulin stimulation of muscle glucose transport (r = -0.58, P = 0.008). |
| 1912 | 8826966 | Insulin stimulation of muscle glucose transport was negatively related to muscle PC-1 content (r = -0.68, P = 0.001) and positively related to insulin receptor content (r = 0.60, P = 0.005). |
| 1913 | 8826966 | Multivariate analysis indicated that both skeletal muscle PC-1 content and insulin receptor content, but not BMI, were independent predictors of insulin-stimulated glucose transport. |
| 1914 | 8826966 | Muscle PC-1 content accounted for 42% and insulin receptor content for 17% of the variance in glucose transport values. |
| 1915 | 8826966 | These studies raise the possibility that increased expression of PC-1 and a decreased insulin receptor content in skeletal muscle may be involved in the insulin resistance of obesity. |
| 1916 | 8826975 | Protein tyrosine phosphatase 1B interacts with the activated insulin receptor. |
| 1917 | 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. |
| 1918 | 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. |
| 1919 | 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. |
| 1920 | 8826975 | A p120 of unknown identity was also precipitated from whole-cell lysates by the PTP1B fusion protein, but IRS-1 (pp185) was not. |
| 1921 | 8826975 | A catalytically inactive [35S]PTP1B-fusion protein bound directly to immobilized insulin receptor kinase domains and was displaced in a concentration-dependent manner. |
| 1922 | 8826975 | Finally, tyrosine-phosphorylated PTP1B was precipitated from whole-cell lysates by an anti-insulin receptor antibody after insulin stimulation. |
| 1923 | 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. |
| 1924 | 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. |
| 1925 | 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. |
| 1926 | 8826975 | Protein tyrosine phosphatase 1B interacts with the activated insulin receptor. |
| 1927 | 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. |
| 1928 | 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. |
| 1929 | 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. |
| 1930 | 8826975 | A p120 of unknown identity was also precipitated from whole-cell lysates by the PTP1B fusion protein, but IRS-1 (pp185) was not. |
| 1931 | 8826975 | A catalytically inactive [35S]PTP1B-fusion protein bound directly to immobilized insulin receptor kinase domains and was displaced in a concentration-dependent manner. |
| 1932 | 8826975 | Finally, tyrosine-phosphorylated PTP1B was precipitated from whole-cell lysates by an anti-insulin receptor antibody after insulin stimulation. |
| 1933 | 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. |
| 1934 | 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. |
| 1935 | 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. |
| 1936 | 8826975 | Protein tyrosine phosphatase 1B interacts with the activated insulin receptor. |
| 1937 | 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. |
| 1938 | 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. |
| 1939 | 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. |
| 1940 | 8826975 | A p120 of unknown identity was also precipitated from whole-cell lysates by the PTP1B fusion protein, but IRS-1 (pp185) was not. |
| 1941 | 8826975 | A catalytically inactive [35S]PTP1B-fusion protein bound directly to immobilized insulin receptor kinase domains and was displaced in a concentration-dependent manner. |
| 1942 | 8826975 | Finally, tyrosine-phosphorylated PTP1B was precipitated from whole-cell lysates by an anti-insulin receptor antibody after insulin stimulation. |
| 1943 | 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. |
| 1944 | 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. |
| 1945 | 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. |
| 1946 | 8826975 | Protein tyrosine phosphatase 1B interacts with the activated insulin receptor. |
| 1947 | 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. |
| 1948 | 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. |
| 1949 | 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. |
| 1950 | 8826975 | A p120 of unknown identity was also precipitated from whole-cell lysates by the PTP1B fusion protein, but IRS-1 (pp185) was not. |
| 1951 | 8826975 | A catalytically inactive [35S]PTP1B-fusion protein bound directly to immobilized insulin receptor kinase domains and was displaced in a concentration-dependent manner. |
| 1952 | 8826975 | Finally, tyrosine-phosphorylated PTP1B was precipitated from whole-cell lysates by an anti-insulin receptor antibody after insulin stimulation. |
| 1953 | 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. |
| 1954 | 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. |
| 1955 | 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. |
| 1956 | 8826975 | Protein tyrosine phosphatase 1B interacts with the activated insulin receptor. |
| 1957 | 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. |
| 1958 | 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. |
| 1959 | 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. |
| 1960 | 8826975 | A p120 of unknown identity was also precipitated from whole-cell lysates by the PTP1B fusion protein, but IRS-1 (pp185) was not. |
| 1961 | 8826975 | A catalytically inactive [35S]PTP1B-fusion protein bound directly to immobilized insulin receptor kinase domains and was displaced in a concentration-dependent manner. |
| 1962 | 8826975 | Finally, tyrosine-phosphorylated PTP1B was precipitated from whole-cell lysates by an anti-insulin receptor antibody after insulin stimulation. |
| 1963 | 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. |
| 1964 | 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. |
| 1965 | 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. |
| 1966 | 8826975 | Protein tyrosine phosphatase 1B interacts with the activated insulin receptor. |
| 1967 | 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. |
| 1968 | 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. |
| 1969 | 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. |
| 1970 | 8826975 | A p120 of unknown identity was also precipitated from whole-cell lysates by the PTP1B fusion protein, but IRS-1 (pp185) was not. |
| 1971 | 8826975 | A catalytically inactive [35S]PTP1B-fusion protein bound directly to immobilized insulin receptor kinase domains and was displaced in a concentration-dependent manner. |
| 1972 | 8826975 | Finally, tyrosine-phosphorylated PTP1B was precipitated from whole-cell lysates by an anti-insulin receptor antibody after insulin stimulation. |
| 1973 | 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. |
| 1974 | 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. |
| 1975 | 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. |
| 1976 | 8826975 | Protein tyrosine phosphatase 1B interacts with the activated insulin receptor. |
| 1977 | 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. |
| 1978 | 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. |
| 1979 | 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. |
| 1980 | 8826975 | A p120 of unknown identity was also precipitated from whole-cell lysates by the PTP1B fusion protein, but IRS-1 (pp185) was not. |
| 1981 | 8826975 | A catalytically inactive [35S]PTP1B-fusion protein bound directly to immobilized insulin receptor kinase domains and was displaced in a concentration-dependent manner. |
| 1982 | 8826975 | Finally, tyrosine-phosphorylated PTP1B was precipitated from whole-cell lysates by an anti-insulin receptor antibody after insulin stimulation. |
| 1983 | 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. |
| 1984 | 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. |
| 1985 | 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. |
| 1986 | 8826975 | Protein tyrosine phosphatase 1B interacts with the activated insulin receptor. |
| 1987 | 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. |
| 1988 | 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. |
| 1989 | 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. |
| 1990 | 8826975 | A p120 of unknown identity was also precipitated from whole-cell lysates by the PTP1B fusion protein, but IRS-1 (pp185) was not. |
| 1991 | 8826975 | A catalytically inactive [35S]PTP1B-fusion protein bound directly to immobilized insulin receptor kinase domains and was displaced in a concentration-dependent manner. |
| 1992 | 8826975 | Finally, tyrosine-phosphorylated PTP1B was precipitated from whole-cell lysates by an anti-insulin receptor antibody after insulin stimulation. |
| 1993 | 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. |
| 1994 | 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. |
| 1995 | 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. |
| 1996 | 8839251 | Glucagon-like peptide-1 (GLP-1) is the major incretin hormone from the distal small intestine which stimulates basal and glucose-induced insulin secretion. |
| 1997 | 8839251 | Using the rat insulinoma cell line RINm5F (Gazdar et al. 1980) we investigated the effects of GLP-1 on insulin secretion, insulin content, and insulin receptor binding. |
| 1998 | 8839251 | During a 1 hour incubation, GLP-1 [1 nM] stimulated insulin secretion 2-fold (p < 0.01 vs controls). |
| 1999 | 8839251 | Incubating RINm5F for 24 h with GLP-1 [1 nM], a 1.6-fold higher cellular insulin content was observed (p < 0.01 vs controls). |
| 2000 | 8839251 | Moreover, GLP-1 induced a 2-fold higher capacity and a 15-fold higher affinity of 125I-insulin binding on the cell surface (p < 0.01 vs controls). |
| 2001 | 8839251 | Taken together, in RINm5F insulinoma cells GLP-1 potently stimulates insulin secretion and insulin content, and improves insulin receptor binding. |
| 2002 | 8839251 | Glucagon-like peptide-1 (GLP-1) is the major incretin hormone from the distal small intestine which stimulates basal and glucose-induced insulin secretion. |
| 2003 | 8839251 | Using the rat insulinoma cell line RINm5F (Gazdar et al. 1980) we investigated the effects of GLP-1 on insulin secretion, insulin content, and insulin receptor binding. |
| 2004 | 8839251 | During a 1 hour incubation, GLP-1 [1 nM] stimulated insulin secretion 2-fold (p < 0.01 vs controls). |
| 2005 | 8839251 | Incubating RINm5F for 24 h with GLP-1 [1 nM], a 1.6-fold higher cellular insulin content was observed (p < 0.01 vs controls). |
| 2006 | 8839251 | Moreover, GLP-1 induced a 2-fold higher capacity and a 15-fold higher affinity of 125I-insulin binding on the cell surface (p < 0.01 vs controls). |
| 2007 | 8839251 | Taken together, in RINm5F insulinoma cells GLP-1 potently stimulates insulin secretion and insulin content, and improves insulin receptor binding. |
| 2008 | 8840133 | Glimepiride did not ameliorate impaired insulin-stimulated insulin receptor autophosphorylation. |
| 2009 | 8840133 | To determine the effect of glimepiride on post-insulin receptor signaling pathway, we measured 2-[3H]glycerol incorporation into diacylglycerol in the cultured rat fibroblast cell line overexpressing human insulin receptors. |
| 2010 | 8840133 | Glimepiride did not ameliorate impaired insulin-stimulated insulin receptor autophosphorylation. |
| 2011 | 8840133 | To determine the effect of glimepiride on post-insulin receptor signaling pathway, we measured 2-[3H]glycerol incorporation into diacylglycerol in the cultured rat fibroblast cell line overexpressing human insulin receptors. |
| 2012 | 8871675 | The importance of insulin receptor (IR) expression in the pathogenesis of diabetes was examined, since it has been shown that the IR is a chemotactic receptor capable of directing cell movement in response to insulin. |
| 2013 | 8899293 | Signaling via the insulin-like growth factor-I receptor: does it differ from insulin receptor signaling? |
| 2014 | 8899293 | The insulin and insulin-like growth factor (IGF-I) receptors while similar in structure and function serve different physiological functions in vivo. |
| 2015 | 8899293 | In non-disease states the insulin receptor is primarily involved in metabolic functions whereas the IGF-I receptor mediates growth and differentiation. |
| 2016 | 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. |
| 2017 | 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. |
| 2018 | 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. |
| 2019 | 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. |
| 2020 | 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. |
| 2021 | 8899293 | Signaling via the insulin-like growth factor-I receptor: does it differ from insulin receptor signaling? |
| 2022 | 8899293 | The insulin and insulin-like growth factor (IGF-I) receptors while similar in structure and function serve different physiological functions in vivo. |
| 2023 | 8899293 | In non-disease states the insulin receptor is primarily involved in metabolic functions whereas the IGF-I receptor mediates growth and differentiation. |
| 2024 | 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. |
| 2025 | 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. |
| 2026 | 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. |
| 2027 | 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. |
| 2028 | 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. |
| 2029 | 8899294 | Inhibition of insulin receptor signaling by TNF: potential role in obesity and non-insulin-dependent diabetes mellitus. |
| 2030 | 8899294 | Tumor necrosis factor (TNF) is one of the proteins produced by adipocytes that has been shown to regulate adipocyte function. |
| 2031 | 8899294 | Interestingly, adipocyte expression of TNF increases with increasing adipocyte mass and expression of TNF is increased in adipocytes isolated from several genetic models of rodent obesity and from obese humans. |
| 2032 | 8899294 | Increased production of TNF by adipocytes, however, may contribute to insulin resistance in obesity and in non-insulin-dependent diabetes mellitus (NIDDM). |
| 2033 | 8899294 | TNF has been shown to inhibit insulin-simulated tyrosine phosphorylation of both the insulin receptor (IR) and insulin receptor substrate (IRS)-1 and to stimulate downregulation of the insulin-sensitive glucose transporter, GLUT4, in adipocytes. |
| 2034 | 8899294 | Inhibition of insulin receptor signaling by TNF: potential role in obesity and non-insulin-dependent diabetes mellitus. |
| 2035 | 8899294 | Tumor necrosis factor (TNF) is one of the proteins produced by adipocytes that has been shown to regulate adipocyte function. |
| 2036 | 8899294 | Interestingly, adipocyte expression of TNF increases with increasing adipocyte mass and expression of TNF is increased in adipocytes isolated from several genetic models of rodent obesity and from obese humans. |
| 2037 | 8899294 | Increased production of TNF by adipocytes, however, may contribute to insulin resistance in obesity and in non-insulin-dependent diabetes mellitus (NIDDM). |
| 2038 | 8899294 | TNF has been shown to inhibit insulin-simulated tyrosine phosphorylation of both the insulin receptor (IR) and insulin receptor substrate (IRS)-1 and to stimulate downregulation of the insulin-sensitive glucose transporter, GLUT4, in adipocytes. |
| 2039 | 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. |
| 2040 | 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. |
| 2041 | 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. |
| 2042 | 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. |
| 2043 | 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. |
| 2044 | 8910437 | In addition, Grb2 association with Shc and activation of MAPK and the p70 S6 kinase were insensitive to insulin stimulation. |
| 2045 | 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. |
| 2046 | 8910597 | Insulin-like growth factor receptor-1 stimulates phosphorylation of the beta2-adrenergic receptor in vivo on sites distinct from those phosphorylated in response to insulin. |
| 2047 | 8910597 | Insulin-like growth factor-1 (IGF-1), another member of the growth factor family operating via receptors with intrinsic tyrosine kinase, is shown in the present work to stimulate in vivo the phosphorylation of the beta2-adrenergic receptor. |
| 2048 | 8910597 | The results of these separate analyses reveal that IGF-1 stimulates phosphorylation predominantly on tyrosyl residues Y132/141 of the second intracellular loop of the beta2-adrenergic receptor rather than the C-terminal region targeted by the activated insulin receptor (Y350/354, Y364), although both growth factors block beta-adrenergic agonist action. |
| 2049 | 8910597 | These data demonstrate selective phosphorylation of a G-protein-linked receptor by receptor tyrosine kinases for insulin and IGF-1 mapping to spatially distinct regions of this heptihelical membrane receptor. |
| 2050 | 8916919 | Characterization of a hybrid receptor formed by dimerization of the insulin receptor-related receptor (IRR) with the insulin receptor (IR): coexpression of cDNAs encoding human IRR and human IR in NIH-3T3 cells. |
| 2051 | 8916919 | In many tissues, the insulin receptor-related receptor (IRR) is colocalized with the homologous receptors for insulin and insulin-like growth factor-I (IGF-I). |
| 2052 | 8916919 | Since a ligand for the IRR has not yet been identified, it has been proposed previously that IRR may be activated and transduce its signal via formation of hybrids with the insulin and IGF-I receptors. |
| 2053 | 8916919 | To test this hypothesis, we have coexpressed the human IRR and the human insulin receptor (IR) in NIH-3T3 cells. |
| 2054 | 8916919 | While insulin was capable of stimulating insulin receptors autophosphorylation in these cells, there was no detectable increase in the total phosphotyrosine content of IRR. |
| 2055 | 8916919 | We conclude that the IRR/IR hybrid receptor does not play a major role in IRR signal transduction in response to insulin in NIH-3T3-hIRR/hIR cells. |
| 2056 | 8916919 | Characterization of a hybrid receptor formed by dimerization of the insulin receptor-related receptor (IRR) with the insulin receptor (IR): coexpression of cDNAs encoding human IRR and human IR in NIH-3T3 cells. |
| 2057 | 8916919 | In many tissues, the insulin receptor-related receptor (IRR) is colocalized with the homologous receptors for insulin and insulin-like growth factor-I (IGF-I). |
| 2058 | 8916919 | Since a ligand for the IRR has not yet been identified, it has been proposed previously that IRR may be activated and transduce its signal via formation of hybrids with the insulin and IGF-I receptors. |
| 2059 | 8916919 | To test this hypothesis, we have coexpressed the human IRR and the human insulin receptor (IR) in NIH-3T3 cells. |
| 2060 | 8916919 | While insulin was capable of stimulating insulin receptors autophosphorylation in these cells, there was no detectable increase in the total phosphotyrosine content of IRR. |
| 2061 | 8916919 | We conclude that the IRR/IR hybrid receptor does not play a major role in IRR signal transduction in response to insulin in NIH-3T3-hIRR/hIR cells. |
| 2062 | 8916919 | Characterization of a hybrid receptor formed by dimerization of the insulin receptor-related receptor (IRR) with the insulin receptor (IR): coexpression of cDNAs encoding human IRR and human IR in NIH-3T3 cells. |
| 2063 | 8916919 | In many tissues, the insulin receptor-related receptor (IRR) is colocalized with the homologous receptors for insulin and insulin-like growth factor-I (IGF-I). |
| 2064 | 8916919 | Since a ligand for the IRR has not yet been identified, it has been proposed previously that IRR may be activated and transduce its signal via formation of hybrids with the insulin and IGF-I receptors. |
| 2065 | 8916919 | To test this hypothesis, we have coexpressed the human IRR and the human insulin receptor (IR) in NIH-3T3 cells. |
| 2066 | 8916919 | While insulin was capable of stimulating insulin receptors autophosphorylation in these cells, there was no detectable increase in the total phosphotyrosine content of IRR. |
| 2067 | 8916919 | We conclude that the IRR/IR hybrid receptor does not play a major role in IRR signal transduction in response to insulin in NIH-3T3-hIRR/hIR cells. |
| 2068 | 8923458 | Overexpression of membrane glycoprotein PC-1 in MDA-MB231 breast cancer cells is associated with inhibition of insulin receptor tyrosine kinase activity. |
| 2069 | 8923458 | MDA-MB231 human breast cancer cells are unresponsive to insulin and contain a glycoprotein inhibitor of insulin-stimulated insulin receptor (IR) tyrosine kinase activity. |
| 2070 | 8923458 | Prior studies in both fibroblasts from insulin- resistant non-insulin-dependent diabetes mellitus patients and transfected cells indicate that overexpression of membrane glycoprotein PC-1 reduces IR tyrosine kinase activity. |
| 2071 | 8923458 | Treatment of these extracts with an antibody to PC-1 significantly reduced their ability to inhibit insulin-stimulated IR tyrosine kinase activity. |
| 2072 | 8923458 | In addition, when cell clones with different PC-1 activity were selected from MDA-MB231 cells, we found an inverse correlation (r = -0.741, P = 0.006) between the PC-1 activity and the insulin-stimulated IR autophosphorylation. |
| 2073 | 8923458 | Overexpression of membrane glycoprotein PC-1 in MDA-MB231 breast cancer cells is associated with inhibition of insulin receptor tyrosine kinase activity. |
| 2074 | 8923458 | MDA-MB231 human breast cancer cells are unresponsive to insulin and contain a glycoprotein inhibitor of insulin-stimulated insulin receptor (IR) tyrosine kinase activity. |
| 2075 | 8923458 | Prior studies in both fibroblasts from insulin- resistant non-insulin-dependent diabetes mellitus patients and transfected cells indicate that overexpression of membrane glycoprotein PC-1 reduces IR tyrosine kinase activity. |
| 2076 | 8923458 | Treatment of these extracts with an antibody to PC-1 significantly reduced their ability to inhibit insulin-stimulated IR tyrosine kinase activity. |
| 2077 | 8923458 | In addition, when cell clones with different PC-1 activity were selected from MDA-MB231 cells, we found an inverse correlation (r = -0.741, P = 0.006) between the PC-1 activity and the insulin-stimulated IR autophosphorylation. |
| 2078 | 8927047 | Administration of these pV(aq) species leads to activation of the insulin receptor tyrosine kinase (IRK), autophosphorylation at tyrosine residues and inhibition of phosphotyrosine phosphatases (PTPs). |
| 2079 | 8927047 | Some pV compounds showed much greater potency as inhibitors of insulin receptor (IR) dephosphorylation than epidermal growth factor receptor (EGFR) dephosphorylation, implying relative specificity as PTP inhibitors. |
| 2080 | 8927047 | Administration of these pV(aq) species leads to activation of the insulin receptor tyrosine kinase (IRK), autophosphorylation at tyrosine residues and inhibition of phosphotyrosine phosphatases (PTPs). |
| 2081 | 8927047 | Some pV compounds showed much greater potency as inhibitors of insulin receptor (IR) dephosphorylation than epidermal growth factor receptor (EGFR) dephosphorylation, implying relative specificity as PTP inhibitors. |
| 2082 | 8927052 | In streptozotocin-induced diabetic rats, the amount of liver glycogen and the activities of the active-form of glycogen synthase, both active and inactive-forms of phosphorylase, and lipogenic enzymes like glucose 6-phosphate dehydrogenase and malic enzyme were decreased and vanadate treatment normalized all of these to near normal levels. |
| 2083 | 8927052 | The insulin-stimulated phosphorylation of insulin receptor beta subunit and its tyrosine kinase activity was increased in streptozotocin-induced diabetic rats after treatment with vanadate. |
| 2084 | 8940181 | One of the peptides, termed peptide HC, whose structure corresponds to residues 1293-1307 of the insulin proreceptor sequence, enhanced insulin-stimulated autophosphorylation of the insulin receptor in cell-free systems and in semipermeabilized Chinese hamster ovary (CHO) cells that had been transfected with an expression plasmid encoding the human insulin receptor (CHO/HIRc) at concentrations where there was no detectable effect on basal autophosphorylation levels or on receptor dephosphorylation. |
| 2085 | 8940181 | A lipophilic analogue of peptide HC, stearyl peptide HC, added to intact CHO/HIRc cells enhanced significantly insulin-stimulated insulin receptor autophosphorylation while having no effect on ligand-stimulated receptor phosphorylation in CHO cells overexpressing either the IGF-1 receptor or epidermal growth factor receptor. |
| 2086 | 8940181 | Addition of stearyl peptide HC to CHO/HIRc cells resulted in a 2.4 +/- 0.3-fold increase in the amount of insulin-stimulated phosphatidylinositol 3-kinase detected in anti-IRS-1 immunoprecipitates and a 2.1 +/- 0.6-fold increase in the levels of tyrosine phosphorylation of mitogen-activated protein kinase in response to insulin. |
| 2087 | 8940181 | However, there was little binding, if any, of the peptide with the IGF-1 receptors or the epidermal growth factor receptors. |
| 2088 | 8940181 | One of the peptides, termed peptide HC, whose structure corresponds to residues 1293-1307 of the insulin proreceptor sequence, enhanced insulin-stimulated autophosphorylation of the insulin receptor in cell-free systems and in semipermeabilized Chinese hamster ovary (CHO) cells that had been transfected with an expression plasmid encoding the human insulin receptor (CHO/HIRc) at concentrations where there was no detectable effect on basal autophosphorylation levels or on receptor dephosphorylation. |
| 2089 | 8940181 | A lipophilic analogue of peptide HC, stearyl peptide HC, added to intact CHO/HIRc cells enhanced significantly insulin-stimulated insulin receptor autophosphorylation while having no effect on ligand-stimulated receptor phosphorylation in CHO cells overexpressing either the IGF-1 receptor or epidermal growth factor receptor. |
| 2090 | 8940181 | Addition of stearyl peptide HC to CHO/HIRc cells resulted in a 2.4 +/- 0.3-fold increase in the amount of insulin-stimulated phosphatidylinositol 3-kinase detected in anti-IRS-1 immunoprecipitates and a 2.1 +/- 0.6-fold increase in the levels of tyrosine phosphorylation of mitogen-activated protein kinase in response to insulin. |
| 2091 | 8940181 | However, there was little binding, if any, of the peptide with the IGF-1 receptors or the epidermal growth factor receptors. |
| 2092 | 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. |
| 2093 | 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. |
| 2094 | 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. |
| 2095 | 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. |
| 2096 | 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. |
| 2097 | 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. |
| 2098 | 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. |
| 2099 | 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. |
| 2100 | 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. |
| 2101 | 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. |
| 2102 | 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. |
| 2103 | 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. |
| 2104 | 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. |
| 2105 | 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. |
| 2106 | 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. |
| 2107 | 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. |
| 2108 | 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. |
| 2109 | 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. |
| 2110 | 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. |
| 2111 | 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. |
| 2112 | 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. |
| 2113 | 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. |
| 2114 | 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. |
| 2115 | 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. |
| 2116 | 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. |
| 2117 | 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. |
| 2118 | 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. |
| 2119 | 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. |
| 2120 | 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. |
| 2121 | 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. |
| 2122 | 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. |
| 2123 | 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. |
| 2124 | 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. |
| 2125 | 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. |
| 2126 | 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. |
| 2127 | 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. |
| 2128 | 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. |
| 2129 | 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. |
| 2130 | 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. |
| 2131 | 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. |
| 2132 | 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. |
| 2133 | 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. |
| 2134 | 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. |
| 2135 | 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. |
| 2136 | 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. |
| 2137 | 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. |
| 2138 | 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. |
| 2139 | 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. |
| 2140 | 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. |
| 2141 | 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. |
| 2142 | 9000697 | High-fat feeding impairs insulin-stimulated GLUT4 recruitment via an early insulin-signaling defect. |
| 2143 | 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). |
| 2144 | 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. |
| 2145 | 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. |
| 2146 | 9003010 | Roles of insulin receptor substrate-1 and Shc on insulin-like growth factor I receptor signaling in early passages of cultured human fibroblasts. |
| 2147 | 9003010 | Insulin-like growth factor-I (IGF-I) improves glucose metabolism and growth in patients with leprechaunism. |
| 2148 | 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. |
| 2149 | 9003010 | Insulin receptor substrate-1 (IRS-1) became tyrosine-phosphorylated and bound growth factor receptor-bound protein 2 (GRB2) quickly by IGF-I. |
| 2150 | 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. |
| 2151 | 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. |
| 2152 | 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. |
| 2153 | 9003010 | Signal transduction pathways following IGF-I receptor or EGF receptor activation were indistinguishable between the normal subject and the patient. |
| 2154 | 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. |
| 2155 | 9006901 | Splice variants of an insulin and growth factor receptor-binding protein with PH and SH2 domains. |
| 2156 | 9006901 | cDNA clones encoding human (h) Grb7 and a previously unknown protein with high homology to hGrb-IR and mGrb10 (where m indicates mouse) were found by screening expressed sequence tag data bases. hGrb7 mRNA expression is greatest in pancreas and restricted to a few other tissues. |
| 2157 | 9006901 | In cells, Grb-IRbeta/Grb10 protein translocates from cytosol to membrane upon insulin stimulation, most likely due to direct interactions with the insulin receptor. |
| 2158 | 9006901 | Studies with mutated receptors and synthetic phosphopeptides show that the hGrb-IRbeta/Grb10 SH2 domain binds at least two sites in the insulin receptor: the kinase activation loop > the juxtamembrane site. hGrb-IRbeta/Grb10 also binds a 135-kDa phosphoprotein in unstimulated 3T3-L1 adipocytes; binding is reduced upon insulin stimulation. |
| 2159 | 9006901 | In addition, the c-Abl SH3 domain binds Grb-IR/Grb10, whereas Fyn, phosphatidylinositol 3-kinase p85, and Grb2 SH3 domains do not. |
| 2160 | 9006901 | The site of c-Abl SH3 domain interaction is highly conserved within the Grb-IR/Grb10/Grb7/Grb14 family. hGrb-IRbeta/Grb10 also binds platelet-derived growth factor and epidermal growth factor receptors, suggesting a broader role in the signaling pathways of numerous receptors. |
| 2161 | 9006901 | We conclude that hGrb-IRbeta/Grb10 is a widely expressed, PH and SH2 domain-containing, SH3 domain-binding protein that functions downstream from activated insulin and growth factor receptors. |
| 2162 | 9006901 | Splice variants of an insulin and growth factor receptor-binding protein with PH and SH2 domains. |
| 2163 | 9006901 | cDNA clones encoding human (h) Grb7 and a previously unknown protein with high homology to hGrb-IR and mGrb10 (where m indicates mouse) were found by screening expressed sequence tag data bases. hGrb7 mRNA expression is greatest in pancreas and restricted to a few other tissues. |
| 2164 | 9006901 | In cells, Grb-IRbeta/Grb10 protein translocates from cytosol to membrane upon insulin stimulation, most likely due to direct interactions with the insulin receptor. |
| 2165 | 9006901 | Studies with mutated receptors and synthetic phosphopeptides show that the hGrb-IRbeta/Grb10 SH2 domain binds at least two sites in the insulin receptor: the kinase activation loop > the juxtamembrane site. hGrb-IRbeta/Grb10 also binds a 135-kDa phosphoprotein in unstimulated 3T3-L1 adipocytes; binding is reduced upon insulin stimulation. |
| 2166 | 9006901 | In addition, the c-Abl SH3 domain binds Grb-IR/Grb10, whereas Fyn, phosphatidylinositol 3-kinase p85, and Grb2 SH3 domains do not. |
| 2167 | 9006901 | The site of c-Abl SH3 domain interaction is highly conserved within the Grb-IR/Grb10/Grb7/Grb14 family. hGrb-IRbeta/Grb10 also binds platelet-derived growth factor and epidermal growth factor receptors, suggesting a broader role in the signaling pathways of numerous receptors. |
| 2168 | 9006901 | We conclude that hGrb-IRbeta/Grb10 is a widely expressed, PH and SH2 domain-containing, SH3 domain-binding protein that functions downstream from activated insulin and growth factor receptors. |
| 2169 | 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. |
| 2170 | 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. |
| 2171 | 9015760 | TNF-alpha caused a dose-dependent decrease in insulin-stimulated IRS-1 phosphorylation and EGF-stimulated receptor autophosphorylation to 47-50% of control. |
| 2172 | 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. |
| 2173 | 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. |
| 2174 | 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. |
| 2175 | 9032245 | Shc and insulin receptor substrate 1 (IRS-1) are cytoplasmic substrates of tyrosine kinase receptors that engage, localize, and activate downstream SH2 enzymes. |
| 2176 | 9032245 | We have designed high-affinity, cellular inhibitors of the Shc PTB domain by incorporating nonnatural, phosphatase-resistant amino acids into short peptides. |
| 2177 | 9032245 | None of the inhibitors bind the IRS-1 PTB domain, consistent with distinct specificities for domains. |
| 2178 | 9032245 | The best inhibitor of the Shc domain was introduced by electroporation into Rat1 fibroblasts that express human insulin receptors. |
| 2179 | 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. |
| 2180 | 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. |
| 2181 | 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. |
| 2182 | 9062339 | The adapter protein Grb10 associates preferentially with the insulin receptor as compared with the IGF-I receptor in mouse fibroblasts. |
| 2183 | 9062339 | Receptor-deficient R- cells (fibroblasts from mice with homologous disruption of the IGF-I receptor gene) and transfected R- cells expressing either insulin receptors (R-IR cells) or IGF-I receptors (R+ cells) were used to investigate the specificity of Grb10 interaction with the two related receptors. |
| 2184 | 9062339 | Hormone-activated insulin receptors in R-IR cells coprecipitated with three species, all recognized as Grb10 isoforms by specific Grb10 antibody. |
| 2185 | 9062339 | Grb10 association with insulin receptors was maximal at 10 nM insulin stimulation and sustained from 5-10 min after hormone stimulation in R-IR cells. |
| 2186 | 9062339 | In conclusion, Grb10 interacts preferentially with insulin vs. |
| 2187 | 9075698 | Specific inhibition of insulin-like growth factor-1 and insulin receptor tyrosine kinase activity and biological function by tyrphostins. |
| 2188 | 9075698 | A series of the synthetic protein tyrosine kinase inhibitors known as tyrphostins were studied for their effect on insulin-like growth factor-1 and insulin-stimulated cellular proliferation on NIH-3T3 fibroblasts overexpressing either receptor, as well as for their ability to inhibit ligand-stimulated receptor autophosphorylation and tyrosine kinase activity toward exogenous substrates. |
| 2189 | 9075698 | Most of the tyrphostins tested presented no clear preference for either receptor, although two of them (AG1024 and AG1034) showed significantly lower IC50s for IGF-1 than for insulin receptors. |
| 2190 | 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. |
| 2191 | 9108124 | The large docking protein IRS-1 is a major substrate for the insulin receptor and other tyrosine kinases. |
| 2192 | 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. |
| 2193 | 9108124 | We examined the expression and function of IRS-1 and IRS-2 in adipocytes from healthy and diabetic individuals. |
| 2194 | 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. |
| 2195 | 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. |
| 2196 | 9108124 | In contrast in NIDDM cells with a low IRS-1 content, IRS-2 became the main docking protein. |
| 2197 | 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. |
| 2198 | 9108124 | The large docking protein IRS-1 is a major substrate for the insulin receptor and other tyrosine kinases. |
| 2199 | 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. |
| 2200 | 9108124 | We examined the expression and function of IRS-1 and IRS-2 in adipocytes from healthy and diabetic individuals. |
| 2201 | 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. |
| 2202 | 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. |
| 2203 | 9108124 | In contrast in NIDDM cells with a low IRS-1 content, IRS-2 became the main docking protein. |
| 2204 | 9109644 | Using isolated rat insulin receptor, LMWCr has been shown to bind to insulin-activated insulin receptor with a dissociation constant of circa 250 pM, resulting in the increase of its tyrosine protein kinase activity. |
| 2205 | 9112375 | Overexpression and activation of the insulin receptor enhances expression of ERCC-1 messenger ribonucleic acid in cultured cells. |
| 2206 | 9112375 | Northern (RNA) blot analysis revealed that overexpression of the insulin receptor or various growth factor receptor tyrosine kinases in Chinese hamster ovary cells increased ERCC-1 messenger RNA (mRNA) levels. |
| 2207 | 9112375 | Insulin enhanced the accumulation of ERCC-1 mRNA in serum-deprived cells expressing wild-type insulin receptors. |
| 2208 | 9112375 | The potential role for activation of the insulin receptor and related growth factor receptors in ERCC-1 gene expression and function remains to be defined. |
| 2209 | 9112375 | Overexpression and activation of the insulin receptor enhances expression of ERCC-1 messenger ribonucleic acid in cultured cells. |
| 2210 | 9112375 | Northern (RNA) blot analysis revealed that overexpression of the insulin receptor or various growth factor receptor tyrosine kinases in Chinese hamster ovary cells increased ERCC-1 messenger RNA (mRNA) levels. |
| 2211 | 9112375 | Insulin enhanced the accumulation of ERCC-1 mRNA in serum-deprived cells expressing wild-type insulin receptors. |
| 2212 | 9112375 | The potential role for activation of the insulin receptor and related growth factor receptors in ERCC-1 gene expression and function remains to be defined. |
| 2213 | 9112375 | Overexpression and activation of the insulin receptor enhances expression of ERCC-1 messenger ribonucleic acid in cultured cells. |
| 2214 | 9112375 | Northern (RNA) blot analysis revealed that overexpression of the insulin receptor or various growth factor receptor tyrosine kinases in Chinese hamster ovary cells increased ERCC-1 messenger RNA (mRNA) levels. |
| 2215 | 9112375 | Insulin enhanced the accumulation of ERCC-1 mRNA in serum-deprived cells expressing wild-type insulin receptors. |
| 2216 | 9112375 | The potential role for activation of the insulin receptor and related growth factor receptors in ERCC-1 gene expression and function remains to be defined. |
| 2217 | 9133538 | Differential activation of mitogen-activated protein kinase by insulin and epidermal growth factor in 3T3-L1 adipocytes: a possible involvement of PI3-kinase in the activation of the MAP kinase by insulin. |
| 2218 | 9133538 | Mitogen-activated protein (MAP) kinase plays crucial roles in cell growth and differentiation. |
| 2219 | 9133538 | It has recently been shown that the MAP kinase cascade in growth factor signaling diverges and cross-talks with other signaling pathways. |
| 2220 | 9133538 | In the present study, we examined the effects of wortmannin, a specific inhibitor of phosphatidylinositol 3-kinase (PI3-kinase), on the activation of Ras, Raf-1 kinase, and MAP kinase by insulin and epidermal growth factor (EGF). |
| 2221 | 9133538 | The effect of LY294002, a structurally distinct PI3-kinase inhibitor, on the activation of Raf-1 kinase by both ligands was also examined. |
| 2222 | 9133538 | In 3T3-L1 adipocytes, 25 nmol/l wortmannin inhibited the insulin-induced activation of Raf-1 kinase to the basal level, whereas the same dose of wortmannin had little effect on the EGF-induced activation of Raf-1 kinase. |
| 2223 | 9133538 | One hundred micromol/l LY294002 blocked insulin-induced activation of Raf-1 kinase without affecting EGF-induced activation of this kinase. |
| 2224 | 9133538 | Twenty-five nmol/l wortmannin inhibited the insulin-induced activation of MAP kinase to the basal level with no effect on the EGF-induced activation of this kinase. |
| 2225 | 9133538 | In contrast, in Chinese hamster ovary cells overexpressing the human insulin receptor (CHO-HIR cells), neither wortmannin nor LY294002 inhibited the insulin-induced activation of Raf-1 kinase, and wortmannin had little effect on the activation of MAP kinase by insulin. |
| 2226 | 9133538 | These results indicate that 1) PI3-kinase or wortmannin-sensitive molecules are involved in the interaction between activated Ras and Raf-1 kinase in the insulin signaling in 3T3-L1 adipocytes, 2) the involvement of PI3-kinase or wortmannin-sensitive molecules in the insulin-induced activation of MAP kinase appears to be cell-type specific, and 3) differential mechanisms to activate Raf-1 kinase and MAP kinase by insulin and EGF exist. |
| 2227 | 9142881 | Insulin receptor mRNA splicing and altered metabolic control in aged and mildly insulin-deficient rats. |
| 2228 | 9142881 | Using reverse transcription-competitive polymerase chain reaction, we measured the abundance of the mRNAs encoding the two spliced isoforms of insulin receptor in aged and mildly insulin-deficient rats. |
| 2229 | 9142881 | Although a decreased level of the variant with exon 11 correlated with insulin resistance of whole body glucose uptake, our results indicated that changes in the expression of the insulin receptor variants were secondary events and thus not the cause of the insulin resistance in old and mildly insulin-deficient rats. |
| 2230 | 9142881 | Insulin receptor mRNA splicing and altered metabolic control in aged and mildly insulin-deficient rats. |
| 2231 | 9142881 | Using reverse transcription-competitive polymerase chain reaction, we measured the abundance of the mRNAs encoding the two spliced isoforms of insulin receptor in aged and mildly insulin-deficient rats. |
| 2232 | 9142881 | Although a decreased level of the variant with exon 11 correlated with insulin resistance of whole body glucose uptake, our results indicated that changes in the expression of the insulin receptor variants were secondary events and thus not the cause of the insulin resistance in old and mildly insulin-deficient rats. |
| 2233 | 9142881 | Insulin receptor mRNA splicing and altered metabolic control in aged and mildly insulin-deficient rats. |
| 2234 | 9142881 | Using reverse transcription-competitive polymerase chain reaction, we measured the abundance of the mRNAs encoding the two spliced isoforms of insulin receptor in aged and mildly insulin-deficient rats. |
| 2235 | 9142881 | Although a decreased level of the variant with exon 11 correlated with insulin resistance of whole body glucose uptake, our results indicated that changes in the expression of the insulin receptor variants were secondary events and thus not the cause of the insulin resistance in old and mildly insulin-deficient rats. |
| 2236 | 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. |
| 2237 | 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. |
| 2238 | 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. |
| 2239 | 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. |
| 2240 | 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. |
| 2241 | 9166661 | G971R showed no changes in IRS-1 phosphorylation and in IRS-1 binding to the insulin receptor compared with WT. |
| 2242 | 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. |
| 2243 | 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. |
| 2244 | 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. |
| 2245 | 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. |
| 2246 | 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. |
| 2247 | 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. |
| 2248 | 9166661 | G971R showed no changes in IRS-1 phosphorylation and in IRS-1 binding to the insulin receptor compared with WT. |
| 2249 | 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. |
| 2250 | 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. |
| 2251 | 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. |
| 2252 | 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. |
| 2253 | 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. |
| 2254 | 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. |
| 2255 | 9166661 | G971R showed no changes in IRS-1 phosphorylation and in IRS-1 binding to the insulin receptor compared with WT. |
| 2256 | 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. |
| 2257 | 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. |
| 2258 | 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. |
| 2259 | 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. |
| 2260 | 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. |
| 2261 | 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. |
| 2262 | 9166661 | G971R showed no changes in IRS-1 phosphorylation and in IRS-1 binding to the insulin receptor compared with WT. |
| 2263 | 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. |
| 2264 | 9166671 | In conclusion, 1) in obese and NIDDM subjects, insulin-mediated GDR and LGU are delayed to a similar degree; 2) mass action normalizes GDR and LGU in NIDDM, but only after several hours of insulin infusion; and 3) The kinetic defect in NIDDM and obesity most likely involves intracellular loci distal to activation of the insulin receptor kinase. |
| 2265 | 9169593 | Insulin regulation of mitogen-activated protein kinase kinase (MEK), mitogen-activated protein kinase and casein kinase in the cell nucleus: a possible role in the regulation of gene expression. |
| 2266 | 9169593 | After insulin receptor activation, many cytoplasmic enzymes, including mitogen-activated protein (MAP) kinase, MAP kinase kinase (MEK) and casein kinase II (CKII) are activated, but exactly how insulin signalling progresses to the nucleus remains poorly understood. |
| 2267 | 9169593 | In Chinese hamster ovary cells overexpressing human insulin receptors [CHO(Hirc)], MEK, CKII and the MAP kinases ERK I and ERK II can be detected by immunoblotting in the nucleus, as well as in the cytoplasm, in the unstimulated state. |
| 2268 | 9169593 | Nuclear localization of MAP kinase is also observed in 3T3-F442A adipocytes, NIH-3T3 cells and Fao hepatoma cells, whereas MEK is found in the nucleus only in Fao and CHO cells. |
| 2269 | 9169593 | Insulin treatment for 5-30 min induces a translocation of MEK from the cytoplasm to the nucleus, whereas the MAP kinases and CKII are not translocated into the nucleus in response to insulin during this period. |
| 2270 | 9169593 | However, nuclear MAP kinase and CKII activities increase by 2-3-fold within 1-10 min after stimulation with insulin. |
| 2271 | 9169593 | By using gel-shift assays, it has been shown that insulin also stimulates nuclear protein binding to an AP-1 site with kinetics similar to MEK translocation and MAP kinase and CKII activation. |
| 2272 | 9169593 | Treatment of the extracts in vitro with protein phosphatase 2A or treatment of the intact cells with 5, 6-dichloro-1-beta-d-ribofuranosylbenzimidazole, a cell-permeable inhibitor of CKII, almost completely blocks the insulin-induced DNA-binding activity, whereas incubation of cells with a MEK inhibitor produces only a slight decrease. |
| 2273 | 9169593 | The latter is true of CKII, which seems to regulate the binding of nuclear proteins to the AP-1 site, possibly by phosphorylation of AP-1 transcription factors. |
| 2274 | 9209829 | Amylin, calcitonin gene-related peptide, calcitonin, and adrenomedullin: a peptide superfamily. |
| 2275 | 9209829 | Amylin (a 37-amino-acid peptide) is generated from a gene located on chromosome 12 (thought to be an evolutionary duplication of chromosome 11) and shares 46% amino acid sequence homology with CGRP and 20% with human CT. |
| 2276 | 9209829 | Amylin is predominantly located in the beta cells of the islets of the pancreas and may be involved in the pathogenesis of type II diabetes by deposition as amyloid within the pancreas, leading to beta cell destruction. |
| 2277 | 9209829 | Adrenomedullin, a recently discovered 52-amino-acid vasoactive peptide from adrenal tissue, shares 24% homology with CGRP and is also a member of this superfamily of peptides. |
| 2278 | 9209829 | Not only does adrenomedullin (13-52) show 24% amino acid homology with CGRP, it also has a biological activity profile similar to that of CGRP.CGRP, CT, and amylin are related to the insulin gene superfamily of peptides, which may all have diverged from a common ancestral gene during evolution. |
| 2279 | 9209829 | When the crystallographic- and nuclear magnetic resonance-based molecular modeling of the three-dimensional structure of CGRP, CT, amylin, and adrenomedullin peptides and their receptors is available, it will lead to a greater understanding of the involvement of this family of peptides in pathophysiology. |
| 2280 | 9209829 | Together, CGRP, CT, amylin and adrenomedullin have overlapping biological effects owing to their structures and cross-reactivity between receptors. |
| 2281 | 9209829 | I propose that CT, CGRP, adrenomedullin, and amylin belong to a family of G-protein-coupled receptors (an "insulin superfamily" of peptides) and therefore share some of the characteristics of insulin, such as growth factor-like effects, and possible interaction at insulin receptor sites as an antagonist. |
| 2282 | 9219356 | The binding constants (kn), reversal constants (k-n), dissociation constants kd = k-n/kn, and residency time constants tau = 1/k-n of 125I-insulin in normal untreated, normal CHAPS-treated, diabetic untreated, and diabetic CHAPS-treated hearts were estimated using a theoretically generated curve-fit to the data. |
| 2283 | 9219356 | Since insulin receptor binding on the capillary endothelial cell surfaces may serve to transport insulin from the intravascular to the subendothelial space, and since streptozotocin-induced diabetes was shown to diminish receptor autophosphorylation and kinase activity and hence internalization of insulin, then one can conclude the following from the data. |
| 2284 | 9219356 | In the normal heart, removal of the capillary endothelial lining with CHAPS did not alter kn, k-n, kd, and tau of insulin binding as compared to the normal untreated, whereas in the diabetic untreated heart these constants were altered, compared to the diabetic treated. |
| 2285 | 9227454 | Growth hormone-induced insulin resistance: role of the insulin receptor, IRS-1, GLUT-1, and GLUT-4. |
| 2286 | 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. |
| 2287 | 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%. |
| 2288 | 9243097 | Effects of angiotensin II on insulin receptor binding and mRNA levels in normal and diabetic rats. |
| 2289 | 9243097 | Because angiotensin II affects tissue sensitivity to insulin in humans, we investigated whether angiotensin II affects insulin receptor binding and mRNA levels in the kidney, liver, and renal arteries of normal rats and rats with streptozotocin-induced diabetes mellitus. |
| 2290 | 9243097 | Angiotensin II significantly decreased plasma renin concentration in both non-diabetic and diabetic rats. |
| 2291 | 9243097 | Angiotensin II infusion did not affect either the number or affinity of insulin receptors in any of the renal regions studied. |
| 2292 | 9243097 | Insulin receptor mRNA levels were significantly greater in the kidney and liver of diabetic rats than in non-diabetics and were not affected by angiotensin II infusion. |
| 2293 | 9243097 | Similar to angiotensin II infusion, captopril treatment did not affect either renal insulin receptor binding or mRNA levels. |
| 2294 | 9243097 | Angiotensin II infusion and captopril treatment do not affect insulin receptor binding and mRNA levels in the kidney, arguing against a role for this peptide in the modulation of renal sensitivity to insulin. |
| 2295 | 9243097 | Effects of angiotensin II on insulin receptor binding and mRNA levels in normal and diabetic rats. |
| 2296 | 9243097 | Because angiotensin II affects tissue sensitivity to insulin in humans, we investigated whether angiotensin II affects insulin receptor binding and mRNA levels in the kidney, liver, and renal arteries of normal rats and rats with streptozotocin-induced diabetes mellitus. |
| 2297 | 9243097 | Angiotensin II significantly decreased plasma renin concentration in both non-diabetic and diabetic rats. |
| 2298 | 9243097 | Angiotensin II infusion did not affect either the number or affinity of insulin receptors in any of the renal regions studied. |
| 2299 | 9243097 | Insulin receptor mRNA levels were significantly greater in the kidney and liver of diabetic rats than in non-diabetics and were not affected by angiotensin II infusion. |
| 2300 | 9243097 | Similar to angiotensin II infusion, captopril treatment did not affect either renal insulin receptor binding or mRNA levels. |
| 2301 | 9243097 | Angiotensin II infusion and captopril treatment do not affect insulin receptor binding and mRNA levels in the kidney, arguing against a role for this peptide in the modulation of renal sensitivity to insulin. |
| 2302 | 9243097 | Effects of angiotensin II on insulin receptor binding and mRNA levels in normal and diabetic rats. |
| 2303 | 9243097 | Because angiotensin II affects tissue sensitivity to insulin in humans, we investigated whether angiotensin II affects insulin receptor binding and mRNA levels in the kidney, liver, and renal arteries of normal rats and rats with streptozotocin-induced diabetes mellitus. |
| 2304 | 9243097 | Angiotensin II significantly decreased plasma renin concentration in both non-diabetic and diabetic rats. |
| 2305 | 9243097 | Angiotensin II infusion did not affect either the number or affinity of insulin receptors in any of the renal regions studied. |
| 2306 | 9243097 | Insulin receptor mRNA levels were significantly greater in the kidney and liver of diabetic rats than in non-diabetics and were not affected by angiotensin II infusion. |
| 2307 | 9243097 | Similar to angiotensin II infusion, captopril treatment did not affect either renal insulin receptor binding or mRNA levels. |
| 2308 | 9243097 | Angiotensin II infusion and captopril treatment do not affect insulin receptor binding and mRNA levels in the kidney, arguing against a role for this peptide in the modulation of renal sensitivity to insulin. |
| 2309 | 9243097 | Effects of angiotensin II on insulin receptor binding and mRNA levels in normal and diabetic rats. |
| 2310 | 9243097 | Because angiotensin II affects tissue sensitivity to insulin in humans, we investigated whether angiotensin II affects insulin receptor binding and mRNA levels in the kidney, liver, and renal arteries of normal rats and rats with streptozotocin-induced diabetes mellitus. |
| 2311 | 9243097 | Angiotensin II significantly decreased plasma renin concentration in both non-diabetic and diabetic rats. |
| 2312 | 9243097 | Angiotensin II infusion did not affect either the number or affinity of insulin receptors in any of the renal regions studied. |
| 2313 | 9243097 | Insulin receptor mRNA levels were significantly greater in the kidney and liver of diabetic rats than in non-diabetics and were not affected by angiotensin II infusion. |
| 2314 | 9243097 | Similar to angiotensin II infusion, captopril treatment did not affect either renal insulin receptor binding or mRNA levels. |
| 2315 | 9243097 | Angiotensin II infusion and captopril treatment do not affect insulin receptor binding and mRNA levels in the kidney, arguing against a role for this peptide in the modulation of renal sensitivity to insulin. |
| 2316 | 9243097 | Effects of angiotensin II on insulin receptor binding and mRNA levels in normal and diabetic rats. |
| 2317 | 9243097 | Because angiotensin II affects tissue sensitivity to insulin in humans, we investigated whether angiotensin II affects insulin receptor binding and mRNA levels in the kidney, liver, and renal arteries of normal rats and rats with streptozotocin-induced diabetes mellitus. |
| 2318 | 9243097 | Angiotensin II significantly decreased plasma renin concentration in both non-diabetic and diabetic rats. |
| 2319 | 9243097 | Angiotensin II infusion did not affect either the number or affinity of insulin receptors in any of the renal regions studied. |
| 2320 | 9243097 | Insulin receptor mRNA levels were significantly greater in the kidney and liver of diabetic rats than in non-diabetics and were not affected by angiotensin II infusion. |
| 2321 | 9243097 | Similar to angiotensin II infusion, captopril treatment did not affect either renal insulin receptor binding or mRNA levels. |
| 2322 | 9243097 | Angiotensin II infusion and captopril treatment do not affect insulin receptor binding and mRNA levels in the kidney, arguing against a role for this peptide in the modulation of renal sensitivity to insulin. |
| 2323 | 9247738 | A similar spectrum of genetic associations for variants spanning INSR has been noted for insulin-dependent diabetic patients with rapidly-progressing renal disease, a subgroup having a strong family history of essential HT. |
| 2324 | 9247738 | Insulin resistance secondary to an INSR 'defect', or other causes, would increase insulin, which has cardiovascular effects, and insulin can raise angiotensinogen. |
| 2325 | 9247738 | Also, insulin is co-secreted with amylin, which can increase renin secretion. |
| 2326 | 9247738 | When combined with observations of insulin resistance in essential HT patients and their pre-HT offspring, the possibility of dys-regulation of INSR merits attention in disease etiology in a proportion of essential HT patients. |
| 2327 | 9247738 | A similar spectrum of genetic associations for variants spanning INSR has been noted for insulin-dependent diabetic patients with rapidly-progressing renal disease, a subgroup having a strong family history of essential HT. |
| 2328 | 9247738 | Insulin resistance secondary to an INSR 'defect', or other causes, would increase insulin, which has cardiovascular effects, and insulin can raise angiotensinogen. |
| 2329 | 9247738 | Also, insulin is co-secreted with amylin, which can increase renin secretion. |
| 2330 | 9247738 | When combined with observations of insulin resistance in essential HT patients and their pre-HT offspring, the possibility of dys-regulation of INSR merits attention in disease etiology in a proportion of essential HT patients. |
| 2331 | 9247738 | A similar spectrum of genetic associations for variants spanning INSR has been noted for insulin-dependent diabetic patients with rapidly-progressing renal disease, a subgroup having a strong family history of essential HT. |
| 2332 | 9247738 | Insulin resistance secondary to an INSR 'defect', or other causes, would increase insulin, which has cardiovascular effects, and insulin can raise angiotensinogen. |
| 2333 | 9247738 | Also, insulin is co-secreted with amylin, which can increase renin secretion. |
| 2334 | 9247738 | When combined with observations of insulin resistance in essential HT patients and their pre-HT offspring, the possibility of dys-regulation of INSR merits attention in disease etiology in a proportion of essential HT patients. |
| 2335 | 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. |
| 2336 | 9250867 | Localization of the rat genes encoding glucagon, glucagon receptor, and insulin receptor, candidates for diabetes mellitus susceptibility loci. |
| 2337 | 9277380 | Maximal in vitro insulin stimulation of insulin receptor autophosphorylation strongly correlated with both low (Mlow)- and high (Mhigh)-dose insulin-stimulated glucose disposal (r = 0.62 and 0.51, P < 0.002 and 0.011, respectively). |
| 2338 | 9285027 | The microvascular complications of NIDDM are the same as for insulin dependent diabetes (IDDM) and are related to the intensity and duration of hyperglycaemia. |
| 2339 | 9285027 | Mutations in the insulin receptor lead to NIDDM in a small number of patients, and mutations in the glucokinase gene lead to maturity onset diabetes of the young (MODY). |
| 2340 | 9292765 | The amount of insulin receptor present in adipocyte membranes was increased in the three animal groups that had been exposed to the low-protein diets while levels of the insulin responsive glucose transporter (GLUT 4) were similar in adipocyte membranes from all groups. |
| 2341 | 9294099 | A recombinant monomeric human insulin analog, which does not bind to the insulin receptor as a consequence of an alteration of a single amino acid at position 25 of the B chain, was shown to be equally effective at diabetes prevention as was intact insulin. |
| 2342 | 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. |
| 2343 | 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). |
| 2344 | 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. |
| 2345 | 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. |
| 2346 | 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. |
| 2347 | 9295312 | In streptozotocin diabetic rats the interaction between IRS proteins and SERCA1 in skeletal muscle and SERCA2 in cardiac muscle was significantly reduced. |
| 2348 | 9312188 | Thiazolidinediones block tumor necrosis factor-alpha-induced inhibition of insulin signaling. |
| 2349 | 9312188 | TNF-alpha has been shown to be an important mediator of insulin resistance linked to obesity. |
| 2350 | 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. |
| 2351 | 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). |
| 2352 | 9312188 | The TZDs do not inhibit all TNF-alpha signaling in that the transcription factor NF-kB is still induced well. |
| 2353 | 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. |
| 2354 | 9335502 | Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function. |
| 2355 | 9335502 | It has been suggested that tumour necrosis factor (TNF)-alpha is a candidate mediator of insulin resistance in obesity, as it is overexpressed in the adipose tissues of rodents and humans and it blocks the action of insulin in cultured cells and whole animals. |
| 2356 | 9335502 | To investigate the role of TNF-alpha in obesity and insulin resistance, we have generated obese mice with a targeted null mutation in the gene encoding TNF-alpha and those encoding the two receptors for TNF-alpha. |
| 2357 | 9335502 | The absence of TNF-alpha resulted in significantly improved insulin sensitivity in both diet-induced obesity and that resulting for the ob/ob model of obesity. |
| 2358 | 9335502 | The TNFalpha-deficient obese mice had lower levels of circulating free fatty acids, and were protected from the obesity-related reduction in the insulin receptor signalling in muscle and fat tissues. |
| 2359 | 9335502 | These results indicate that TNF-alpha is an important mediator of insulin resistance in obesity through its effects on several important sites of insulin action. |
| 2360 | 9343928 | We have synthesized a tris-sulfotyrosyl dodecapeptide (3S-peptide-I) that corresponds to the major autophosphorylation domain within the insulin receptor beta-subunit and showed that it potently inhibited insulin receptor dephosphorylation by protein tyrosine phosphatases (PTPases) in vitro. 3S-peptide-I also inhibited tyrosine dephosphorylation of a synthetic peptide by the recombinant PTPase PTP-1B, indicating that 3S-peptide-I interacts directly with PTPase, causing its inactivation. |
| 2361 | 9343928 | The peptide had no effect on the activity of serine/threonine phosphatases, PP-1 and PP-2A, or alkaline phosphatase. |
| 2362 | 9343928 | Furthermore, we found that the introduction of a N-stearyl derivative of 3S-peptide-I in CHO/HIRc cells caused a significant increase in insulin-stimulated phosphorylation of the insulin receptor. |
| 2363 | 9343928 | In contrast, ligand-stimulated phosphorylation of epidermal growth factor (EGF) receptor in CHO cells overexpressing EGF receptors was not affected by the presence of N-stearyl-3S-peptide-I. |
| 2364 | 9343928 | We have synthesized a tris-sulfotyrosyl dodecapeptide (3S-peptide-I) that corresponds to the major autophosphorylation domain within the insulin receptor beta-subunit and showed that it potently inhibited insulin receptor dephosphorylation by protein tyrosine phosphatases (PTPases) in vitro. 3S-peptide-I also inhibited tyrosine dephosphorylation of a synthetic peptide by the recombinant PTPase PTP-1B, indicating that 3S-peptide-I interacts directly with PTPase, causing its inactivation. |
| 2365 | 9343928 | The peptide had no effect on the activity of serine/threonine phosphatases, PP-1 and PP-2A, or alkaline phosphatase. |
| 2366 | 9343928 | Furthermore, we found that the introduction of a N-stearyl derivative of 3S-peptide-I in CHO/HIRc cells caused a significant increase in insulin-stimulated phosphorylation of the insulin receptor. |
| 2367 | 9343928 | In contrast, ligand-stimulated phosphorylation of epidermal growth factor (EGF) receptor in CHO cells overexpressing EGF receptors was not affected by the presence of N-stearyl-3S-peptide-I. |
| 2368 | 9346913 | Heterologous pleckstrin homology domains do not couple IRS-1 to the insulin receptor. |
| 2369 | 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. |
| 2370 | 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. |
| 2371 | 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. |
| 2372 | 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. |
| 2373 | 9346913 | Thus, tyrosine phosphorylation of IRS-1 by the insulin receptor specifically requires a PH domain derived from IRS proteins. |
| 2374 | 9346913 | Heterologous pleckstrin homology domains do not couple IRS-1 to the insulin receptor. |
| 2375 | 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. |
| 2376 | 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. |
| 2377 | 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. |
| 2378 | 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. |
| 2379 | 9346913 | Thus, tyrosine phosphorylation of IRS-1 by the insulin receptor specifically requires a PH domain derived from IRS proteins. |
| 2380 | 9346913 | Heterologous pleckstrin homology domains do not couple IRS-1 to the insulin receptor. |
| 2381 | 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. |
| 2382 | 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. |
| 2383 | 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. |
| 2384 | 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. |
| 2385 | 9346913 | Thus, tyrosine phosphorylation of IRS-1 by the insulin receptor specifically requires a PH domain derived from IRS proteins. |
| 2386 | 9346913 | Heterologous pleckstrin homology domains do not couple IRS-1 to the insulin receptor. |
| 2387 | 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. |
| 2388 | 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. |
| 2389 | 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. |
| 2390 | 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. |
| 2391 | 9346913 | Thus, tyrosine phosphorylation of IRS-1 by the insulin receptor specifically requires a PH domain derived from IRS proteins. |
| 2392 | 9346913 | Heterologous pleckstrin homology domains do not couple IRS-1 to the insulin receptor. |
| 2393 | 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. |
| 2394 | 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. |
| 2395 | 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. |
| 2396 | 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. |
| 2397 | 9346913 | Thus, tyrosine phosphorylation of IRS-1 by the insulin receptor specifically requires a PH domain derived from IRS proteins. |
| 2398 | 9349593 | A 973 valine to methionine mutation of the human insulin receptor: interaction with insulin-receptor substrate-1 and Shc in HEK 293 cells. |
| 2399 | 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). |
| 2400 | 9349593 | This mutant was transiently overexpressed in HEK 293 cells either alone or together with insulin-receptor substrate-1 (IRS-1) or Shc. |
| 2401 | 9349593 | Insulin stimulated autophosphorylation, phosphorylation of the substrates IRS-1 and Shc as well as activation of phosphatidylinositol-3 (PI3)-kinase were studied. |
| 2402 | 9349593 | Human insulin receptor with a juxtamembrane deletion HIR-deltaJM which is known to impair HIR/IRS-1 interaction was used as control. |
| 2403 | 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. |
| 2404 | 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. |
| 2405 | 9349593 | A 973 valine to methionine mutation of the human insulin receptor: interaction with insulin-receptor substrate-1 and Shc in HEK 293 cells. |
| 2406 | 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). |
| 2407 | 9349593 | This mutant was transiently overexpressed in HEK 293 cells either alone or together with insulin-receptor substrate-1 (IRS-1) or Shc. |
| 2408 | 9349593 | Insulin stimulated autophosphorylation, phosphorylation of the substrates IRS-1 and Shc as well as activation of phosphatidylinositol-3 (PI3)-kinase were studied. |
| 2409 | 9349593 | Human insulin receptor with a juxtamembrane deletion HIR-deltaJM which is known to impair HIR/IRS-1 interaction was used as control. |
| 2410 | 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. |
| 2411 | 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. |
| 2412 | 9349593 | A 973 valine to methionine mutation of the human insulin receptor: interaction with insulin-receptor substrate-1 and Shc in HEK 293 cells. |
| 2413 | 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). |
| 2414 | 9349593 | This mutant was transiently overexpressed in HEK 293 cells either alone or together with insulin-receptor substrate-1 (IRS-1) or Shc. |
| 2415 | 9349593 | Insulin stimulated autophosphorylation, phosphorylation of the substrates IRS-1 and Shc as well as activation of phosphatidylinositol-3 (PI3)-kinase were studied. |
| 2416 | 9349593 | Human insulin receptor with a juxtamembrane deletion HIR-deltaJM which is known to impair HIR/IRS-1 interaction was used as control. |
| 2417 | 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. |
| 2418 | 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. |
| 2419 | 9349593 | A 973 valine to methionine mutation of the human insulin receptor: interaction with insulin-receptor substrate-1 and Shc in HEK 293 cells. |
| 2420 | 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). |
| 2421 | 9349593 | This mutant was transiently overexpressed in HEK 293 cells either alone or together with insulin-receptor substrate-1 (IRS-1) or Shc. |
| 2422 | 9349593 | Insulin stimulated autophosphorylation, phosphorylation of the substrates IRS-1 and Shc as well as activation of phosphatidylinositol-3 (PI3)-kinase were studied. |
| 2423 | 9349593 | Human insulin receptor with a juxtamembrane deletion HIR-deltaJM which is known to impair HIR/IRS-1 interaction was used as control. |
| 2424 | 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. |
| 2425 | 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. |
| 2426 | 9349593 | A 973 valine to methionine mutation of the human insulin receptor: interaction with insulin-receptor substrate-1 and Shc in HEK 293 cells. |
| 2427 | 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). |
| 2428 | 9349593 | This mutant was transiently overexpressed in HEK 293 cells either alone or together with insulin-receptor substrate-1 (IRS-1) or Shc. |
| 2429 | 9349593 | Insulin stimulated autophosphorylation, phosphorylation of the substrates IRS-1 and Shc as well as activation of phosphatidylinositol-3 (PI3)-kinase were studied. |
| 2430 | 9349593 | Human insulin receptor with a juxtamembrane deletion HIR-deltaJM which is known to impair HIR/IRS-1 interaction was used as control. |
| 2431 | 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. |
| 2432 | 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. |
| 2433 | 9349602 | Furthermore, low concentrations of bpV(pic) did not affect insulin-stimulated glucose uptake, although tyrosine phosphorylation of the insulin receptor beta-subunit was clearly increased by bpV(pic). |
| 2434 | 9354853 | Changes in the signalling status of the small GTP-binding proteins Rac and Rho do not influence insulin-stimulated hexose transport. |
| 2435 | 9354853 | Post-receptor signalling molecules that convey the signal from the activated insulin receptor to the actual process of Glut4 translocation and hexose uptake are poorly understood. |
| 2436 | 9354853 | Various studies have suggested a requirement of the lipid kinase phosphatidylinositol-3 kinase (PI3-kinase) in this process. |
| 2437 | 9354853 | PI3kinase regulates the activation status of the small GTP-binding protein Rac which, in turn, is able to activate another G-protein Rho. |
| 2438 | 9354853 | Rac and Rho are known to regulate the structure of the membrane- and cytoplasmic actin-cytoskeleton. |
| 2439 | 9354853 | We have examined whether Rac and Rho transfer the signals generated by PI3kinase towards insulin-stimulated hexose uptake. |
| 2440 | 9354853 | We conclude that Rac and Rho are unlikely to be involved in insulin-stimulated hexose transport, suggesting a possible contribution of other signalling pathways, downstream of PI3kinase to this process. |
| 2441 | 9356012 | TNF-alpha-induced insulin resistance in vivo and its prevention by troglitazone. |
| 2442 | 9356012 | Tumor necrosis factor (TNF)-alpha may play a role in the insulin resistance of obesity and NIDDM. |
| 2443 | 9356012 | To determine whether this drug could prevent the development of TNF-alpha-induced insulin resistance, glucose turnover was assessed in rats infused with cytokine and pretreated with troglitazone. |
| 2444 | 9356012 | TNF-alpha infusion resulted in a pronounced reduction in submaximal insulin-stimulated glucose disposal rate (GDR) (97 +/- 10 vs. 141 +/- 4 micromol x kg[-1] x min[-1], P < 0.05), maximal GDR (175 +/- 8 vs. 267 +/- 6 micromol x kg[-1] x min[-1], P < 0.01), and in insulin receptor-tyrosine kinase activity (IR-TKA) (248 +/- 39 vs. 406 +/- 32 fmol ATP/fmol IR, P < 0.05). |
| 2445 | 9361682 | Dissociation of the insulin-insulin receptor complex plays a crucial role in the processing of both insulin and the insulin receptor, and the acidification of endocytic vesicles may be the mechanism by which internalized insulin is dissociated from its receptor and properly sorted and processed. |
| 2446 | 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. |
| 2447 | 9368055 | Insulin receptor substrates-1 and -2 (IRS-1 and -2) are important substrates of the insulin receptor tyrosine kinase. |
| 2448 | 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. |
| 2449 | 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. |
| 2450 | 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. |
| 2451 | 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). |
| 2452 | 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). |
| 2453 | 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). |
| 2454 | 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. |
| 2455 | 9388210 | Inhibition of insulin receptor activation by insulin-like growth factor binding proteins. |
| 2456 | 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. |
| 2457 | 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. |
| 2458 | 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. |
| 2459 | 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. |
| 2460 | 9388210 | Inhibition of insulin receptor activation by insulin-like growth factor binding proteins. |
| 2461 | 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. |
| 2462 | 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. |
| 2463 | 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. |
| 2464 | 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. |
| 2465 | 9392479 | The clinical use of ACE inhibitors has been associated with increased insulin sensitivity. |
| 2466 | 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. |
| 2467 | 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. |
| 2468 | 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. |
| 2469 | 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. |
| 2470 | 9392479 | Losartan, an ANG receptor blocker, had no significant effect on insulin-stimulated IRS-1 phosphorylation in both tissues. |
| 2471 | 9392479 | The acute administration of bradykinin increased insulin-stimulated tyrosine phosphorylation of the insulin receptor and IRS-1 in the liver and muscle. |
| 2472 | 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. |
| 2473 | 9392479 | The clinical use of ACE inhibitors has been associated with increased insulin sensitivity. |
| 2474 | 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. |
| 2475 | 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. |
| 2476 | 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. |
| 2477 | 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. |
| 2478 | 9392479 | Losartan, an ANG receptor blocker, had no significant effect on insulin-stimulated IRS-1 phosphorylation in both tissues. |
| 2479 | 9392479 | The acute administration of bradykinin increased insulin-stimulated tyrosine phosphorylation of the insulin receptor and IRS-1 in the liver and muscle. |
| 2480 | 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. |
| 2481 | 9398630 | A conserved region in the first intron of the insulin receptor gene binds nuclear proteins during adipocyte differentiation. |
| 2482 | 9398630 | The insulin receptor gene is induced 8 to 10-fold during adipocyte differentiation. |
| 2483 | 9398630 | Plasmids containing the promoter, exon 1 and a portion of the first intron from either the mouse or human gene are able to modulate the expression of an insulin receptor/CAT gene 3 to 7-fold during differentiation. |
| 2484 | 9398630 | A conserved region in the first intron of the insulin receptor gene binds nuclear proteins during adipocyte differentiation. |
| 2485 | 9398630 | The insulin receptor gene is induced 8 to 10-fold during adipocyte differentiation. |
| 2486 | 9398630 | Plasmids containing the promoter, exon 1 and a portion of the first intron from either the mouse or human gene are able to modulate the expression of an insulin receptor/CAT gene 3 to 7-fold during differentiation. |
| 2487 | 9398630 | A conserved region in the first intron of the insulin receptor gene binds nuclear proteins during adipocyte differentiation. |
| 2488 | 9398630 | The insulin receptor gene is induced 8 to 10-fold during adipocyte differentiation. |
| 2489 | 9398630 | Plasmids containing the promoter, exon 1 and a portion of the first intron from either the mouse or human gene are able to modulate the expression of an insulin receptor/CAT gene 3 to 7-fold during differentiation. |
| 2490 | 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. |
| 2491 | 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. |
| 2492 | 9398740 | The mutations did not alter the level of expression or the extent of insulin receptor-mediated tyrosine phosphorylation of recombinant IRS-1. |
| 2493 | 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. |
| 2494 | 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. |
| 2495 | 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. |
| 2496 | 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%). |
| 2497 | 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. |
| 2498 | 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. |
| 2499 | 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. |
| 2500 | 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. |
| 2501 | 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. |
| 2502 | 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. |
| 2503 | 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. |
| 2504 | 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. |
| 2505 | 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. |
| 2506 | 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. |
| 2507 | 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. |
| 2508 | 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. |
| 2509 | 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. |
| 2510 | 9434573 | [Insulin receptor-related receptor (IRR)]. |
| 2511 | 9439552 | In gastrocnemious muscles, the protein content of GLUT4 and the insulin binding and tyrosine kinase activity of partially purified solubilized insulin receptors were measured. |
| 2512 | 9439552 | In conclusion, gliclazide has a glucose-lowering effect in STZ-diabetic rats that could be attributed to an increase in muscle glucose clearance by a post-insulin receptor mechanism, probably related to a normalization of GLUT4 content. |
| 2513 | 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). |
| 2514 | 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. |
| 2515 | 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. |
| 2516 | 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. |
| 2517 | 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. |
| 2518 | 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. |
| 2519 | 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. |
| 2520 | 9441865 | Differential effects of Wilms tumor WT1 splice variants on the insulin receptor promoter. |
| 2521 | 9441865 | We show that the +KTS variant effectively represses promoter activity under all conditions tested but the -KTS variant was only able to repress in the presence of cotransfected C/EBP beta or a dominant-negative p53 mutation. |
| 2522 | 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. |
| 2523 | 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). |
| 2524 | 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. |
| 2525 | 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. |
| 2526 | 9461521 | Downstream signalling of IRS-1 was then analysed by monitoring IRS-1-associated phosphatidylinositol 3-kinase (PI 3-kinase) activity in cardiomyocytes. |
| 2527 | 9461521 | A stable (2 and 15 min incubation with PIG-P) 7-fold stimulation corresponding to about 50% of insulin action could be detected. |
| 2528 | 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. |
| 2529 | 9461521 | These data suggest divergent upstream signalling by insulin and PIG-P involving phosphoproteins not affected by insulin. |
| 2530 | 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. |
| 2531 | 9493493 | The aetiology of insulin resistance is likely to be multifactorial, but the present review focuses on candidate post-receptor mechanisms of insulin resistance, particularly protein kinase C (PKC), and the metabolic and genetic significance of beta3-adrenoceptors (beta3-AR) in adipose tissue. 2. |
| 2532 | 9493493 | Multiple lines of evidence suggest that isoform-selective activation of PKC phosphorylates and down-regulates one or more substrates involved in glucose transport and metabolism (e.g. glycogen synthase and the insulin receptor) and recent studies have shown increased expression of calcium-independent isozymes (PKC-epsilon and PKC-theta) in the membrane fraction of skeletal muscle in fructose- and fat-fed rat models of insulin resistance. |
| 2533 | 9493493 | New pharmacological approaches to NIDDM and obesity have focused on insulin-sensitizing agents (e.g. troglitazone), beta3-AR agonists, anti-lipolytic drugs (e.g. the adenosine A1 receptor agonist GR79236) and selective inhibitors of PKC isoforms (e.g. the inhibitor of PKC-beta LY333531). |
| 2534 | 9496228 | Insulin-specific binding and 95 kDa autophosphorylation of insulin receptor in OLETF rats were not different from those in LETO rats. |
| 2535 | 9496228 | Insulin-induced diacylglycerol (DG) production and Mono Q column-purified protein kinase C (PKC) translocation in adipocytes of OLETF rats were decreased compared with those of LETO rats. |
| 2536 | 9496228 | Insulin-induced PKC beta translocation from cytosol to membrane was also decreased in adipocytes of OLETF rats. |
| 2537 | 9496228 | Analysis of mRNA levels of PKC isoforms in adipocytes of OLETF rats showed decreases of basal level and insulin-induced delayed responses of PKC beta I, beta II, epsilon and zeta mRNA in OLETF rats. |
| 2538 | 9496228 | On the other hand, insulin- or phorbol ester-induced phosphatidylinositol 3-kinase (PI 3-kinase) activation was decreased in adipocytes of OLETF rats compared with those of LETO rats. |
| 2539 | 9507006 | Identification of sirm, a novel insulin-regulated SH3 binding protein that associates with Grb-2 and FYN. |
| 2540 | 9507006 | During studies of gene expression in livers of insulin receptor-deficient mice, we identified a novel cDNA, which we have termed sirm (Son of Insulin Receptor Mutant mice). sirm is largely, albeit not exclusively, expressed in insulin-responsive tissues. |
| 2541 | 9507006 | The product of the sirm gene is a serine/threonine-rich protein with several proline-rich motifs and an NPNY motif, conforming to the consensus sequence recognized by the phosphotyrosine binding domains of insulin receptor substrate and Shc proteins. |
| 2542 | 9507006 | Based on the sequences of the proline-rich domains, we sought to determine whether Sirm binds to the SH3 domains of FYN and Grb-2. |
| 2543 | 9507006 | We demonstrate here that Sirm binds to FYN and Grb-2 in 3T3-L1 adipocytes and that insulin treatment results in the dissociation of the Sirm.FYN and Sirm.Grb-2 complexes. |
| 2544 | 9507006 | Identification of sirm, a novel insulin-regulated SH3 binding protein that associates with Grb-2 and FYN. |
| 2545 | 9507006 | During studies of gene expression in livers of insulin receptor-deficient mice, we identified a novel cDNA, which we have termed sirm (Son of Insulin Receptor Mutant mice). sirm is largely, albeit not exclusively, expressed in insulin-responsive tissues. |
| 2546 | 9507006 | The product of the sirm gene is a serine/threonine-rich protein with several proline-rich motifs and an NPNY motif, conforming to the consensus sequence recognized by the phosphotyrosine binding domains of insulin receptor substrate and Shc proteins. |
| 2547 | 9507006 | Based on the sequences of the proline-rich domains, we sought to determine whether Sirm binds to the SH3 domains of FYN and Grb-2. |
| 2548 | 9507006 | We demonstrate here that Sirm binds to FYN and Grb-2 in 3T3-L1 adipocytes and that insulin treatment results in the dissociation of the Sirm.FYN and Sirm.Grb-2 complexes. |
| 2549 | 9518262 | Overexpression of membrane glycoprotein PC-1 can influence insulin action at a post-receptor site. |
| 2550 | 9518262 | An elevated content of membrane glycoprotein PC-1 has been observed in cells and tissues of insulin resistant patients. |
| 2551 | 9518262 | In addition, in vitro overexpression of PC-1 in cultured cells induces insulin resistance associated with diminished insulin receptor tyrosine kinase activity. |
| 2552 | 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. |
| 2553 | 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). |
| 2554 | 9518262 | In CHO IR PC-1 cells, insulin receptor tyrosine kinase activity was unchanged, following insulin treatment of cells. |
| 2555 | 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. |
| 2556 | 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. |
| 2557 | 9518262 | In these cells, however, insulin stimulation of p70 ribosomal S6 kinase activity was diminished. |
| 2558 | 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. |
| 2559 | 9518262 | Overexpression of membrane glycoprotein PC-1 can influence insulin action at a post-receptor site. |
| 2560 | 9518262 | An elevated content of membrane glycoprotein PC-1 has been observed in cells and tissues of insulin resistant patients. |
| 2561 | 9518262 | In addition, in vitro overexpression of PC-1 in cultured cells induces insulin resistance associated with diminished insulin receptor tyrosine kinase activity. |
| 2562 | 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. |
| 2563 | 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). |
| 2564 | 9518262 | In CHO IR PC-1 cells, insulin receptor tyrosine kinase activity was unchanged, following insulin treatment of cells. |
| 2565 | 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. |
| 2566 | 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. |
| 2567 | 9518262 | In these cells, however, insulin stimulation of p70 ribosomal S6 kinase activity was diminished. |
| 2568 | 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. |
| 2569 | 9518262 | Overexpression of membrane glycoprotein PC-1 can influence insulin action at a post-receptor site. |
| 2570 | 9518262 | An elevated content of membrane glycoprotein PC-1 has been observed in cells and tissues of insulin resistant patients. |
| 2571 | 9518262 | In addition, in vitro overexpression of PC-1 in cultured cells induces insulin resistance associated with diminished insulin receptor tyrosine kinase activity. |
| 2572 | 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. |
| 2573 | 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). |
| 2574 | 9518262 | In CHO IR PC-1 cells, insulin receptor tyrosine kinase activity was unchanged, following insulin treatment of cells. |
| 2575 | 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. |
| 2576 | 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. |
| 2577 | 9518262 | In these cells, however, insulin stimulation of p70 ribosomal S6 kinase activity was diminished. |
| 2578 | 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. |
| 2579 | 9518262 | Overexpression of membrane glycoprotein PC-1 can influence insulin action at a post-receptor site. |
| 2580 | 9518262 | An elevated content of membrane glycoprotein PC-1 has been observed in cells and tissues of insulin resistant patients. |
| 2581 | 9518262 | In addition, in vitro overexpression of PC-1 in cultured cells induces insulin resistance associated with diminished insulin receptor tyrosine kinase activity. |
| 2582 | 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. |
| 2583 | 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). |
| 2584 | 9518262 | In CHO IR PC-1 cells, insulin receptor tyrosine kinase activity was unchanged, following insulin treatment of cells. |
| 2585 | 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. |
| 2586 | 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. |
| 2587 | 9518262 | In these cells, however, insulin stimulation of p70 ribosomal S6 kinase activity was diminished. |
| 2588 | 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. |
| 2589 | 9518262 | Overexpression of membrane glycoprotein PC-1 can influence insulin action at a post-receptor site. |
| 2590 | 9518262 | An elevated content of membrane glycoprotein PC-1 has been observed in cells and tissues of insulin resistant patients. |
| 2591 | 9518262 | In addition, in vitro overexpression of PC-1 in cultured cells induces insulin resistance associated with diminished insulin receptor tyrosine kinase activity. |
| 2592 | 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. |
| 2593 | 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). |
| 2594 | 9518262 | In CHO IR PC-1 cells, insulin receptor tyrosine kinase activity was unchanged, following insulin treatment of cells. |
| 2595 | 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. |
| 2596 | 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. |
| 2597 | 9518262 | In these cells, however, insulin stimulation of p70 ribosomal S6 kinase activity was diminished. |
| 2598 | 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. |
| 2599 | 9518262 | Overexpression of membrane glycoprotein PC-1 can influence insulin action at a post-receptor site. |
| 2600 | 9518262 | An elevated content of membrane glycoprotein PC-1 has been observed in cells and tissues of insulin resistant patients. |
| 2601 | 9518262 | In addition, in vitro overexpression of PC-1 in cultured cells induces insulin resistance associated with diminished insulin receptor tyrosine kinase activity. |
| 2602 | 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. |
| 2603 | 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). |
| 2604 | 9518262 | In CHO IR PC-1 cells, insulin receptor tyrosine kinase activity was unchanged, following insulin treatment of cells. |
| 2605 | 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. |
| 2606 | 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. |
| 2607 | 9518262 | In these cells, however, insulin stimulation of p70 ribosomal S6 kinase activity was diminished. |
| 2608 | 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. |
| 2609 | 9519710 | Possibility of distinct insulin-signaling pathways beyond phosphatidylinositol 3-kinase-mediating glucose transport and lipogenesis. |
| 2610 | 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. |
| 2611 | 9519710 | Englitazone did not increase IR, IRS-1/IRS-2, pp60, or MAPK phosphorylation, nor did it enhance insulin's stimulation of these parameters. |
| 2612 | 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. |
| 2613 | 9565570 | Differential compartmentalization and trafficking of insulin receptor substrate (IRS)-1 and IRS-2. |
| 2614 | 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. |
| 2615 | 9565570 | Insulin stimulation induces rapid tyrosine phosphorylation of both IRS-1 and IRS-2. |
| 2616 | 9565570 | Furthermore, after insulin stimulation, both IRS-1 and IRS-2 translocate from IM to cytosol with a t1/2 of 3.5 min. |
| 2617 | 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. |
| 2618 | 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. |
| 2619 | 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. |
| 2620 | 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. |
| 2621 | 9565570 | Differential compartmentalization and trafficking of insulin receptor substrate (IRS)-1 and IRS-2. |
| 2622 | 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. |
| 2623 | 9565570 | Insulin stimulation induces rapid tyrosine phosphorylation of both IRS-1 and IRS-2. |
| 2624 | 9565570 | Furthermore, after insulin stimulation, both IRS-1 and IRS-2 translocate from IM to cytosol with a t1/2 of 3.5 min. |
| 2625 | 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. |
| 2626 | 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. |
| 2627 | 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. |
| 2628 | 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. |
| 2629 | 9568681 | Tumor necrosis factor-alpha acutely inhibits insulin signaling in human adipocytes: implication of the p80 tumor necrosis factor receptor. |
| 2630 | 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. |
| 2631 | 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. |
| 2632 | 9568681 | Interaction of TNF-alpha with insulin signaling was determined by quantification of insulin receptor substrate (IRS)-1-associated PI 3-kinase activity. |
| 2633 | 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. |
| 2634 | 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. |
| 2635 | 9568681 | The modulation of insulin signaling by TNF-alpha was found to be paralleled by a comparable inhibition of insulin-stimulated glucose transport. |
| 2636 | 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. |
| 2637 | 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. |
| 2638 | 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. |
| 2639 | 9568681 | Tumor necrosis factor-alpha acutely inhibits insulin signaling in human adipocytes: implication of the p80 tumor necrosis factor receptor. |
| 2640 | 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. |
| 2641 | 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. |
| 2642 | 9568681 | Interaction of TNF-alpha with insulin signaling was determined by quantification of insulin receptor substrate (IRS)-1-associated PI 3-kinase activity. |
| 2643 | 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. |
| 2644 | 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. |
| 2645 | 9568681 | The modulation of insulin signaling by TNF-alpha was found to be paralleled by a comparable inhibition of insulin-stimulated glucose transport. |
| 2646 | 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. |
| 2647 | 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. |
| 2648 | 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. |
| 2649 | 9578588 | Vanadyl sulfate-stimulated glycogen synthesis is associated with activation of phosphatidylinositol 3-kinase and is independent of insulin receptor tyrosine phosphorylation. |
| 2650 | 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. |
| 2651 | 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. |
| 2652 | 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. |
| 2653 | 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). |
| 2654 | 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. |
| 2655 | 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. |
| 2656 | 9578588 | Vanadyl sulfate-stimulated glycogen synthesis is associated with activation of phosphatidylinositol 3-kinase and is independent of insulin receptor tyrosine phosphorylation. |
| 2657 | 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. |
| 2658 | 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. |
| 2659 | 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. |
| 2660 | 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). |
| 2661 | 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. |
| 2662 | 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. |
| 2663 | 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. |
| 2664 | 9582514 | A proliferative effect of insulin-like growth factor-I (IGF-I) was previously shown in pancreatic islets. |
| 2665 | 9582514 | However, the mechanism under which IGF-I actions are exerted in insulin-secreting cells is not clear. |
| 2666 | 9582514 | Under basal conditions, IGF-I did not induce insulin release or changes in cytosolic free Ca2+ concentration. |
| 2667 | 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. |
| 2668 | 9582514 | Instead, tyrosine-phosphorylated IRS-2 was detected and stimulated by IGF-I when western blotting was performed using antibody against IRS-2. |
| 2669 | 9582514 | These results indicate that IRS-1 is not likely to be involved in IGF-I signalling in RINm5F cells. |
| 2670 | 9582514 | Hence, IGF-I stimulated DNA synthesis in RINm5F cells was associated with phosphorylation of IGF-I receptors and IRS-2. |
| 2671 | 9593725 | Association of the insulin receptor with phospholipase C-gamma (PLCgamma) in 3T3-L1 adipocytes suggests a role for PLCgamma in metabolic signaling by insulin. |
| 2672 | 9593725 | Phospholipase C-gamma (PLCgamma) is the isozyme of PLC phosphorylated by multiple tyrosine kinases including epidermal growth factor, platelet-derived growth factor, nerve growth factor receptors, and nonreceptor tyrosine kinases. |
| 2673 | 9593725 | To determine the functional significance of the interaction of PLCgamma and the IR, we used a specific inhibitor of PLC, U73122, or microinjection of SH2 domain glutathione S-transferase fusion proteins derived from PLCgamma to block insulin-stimulated GLUT4 translocation. |
| 2674 | 9593725 | U73122 selectively inhibits mitogen-activated protein kinase, leaving the Akt and p70 S6 kinase pathways unperturbed. |
| 2675 | 9609117 | Protein tyrosine phosphatases (PTPs) play a critical role in regulating insulin action in part through dephosphorylation of the active (autophosphorylated) form of the insulin receptor (IRK) and attenuation of its tyrosine kinase activity. |
| 2676 | 9609117 | This process was accompanied by a lowering of blood glucose levels in both normal and diabetic rats thus implicating the IRK-associated PTP(s) as a suitable target for defining a novel class of insulin mimetic agents. |
| 2677 | 9609118 | In cellular and molecular studies, the transmembrane, receptor-type PTPase LAR and the intracellular, non-receptor enzyme PTP1B have been shown to have a direct impact on insulin action in intact cell models. |
| 2678 | 9609118 | Since insulin signalling can be enhanced by reducing the abundance or activity of specific PTPases, pharmaceutical agents directed at blocking the interaction between individual PTPases and the insulin receptor may have potential clinical relevance to the treatment of insulin-resistant states such as obesity and Type II diabetes mellitus. |
| 2679 | 9609127 | Membrane glycoprotein PC-1 and insulin resistance. |
| 2680 | 9609127 | We have isolated an inhibitor of insulin receptor tyrosine kinase activity from cultured fibroblasts of an insulin resistant NIDDM patient and identified it as membrane glycoprotein PC-1. |
| 2681 | 9609127 | Subsequently we have demonstrated that expression of PC-1 is elevated in fibroblasts from other insulin resistant subjects, both with and without NIDDM. |
| 2682 | 9609127 | Studies in muscle, the primary site for insulin-mediated glucose disposal, have shown that the levels of PC-1 in this tissue are inversely correlated to insulin action both in vivo and in vitro. |
| 2683 | 9609127 | Transfection of PC-1 into cultured cells has confirmed that overexpression of PC-1 can produce impairments in insulin receptor tyrosine kinase activity and the subsequent cellular responses to insulin. |
| 2684 | 9609127 | Preliminary data suggests a direct interaction between PC-1 and the insulin receptor. |
| 2685 | 9609127 | However, the mechanisms whereby PC-1 inhibits insulin receptor signaling remain to be determined. |
| 2686 | 9609127 | Membrane glycoprotein PC-1 and insulin resistance. |
| 2687 | 9609127 | We have isolated an inhibitor of insulin receptor tyrosine kinase activity from cultured fibroblasts of an insulin resistant NIDDM patient and identified it as membrane glycoprotein PC-1. |
| 2688 | 9609127 | Subsequently we have demonstrated that expression of PC-1 is elevated in fibroblasts from other insulin resistant subjects, both with and without NIDDM. |
| 2689 | 9609127 | Studies in muscle, the primary site for insulin-mediated glucose disposal, have shown that the levels of PC-1 in this tissue are inversely correlated to insulin action both in vivo and in vitro. |
| 2690 | 9609127 | Transfection of PC-1 into cultured cells has confirmed that overexpression of PC-1 can produce impairments in insulin receptor tyrosine kinase activity and the subsequent cellular responses to insulin. |
| 2691 | 9609127 | Preliminary data suggests a direct interaction between PC-1 and the insulin receptor. |
| 2692 | 9609127 | However, the mechanisms whereby PC-1 inhibits insulin receptor signaling remain to be determined. |
| 2693 | 9609127 | Membrane glycoprotein PC-1 and insulin resistance. |
| 2694 | 9609127 | We have isolated an inhibitor of insulin receptor tyrosine kinase activity from cultured fibroblasts of an insulin resistant NIDDM patient and identified it as membrane glycoprotein PC-1. |
| 2695 | 9609127 | Subsequently we have demonstrated that expression of PC-1 is elevated in fibroblasts from other insulin resistant subjects, both with and without NIDDM. |
| 2696 | 9609127 | Studies in muscle, the primary site for insulin-mediated glucose disposal, have shown that the levels of PC-1 in this tissue are inversely correlated to insulin action both in vivo and in vitro. |
| 2697 | 9609127 | Transfection of PC-1 into cultured cells has confirmed that overexpression of PC-1 can produce impairments in insulin receptor tyrosine kinase activity and the subsequent cellular responses to insulin. |
| 2698 | 9609127 | Preliminary data suggests a direct interaction between PC-1 and the insulin receptor. |
| 2699 | 9609127 | However, the mechanisms whereby PC-1 inhibits insulin receptor signaling remain to be determined. |
| 2700 | 9609127 | Membrane glycoprotein PC-1 and insulin resistance. |
| 2701 | 9609127 | We have isolated an inhibitor of insulin receptor tyrosine kinase activity from cultured fibroblasts of an insulin resistant NIDDM patient and identified it as membrane glycoprotein PC-1. |
| 2702 | 9609127 | Subsequently we have demonstrated that expression of PC-1 is elevated in fibroblasts from other insulin resistant subjects, both with and without NIDDM. |
| 2703 | 9609127 | Studies in muscle, the primary site for insulin-mediated glucose disposal, have shown that the levels of PC-1 in this tissue are inversely correlated to insulin action both in vivo and in vitro. |
| 2704 | 9609127 | Transfection of PC-1 into cultured cells has confirmed that overexpression of PC-1 can produce impairments in insulin receptor tyrosine kinase activity and the subsequent cellular responses to insulin. |
| 2705 | 9609127 | Preliminary data suggests a direct interaction between PC-1 and the insulin receptor. |
| 2706 | 9609127 | However, the mechanisms whereby PC-1 inhibits insulin receptor signaling remain to be determined. |
| 2707 | 9631656 | Two recent papers report that daf-2 encodes a member of the insulin-receptor family and that age-1 encodes a PI3 kinase subunit, a second-messenger producing enzyme known to act downstream of the mammalian insulin receptor. |
| 2708 | 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. |
| 2709 | 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. |
| 2710 | 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. |
| 2711 | 9648831 | Moreover, serum also activated MAP-kinase (erk-1 and erk-2 isoforms) and 70 kD S6 kinase. |
| 2712 | 9648833 | Elevated PC-1 content in cultured skin fibroblasts correlates with decreased in vivo and in vitro insulin action in nondiabetic subjects: evidence that PC-1 may be an intrinsic factor in impaired insulin receptor signaling. |
| 2713 | 9648833 | Membrane glycoprotein PC-1 inhibits insulin receptor (IR) tyrosine kinase activity and subsequent cellular signaling. |
| 2714 | 9648833 | PC-1 content is elevated in muscle and adipose tissue from insulin-resistant subjects, and its elevation correlates with in vivo insulin resistance. |
| 2715 | 9648833 | To determine whether elevated PC-1 content is a primary cause of insulin resistance, we have now measured PC-1 content in cultured skin fibroblasts from nonobese nondiabetic insulin-resistant subjects and found that 1) PC-1 content was significantly higher in these cells when compared with cells from insulin-sensitive subjects (6.7 +/- 0.9 vs. 3.1 +/- 0.6 ng/0.1 mg protein, mean +/- SE, P < 0.01); 2) PC-1 content in fibroblasts was highly correlated with PC-1 content in muscle tissue (r = 0.95, P = 0.01); 3) PC-1 content in fibroblasts negatively correlated with both decreased in vivo insulin sensitivity and decreased in vitro IR autophosphorylation; and 4) in cells from insulin-resistant subjects, insulin stimulation of glycogen synthetase was decreased. |
| 2716 | 9648833 | These studies indicate, therefore, that the elevation of PC-1 content may be a primary factor in the cause of insulin resistance. |
| 2717 | 9648833 | Elevated PC-1 content in cultured skin fibroblasts correlates with decreased in vivo and in vitro insulin action in nondiabetic subjects: evidence that PC-1 may be an intrinsic factor in impaired insulin receptor signaling. |
| 2718 | 9648833 | Membrane glycoprotein PC-1 inhibits insulin receptor (IR) tyrosine kinase activity and subsequent cellular signaling. |
| 2719 | 9648833 | PC-1 content is elevated in muscle and adipose tissue from insulin-resistant subjects, and its elevation correlates with in vivo insulin resistance. |
| 2720 | 9648833 | To determine whether elevated PC-1 content is a primary cause of insulin resistance, we have now measured PC-1 content in cultured skin fibroblasts from nonobese nondiabetic insulin-resistant subjects and found that 1) PC-1 content was significantly higher in these cells when compared with cells from insulin-sensitive subjects (6.7 +/- 0.9 vs. 3.1 +/- 0.6 ng/0.1 mg protein, mean +/- SE, P < 0.01); 2) PC-1 content in fibroblasts was highly correlated with PC-1 content in muscle tissue (r = 0.95, P = 0.01); 3) PC-1 content in fibroblasts negatively correlated with both decreased in vivo insulin sensitivity and decreased in vitro IR autophosphorylation; and 4) in cells from insulin-resistant subjects, insulin stimulation of glycogen synthetase was decreased. |
| 2721 | 9648833 | These studies indicate, therefore, that the elevation of PC-1 content may be a primary factor in the cause of insulin resistance. |
| 2722 | 9651378 | Insulin-like growth factor I (IGF-I)-stimulated pancreatic beta-cell growth is glucose-dependent. |
| 2723 | 9651378 | Synergistic activation of insulin receptor substrate-mediated signal transduction pathways by glucose and IGF-I in INS-1 cells. |
| 2724 | 9651378 | Insulin-like growth factor I (IGF-I)-induced INS-1 cell proliferation was glucose-dependent only in the physiologically relevant concentration range (6-18 mM glucose). |
| 2725 | 9651378 | Glucose metabolism and phosphatidylinositol 3'-kinase (PI 3'-kinase) activation were necessary for both glucose and IGF-I-stimulated INS-1 cell proliferation. |
| 2726 | 9651378 | IGF-I and 15 mM glucose increased tyrosine phosphorylation mediated recruitment of Grb2/mSOS and PI 3'-kinase to IRS-2 and pp60. |
| 2727 | 9651378 | Glucose and IGF-I also induced Shc association with Grb2/mSOS. |
| 2728 | 9651378 | In contrast, p70(S6K) was activated with increasing glucose concentration (between 6 and 18 mM), and potentiated by IGF-I in the same glucose concentration range which correlated with INS-1 cell proliferation rate. |
| 2729 | 9651378 | Thus, glucose and IGF-I-induced beta-cell proliferation were mediated via a signaling mechanism that was facilitated by mitogen-activated protein kinase but dependent on IRS-mediated induction of PI 3'-kinase activity and downstream activation of p70(S6K). |
| 2730 | 9651378 | The glucose dependence of IGF-I mediated INS-1 cell proliferation emphasizes beta-cell signaling mechanisms are rather unique in being tightly linked to glycolytic metabolic flux. |
| 2731 | 9660977 | Exocytosis of insulin promotes insulin gene transcription via the insulin receptor/PI-3 kinase/p70 s6 kinase and CaM kinase pathways. |
| 2732 | 9660977 | We show that secreted insulin acts via beta-cell insulin receptors and up-regulates insulin gene transcription by signaling through the IRS-2/PI-3 kinase/p70 s6k and CaM kinase pathways. |
| 2733 | 9685802 | [Tumor necrosis factor-alpha; a possible pathogenic factor in obesity in insulin resistant and non-insulin-dependent diabetes mellitus?]. |
| 2734 | 9685802 | The role of tumor necrosis factor (TNF)-alpha in the development of insulin resistance has repeatedly been emphasized in the past few years. |
| 2735 | 9685802 | The present paper summarizes the data (including the authors' observations as well) focusing on the potential role of TNF-alpha in the pathogenesis of obesity and non-insulin-dependent diabetes mellitus: alteration of insulin receptor function, lipid metabolism, expression of sulphonylurea receptors, all of them suggested to be related to the TNF-alpha. |
| 2736 | 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. |
| 2737 | 9690058 | No mutations were found in glucokinase, glucagon receptor and mitochondrial genes in any of the 49 probands. |
| 2738 | 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. |
| 2739 | 9703324 | The insulin receptor (IR) is expressed by insulin-secreting beta-cells, but its cellular function is unknown. |
| 2740 | 9704223 | Similar frequencies of HLA-DR2, DR3, and DR4 antigens in healthy pregnant women and women with GDM and low prevalences of markers for autoimmune destruction of the beta-cells in GDM pregnancy rule out the possibility that GDM is a disease of autoimmune origin. |
| 2741 | 9704223 | Insulin receptor binding to target tissues is largely unaffected by normal and GDM pregnancy; the same is true for basal and insulin-stimulated insulin receptor-bound tyrosine kinase activity. |
| 2742 | 9704223 | Hormones that circulate in high concentrations in pregnancy (e.g., progesterone, cortisol, prolactin, human placental lactogen, and estrogen) have all been shown, in animal models, to be able to influence beta-cell function and/or the peripheral tissue sensitivity to insulin, but whether they play similar roles in human pregnancy remains to be investigated. |
| 2743 | 9714125 | Relation between plasma tumor necrosis factor-alpha and insulin sensitivity in elderly men with non-insulin-dependent diabetes mellitus. |
| 2744 | 9714125 | TNF-alpha decreases insulin-dependent glucose uptake by inhibiting autophosphorylation of the insulin receptor, suggesting that TNF-alpha may play a role in insulin resistance. |
| 2745 | 9714125 | In this study, we analyzed plasma levels of TNF-alpha in 40 70-year-old men with newly detected non-insulin-dependent diabetes mellitus and in 20 age-matched controls. |
| 2746 | 9714125 | The plasma levels of TNF-alpha were higher in patients (4.00+/-1.53 pg/mL in moderately insulin resistant and 4.91+/-1.43 pg/mL in severely insulin resistant subjects) than in controls (3.27+/-0.79 pg/mL, P<0.001). |
| 2747 | 9714125 | The finding of an association between high plasma levels of TNF-alpha and several metabolic abnormalities characteristic for the insulin resistance syndrome suggests that TNF-alpha may be involved in the pathogenesis of non-insulin-dependent diabetes mellitus. |
| 2748 | 9753293 | Prolonged oxidative stress impairs insulin-induced GLUT4 translocation in 3T3-L1 adipocytes. |
| 2749 | 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. |
| 2750 | 9753293 | The net effect of insulin on 2-deoxyglucose uptake activity was reduced in oxidized cells and could be attributed to GLUT1 translocation. |
| 2751 | 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. |
| 2752 | 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. |
| 2753 | 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. |
| 2754 | 9762007 | Enzyme studies done in vitro show that the bioactive compound(s) can stimulate autophosphorylation of a truncated form of the insulin receptor and can inhibit PTP-1, a rat homolog of a tyrosine phosphatase (PTP-1B) that inactivates the insulin receptor. |
| 2755 | 9762007 | It is suggested, then, that a cinnamon compound(s), like insulin, affects protein phosphorylation-dephosphorylation reactions in the intact adipocyte. |
| 2756 | 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. |
| 2757 | 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. |
| 2758 | 9774692 | By contrast, insulin stimulated the PI 3-kinase cascade, inhibited apoptosis, and promoted replication of 32DIR cells expressing IRS-1. |
| 2759 | 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. |
| 2760 | 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. |
| 2761 | 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. |
| 2762 | 9774692 | Thus, phosphotyrosine-independent IRS-1-linked pathways may be critical for survival and growth of IL-3-deprived 32D cells during insulin stimulation. |
| 2763 | 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. |
| 2764 | 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. |
| 2765 | 9774692 | By contrast, insulin stimulated the PI 3-kinase cascade, inhibited apoptosis, and promoted replication of 32DIR cells expressing IRS-1. |
| 2766 | 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. |
| 2767 | 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. |
| 2768 | 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. |
| 2769 | 9774692 | Thus, phosphotyrosine-independent IRS-1-linked pathways may be critical for survival and growth of IL-3-deprived 32D cells during insulin stimulation. |
| 2770 | 9798138 | Furthermore, in order to clarify the possible mechanisms leading to the insulin disorders of the syndrome, we review the available data about the insulin receptor abnormalities, as well as those concerning the insulin resistance and the exaggerated insulin secretion. |
| 2771 | 9803467 | TDs act at various levels of glucose and lipid metabolism--ameliorate some defects in the signalling cascade distal to the insulin receptor and improve glucose uptake in insulin-resistant tissues via increased expression of glucose transporters GLUT1 and GLUT4. |
| 2772 | 9803467 | TDs bind to peroxisome proliferator activating receptors gamma (PPAR gamma), members of the steroid/thyroid hormone nuclear receptor superfamily of transcription factors involved in adipocyte differentiation and glucose and lipid homeostasis. |
| 2773 | 9803467 | Activation of PPAR gamma results in the expression of adipocyte-specific genes and differentiation of various cell types in mature adipocytes capable of active glucose uptake and energy storage in the form of lipids. |
| 2774 | 9803467 | These effects are most likely also mediated by stimulation of PPAR gamma. |
| 2775 | 9803467 | In mature adipocytes, PPAR gamma stimulation inhibits stearoyl-CoA desaturase 1 (SCD1) enzyme activity resulting in a change of cell membrane fatty acid composition. |
| 2776 | 9803467 | A key role of TDs effects in vascular remodelling is played by inhibition of the mitogen-activated protein (MAP) kinase pathway. |
| 2777 | 9803467 | A recently reported link between MAP kinase signalling pathway and PPAR gamma |
| 2778 | 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. |
| 2779 | 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. |
| 2780 | 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. |
| 2781 | 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. |
| 2782 | 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. |
| 2783 | 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. |
| 2784 | 9814992 | Gel filtration chromatography, competition of insulin binding, and activation of the insulin receptor kinase activity demonstrated that this mature insulin was functionally identical to that of authentic processed insulin. |
| 2785 | 9829343 | There was no significant difference in insulin receptor tyrosine phosphatase activity between control subjects and diabetic subjects (0.173 +/- 0.062 vs 0.209 - +/- 0.057 autophosphorylated insulin receptors units/insulin receptors units). |
| 2786 | 9843961 | Thiazolidinediones and insulin resistance: peroxisome proliferatoractivated receptor gamma activation stimulates expression of the CAP gene. |
| 2787 | 9843961 | c-Cbl-associated protein (CAP) is a signaling protein that interacts with both c-Cbl and the insulin receptor that may be involved in the specific insulin-stimulated tyrosine phosphorylation of c-Cbl. |
| 2788 | 9843961 | The restricted expression of CAP in cells metabolically sensitive to insulin suggests an important potential role in insulin action. |
| 2789 | 9843961 | The expression of CAP mRNA and proteins are increased in 3T3-L1 adipocytes by the insulin sensitizing thiazolidinedione drugs, which are activators of the peroxisome proliferator-activated receptor gamma (PPARgamma). |
| 2790 | 9843961 | The stimulation of CAP expression by PPARgamma activators results from increased transcription. |
| 2791 | 9843961 | This increased expression of CAP was accompanied by a potentiation of insulin-stimulated c-Cbl tyrosine phosphorylation. |
| 2792 | 9843961 | Thus, CAP is the first PPARgamma-sensitive gene identified that participates in insulin signaling and may play a role in thiazolidinedione-induced insulin sensitization. |
| 2793 | 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). |
| 2794 | 9844354 | Insulin receptors interact at least with three cascade reactions, phosphorylating G proteins and IRS-1, that activate PLC "ras" and PI-3-K. |
| 2795 | 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. |
| 2796 | 9855864 | The insulin receptor gene on chromosome 19p13 and at least five glucose transporter genes contribute to Type 2 diabetes susceptibility, and further associations may emerge from study of the glycogen synthase gene, the glucokinase gene, the MODY genes, and the leptin gene. |
| 2797 | 9862421 | TNF inhibits insulin induced STAT5 activation in differentiated mouse muscle cells pmi28. |
| 2798 | 9862421 | Tumor necrosis factor (TNF) plays a central role in the state of insulin resistance leading to type II diabetes. |
| 2799 | 9862421 | We here describe the crosstalk of TNF with insulin signaling cascades in the mouse muscle cell line pmi28. |
| 2800 | 9862421 | TNF downregulated insulin induced insulin receptor kinase activity and insulin induced activation of the transcription factor STAT5. |
| 2801 | 9862421 | Our results provide evidence that the inhibitory crosstalk between TNF and insulin in skeletal muscle cells comprises an interference with the expression of STAT5 regulated genes which may play an important role in the manifestation and/or progression of insulin resistance in muscle cells. |
| 2802 | 9886967 | DHEA improves glucose uptake via activations of protein kinase C and phosphatidylinositol 3-kinase. |
| 2803 | 9886967 | Pretreatment with DHEA increased insulin-induced 2-[3H]DG uptake without alterations of insulin specific binding and autophosphorylation of insulin receptor. |
| 2804 | 9890920 | A phosphotyrosyl mimetic peptide reverses impairment of insulin-stimulated translocation of GLUT4 caused by overexpression of PTP1B in rat adipose cells. |
| 2805 | 9890920 | Protein tyrosine phosphatases (PTPases) PTP1B and PTPalpha are known to dephosphorylate the insulin receptor and may contribute to insulin resistance in diseases such as diabetes. |
| 2806 | 9890920 | We previously reported that overexpression of PTP1B in rat adipose cells significantly impairs insulin-stimulated translocation of GLUT4 [Chen, H., et al. (1997) J. |
| 2807 | 9890920 | In the present study, we treated adipose cells with a PTPase inhibitor containing the phosphotyrosyl mimetic difluorophosphonomethyl phenylalanine (F2Pmp) to determine whether we could improve the insulin resistance caused by overexpression of PTP1B or PTPalpha. |
| 2808 | 9890920 | Rat adipose cells transfected by electroporation with either PTP1B or PTPalpha were treated without or with the inhibitor, and effects on insulin-stimulated translocation of a cotransfected epitope-tagged GLUT4 were studied. |
| 2809 | 9890920 | The IC50 of the F2Pmp-containing inhibitor is 180 nM for PTP1B and 10 mM for PTPalpha in vitro. |
| 2810 | 9890920 | As expected, in the absence of the inhibitor, overexpression of either PTP1B or PTPalpha caused a significant decrease in the amount of GLUT4 at the cell surface both in the absence and in the presence of insulin when compared with control cells transfected with epitope-tagged GLUT4 alone. |
| 2811 | 9890920 | Interestingly, the insulin resistance caused by overexpression of PTP1B (but not PTPalpha) was reversed by treating the transfected cells with the F2Pmp-containing inhibitor. |
| 2812 | 9890920 | Furthermore, the inhibitor blocked the insulin-stimulated association of PTP1B with the insulin receptor. |
| 2813 | 9890920 | We conclude that the F2Pmp-containing compound is a potent and specific inhibitor of overexpressed PTP1B that may be useful for designing rational therapies for treating insulin resistant diseases such as diabetes. |
| 2814 | 9890920 | A phosphotyrosyl mimetic peptide reverses impairment of insulin-stimulated translocation of GLUT4 caused by overexpression of PTP1B in rat adipose cells. |
| 2815 | 9890920 | Protein tyrosine phosphatases (PTPases) PTP1B and PTPalpha are known to dephosphorylate the insulin receptor and may contribute to insulin resistance in diseases such as diabetes. |
| 2816 | 9890920 | We previously reported that overexpression of PTP1B in rat adipose cells significantly impairs insulin-stimulated translocation of GLUT4 [Chen, H., et al. (1997) J. |
| 2817 | 9890920 | In the present study, we treated adipose cells with a PTPase inhibitor containing the phosphotyrosyl mimetic difluorophosphonomethyl phenylalanine (F2Pmp) to determine whether we could improve the insulin resistance caused by overexpression of PTP1B or PTPalpha. |
| 2818 | 9890920 | Rat adipose cells transfected by electroporation with either PTP1B or PTPalpha were treated without or with the inhibitor, and effects on insulin-stimulated translocation of a cotransfected epitope-tagged GLUT4 were studied. |
| 2819 | 9890920 | The IC50 of the F2Pmp-containing inhibitor is 180 nM for PTP1B and 10 mM for PTPalpha in vitro. |
| 2820 | 9890920 | As expected, in the absence of the inhibitor, overexpression of either PTP1B or PTPalpha caused a significant decrease in the amount of GLUT4 at the cell surface both in the absence and in the presence of insulin when compared with control cells transfected with epitope-tagged GLUT4 alone. |
| 2821 | 9890920 | Interestingly, the insulin resistance caused by overexpression of PTP1B (but not PTPalpha) was reversed by treating the transfected cells with the F2Pmp-containing inhibitor. |
| 2822 | 9890920 | Furthermore, the inhibitor blocked the insulin-stimulated association of PTP1B with the insulin receptor. |
| 2823 | 9890920 | We conclude that the F2Pmp-containing compound is a potent and specific inhibitor of overexpressed PTP1B that may be useful for designing rational therapies for treating insulin resistant diseases such as diabetes. |
| 2824 | 9892238 | Enhanced insulin-stimulated activation of phosphatidylinositol 3-kinase in the liver of high-fat-fed rats. |
| 2825 | 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. |
| 2826 | 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. |
| 2827 | 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. |
| 2828 | 9892238 | The tyrosine phosphorylation levels of IRS-1 and IRS-2 were not significantly altered, however. |
| 2829 | 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. |
| 2830 | 9915838 | Using an in situ electroporation system which permits the introduction of glutathione S-transferase (GST) fusion proteins into cells, we found that c-CrkII bound to p130(cas), but not to paxillin in serum-starved rat-1 fibroblasts overexpressing the human insulin receptor (HIRc cells) in vivo. 17 nM insulin stimulation dissociated the binding of c-CrkII to p130(cas), whereas 13 nM insulin-like growth factor-I, 16 nM epidermal growth factor (EGF), and 10% serum each showed little or no effect. |
| 2831 | 9915838 | Microinjection of either GST-Crk-SH2 or -Crk-(N)SH3 domains, or anti-Crk antibody each inhibited stress fiber formation before and after insulin-like growth factor-I, EGF, and serum stimulation. |
| 2832 | 9915838 | Microinjection of the Crk-inhibitory reagents also inhibited DNA synthesis after insulin-like growth factor-I, EGF, and serum stimulation, but not after insulin. |
| 2833 | 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. |
| 2834 | 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. |
| 2835 | 9932214 | The MAP kinase pathway does not appear to play a significant role in the transmission of the metabolic effects of insulin. |
| 2836 | 9972281 | Insulin-like growth factor-I receptor signal transduction: at the interface between physiology and cell biology. |
| 2837 | 9972281 | The insulin-like growth factor-I receptor (IGF-IR) mediates the biological actions of IGF-I and IGF-II. |
| 2838 | 9972281 | The insulin-receptor substrate (IRS), SHC, GRB2, CRKII and CRKL adaptor proteins have all been implicated in transmitting signals to the nucleus of the cell. |
| 2839 | 9988280 | Increased insulin sensitivity and hypoglycaemia in mice lacking the p85 alpha subunit of phosphoinositide 3-kinase. |
| 2840 | 9988280 | Although a role for phosphoinositide-3-kinase (PI3K) activity in insulin-stimulated glucose transport and glucose transporter isoform 4 (Glut4) translocation has been suggested in vitro, its role in vivo and the molecular link between activation of PI3K and translocation has not yet been elucidated. |
| 2841 | 9988280 | To determine the role of PI3K in glucose homeostasis, we generated mice with a targeted disruption of the gene encoding the p85alpha regulatory subunit of PI3K (Pik3r1; refs 3-5). |
| 2842 | 9988280 | Insulin-stimulated PI3K activity associated with insulin receptor substrates (IRSs) was mediated via full-length p85 alpha in wild-type mice, but via the p50 alpha alternative splicing isoform of the same gene in Pik3r1-/- mice. |
| 2843 | 9988280 | This isoform switch was associated with an increase in insulin-induced generation of phosphatidylinositol(3,4,5)triphosphate (PtdIns(3,4,5)P3) in Pik3r1-/- adipocytes and facilitation of Glut4 translocation from the low-density microsome (LDM) fraction to the plasma membrane (PM). |
| 2844 | 10025399 | These data indicate an important functional role for the insulin receptor in glucose sensing by the pancreatic beta cell and suggest that defects in insulin signaling at the level of the beta cell may contribute to the observed alterations in insulin secretion in type 2 diabetes. |
| 2845 | 10066179 | Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene. |
| 2846 | 10066179 | Protein tyrosine phosphatase-1B (PTP-1B) has been implicated in the negative regulation of insulin signaling. |
| 2847 | 10066179 | Disruption of the mouse homolog of the gene encoding PTP-1B yielded healthy mice that, in the fed state, had blood glucose concentrations that were slightly lower and concentrations of circulating insulin that were one-half those of their PTP-1B+/+ littermates. |
| 2848 | 10066179 | The PTP-1B-/- mice showed increased phosphorylation of the insulin receptor in liver and muscle tissue after insulin injection in comparison to PTP-1B+/+ mice. |
| 2849 | 10066179 | On a high-fat diet, the PTP-1B-/- and PTP-1B+/- mice were resistant to weight gain and remained insulin sensitive, whereas the PTP-1B+/+ mice rapidly gained weight and became insulin resistant. |
| 2850 | 10066179 | These results demonstrate that PTP-1B has a major role in modulating both insulin sensitivity and fuel metabolism, thereby establishing it as a potential therapeutic target in the treatment of type 2 diabetes and obesity. |
| 2851 | 10066387 | Insulin-inducible changes in the relative ratio of PTP1B splice variants. |
| 2852 | 10066387 | The skeletal muscle activity of protein tyrosine phosphates 1B (PTP1B), a modulator of insulin and IGF-1 signaling, is reduced in obese nondiabetic subjects and in subjects with type 2 diabetes in comparison with leaner, nondiabetic controls. |
| 2853 | 10066387 | PTP1B mRNA, like many other signaling molecules, including the insulin receptor, is alternatively spliced. |
| 2854 | 10066387 | Since we have shown that the ratio of the insulin receptor splice variants is modulated by insulin in vitro and is related to insulin levels in vivo, we hypothesized that the relative ratios of the alternatively spliced PTP1B mRNA might also vary in humans in proportion to the degree of hyperinsulinemia. |
| 2855 | 10066387 | Insulin-inducible changes in the relative ratio of PTP1B splice variants. |
| 2856 | 10066387 | The skeletal muscle activity of protein tyrosine phosphates 1B (PTP1B), a modulator of insulin and IGF-1 signaling, is reduced in obese nondiabetic subjects and in subjects with type 2 diabetes in comparison with leaner, nondiabetic controls. |
| 2857 | 10066387 | PTP1B mRNA, like many other signaling molecules, including the insulin receptor, is alternatively spliced. |
| 2858 | 10066387 | Since we have shown that the ratio of the insulin receptor splice variants is modulated by insulin in vitro and is related to insulin levels in vivo, we hypothesized that the relative ratios of the alternatively spliced PTP1B mRNA might also vary in humans in proportion to the degree of hyperinsulinemia. |
| 2859 | 10067653 | However, a naturally-occurring oligopeptide, low-molecular-weight chromium-binding substance (LMWCr), has been found in our laboratory to activate insulin receptor kinase activity up to 7-fold with a dissociation constant of 250 picomolar in the presence of 100 nanomolar insulin, and it has been partially characterized in terms of structural and spectroscopic properties. |
| 2860 | 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. |
| 2861 | 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. |
| 2862 | 10067837 | In diabetic rats, there was 2-fold higher insulin receptor content and insulin-stimulated receptor tyrosine phosphorylation in comparison with control rats. |
| 2863 | 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. |
| 2864 | 10077007 | Action of insulin receptor substrate-3 (IRS-3) and IRS-4 to stimulate translocation of GLUT4 in rat adipose cells. |
| 2865 | 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. |
| 2866 | 10077007 | Nevertheless, as demonstrated in this study, both IRS-3 and IRS-4 can also stimulate translocation of GLUT4. |
| 2867 | 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. |
| 2868 | 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. |
| 2869 | 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). |
| 2870 | 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. |
| 2871 | 10077007 | Action of insulin receptor substrate-3 (IRS-3) and IRS-4 to stimulate translocation of GLUT4 in rat adipose cells. |
| 2872 | 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. |
| 2873 | 10077007 | Nevertheless, as demonstrated in this study, both IRS-3 and IRS-4 can also stimulate translocation of GLUT4. |
| 2874 | 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. |
| 2875 | 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. |
| 2876 | 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). |
| 2877 | 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. |
| 2878 | 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. |
| 2879 | 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. |
| 2880 | 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). |
| 2881 | 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. |
| 2882 | 10098523 | The insulin-sensitive glucose transporter (GLUT4) is involved in early bone growth in control and diabetic mice, but is regulated through the insulin-like growth factor I receptor. |
| 2883 | 10098523 | Using in situ hybridization and immunohistochemistry techniques, we demonstrated the novel existence of the insulin-sensitive glucose transporter (GLUT4), as well as GLUT1, in juvenile-derived murine mandibular condyles and in the humeral growth plate-two models for endochondral bone formation. |
| 2884 | 10098523 | Insulin-like growth factor (IGF) I receptors (IGF-I-R), but not insulin receptors (IR), were shown to have cellular distribution similar to GLUT4, being more abundant in mature chondrocytes. |
| 2885 | 10098523 | Further, in the skeletal growth centers of streptozotocin-induced diabetic mice, GLUT4, IGF-I, and IGF-I and insulin receptor levels, but not GLUT1 were markedly reduced. |
| 2886 | 10098523 | The decrease in GLUT4 and in IGF-I and insulin receptors was associated with severe histological changes in the mandibular condyles and humeral growth plate. |
| 2887 | 10098523 | Insulin therapy restored IR levels to normalcy, whereas IGF-I-R and GLUT4 levels were only partially recovered. |
| 2888 | 10098523 | Further, during early bone growth GLUT4 may be regulated through the IGF-I receptor rather than via the insulin receptor. |
| 2889 | 10098523 | We propose that skeletal growth retardation in type I diabetes may be associated with reduced expression of the GLUT4 and IGF-I receptor in the bone growth center. |
| 2890 | 10098523 | The insulin-sensitive glucose transporter (GLUT4) is involved in early bone growth in control and diabetic mice, but is regulated through the insulin-like growth factor I receptor. |
| 2891 | 10098523 | Using in situ hybridization and immunohistochemistry techniques, we demonstrated the novel existence of the insulin-sensitive glucose transporter (GLUT4), as well as GLUT1, in juvenile-derived murine mandibular condyles and in the humeral growth plate-two models for endochondral bone formation. |
| 2892 | 10098523 | Insulin-like growth factor (IGF) I receptors (IGF-I-R), but not insulin receptors (IR), were shown to have cellular distribution similar to GLUT4, being more abundant in mature chondrocytes. |
| 2893 | 10098523 | Further, in the skeletal growth centers of streptozotocin-induced diabetic mice, GLUT4, IGF-I, and IGF-I and insulin receptor levels, but not GLUT1 were markedly reduced. |
| 2894 | 10098523 | The decrease in GLUT4 and in IGF-I and insulin receptors was associated with severe histological changes in the mandibular condyles and humeral growth plate. |
| 2895 | 10098523 | Insulin therapy restored IR levels to normalcy, whereas IGF-I-R and GLUT4 levels were only partially recovered. |
| 2896 | 10098523 | Further, during early bone growth GLUT4 may be regulated through the IGF-I receptor rather than via the insulin receptor. |
| 2897 | 10098523 | We propose that skeletal growth retardation in type I diabetes may be associated with reduced expression of the GLUT4 and IGF-I receptor in the bone growth center. |
| 2898 | 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. |
| 2899 | 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. |
| 2900 | 10102697 | In addition, STZ-diabetes resulted in decreased IRS-1 and increased IRS-2 protein levels in myocardium. |
| 2901 | 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. |
| 2902 | 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. |
| 2903 | 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. |
| 2904 | 10102697 | In addition, STZ-diabetes resulted in decreased IRS-1 and increased IRS-2 protein levels in myocardium. |
| 2905 | 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. |
| 2906 | 10189226 | Non-insulin-dependent diabetes mellitus developed only after the knock-out of the insulin receptor gene in beta-cells and resulted from the inability of glucose to penetrate into beta-cells and stimulate insulin secretion. |
| 2907 | 10199131 | Until now five genes (HNF-4 alpha, glucokinase, HNF-1 alpha, IPF-1 and HNF-1 beta), whose mutation can result in MODY, insulin and insulin receptor genes, and mitochondria DNA have been reported to be responsible for diabetes. |
| 2908 | 10206484 | Insulin resistance expressed in Psammomys at stages B and C was demonstrated by nonsuppression of the hepatic gluconeogenesis enzyme phosphoenolpyruvate carboxykinase by the endogenous hyperinsulinemia and by the reduced capacity of insulin to activate muscle and liver tyrosine kinase of the insulin receptor. |
| 2909 | 10212828 | We have achieved significant progress in understanding the central role of the insulin receptor in an increasingly complicated web of intracellular signal transduction leading to the ultimate biological actions of insulin on glucose, lipid, and other metabolic pathways. |
| 2910 | 10212829 | Because of the potential role of the transmembrane PTPase LAR in the regulation of insulin signaling, we assessed the effect of 3S-peptide-I on recombinant LAR PTPase activity and in McA-RH7777 rat hepatoma cells overexpressing full-length LAR protein (McA4B/LAR). 3S-peptide-I significantly reduced insulin receptor dephosphorylation by recombinant LAR (p < 0.001) while blocking dephosphorylation of the insulin receptor by approximately 72% in semi-permeabilized McA4B/LAR cells (p < 0.001). |
| 2911 | 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?) |
| 2912 | 10318852 | Membrane-targeted phosphatidylinositol 3-kinase mimics insulin actions and induces a state of cellular insulin resistance. |
| 2913 | 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. |
| 2914 | 10318852 | Interestingly p110(CAAX) did not activate MAP kinase, despite its stimulation of p21(ras). |
| 2915 | 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. |
| 2916 | 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. |
| 2917 | 10319913 | GLUT-4, tumor necrosis factor, essential fatty acids and daf-genes and their role in insulin resistance and non-insulin dependent diabetes mellitus. |
| 2918 | 10319913 | It is now believed that the GLUT-4 receptor, tumor necrosis factor-alpha (TNF-alpha), essential fatty acids (EFAs) and their metabolites and daf-genes have an important role in the development of obesity and non-insulin dependent diabetes mellitus (NIDDM). |
| 2919 | 10319913 | The protein encoded by daf-2 is 35% identical to the human insulin receptor, daf-7 codes a transforming growth factor-beta (TGF-beta) type signal and daf-16 can enhance superoxide dismutase (SOD) expression. |
| 2920 | 10319913 | EFAs and their metabolites can alter the cell membrane fluidity and enhance the expression of GLUT-4 and insulin receptors. |
| 2921 | 10319913 | EFAs can suppress TNF-alpha production and secretion, a mechanism that may have relevance to the role of these fatty acids in the pathogenesis of insulin resistance, obesity and NIDDM. |
| 2922 | 10319913 | Melatonin has anti-oxidant actions similar to daf-16, TGF-beta and SOD. |
| 2923 | 10319913 | Based on this evidence, it is proposed that GLUT-4, TNF-alpha, EFAs, daf-genes, melatonin and leptin interact with each other in ways which may have relevance to the development or abrogation of insulin resistance, obesity, NIDDM, complications due to NIDDM, longevity and ageing. |
| 2924 | 10320052 | Mechanisms of TNF-alpha-induced insulin resistance. |
| 2925 | 10320052 | There is now substantial evidence linking TNF-alpha to the presentation of insulin resistance in humans, animals and in vitro systems. |
| 2926 | 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. |
| 2927 | 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. |
| 2928 | 10320052 | This finding suggests that deletion of TNF-alpha leads to increased insulin sensitivity, ie decreased insulin resistance. |
| 2929 | 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. |
| 2930 | 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. |
| 2931 | 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. |
| 2932 | 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. |
| 2933 | 10320052 | Other possible mediators of TNF-alpha-induced insulin resistance include circulating free fatty acids (FFAs) and leptin. |
| 2934 | 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. |
| 2935 | 10320053 | We found that the insulin-stimulated activation of MAP kinase was defective in obese, insulin-resistant mice. |
| 2936 | 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. |
| 2937 | 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. |
| 2938 | 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. |
| 2939 | 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. |
| 2940 | 10320053 | Such a process could contribute to the defective IRS-1 tyrosine phosphorylation in insulin-resistant animals. |
| 2941 | 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. |
| 2942 | 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. |
| 2943 | 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. |
| 2944 | 10320053 | We found that the insulin-stimulated activation of MAP kinase was defective in obese, insulin-resistant mice. |
| 2945 | 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. |
| 2946 | 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. |
| 2947 | 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. |
| 2948 | 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. |
| 2949 | 10320053 | Such a process could contribute to the defective IRS-1 tyrosine phosphorylation in insulin-resistant animals. |
| 2950 | 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. |
| 2951 | 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. |
| 2952 | 10320054 | Crosstalk between insulin and angiotensin II signalling systems. |
| 2953 | 10320054 | Pharmacological inhibition of the renin-angiotensin system has been found to reduce not only hypertension, but also insulin resistance. |
| 2954 | 10320054 | This raises the possibility that the renin-angiotensin system may interact with insulin signalling. |
| 2955 | 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). |
| 2956 | 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. |
| 2957 | 10320054 | This leads to binding of IRS-1 and IRS-2 to PI3-kinase. |
| 2958 | 10320054 | Moreover, AII inhibits insulin-stimulated IRS-1/IRS-2-associated PI3-kinase activity. |
| 2959 | 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. |
| 2960 | 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. |
| 2961 | 10320054 | Overactivity of the renin-angiotensin system is likely to impair insulin signalling and contribute to insulin resistance observed in essential hypertension. |
| 2962 | 10320054 | Crosstalk between insulin and angiotensin II signalling systems. |
| 2963 | 10320054 | Pharmacological inhibition of the renin-angiotensin system has been found to reduce not only hypertension, but also insulin resistance. |
| 2964 | 10320054 | This raises the possibility that the renin-angiotensin system may interact with insulin signalling. |
| 2965 | 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). |
| 2966 | 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. |
| 2967 | 10320054 | This leads to binding of IRS-1 and IRS-2 to PI3-kinase. |
| 2968 | 10320054 | Moreover, AII inhibits insulin-stimulated IRS-1/IRS-2-associated PI3-kinase activity. |
| 2969 | 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. |
| 2970 | 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. |
| 2971 | 10320054 | Overactivity of the renin-angiotensin system is likely to impair insulin signalling and contribute to insulin resistance observed in essential hypertension. |
| 2972 | 10320380 | The compound was selective for insulin receptor versus insulin-like growth factor I (IGFI) receptor and other receptor tyrosine kinases. |
| 2973 | 10329736 | Interaction of insulin receptor substrate 3 with insulin receptor, insulin receptor-related receptor, insulin-like growth factor-1 receptor, and downstream signaling proteins. |
| 2974 | 10329736 | IRS3 is considerably shorter than IRS1, IRS2, and IRS4, and is predicted to interact with a distinct group of downstream signaling molecules. |
| 2975 | 10329736 | As determined in a modified yeast two-hybrid system, mIRS3 bound strongly to the p85 subunit of phosphatidylinositol 3-kinase. |
| 2976 | 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. |
| 2977 | 10329736 | Insulin stimulation promoted the association of mIRS3 with p85, SHP2, Nck, and Shc. |
| 2978 | 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. |
| 2979 | 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. |
| 2980 | 10331419 | Endothelin-1 modulates insulin signaling through phosphatidylinositol 3-kinase pathway in vascular smooth muscle cells. |
| 2981 | 10331419 | ET-1 increased the level of serine phosphorylation of insulin receptor beta subunit but increased both tyrosine and serine phosphorylation of insulin receptor substrate (IRS)-2. |
| 2982 | 10331419 | Pretreatment of cells with ET-1 (10 nmol/l) inhibited insulin-stimulated PI 3-kinase activity associated with IRS-2 by 50-60% and inhibited the association of p85 subunit of PI 3-kinase to IRS-2. |
| 2983 | 10331419 | The inhibition of insulin-stimulated PI 3-kinase activity by ET-1 was prevented by BQ-123, a selective ET(A) receptor antagonist, but was not affected by pertussis toxin. |
| 2984 | 10331419 | Treatment of cells with phorbol 12-myristate 13-acetate, an activator of protein kinase C (PKC), reduced both insulin-stimulated PI 3-kinase activity by 57% and the association of IRS-2 to the p85 subunit of PI 3-kinase by 40%, whereas GF109203X, a specific inhibitor of PKC, partially prevented the inhibitory effect of ET-1 on insulin-induced PI 3-kinase activity. |
| 2985 | 10331419 | These results suggested that ET-1 could interfere with insulin signaling in SMCs by both PKC-dependent and -independent pathways. |
| 2986 | 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. |
| 2987 | 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. |
| 2988 | 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. |
| 2989 | 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. |
| 2990 | 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. |
| 2991 | 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. |
| 2992 | 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). |
| 2993 | 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. |
| 2994 | 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. |
| 2995 | 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. |
| 2996 | 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. |
| 2997 | 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. |
| 2998 | 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. |
| 2999 | 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. |
| 3000 | 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. |
| 3001 | 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. |
| 3002 | 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. |
| 3003 | 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). |
| 3004 | 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. |
| 3005 | 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. |
| 3006 | 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. |
| 3007 | 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. |
| 3008 | 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. |
| 3009 | 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. |
| 3010 | 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. |
| 3011 | 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. |
| 3012 | 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. |
| 3013 | 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. |
| 3014 | 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). |
| 3015 | 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. |
| 3016 | 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. |
| 3017 | 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. |
| 3018 | 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. |
| 3019 | 10342810 | Insulin receptor-related receptor is expressed in pancreatic beta-cells and stimulates tyrosine phosphorylation of insulin receptor substrate-1 and -2. |
| 3020 | 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. |
| 3021 | 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. |
| 3022 | 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. |
| 3023 | 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. |
| 3024 | 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. |
| 3025 | 10342810 | Insulin receptor-related receptor is expressed in pancreatic beta-cells and stimulates tyrosine phosphorylation of insulin receptor substrate-1 and -2. |
| 3026 | 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. |
| 3027 | 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. |
| 3028 | 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. |
| 3029 | 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. |
| 3030 | 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. |
| 3031 | 10342810 | Insulin receptor-related receptor is expressed in pancreatic beta-cells and stimulates tyrosine phosphorylation of insulin receptor substrate-1 and -2. |
| 3032 | 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. |
| 3033 | 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. |
| 3034 | 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. |
| 3035 | 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. |
| 3036 | 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. |
| 3037 | 10342814 | The mouse ob gene encodes leptin, an adipocyte hormone that regulates body weight and energy expenditure. |
| 3038 | 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. |
| 3039 | 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. |
| 3040 | 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. |
| 3041 | 10342814 | In addition, leptin stimulated hepatic glucose production, which was associated with increased glucose-6-phosphatase activity. |
| 3042 | 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. |
| 3043 | 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. |
| 3044 | 10342815 | Free fatty acid-induced insulin resistance is associated with activation of protein kinase C theta and alterations in the insulin signaling cascade. |
| 3045 | 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). |
| 3046 | 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. |
| 3047 | 10389840 | Thus, we considered it necessary to investigate the effect of PC-1 using highly insulin-sensitive cells. |
| 3048 | 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. |
| 3049 | 10389840 | We found that PC-1 was highly expressed in insulin-responsive tissues, such as liver and adipose tissue, in normal rats. |
| 3050 | 10389840 | Thus, PC-1 expression levels were not associated with high-fat-diet-induced insulin resistance or hyperglycemia. |
| 3051 | 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. |
| 3052 | 10389840 | These results strongly suggest that increased PC-1 expression is not causally related to insulin resistance. |
| 3053 | 10410831 | The authors review the potential roles of some important receptors, such as the insulin receptor, beta 3-adrenergic receptor, leptin receptor and peroxisome proliferator-activated receptor gamma, in the pathogenesis of human type 2 diabetes. |
| 3054 | 10410831 | They emphasize the significance of effective glycemic control by examining the evidence that strongly suggests the association of chronic complications of type 2 diabetes with abnormalities of receptors for the advanced glycation end products, transforming growth factor-beta and platelet-derived growth factor. |
| 3055 | 10417963 | Targeted gene mutations define the roles of insulin and IGF-I receptors in mouse embryonic development. |
| 3056 | 10417963 | Insulin-like growth factors (IGFs) and their receptors regulate embryonic and post-natal growth. |
| 3057 | 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. |
| 3058 | 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. |
| 3059 | 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. |
| 3060 | 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. |
| 3061 | 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. |
| 3062 | 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. |
| 3063 | 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). |
| 3064 | 10426374 | We also demonstrated that glucosamine infusion results in O-linked N-acetylglucosamine modification of IRS-1 and IRS-2. |
| 3065 | 10443650 | Mutations in the insulin receptor gene cause the severe insulin-resistant syndromes leprechaunism and Rabson-Mendenhall syndrome, whose metabolic features include fasting hypoglycemia, post-prandial hyperglycemia, and extremely elevated insulin levels. |
| 3066 | 10444024 | Protein tyrosine phosphatases (PTPs) are required for the dephosphorylation of the insulin receptor (IR) and its initial cellular substrates, and it has recently been reported that PTP-1B may play a role in the pathogenesis of insulin resistance in obesity and type 2 diabetes mellitus (DM). |
| 3067 | 10444024 | These data suggest that the insulin resistance of obesity and DM2 is characterized by the increased expression of a catalytically impaired PTP-1B in adipose tissue and that impaired PTP-1B activity may be pathogenic for insulin resistance in these conditions. |
| 3068 | 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. |
| 3069 | 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. |
| 3070 | 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. |
| 3071 | 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. |
| 3072 | 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. |
| 3073 | 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. |
| 3074 | 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. |
| 3075 | 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. |
| 3076 | 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. |
| 3077 | 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. |
| 3078 | 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. |
| 3079 | 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. |
| 3080 | 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. |
| 3081 | 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. |
| 3082 | 10471495 | Irs-2 coordinates Igf-1 receptor-mediated beta-cell development and peripheral insulin signalling. |
| 3083 | 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. |
| 3084 | 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. |
| 3085 | 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. |
| 3086 | 10471495 | To establish a role for the Igf-1 receptor in beta-cells, we intercrossed mice heterozygous for null alleles of Igf1r and Irs2. |
| 3087 | 10471495 | Our results reveal that Igf-1 receptors promote beta-cell development and survival through the Irs-2 signalling pathway. |
| 3088 | 10471495 | Thus, Irs-2 integrates the effects of insulin in peripheral target tissues with Igf-1 in pancreatic beta-cells to maintain glucose homeostasis. |
| 3089 | 10480624 | A polymorphism (K121Q) of the human glycoprotein PC-1 gene coding region is strongly associated with insulin resistance. |
| 3090 | 10480624 | Plasma cell differentiation antigen (PC-1) glycoprotein inhibits insulin receptor signaling and is associated with insulin resistance. |
| 3091 | 10480624 | We describe here a novel polymorphism in exon 4 of the PC-1 gene (K121Q) and demonstrate that it is strongly associated with insulin resistance in 121 healthy nonobese (BMI <30 kg/m2) nondiabetic (by oral glucose tolerance test [OGTT]) Caucasians from Sicily. |
| 3092 | 10480624 | These results suggest a cause-effect relationship between the Q carrying genotype and the insulin resistance phenotype, and raise the possibility that PC-1 genotyping could identify individuals who are at risk of developing insulin resistance, a condition that predisposes to type 2 diabetes and coronary artery disease. |
| 3093 | 10499882 | Increased activity of membrane glycoprotein PC-1 in the fibroblasts from non-insulin-dependent diabetes mellitus patients with insulin resistance. |
| 3094 | 10499882 | Membrane glycoprotein PC-1 (plasma cell antigen-1), which inhibits insulin receptor tyrosine kinase activity, was isolated from fibroblasts of NIDDM patients. |
| 3095 | 10499882 | Because PC-1 content in skeletal muscle and adipose tissue correlated with whole body insulin sensitivity, PC-1 might play a role in insulin resistance. |
| 3096 | 10499882 | In order to know whether PC-1 activity of fibroblasts is also elevated in Japanese NIDDM patients, and whether PC-1 activity correlates with the parameters of insulin resistance in vivo or not, we measured PC-1 activity of cultured fibroblasts from 17 patients with NIDDM and seven healthy controls. |
| 3097 | 10499882 | PC-1 activity of the patients with insulin resistance (glucose infusion rate < 3.0 mg/kg per min, n = 7) was elevated to 99.9 +/- 31.9 nmol/mg per min, while that of the other patients (n = 4) was 55.3 +/- 7.5 nmol/mg per min (P = 0.003). |
| 3098 | 10499882 | In conclusion, glycoprotein PC-1 activity of dermal fibroblasts is correlated with insulin resistance in patients with NIDDM. |
| 3099 | 10512356 | Calorie restriction increases insulin-stimulated glucose transport in skeletal muscle from IRS-1 knockout mice. |
| 3100 | 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). |
| 3101 | 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). |
| 3102 | 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. |
| 3103 | 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. |
| 3104 | 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. |
| 3105 | 10542046 | Tumour necrosis factor (TNF) and nonesterified fatty acids have been proposed to be crucial factors in the development of the insulin-resistant state. |
| 3106 | 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. |
| 3107 | 10542046 | Rather, TNF increased membrane expression of GLUT1 and glucose transport in these muscle cells. |
| 3108 | 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. |
| 3109 | 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. |
| 3110 | 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. |
| 3111 | 10576523 | Metformin improves insulin sensitivity by increasing insulin-mediated insulin receptor tyrosine kinase activity, which activates post-receptor insulin signalling pathways. |
| 3112 | 10576524 | Although the molecular mechanism(s) of insulin resistance in PCOS is unclear, excessive insulin-independent serine phosphorylation of the beta subunit of the insulin receptor, as reported in some patients with PCOS, has been put forward as a new mechanism for insulin resistance. |
| 3113 | 10594015 | IRS-4 mediates protein kinase B signaling during insulin stimulation without promoting antiapoptosis. |
| 3114 | 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. |
| 3115 | 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)). |
| 3116 | 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. |
| 3117 | 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. |
| 3118 | 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). |
| 3119 | 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. |
| 3120 | 10594015 | Consequently, 32D(IR) cells expressing IRS-4 proliferated slowly during insulin stimulation. |
| 3121 | 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. |
| 3122 | 10594015 | IRS-4 mediates protein kinase B signaling during insulin stimulation without promoting antiapoptosis. |
| 3123 | 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. |
| 3124 | 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)). |
| 3125 | 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. |
| 3126 | 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. |
| 3127 | 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). |
| 3128 | 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. |
| 3129 | 10594015 | Consequently, 32D(IR) cells expressing IRS-4 proliferated slowly during insulin stimulation. |
| 3130 | 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. |
| 3131 | 10615944 | Membrane glycoprotein PC-1 inhibition of insulin receptor function occurs via direct interaction with the receptor alpha-subunit. |
| 3132 | 10615944 | Plasma cell membrane glycoprotein-1 (PC-1) inhibits insulin receptor (IR) tyrosine kinase activity and subsequent cellular signaling. |
| 3133 | 10615944 | PC-1 content is elevated in fibroblasts, muscle, and adipose tissue from insulin-resistant subjects, and its elevation correlates with in vivo insulin resistance. |
| 3134 | 10615944 | These studies also raise the possibility that monoclonal antibodies to PC-1 could be a new treatment for insulin resistance. |
| 3135 | 10615944 | Membrane glycoprotein PC-1 inhibition of insulin receptor function occurs via direct interaction with the receptor alpha-subunit. |
| 3136 | 10615944 | Plasma cell membrane glycoprotein-1 (PC-1) inhibits insulin receptor (IR) tyrosine kinase activity and subsequent cellular signaling. |
| 3137 | 10615944 | PC-1 content is elevated in fibroblasts, muscle, and adipose tissue from insulin-resistant subjects, and its elevation correlates with in vivo insulin resistance. |
| 3138 | 10615944 | These studies also raise the possibility that monoclonal antibodies to PC-1 could be a new treatment for insulin resistance. |
| 3139 | 10619408 | Signalling via receptor tyrosine kinase modulates the expression of the DNA repair enzyme XPD in cultured cells. |
| 3140 | 10619408 | Herein, we evaluate the mechanism(s) that regulate the expression of the DNA repair enzyme XPD. |
| 3141 | 10619408 | CHO cells transfected with the human insulin receptor (CHO/HIRc) showed a threefold increase in the level of XPD mRNA when compared to control CHO/neo cells (P < 0.01). |
| 3142 | 10619408 | The addition of insulin to serum-starved cells led to an increase in XPD mRNA levels in both CHO/neo and CHO/HIRc cells, in a time and dose dependent fashion. |
| 3143 | 10619408 | Insulin acted primarily by inducing XPD transcription. |
| 3144 | 10619408 | Moreover, inhibition of protein synthesis by cyclohexamide induced a marked degradation of XPD mRNA levels in insulin treated cells. |
| 3145 | 10619408 | Site-directed mutagenesis of the tyrosine-kinase domain of the insulin receptor abolished the increase in XPD mRNA resulting from the transfection with wild type insulin receptors (P < 0.001). |
| 3146 | 10619408 | Western blot analysis of cell extracts from CHO/neo and CHO/HIRc cells revealed an increase in XPD counterpart protein was also induced by transfecting cells with the human insulin receptor. |
| 3147 | 10619408 | Signalling via receptor tyrosine kinase modulates the expression of the DNA repair enzyme XPD in cultured cells. |
| 3148 | 10619408 | Herein, we evaluate the mechanism(s) that regulate the expression of the DNA repair enzyme XPD. |
| 3149 | 10619408 | CHO cells transfected with the human insulin receptor (CHO/HIRc) showed a threefold increase in the level of XPD mRNA when compared to control CHO/neo cells (P < 0.01). |
| 3150 | 10619408 | The addition of insulin to serum-starved cells led to an increase in XPD mRNA levels in both CHO/neo and CHO/HIRc cells, in a time and dose dependent fashion. |
| 3151 | 10619408 | Insulin acted primarily by inducing XPD transcription. |
| 3152 | 10619408 | Moreover, inhibition of protein synthesis by cyclohexamide induced a marked degradation of XPD mRNA levels in insulin treated cells. |
| 3153 | 10619408 | Site-directed mutagenesis of the tyrosine-kinase domain of the insulin receptor abolished the increase in XPD mRNA resulting from the transfection with wild type insulin receptors (P < 0.001). |
| 3154 | 10619408 | Western blot analysis of cell extracts from CHO/neo and CHO/HIRc cells revealed an increase in XPD counterpart protein was also induced by transfecting cells with the human insulin receptor. |
| 3155 | 10619408 | Signalling via receptor tyrosine kinase modulates the expression of the DNA repair enzyme XPD in cultured cells. |
| 3156 | 10619408 | Herein, we evaluate the mechanism(s) that regulate the expression of the DNA repair enzyme XPD. |
| 3157 | 10619408 | CHO cells transfected with the human insulin receptor (CHO/HIRc) showed a threefold increase in the level of XPD mRNA when compared to control CHO/neo cells (P < 0.01). |
| 3158 | 10619408 | The addition of insulin to serum-starved cells led to an increase in XPD mRNA levels in both CHO/neo and CHO/HIRc cells, in a time and dose dependent fashion. |
| 3159 | 10619408 | Insulin acted primarily by inducing XPD transcription. |
| 3160 | 10619408 | Moreover, inhibition of protein synthesis by cyclohexamide induced a marked degradation of XPD mRNA levels in insulin treated cells. |
| 3161 | 10619408 | Site-directed mutagenesis of the tyrosine-kinase domain of the insulin receptor abolished the increase in XPD mRNA resulting from the transfection with wild type insulin receptors (P < 0.001). |
| 3162 | 10619408 | Western blot analysis of cell extracts from CHO/neo and CHO/HIRc cells revealed an increase in XPD counterpart protein was also induced by transfecting cells with the human insulin receptor. |
| 3163 | 10640820 | The assignment of the human insulin receptor-related receptor gene (INSRR) to chromosome 1q21-->q23 by the use of radiation hybrid mapping. |
| 3164 | 10642598 | Tissue-specific insulin resistance in mice with mutations in the insulin receptor, IRS-1, and IRS-2. |
| 3165 | 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. |
| 3166 | 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. |
| 3167 | 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. |
| 3168 | 10642598 | In contrast, ir/irs-2(+/-) mice develop severe insulin resistance in liver, mild insulin resistance in skeletal muscle, and modest beta-cell hyperplasia. |
| 3169 | 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. |
| 3170 | 10642598 | Tissue-specific insulin resistance in mice with mutations in the insulin receptor, IRS-1, and IRS-2. |
| 3171 | 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. |
| 3172 | 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. |
| 3173 | 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. |
| 3174 | 10642598 | In contrast, ir/irs-2(+/-) mice develop severe insulin resistance in liver, mild insulin resistance in skeletal muscle, and modest beta-cell hyperplasia. |
| 3175 | 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. |
| 3176 | 10666005 | Accordingly, it was later renamed glucose-dependent insulinotropic polypeptide because its action on insulin release depends upon an increase in circulating levels of glucose. |
| 3177 | 10666005 | The GIP receptor is a G-protein-coupled receptor belonging to the family of secretin/VIP receptors. |
| 3178 | 10666005 | GIP receptor mRNA is widely distributed in peripheral organs, including the pancreas, gut, adipose tissue, heart, adrenal cortex, and brain, suggesting it may have other functions in addition to the ones mentioned above. |
| 3179 | 10666005 | In addition to stimulating insulin release, GIP has been shown to amplify the effect of insulin on target tissues. |
| 3180 | 10666005 | In adipose tissue, GIP has been reported to (1) stimulate fatty acid synthesis, (2) enhance insulin-stimulated incorporation of fatty acids into triglycerides, (3) increase insulin receptor affinity, and (4) increase sensitivity of insulin-stimulated glucose transport. |
| 3181 | 10675357 | Insulin resistance differentially affects the PI 3-kinase- and MAP kinase-mediated signaling in human muscle. |
| 3182 | 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. |
| 3183 | 10675357 | Insulin stimulation of the MAP kinase pathway was normal in obese and diabetic subjects. |
| 3184 | 10675357 | Insulin stimulation of glucose-disposal correlated with association of p85 with IRS-1. |
| 3185 | 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. |
| 3186 | 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. |
| 3187 | 10675357 | Insulin resistance differentially affects the PI 3-kinase- and MAP kinase-mediated signaling in human muscle. |
| 3188 | 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. |
| 3189 | 10675357 | Insulin stimulation of the MAP kinase pathway was normal in obese and diabetic subjects. |
| 3190 | 10675357 | Insulin stimulation of glucose-disposal correlated with association of p85 with IRS-1. |
| 3191 | 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. |
| 3192 | 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. |
| 3193 | 10688912 | Selective interaction between leptin and insulin signaling pathways in a hepatic cell line. |
| 3194 | 10688912 | Leptin is a 16-kDa hormone secreted by adipocytes and plays an important role in control of feeding behavior and energy expenditure. |
| 3195 | 10688912 | In obesity, circulating levels of leptin and insulin are high because of the presence of increased body fat mass and insulin resistance. |
| 3196 | 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. |
| 3197 | 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. |
| 3198 | 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. |
| 3199 | 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. |
| 3200 | 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. |
| 3201 | 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. |
| 3202 | 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. |
| 3203 | 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. |
| 3204 | 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. |
| 3205 | 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. |
| 3206 | 10707547 | Studies of mice with muscle specific-knockout of the insulin receptor demonstrated that although skeletal muscle was insulin resistant, glucose tolerance was near normal at the whole body, indicating the possible importance of liver. beta cell specific disruption of the insulin receptor indicated that primary insulin resistance at the beta cells resulted in a defect of insulin secretion and impaired glucose tolerance. |
| 3207 | 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. |
| 3208 | 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. |
| 3209 | 10707567 | In muscle cells, the number of insulin receptor, the function of glucose transporter 4 and the activity of tyrosine kinase decrease. |
| 3210 | 10707567 | The rink of body fat accumulation and insulin resistance in muscle is thought through free fatty acid and tumor necrosis factor alpha secreted in adipose tissue. |
| 3211 | 10720068 | Insulin receptor (IR) binding, tyrosine kinase activity, IR messenger RNA (mRNA), IR substrate-1 content, GLUT-4, and GLUT-4 mRNA content were all normal in pancreatic cancer patients. |
| 3212 | 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). |
| 3213 | 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. |
| 3214 | 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. |
| 3215 | 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). |
| 3216 | 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. |
| 3217 | 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. |
| 3218 | 10741568 | Because numerous responses to insulin are affected, we undertook studies to determine whether protein tyrosine phosphatases (PTPs) activities are altered in patients with diabetes syndrome. |
| 3219 | 10741568 | We determined the activity of the cytosolic acid PTP in basal and insulin-dependent states. |
| 3220 | 10741568 | Mean basal PTP activities, were found to be significantly higher in diabetics than in normal subjects (type 1 diabetics: 0.36 +/- 0.01 vs 0.28 +/- 0.01 mmol p-nitrophenolate/h per g hemoglobin (Hb), P < 0.001; type 2 diabetics: 0.35 +/- 0.01 vs 0.28 +/- 0.01 mmol p-nitrophenolate/h per g Hb, P < 0.001). |
| 3221 | 10741568 | Insulin, at concentrations above physiological levels (1 mIU/ml), inhibited the PTP activities in erythrocytes from normal subjects (-15 +/- 4.1%, P < 0.01). |
| 3222 | 10741568 | The overall data suggest that erythrocyte acid phosphatase may have a role in the modulation of glycolytic rates through the control of insulin receptor phosphorylation. |
| 3223 | 10744689 | Phosphorylation of PDE3B by phosphatidylinositol 3-kinase associated with the insulin receptor. |
| 3224 | 10744689 | Phosphatidylinositol 3-kinase mediates several actions of insulin including its antilipolytic effect. |
| 3225 | 10744689 | This effect is elicited by the insulin-stimulated serine phosphorylation and activation of cGMP-inhibited phosphodiesterase (PDE3B). |
| 3226 | 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. |
| 3227 | 10744689 | Phosphorylation of PDE3B by phosphatidylinositol 3-kinase associated with the insulin receptor. |
| 3228 | 10744689 | Phosphatidylinositol 3-kinase mediates several actions of insulin including its antilipolytic effect. |
| 3229 | 10744689 | This effect is elicited by the insulin-stimulated serine phosphorylation and activation of cGMP-inhibited phosphodiesterase (PDE3B). |
| 3230 | 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. |
| 3231 | 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. |
| 3232 | 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. |
| 3233 | 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. |
| 3234 | 10744748 | Gab-1 is capable of regulating these biological end points despite the absence of IGF-1 stimulated tyrosine phosphorylation. |
| 3235 | 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. |
| 3236 | 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. |
| 3237 | 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. |
| 3238 | 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. |
| 3239 | 10751417 | Consistent with this, mice in which the PTP1B gene was disrupted exhibit increased insulin sensitivity. |
| 3240 | 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. |
| 3241 | 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. |
| 3242 | 10751417 | Phosphorylation of p42 and p44 MAP kinase (MAPK) was reduced approximately 32%. |
| 3243 | 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. |
| 3244 | 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. |
| 3245 | 10778531 | GLUT-4, tumour necrosis factor, essential fatty acids and daf-genes and their role in glucose homeostasis, insulin resistance, non-insulin dependent diabetes mellitus, and longevity. |
| 3246 | 10778531 | GLUT-4 receptor, tumor necrosis factor-alpha (TNF-alpha), essential fatty acids (EFAs) and their metabolites and daf-genes seem to play an important and essential role in the maintenance of glucose homeostasis, and in the pathobiology of obesity and non-insulin dependent diabetes mellitus (NIDDM). |
| 3247 | 10778531 | Daf-genes encode for proteins which are 35% identical to the human insulin receptor, a transforming growth factor-beta (TGF-beta) type signal and can also enhance the expression of superoxide dismutase (SOD). |
| 3248 | 10778531 | On the other hand, EFAs and their metabolites can increase the cell membrane fluidity and thus, enhance the expression of GLUT-4 and insulin receptors. |
| 3249 | 10778531 | In addition, EFAs can suppress TNF-alpha production and secretion and thus, are capable of reversing insulin resistance. |
| 3250 | 10778531 | Melatonin has anti-oxidant actions similar to daf-16, TGF-beta and SOD. |
| 3251 | 10778531 | Hence, it is likely that there is a close interaction between GLUT-4, TNF-alpha, EFAs, daf-genes, melatonin and leptin that may have relevance to the development of insulin resistance, obesity, NIDDM, complications due to NIDDM, longevity and ageing. |
| 3252 | 10793405 | Only a minority of cases of type 2 diabetes are caused by a single-gene defect, such as maturity-onset diabetes of youth (mutated MODY gene), syndrome of insulin resistance (insulin receptor defect), and maternally inherited diabetes and deafness (mitochondrial gene defect). |
| 3253 | 10802154 | We have previously shown that bradykinin potentiated insulin-induced glucose uptake through GLUT4 translocation in canine adipocytes and skeletal muscles. |
| 3254 | 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. |
| 3255 | 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. |
| 3256 | 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. |
| 3257 | 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. |
| 3258 | 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). |
| 3259 | 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. |
| 3260 | 10802154 | We have previously shown that bradykinin potentiated insulin-induced glucose uptake through GLUT4 translocation in canine adipocytes and skeletal muscles. |
| 3261 | 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. |
| 3262 | 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. |
| 3263 | 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. |
| 3264 | 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. |
| 3265 | 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). |
| 3266 | 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. |
| 3267 | 10802154 | We have previously shown that bradykinin potentiated insulin-induced glucose uptake through GLUT4 translocation in canine adipocytes and skeletal muscles. |
| 3268 | 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. |
| 3269 | 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. |
| 3270 | 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. |
| 3271 | 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. |
| 3272 | 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). |
| 3273 | 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. |
| 3274 | 10802154 | We have previously shown that bradykinin potentiated insulin-induced glucose uptake through GLUT4 translocation in canine adipocytes and skeletal muscles. |
| 3275 | 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. |
| 3276 | 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. |
| 3277 | 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. |
| 3278 | 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. |
| 3279 | 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). |
| 3280 | 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. |
| 3281 | 10802154 | We have previously shown that bradykinin potentiated insulin-induced glucose uptake through GLUT4 translocation in canine adipocytes and skeletal muscles. |
| 3282 | 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. |
| 3283 | 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. |
| 3284 | 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. |
| 3285 | 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. |
| 3286 | 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). |
| 3287 | 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. |
| 3288 | 10829031 | Essential role of insulin receptor substrate-2 in insulin stimulation of Glut4 translocation and glucose uptake in brown adipocytes. |
| 3289 | 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. |
| 3290 | 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. |
| 3291 | 10829031 | In differentiated IRS-2 KO adipocytes, insulin-induced glucose uptake was decreased by 50% compared with their wild type counterparts. |
| 3292 | 10829031 | This was the result of a decrease in insulin-stimulated Glut4 translocation to the plasma membrane. |
| 3293 | 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. |
| 3294 | 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. |
| 3295 | 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. |
| 3296 | 10834933 | Reduced glucose uptake precedes insulin signaling defects in adipocytes from heterozygous GLUT4 knockout mice. |
| 3297 | 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. |
| 3298 | 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. |
| 3299 | 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. |
| 3300 | 10834933 | The expression of GLUT4 protein and the maximal insulin-stimulated glucose transport was 50% decreased in adipocytes from all three groups. |
| 3301 | 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. |
| 3302 | 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. |
| 3303 | 10834933 | Insulin-stimulated, IRS-1-associated PI3 kinase activity was decreased by 20% in N/H and 68% reduced in H/H GLUT4(+/-) adipocytes. |
| 3304 | 10834933 | However, total insulin-stimulated PI3 kinase activity was normal in H/H GLUT4(+/-) adipocytes. |
| 3305 | 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. |
| 3306 | 10842663 | We demonstrate that fatty acids and amino acids inhibit early post-receptor steps in insulin action, including tyrosine phosphorylation of insulin receptor substrate (IRS) proteins and activation of phosphatidylinositol 3-kinase (PI3-kinase), both in vitro and in several in vivo models. |
| 3307 | 10842663 | Similarly, activation of the hexosamine pathway by infusion of glucosamine also reduces insulin-stimulated phosphorylation of IRS proteins, activation of PI3-kinase, and activation of glycogen synthase. |
| 3308 | 10842664 | Role of PC-1 in the etiology of insulin resistance. |
| 3309 | 10842664 | In cultured fibroblasts from an insulin resistant patient with Type 2 diabetes, we first identified membrane glycoprotein PC-1 as an inhibitor of the insulin receptor tyrosine kinase activity. |
| 3310 | 10842664 | PC-1 is overexpressed in fibroblasts from other insulin resistant subjects, both with and without Type 2 diabetes. |
| 3311 | 10842664 | Studies in muscle and fat of insulin resistant subjects two primary tissues for insulin activation, reveal that elevated levels of PC-1 are inversely correlated with decreased insulin action both in vivo and in vitro. |
| 3312 | 10842664 | Transfection and expression of PC-1 in cultured cells demonstrate that overexpression of PC-1 produces impairments in insulin receptor tyrosine kinase activity, and the subsequent cellular responses to insulin. |
| 3313 | 10842664 | These studies indicate, therefore, that PC-1 is a major factor in the etiology of insulin resistance, and is a potential new therapeutic target for anti-diabetic therapy. |
| 3314 | 10842664 | Role of PC-1 in the etiology of insulin resistance. |
| 3315 | 10842664 | In cultured fibroblasts from an insulin resistant patient with Type 2 diabetes, we first identified membrane glycoprotein PC-1 as an inhibitor of the insulin receptor tyrosine kinase activity. |
| 3316 | 10842664 | PC-1 is overexpressed in fibroblasts from other insulin resistant subjects, both with and without Type 2 diabetes. |
| 3317 | 10842664 | Studies in muscle and fat of insulin resistant subjects two primary tissues for insulin activation, reveal that elevated levels of PC-1 are inversely correlated with decreased insulin action both in vivo and in vitro. |
| 3318 | 10842664 | Transfection and expression of PC-1 in cultured cells demonstrate that overexpression of PC-1 produces impairments in insulin receptor tyrosine kinase activity, and the subsequent cellular responses to insulin. |
| 3319 | 10842664 | These studies indicate, therefore, that PC-1 is a major factor in the etiology of insulin resistance, and is a potential new therapeutic target for anti-diabetic therapy. |
| 3320 | 10842668 | The faK mutation is a premature stop codon in the extracellular domain of the leptin receptor, resulting in a natural receptor knockout. |
| 3321 | 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. |
| 3322 | 10842668 | Moxonidine enhanced expression and insulin-stimulated phosphorylation of IRS-1 in skeletal muscle by 74 and 27%, respectively. |
| 3323 | 10844410 | The insulin receptor (IR) in two brothers with a rare syndrome of congenital muscle fiber type disproportion myopathy (CFTDM) associated with diabetes and severe insulin resistance was studied. |
| 3324 | 10844410 | A third brother who inherited both normal alleles has an normal muscle phenotype and insulin sensitivity, suggesting a direct linkage of these IR mutations with the CFTDM phenotype. |
| 3325 | 10866040 | 5-aminoimidazole-4-carboxamide riboside mimics the effects of insulin on the expression of the 2 key gluconeogenic genes PEPCK and glucose-6-phosphatase. |
| 3326 | 10866040 | Insulin regulates the rate of expression of many hepatic genes, including PEPCK, glucose-6-phosphatase (G6Pase), and glucose-6-phosphate dehydrogenase (G6PDHase). |
| 3327 | 10866040 | We demonstrate here that treatment of hepatoma cells with 5-aminoimidazole-4-carboxamide riboside (AICAR), an agent that activates AMP-activated protein kinase (AMPK), mimics the ability of insulin to repress PEPCK gene transcription. |
| 3328 | 10866040 | Several lines of evidence suggest that the insulin-mimetic effects of AICAR are mediated by activation of AMPK. |
| 3329 | 10866040 | Also, insulin does not activate AMPK in H4IIE cells, suggesting that this protein kinase does not link the insulin receptor to the PEPCK and G6Pase gene promoters. |
| 3330 | 10866040 | Instead, AMPK and insulin may lie on distinct pathways that converge at a point upstream of these 2 gene promoters. |
| 3331 | 10866040 | Our results also suggest that activation of AMPK would inhibit hepatic gluconeogenesis in an insulin-independent manner and thus help to reverse the hyperglycemia associated with type 2 diabetes. |
| 3332 | 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. |
| 3333 | 10866039 | Coexpression of HIR with IRS-1, IRS-2, and SHC strongly enhanced tyrosine phosphorylation of these proteins. |
| 3334 | 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. |
| 3335 | 10866053 | In this study, we compared the insulin and IGF-I receptor binding properties and metabolic and mitogenic potencies of insulin aspart (B28Asp human insulin), insulin lispro (B28Lys,B29Pro human insulin), insulin glargine (A21Gly,B31Arg,B32Arg human insulin), insulin detemir (NN304) [B29Lys(epsilon-tetradecanoyl), desB30 human insulin], and reference insulin analogs. |
| 3336 | 10866053 | Mitogenic potencies in general correlated better with IGF-I receptor affinities than with insulin receptor off-rates. |
| 3337 | 10866053 | The 2 rapid-acting insulin analogs aspart and lispro resembled human insulin on all parameters, except for a slightly elevated IGF-I receptor affinity of lispro. |
| 3338 | 10866053 | The combination of the B31B32diArg and A21Gly substitutions provided insulin glargine with a 6- to 8-fold increased IGF-I receptor affinity and mitogenic potency compared with human insulin. |
| 3339 | 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. |
| 3340 | 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). |
| 3341 | 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. |
| 3342 | 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. |
| 3343 | 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. |
| 3344 | 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). |
| 3345 | 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. |
| 3346 | 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. |
| 3347 | 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. |
| 3348 | 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). |
| 3349 | 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. |
| 3350 | 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. |
| 3351 | 10871196 | In contrast, on the genetic background of 129/Sv mice, the same mutation causes severe hyperinsulinemia, suggesting that the 129/Sv strain harbors alleles that interact with the insulin receptor mutation and predispose to insulin resistance. |
| 3352 | 10871198 | Decreased insulin receptor tyrosine kinase activity and plasma cell membrane glycoprotein-1 overexpression in skeletal muscle from obese women with gestational diabetes mellitus (GDM): evidence for increased serine/threonine phosphorylation in pregnancy and GDM. |
| 3353 | 10871198 | The membrane protein plasma cell membrane glycoprotein-1 (PC-1) has been identified as an inhibitor of insulin receptor tyrosine kinase (IRTK) activity. |
| 3354 | 10871198 | We investigated insulin receptor function and PC-1 levels in muscle from three groups of obese subjects: women with GDM, pregnant women with normal glucose tolerance, and nonpregnant control subjects. |
| 3355 | 10871198 | IRTK activity, insulin receptor tyrosine phosphorylation, and protein levels of membrane glycoprotein PC-1 were determined in rectus abdominus muscle biopsies obtained at the time of either elective cesarean section or gynecological surgery. |
| 3356 | 10871198 | Treatment of the insulin receptors with alkaline phosphatase to dephosphorylate serine/threonine residues increased insulin-stimulated IRTK activity significantly in pregnant control and GDM subjects (P < 0.05), but these rates were still lower compared with nonpregnant control subjects (P < 0.05). |
| 3357 | 10871198 | PC-1 content was negatively correlated with insulin receptor phosphorylation (r = -0.55, P < 0.05) and IRTK activity (r = -0.66, P < 0.05). |
| 3358 | 10871198 | These results indicate that pregnant control and GDM subjects had increased PC-1 content and suggest excessive phosphorylation of serine/threonine residues in muscle insulin receptors and that both may contribute to decreased IRTK activity. |
| 3359 | 10871198 | Decreased insulin receptor tyrosine kinase activity and plasma cell membrane glycoprotein-1 overexpression in skeletal muscle from obese women with gestational diabetes mellitus (GDM): evidence for increased serine/threonine phosphorylation in pregnancy and GDM. |
| 3360 | 10871198 | The membrane protein plasma cell membrane glycoprotein-1 (PC-1) has been identified as an inhibitor of insulin receptor tyrosine kinase (IRTK) activity. |
| 3361 | 10871198 | We investigated insulin receptor function and PC-1 levels in muscle from three groups of obese subjects: women with GDM, pregnant women with normal glucose tolerance, and nonpregnant control subjects. |
| 3362 | 10871198 | IRTK activity, insulin receptor tyrosine phosphorylation, and protein levels of membrane glycoprotein PC-1 were determined in rectus abdominus muscle biopsies obtained at the time of either elective cesarean section or gynecological surgery. |
| 3363 | 10871198 | Treatment of the insulin receptors with alkaline phosphatase to dephosphorylate serine/threonine residues increased insulin-stimulated IRTK activity significantly in pregnant control and GDM subjects (P < 0.05), but these rates were still lower compared with nonpregnant control subjects (P < 0.05). |
| 3364 | 10871198 | PC-1 content was negatively correlated with insulin receptor phosphorylation (r = -0.55, P < 0.05) and IRTK activity (r = -0.66, P < 0.05). |
| 3365 | 10871198 | These results indicate that pregnant control and GDM subjects had increased PC-1 content and suggest excessive phosphorylation of serine/threonine residues in muscle insulin receptors and that both may contribute to decreased IRTK activity. |
| 3366 | 10871198 | Decreased insulin receptor tyrosine kinase activity and plasma cell membrane glycoprotein-1 overexpression in skeletal muscle from obese women with gestational diabetes mellitus (GDM): evidence for increased serine/threonine phosphorylation in pregnancy and GDM. |
| 3367 | 10871198 | The membrane protein plasma cell membrane glycoprotein-1 (PC-1) has been identified as an inhibitor of insulin receptor tyrosine kinase (IRTK) activity. |
| 3368 | 10871198 | We investigated insulin receptor function and PC-1 levels in muscle from three groups of obese subjects: women with GDM, pregnant women with normal glucose tolerance, and nonpregnant control subjects. |
| 3369 | 10871198 | IRTK activity, insulin receptor tyrosine phosphorylation, and protein levels of membrane glycoprotein PC-1 were determined in rectus abdominus muscle biopsies obtained at the time of either elective cesarean section or gynecological surgery. |
| 3370 | 10871198 | Treatment of the insulin receptors with alkaline phosphatase to dephosphorylate serine/threonine residues increased insulin-stimulated IRTK activity significantly in pregnant control and GDM subjects (P < 0.05), but these rates were still lower compared with nonpregnant control subjects (P < 0.05). |
| 3371 | 10871198 | PC-1 content was negatively correlated with insulin receptor phosphorylation (r = -0.55, P < 0.05) and IRTK activity (r = -0.66, P < 0.05). |
| 3372 | 10871198 | These results indicate that pregnant control and GDM subjects had increased PC-1 content and suggest excessive phosphorylation of serine/threonine residues in muscle insulin receptors and that both may contribute to decreased IRTK activity. |
| 3373 | 10871198 | Decreased insulin receptor tyrosine kinase activity and plasma cell membrane glycoprotein-1 overexpression in skeletal muscle from obese women with gestational diabetes mellitus (GDM): evidence for increased serine/threonine phosphorylation in pregnancy and GDM. |
| 3374 | 10871198 | The membrane protein plasma cell membrane glycoprotein-1 (PC-1) has been identified as an inhibitor of insulin receptor tyrosine kinase (IRTK) activity. |
| 3375 | 10871198 | We investigated insulin receptor function and PC-1 levels in muscle from three groups of obese subjects: women with GDM, pregnant women with normal glucose tolerance, and nonpregnant control subjects. |
| 3376 | 10871198 | IRTK activity, insulin receptor tyrosine phosphorylation, and protein levels of membrane glycoprotein PC-1 were determined in rectus abdominus muscle biopsies obtained at the time of either elective cesarean section or gynecological surgery. |
| 3377 | 10871198 | Treatment of the insulin receptors with alkaline phosphatase to dephosphorylate serine/threonine residues increased insulin-stimulated IRTK activity significantly in pregnant control and GDM subjects (P < 0.05), but these rates were still lower compared with nonpregnant control subjects (P < 0.05). |
| 3378 | 10871198 | PC-1 content was negatively correlated with insulin receptor phosphorylation (r = -0.55, P < 0.05) and IRTK activity (r = -0.66, P < 0.05). |
| 3379 | 10871198 | These results indicate that pregnant control and GDM subjects had increased PC-1 content and suggest excessive phosphorylation of serine/threonine residues in muscle insulin receptors and that both may contribute to decreased IRTK activity. |
| 3380 | 10871198 | Decreased insulin receptor tyrosine kinase activity and plasma cell membrane glycoprotein-1 overexpression in skeletal muscle from obese women with gestational diabetes mellitus (GDM): evidence for increased serine/threonine phosphorylation in pregnancy and GDM. |
| 3381 | 10871198 | The membrane protein plasma cell membrane glycoprotein-1 (PC-1) has been identified as an inhibitor of insulin receptor tyrosine kinase (IRTK) activity. |
| 3382 | 10871198 | We investigated insulin receptor function and PC-1 levels in muscle from three groups of obese subjects: women with GDM, pregnant women with normal glucose tolerance, and nonpregnant control subjects. |
| 3383 | 10871198 | IRTK activity, insulin receptor tyrosine phosphorylation, and protein levels of membrane glycoprotein PC-1 were determined in rectus abdominus muscle biopsies obtained at the time of either elective cesarean section or gynecological surgery. |
| 3384 | 10871198 | Treatment of the insulin receptors with alkaline phosphatase to dephosphorylate serine/threonine residues increased insulin-stimulated IRTK activity significantly in pregnant control and GDM subjects (P < 0.05), but these rates were still lower compared with nonpregnant control subjects (P < 0.05). |
| 3385 | 10871198 | PC-1 content was negatively correlated with insulin receptor phosphorylation (r = -0.55, P < 0.05) and IRTK activity (r = -0.66, P < 0.05). |
| 3386 | 10871198 | These results indicate that pregnant control and GDM subjects had increased PC-1 content and suggest excessive phosphorylation of serine/threonine residues in muscle insulin receptors and that both may contribute to decreased IRTK activity. |
| 3387 | 10880357 | Skeletal muscle insulin responsiveness was unaffected by GSH depletion, based on normal glucose response to exogenous insulin, 2-deoxyglucose uptake measurements in isolated soleus muscle, and on normal skeletal muscle expression of GLUT4 protein. |
| 3388 | 10880357 | Adipocyte insulin responsiveness in vitro was assessed in 3T3-L1 adipocytes, which displayed decreased insulin-stimulated tyrosine phosphorylation of insulin-receptor-substrate proteins and of the insulin receptor, but exaggerated protein kinase B phosphorylation. |
| 3389 | 10880357 | In conclusion, GSH depletion by BSO results in impaired glucose tolerance, but preserved adipocyte and skeletal muscle insulin responsiveness. |
| 3390 | 10886503 | Differential roles of insulin receptor and insulin-like growth factor-1 receptor in differentiation of murine skin keratinocytes. |
| 3391 | 10886503 | The insulin receptor and the insulin-like growth factor-1 receptor are widely expressed tyrosine kinases that mediate insulin and insulin-like growth factor-1 signaling. |
| 3392 | 10886503 | We have studied the regulation of insulin receptor and insulin-like growth factor-1 receptor in the differentiation of cultured murine keratinocytes. |
| 3393 | 10886503 | Insulin binding to skin keratinocytes, however, increased during calcium-induced differentiation, whereas insulin-like growth factor-1 binding decreased. |
| 3394 | 10886503 | In proliferating keratinocytes both receptors became phosphorylated upon ligand binding, insulin-like growth factor-1 receptor to a greater extent. |
| 3395 | 10886503 | Terminal differentiation resulted in a decrease in insulin receptor autophosphorylation, whereas insulin-like growth factor-1 receptor autophosphorylation was abolished. |
| 3396 | 10886503 | Finally, due to the change in the receptor's activity during keratinocyte differentiation, the role of insulin and insulin-like growth factor-1 in the differentiation process was examined. |
| 3397 | 10886503 | The expected increase in the expression of keratins 1 and 10 during calcium-induced differentiation was facilitated in the presence of insulin, whereas this induction was inhibited in the presence of insulin-like growth factor-1. |
| 3398 | 10886503 | In conclusion, these results demonstrate that insulin and insulin-like growth factor-1 signaling pathways are differentially involved in skin differentiation, suggesting that abnormal insulin signaling, as occurs in diabetes, may lead to skin pathology. |
| 3399 | 10886503 | Differential roles of insulin receptor and insulin-like growth factor-1 receptor in differentiation of murine skin keratinocytes. |
| 3400 | 10886503 | The insulin receptor and the insulin-like growth factor-1 receptor are widely expressed tyrosine kinases that mediate insulin and insulin-like growth factor-1 signaling. |
| 3401 | 10886503 | We have studied the regulation of insulin receptor and insulin-like growth factor-1 receptor in the differentiation of cultured murine keratinocytes. |
| 3402 | 10886503 | Insulin binding to skin keratinocytes, however, increased during calcium-induced differentiation, whereas insulin-like growth factor-1 binding decreased. |
| 3403 | 10886503 | In proliferating keratinocytes both receptors became phosphorylated upon ligand binding, insulin-like growth factor-1 receptor to a greater extent. |
| 3404 | 10886503 | Terminal differentiation resulted in a decrease in insulin receptor autophosphorylation, whereas insulin-like growth factor-1 receptor autophosphorylation was abolished. |
| 3405 | 10886503 | Finally, due to the change in the receptor's activity during keratinocyte differentiation, the role of insulin and insulin-like growth factor-1 in the differentiation process was examined. |
| 3406 | 10886503 | The expected increase in the expression of keratins 1 and 10 during calcium-induced differentiation was facilitated in the presence of insulin, whereas this induction was inhibited in the presence of insulin-like growth factor-1. |
| 3407 | 10886503 | In conclusion, these results demonstrate that insulin and insulin-like growth factor-1 signaling pathways are differentially involved in skin differentiation, suggesting that abnormal insulin signaling, as occurs in diabetes, may lead to skin pathology. |
| 3408 | 10886503 | Differential roles of insulin receptor and insulin-like growth factor-1 receptor in differentiation of murine skin keratinocytes. |
| 3409 | 10886503 | The insulin receptor and the insulin-like growth factor-1 receptor are widely expressed tyrosine kinases that mediate insulin and insulin-like growth factor-1 signaling. |
| 3410 | 10886503 | We have studied the regulation of insulin receptor and insulin-like growth factor-1 receptor in the differentiation of cultured murine keratinocytes. |
| 3411 | 10886503 | Insulin binding to skin keratinocytes, however, increased during calcium-induced differentiation, whereas insulin-like growth factor-1 binding decreased. |
| 3412 | 10886503 | In proliferating keratinocytes both receptors became phosphorylated upon ligand binding, insulin-like growth factor-1 receptor to a greater extent. |
| 3413 | 10886503 | Terminal differentiation resulted in a decrease in insulin receptor autophosphorylation, whereas insulin-like growth factor-1 receptor autophosphorylation was abolished. |
| 3414 | 10886503 | Finally, due to the change in the receptor's activity during keratinocyte differentiation, the role of insulin and insulin-like growth factor-1 in the differentiation process was examined. |
| 3415 | 10886503 | The expected increase in the expression of keratins 1 and 10 during calcium-induced differentiation was facilitated in the presence of insulin, whereas this induction was inhibited in the presence of insulin-like growth factor-1. |
| 3416 | 10886503 | In conclusion, these results demonstrate that insulin and insulin-like growth factor-1 signaling pathways are differentially involved in skin differentiation, suggesting that abnormal insulin signaling, as occurs in diabetes, may lead to skin pathology. |
| 3417 | 10886503 | Differential roles of insulin receptor and insulin-like growth factor-1 receptor in differentiation of murine skin keratinocytes. |
| 3418 | 10886503 | The insulin receptor and the insulin-like growth factor-1 receptor are widely expressed tyrosine kinases that mediate insulin and insulin-like growth factor-1 signaling. |
| 3419 | 10886503 | We have studied the regulation of insulin receptor and insulin-like growth factor-1 receptor in the differentiation of cultured murine keratinocytes. |
| 3420 | 10886503 | Insulin binding to skin keratinocytes, however, increased during calcium-induced differentiation, whereas insulin-like growth factor-1 binding decreased. |
| 3421 | 10886503 | In proliferating keratinocytes both receptors became phosphorylated upon ligand binding, insulin-like growth factor-1 receptor to a greater extent. |
| 3422 | 10886503 | Terminal differentiation resulted in a decrease in insulin receptor autophosphorylation, whereas insulin-like growth factor-1 receptor autophosphorylation was abolished. |
| 3423 | 10886503 | Finally, due to the change in the receptor's activity during keratinocyte differentiation, the role of insulin and insulin-like growth factor-1 in the differentiation process was examined. |
| 3424 | 10886503 | The expected increase in the expression of keratins 1 and 10 during calcium-induced differentiation was facilitated in the presence of insulin, whereas this induction was inhibited in the presence of insulin-like growth factor-1. |
| 3425 | 10886503 | In conclusion, these results demonstrate that insulin and insulin-like growth factor-1 signaling pathways are differentially involved in skin differentiation, suggesting that abnormal insulin signaling, as occurs in diabetes, may lead to skin pathology. |
| 3426 | 10893327 | Glucagon-like peptide-1 improves insulin and proinsulin binding on RINm5F cells and human monocytes. |
| 3427 | 10893327 | The present study tested the hypothesis that GLP-1 may modulate insulin receptor binding. |
| 3428 | 10893327 | In addition, we investigated the effect of GLP-1 on insulin receptor binding on monocytes isolated from type 1 and type 2 diabetes patients and healthy volunteers. |
| 3429 | 10893327 | In RINm5F cells, GLP-1 increased the capacity and affinity of insulin binding in a time- and concentration-dependent manner. |
| 3430 | 10893327 | The GLP-1 receptor agonist exendin-4 showed similar effects, whereas the receptor antagonist exendin-(9---39) amide inhibited the GLP-1-induced increase in insulin receptor binding. |
| 3431 | 10893327 | The GLP-1 effect was potentiated by the adenylyl cyclase activator forskolin and the stable cAMP analog Sp-5, 6-dichloro-1-beta-D-ribofuranosyl-benzimidazole-3', 5'-monophosphorothioate but was antagonized by the intracellular Ca(2+) chelator 1,2-bis(0-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-AM. |
| 3432 | 10893327 | Glucagon, gastric inhibitory peptide (GIP), and GIP-(1---30) did not affect insulin binding. |
| 3433 | 10893327 | In isolated monocytes, 24 h incubation with 100 nM GLP-1 significantly (P<0.05) increased the diminished number of high-capacity/low-affinity insulin binding sites per cell in type 1 diabetics (9,000+/-3,200 vs. 18,500+/-3,600) and in type 2 diabetics (15,700+/-2,100 vs. 28,900+/-1,800) compared with nondiabetic control subjects (25,100+/-2,700 vs. 26,200+/-4,200). |
| 3434 | 10893327 | Diabetologia 39: 421-432, 1996), we further investigated the effect of GLP-1 on proinsulin binding in RINm5F cells and monocytes. |
| 3435 | 10893327 | In both cell types, GLP-1 induced a significant increase in proinsulin binding. |
| 3436 | 10893327 | We conclude that, in RINm5F cells and in isolated human monocytes, GLP-1 specifically increases the number of high-capacity insulin binding sites that may be functional proinsulin receptors. |
| 3437 | 10893327 | Glucagon-like peptide-1 improves insulin and proinsulin binding on RINm5F cells and human monocytes. |
| 3438 | 10893327 | The present study tested the hypothesis that GLP-1 may modulate insulin receptor binding. |
| 3439 | 10893327 | In addition, we investigated the effect of GLP-1 on insulin receptor binding on monocytes isolated from type 1 and type 2 diabetes patients and healthy volunteers. |
| 3440 | 10893327 | In RINm5F cells, GLP-1 increased the capacity and affinity of insulin binding in a time- and concentration-dependent manner. |
| 3441 | 10893327 | The GLP-1 receptor agonist exendin-4 showed similar effects, whereas the receptor antagonist exendin-(9---39) amide inhibited the GLP-1-induced increase in insulin receptor binding. |
| 3442 | 10893327 | The GLP-1 effect was potentiated by the adenylyl cyclase activator forskolin and the stable cAMP analog Sp-5, 6-dichloro-1-beta-D-ribofuranosyl-benzimidazole-3', 5'-monophosphorothioate but was antagonized by the intracellular Ca(2+) chelator 1,2-bis(0-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-AM. |
| 3443 | 10893327 | Glucagon, gastric inhibitory peptide (GIP), and GIP-(1---30) did not affect insulin binding. |
| 3444 | 10893327 | In isolated monocytes, 24 h incubation with 100 nM GLP-1 significantly (P<0.05) increased the diminished number of high-capacity/low-affinity insulin binding sites per cell in type 1 diabetics (9,000+/-3,200 vs. 18,500+/-3,600) and in type 2 diabetics (15,700+/-2,100 vs. 28,900+/-1,800) compared with nondiabetic control subjects (25,100+/-2,700 vs. 26,200+/-4,200). |
| 3445 | 10893327 | Diabetologia 39: 421-432, 1996), we further investigated the effect of GLP-1 on proinsulin binding in RINm5F cells and monocytes. |
| 3446 | 10893327 | In both cell types, GLP-1 induced a significant increase in proinsulin binding. |
| 3447 | 10893327 | We conclude that, in RINm5F cells and in isolated human monocytes, GLP-1 specifically increases the number of high-capacity insulin binding sites that may be functional proinsulin receptors. |
| 3448 | 10893327 | Glucagon-like peptide-1 improves insulin and proinsulin binding on RINm5F cells and human monocytes. |
| 3449 | 10893327 | The present study tested the hypothesis that GLP-1 may modulate insulin receptor binding. |
| 3450 | 10893327 | In addition, we investigated the effect of GLP-1 on insulin receptor binding on monocytes isolated from type 1 and type 2 diabetes patients and healthy volunteers. |
| 3451 | 10893327 | In RINm5F cells, GLP-1 increased the capacity and affinity of insulin binding in a time- and concentration-dependent manner. |
| 3452 | 10893327 | The GLP-1 receptor agonist exendin-4 showed similar effects, whereas the receptor antagonist exendin-(9---39) amide inhibited the GLP-1-induced increase in insulin receptor binding. |
| 3453 | 10893327 | The GLP-1 effect was potentiated by the adenylyl cyclase activator forskolin and the stable cAMP analog Sp-5, 6-dichloro-1-beta-D-ribofuranosyl-benzimidazole-3', 5'-monophosphorothioate but was antagonized by the intracellular Ca(2+) chelator 1,2-bis(0-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-AM. |
| 3454 | 10893327 | Glucagon, gastric inhibitory peptide (GIP), and GIP-(1---30) did not affect insulin binding. |
| 3455 | 10893327 | In isolated monocytes, 24 h incubation with 100 nM GLP-1 significantly (P<0.05) increased the diminished number of high-capacity/low-affinity insulin binding sites per cell in type 1 diabetics (9,000+/-3,200 vs. 18,500+/-3,600) and in type 2 diabetics (15,700+/-2,100 vs. 28,900+/-1,800) compared with nondiabetic control subjects (25,100+/-2,700 vs. 26,200+/-4,200). |
| 3456 | 10893327 | Diabetologia 39: 421-432, 1996), we further investigated the effect of GLP-1 on proinsulin binding in RINm5F cells and monocytes. |
| 3457 | 10893327 | In both cell types, GLP-1 induced a significant increase in proinsulin binding. |
| 3458 | 10893327 | We conclude that, in RINm5F cells and in isolated human monocytes, GLP-1 specifically increases the number of high-capacity insulin binding sites that may be functional proinsulin receptors. |
| 3459 | 10905474 | Secretion of tumor necrosis factor-alpha shows a strong relationship to insulin-stimulated glucose transport in human adipose tissue. |
| 3460 | 10905474 | Some animal models suggest that tumor necrosis factor (TNF)-alpha is a key component in obesity-linked insulin resistance because it inhibits insulin receptor signaling and glucose transport in insulin-sensitive tissues. |
| 3461 | 10905474 | However, in vivo data in humans have given conflicting results regarding the relationship between circulating TNF-alpha levels and insulin sensitivity. |
| 3462 | 10905474 | In the present study, the potential local role of TNF-alpha on insulin action in human subcutaneous adipose tissue was studied in 42 obese women (BMI 39+/-10 kg/m2). |
| 3463 | 10905474 | We found a strong inverse correlation between adipose TNF-alpha secretion and maximum insulin-stimulated glucose transport in adipocytes that was independent of fat cell volume, age, and BMI (P < 0.001, r = 0.58). |
| 3464 | 10905474 | As much as one-third of the variation in insulin-stimulated glucose transport could be accounted for by variations in TNF-alpha secretion. |
| 3465 | 10905474 | Furthermore, subcutaneous adipose tissue of 4 obese women (BMI 40+/-4) incubated with TNF-A for 24 h showed a one-third concentration-dependent inhibition of insulin-stimulated glucose transport (P < 0.01). |
| 3466 | 10905474 | In conclusion, adipose TNF-alpha may be an important specific and local factor in adipose tissue that influences the ability of insulin to stimulate glucose transport in human fat cells, at least in obese women. |
| 3467 | 10905496 | Divergent regulation of Akt1 and Akt2 isoforms in insulin target tissues of obese Zucker rats. |
| 3468 | 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. |
| 3469 | 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. |
| 3470 | 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. |
| 3471 | 10905496 | Insulin-stimulated Akt2 activity decreased 29% in muscle and 37% in liver but increased 24% in adipose tissue. |
| 3472 | 10905496 | Akt2 protein levels were reduced 56% in muscle and 35% in liver of obese rats, but Akt1 expression was unaltered. |
| 3473 | 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. |
| 3474 | 10905496 | In adipose tissue of obese rats, in spite of an 86% reduction in insulin-stimulated PI3K activity, activation of Akt2 was increased. |
| 3475 | 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. |
| 3476 | 10905496 | These findings suggest that PI3K-dependent effects on glucose transport in adipocytes are not mediated primarily by Akt2. |
| 3477 | 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. |
| 3478 | 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. |
| 3479 | 10958681 | Cellular compartmentalization in insulin action: altered signaling by a lipid-modified IRS-1. |
| 3480 | 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. |
| 3481 | 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. |
| 3482 | 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. |
| 3483 | 10958681 | By contrast, IRS-CAAX-expressing cells demonstrated increased signaling by mitogen-activated protein kinase, Akt, and p70(S6) kinase in response to insulin. |
| 3484 | 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. |
| 3485 | 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. |
| 3486 | 10958681 | Cellular compartmentalization in insulin action: altered signaling by a lipid-modified IRS-1. |
| 3487 | 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. |
| 3488 | 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. |
| 3489 | 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. |
| 3490 | 10958681 | By contrast, IRS-CAAX-expressing cells demonstrated increased signaling by mitogen-activated protein kinase, Akt, and p70(S6) kinase in response to insulin. |
| 3491 | 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. |
| 3492 | 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. |
| 3493 | 10959776 | New approaches with mechanisms different from current therapies are being explored, including novel ligands of peroxisome proliferator-activated receptor, glucagon receptor antagonists, dipeptidyl peptidase IV inhibitors, and insulin receptor activators. |
| 3494 | 10963820 | We report a case of chronic hepatitis C presenting insulin-dependent diabetes mellitus (IDDM) associated with various autoantibodies including possible anti-insulin receptor antibody (AIRA) during interferon (IFN) therapy. |
| 3495 | 10963820 | Administration of IFN was stopped and insulin treatment was started, but plasma glucose level was not controlled well. |
| 3496 | 10963820 | It is likely that IFN therapy induced the immunological disturbance and resulted in occurrence of various autoantibodies and IDDM in the patient. |
| 3497 | 10967116 | We recently described the identification of a non-peptidyl fungal metabolite (l-783,281, compound 1), which induced activation of human insulin receptor (IR) tyrosine kinase and mediated insulin-like effects in cells, as well as decreased blood glucose levels in murine models of Type 2 diabetes (Zhang, B., Salituro, G., Szalkowski, D., Li, Z., Zhang, Y., Royo, I., Vilella, D., Diez, M. |
| 3498 | 10967116 | Here we report the characterization of an active analog (compound 2) with enhanced IR kinase activation potency and selectivity over related receptors (insulin-like growth factor I receptor, epidermal growth factor receptor, and platelet-derived growth factor receptor). |
| 3499 | 10969849 | The K121Q variant of the human PC-1 gene is not associated with insulin resistance or type 2 diabetes among Danish Caucasians. |
| 3500 | 10969849 | The human plasma-cell membrane differentiation antigen-1 (PC-1) has been shown to inhibit insulin receptor tyrosine kinase activity. |
| 3501 | 10969849 | Recently, a K121Q polymorphism in the human PC-1 gene was found in a Sicilian population and was shown to be strongly associated with insulin resistance. |
| 3502 | 10969849 | In addition, among the 226 offspring, the variations in serum insulin and serum C-peptide responses measured during an OGTT were not related to the PC-1 genotype. |
| 3503 | 10969849 | In conclusion, the K121Q polymorphism of the human PC-1 gene is not associated with type 2 diabetes or insulin resistance among Danish Caucasians. |
| 3504 | 10973656 | Expression of insulin-receptor substrate-1 and -2 in ovaries from women with insulin resistance and from controls. |
| 3505 | 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. |
| 3506 | 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. |
| 3507 | 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. |
| 3508 | 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. |
| 3509 | 10987675 | Insulin-like growth factor-I and diabetes. |
| 3510 | 10987675 | Although diabetes is a heterogeneous condition, IGF-I has been shown to improve glycaemic control and reduce insulin requirements in both IDDM and NIDDM. |
| 3511 | 10987675 | In IDDM, the therapeutic rationale for IGF-I is as a replacement therapy "topping up" low circulating IGF-I levels. |
| 3512 | 10987675 | At high doses, IGF-I may mimic insulin, but at levels resulting in unacceptable "acromegalic" IGF-I levels and side-effects. |
| 3513 | 10987675 | The most exciting data concerning IGF-I is with a low dose where IGF-I improves insulin sensitivity by an unknown mechanism. |
| 3514 | 10987675 | This may be mediated via the IGF-I receptor, by cross-reactivity with the insulin receptor, or by activation of hybrid receptors. |
| 3515 | 10987675 | Detailed genetic characterization of these syndromes following treatment with IGF-I may also help to characterize the mechanism of action of IGF-I and its interactions with the insulin receptor. |
| 3516 | 10987675 | Insulin-like growth factor-I and diabetes. |
| 3517 | 10987675 | Although diabetes is a heterogeneous condition, IGF-I has been shown to improve glycaemic control and reduce insulin requirements in both IDDM and NIDDM. |
| 3518 | 10987675 | In IDDM, the therapeutic rationale for IGF-I is as a replacement therapy "topping up" low circulating IGF-I levels. |
| 3519 | 10987675 | At high doses, IGF-I may mimic insulin, but at levels resulting in unacceptable "acromegalic" IGF-I levels and side-effects. |
| 3520 | 10987675 | The most exciting data concerning IGF-I is with a low dose where IGF-I improves insulin sensitivity by an unknown mechanism. |
| 3521 | 10987675 | This may be mediated via the IGF-I receptor, by cross-reactivity with the insulin receptor, or by activation of hybrid receptors. |
| 3522 | 10987675 | Detailed genetic characterization of these syndromes following treatment with IGF-I may also help to characterize the mechanism of action of IGF-I and its interactions with the insulin receptor. |
| 3523 | 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. |
| 3524 | 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. |
| 3525 | 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. |
| 3526 | 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. |
| 3527 | 11027274 | The gene for the p85alpha regulatory subunit yields three splicing variants, p85alpha, AS53/p55alpha, and p50alpha. |
| 3528 | 11027274 | To determine if these regulatory subunits differ in their effects on enzyme activity and signal transduction from insulin receptor substrate (IRS) proteins under physiological conditions, we expressed each regulatory subunit in fully differentiated L6 myotubes using adenovirus-mediated gene transfer with or without coexpression of the p110alpha catalytic subunit. |
| 3529 | 11027274 | Insulin stimulation of two kinases downstream from PI-3 kinase, Akt and p70 S6 kinase (p70(S6K)), was decreased in cells expressing p85alpha or AS53 but not in cells expressing p50alpha. |
| 3530 | 11027274 | Similar inhibition of PI 3-kinase, Akt, and p70(S6K) was observed, even when p110alpha was coexpressed with p85alpha or AS53. |
| 3531 | 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. |
| 3532 | 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. |
| 3533 | 11095457 | Hybrid receptors (HRs), insulin receptor (IR)/insulin-like growth factor I receptor (IGF-I-R) heterodimers have been reported increased in skeletal muscle of obese and type 2 diabetic patients and to contribute to the patient insulin resistance. |
| 3534 | 11113178 | Insulin receptor substrate 3 (IRS-3) and IRS-4 impair IRS-1- and IRS-2-mediated signaling. |
| 3535 | 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. |
| 3536 | 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. |
| 3537 | 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. |
| 3538 | 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. |
| 3539 | 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. |
| 3540 | 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. |
| 3541 | 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. |
| 3542 | 11113178 | Insulin receptor substrate 3 (IRS-3) and IRS-4 impair IRS-1- and IRS-2-mediated signaling. |
| 3543 | 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. |
| 3544 | 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. |
| 3545 | 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. |
| 3546 | 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. |
| 3547 | 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. |
| 3548 | 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. |
| 3549 | 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. |
| 3550 | 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. |
| 3551 | 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. |
| 3552 | 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. |
| 3553 | 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. |
| 3554 | 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). |
| 3555 | 11113183 | In conclusion, RSK2 likely plays a major role in feedback inhibition of the ERK pathway in skeletal muscle. |
| 3556 | 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. |
| 3557 | 11113183 | RSK2 knockout mice may be a good animal model for the study of Coffin-Lowry syndrome. |
| 3558 | 11113206 | The most widely distributed members of the family of insulin receptor substrate (IRS) proteins are IRS-1 and IRS-2. |
| 3559 | 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. |
| 3560 | 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. |
| 3561 | 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%). |
| 3562 | 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. |
| 3563 | 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. |
| 3564 | 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. |
| 3565 | 11113206 | Thus, IRS-1 appears to be an important mediator of brown adipocyte maturation. |
| 3566 | 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. |
| 3567 | 11120660 | Diversification of cardiac insulin signaling involves the p85 alpha/beta subunits of phosphatidylinositol 3-kinase. |
| 3568 | 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. |
| 3569 | 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. |
| 3570 | 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. |
| 3571 | 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. |
| 3572 | 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. |
| 3573 | 11120660 | No p85 beta could be detected in GLUT-4-containing vesicles. |
| 3574 | 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. |
| 3575 | 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. |
| 3576 | 11126235 | Molecular mechanisms of insulin resistance and the role of the adipocyte. |
| 3577 | 11126235 | The role of TNFalpha in insulin resistance and other pathologies associated with obesity, have been examined in several experimental systems including obese mice with homozygous null mutations at the TNFalpha or TNF receptor loci. |
| 3578 | 11126235 | Analysis of these animals demonstrated that the genetic absence of TNF signaling in obesity: (i) significantly improves insulin receptor signaling capacity and consequently insulin sensitivity; (ii) prevents brown adipose tissue atrophy and beta3-adrenoreceptor deficiency and improves thermo-adaptive responses, (iii) decreases the elevated PAI-1 and TGFbeta production; and (iv) lowers hyperlipidemia and hyperleptinemia. |
| 3579 | 11147570 | (II) The underlying molecular mechanisms seemed to rely on beta cells on a sulfonylurea receptor protein, SURX, associated with the ATP-sensitive potassium channel (K(ATP)) and different from SUR1 for glibenclamide, and in muscle and adipose cells on: (a) the increased production of diacylglycerol and activation of protein kinase C; (b) the enhanced expression of glucose transporter isoforms; and (c) the insulin receptor-independent activation of the insulin receptor substrate/phosphatidylinositol-3-kinase pathway. |
| 3580 | 11160042 | Activation of the insulin receptor initiates signaling through both the phosphatidylinositol (PI) 3-kinase and the mitogen-activated protein kinase [MAPK, also referred to as extracellular signal-regulated kinases (ERK1/2)] pathways. |
| 3581 | 11160042 | Acute exercise has no effect on the PI3-kinase pathway signaling elements but does activate the MAPK pathway, which may play a role in the adaptation of muscle to exercise. |
| 3582 | 11160042 | It is unknown whether training produces a chronic effect on basal activity or insulin response of the MAPK pathway. |
| 3583 | 11160042 | The present study was undertaken to determine whether exercise training improves the activity of the MAPK pathway or its response to insulin in obese Zucker rats, a well-characterized model of insulin resistance. |
| 3584 | 11160042 | Compared with lean Zucker rats, untrained obese Zucker rats had reduced basal and insulin-stimulated activities of ERK2 and its downstream target p90 ribosomal S6 kinase (RSK2). |
| 3585 | 11160042 | Seven weeks of training significantly increased basal and insulin-stimulated ERK2 and RSK2 activities, as well as insulin stimulation of MAPK kinase activity. |
| 3586 | 11160042 | The training-induced increase in basal ERK2 activity was correlated with the increase in citrate synthase activity. |
| 3587 | 11160042 | Therefore, 7 wk of training increases basal and insulin-stimulated ERK2 activity. |
| 3588 | 11160869 | The sulfonylurea glimepiride regulates intracellular routing of the insulin-receptor complexes through their interaction with specific protein kinase C isoforms. |
| 3589 | 11160869 | Because interaction of insulin receptors with PKC plays an important role in controlling the intracellular sorting of the insulin-receptor complex, we investigated the possibility that the sulfonylurea glimepiride may influence intracellular routing of insulin and its receptor through a mechanism involving PKC, and that changes in these processes may be associated with improved insulin action. |
| 3590 | 11160869 | Using human hepatoma Hep-G2 cells, we found that glimepiride did not affect insulin binding, insulin receptor isoform expression, and insulin-induced receptor internalization. |
| 3591 | 11160869 | By contrast, glimepiride significantly increased intracellular dissociation of the insulin-receptor complex, degradation of insulin, recycling of internalized insulin receptors, release of internalized radioactivity, and prevented insulin-induced receptor down-regulation. |
| 3592 | 11160869 | Results indicate that glimepiride increases intracellular sorting of the insulin-receptor complex toward the degradative route, which is associated with both an increased association of the insulin receptor with PKCs and improved insulin action. |
| 3593 | 11160869 | The sulfonylurea glimepiride regulates intracellular routing of the insulin-receptor complexes through their interaction with specific protein kinase C isoforms. |
| 3594 | 11160869 | Because interaction of insulin receptors with PKC plays an important role in controlling the intracellular sorting of the insulin-receptor complex, we investigated the possibility that the sulfonylurea glimepiride may influence intracellular routing of insulin and its receptor through a mechanism involving PKC, and that changes in these processes may be associated with improved insulin action. |
| 3595 | 11160869 | Using human hepatoma Hep-G2 cells, we found that glimepiride did not affect insulin binding, insulin receptor isoform expression, and insulin-induced receptor internalization. |
| 3596 | 11160869 | By contrast, glimepiride significantly increased intracellular dissociation of the insulin-receptor complex, degradation of insulin, recycling of internalized insulin receptors, release of internalized radioactivity, and prevented insulin-induced receptor down-regulation. |
| 3597 | 11160869 | Results indicate that glimepiride increases intracellular sorting of the insulin-receptor complex toward the degradative route, which is associated with both an increased association of the insulin receptor with PKCs and improved insulin action. |
| 3598 | 11160869 | The sulfonylurea glimepiride regulates intracellular routing of the insulin-receptor complexes through their interaction with specific protein kinase C isoforms. |
| 3599 | 11160869 | Because interaction of insulin receptors with PKC plays an important role in controlling the intracellular sorting of the insulin-receptor complex, we investigated the possibility that the sulfonylurea glimepiride may influence intracellular routing of insulin and its receptor through a mechanism involving PKC, and that changes in these processes may be associated with improved insulin action. |
| 3600 | 11160869 | Using human hepatoma Hep-G2 cells, we found that glimepiride did not affect insulin binding, insulin receptor isoform expression, and insulin-induced receptor internalization. |
| 3601 | 11160869 | By contrast, glimepiride significantly increased intracellular dissociation of the insulin-receptor complex, degradation of insulin, recycling of internalized insulin receptors, release of internalized radioactivity, and prevented insulin-induced receptor down-regulation. |
| 3602 | 11160869 | Results indicate that glimepiride increases intracellular sorting of the insulin-receptor complex toward the degradative route, which is associated with both an increased association of the insulin receptor with PKCs and improved insulin action. |
| 3603 | 11160869 | The sulfonylurea glimepiride regulates intracellular routing of the insulin-receptor complexes through their interaction with specific protein kinase C isoforms. |
| 3604 | 11160869 | Because interaction of insulin receptors with PKC plays an important role in controlling the intracellular sorting of the insulin-receptor complex, we investigated the possibility that the sulfonylurea glimepiride may influence intracellular routing of insulin and its receptor through a mechanism involving PKC, and that changes in these processes may be associated with improved insulin action. |
| 3605 | 11160869 | Using human hepatoma Hep-G2 cells, we found that glimepiride did not affect insulin binding, insulin receptor isoform expression, and insulin-induced receptor internalization. |
| 3606 | 11160869 | By contrast, glimepiride significantly increased intracellular dissociation of the insulin-receptor complex, degradation of insulin, recycling of internalized insulin receptors, release of internalized radioactivity, and prevented insulin-induced receptor down-regulation. |
| 3607 | 11160869 | Results indicate that glimepiride increases intracellular sorting of the insulin-receptor complex toward the degradative route, which is associated with both an increased association of the insulin receptor with PKCs and improved insulin action. |
| 3608 | 11160869 | The sulfonylurea glimepiride regulates intracellular routing of the insulin-receptor complexes through their interaction with specific protein kinase C isoforms. |
| 3609 | 11160869 | Because interaction of insulin receptors with PKC plays an important role in controlling the intracellular sorting of the insulin-receptor complex, we investigated the possibility that the sulfonylurea glimepiride may influence intracellular routing of insulin and its receptor through a mechanism involving PKC, and that changes in these processes may be associated with improved insulin action. |
| 3610 | 11160869 | Using human hepatoma Hep-G2 cells, we found that glimepiride did not affect insulin binding, insulin receptor isoform expression, and insulin-induced receptor internalization. |
| 3611 | 11160869 | By contrast, glimepiride significantly increased intracellular dissociation of the insulin-receptor complex, degradation of insulin, recycling of internalized insulin receptors, release of internalized radioactivity, and prevented insulin-induced receptor down-regulation. |
| 3612 | 11160869 | Results indicate that glimepiride increases intracellular sorting of the insulin-receptor complex toward the degradative route, which is associated with both an increased association of the insulin receptor with PKCs and improved insulin action. |
| 3613 | 11163213 | Molecular basis for the dephosphorylation of the activation segment of the insulin receptor by protein tyrosine phosphatase 1B. |
| 3614 | 11163213 | The protein tyrosine phosphatase PTP1B is responsible for negatively regulating insulin signaling by dephosphorylating the phosphotyrosine residues of the insulin receptor kinase (IRK) activation segment. |
| 3615 | 11163213 | Molecular basis for the dephosphorylation of the activation segment of the insulin receptor by protein tyrosine phosphatase 1B. |
| 3616 | 11163213 | The protein tyrosine phosphatase PTP1B is responsible for negatively regulating insulin signaling by dephosphorylating the phosphotyrosine residues of the insulin receptor kinase (IRK) activation segment. |
| 3617 | 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. |
| 3618 | 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. |
| 3619 | 11171610 | The aim of this study was to investigate the possibility that this deterioration of glucose tolerance is associated with changes in adipocyte insulin action. |
| 3620 | 11171610 | These changes in insulin action were not related to altered expression of insulin receptors or insulin receptor tyrosine phosphorylation; however, they were associated with reduced phosphatidylinositol 3-kinase and protein kinase B activation. |
| 3621 | 11171610 | These results demonstrate that reduced glucose tolerance observed in late adult life after early growth restriction is associated with adipocyte insulin resistance. |
| 3622 | 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. |
| 3623 | 11212327 | In recent years, a number of cross-talk systems have been identified which feed into the insulin signalling cascade at the level of insulin receptor substrate (IRS) tyrosine phosphorylation, e.g., receptor and non-receptor tyrosine kinases and G-protein-coupled receptors. |
| 3624 | 11212327 | At the molecular level, a number of negative modulator and feedback systems somehow interacting with the beta-subunit (catecholamine-, phorbolester-, or tumor necrosis factor-alpha-induced serine/threonine phosphorylation, carboxy-terminal trimming by a thiol-dependent protease, association of inhibitory/regulatory proteins such as RAD, PC1, PED, alpha2-HS-glycoprotein) have been identified as candidate mechanisms for the impairment of insulin receptor function by elevations in the activity and/or amount of the corresponding modification enzymes/inhibitors. |
| 3625 | 11212327 | Both decreased responsiveness and sensitivity of the insulin receptor beta-subunit for insulin-induced tyrosine autophosphorylation have been demonstrated in several cellular and animal models of metabolic insulin resistance as well as in the adipose tissue and skeletal muscle of diabetic patients and obese Pima Indians compared to non-obese subjects. |
| 3626 | 11212327 | In recent years, a number of cross-talk systems have been identified which feed into the insulin signalling cascade at the level of insulin receptor substrate (IRS) tyrosine phosphorylation, e.g., receptor and non-receptor tyrosine kinases and G-protein-coupled receptors. |
| 3627 | 11212327 | At the molecular level, a number of negative modulator and feedback systems somehow interacting with the beta-subunit (catecholamine-, phorbolester-, or tumor necrosis factor-alpha-induced serine/threonine phosphorylation, carboxy-terminal trimming by a thiol-dependent protease, association of inhibitory/regulatory proteins such as RAD, PC1, PED, alpha2-HS-glycoprotein) have been identified as candidate mechanisms for the impairment of insulin receptor function by elevations in the activity and/or amount of the corresponding modification enzymes/inhibitors. |
| 3628 | 11212327 | Both decreased responsiveness and sensitivity of the insulin receptor beta-subunit for insulin-induced tyrosine autophosphorylation have been demonstrated in several cellular and animal models of metabolic insulin resistance as well as in the adipose tissue and skeletal muscle of diabetic patients and obese Pima Indians compared to non-obese subjects. |
| 3629 | 11212327 | In recent years, a number of cross-talk systems have been identified which feed into the insulin signalling cascade at the level of insulin receptor substrate (IRS) tyrosine phosphorylation, e.g., receptor and non-receptor tyrosine kinases and G-protein-coupled receptors. |
| 3630 | 11212327 | At the molecular level, a number of negative modulator and feedback systems somehow interacting with the beta-subunit (catecholamine-, phorbolester-, or tumor necrosis factor-alpha-induced serine/threonine phosphorylation, carboxy-terminal trimming by a thiol-dependent protease, association of inhibitory/regulatory proteins such as RAD, PC1, PED, alpha2-HS-glycoprotein) have been identified as candidate mechanisms for the impairment of insulin receptor function by elevations in the activity and/or amount of the corresponding modification enzymes/inhibitors. |
| 3631 | 11212327 | Both decreased responsiveness and sensitivity of the insulin receptor beta-subunit for insulin-induced tyrosine autophosphorylation have been demonstrated in several cellular and animal models of metabolic insulin resistance as well as in the adipose tissue and skeletal muscle of diabetic patients and obese Pima Indians compared to non-obese subjects. |
| 3632 | 11223878 | We review this evidence, and speculate on how PI-3 kinase-independent and -dependent signaling pathways both diverge from the insulin receptor and converge at discrete targets to insure the specificity of insulin action. |
| 3633 | 11237210 | Ras activation of the Raf kinase: tyrosine kinase recruitment of the MAP kinase cascade. |
| 3634 | 11237210 | Nevertheless, based on the hypothesis that insulin-stimulated Ser/Thr phosphorylation reflected the activation of protein (Ser/Thr) kinases downstream of the insulin receptor, we sought to detect and purify these putative, insulin-responsive protein (Ser/Thr) kinases. |
| 3635 | 11237210 | The first of these insulin-activated protein kinase networks to be fully elucidated was the Ras-Raf-mitogen-activated protein kinase (MAPK) cascade. |
| 3636 | 11237210 | This chapter will summarize briefly the way in which work from this and other laboratories on insulin signaling led to the discovery of the mammalian MAP kinase cascade and, in turn, to the identification of unique role of the Raf kinases in RTK activation of this protein (Ser/Thr) kinase cascade. |
| 3637 | 11237218 | The explanations for tissue-specific and signaling pathway-specific differences in insulin action in PCOS are unknown but may involve differential roles of insulin receptor substrate (IRS)-1 and IRS-2 in insulin signal transduction. |
| 3638 | 11238471 | A generally accepted paradigm is that insulin receptors, acting through insulin receptor substrates, stimulate the lipid kinase activity of phosphatidylinositol 3-kinase. |
| 3639 | 11238471 | Among the latter, Akt (a product of the akt protooncogene) and atypical protein kinase C isoforms are thought to be involved in insulin regulation of glucose transport and oxidation; glycogen, lipid, and protein synthesis; and modulation of gene expression. |
| 3640 | 11238471 | Moreover, there exists substantial evidence for insulin receptor substrate- and/or phosphatidylinositol 3-kinase-independent pathways of insulin action. |
| 3641 | 11238471 | A generally accepted paradigm is that insulin receptors, acting through insulin receptor substrates, stimulate the lipid kinase activity of phosphatidylinositol 3-kinase. |
| 3642 | 11238471 | Among the latter, Akt (a product of the akt protooncogene) and atypical protein kinase C isoforms are thought to be involved in insulin regulation of glucose transport and oxidation; glycogen, lipid, and protein synthesis; and modulation of gene expression. |
| 3643 | 11238471 | Moreover, there exists substantial evidence for insulin receptor substrate- and/or phosphatidylinositol 3-kinase-independent pathways of insulin action. |
| 3644 | 11246877 | Interestingly, despite the presence of insulin resistance, high salt-fed rats showed enhanced insulin-induced tyrosine phosphorylation of insulin receptor substrate (IRS)-1, IRS-2 (liver and muscle), and IRS-3 (liver only). |
| 3645 | 11246877 | Insulin-induced phosphorylation of Ser-473 of Akt and Ser-21 of glycogen synthase kinase-3 also increased 2.9- and 2-fold, respectively, in the liver of the high salt-fed rats. |
| 3646 | 11246877 | The following can be concluded: 1) a high-salt diet may be a factor promoting insulin resistance, 2) the insulin-signaling step impaired by high salt intake is likely to be downstream from PI 3-kinase or Akt activation, and 3) this unique insulin resistance mechanism may contribute to the development of diabetes in patients with hypertension. |
| 3647 | 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. |
| 3648 | 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. |
| 3649 | 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. |
| 3650 | 11272176 | Insulin receptor substrate (IRS) proteins mediate a variety of the metabolic and growth-promoting actions of insulin and IGF-1. |
| 3651 | 11272176 | After phosphorylation by activated receptors, these intracellular signaling molecules recruit various downstream effector pathways including phosphatidylinositol 3-kinase and Grb2. |
| 3652 | 11272176 | Ablation of the IRS-2 gene produces a diabetic phenotype; mice lacking IRS-2 display peripheral insulin resistance and beta-cell dysfunction characterized by a 50% reduction in beta-cell mass. |
| 3653 | 11287365 | Inhibitory effect of hyperglycemia on insulin-induced Akt/protein kinase B activation in skeletal muscle. |
| 3654 | 11287365 | Similarly, insulin-induced phosphorylation and activation of Akt/protein kinase B (PKB) and GLUT-4 translocation were severely impaired. |
| 3655 | 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. |
| 3656 | 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. |
| 3657 | 11287365 | In addition, the enhanced PI 3-kinase activation and phosphorylation of IR and IRS-1 and -2 were reduced to normal levels. |
| 3658 | 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. |
| 3659 | 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). |
| 3660 | 11289049 | When overexpressed, the membrane glycoprotein PC-1 may play a role in human insulin resistance through the inhibition of insulin receptor (IR) autophosphorylation. |
| 3661 | 11289049 | A PC-1 variant (K121Q, with lysine 121 replaced by glutamine) is also associated with whole-body insulin resistance when not overexpressed. |
| 3662 | 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. |
| 3663 | 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. |
| 3664 | 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. |
| 3665 | 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). |
| 3666 | 11289049 | When overexpressed, the membrane glycoprotein PC-1 may play a role in human insulin resistance through the inhibition of insulin receptor (IR) autophosphorylation. |
| 3667 | 11289049 | A PC-1 variant (K121Q, with lysine 121 replaced by glutamine) is also associated with whole-body insulin resistance when not overexpressed. |
| 3668 | 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. |
| 3669 | 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. |
| 3670 | 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. |
| 3671 | 11334410 | Altered nephrogenesis due to maternal diabetes is associated with increased expression of IGF-II/mannose-6-phosphate receptor in the fetal kidney. |
| 3672 | 11334410 | It has also been shown that both IGF-I and IGF-II are produced within developing metanephros and promote renal organogenesis. |
| 3673 | 11334410 | IGF-II was produced throughout fetal nephrogenesis, whereas IGF-I protein was not detected, suggesting a critical role of IGF-II in kidney development. |
| 3674 | 11334410 | Similarly, the amounts of IGF-I receptor and insulin receptor were not altered. |
| 3675 | 11334410 | By contrast, there was an increase in production of IGF-II/mannose-6-phosphate receptor throughout nephrogenesis. |
| 3676 | 11334412 | Pioglitazone ameliorates tumor necrosis factor-alpha-induced insulin resistance by a mechanism independent of adipogenic activity of peroxisome proliferator--activated receptor-gamma. |
| 3677 | 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. |
| 3678 | 11334412 | The insulin resistance induced by TNF-alpha is antagonized by thiazolidinediones (TZDs), a new class of insulin-sensitizing drugs. |
| 3679 | 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. |
| 3680 | 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. |
| 3681 | 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. |
| 3682 | 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. |
| 3683 | 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. |
| 3684 | 11334415 | Liver-specific igf-1 gene deletion leads to muscle insulin insensitivity. |
| 3685 | 11334415 | Insulin and insulin-like growth factors (IGFs) mediate a variety of signals involved in mammalian development and metabolism. |
| 3686 | 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. |
| 3687 | 11334415 | In contrast, IGF-I-induced autophosphorylation of its cognate receptor and phosphorylation of IRS-1 were normal in muscle of LID mice. |
| 3688 | 11334415 | Recombinant human IGF-I treatment of the LID mice caused a reduction in insulin levels and an increase in insulin sensitivity. |
| 3689 | 11334415 | These data provide evidence of the role of circulating IGF-I as an important component of overall insulin action in peripheral tissues. |
| 3690 | 11368237 | Insulin-stimulated tyrosine kinase activity in gastrocnemius muscle was higher in the db/db genotype, and insulin receptor concentration was not altered. |
| 3691 | 11375323 | Protein kinase C (PKC)-alpha activation inhibits PKC-zeta and mediates the action of PED/PEA-15 on glucose transport in the L6 skeletal muscle cells. |
| 3692 | 11375323 | Overexpression of the PED/PEA-15 protein in muscle and adipose cells increases glucose transport and impairs further insulin induction. |
| 3693 | 11375323 | Like glucose transport, protein kinase C (PKC)-alpha and -beta are also constitutively activated and are not further stimulatable by insulin in L6 skeletal muscle cells overexpressing PED (L6(PED)). |
| 3694 | 11375323 | PKC-zeta features no basal change but completely loses insulin sensitivity in L6(PED). |
| 3695 | 11375323 | Blockage of PKC-alpha and -beta also restores insulin activation of PKC-zeta in L6(PED) cells, with that of PKC-alpha sixfold more effective than PKC-beta. |
| 3696 | 11375323 | In L6(WT), fivefold overexpression of PKC-alpha or -beta increases basal 2-DG uptake and impairs further insulin induction with no effect on insulin receptor or insulin receptor substrate phosphorylation. |
| 3697 | 11375323 | In these cells, overexpression of PKC-alpha blocks insulin induction of PKC-zeta activity. |
| 3698 | 11375323 | PKC-beta is 10-fold less effective than PKC-alpha in inhibiting PKC-zeta stimulation. |
| 3699 | 11375323 | Expression of the dominant-negative K(281)-->W PKC-zeta mutant simultaneously inhibits insulin activation of PKC-zeta and 2-DG uptake in the L6(WT) cells. |
| 3700 | 11375323 | We conclude that activation of classic PKCs, mainly PKC-alpha, inhibits PKC-zeta and may mediate the action of PED on glucose uptake in L6 skeletal muscle cells. |
| 3701 | 11375339 | The HIV protease inhibitor indinavir impairs sterol regulatory element-binding protein-1 intranuclear localization, inhibits preadipocyte differentiation, and induces insulin resistance. |
| 3702 | 11375339 | Protease inhibitors used in the treatment of HIV infection have been causally associated with lipodystrophy and insulin resistance and were shown to alter adipocyte differentiation in cultured cells. |
| 3703 | 11375339 | However, adipose conversion was inhibited by indinavir (by 50-60%), as shown by 1) the decrease in the number of newly formed adipocytes; 2) the lower level of the adipogenic protein markers, sterol regulatory element-binding protein-1 (SREBP-1), peroxisome proliferator-activated receptor-gamma (PPAR-gamma), and the insulin receptor (IR); and 3) the lack of SREBP-1 and PPAR-gamma immunoreactivity in the nucleus of most indinavir-treated cells. |
| 3704 | 11375339 | Defective expression and nuclear localization of PPAR-gamma probably resulted from the decreased level of nuclear SREBP-1. |
| 3705 | 11375344 | Recently, HPI therapy has been linked to the development of a metabolic syndrome in which adipocyte insulin resistance appears to play a major role. |
| 3706 | 11375344 | Impaired insulin stimulation of glucose up take occurred at nelfinavir concentrations >10 micromol/l (EC(50) = 20 micromol/l) and could be attributed to impaired GLUT4 translocation. |
| 3707 | 11375344 | Potential underlying mechanisms for these metabolic effects included both impaired insulin stimulation of protein kinase B Ser 473 phosphorylation with preserved insulin receptor substrate tyrosine phosphorylation and decreased expression of the lipolysis regulator perilipin. |
| 3708 | 11375344 | This study demonstrates that nelfinavir induces insulin resistance and activates basal lipolysis in differentiated 3T3-L1 adipocytes, providing potential cellular mechanisms that may contribute to altered adipocyte metabolism in treated HIV patients. |
| 3709 | 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. |
| 3710 | 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. |
| 3711 | 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. |
| 3712 | 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%. |
| 3713 | 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. |
| 3714 | 11375348 | The antilipolytic effect of insulin in IRS-1 null adipocytes, however, was comparable to that in wild-type mice. |
| 3715 | 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. |
| 3716 | 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. |
| 3717 | 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. |
| 3718 | 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. |
| 3719 | 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%. |
| 3720 | 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. |
| 3721 | 11375348 | The antilipolytic effect of insulin in IRS-1 null adipocytes, however, was comparable to that in wild-type mice. |
| 3722 | 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. |
| 3723 | 11401301 | PTP1B has been implicated in the negative regulation of the insulin signaling pathway by dephosphorylating the activated insulin receptor. |
| 3724 | 11401301 | Both a binding and kinetic assay was then performed in the same 96-well plate with the inhibition results determined for the PTP1B(C215S) (binding assay) and CD45 (activity assay). |
| 3725 | 11404218 | Numerous studies have shown a correlation between changes in protein kinase C (PKC) distribution and/or activity and insulin resistance in skeletal muscle. |
| 3726 | 11404218 | Muscles preincubated for 1 h with 1 microM phorbol 12,13-dibutyrate (PDBu) showed an impaired ability of insulin to stimulate glucose incorporation into glycogen and a translocation of PKC-alpha, -betaI, -theta, and -epsilon, and probably -betaII, from the cytosol to membranes. |
| 3727 | 11404218 | Preincubation with 1 microM PDBu decreased activation of the insulin receptor tyrosine kinase by insulin and to an even greater extent the phosphorylation of Akt/protein kinase B and glycogen synthase kinase-3. |
| 3728 | 11404500 | Temporary reversal by topotecan of marked insulin resistance in a patient with myelodysplastic syndrome: case report and possible mechanism for tumor necrosis factor alpha (TNF-alpha)-induced insulin resistance. |
| 3729 | 11404500 | 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. |
| 3730 | 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. |
| 3731 | 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. |
| 3732 | 11423472 | Transcriptional regulation of plasminogen activator inhibitor type 1 gene by insulin: insights into the signaling pathway. |
| 3733 | 11423472 | Impairment of the fibrinolytic system, caused primarily by increases in the plasma levels of plasminogen activator inhibitor (PAI) type 1, are frequently found in diabetes and the insulin-resistance syndrome. |
| 3734 | 11423472 | Among the factors responsible for the increases of PAI-1, insulin has recently attracted attention. |
| 3735 | 11423472 | In this study, we analyzed the effects of insulin on PAI-1 biosynthesis in HepG2 cells, paying particular attention to the signaling network evoked by this hormone. |
| 3736 | 11423472 | Experiments performed in CHO cells overexpressing the insulin receptor indicate that insulin increases PAI-1 gene transcription through interaction with its receptor. |
| 3737 | 11423472 | By using inhibitors of the different signaling pathways evoked by insulin-receptor binding, it has been shown that the biosynthesis of PAI-1 is due to phosphatidylinositol (PI) 3-kinase activation, followed by protein kinase C and ultimately by mitogen-activated protein (MAP) kinase activation and extracellular signal-regulated kinase 2 phosphorylation. |
| 3738 | 11423472 | Transfection of HepG2 cells with several truncations of the PAI-1 promoter coupled to a CAT gene allowed us to recognize two major response elements located in the regions between -804 and -708 and between -211 and -54. |
| 3739 | 11423472 | Electrophoretic mobility shift assay identified three binding sites for insulin-induced factors, all colocalized with putative Sp1 binding sites. |
| 3740 | 11423472 | Using supershifting antibodies, the binding of Sp1 could only be confirmed at the binding site located just upstream from the transcription start site of the PAI-1 promoter. |
| 3741 | 11423472 | A construct comprising four tandem repeat copies of the -93/-62 region of the PAI-1 promoter linked to CAT was transcriptionally activated in HepG2 cells by insulin. |
| 3742 | 11423472 | These results outline the central role of MAP kinase activation in the regulation of PAI-1 induced by insulin. |
| 3743 | 11423472 | Transcriptional regulation of plasminogen activator inhibitor type 1 gene by insulin: insights into the signaling pathway. |
| 3744 | 11423472 | Impairment of the fibrinolytic system, caused primarily by increases in the plasma levels of plasminogen activator inhibitor (PAI) type 1, are frequently found in diabetes and the insulin-resistance syndrome. |
| 3745 | 11423472 | Among the factors responsible for the increases of PAI-1, insulin has recently attracted attention. |
| 3746 | 11423472 | In this study, we analyzed the effects of insulin on PAI-1 biosynthesis in HepG2 cells, paying particular attention to the signaling network evoked by this hormone. |
| 3747 | 11423472 | Experiments performed in CHO cells overexpressing the insulin receptor indicate that insulin increases PAI-1 gene transcription through interaction with its receptor. |
| 3748 | 11423472 | By using inhibitors of the different signaling pathways evoked by insulin-receptor binding, it has been shown that the biosynthesis of PAI-1 is due to phosphatidylinositol (PI) 3-kinase activation, followed by protein kinase C and ultimately by mitogen-activated protein (MAP) kinase activation and extracellular signal-regulated kinase 2 phosphorylation. |
| 3749 | 11423472 | Transfection of HepG2 cells with several truncations of the PAI-1 promoter coupled to a CAT gene allowed us to recognize two major response elements located in the regions between -804 and -708 and between -211 and -54. |
| 3750 | 11423472 | Electrophoretic mobility shift assay identified three binding sites for insulin-induced factors, all colocalized with putative Sp1 binding sites. |
| 3751 | 11423472 | Using supershifting antibodies, the binding of Sp1 could only be confirmed at the binding site located just upstream from the transcription start site of the PAI-1 promoter. |
| 3752 | 11423472 | A construct comprising four tandem repeat copies of the -93/-62 region of the PAI-1 promoter linked to CAT was transcriptionally activated in HepG2 cells by insulin. |
| 3753 | 11423472 | These results outline the central role of MAP kinase activation in the regulation of PAI-1 induced by insulin. |
| 3754 | 11440359 | Activation of DAG-sensitive PKC isoforms, such as PKC-theta and PKC-epsilon, down-regulates insulin receptor signalling and could be an important biochemical mechanism linking dysregulated lipid metabolism and insulin resistance in muscle. |
| 3755 | 11440359 | On the other hand, atypical PKC isozymes, such as PKC-zeta and PKC-lambda, have been identified as downstream targets of PI-3-kinase involved in insulin-stimulated glucose uptake, especially in adipocytes. |
| 3756 | 11440359 | Glucose-induced de novo synthesis of (palmitate-rich) DAG and sustained isozyme-selective PKC activation (especially but not exclusively PKC-beta) has been strongly implicated in the pathogenesis of diabetic microangiopathy and macroangiopathy through a host of undesirable effects on endothelial function, VSM contractility and growth, angiogenesis, gene transcription (in part by MAP-kinase activation) and vascular permeability. |
| 3757 | 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). |
| 3758 | 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. |
| 3759 | 11443207 | The inverse relationships between plasma insulin and insulin-like growth factor-binding protein-1 levels were maintained, suggesting persistent hepatic effects of insulin. |
| 3760 | 11443207 | Thus, the differences between congenital insulin deficiency vs. insulin receptor deficiency in humans may be explained by persistent insulinomimetic activity of the grossly elevated plasma insulin presumably being mediated through the type 1 insulin-like growth factor receptor. |
| 3761 | 11463381 | Selective insulin signaling through A and B insulin receptors regulates transcription of insulin and glucokinase genes in pancreatic beta cells. |
| 3762 | 11463381 | We show here that insulin activates the transcription of its own gene and that of the beta cell glucokinase gene (betaGK) by different mechanisms. |
| 3763 | 11463381 | Whereas insulin gene transcription is promoted by signaling through insulin receptor A type (Ex11-), PI3K class Ia, and p70s6k, insulin stimulates the betaGK gene by signaling via insulin receptor B type (Ex11+), PI3K class II-like activity, and PKB (c-Akt). |
| 3764 | 11463381 | Our data provide evidence for selectivity in insulin action via the two isoforms of the insulin receptor, the molecular basis being preferential signaling through different PI3K and protein kinases. |
| 3765 | 11463381 | Selective insulin signaling through A and B insulin receptors regulates transcription of insulin and glucokinase genes in pancreatic beta cells. |
| 3766 | 11463381 | We show here that insulin activates the transcription of its own gene and that of the beta cell glucokinase gene (betaGK) by different mechanisms. |
| 3767 | 11463381 | Whereas insulin gene transcription is promoted by signaling through insulin receptor A type (Ex11-), PI3K class Ia, and p70s6k, insulin stimulates the betaGK gene by signaling via insulin receptor B type (Ex11+), PI3K class II-like activity, and PKB (c-Akt). |
| 3768 | 11463381 | Our data provide evidence for selectivity in insulin action via the two isoforms of the insulin receptor, the molecular basis being preferential signaling through different PI3K and protein kinases. |
| 3769 | 11463843 | Preserved pancreatic beta-cell development and function in mice lacking the insulin receptor-related receptor. |
| 3770 | 11463843 | The insulin receptor-related receptor (IRR) is an orphan receptor of the insulin receptor gene (Ir) subfamily. |
| 3771 | 11463843 | It is expressed at considerably higher levels in beta cells than either insulin or IGF-1 receptors, and it has been shown to engage in heterodimer formation with insulin or IGF-1 receptors. |
| 3772 | 11463843 | To address whether IRR plays a physiologic role in beta-cell development and regulation of insulin secretion, we have characterized mice lacking IRR and generated a combined knockout of Ir and Irr. |
| 3773 | 11463843 | Moreover, lack of IRR does not impair compensatory beta-cell hyperplasia in insulin-resistant Ir(+/-) mice, nor does it affect beta-cell development and function in Ir(-/-) mice. |
| 3774 | 11463843 | We conclude that glucose-stimulated insulin secretion and embryonic beta-cell development occur normally in mice lacking Irr. |
| 3775 | 11463843 | Preserved pancreatic beta-cell development and function in mice lacking the insulin receptor-related receptor. |
| 3776 | 11463843 | The insulin receptor-related receptor (IRR) is an orphan receptor of the insulin receptor gene (Ir) subfamily. |
| 3777 | 11463843 | It is expressed at considerably higher levels in beta cells than either insulin or IGF-1 receptors, and it has been shown to engage in heterodimer formation with insulin or IGF-1 receptors. |
| 3778 | 11463843 | To address whether IRR plays a physiologic role in beta-cell development and regulation of insulin secretion, we have characterized mice lacking IRR and generated a combined knockout of Ir and Irr. |
| 3779 | 11463843 | Moreover, lack of IRR does not impair compensatory beta-cell hyperplasia in insulin-resistant Ir(+/-) mice, nor does it affect beta-cell development and function in Ir(-/-) mice. |
| 3780 | 11463843 | We conclude that glucose-stimulated insulin secretion and embryonic beta-cell development occur normally in mice lacking Irr. |
| 3781 | 11463859 | This unique RXR ligand triggers cellular RXR:PPARgamma-dependent pathways including adipocyte differentiation and inhibition of TNFalpha-mediated hypophosphorylation of the insulin receptor, but does not activate key farnesoid X receptor and liver X receptor target genes. |
| 3782 | 11473053 | Growth hormone induces cellular insulin resistance by uncoupling phosphatidylinositol 3-kinase and its downstream signals in 3T3-L1 adipocytes. |
| 3783 | 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. |
| 3784 | 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. |
| 3785 | 11473053 | Fractionation studies indicated that chronic GH treatment reduces insulin-stimulated translocation of Akt from the cytosol to the plasma membrane. |
| 3786 | 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. |
| 3787 | 11473054 | Defective insulin-induced GLUT4 translocation in skeletal muscle of high fat-fed rats is associated with alterations in both Akt/protein kinase B and atypical protein kinase C (zeta/lambda) activities. |
| 3788 | 11473054 | Insulin stimulated the translocation of GLUT4 to both the plasma membrane and the transverse (T)-tubules in chow-fed rats. |
| 3789 | 11473054 | In marked contrast, GLUT4 translocation was completely abrogated in the muscle of insulin-stimulated high fat-fed rats. |
| 3790 | 11473054 | High-fat feeding markedly decreased insulin receptor substrate (IRS)-1-associated phosphatidylinositol (PI) 3-kinase activity but not insulin-induced tyrosine phosphorylation of the insulin receptor and IRS proteins in muscle. |
| 3791 | 11473054 | Impairment of PI 3-kinase function was associated with defective Akt/protein kinase B kinase activity (-40%, P < 0.01) in insulin-stimulated muscle of high fat-fed rats, despite unaltered phosphorylation (Ser473/Thr308) of the enzyme. |
| 3792 | 11473054 | We identified PI 3-kinase as the first step of the insulin signaling pathway to be impaired by high-fat feeding, and this was associated with alterations in both Akt and aPKC kinase activities. |
| 3793 | 11478333 | Activation of the insulin receptor by its ligand, or cross-activation of the insulin-like growth factor-I receptor, has been shown to be mitogenic and promote tumorigenesis in various model systems. |
| 3794 | 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. |
| 3795 | 11498021 | Deletion of Irs1 produces a mild metabolic phenotype with compensated insulin resistance but also causes marked growth retardation. |
| 3796 | 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. |
| 3797 | 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. |
| 3798 | 11498021 | Additionally, IRS-2(-/-) females display increased food intake and develop obesity, despite elevated leptin levels, suggesting abnormalities in hypothalamic function. |
| 3799 | 11513557 | Polymorphism screening of the insulin receptor-related receptor gene (INSRR) on 1q in Pima Indians. |
| 3800 | 11513557 | INSRR coding for the insulin receptor-related receptor (IRR) is located within the 1q21-q23 region linked with type-2 diabetes mellitus in Pima Indians and Caucasians. |
| 3801 | 11513557 | Although the ligand and biological function of this receptor are not yet known, its tyrosine kinase phosphorylates proteins involved in insulin signaling, and IRR may also play a role in the control of the insulin producing beta-cell mass. |
| 3802 | 11513557 | Polymorphism screening of the insulin receptor-related receptor gene (INSRR) on 1q in Pima Indians. |
| 3803 | 11513557 | INSRR coding for the insulin receptor-related receptor (IRR) is located within the 1q21-q23 region linked with type-2 diabetes mellitus in Pima Indians and Caucasians. |
| 3804 | 11513557 | Although the ligand and biological function of this receptor are not yet known, its tyrosine kinase phosphorylates proteins involved in insulin signaling, and IRR may also play a role in the control of the insulin producing beta-cell mass. |
| 3805 | 11515104 | The insulin receptor-related receptor (Insrr) gene maps to mouse chromosome 3. |
| 3806 | 11522683 | We show that skeletal muscle from SHRSP animals exhibits a marked decrease in insulin-stimulated glucose transport compared with WKY animals (fold increase in response to insulin: 1.4 +/- 0.15 in SHRSP, 2.29 +/- 0.22 in WKY; n = 4, P = 0.02), but the stimulation of glucose transport in response to activation of AMP-activated protein kinase was similar between the two strains. |
| 3807 | 11522683 | Moreover, analysis of the levels and subcellular distribution of insulin receptor substrates 1 and 2, the p85alpha subunit of phosphatidylinositol 3'-kinase, and protein kinase B (PKB)/cAKT in skeletal muscle did not identify any differences between the two strains; the insulin-dependent activation of PKB/cAKT was not different between the two strains. |
| 3808 | 11522683 | Increased cellular levels of the soluble N-ethylmaleimide attachment protein receptor (SNARE) proteins syntaxin 4 and vesicle-associated membrane protein (VAMP)-2 were also observed in the insulin-resistant SHRSP strain. |
| 3809 | 11522683 | Taken together, these data suggest that the insulin resistance observed in the SHRSP is manifest at the level of skeletal muscle, that muscle cell glucose transport exhibits a blunted response to insulin but unchanged responses to activation of AMP-activated protein kinase, that alterations in key molecules in both GLUT4 trafficking and insulin signal compartmentalization may underlie these defects in insulin action, and that the insulin resistance of these muscles appears to be of genetic origin rather than a paracrine or autocrine effect, since the insulin resistance is also observed in cultured myoblasts over several passages. |
| 3810 | 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. |
| 3811 | 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. |
| 3812 | 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. |
| 3813 | 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). |
| 3814 | 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). |
| 3815 | 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. |
| 3816 | 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. |
| 3817 | 11526109 | In response to insulin, recombinant IRS-1 translocated to the plasma membrane. |
| 3818 | 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. |
| 3819 | 11544611 | One well-known pathway represents a phosphorylation cascade initiated by the tyrosine kinase activity of the insulin receptor followed by involvement of different MAP-kinases. |
| 3820 | 11546773 | Regulation of insulin/insulin-like growth factor-1 signaling by proteasome-mediated degradation of insulin receptor substrate-2. |
| 3821 | 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. |
| 3822 | 11546773 | IRS-2 is an important IRS protein, as it mediates peripheral insulin action and beta-cell survival. |
| 3823 | 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. |
| 3824 | 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. |
| 3825 | 11546773 | Insulin/IGF1-induced ubiquitination and degradation of IRS-2 was blocked by inhibitors of phosphatidylinositol 3-kinase (wortmannin or LY294002) or mTOR (rapamycin). |
| 3826 | 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. |
| 3827 | 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. |
| 3828 | 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. |
| 3829 | 11557972 | Here we show that the transcriptional coactivator PGC-1 is strongly induced in liver in fasting mice and in three mouse models of insulin action deficiency: streptozotocin-induced diabetes, ob/ob genotype and liver insulin-receptor knockout. |
| 3830 | 11557972 | Adenoviral-mediated expression of PGC-1 in hepatocytes in culture or in vivo strongly activates an entire programme of key gluconeogenic enzymes, including phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase, leading to increased glucose output. |
| 3831 | 11557972 | Full transcriptional activation of the PEPCK promoter requires coactivation of the glucocorticoid receptor and the liver-enriched transcription factor HNF-4alpha (hepatic nuclear factor-4alpha) by PGC-1. |
| 3832 | 11557972 | These results implicate PGC-1 as a key modulator of hepatic gluconeogenesis and as a central target of the insulin-cAMP axis in liver. |
| 3833 | 11563968 | Intact actin microfilaments are required for insulin-regulated glucose transporter isoform 4 (GLUT4) translocation to the plasma membrane. |
| 3834 | 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. |
| 3835 | 11563968 | This was paralleled by a slight reduction in the insulin-induced tyrosine phosphorylation of insulin receptor substrate (IRS)-1 and IRS-2. |
| 3836 | 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. |
| 3837 | 11563968 | Insulin stimulation increased cell surface GLUT4 2-fold in control cells, whereas LO inhibition abrogated the insulin-stimulated GLUT4 translocation. |
| 3838 | 11563968 | LO inhibition blocks GLUT4 translocation without affecting downstream insulin signalling. |
| 3839 | 11570877 | Insulin regulation of gene expression through the forkhead transcription factor Foxo1 (Fkhr) requires kinases distinct from Akt. |
| 3840 | 11570877 | Insulin inhibits expression of certain liver genes through the phosphoinositol (PI) 3-kinase/Akt pathway. |
| 3841 | 11570877 | The forkhead proteins (Foxo1, Foxo3, and Foxo4, previously known as Fkhr or Afx) are transcriptional enhancers, the activity of which is inhibited by insulin through phosphorylation-dependent translocation and nuclear exclusion. |
| 3842 | 11570877 | We have also shown that T(24) fails to be phosphorylated in hepatocytes lacking insulin receptors, and we have suggested that this residue is targeted by a kinase distinct from Akt. |
| 3843 | 11570877 | In this study, we have further analyzed the ability of Akt to phosphorylate different Foxo1 sites in control and insulin receptor-deficient hepatocytes. |
| 3844 | 11570877 | Expression of a dominant negative Akt (Akt-AA) in control hepatocytes led to complete inhibition of endogenous Akt, but failed to inhibit Foxo1 T(24) phosphorylation and, consequently, insulin suppression of IGFBP-1 promoter activity. |
| 3845 | 11570877 | Conversely, expression of a constitutively active Akt (Akt-Myr) in insulin receptor-deficient hepatocytes led to an overall increase in the level of Foxo1 phosphorylation, but failed to induce T(24) and S(316) phosphorylation. |
| 3846 | 11570877 | These data indicate that the Foxo1 T(24) and S(316) kinases are distinct from Akt, and suggest that the pathways required for insulin regulation of hepatic gene expression diverge downstream of PI 3-kinase. |
| 3847 | 11570877 | Insulin regulation of gene expression through the forkhead transcription factor Foxo1 (Fkhr) requires kinases distinct from Akt. |
| 3848 | 11570877 | Insulin inhibits expression of certain liver genes through the phosphoinositol (PI) 3-kinase/Akt pathway. |
| 3849 | 11570877 | The forkhead proteins (Foxo1, Foxo3, and Foxo4, previously known as Fkhr or Afx) are transcriptional enhancers, the activity of which is inhibited by insulin through phosphorylation-dependent translocation and nuclear exclusion. |
| 3850 | 11570877 | We have also shown that T(24) fails to be phosphorylated in hepatocytes lacking insulin receptors, and we have suggested that this residue is targeted by a kinase distinct from Akt. |
| 3851 | 11570877 | In this study, we have further analyzed the ability of Akt to phosphorylate different Foxo1 sites in control and insulin receptor-deficient hepatocytes. |
| 3852 | 11570877 | Expression of a dominant negative Akt (Akt-AA) in control hepatocytes led to complete inhibition of endogenous Akt, but failed to inhibit Foxo1 T(24) phosphorylation and, consequently, insulin suppression of IGFBP-1 promoter activity. |
| 3853 | 11570877 | Conversely, expression of a constitutively active Akt (Akt-Myr) in insulin receptor-deficient hepatocytes led to an overall increase in the level of Foxo1 phosphorylation, but failed to induce T(24) and S(316) phosphorylation. |
| 3854 | 11570877 | These data indicate that the Foxo1 T(24) and S(316) kinases are distinct from Akt, and suggest that the pathways required for insulin regulation of hepatic gene expression diverge downstream of PI 3-kinase. |
| 3855 | 11574417 | Study of insulin signaling indicated that insulin-induced tyrosine phosphorylation of the insulin receptor (IR) was blunted in HiIMCL compared with LoIMCL (57 vs. 142% above basal, P < 0.05), while protein expression of the IR was unaltered. |
| 3856 | 11587536 | Insulin-like growth factor type 1 upregulates uncoupling protein 3. |
| 3857 | 11587536 | In this study the expression of uncoupling protein 3 (UCP3) and its regulation by insulin-like growth factor 1 (IGF-I) and insulin in human neuroblastoma SH-SY5Y cells were characterized. |
| 3858 | 11587536 | IGF-I induced a time- and concentration-dependent induction of UCP3 protein reaching a twofold expression after 72 h with 10 nM IGF-I. |
| 3859 | 11587536 | Extremely high insulin concentrations (860 nM) and 10 nM trIGF-I, a truncated form of IGF-I with the same affinity for the IGF-I receptor as the full-length IGF-I, but with lower activity on the insulin receptor, also upregulated UCP3. |
| 3860 | 11587536 | We conclude that SH-SY5Y cells express UCP3 natively and that the expression is regulated by IGF-I via the IGF-I receptor. |
| 3861 | 11606465 | Insulin and IGF-1 induce different patterns of gene expression in mouse fibroblast NIH-3T3 cells: identification by cDNA microarray analysis. |
| 3862 | 11606465 | The IGF-1 receptor and the related insulin receptor are similar in structure and activate many of the same postreceptor signaling pathways, yet they mediate distinct biological functions. |
| 3863 | 11606465 | In this study, we have used cDNA microarrays to monitor the gene expression patterns that are regulated by insulin and IGF-1. |
| 3864 | 11606465 | Mouse fibroblast NIH-3T3 cells expressing either the wild-type human IGF receptor or the insulin receptor were stimulated with either IGF-1 or insulin, respectively. |
| 3865 | 11606465 | Nine genes, none of which was previously known to be insulin responsive, were up-regulated by insulin but not by IGF-1. |
| 3866 | 11606465 | Interestingly, more than half of the genes up-regulated by IGF-1 are associated with mitogenesis and differentiation, whereas none of the genes specifically up-regulated by insulin are associated with these processes. |
| 3867 | 11606465 | Our results indicate that under the conditions used in this study, IGF-1 is a more potent activator of the mitogenic pathway than insulin in mouse fibroblast NIH-3T3 cells. |
| 3868 | 11606465 | Insulin and IGF-1 induce different patterns of gene expression in mouse fibroblast NIH-3T3 cells: identification by cDNA microarray analysis. |
| 3869 | 11606465 | The IGF-1 receptor and the related insulin receptor are similar in structure and activate many of the same postreceptor signaling pathways, yet they mediate distinct biological functions. |
| 3870 | 11606465 | In this study, we have used cDNA microarrays to monitor the gene expression patterns that are regulated by insulin and IGF-1. |
| 3871 | 11606465 | Mouse fibroblast NIH-3T3 cells expressing either the wild-type human IGF receptor or the insulin receptor were stimulated with either IGF-1 or insulin, respectively. |
| 3872 | 11606465 | Nine genes, none of which was previously known to be insulin responsive, were up-regulated by insulin but not by IGF-1. |
| 3873 | 11606465 | Interestingly, more than half of the genes up-regulated by IGF-1 are associated with mitogenesis and differentiation, whereas none of the genes specifically up-regulated by insulin are associated with these processes. |
| 3874 | 11606465 | Our results indicate that under the conditions used in this study, IGF-1 is a more potent activator of the mitogenic pathway than insulin in mouse fibroblast NIH-3T3 cells. |
| 3875 | 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. |
| 3876 | 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. |
| 3877 | 11606564 | In 32D myeloid progenitor cells, phosphorylation of Ser(307) inhibited insulin stimulation of the phosphatidylinositol 3-kinase and MAPK cascades. |
| 3878 | 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. |
| 3879 | 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. |
| 3880 | 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). |
| 3881 | 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. |
| 3882 | 11641236 | Defects in muscle IRS-1 expression and function have been reported in insulin-resistant states such as obesity and type 2 diabetes. |
| 3883 | 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. |
| 3884 | 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). |
| 3885 | 11684411 | Recent studies reveal that agents that induce insulin resistance exploit phosphorylation-based negative-feedback control mechanisms, otherwise utilized by insulin itself, to uncouple the insulin receptor from its downstream effectors and thereby terminate insulin signal transduction. |
| 3886 | 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. |
| 3887 | 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. |
| 3888 | 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. |
| 3889 | 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. |
| 3890 | 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. |
| 3891 | 11707432 | Taken together, the increased synthesis of cellular GM3 by TNF may participate in the pathological conditions of insulin resistance in type 2 diabetes. |
| 3892 | 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. |
| 3893 | 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. |
| 3894 | 11723053 | Insulin-induced phosphorylation of Akt on Thr-308 was increased fivefold in diabetic heart, whereas Akt phosphorylation on Ser-473 was normal. |
| 3895 | 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. |
| 3896 | 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. |
| 3897 | 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. |
| 3898 | 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. |
| 3899 | 11739098 | After saline injection, tyrosine phosphorylation (pY) of IR, IRS-1, and IRS-2 was not significantly different between groups. |
| 3900 | 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. |
| 3901 | 11739098 | In addition, association of IRS-1 and IRS-2 with p85 was significantly reduced in HSD vs. |
| 3902 | 11739098 | These data demonstrate that an HSD impairs insulin-stimulated early postreceptor signaling (pY of IRS proteins, IRS interaction with p85). |
| 3903 | 11739335 | Distinct and overlapping functions of insulin and IGF-I receptors. |
| 3904 | 11739335 | IGF-I receptor mediates IGF-I and IGF-II action on prenatal growth and IGF-I action on postnatal growth. |
| 3905 | 11739335 | Insulin receptor mediates prenatal growth in response to IGF-II and postnatal metabolism in response to insulin. |
| 3906 | 11739335 | The ability of the insulin receptor to act as a bona fide IGF-II-dependent growth promoter is underscored by its rescue of double knockout Igf1r/Igf2r mice. |
| 3907 | 11739335 | Thus, IGF-II is a true bifunctional ligand that is able to stimulate both insulin and IGF-I receptor signaling, although with different potencies. |
| 3908 | 11739335 | In contrast, the IGF-II/cation-independent mannose-6-phosphate receptor regulates IGF-II clearance. |
| 3909 | 11739335 | The growth retardation of mice lacking IGF-I and/or insulin receptors is due to reduced cell number, resulting from decreased proliferation. |
| 3910 | 11739335 | Distinct and overlapping functions of insulin and IGF-I receptors. |
| 3911 | 11739335 | IGF-I receptor mediates IGF-I and IGF-II action on prenatal growth and IGF-I action on postnatal growth. |
| 3912 | 11739335 | Insulin receptor mediates prenatal growth in response to IGF-II and postnatal metabolism in response to insulin. |
| 3913 | 11739335 | The ability of the insulin receptor to act as a bona fide IGF-II-dependent growth promoter is underscored by its rescue of double knockout Igf1r/Igf2r mice. |
| 3914 | 11739335 | Thus, IGF-II is a true bifunctional ligand that is able to stimulate both insulin and IGF-I receptor signaling, although with different potencies. |
| 3915 | 11739335 | In contrast, the IGF-II/cation-independent mannose-6-phosphate receptor regulates IGF-II clearance. |
| 3916 | 11739335 | The growth retardation of mice lacking IGF-I and/or insulin receptors is due to reduced cell number, resulting from decreased proliferation. |
| 3917 | 11742842 | The relationship of leptin gene expression to adipocyte volume was investigated in lean 10-wk-old male C57BL/6J mice. mRNA levels for leptin, insulin receptor, glucocorticoid receptor, and tumor necrosis factor (TNF)-alpha in inguinal, epididymal, and retroperitoneal adipose tissues were quantified and related to adipocyte volume. |
| 3918 | 11742842 | Leptin mRNA levels were highly correlated with adipocyte volume within each fat depot. |
| 3919 | 11742842 | Multiple regression analysis of pooled data from the three depots showed that leptin mRNA levels were strongly correlated with adipocyte volumes (beta = 0.84, P < 0.001) and, to a smaller degree, with glucocorticoid receptor mRNA levels (beta = 0.36, P < 0.001). |
| 3920 | 11742842 | Rates of leptin secretion in vitro were strongly correlated with leptin mRNA levels (r = 0.89, P < 0.001). mRNA levels for TNF-alpha, insulin receptor, and glucocorticoid receptor showed no significant correlation with adipocyte volume. |
| 3921 | 11742842 | The strong correlation between leptin gene expression and adipocyte volume supports leptin's physiological role as a humoral signal of fat mass. |
| 3922 | 11742842 | The relationship of leptin gene expression to adipocyte volume was investigated in lean 10-wk-old male C57BL/6J mice. mRNA levels for leptin, insulin receptor, glucocorticoid receptor, and tumor necrosis factor (TNF)-alpha in inguinal, epididymal, and retroperitoneal adipose tissues were quantified and related to adipocyte volume. |
| 3923 | 11742842 | Leptin mRNA levels were highly correlated with adipocyte volume within each fat depot. |
| 3924 | 11742842 | Multiple regression analysis of pooled data from the three depots showed that leptin mRNA levels were strongly correlated with adipocyte volumes (beta = 0.84, P < 0.001) and, to a smaller degree, with glucocorticoid receptor mRNA levels (beta = 0.36, P < 0.001). |
| 3925 | 11742842 | Rates of leptin secretion in vitro were strongly correlated with leptin mRNA levels (r = 0.89, P < 0.001). mRNA levels for TNF-alpha, insulin receptor, and glucocorticoid receptor showed no significant correlation with adipocyte volume. |
| 3926 | 11742842 | The strong correlation between leptin gene expression and adipocyte volume supports leptin's physiological role as a humoral signal of fat mass. |
| 3927 | 11752399 | Increased insulin sensitivity in mice lacking p85beta subunit of phosphoinositide 3-kinase. |
| 3928 | 11752399 | On the basis of ex vivo studies using insulin-responsive cells, activation of a Class IA phosphoinositide 3-kinase (PI3K) seems to be required for a wide variety of cellular responses downstream of insulin. |
| 3929 | 11752399 | In mammals, insulin-responsive tissues express both the p85alpha and p85beta isoforms of the regulatory subunit. |
| 3930 | 11752399 | Surprisingly, recent studies have revealed that disruption of the p85alpha gene in the mouse (p85alpha(-/-) mice) results in hypoglycemia with decreased plasma insulin, and the p85alpha(+/-) mice exhibit significantly increased insulin sensitivity. |
| 3931 | 11752399 | These results suggest either that p85alpha negatively regulates insulin signaling, or that p85beta, which mediates the major fraction of Class IA PI3K signaling in the absence of p85alpha, is more efficient than p85alpha in mediating insulin responses. |
| 3932 | 11752399 | As with the p85alpha(-/-) mice, the p85beta(-/-) mice showed hypoinsulinemia, hypoglycemia, and improved insulin sensitivity. |
| 3933 | 11752399 | Moreover, insulin-induced activation of AKT was significantly up-regulated in muscle from the p85beta(-/-) mice. |
| 3934 | 11752399 | In addition, insulin-dependent tyrosine phosphorylation of insulin receptor substrate-2 was enhanced in the p85beta(-/-) mice, a phenotype not observed in the p85alpha(-/-) mice. |
| 3935 | 11752399 | These results indicate that in addition to their roles in recruiting the catalytic subunit of PI3K to the insulin receptor substrate proteins, both p85alpha and p85beta play negative roles in insulin signaling. |
| 3936 | 11756318 | Phosphatidylinositol 3-kinase redistribution is associated with skeletal muscle insulin resistance in gestational diabetes mellitus. |
| 3937 | 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. |
| 3938 | 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. |
| 3939 | 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. |
| 3940 | 11756318 | Phosphatidylinositol 3-kinase redistribution is associated with skeletal muscle insulin resistance in gestational diabetes mellitus. |
| 3941 | 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. |
| 3942 | 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. |
| 3943 | 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. |
| 3944 | 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. |
| 3945 | 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. |
| 3946 | 11782469 | Insulin stimulates phosphorylation of the beta 2-adrenergic receptor by the insulin receptor, creating a potent feedback inhibitor of its tyrosine kinase. |
| 3947 | 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). |
| 3948 | 11782469 | A Y364A mutant form of the beta(2)-adrenergic, in contrast, loses it ability to inhibit insulin-stimulated phosphorylation of IRS-1,2. |
| 3949 | 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. |
| 3950 | 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. |
| 3951 | 11782469 | Insulin stimulates phosphorylation of the beta 2-adrenergic receptor by the insulin receptor, creating a potent feedback inhibitor of its tyrosine kinase. |
| 3952 | 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). |
| 3953 | 11782469 | A Y364A mutant form of the beta(2)-adrenergic, in contrast, loses it ability to inhibit insulin-stimulated phosphorylation of IRS-1,2. |
| 3954 | 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. |
| 3955 | 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. |
| 3956 | 11782469 | Insulin stimulates phosphorylation of the beta 2-adrenergic receptor by the insulin receptor, creating a potent feedback inhibitor of its tyrosine kinase. |
| 3957 | 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). |
| 3958 | 11782469 | A Y364A mutant form of the beta(2)-adrenergic, in contrast, loses it ability to inhibit insulin-stimulated phosphorylation of IRS-1,2. |
| 3959 | 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. |
| 3960 | 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. |
| 3961 | 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. |
| 3962 | 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. |
| 3963 | 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. |
| 3964 | 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. |
| 3965 | 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. |
| 3966 | 11788655 | However, the decrease in Shc gene expression by insulin was not significantly different between the study groups. |
| 3967 | 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. |
| 3968 | 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. |
| 3969 | 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. |
| 3970 | 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. |
| 3971 | 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. |
| 3972 | 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. |
| 3973 | 11788655 | However, the decrease in Shc gene expression by insulin was not significantly different between the study groups. |
| 3974 | 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. |
| 3975 | 11795838 | Insulin resistance was found to be the outcome of reduced activation of muscle insulin receptor tyrosine kinase by insulin, in association with diminished GLUT4 protein and DNA content and overexpression of PKC isoenzymes, notably of PKCepsilon. |
| 3976 | 11795838 | PKCepsilon was also found to attenuate the activity of PKB and to promote the degradation of insulin receptor, as determined by co-incubation in HEK 293 cells. |
| 3977 | 11795838 | Insulin resistance was found to be the outcome of reduced activation of muscle insulin receptor tyrosine kinase by insulin, in association with diminished GLUT4 protein and DNA content and overexpression of PKC isoenzymes, notably of PKCepsilon. |
| 3978 | 11795838 | PKCepsilon was also found to attenuate the activity of PKB and to promote the degradation of insulin receptor, as determined by co-incubation in HEK 293 cells. |
| 3979 | 11806712 | Protein tyrosine phosphatase 1B (PTP1B) negatively regulates insulin signaling in part by dephosphorylating key tyrosine residues within the regulatory domain of the beta-subunit of the insulin receptor (IR), thereby attenuating receptor tyrosine kinase activity. |
| 3980 | 11806712 | Inhibition of PTP1B is therefore anticipated to improve insulin resistance and has recently become the focus of discovery efforts aimed at identifying new drugs to treat type II diabetes. |
| 3981 | 11806712 | The most potent analogue arising from this effort was triacid 71, which inhibits PTP1B competitively with a K(i) = 0.22 microM without inhibiting SHP-2 or LAR at concentrations up to 100 microM. |
| 3982 | 11812758 | Because the increase in PI 3-kinase activity cannot be explained by increased insulin receptor substrate (IRS)-1 signaling, the present study examined whether this effect is mediated by enhanced IRS-2 signaling. |
| 3983 | 11812758 | In wild-type (WT) mice, insulin increased IRS-2 tyrosine phosphorylation (approximately 2.5-fold) and IRS-2-associated PI 3-kinase activity (approximately 3-fold). |
| 3984 | 11812758 | Treadmill exercise, per se, had no effect on IRS-2 signaling, but in the period immediately after exercise, there was a further increase in insulin-stimulated IRS-2 tyrosine phosphorylation (approximately 3.5-fold) and IRS-2-associated PI 3-kinase activity (approximately 5-fold). |
| 3985 | 11812758 | In IRS-2-deficient (IRS-2(-/-)) mice, the increase in insulin-stimulated, phosphotyrosine-associated PI 3-kinase activity was attenuated as compared with WT mice. |
| 3986 | 11812758 | However, in IRS-2(-/-) mice, the insulin-stimulated, phosphotyrosine-associated PI 3-kinase response after exercise was slightly higher than the insulin-stimulated response alone. |
| 3987 | 11812758 | In conclusion, IRS-2 tyrosine phosphorylation and associated PI 3-kinase activity are markedly enhanced by insulin in the immediate period after exercise. |
| 3988 | 11812758 | IRS-2 signaling can partially account for the increase in insulin-stimulated phosphotyrosine-associated PI 3-kinase activity after exercise. |
| 3989 | 11826398 | Insulin signaling in the transcriptional and posttranscriptional regulation of CYP2E1 expression. |
| 3990 | 11826398 | Diabetes has been reported to increase the expression of cytochrome P450 (CYP) 2E1 messenger RNA (mRNA) and protein several-fold, and enhanced expression has been associated with elevated ketone bodies. |
| 3991 | 11826398 | Primary cultured rat hepatocytes were used to explore ketone body and insulin regulation of CYP2E1 expression. |
| 3992 | 11826398 | Insulin produced a concentration-dependent decrease in CYP2E1 mRNA levels, and insulin receptor immunoprecipitation showed a correspondence between receptor phosphorylation and the decrease in CYP2E1 mRNA levels at physiologic levels of insulin. |
| 3993 | 11826398 | The phosphatidylinositol 3-kinase (PI3-kinase) inhibitors wortmannin or LY294002 and rapamycin, an inhibitor of p70 S6 kinase phosphorylation, ameliorated the insulin-mediated decrease in CYP2E1 mRNA levels. |
| 3994 | 11826398 | Geldanamycin, which inhibits Src kinase, also abrogated the insulin-mediated decrease in CYP2E1 mRNA levels. |
| 3995 | 11826398 | In contrast, the protein kinase C (PKC) inhibitor bisindolylmaleimide, the mitogen-activated protein kinase kinase (MEK) inhibitor PD98059, and the p38 mitogen-activated protein (MAP) kinase inhibitor SB202190 did not affect the insulin-mediated decrease in CYP2E1. |
| 3996 | 11826398 | CYP2E1 mRNA half-life decreased from approximately 48 hours in the absence of insulin to approximately 15 hours at 10 nmol/L insulin, and this decrease was prevented by wortmannin. |
| 3997 | 11826398 | The half-life of CYP2B mRNA was increased by insulin, whereas that of CYP3A was unaffected. |
| 3998 | 11826398 | Analysis of CYP2E1 gene transcription using heterogeneous nuclear RNA (hnRNA) showed that insulin suppressed CYP2E1 transcription. |
| 3999 | 11826398 | In conclusion, these data show involvement of transcriptional and posttranscriptional mechanisms in the insulin-mediated regulation of CYP2E1 and implicate PI3-kinase, p70 S6 kinase, and Src kinase in mediating these effects. |
| 4000 | 11832353 | Downregulated IRS-1 and PPARgamma in obese women with gestational diabetes: relationship to FFA during pregnancy. |
| 4001 | 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. |
| 4002 | 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). |
| 4003 | 11832353 | Thus GDM women have decreased IRS-1, which may contribute to reduced insulin suppression of lipolysis with advancing gestation. |
| 4004 | 11834135 | The molecular basis of this insulin resistance has been reported to involve reduced insulin receptor autophosphorylation, reduced expression and translocation of insulin-responsive glucose transporters and defects of the insulin signalling pathway distal to the insulin receptor. |
| 4005 | 11872675 | Increased insulin sensitivity in IGF-I receptor--deficient brown adipocytes. |
| 4006 | 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(+/+)). |
| 4007 | 11872675 | IGF-IR(-/-) brown adipocytes lacked IGF-IR protein expression; insulin receptor (IR) expression remained unchanged as compared with wild-type cells. |
| 4008 | 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. |
| 4009 | 11872675 | Downstream, the association IRS-1/growth factor receptor binding protein-2 (Grb-2) was augmented in the IGF-IR(-/-) brown adipocyte cell line. |
| 4010 | 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. |
| 4011 | 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. |
| 4012 | 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. |
| 4013 | 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. |
| 4014 | 11872675 | However, PTP1B/Grb-2 association remained unchanged in both cell types, regardless of insulin stimulation. |
| 4015 | 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. |
| 4016 | 11887456 | Evidence points to an increased cytokine response in type 2 diabetes, especially the proinflammatory cytokines interleukin (IL)-1 beta, IL-6, and tumor necrosis factor (TNF)-alpha. |
| 4017 | 11887456 | Persistent elevation of IL-1 beta, IL-6, and TNF-alpha in the diabetic state have an effect on the liver, stimulate the release of acute-phase proteins, produce the characteristic dysregulation of lipid metabolism associated with type 2 diabetes, and have effects on pancreatic beta cells as well. |
| 4018 | 11887456 | In addition, TNF-alpha, a potent inhibitor of the tyrosine kinase activity of the insulin receptor, has been implicated as an etiologic factor for insulin resistance. |
| 4019 | 11897712 | Immunohistochemistry for proliferating cell nuclear antigen within the pancreatic ductal epithelium showed no differences in labeling index between insulin-deficient and control mice, and no change in the number of beta-cells associated with ducts, but the relative size distribution of the islets was altered so that fewer islets under 5,000 microm(2) and more islets greater than 10,000 microm(2) were present in Ins1-/-, Ins2-/- animals. |
| 4020 | 11897712 | This was supported by an increase in the number of cells containing immunoreactive proliferating cell nuclear antigen in both islet alpha- and beta-cells at E18.5 in insulin-deficient mice, and a significantly lower incidence of apoptotic cells, as determined by molecular histochemistry using the terminal deoxynucleotidyl transferase-mediated deoxy-UTP nick end labeling reaction. |
| 4021 | 11897712 | The density of blood vessels within sections of whole pancreas, or within islets, was determined by immunohistochemistry for the endothelial cell marker CD31 and was found to be increased 2-fold in insulin-deficient mice compared with controls at E18.5. |
| 4022 | 11897712 | However, no changes were found in the steady-state expression of mRNAs encoding vascular endothelial growth factor, its receptor Flk-1, IGF-I or -II, the IGF-I and insulin receptors, or insulin receptor substrates-1 or -2 in pancreata from Ins1-/-, Ins2-/- mice compared with Ins1-/-, Ins2+/- controls. |
| 4023 | 11912555 | In obese humans, insulin resistance is accompanied by elevated levels of plasma cell membrane glycoprotein (PC-1) and decreased insulin receptor (IR) tyrosine kinase activity in skeletal muscle. |
| 4024 | 11912555 | We measured PC-1 levels in these muscle samples to determine whether PC-1 content is elevated in this primate model of insulin resistance. |
| 4025 | 11912555 | We conclude that insulin resistance secondary to obesity in rhesus monkeys is associated with increased levels of PC-1 and decreased IR signaling capacity in skeletal muscle. |
| 4026 | 11912559 | Tumor necrosis factor-alpha inhibits insulin-induced increase in endothelial nitric oxide synthase and reduces insulin receptor content and phosphorylation in human aortic endothelial cells. |
| 4027 | 11912559 | We have recently demonstrated that insulin also inhibits the expression of intracellular adhesion molecule-1 (ICAM-1) and monocyte chemoattractant protein-1 (MCP-1), 2 major proinflammatory mediators, by human aortic endothelial cells (HAEC) and the proinflammatory mediator, nuclear factor (NF-kappa B), in the nucleus in parallel with an increase in endothelial nitric oxide synthase (e-NOS) expression. |
| 4028 | 11912559 | The inhibition of ICAM-1 by insulin is NO dependent. |
| 4029 | 11912559 | Because tumor necrosis factor-alpha (TNF-a ) is proinflammatory and may thus inhibit the action of insulin at the endothelial cell level, we have now investigated whether TNF-a affects (1) insulin receptor content; (2) insulin receptor (IR) autophosphorylation induced by insulin, and (3) e-NOS expression by the endothelial cells. |
| 4030 | 11912559 | TNF-alpha also inhibited tyrosine autophosphorylation of the IR in HAEC induced by insulin and reduced IR beta-subunit protein expression in HAEC. |
| 4031 | 11912559 | These effects of insulin and TNF-alpha were independent of cell proliferation, as cell counts did not change with insulin or TNF-alpha. |
| 4032 | 11912559 | Although the inhibition of IR autophosphorylation by TNF-alpha is known to occur at the adipocyte level, the data on the inhibitory effect of TNF-alpha on insulin-induced e-NOS expression and IRP contents are novel. |
| 4033 | 11912559 | Tumor necrosis factor-alpha inhibits insulin-induced increase in endothelial nitric oxide synthase and reduces insulin receptor content and phosphorylation in human aortic endothelial cells. |
| 4034 | 11912559 | We have recently demonstrated that insulin also inhibits the expression of intracellular adhesion molecule-1 (ICAM-1) and monocyte chemoattractant protein-1 (MCP-1), 2 major proinflammatory mediators, by human aortic endothelial cells (HAEC) and the proinflammatory mediator, nuclear factor (NF-kappa B), in the nucleus in parallel with an increase in endothelial nitric oxide synthase (e-NOS) expression. |
| 4035 | 11912559 | The inhibition of ICAM-1 by insulin is NO dependent. |
| 4036 | 11912559 | Because tumor necrosis factor-alpha (TNF-a ) is proinflammatory and may thus inhibit the action of insulin at the endothelial cell level, we have now investigated whether TNF-a affects (1) insulin receptor content; (2) insulin receptor (IR) autophosphorylation induced by insulin, and (3) e-NOS expression by the endothelial cells. |
| 4037 | 11912559 | TNF-alpha also inhibited tyrosine autophosphorylation of the IR in HAEC induced by insulin and reduced IR beta-subunit protein expression in HAEC. |
| 4038 | 11912559 | These effects of insulin and TNF-alpha were independent of cell proliferation, as cell counts did not change with insulin or TNF-alpha. |
| 4039 | 11912559 | Although the inhibition of IR autophosphorylation by TNF-alpha is known to occur at the adipocyte level, the data on the inhibitory effect of TNF-alpha on insulin-induced e-NOS expression and IRP contents are novel. |
| 4040 | 11916914 | Activation of IRS-2-mediated signal transduction by IGF-1, but not TGF-alpha or EGF, augments pancreatic beta-cell proliferation. |
| 4041 | 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. |
| 4042 | 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. |
| 4043 | 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. |
| 4044 | 11916914 | Phosphorylation of p70(S6K) was also increased by IGF-1/glucose, but not by TGF-alpha/EGF, despite upstream PKB activation. |
| 4045 | 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. |
| 4046 | 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. |
| 4047 | 11916914 | Neither IRS-1 nor IRS-2 overexpression induced a beta-cell proliferative response to TGF-alpha/EGF. |
| 4048 | 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. |
| 4049 | 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. |
| 4050 | 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. |
| 4051 | 11916925 | IRS-1- associated PI3 kinase activation and insulin receptor autophosphorylation were comparable in the two groups. |
| 4052 | 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. |
| 4053 | 11916925 | This is associated with impaired IRS-2-associated PI3 kinase activation and PKC-zeta/lambda activation. |
| 4054 | 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. |
| 4055 | 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. |
| 4056 | 11916925 | IRS-1- associated PI3 kinase activation and insulin receptor autophosphorylation were comparable in the two groups. |
| 4057 | 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. |
| 4058 | 11916925 | This is associated with impaired IRS-2-associated PI3 kinase activation and PKC-zeta/lambda activation. |
| 4059 | 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. |
| 4060 | 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. |
| 4061 | 11916925 | IRS-1- associated PI3 kinase activation and insulin receptor autophosphorylation were comparable in the two groups. |
| 4062 | 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. |
| 4063 | 11916925 | This is associated with impaired IRS-2-associated PI3 kinase activation and PKC-zeta/lambda activation. |
| 4064 | 11922615 | However, in contrast to insulin, shikonin-stimulated glucose uptake was not strongly inhibited by wortmannin, a specific inhibitor of phosphatidylinositol 3-kinase (PI3K). |
| 4065 | 11922615 | In vitro phosphorylation analyses revealed that shikonin did not induce tyrosine phosphorylation of the insulin receptor, but significantly induced both Thr-308 and Ser-473 phosphorylation of Akt. |
| 4066 | 11922615 | Our results suggest that in 3T3-L1 adipocytes, shikonin action is not mediated primarily via the insulin receptor/PI3K pathway, but rather via another distinct tyrosine kinase-dependent pathway leading to glucose uptake involving Akt phosphorylation. |
| 4067 | 11922615 | However, in contrast to insulin, shikonin-stimulated glucose uptake was not strongly inhibited by wortmannin, a specific inhibitor of phosphatidylinositol 3-kinase (PI3K). |
| 4068 | 11922615 | In vitro phosphorylation analyses revealed that shikonin did not induce tyrosine phosphorylation of the insulin receptor, but significantly induced both Thr-308 and Ser-473 phosphorylation of Akt. |
| 4069 | 11922615 | Our results suggest that in 3T3-L1 adipocytes, shikonin action is not mediated primarily via the insulin receptor/PI3K pathway, but rather via another distinct tyrosine kinase-dependent pathway leading to glucose uptake involving Akt phosphorylation. |
| 4070 | 11924926 | In humans, mutations in leptin, leptin receptor, proopiomelanocortin (POMC), melanocortin-4 receptor (MC4R) and prohormone convertase 1 (PC1) have been described in patients with severe obesity. |
| 4071 | 11924926 | Most of these obesity disorders, with the exception of the MC4R mutations, exhibit recessive inheritance and a distinct phenotype with varying degrees of hypothalamic dysfunction, and they unravel the critical role of the central leptin and melanocortin pathways in human appetite control and energy homeostasis. |
| 4072 | 11924926 | To date, six MODY genes have been identified, the glucokinase gene and five beta cell-specific transcription factor genes, hepatocyte nuclear factor-1alpha (HNF-1alpha), HNF-1beta, HNF-4alpha, insulin promoter factor-1 (IPF-1) and NeuroD1/BETA2. |
| 4073 | 11924926 | At the other end of the spectrum are the inherited syndromes of insulin resistance that are caused by mutations in the insulin receptor gene and in the adipocyte-specific transcription factor PPARgamma. |
| 4074 | 11938554 | Indeed NF-kappa B activity is increased, while Sp1 activity drops in this context. |
| 4075 | 11938554 | Hence, NF-kappa B activity precociously increases in the states of insulin resistance before hyperglycemia sets in. |
| 4076 | 11938554 | This activity can be restored by antioxydants in the cell culture medium, Sp1 being necessary to insulin receptor expression, the question arises whether this drop in activity modifies significantly the insulin expression. |
| 4077 | 11954667 | The protein content of insulin receptors and SRC homology adaptor protein (SHC) did not change significantly along the time frame analyzed. |
| 4078 | 11954667 | However, insulin-induced tyrosine phosphorylation of the insulin receptor and SHC, and the association of SHC/growth factor receptor binding protein-2 (GRB2) decreased significantly from d 1 to wk 60 of life in both types of tissues. |
| 4079 | 11954667 | Moreover, the expression of SH protein tyrosine phosphatase-2 (SHP2), a tyrosine phosphatase involved in insulin signal transduction and regulation of the insulin signal, decreased significantly with age progression, in both the forebrain cortex and the cerebellum of rats. |
| 4080 | 11960490 | PTP1B negatively regulates insulin signaling, in part, by dephosphorylating key tyrosine residues within the regulatory domain of the beta-subunit of the insulin receptor, thereby attenuating receptor kinase activity. |
| 4081 | 11960490 | Inhibitors of PTP1B would therefore have the potential of prolonging the phosphorylated (activated) state of the insulin receptor and are anticipated to be a novel treatment of the insulin resistance characteristic of type 2 diabetes. |
| 4082 | 11960490 | PTP1B negatively regulates insulin signaling, in part, by dephosphorylating key tyrosine residues within the regulatory domain of the beta-subunit of the insulin receptor, thereby attenuating receptor kinase activity. |
| 4083 | 11960490 | Inhibitors of PTP1B would therefore have the potential of prolonging the phosphorylated (activated) state of the insulin receptor and are anticipated to be a novel treatment of the insulin resistance characteristic of type 2 diabetes. |
| 4084 | 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. |
| 4085 | 11964395 | Conversely, GLUT2 and glucokinase mRNA levels were appropriately regulated by insulin, suggesting that insulin resistance is selective to gluconeogenic gene expression. |
| 4086 | 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. |
| 4087 | 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. |
| 4088 | 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. |
| 4089 | 12023872 | Receptors for insulin and insulin-like growth factor-1 and insulin receptor substrate-1 mediate pathways that regulate islet function. |
| 4090 | 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. |
| 4091 | 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. |
| 4092 | 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. |
| 4093 | 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. |
| 4094 | 12028370 | Gene knockout experiments have helped to define key signalling molecules that affect insulin action, including insulin and insulin-like growth factor-1 (IGF-1) receptors, insulin receptor substrate (IRS) proteins and various downstream effector proteins. beta-cell function is also a tightly regulated process, with numerous factors (including certain signalling molecules) having an impact on insulin production, insulin secretion and beta-cell mass. |
| 4095 | 12031977 | Plasma adiponectin concentration is associated with skeletal muscle insulin receptor tyrosine phosphorylation, and low plasma concentration precedes a decrease in whole-body insulin sensitivity in humans. |
| 4096 | 12031977 | Adiponectin, the most abundant adipose-specific protein, has been found to be negatively associated with degree of adiposity and positively associated with insulin sensitivity in Pima Indians and other populations. |
| 4097 | 12031977 | Moreover, adiponectin administration to rodents has been shown to increase insulin-induced tyrosine phosphorylation of the insulin receptor (IR) and also increase whole-body insulin sensitivity. |
| 4098 | 12031977 | To further characterize the relationship between plasma adiponectin concentration and insulin sensitivity in humans, we examined 1) the cross-sectional association between plasma adiponectin concentration and skeletal muscle IR tyrosine phosphorylation and 2) the prospective effect of plasma adiponectin concentration at baseline on change in insulin sensitivity. |
| 4099 | 12031977 | Fasting plasma adiponectin concentration, body composition (hydrodensitometry or dual energy X-ray absorptiometry), insulin sensitivity (insulin-stimulated glucose disposal, hyperinsulinemic clamp), and glucose tolerance (75-g oral glucose tolerance test) were measured in 55 Pima Indians (47 men and 8 women, aged 31 +/- 8 years, body fat 29 +/- 8% [mean +/- SD]; 50 with normal glucose tolerance, 3 with impaired glucose tolerance, and 2 with diabetes). |
| 4100 | 12031977 | Cross-sectionally, plasma adiponectin concentration was positively associated with insulin-stimulated glucose disposal (r = 0.58, P < 0.0001) and negatively associated with percent body fat (r = -0.62, P < 0.0001) in the whole group. |
| 4101 | 12031977 | Longitudinally, after adjustment for age, sex, and percent body fat, low plasma adiponectin concentration at baseline was associated with a decrease in insulin sensitivity (P = 0.04). |
| 4102 | 12031977 | Prospectively, low plasma adiponectin concentration at baseline precedes a decrease in insulin sensitivity. |
| 4103 | 12031977 | Our data indicate that adiponectin plays an important role in regulation of insulin sensitivity in humans. |
| 4104 | 12031977 | Plasma adiponectin concentration is associated with skeletal muscle insulin receptor tyrosine phosphorylation, and low plasma concentration precedes a decrease in whole-body insulin sensitivity in humans. |
| 4105 | 12031977 | Adiponectin, the most abundant adipose-specific protein, has been found to be negatively associated with degree of adiposity and positively associated with insulin sensitivity in Pima Indians and other populations. |
| 4106 | 12031977 | Moreover, adiponectin administration to rodents has been shown to increase insulin-induced tyrosine phosphorylation of the insulin receptor (IR) and also increase whole-body insulin sensitivity. |
| 4107 | 12031977 | To further characterize the relationship between plasma adiponectin concentration and insulin sensitivity in humans, we examined 1) the cross-sectional association between plasma adiponectin concentration and skeletal muscle IR tyrosine phosphorylation and 2) the prospective effect of plasma adiponectin concentration at baseline on change in insulin sensitivity. |
| 4108 | 12031977 | Fasting plasma adiponectin concentration, body composition (hydrodensitometry or dual energy X-ray absorptiometry), insulin sensitivity (insulin-stimulated glucose disposal, hyperinsulinemic clamp), and glucose tolerance (75-g oral glucose tolerance test) were measured in 55 Pima Indians (47 men and 8 women, aged 31 +/- 8 years, body fat 29 +/- 8% [mean +/- SD]; 50 with normal glucose tolerance, 3 with impaired glucose tolerance, and 2 with diabetes). |
| 4109 | 12031977 | Cross-sectionally, plasma adiponectin concentration was positively associated with insulin-stimulated glucose disposal (r = 0.58, P < 0.0001) and negatively associated with percent body fat (r = -0.62, P < 0.0001) in the whole group. |
| 4110 | 12031977 | Longitudinally, after adjustment for age, sex, and percent body fat, low plasma adiponectin concentration at baseline was associated with a decrease in insulin sensitivity (P = 0.04). |
| 4111 | 12031977 | Prospectively, low plasma adiponectin concentration at baseline precedes a decrease in insulin sensitivity. |
| 4112 | 12031977 | Our data indicate that adiponectin plays an important role in regulation of insulin sensitivity in humans. |
| 4113 | 12031982 | Differential effects of tumor necrosis factor-alpha on protein kinase C isoforms alpha and delta mediate inhibition of insulin receptor signaling. |
| 4114 | 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. |
| 4115 | 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. |
| 4116 | 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. |
| 4117 | 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. |
| 4118 | 12031982 | Insulin induced PKCdelta specifically to coprecipitate with IR, an effect blocked by TNF-alpha. |
| 4119 | 12031982 | Both PKCalpha and -delta are constitutively associated with IRS-1. |
| 4120 | 12031982 | Whereas insulin decreased coprecipitation of IRS-1 with PKCalpha, it increased coprecipitation of IRS-1 with PKCdelta. |
| 4121 | 12031982 | TNF-alpha blocked the effects of insulin on association of both PKCs with IRS-1. |
| 4122 | 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. |
| 4123 | 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. |
| 4124 | 12031982 | Blockade of PKCalpha antagonized the inhibitory effects of TNF-alpha on both insulin-induced IR tyrosine phosphorylation and IR signaling to PI3-K. |
| 4125 | 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. |
| 4126 | 12031982 | Differential effects of tumor necrosis factor-alpha on protein kinase C isoforms alpha and delta mediate inhibition of insulin receptor signaling. |
| 4127 | 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. |
| 4128 | 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. |
| 4129 | 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. |
| 4130 | 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. |
| 4131 | 12031982 | Insulin induced PKCdelta specifically to coprecipitate with IR, an effect blocked by TNF-alpha. |
| 4132 | 12031982 | Both PKCalpha and -delta are constitutively associated with IRS-1. |
| 4133 | 12031982 | Whereas insulin decreased coprecipitation of IRS-1 with PKCalpha, it increased coprecipitation of IRS-1 with PKCdelta. |
| 4134 | 12031982 | TNF-alpha blocked the effects of insulin on association of both PKCs with IRS-1. |
| 4135 | 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. |
| 4136 | 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. |
| 4137 | 12031982 | Blockade of PKCalpha antagonized the inhibitory effects of TNF-alpha on both insulin-induced IR tyrosine phosphorylation and IR signaling to PI3-K. |
| 4138 | 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. |
| 4139 | 12067836 | Considerable evidence suggests that atypical protein kinase C isoforms (aPKCs), serving downstream of insulin receptor substrates and phosphatidylinositol (PI) 3-kinase, are required for insulin-stimulated glucose transport in skeletal muscle and adipocytes. |
| 4140 | 12067836 | More recent findings further suggest that aPKCs are activated and required for glucose transport responses while serving downstream of 1) proline-rich tyrosine kinase-2, extracellular signal-regulated kinase, and phospholipase D, as during the actions of high concentrations of carbohydrates (glucose, sorbitol) and agents that activate 5'-AMP-activated protein kinase (exercise, 5-amino-imidazole-4-carboxamide-1-beta-D-riboside, dinitrophenol), and 2) Cbl-dependent PI 3-kinase, as during the action of insulin-sensitizing thiazolidinediones. |
| 4141 | 12076180 | The relationship between the insulin and angiotensin II (Ang II) signalling pathways needs to be fully clarified in order to prevent or correct the target organ damage resulting from changes in the cross-talk of these two hormonal systems. |
| 4142 | 12076180 | Moreover, the fact that Ang II utilises the insulin-receptor substrate (IRS)-1 to relay signals towards their intracellular destination, provides the biochemical explanation of how these two systems interact in a healthy organism and in a diseased one. |
| 4143 | 12076180 | Since it is overactivity of the renin-angiotensin system that seems to impair the intracellular response to insulin signalling, cardiovascular drugs that modulate the cellular transmission of Ang II have attracted particular interest. |
| 4144 | 12076180 | As well as the already widely-used ACE inhibitors, selective blockers of the Ang II type 1 receptor (AT(1)) have been shown to be clinically effective in the control of haemodynamic parameters, but with perhaps a less striking effect on glucose homeostasis. |
| 4145 | 12076180 | The inhibition of Ang II by ACE-inhibitors frequently showed a positive effect on glycaemia and insulin sensitivity, while information on the effects of AT(1) receptor antagonists on glucose homeostasis is more limited and controversial. |
| 4146 | 12076180 | Several investigators have focused on the effects of the nuclear factors involved in gene transcriptions, especially with respect to the agonists/antagonists of peroxisome proliferator-activated receptors (PPARs) and their intriguing interconnections with the insulin and Ang II subcellular pathways. |
| 4147 | 12076180 | In fact, in vitro and in vivo experimental studies have shown that thiazolidinediones (selective PPAR-gamma ligands) are not only powerful insulin sensitisers, but also have anti-hypertensive and anti-atherosclerotic properties. |
| 4148 | 12076180 | Although a clearer picture is now emerging of the pathophysiological interaction between insulin and Ang II, especially from pre-clinical studies, there is much to be done before experimental findings can be used in daily clinical practice. |
| 4149 | 12079834 | Interestingly, this was associated with a decreased activation of Akt/PKB, but not its upstream regulator, PI3-kinase. |
| 4150 | 12079834 | Hyperglycemia-induced insulin resistance also has been described in adipocytes, where it has been linked to activation of novel and conventional protein kinase C isoforms that phosphorylate the insulin receptor and IRS. |
| 4151 | 12079834 | Here, it was associated with an increased propensity to apoptosis and, as in muscle, with an impaired ability of insulin to activate Akt. |
| 4152 | 12079834 | Whether AMPK activation can reverse or prevent insulin resistance in all of these cells remains to be determined. |
| 4153 | 12082100 | Differential roles of insulin receptor substrates in the anti-apoptotic function of insulin-like growth factor-1 and insulin. |
| 4154 | 12082100 | Insulin-like growth factor-1 (IGF-1) and insulin are known to prevent apoptosis. |
| 4155 | 12082100 | The signaling network of IGF-1 and insulin occurs via multiple pathways involving different insulin receptor substrates (IRSs). |
| 4156 | 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. |
| 4157 | 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. |
| 4158 | 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%. |
| 4159 | 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. |
| 4160 | 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. |
| 4161 | 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. |
| 4162 | 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. |
| 4163 | 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. |
| 4164 | 12082100 | Differential roles of insulin receptor substrates in the anti-apoptotic function of insulin-like growth factor-1 and insulin. |
| 4165 | 12082100 | Insulin-like growth factor-1 (IGF-1) and insulin are known to prevent apoptosis. |
| 4166 | 12082100 | The signaling network of IGF-1 and insulin occurs via multiple pathways involving different insulin receptor substrates (IRSs). |
| 4167 | 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. |
| 4168 | 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. |
| 4169 | 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%. |
| 4170 | 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. |
| 4171 | 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. |
| 4172 | 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. |
| 4173 | 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. |
| 4174 | 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. |
| 4175 | 12086932 | Peroxisome proliferator-activated receptor (PPAR)-gamma plays an important role in adipogenesis. |
| 4176 | 12086932 | Furthermore, overexpression of this mutant reduced the abundance of mRNAs for several key enzymes that contribute to triglyceride and free fatty acid metabolism as well as the amounts of GLUT4, insulin receptor, insulin receptor substrate (IRS), and C/EBPalpha mRNAs. |
| 4177 | 12086932 | It also reduced both the concentration of IRS2 and the insulin-stimulated glucose uptake. |
| 4178 | 12086949 | Upregulation of uptake activity occurred without any change in total cellular GLUT1 or GLUT4 protein content. |
| 4179 | 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. |
| 4180 | 12086949 | Despite upregulation of IRS-1, maximal insulin stimulation of Akt phosphorylation was unaltered by INH treatment. |
| 4181 | 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. |
| 4182 | 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. |
| 4183 | 12088865 | Insulin but not insulin-like growth factor-1 promotes the primordial to primary follicle transition. |
| 4184 | 12088865 | The current study utilizes a rat ovarian organ culture system to investigate the role of insulin and insulin-like growth factor-1 (IGF-1) in this process. |
| 4185 | 12088865 | Ovaries were also treated with epidermal growth factor (EGF) and hepatocyte growth factor (HGF) and neither had an effect on the primordial to primary follicle transition. |
| 4186 | 12088865 | Previous experiments have shown that kit ligand (KL), basic fibroblast growth factor (bFGF) and leukemia inhibitory factor (LIF) promote the primordial to primary follicle transition. |
| 4187 | 12088865 | Insulin was shown to have an additive effect with KL and LIF, but not bFGF. |
| 4188 | 12088865 | The fact that insulin can influence the primordial to primary follicle transition at low concentrations (i.e. 5 ng/ml) and that IGF-1 has no effect suggests that insulin is acting at the insulin receptor, not the IGF-1 receptor. |
| 4189 | 12088865 | The observation that insulin has an additive effect with KL and LIF, but not bFGF, suggests the insulin's site of action is likely the oocyte. |
| 4190 | 12128284 | Regulation of insulin action by CEACAM1. |
| 4191 | 12128284 | Earlier studies in transfected cells suggested that the carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), a substrate of the insulin receptor in liver, upregulates receptor-mediated insulin endocytosis and degradation in a phosphorylation-dependent manner. |
| 4192 | 12128284 | The transgenic mouse demonstrated that CEACAM1 increases insulin clearance to maintain insulin sensitivity. |
| 4193 | 12128284 | Because insulin resistance is the hallmark of type 2 diabetes, understanding the mechanism of CEACAM1 regulation of insulin clearance and action might lead to novel therapeutic strategies against this disease. |
| 4194 | 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. |
| 4195 | 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. |
| 4196 | 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. |
| 4197 | 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. |
| 4198 | 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. |
| 4199 | 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. |
| 4200 | 12138086 | EGF mimics the effects of insulin on both the metabolic and mitogenic pathways but utilize in part different signaling pathways. |
| 4201 | 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. |
| 4202 | 12145147 | Insulin-induced tyrosine phosphorylation of insulin receptor substrate (IRS)-1 was completely blocked, with unaltered expression of IRS-1. |
| 4203 | 12145147 | Troglitazone increased insulin action on IRS-1 phosphorylation, in both the absence and presence of co-culture. |
| 4204 | 12145147 | Insulin-regulated activation of Akt kinase in the myocytes was significantly reduced after co-culture, with troglitazone restoring insulin action. |
| 4205 | 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. |
| 4206 | 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. |
| 4207 | 12145157 | Improved insulin sensitivity and resistance to weight gain in mice null for the Ahsg gene. |
| 4208 | 12145157 | Fetuin inhibits insulin-induced insulin receptor (IR) autophosphorylation and tyrosine kinase activity in vitro, in intact cells, and in vivo. |
| 4209 | 12145157 | Here, we explore insulin signaling, glucose homeostasis, and the effect of a high-fat diet on weight gain, body fat composition, and glucose disposal in mice carrying two null alleles for the gene encoding fetuin, Ahsg (B6, 129-Ahsg(tm1Mbl)). |
| 4210 | 12145157 | Fetuin knockout (KO) mice demonstrate increased basal and insulin-stimulated phosphorylation of IR and the downstream signaling molecules mitogen-activated protein kinase (MAPK) and Akt in liver and skeletal muscle. |
| 4211 | 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. |
| 4212 | 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. |
| 4213 | 12169433 | Failure of IRS-2 signaling might explain the eventual loss of compensatory hyperinsulinemia during prolonged periods of peripheral insulin resistance. |
| 4214 | 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. |
| 4215 | 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. |
| 4216 | 12171564 | Recent advances include the discovery of a"small molecule" allosteric binding site on the insulin receptor, inhibitors of glycogen synthase kinase-3(GSK-3) which improve insulin sensitivity in diabetic animal models and inhibitors of protein kinase C- beta that are presently being evaluated in clinical trials for diabetic retinopathy. |
| 4217 | 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. |
| 4218 | 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. |
| 4219 | 12176670 | There was no difference in insulin sensitivity between lean IRS-1(+/-) and lean WT. |
| 4220 | 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. |
| 4221 | 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. |
| 4222 | 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. |
| 4223 | 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. |
| 4224 | 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. |
| 4225 | 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). |
| 4226 | 12196460 | Troglitazone did not alter insulin receptor number or IRS-1, IRS-2, PKB, PDK-1, or GLUT-4 protein expression. |
| 4227 | 12196460 | We conclude that increased PKB phosphorylation may contribute to the insulin-sensitizing effects of thiazolidinediones in human skeletal muscle. |
| 4228 | 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. |
| 4229 | 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). |
| 4230 | 12196460 | Troglitazone did not alter insulin receptor number or IRS-1, IRS-2, PKB, PDK-1, or GLUT-4 protein expression. |
| 4231 | 12196460 | We conclude that increased PKB phosphorylation may contribute to the insulin-sensitizing effects of thiazolidinediones in human skeletal muscle. |
| 4232 | 12213574 | Dose-dependent effects of insulin, insulin-like growth factor 1 and epidermal growth factor on BRET signal were in agreement with known pharmacological properties of these ligands. |
| 4233 | 12213574 | This methodology allows for rapid analysis of the effects of agonists on insulin receptor activity and could, therefore, be used in high-throughput screening for the discovery of molecules with insulin-like properties. |
| 4234 | 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. |
| 4235 | 12213887 | The IRS-1 Gly(972)Arg allele frequencies were identical in whites and African-Americans [0.95 (Gly) and 0.05 (Arg)]. |
| 4236 | 12231074 | Defects in muscle glycogen synthesis play a significant role in insulin resistance, and 3 potentially rate-controlling steps in muscle glucose metabolism have been implicated in its pathogenesis: glycogen synthase, hexokinase, and GLUT4 (the major insulin-stimulated glucose transporter). |
| 4237 | 12231074 | These alterations in glucose transport activity are likely the result of dysregulation of intramyocellular fatty acid metabolism, whereby fatty acids cause insulin resistance by activation of a serine kinase cascade, leading to decreased insulin-stimulated insulin receptor substrate (IRS)-1 tyrosine phosphorylation and decreased IRS-1-associated phosphatidylinositol 3-kinase activity, a required step in insulin-stimulated glucose transport into muscle. |
| 4238 | 12242462 | Improved metabolic disorders of insulin receptor-deficient mice by transgenic overexpression of glucokinase in the liver. |
| 4239 | 12351430 | Skeletal muscle insulin resistance in obesity-associated type 2 diabetes in monkeys is linked to a defect in insulin activation of protein kinase C-zeta/lambda/iota. |
| 4240 | 12351430 | Insulin increased activities of insulin receptor substrate (IRS)-1-dependent phosphatidylinositol (PI) 3-kinase and its downstream effectors, atypical protein kinase Cs (aPKCs) (zeta/lambda/iota) and protein kinase B (PKB) in muscles of nondiabetic monkeys. |
| 4241 | 12351437 | Different regulated expression of the tyrosine phosphatase-like proteins IA-2 and phogrin by glucose and insulin in pancreatic islets: relationship to development of insulin secretory responses in early life. |
| 4242 | 12351437 | IA-2 and phogrin are tyrosine phosphatase-like proteins that may mediate interactions between secretory granules and cytoskeleton in islets and neuroendocrine tissues. |
| 4243 | 12351437 | We investigated factors that regulate IA-2 and phogrin expression and their relationship to maturation of insulin secretory responses that occur after birth. |
| 4244 | 12351437 | Islet content of IA-2, but not phogrin, increased during the first 10 days of life in rats, when insulin secretion in response to glucose increased to adult levels. |
| 4245 | 12351437 | In cultured 5-day-old rat islets, IA-2 protein and mRNA was increased by glucose and agents that potentiate insulin secretion by the cAMP pathway. |
| 4246 | 12351437 | Addition of insulin increased IA-2 protein levels and insulin biosynthesis without affecting IA-2 mRNA. |
| 4247 | 12351437 | Blocking insulin secretion with diazoxide or insulin action with insulin receptor antibodies inhibited glucose-induced increases in IA-2 protein, but not those of mRNA. |
| 4248 | 12351437 | Thus, IA-2 is regulated at the mRNA level by glucose and elevated cAMP, whereas locally secreted insulin modulates IA-2 protein levels by stimulating biosynthesis. |
| 4249 | 12360255 | Structural biology of insulin and IGF1 receptors: implications for drug design. |
| 4250 | 12360255 | Here, we discuss recent progress in understanding the structure-function relationships of the insulin and insulin-like growth factor 1 (IGF1) receptors, their mechanism of activation and their implications for the design of insulin-receptor agonists for diabetes therapy and IGF1-receptor antagonists for cancer therapy. |
| 4251 | 12365822 | These include agents to improve and partially mimic insulin action, such as peroxisome proliferator-activated receptor-gamma (PPARgamma) agonists, stimulants of intracellular insulin signalling intermediates, and inhibitors of substances that deactivate insulin receptor tyrosine kinase activity. |
| 4252 | 12409500 | Gliclazide increases insulin receptor tyrosine phosphorylation but not p38 phosphorylation in insulin-resistant skeletal muscle cells. |
| 4253 | 12409500 | Although insulin receptor substrate-1 tyrosine phosphorylation was unaffected by gliclazide treatment, phosphatidylinositol 3-kinase activity was partially restored by treatment with gliclazide. |
| 4254 | 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. |
| 4255 | 12409500 | Treatment with gliclazide could not restore p38 phosphorylation in insulin-resistant cells. |
| 4256 | 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. |
| 4257 | 12417015 | PKC beta I and PKC beta II are DAG- and Ca(2+)-dependent conventional or classical isoforms of protein kinase C. |
| 4258 | 12417015 | This minireview will focus mainly on two areas of signal transduction where the roles of PKC beta I and PKC beta II are relatively well-characterized: immunoreceptor and insulin receptor systems. |
| 4259 | 12429837 | pp60Src mediates insulin-stimulated sequestration of the beta(2)-adrenergic receptor: insulin stimulates pp60Src phosphorylation and activation. |
| 4260 | 12429837 | Insulin stimulates a rapid phosphorylation and sequestration of the beta(2)-adrenergic receptor. |
| 4261 | 12429837 | Analysis of the signaling downstream of the insulin receptor with enzyme inhibitors revealed roles for both phosphatidylinositol 3-kinase and pp60Src. |
| 4262 | 12429837 | Inhibition of Src with PP2, like the inhibition of phosphatidylinositol 3-kinase with LY294002 [2-(4-morpholynyl)-8-phenyl-4H-1-benzopyran-4-one], blocked the activation of Src as well as insulin-stimulated sequestration of the beta(2)-adrenergic receptor. |
| 4263 | 12429837 | Inhibition of Src with PP2 blocks the ability of insulin to sequester beta(2)-adrenergic receptors and the translocation of the GLUT4 glucose transporters. |
| 4264 | 12429837 | Insulin stimulates Src to associate with the beta(2)-adrenergic receptor/AKAP250/protein kinase A/protein kinase C signaling complex. |
| 4265 | 12429837 | We report a novel positioning of Src, mediating signals from insulin to phosphatidylinositol 3-kinase and to beta(2)-adrenergic receptor trafficking. |
| 4266 | 12436329 | It has been well established that the insulin-stimulated redistribution of the insulin responsive glucose transporter, GLUT-4, from intracellular storage sites to the plasma membrane depends on the production of phosphoinositide 3,4,5 trisphosphate by the Class IA Phosphatidylinositol 3' kinase. |
| 4267 | 12436329 | Recent discoveries however, have shown the presence of a second insulin signalling pathway leading to GLUT-4 translocation, a pathway dependent on insulin receptor signalling emanating from caveolae or lipid rafts at the plasma membrane. |
| 4268 | 12436329 | This pathway begins with the phosphorylation of the adaptor protein Cbl by the insulin receptor, and results in the activation of a small GTP binding protein, TC10, a member of the Rho family. |
| 4269 | 12436329 | TC10 is able to modulate actin structure in 3T3L1 adipocytes, and its overexpression inhibits insulin-stimulated GLUT-4 translocation, an inhibition completely dependent on localization of TC10 to the caveolae or lipid rafts. |
| 4270 | 12436329 | The spatial compartmentalization of insulin signalling from caveolae or lipid rafts provides a novel signalling pathway that functions in concert with general signalling mechanisms in the control of actin dynamics regulating insulin-dependent GLUT-4 translocation. |
| 4271 | 12436329 | It has been well established that the insulin-stimulated redistribution of the insulin responsive glucose transporter, GLUT-4, from intracellular storage sites to the plasma membrane depends on the production of phosphoinositide 3,4,5 trisphosphate by the Class IA Phosphatidylinositol 3' kinase. |
| 4272 | 12436329 | Recent discoveries however, have shown the presence of a second insulin signalling pathway leading to GLUT-4 translocation, a pathway dependent on insulin receptor signalling emanating from caveolae or lipid rafts at the plasma membrane. |
| 4273 | 12436329 | This pathway begins with the phosphorylation of the adaptor protein Cbl by the insulin receptor, and results in the activation of a small GTP binding protein, TC10, a member of the Rho family. |
| 4274 | 12436329 | TC10 is able to modulate actin structure in 3T3L1 adipocytes, and its overexpression inhibits insulin-stimulated GLUT-4 translocation, an inhibition completely dependent on localization of TC10 to the caveolae or lipid rafts. |
| 4275 | 12436329 | The spatial compartmentalization of insulin signalling from caveolae or lipid rafts provides a novel signalling pathway that functions in concert with general signalling mechanisms in the control of actin dynamics regulating insulin-dependent GLUT-4 translocation. |
| 4276 | 12447443 | A central role for JNK in obesity and insulin resistance. |
| 4277 | 12447443 | The c-Jun amino-terminal kinases (JNKs) can interfere with insulin action in cultured cells and are activated by inflammatory cytokines and free fatty acids, molecules that have been implicated in the development of type 2 diabetes. |
| 4278 | 12447443 | Furthermore, an absence of JNK1 results in decreased adiposity, significantly improved insulin sensitivity and enhanced insulin receptor signalling capacity in two different models of mouse obesity. |
| 4279 | 12447443 | Thus, JNK is a crucial mediator of obesity and insulin resistance and a potential target for therapeutics. |
| 4280 | 12453891 | Interleukin-6 induces cellular insulin resistance in hepatocytes. |
| 4281 | 12453891 | Interleukin (IL)-6 is one of several proinflammatory cytokines that have been associated with insulin resistance and type 2 diabetes. |
| 4282 | 12453891 | Nonetheless, little evidence supports a direct role for IL-6 in mediating insulin resistance. |
| 4283 | 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. |
| 4284 | 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. |
| 4285 | 12453891 | In addition, insulin-dependent activation of Akt, important in mediating insulin's downstream metabolic actions, is markedly inhibited by IL-6 treatment. |
| 4286 | 12453891 | Finally, a 1.5-h preincubation of primary hepatocytes with IL-6 inhibits insulin-induced glycogen synthesis by 75%. |
| 4287 | 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. |
| 4288 | 12470244 | This review focuses on the insulin receptor as a target for therapeutic intervention, and describes the recent discovery of small molecules that act on the receptor and either enhance or directly emulate the actions of insulin both in vitro and in vivo. |
| 4289 | 12471165 | Combined knockout studies of insulin and Igf1 receptors indicate that the insulin receptor also promotes embryonic growth. |
| 4290 | 12471165 | Experimental crosses of mice with insulin receptor haploinsufficiency have been instrumental to the genetic analysis of insulin action by enabling us to assign specific roles to different insulin receptor substrates and identify novel elements in insulin signaling. |
| 4291 | 12471165 | Combined knockout studies of insulin and Igf1 receptors indicate that the insulin receptor also promotes embryonic growth. |
| 4292 | 12471165 | Experimental crosses of mice with insulin receptor haploinsufficiency have been instrumental to the genetic analysis of insulin action by enabling us to assign specific roles to different insulin receptor substrates and identify novel elements in insulin signaling. |
| 4293 | 12475767 | Increased insulin resistance in obese children who have both 972 IRS-1 and 1057 IRS-2 polymorphisms. |
| 4294 | 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. |
| 4295 | 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. |
| 4296 | 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). |
| 4297 | 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). |
| 4298 | 12475767 | These observations are reminiscent of the insulin sensitivity phenotypes in double IRS-1(+/-) IRS-2(+/-) heterozygous knockout mice. |
| 4299 | 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. |
| 4300 | 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. |
| 4301 | 12475786 | Overexpression of the insulin receptor and IRS-1 in beta-cells results in increased insulin secretion and increased cytosolic Ca(2+). |
| 4302 | 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. |
| 4303 | 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. |
| 4304 | 12475786 | Overexpression of the insulin receptor and IRS-1 in beta-cells results in increased insulin secretion and increased cytosolic Ca(2+). |
| 4305 | 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. |
| 4306 | 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. |
| 4307 | 12475786 | Overexpression of the insulin receptor and IRS-1 in beta-cells results in increased insulin secretion and increased cytosolic Ca(2+). |
| 4308 | 12476961 | Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of the insulin signal transduction cascade, initiated when insulin binds to the insulin receptor. |
| 4309 | 12476961 | PTP1B-deficient mice are more sensitive to insulin, and have improved glycemic control and resistance to diet-induced obesity than wild-type control mice. |
| 4310 | 12476961 | Diabetic mice treated with PTP1B antisense oligonucleotides intraperitoneally have lower PTP1B protein levels in liver and fat, reduced plasma insulin, blood glucose and hemoglobin A1c (HbA1c) levels. |
| 4311 | 12476961 | These studies validate PTP1B as a promising drug discovery target for the treatment of insulin resistance, diabetes and obesity. |
| 4312 | 12493745 | Impact of genetic background and ablation of insulin receptor substrate (IRS)-3 on IRS-2 knock-out mice. |
| 4313 | 12493745 | When mice with diabetes were excluded from the analysis of glucose and insulin tolerance test, IRS-2(-/-)IRS-3(-/-) showed a degree of glucose intolerance and insulin resistance similar to those of IRS-2(-/-) mice. |
| 4314 | 12493745 | Both IRS-2(-/-) and IRS-2(-/-)IRS-3(-/-) mice had moderately reduced beta-cell mass despite having insulin resistance. |
| 4315 | 12493745 | Insulin-positive beta-cells were decreased to nearly zero in IRS-2(-/-) mice with diabetes. |
| 4316 | 12493745 | Although Pdx1 and glucose transporter 2 expressions were essentially unaltered in islets from IRS-2(-/-) mice without diabetes, they were dramatically decreased in IRS-2(-/-) mice with diabetes. |
| 4317 | 12502490 | Dietary cod protein restores insulin-induced activation of phosphatidylinositol 3-kinase/Akt and GLUT4 translocation to the T-tubules in skeletal muscle of high-fat-fed obese rats. |
| 4318 | 12502490 | Insulin-induced tyrosine phosphorylation of the insulin receptor and insulin receptor substrate (IRS) proteins were similar in muscle of chow- and high-fat-fed rats regardless of the dietary protein source. |
| 4319 | 12502490 | The activation of the downstream kinase Akt/PKB by insulin, assessed by in vitro kinase assay and phosphorylation of GSK-3beta, were also impaired in muscle of high-fat-fed rats consuming casein or soy protein, but these defects were also fully prevented by dietary cod protein. |
| 4320 | 12502490 | Normalization of PI 3-kinase/Akt activation by insulin in rats fed high-fat diets with cod protein was associated with improved translocation of GLUT4 to the T-tubules but not to the plasma membrane. |
| 4321 | 12502490 | Taken together, these results show that dietary cod protein is a natural insulin-sensitizing agent that appears to prevent obesity-linked muscle insulin resistance by normalizing insulin activation of the PI 3-kinase/Akt pathway and by selectively improving GLUT4 translocation to the T-tubules. |
| 4322 | 12502489 | Reduction of protein tyrosine phosphatase 1B increases insulin-dependent signaling in ob/ob mice. |
| 4323 | 12502489 | Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of insulin receptor (IR) signal transduction and a drug target for treatment of type 2 diabetes. |
| 4324 | 12502489 | Using PTP1B antisense oligonucleotides (ASOs), effects of decreased PTP1B levels on insulin signaling in diabetic ob/ob mice were examined. |
| 4325 | 12502489 | However, in PTP1B ASO-treated mice, in which PTP1B protein was decreased by 60% in liver, similar stimulation with insulin resulted in increased tyrosine phosphorylation of the IR and IR substrate (IRS)-1 and -2 by threefold, fourfold, and threefold, respectively. |
| 4326 | 12502489 | Protein kinase B (PKB) serine phosphorylation was increased sevenfold in liver of PTP1B ASO-treated mice upon insulin stimulation, while phosphorylation of PKB substrates, glycogen synthase kinase (GSK)-3alpha and -3beta, was increased more than twofold. |
| 4327 | 12502489 | Peripheral insulin signaling was increased by PTP1B ASO, as evidenced by increased phosphorylation of PKB in muscle of insulin-stimulated PTP1B ASO-treated animals despite the lack of measurable effects on muscle PTP1B protein. |
| 4328 | 12502489 | These results indicate that reduction of PTP1B is sufficient to increase insulin-dependent metabolic signaling and improve insulin sensitivity in a diabetic animal model. |
| 4329 | 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. |
| 4330 | 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. |
| 4331 | 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. |
| 4332 | 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. |
| 4333 | 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. |
| 4334 | 12502902 | Glucosamine had no effect on the insulin-stimulated tyrosine phosphorylation of the insulin receptor and insulin receptor substrate (IRS)-1. |
| 4335 | 12502902 | Glucosamine infusion also inhibited insulin-stimulated PI 3-kinase activity associated with IRS-1, 2, 3 by 30%, 43%, and 44%, respectively. |
| 4336 | 12502902 | There was no difference in the association of the 85kDa subunit of PI 3-kinase with the IRS-1 and IRS-2 protein. |
| 4337 | 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%. |
| 4338 | 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. |
| 4339 | 12502902 | Glucosamine had no effect on the insulin-stimulated tyrosine phosphorylation of the insulin receptor and insulin receptor substrate (IRS)-1. |
| 4340 | 12502902 | Glucosamine infusion also inhibited insulin-stimulated PI 3-kinase activity associated with IRS-1, 2, 3 by 30%, 43%, and 44%, respectively. |
| 4341 | 12502902 | There was no difference in the association of the 85kDa subunit of PI 3-kinase with the IRS-1 and IRS-2 protein. |
| 4342 | 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%. |
| 4343 | 12504077 | Reduction of protein-tyrosine phosphatase-1B increases insulin signaling in FAO hepatoma cells. |
| 4344 | 12504077 | Protein-tyrosine phosphatase-1B (PTP1B) has been implicated as a negative regulator of insulin signaling. |
| 4345 | 12504077 | PTP1B dephosphorylates the insulin receptor and insulin receptor substrates (IRS-1/2), inhibiting the insulin-signaling pathway. |
| 4346 | 12504077 | PTP1B has been reported to be elevated in diabetes and insulin-resistant states. |
| 4347 | 12504077 | Conversely, PTP1B null mice have increased insulin sensitivity. |
| 4348 | 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. |
| 4349 | 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. |
| 4350 | 12504077 | These results demonstrate that reduction of PTP1B can modulate key insulin signaling events downstream of the insulin receptor. |
| 4351 | 12504077 | Reduction of protein-tyrosine phosphatase-1B increases insulin signaling in FAO hepatoma cells. |
| 4352 | 12504077 | Protein-tyrosine phosphatase-1B (PTP1B) has been implicated as a negative regulator of insulin signaling. |
| 4353 | 12504077 | PTP1B dephosphorylates the insulin receptor and insulin receptor substrates (IRS-1/2), inhibiting the insulin-signaling pathway. |
| 4354 | 12504077 | PTP1B has been reported to be elevated in diabetes and insulin-resistant states. |
| 4355 | 12504077 | Conversely, PTP1B null mice have increased insulin sensitivity. |
| 4356 | 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. |
| 4357 | 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. |
| 4358 | 12504077 | These results demonstrate that reduction of PTP1B can modulate key insulin signaling events downstream of the insulin receptor. |
| 4359 | 12510059 | Modulation of insulin-stimulated degradation of human insulin receptor substrate-1 by Serine 312 phosphorylation. |
| 4360 | 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. |
| 4361 | 12510059 | An additional mechanism for modulating insulin signaling is via the down-regulation of IRS-1 protein levels. |
| 4362 | 12510059 | Insulin-induced degradation of IRS-1 has been well documented, both in cells as well as in patients with diabetes. |
| 4363 | 12510059 | In the present study we have examined the potential role of different signaling cascades in the insulin-induced degradation of IRS-1. |
| 4364 | 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. |
| 4365 | 12510059 | Conversely, overexpression of this enzyme potentiated insulin-stimulated IRS-1 degradation. |
| 4366 | 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. |
| 4367 | 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. |
| 4368 | 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. |
| 4369 | 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. |
| 4370 | 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. |
| 4371 | 12514263 | The expression of glucose-6-phosphatase (G6Pase) mRNA is repressed by insulin and stimulated by cAMP and dexamethasone, with the insulin effect dominant. |
| 4372 | 12514263 | Insulin receptor substrate (IRS) phosphorylation, IRS-association with phosphatidylinositol 3 (PI3)-kinase and activation of protein kinase B (PKB) were not significantly different among the refed groups. |
| 4373 | 12530968 | The forkhead transcription factor Foxo1 regulates adipocyte differentiation. |
| 4374 | 12530968 | The forkhead transcription factor Foxo1 is regulated by insulin via Akt-dependent phosphorylation and nuclear exclusion. |
| 4375 | 12530968 | We show that Foxo1 is induced in the early stages of adipocyte differentiation but that its activation is delayed until the end of the clonal expansion phase. |
| 4376 | 12530968 | Constitutively active Foxo1 prevents the differentiation of preadipocytes, while dominant-negative Foxo1 restores adipocyte differentiation of fibroblasts from insulin receptor-deficient mice. |
| 4377 | 12530968 | We propose that Foxo1 plays an important role in the integration of hormone-activated signaling pathways with the complex transcriptional cascade that promotes adipocyte differentiation. |
| 4378 | 12540590 | Insulin activation of phosphatidylinositol 3-kinase in the hypothalamic arcuate nucleus: a key mediator of insulin-induced anorexia. |
| 4379 | 12540590 | In peripheral tissues, insulin signaling involves activation of the insulin receptor substrate (IRS)-phosphatidylinositol 3-kinase (PI3K) enzyme system. |
| 4380 | 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. |
| 4381 | 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. |
| 4382 | 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. |
| 4383 | 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. |
| 4384 | 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. |
| 4385 | 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. |
| 4386 | 12540590 | Insulin activation of phosphatidylinositol 3-kinase in the hypothalamic arcuate nucleus: a key mediator of insulin-induced anorexia. |
| 4387 | 12540590 | In peripheral tissues, insulin signaling involves activation of the insulin receptor substrate (IRS)-phosphatidylinositol 3-kinase (PI3K) enzyme system. |
| 4388 | 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. |
| 4389 | 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. |
| 4390 | 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. |
| 4391 | 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. |
| 4392 | 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. |
| 4393 | 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. |
| 4394 | 12554784 | TNFalpha, which activates three different MAPKs [ERK, p38, and jun amino terminal kinase (JNK)], also induces insulin resistance. |
| 4395 | 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. |
| 4396 | 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. |
| 4397 | 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. |
| 4398 | 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. |
| 4399 | 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. |
| 4400 | 12560330 | Suppressor of cytokine signaling-3 (SOCS-3), a potential mediator of interleukin-6-dependent insulin resistance in hepatocytes. |
| 4401 | 12560330 | Interleukin-6 (IL-6) is one of several pro-inflammatory cytokines implicated in insulin resistance during infection, cachexia, and obesity. |
| 4402 | 12560330 | We recently demonstrated that IL-6 inhibits insulin signaling in hepatocytes (Senn, J. |
| 4403 | 12560330 | Members of the suppressors of cytokine signaling (SOCS) family associate with the insulin receptor (IR), and their ectopic expression inhibits IR signaling. |
| 4404 | 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. |
| 4405 | 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. |
| 4406 | 12560330 | IL-6 induced SOCS-3 transcript at 30 min with a maximum effect at 1 h. |
| 4407 | 12560330 | SOCS-3 induction by IL-6 paralleled IL-6-dependent inhibition of IR signal transduction. |
| 4408 | 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. |
| 4409 | 12560330 | SOCS-3 was also a direct inhibitor of insulin receptor autophosphorylation in vitro. |
| 4410 | 12560330 | In mice exposed to IL-6 for 60-90 min, hepatic SOCS-3 expression was increased. |
| 4411 | 12560330 | This was associated with inhibition of hepatic insulin-dependent receptor autophosphorylation and IRS-1 tyrosine phosphorylation. |
| 4412 | 12560330 | These data suggest that induction of SOCS-3 in liver may be an important mechanism of IL-6-mediated insulin resistance. |
| 4413 | 12560330 | Suppressor of cytokine signaling-3 (SOCS-3), a potential mediator of interleukin-6-dependent insulin resistance in hepatocytes. |
| 4414 | 12560330 | Interleukin-6 (IL-6) is one of several pro-inflammatory cytokines implicated in insulin resistance during infection, cachexia, and obesity. |
| 4415 | 12560330 | We recently demonstrated that IL-6 inhibits insulin signaling in hepatocytes (Senn, J. |
| 4416 | 12560330 | Members of the suppressors of cytokine signaling (SOCS) family associate with the insulin receptor (IR), and their ectopic expression inhibits IR signaling. |
| 4417 | 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. |
| 4418 | 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. |
| 4419 | 12560330 | IL-6 induced SOCS-3 transcript at 30 min with a maximum effect at 1 h. |
| 4420 | 12560330 | SOCS-3 induction by IL-6 paralleled IL-6-dependent inhibition of IR signal transduction. |
| 4421 | 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. |
| 4422 | 12560330 | SOCS-3 was also a direct inhibitor of insulin receptor autophosphorylation in vitro. |
| 4423 | 12560330 | In mice exposed to IL-6 for 60-90 min, hepatic SOCS-3 expression was increased. |
| 4424 | 12560330 | This was associated with inhibition of hepatic insulin-dependent receptor autophosphorylation and IRS-1 tyrosine phosphorylation. |
| 4425 | 12560330 | These data suggest that induction of SOCS-3 in liver may be an important mechanism of IL-6-mediated insulin resistance. |
| 4426 | 12560330 | Suppressor of cytokine signaling-3 (SOCS-3), a potential mediator of interleukin-6-dependent insulin resistance in hepatocytes. |
| 4427 | 12560330 | Interleukin-6 (IL-6) is one of several pro-inflammatory cytokines implicated in insulin resistance during infection, cachexia, and obesity. |
| 4428 | 12560330 | We recently demonstrated that IL-6 inhibits insulin signaling in hepatocytes (Senn, J. |
| 4429 | 12560330 | Members of the suppressors of cytokine signaling (SOCS) family associate with the insulin receptor (IR), and their ectopic expression inhibits IR signaling. |
| 4430 | 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. |
| 4431 | 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. |
| 4432 | 12560330 | IL-6 induced SOCS-3 transcript at 30 min with a maximum effect at 1 h. |
| 4433 | 12560330 | SOCS-3 induction by IL-6 paralleled IL-6-dependent inhibition of IR signal transduction. |
| 4434 | 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. |
| 4435 | 12560330 | SOCS-3 was also a direct inhibitor of insulin receptor autophosphorylation in vitro. |
| 4436 | 12560330 | In mice exposed to IL-6 for 60-90 min, hepatic SOCS-3 expression was increased. |
| 4437 | 12560330 | This was associated with inhibition of hepatic insulin-dependent receptor autophosphorylation and IRS-1 tyrosine phosphorylation. |
| 4438 | 12560330 | These data suggest that induction of SOCS-3 in liver may be an important mechanism of IL-6-mediated insulin resistance. |
| 4439 | 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. |
| 4440 | 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. |
| 4441 | 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. |
| 4442 | 12594228 | Co-treatment of cells with insulin and LY294002, while reducing total IRS-1 phosphorylation, increased its phosphotyrosine content, enhancing IRS-1/PI3K association. |
| 4443 | 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. |
| 4444 | 12594228 | Contrarily, insulin-induced IRS-2 down-regulation occurred via a PI3K/mTOR pathway. |
| 4445 | 12594228 | Suppression of IRS-1/2 down-regulation by LY294002 rescued the responsiveness of PKB and MAPK toward acute insulin stimulation. |
| 4446 | 12594228 | Conversely, adenoviral-driven expression of constitutively active PI3K induced an insulin-independent reduction in IRS-1/2 protein levels. |
| 4447 | 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. |
| 4448 | 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. |
| 4449 | 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. |
| 4450 | 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. |
| 4451 | 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. |
| 4452 | 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. |
| 4453 | 12594228 | Co-treatment of cells with insulin and LY294002, while reducing total IRS-1 phosphorylation, increased its phosphotyrosine content, enhancing IRS-1/PI3K association. |
| 4454 | 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. |
| 4455 | 12594228 | Contrarily, insulin-induced IRS-2 down-regulation occurred via a PI3K/mTOR pathway. |
| 4456 | 12594228 | Suppression of IRS-1/2 down-regulation by LY294002 rescued the responsiveness of PKB and MAPK toward acute insulin stimulation. |
| 4457 | 12594228 | Conversely, adenoviral-driven expression of constitutively active PI3K induced an insulin-independent reduction in IRS-1/2 protein levels. |
| 4458 | 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. |
| 4459 | 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. |
| 4460 | 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. |
| 4461 | 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. |
| 4462 | 12609497 | Insulin and leptin revisited: adiposity signals with overlapping physiological and intracellular signaling capabilities. |
| 4463 | 12609497 | The adipocyte-derived hormone leptin and the pancreatic beta cell-derived hormone insulin each function as afferent signals to the hypothalamus in an endocrine feedback loop that regulates body adiposity. |
| 4464 | 12609497 | Defects in either insulin or leptin signaling in the brain result in hyperphagia, disordered glucose homeostasis, and reproductive dysfunction. |
| 4465 | 12609497 | To explain this striking physiological overlap, we hypothesize that hypothalamic insulin and leptin signaling converge upon a single intracellular signal transduction pathway, known as the insulin-receptor-substrate phosphatidylinositol 3-kinase pathway. |
| 4466 | 12609497 | Here we synthesize data from a variety of model systems in which such "cross-talk" between insulin and leptin signal transduction has either been observed or can be inferred, discuss our own data demonstrating that insulin and leptin both activate hypothalamic phosphatidylinositol 3-kinase signaling, and discuss the significance of such convergence with respect to neuronal function in normal individuals and in pathological states such as obesity. |
| 4467 | 12609497 | Identification of the key early molecular events mediating the action of both insulin and leptin in hypothalamic neurons promises new insight into the regulation of these neurons in health and disease. |
| 4468 | 12618360 | Resistin inhibits glucose uptake in L6 cells independently of changes in insulin signaling and GLUT4 translocation. |
| 4469 | 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. |
| 4470 | 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. |
| 4471 | 12618360 | Incubation with recombinant resistin resulted in a dose-dependent inhibition of insulin-stimulated 2-deoxyglucose (2-DG) uptake. |
| 4472 | 12618360 | The inhibitory effect of resistin on insulin-stimulated 2-DG uptake was not the result of impaired GLUT4 translocation to the plasma membrane. |
| 4473 | 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. |
| 4474 | 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. |
| 4475 | 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. |
| 4476 | 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. |
| 4477 | 12624425 | The present review will summarize some of the different knockouts and transgenics generated recently to study type 2 diabetes and critically evaluate the techniques used to examine the function of the insulin receptor in two nonclassical insulin target tissues--the pancreatic islet and the central nervous system. |
| 4478 | 12643127 | Extreme forms of insulin resistance may be caused rarely by mutations in the genes for the insulin receptor and peroxisome proliferator-activated receptor gamma. |
| 4479 | 12649327 | Antisense protein tyrosine phosphatase 1B reverses activation of p38 mitogen-activated protein kinase in liver of ob/ob mice. |
| 4480 | 12649327 | Phosphorylation of stress-activated kinase p38, a MAPK family member, was increased in liver of ob/ob diabetic mice relative to lean littermates. |
| 4481 | 12649327 | Treatment of ob/ob mice with protein tyrosine phosphatase 1B (PTP1B) antisense oligonucleotides (ASO) reduced phosphorylation of p38 in liver-to below lean littermate levels-and normalized plasma glucose while reducing plasma insulin. |
| 4482 | 12649327 | Phosphorylation of ERK, but not JNK, was also decreased in ASO-treated mice. |
| 4483 | 12649327 | PTP1B ASO decreased TNFalpha protein levels and phosphorylation of the transcription factor cAMP response element binding protein (CREB) in liver, both of which can occur through decreased phosphorylation of p38 and both of which have been implicated in insulin resistance or hyperglycemia. |
| 4484 | 12649327 | Decreased p38 phosphorylation was not directly due to decreased phosphorylation of the kinases that normally phosphorylate p38-MKK3 and MKK6. |
| 4485 | 12649327 | Additionally, p38 phosphorylation was not enhanced in liver upon insulin stimulation of ASO-treated ob/ob mice (despite increased activation of other signaling molecules) corroborating that p38 is not directly affected via the insulin receptor. |
| 4486 | 12649327 | Instead, decreased phosphorylation of p38 may be due to increased expression of MAPK phosphatases, particularly the p38/ERK phosphatase PAC1 (phosphatase of activated cells). |
| 4487 | 12649327 | This study demonstrates that reduction of PTP1B protein using ASO reduces activation of p38 and its substrates TNFalpha and CREB in liver of diabetic mice, which correlates with decreased hyperglycemia and hyperinsulinemia. |
| 4488 | 12663463 | Tanis overexpression reduced glucose uptake, basal and insulin-stimulated glycogen synthesis, and glycogen content and attenuated the suppression of PEPCK gene expression by insulin, but it did not affect insulin-stimulated insulin receptor phosphorylation or triglyceride synthesis. |
| 4489 | 12663464 | Defective signaling through Akt-2 and -3 but not Akt-1 in insulin-resistant human skeletal muscle: potential role in insulin resistance. |
| 4490 | 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. |
| 4491 | 12663464 | It is unknown, however, which Akt isoform shows impaired activation in insulin resistance. |
| 4492 | 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. |
| 4493 | 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. |
| 4494 | 12663464 | Insulin activated all Akt isoforms in lean muscles, whereas only Akt-1 was activated in obese muscles. |
| 4495 | 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. |
| 4496 | 12663464 | In contrast, insulin- or EGF-stimulated phosphotyrosine-associated PI3K activity was not different between lean and obese muscles. |
| 4497 | 12665574 | A nucleoprotein complex containing Sp1, C/EBP beta, and HMGI-Y controls human insulin receptor gene transcription. |
| 4498 | 12665574 | Recently, we demonstrated that HMGI-Y is required for proper transcription of the insulin receptor (IR) gene. |
| 4499 | 12665574 | Here we provide evidence that transcriptional activation of the human IR promoter requires the assembly of a transcriptionally active multiprotein-DNA complex which includes, in addition to HMGI-Y, the ubiquitously expressed transcription factor Sp1 and the CCAAT-enhancer binding protein beta (C/EBP beta). |
| 4500 | 12665574 | We show that HMGI-Y physically interacts with Sp1 and C/EBP beta and facilitates the binding of both factors to the IR promoter in vitro. |
| 4501 | 12665574 | Together, these findings demonstrate that HMGI-Y plays significant molecular roles in the transcriptional activities of these factors in the context of the IR gene and provide concordant support for the hypothesis that, in affected individuals, a putative defect in these nuclear proteins may cause decreased IR expression with subsequent impairment of insulin signaling and action. |
| 4502 | 12665574 | A nucleoprotein complex containing Sp1, C/EBP beta, and HMGI-Y controls human insulin receptor gene transcription. |
| 4503 | 12665574 | Recently, we demonstrated that HMGI-Y is required for proper transcription of the insulin receptor (IR) gene. |
| 4504 | 12665574 | Here we provide evidence that transcriptional activation of the human IR promoter requires the assembly of a transcriptionally active multiprotein-DNA complex which includes, in addition to HMGI-Y, the ubiquitously expressed transcription factor Sp1 and the CCAAT-enhancer binding protein beta (C/EBP beta). |
| 4505 | 12665574 | We show that HMGI-Y physically interacts with Sp1 and C/EBP beta and facilitates the binding of both factors to the IR promoter in vitro. |
| 4506 | 12665574 | Together, these findings demonstrate that HMGI-Y plays significant molecular roles in the transcriptional activities of these factors in the context of the IR gene and provide concordant support for the hypothesis that, in affected individuals, a putative defect in these nuclear proteins may cause decreased IR expression with subsequent impairment of insulin signaling and action. |
| 4507 | 12670229 | Protein tyrosine phosphatase 1B (PTP1B) is an enzyme that downregulates the insulin receptor. |
| 4508 | 12670229 | Inhibition of PTP1B is expected to improve insulin action, and the design of small molecule PTP1B inhibitors to treat type II diabetes has received considerable attention. |
| 4509 | 12678842 | Compelling evidence for the existence of an insulin receptor specific PTP has come from the remarkable phenotype of the PTP1B deficient mouse. |
| 4510 | 12678842 | PTP1B deficient mice display an insulin sensitive phenotype and are able to maintain glucose homeostasis with about half the level of circulating insulin. |
| 4511 | 12678842 | In response to insulin administration PTP1B deficient mice have a significant increase in insulin receptor phosphorylation in liver and muscle compared to wild type controls. |
| 4512 | 12678842 | These observations strongly support PTP1B as a negative regulator of insulin action, thereby making it an ideal therapeutic target for intervention in type 2 diabetes and obesity. |
| 4513 | 12678842 | Compelling evidence for the existence of an insulin receptor specific PTP has come from the remarkable phenotype of the PTP1B deficient mouse. |
| 4514 | 12678842 | PTP1B deficient mice display an insulin sensitive phenotype and are able to maintain glucose homeostasis with about half the level of circulating insulin. |
| 4515 | 12678842 | In response to insulin administration PTP1B deficient mice have a significant increase in insulin receptor phosphorylation in liver and muscle compared to wild type controls. |
| 4516 | 12678842 | These observations strongly support PTP1B as a negative regulator of insulin action, thereby making it an ideal therapeutic target for intervention in type 2 diabetes and obesity. |
| 4517 | 12678846 | The leukocyte common antigen-related protein LAR: candidate PTP for inhibitory targeting. |
| 4518 | 12678846 | The leukocyte common antigen-related protein, LAR, is a receptor-like protein tyrosine phosphatase (PTP) which has a wide tissue distribution. |
| 4519 | 12678846 | Current evidence supports a role for LAR in cadherin complexes where it associates with and dephosphorylates beta-catenin, a pathway which may be critical for cadherin complex stability and cell-cell association. |
| 4520 | 12678846 | Finally, considerable data support a role for LAR in negatively regulating the insulin receptor signaling. |
| 4521 | 12678846 | Now that targeting of specific PTPs for therapeutic inhibition is a reality, the clinically relevant pathways requiring LAR must be identified. |
| 4522 | 12678846 | Inhibition of LAR might improve insulin sensitivity in patients with insulin resistance and type 2 diabetes. |
| 4523 | 12678846 | Unfortunately, the LAR knockout mouse displays no improvement in insulin sensitivity but rather has defects in terminal mammary gland development and in basal forebrain cholinergic neurons. |
| 4524 | 12686100 | Semicarbazide-sensitive amine oxidase activity exerts insulin-like effects on glucose metabolism and insulin-signaling pathways in adipose cells. |
| 4525 | 12686100 | Semicarbazide-sensitive amine oxidase (SSAO) is very abundant at the plasma membrane in adipocytes. |
| 4526 | 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. |
| 4527 | 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. |
| 4528 | 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. |
| 4529 | 12730204 | As compared with the wild type, insulin-stimulated phosphorylation of the insulin receptor (IR) and insulin receptor substrate I was significantly reduced, and activities of phosphatidylinositol 3-kinase and glycogen synthase were low in transgenic muscle. |
| 4530 | 12730204 | In response to insulin, NEU3 was found to undergo tyrosine phosphorylation and subsequent association with the Grb2 protein, thus being activated and causing negative regulation of insulin signaling. |
| 4531 | 12730204 | In fact, accumulation of GM1 and GM2, the possible sialidase products in transgenic tissues, caused inhibition of IR phosphorylation in vitro, and blocking of association with Grb2 resulted in reversion of impaired insulin signaling in L6 cells. |
| 4532 | 12730204 | The data indicate that NEU3 indeed participates in the control of insulin signaling, probably via modulation of gangliosides and interaction with Grb2, and that the mice can serve as a valuable model for human insulin-resistant diabetes. |
| 4533 | 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. |
| 4534 | 12730241 | Both proteins are tyrosine-phosphorylated in response to insulin and IGF-1 in transfected cells, although the kinetics differ. |
| 4535 | 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. |
| 4536 | 12730241 | IRS5/DOK4 and IRS6/DOK5 represent two new signaling proteins with potential roles in insulin and IGF-1 action. |
| 4537 | 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. |
| 4538 | 12730241 | Both proteins are tyrosine-phosphorylated in response to insulin and IGF-1 in transfected cells, although the kinetics differ. |
| 4539 | 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. |
| 4540 | 12730241 | IRS5/DOK4 and IRS6/DOK5 represent two new signaling proteins with potential roles in insulin and IGF-1 action. |
| 4541 | 12734206 | Interaction of filamin A with the insulin receptor alters insulin-dependent activation of the mitogen-activated protein kinase pathway. |
| 4542 | 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. |
| 4543 | 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. |
| 4544 | 12734206 | Insulin-dependent translocation of Shc, SOS1, and MAPK to lipid raft microdomains was markedly attenuated by FLNa expression. |
| 4545 | 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. |
| 4546 | 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. |
| 4547 | 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. |
| 4548 | 12734206 | Taken together, these results indicate that FLNa interacts constitutively with the IR to exert an inhibitory tone along the MAPK activation pathway. |
| 4549 | 12734206 | Interaction of filamin A with the insulin receptor alters insulin-dependent activation of the mitogen-activated protein kinase pathway. |
| 4550 | 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. |
| 4551 | 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. |
| 4552 | 12734206 | Insulin-dependent translocation of Shc, SOS1, and MAPK to lipid raft microdomains was markedly attenuated by FLNa expression. |
| 4553 | 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. |
| 4554 | 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. |
| 4555 | 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. |
| 4556 | 12734206 | Taken together, these results indicate that FLNa interacts constitutively with the IR to exert an inhibitory tone along the MAPK activation pathway. |
| 4557 | 12740011 | Early growth restriction leads to down regulation of protein kinase C zeta and insulin resistance in skeletal muscle. |
| 4558 | 12740011 | This impaired insulin action was not related to changes in expression of either the insulin receptor or glucose transporter 4 (GLUT 4). |
| 4559 | 12740011 | However, LP muscle expressed significantly less (P<0.001) of the zeta isoform of protein kinase C (PKC zeta) compared with controls. |
| 4560 | 12746630 | The discovery of pharmacological agents that specifically stimulate the autophosphorylation of the insulin receptor or inhibit its dephosphorylation will be of great importance for the treatment of insulin resistant or insulin deficient patients. |
| 4561 | 12746630 | This methodology allows for rapid analysis of the effects of agonists on insulin receptor activity and may therefore be used in high-throughput screening for the discovery of molecules with insulin-like properties. |
| 4562 | 12746630 | More recently, we demonstrated that the BRET methodology could also be used to monitor the interaction of the insulin receptor with protein tyrosine-phosphatase 1B, one of the main tyrosine-phosphatase that controls its activity. |
| 4563 | 12746630 | HEK cells were co-transfected with the insulin receptor fused to Renilla luciferase and a substrate-trapping mutant of PTP1B (PTP1B-D181A) fused to YFP. |
| 4564 | 12746630 | Therefore, this methodology can also be used in high-throughput screening for the search of molecules that will specifically disrupt the interaction between the insulin receptor and PTP1B. |
| 4565 | 12746630 | The discovery of pharmacological agents that specifically stimulate the autophosphorylation of the insulin receptor or inhibit its dephosphorylation will be of great importance for the treatment of insulin resistant or insulin deficient patients. |
| 4566 | 12746630 | This methodology allows for rapid analysis of the effects of agonists on insulin receptor activity and may therefore be used in high-throughput screening for the discovery of molecules with insulin-like properties. |
| 4567 | 12746630 | More recently, we demonstrated that the BRET methodology could also be used to monitor the interaction of the insulin receptor with protein tyrosine-phosphatase 1B, one of the main tyrosine-phosphatase that controls its activity. |
| 4568 | 12746630 | HEK cells were co-transfected with the insulin receptor fused to Renilla luciferase and a substrate-trapping mutant of PTP1B (PTP1B-D181A) fused to YFP. |
| 4569 | 12746630 | Therefore, this methodology can also be used in high-throughput screening for the search of molecules that will specifically disrupt the interaction between the insulin receptor and PTP1B. |
| 4570 | 12746630 | The discovery of pharmacological agents that specifically stimulate the autophosphorylation of the insulin receptor or inhibit its dephosphorylation will be of great importance for the treatment of insulin resistant or insulin deficient patients. |
| 4571 | 12746630 | This methodology allows for rapid analysis of the effects of agonists on insulin receptor activity and may therefore be used in high-throughput screening for the discovery of molecules with insulin-like properties. |
| 4572 | 12746630 | More recently, we demonstrated that the BRET methodology could also be used to monitor the interaction of the insulin receptor with protein tyrosine-phosphatase 1B, one of the main tyrosine-phosphatase that controls its activity. |
| 4573 | 12746630 | HEK cells were co-transfected with the insulin receptor fused to Renilla luciferase and a substrate-trapping mutant of PTP1B (PTP1B-D181A) fused to YFP. |
| 4574 | 12746630 | Therefore, this methodology can also be used in high-throughput screening for the search of molecules that will specifically disrupt the interaction between the insulin receptor and PTP1B. |
| 4575 | 12746630 | The discovery of pharmacological agents that specifically stimulate the autophosphorylation of the insulin receptor or inhibit its dephosphorylation will be of great importance for the treatment of insulin resistant or insulin deficient patients. |
| 4576 | 12746630 | This methodology allows for rapid analysis of the effects of agonists on insulin receptor activity and may therefore be used in high-throughput screening for the discovery of molecules with insulin-like properties. |
| 4577 | 12746630 | More recently, we demonstrated that the BRET methodology could also be used to monitor the interaction of the insulin receptor with protein tyrosine-phosphatase 1B, one of the main tyrosine-phosphatase that controls its activity. |
| 4578 | 12746630 | HEK cells were co-transfected with the insulin receptor fused to Renilla luciferase and a substrate-trapping mutant of PTP1B (PTP1B-D181A) fused to YFP. |
| 4579 | 12746630 | Therefore, this methodology can also be used in high-throughput screening for the search of molecules that will specifically disrupt the interaction between the insulin receptor and PTP1B. |
| 4580 | 12746630 | The discovery of pharmacological agents that specifically stimulate the autophosphorylation of the insulin receptor or inhibit its dephosphorylation will be of great importance for the treatment of insulin resistant or insulin deficient patients. |
| 4581 | 12746630 | This methodology allows for rapid analysis of the effects of agonists on insulin receptor activity and may therefore be used in high-throughput screening for the discovery of molecules with insulin-like properties. |
| 4582 | 12746630 | More recently, we demonstrated that the BRET methodology could also be used to monitor the interaction of the insulin receptor with protein tyrosine-phosphatase 1B, one of the main tyrosine-phosphatase that controls its activity. |
| 4583 | 12746630 | HEK cells were co-transfected with the insulin receptor fused to Renilla luciferase and a substrate-trapping mutant of PTP1B (PTP1B-D181A) fused to YFP. |
| 4584 | 12746630 | Therefore, this methodology can also be used in high-throughput screening for the search of molecules that will specifically disrupt the interaction between the insulin receptor and PTP1B. |
| 4585 | 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. |
| 4586 | 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. |
| 4587 | 12765939 | In contrast to IRS-1, the signaling through IRS-2 was not altered. |
| 4588 | 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. |
| 4589 | 12765939 | Moreover, increased MAPK activity seems to play a role in the phosphorylation of IRS-1 on serine residue in human muscle cells. |
| 4590 | 12765938 | We found that 53 and 66% decreases in insulin-stimulated glucose uptake and insulin receptor substrate (IRS)-1-associated phosphatidylinositol (PI) 3-kinase activity in skeletal muscle of fatless mice were normalized after rosiglitazone treatment. |
| 4591 | 12782313 | Exposure of pancreatic islets to palmitate caused up-regulation of several insulin-induced activities including tyrosine phosphorylation of insulin receptor and pp185. |
| 4592 | 12788928 | Studies of mice with tissue-specific ablation of Insr have indicated that both canonical (e.g. muscle and adipose tissue) and noncanonical (e.g. liver, pancreatic beta-cells, and brain) insulin target tissues can contribute to insulin resistance, albeit in a pathogenically distinct fashion. |
| 4593 | 12788928 | Furthermore, experimental crosses of Insr mutants with mice carrying mutations that affect insulin action at more distal steps of the insulin signaling cascade have begun to unravel the genetics of type 2 diabetes. |
| 4594 | 12788928 | Studies of mice with tissue-specific ablation of Insr have indicated that both canonical (e.g. muscle and adipose tissue) and noncanonical (e.g. liver, pancreatic beta-cells, and brain) insulin target tissues can contribute to insulin resistance, albeit in a pathogenically distinct fashion. |
| 4595 | 12788928 | Furthermore, experimental crosses of Insr mutants with mice carrying mutations that affect insulin action at more distal steps of the insulin signaling cascade have begun to unravel the genetics of type 2 diabetes. |
| 4596 | 12788932 | Tissue-specific ablation of the GLUT4 glucose transporter or the insulin receptor challenges assumptions about insulin action and glucose homeostasis. |
| 4597 | 12790799 | It is possible that activation of protein kinase C (PKC) isoforms by free fatty acids (FFA) plays a role in the failure of pancreatic beta-cell mass expansion to compensate for peripheral insulin resistance in the pathogenesis of type-2 diabetes. |
| 4598 | 12790799 | The effect of lipid moieties on activation of conventional (PKC-alpha and -beta1), novel (PKC-delta) and atypical (PKC-zeta) PKC isoforms was evaluated in an in vitro assay, using biotinylated neurogranin as a substrate. |
| 4599 | 12790799 | It was found that FFA (0.4 mM oleate/complexed to 0.5% bovine serum albumin) inhibited IGF-I-induced activation of protein kinase B (PKB) in the pancreatic beta-cell line (INS-1), but this was alleviated in the presence of the general PKC inhibitor (Gö6850; 1 microM). |
| 4600 | 12790799 | To further investigate whether conventional or novel PKC isoforms adversely affect beta-cell proliferation, the effect of phorbol ester (phorbol 12-myristate 13-acetate; PMA)-mediated activation of these PKC isoforms on glucose/IGF-I-induced INS-1 cell mitogenesis, and insulin receptor substrate (IRS)-mediated signal transduction was investigated. |
| 4601 | 12790799 | PMA inhibited IGF-I-induced activation of PKB, correlating with inhibition of IGF-I-induced association of IRS-2 with the p85 regulatory subunit of phosphatidylinositol-3 kinase. |
| 4602 | 12790799 | Thus, FFA/PMA-induced activation of novel PKC isoforms can inhibit glucose/IGF-I-mediated beta-cell mitogenesis, in part by decreasing PKB activation, despite an upregulation of Erk1/2. |
| 4603 | 12802339 | Here we report the crystal structures of the regulatory sulphenic and irreversible sulphinic and sulphonic acids of protein tyrosine phosphatase 1B (PTP1B), an important enzyme in the negative regulation of the insulin receptor and a therapeutic target in type II diabetes and obesity. |
| 4604 | 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). |
| 4605 | 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. |
| 4606 | 12813019 | Knockout of insulin and IGF-1 receptors on vascular endothelial cells protects against retinal neovascularization. |
| 4607 | 12813019 | Both insulin and IGF-1 have been implicated in control of retinal endothelial cell growth, neovascularization, and diabetic retinopathy. |
| 4608 | 12813019 | To precisely define the role of insulin and IGF-1 signaling in endothelium in these processes, we have used the oxygen-induced retinopathy model to study mice with a vascular endothelial cell-specific knockout of the insulin receptor (VENIRKO) or IGF-1 receptor (VENIFARKO). |
| 4609 | 12813019 | This is associated with a blunted rise in VEGF, eNOS, and endothelin-1. |
| 4610 | 12813019 | These data indicate that both insulin and IGF-1 signaling in endothelium play a role in retinal neovascularization through the expression of vascular mediators, with the effect of insulin being most important in this process. |
| 4611 | 12837769 | Northern blot analysis of cells demonstrated that this inhibition was accompanied with attenuated expression of adipocyte-specific fatty acid-binding protein and lipoprotein lipase. |
| 4612 | 12837769 | LA treatment of 3T3-L1 pre-adipocytes also resulted in prolonged activation of major mitogen-activated protein kinase signaling pathways but showed little or no effect on the activity of the insulin receptor/Akt signaling pathway. |
| 4613 | 12837769 | These findings suggest that LA inhibits insulin or the hormonal mixture-induced differentiation of 3T3-L1 pre-adipocytes by modulating activity and/or expression of pro- or anti-adipogenic transcription factors mainly through activating the MAPK pathways. |
| 4614 | 12866989 | A complete biochemical signaling pathway linking the insulin receptor to activation of endothelial nitric oxide synthase in vascular endothelium has recently been elucidated. |
| 4615 | 12882907 | Activation of protein kinase C-zeta by insulin and phosphatidylinositol-3,4,5-(PO4)3 is defective in muscle in type 2 diabetes and impaired glucose tolerance: amelioration by rosiglitazone and exercise. |
| 4616 | 12882907 | Atypical protein kinase C (aPKC) and protein kinase B (PKB), operating downstream of phosphatidylinositol (PI) 3-kinase and its lipid product, PI-3,4,5-(PO(4))(3) (PIP(3)), apparently mediate insulin effects on glucose transport. |
| 4617 | 12882907 | In both IGT and diabetes, aPKC activation was markedly (70-80%) diminished, most likely reflecting impaired activation of insulin receptor substrate (IRS)-1-dependent PI 3-kinase and decreased ability of PIP(3) to directly activate aPKCs; additionally, muscle PKC-zeta levels were diminished by 40%. |
| 4618 | 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. |
| 4619 | 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. |
| 4620 | 12882908 | Phosphoinositide-dependent protein kinase-1 (PDK-1), also downstream of PI3K, mediates activation of atypical PKC isoforms and Akt. |
| 4621 | 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. |
| 4622 | 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. |
| 4623 | 12882908 | Importantly, weight loss in obese subjects normalizes PKClambda/zeta activation and increases IRS-1 phosphorylation and PI3K activity. |
| 4624 | 12882908 | Insulin also stimulates PDK-1 activity approximately twofold with no impairment in obese or diabetic subjects. |
| 4625 | 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. |
| 4626 | 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. |
| 4627 | 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). |
| 4628 | 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). |
| 4629 | 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). |
| 4630 | 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. |
| 4631 | 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. |
| 4632 | 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). |
| 4633 | 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). |
| 4634 | 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). |
| 4635 | 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. |
| 4636 | 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. |
| 4637 | 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). |
| 4638 | 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). |
| 4639 | 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). |
| 4640 | 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. |
| 4641 | 12898468 | Physical exercise enhances protein kinase C delta activity and insulin receptor tyrosine phosphorylation in diabetes-prone psammomys obesus. |
| 4642 | 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. |
| 4643 | 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. |
| 4644 | 12904469 | Insulin receptor substrate-2 deficiency impairs brain growth and promotes tau phosphorylation. |
| 4645 | 12904469 | Many factors are responsible for brain growth, patterning, and survival, including the insulin-insulin-like growth factor (IGF)-signaling cascades that are mediated by tyrosine phosphorylation of insulin receptor substrate (IRS) proteins. |
| 4646 | 12904469 | Irs2 signaling mediates peripheral insulin action and pancreatic beta-cell function, and its failure causes diabetes in mice. |
| 4647 | 12904469 | Thus, dysregulation of the Irs2 branch of the insulin-Igf-signaling cascade reveals a molecular link between diabetes and neurodegenerative disease. |
| 4648 | 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. |
| 4649 | 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. |
| 4650 | 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. |
| 4651 | 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. |
| 4652 | 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. |
| 4653 | 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. |
| 4654 | 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. |
| 4655 | 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. |
| 4656 | 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. |
| 4657 | 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. |
| 4658 | 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. |
| 4659 | 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. |
| 4660 | 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. |
| 4661 | 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. |
| 4662 | 12941959 | Using transgenic mice expressing activated calcineurin in skeletal muscle, we report that skeletal muscle reprogramming by calcineurin activation leads to improved insulin-stimulated 2-deoxyglucose uptake in extensor digitorum longus (EDL) muscles compared with wild-type mice, concomitant with increased protein expression of the insulin receptor, Akt, glucose transporter 4, and peroxisome proliferator-activated receptor-gamma co-activator 1. |
| 4663 | 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. |
| 4664 | 12952969 | Several studies have shown a relationship between interleukin (IL) 6 levels and insulin resistance. |
| 4665 | 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). |
| 4666 | 12952969 | IL-6, in contrast to TNF-alpha, did not increase pS-307 of insulin-receptor substrate (IRS)-1 or JNK activation. |
| 4667 | 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. |
| 4668 | 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. |
| 4669 | 12952969 | Consistent with the reduced GLUT-4 mRNA, insulin-stimulated glucose transport was also significantly reduced by IL-6. |
| 4670 | 12952969 | An important interaction with TNF-alpha was found because TNF-alpha markedly increased IL-6 mRNA and protein secretion. |
| 4671 | 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. |
| 4672 | 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. |
| 4673 | 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. |
| 4674 | 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. |
| 4675 | 12952969 | Several studies have shown a relationship between interleukin (IL) 6 levels and insulin resistance. |
| 4676 | 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). |
| 4677 | 12952969 | IL-6, in contrast to TNF-alpha, did not increase pS-307 of insulin-receptor substrate (IRS)-1 or JNK activation. |
| 4678 | 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. |
| 4679 | 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. |
| 4680 | 12952969 | Consistent with the reduced GLUT-4 mRNA, insulin-stimulated glucose transport was also significantly reduced by IL-6. |
| 4681 | 12952969 | An important interaction with TNF-alpha was found because TNF-alpha markedly increased IL-6 mRNA and protein secretion. |
| 4682 | 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. |
| 4683 | 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. |
| 4684 | 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. |
| 4685 | 12960377 | Stearoyl-CoA desaturase 1 deficiency elevates insulin-signaling components and down-regulates protein-tyrosine phosphatase 1B in muscle. |
| 4686 | 12960377 | We have shown previously that mice with a targeted disruption in the stearoyl-CoA desaturase 1 gene (SCD1-/-) have increased insulin sensitivity compared with control mice. |
| 4687 | 12960377 | Here we show that the SCD1-/- mice have increased insulin signaling in muscle. |
| 4688 | 12960377 | The tyrosine phosphorylation of insulin-like growth factor-1 receptor was similar between SCD1+/+ and SCD1-/- mice. |
| 4689 | 12960377 | The association of insulin receptor substrates 1 and 2 with alphap85 subunit of phosphatidylinositol 3-kinase as well as the phosphorylation of Akt-Ser-473 and Akt-Thr-308 are also elevated in the SCD1-/- mice. |
| 4690 | 12960377 | Interestingly, the mRNA levels, protein mass, and activity of the protein-tyrosine phosphatase-1B implicated in the attenuation of the insulin signal are reduced in the SCD1-/- mice, whereas the levels of the leukocyte antigen-related protein phosphatase are similar between two groups of mice. |
| 4691 | 12960377 | The content of glucose transporter 4 in the plasma membrane and basal as well as insulin-mediated glucose uptake are increased in the SCD1-/- mice. |
| 4692 | 12960377 | We hypothesize that loss of SCD1 function induces increased insulin signaling at least in part by a reduction in the expression of protein-tyrosine phosphatase 1B. |
| 4693 | 12969331 | Mammalian insulin and insulin-like growth factors (IGFs) signal through several receptors with different ligand specificities to regulate metabolism and growth. |
| 4694 | 12969331 | Recent analysis in Drosophila melanogaster has revealed that insulin-like molecules (known as DILPs in flies) also control growth and metabolism, but probably do so by signaling through a single insulin receptor (InR). |
| 4695 | 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. |
| 4696 | 12970360 | Here, we have investigated the action of human glycated albumin (HGA) on insulin signaling in L6 skeletal muscle cells. |
| 4697 | 12970360 | Further, HGA reduced insulin-stimulated serine phosphorylation of PKB and GSK3, but did not alter ERK1/2 activation. |
| 4698 | 12970360 | HGA did not affect either insulin receptor kinase activity or insulin-induced Shc phosphorylation on tyrosine. |
| 4699 | 12970360 | In contrast, insulin-dependent IRS-1 and IRS-2 tyrosine phosphorylation was severely reduced in cells preincubated with HGA for 24 h. |
| 4700 | 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. |
| 4701 | 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. |
| 4702 | 12970360 | BDM also blocked the action of HGA on insulin-stimulated PKB and GSK3 alpha. |
| 4703 | 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. |
| 4704 | 12970360 | Here, we have investigated the action of human glycated albumin (HGA) on insulin signaling in L6 skeletal muscle cells. |
| 4705 | 12970360 | Further, HGA reduced insulin-stimulated serine phosphorylation of PKB and GSK3, but did not alter ERK1/2 activation. |
| 4706 | 12970360 | HGA did not affect either insulin receptor kinase activity or insulin-induced Shc phosphorylation on tyrosine. |
| 4707 | 12970360 | In contrast, insulin-dependent IRS-1 and IRS-2 tyrosine phosphorylation was severely reduced in cells preincubated with HGA for 24 h. |
| 4708 | 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. |
| 4709 | 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. |
| 4710 | 12970360 | BDM also blocked the action of HGA on insulin-stimulated PKB and GSK3 alpha. |
| 4711 | 14502098 | Experimental studies show that metformin-mediated improvements in insulin sensitivity may be associated with several mechanisms, including increased insulin receptor tyrosine kinase activity, enhanced glycogen synthesis, and an increase in the recruitment and activity of GLUT4 glucose transporters. |
| 4712 | 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. |
| 4713 | 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. |
| 4714 | 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. |
| 4715 | 14514640 | Insulin and naringenin induced PI3K-dependent increases in cytosolic and nuclear SREBP-1 and LDLr expression. |
| 4716 | 14514640 | Similar PI3K-mediated increases in SREBP-1 were observed in McA-RH7777 rat hepatoma cells, which express predominantly SREBP-1c. |
| 4717 | 14514640 | Reductions in HepG2 cell media apoB with naringenin were partially attenuated by wortmannin, whereas the effect of insulin was completely blocked. |
| 4718 | 14514640 | Both treatments reduced apoB100 secretion in wild-type and LDLr(-/-) mouse hepatocytes to the same extent. |
| 4719 | 14514640 | Insulin and naringenin increased HepG2 cell PI3K activity and decreased insulin receptor substrate (IRS)-2 levels. |
| 4720 | 14514640 | In sharp contrast to insulin, naringenin did not induce tyrosine phosphorylation of IRS-1. |
| 4721 | 14514640 | We conclude that naringenin increases LDLr expression in HepG2 cells via PI3K-mediated upregulation of SREBP-1, independent of IRS-1 phosphorylation. |
| 4722 | 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. |
| 4723 | 14523643 | Spatiotemporal distribution of insulin-like growth factor receptors during nephrogenesis in fetuses from normal and diabetic rats. |
| 4724 | 14523643 | The effect of maternal diabetes on insulin-like growth factors and their receptors in the fetal kidney is associated with an increase in both mRNA and protein of the insulin-like growth factor II/mannose 6-phosphate receptor. |
| 4725 | 14523643 | The spatial and temporal distribution of the three insulin-like growth factor receptors (insulin-like growth factor I receptor, insulin-like growth factor II/mannose 6-phosphate receptor and insulin receptor) in rat metanephros during both normal and streptozotocin-induced diabetic renal development was investigated using in situ hybridization and immunohistochemistry. |
| 4726 | 14523643 | Insulin-like growth factor I receptor expression was ubiquitous and continuously present during metanephric development. |
| 4727 | 14523643 | Insulin-like growth factor II/mannose 6-phosphate receptor expression was ubiquitous in the early stages of development and was dramatically decreased at the late stages of normal kidney development. |
| 4728 | 14523643 | Insulin receptor and insulin-like growth factor I receptor expressions were unchanged in diabetic metanephroi. |
| 4729 | 14523643 | Although the spatial expression of insulin-like growth factor II/mannose 6-phosphate receptor was unaffected by hyperglycemia, its expression was not downregulated in the mesenchyme of the nephrogenic zone of diabetic fetuses on gestational day 20. |
| 4730 | 14523643 | This study suggests a crucial role of insulin-like growth factor II/mannose 6-phosphate receptor in the pathogenesis of the impaired nephrogenesis in fetuses of diabetic mothers. |
| 4731 | 14523643 | Spatiotemporal distribution of insulin-like growth factor receptors during nephrogenesis in fetuses from normal and diabetic rats. |
| 4732 | 14523643 | The effect of maternal diabetes on insulin-like growth factors and their receptors in the fetal kidney is associated with an increase in both mRNA and protein of the insulin-like growth factor II/mannose 6-phosphate receptor. |
| 4733 | 14523643 | The spatial and temporal distribution of the three insulin-like growth factor receptors (insulin-like growth factor I receptor, insulin-like growth factor II/mannose 6-phosphate receptor and insulin receptor) in rat metanephros during both normal and streptozotocin-induced diabetic renal development was investigated using in situ hybridization and immunohistochemistry. |
| 4734 | 14523643 | Insulin-like growth factor I receptor expression was ubiquitous and continuously present during metanephric development. |
| 4735 | 14523643 | Insulin-like growth factor II/mannose 6-phosphate receptor expression was ubiquitous in the early stages of development and was dramatically decreased at the late stages of normal kidney development. |
| 4736 | 14523643 | Insulin receptor and insulin-like growth factor I receptor expressions were unchanged in diabetic metanephroi. |
| 4737 | 14523643 | Although the spatial expression of insulin-like growth factor II/mannose 6-phosphate receptor was unaffected by hyperglycemia, its expression was not downregulated in the mesenchyme of the nephrogenic zone of diabetic fetuses on gestational day 20. |
| 4738 | 14523643 | This study suggests a crucial role of insulin-like growth factor II/mannose 6-phosphate receptor in the pathogenesis of the impaired nephrogenesis in fetuses of diabetic mothers. |
| 4739 | 14551916 | Polymorphisms in five of 15 genes (33%) encoding molecules known to primarily influence pancreatic beta-cell function-ABCC8 (sulphonylurea receptor), KCNJ11 (KIR6.2), SLC2A2 (GLUT2), HNF4A (HNF4alpha), and INS (insulin)-significantly altered disease risk, and in three genes, the risk allele, haplotype, or both had a biologically consistent effect on a relevant physiological trait in the QT study. |
| 4740 | 14551916 | We examined 35 genes predicted to have their major influence on insulin action, and three (9%)-INSR, PIK3R1, and SOS1-showed significant associations with diabetes. |
| 4741 | 14556646 | Rosiglitazone, an agonist of peroxisome-proliferator-activated receptor gamma (PPARgamma), decreases inhibitory serine phosphorylation of IRS1 in vitro and in vivo. |
| 4742 | 14556646 | Peroxisome-proliferator-activated receptor gamma agonists such as rosiglitazone, a thiazolidinedione, improve insulin sensitivity in vivo, but the underlying mechanism(s) remains unclear. |
| 4743 | 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. |
| 4744 | 14556646 | In the present study, we investigated whether rosiglitazone improves insulin sensitivity by decreasing IRS1 inhibitory serine phosphorylation. |
| 4745 | 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. |
| 4746 | 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. |
| 4747 | 14556646 | Treatment with rosiglitazone at 30 mg/kg body weight for 24 and 48 h increased insulin signalling and decreased IRS1 S307 phosphorylation concomitantly. |
| 4748 | 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. |
| 4749 | 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. |
| 4750 | 14560955 | The p70 S6 kinase (p70 S6K) was the first signaling element in mammalian cells shown to be inhibited by rapamycin. |
| 4751 | 14560955 | The activity of the p70 S6K in mammalian cell is upregulated by extracellular amino acids (especially leucine) and by signals from receptor tyrosine kinases (RTKs), primarily through activation of the type 1A PI-3 kinase. |
| 4752 | 14560955 | The amino acid-/rapamycin-sensitive input and the PI-3 kinase input are co-dominant but largely independent, in that deletion of the amino-terminal and carboxy-terminal noncatalytic sequences flanking the p70 S6K catalytic domain renders the kinase insensitive to inhibition by both rapamycin and by withdrawal of amino acids, whereas this p70 S6K mutant remains responsive to activation by RTKs and to inhibition by wortmannin. |
| 4753 | 14560955 | At a molecular level, this dual control of p70 S6K activity is attributable to phosphorylation of the two p70 S6K sites: The Ptd Ins 3,4,5P3-dependent kinasel (PDK1) phosphorylates p70 S6K at a Thr on the activation loop, whereas mTOR phosphorylates a Thr located in a hydrophobic motif carboxyterminal to the catalytic domain. |
| 4754 | 14560955 | Together these two phosphorylations engender a strong, positively cooperative activation of p70 S6K, so that each is indispensable for physiologic regulation. |
| 4755 | 14560955 | Like RTKs, the p70 S6K appears early in metazoan evolution and comes to represent an important site at which the more ancient, nutrient-responsive TOR pathway converges with the RTK/PI-3 kinase pathway in the control of cell growth. |
| 4756 | 14560955 | Dual regulation of p70 S6K is seen in Drosophila; however, this convergence is not yet evident in Caenorhabditis elegans, wherein nutrient activation of the insulin receptor (InsR) pathway negatively regulates dauer development and longevity, whereas the TOR pathway regulates overall mRNA translation through effectors distinct from p70 S6K, as in yeast. |
| 4757 | 14560955 | The C. elegans TOR and InsR pathways show none of the cross- or convergent regulation seen in mammalian cells. |
| 4758 | 14560955 | The p70 S6 kinase (p70 S6K) was the first signaling element in mammalian cells shown to be inhibited by rapamycin. |
| 4759 | 14560955 | The activity of the p70 S6K in mammalian cell is upregulated by extracellular amino acids (especially leucine) and by signals from receptor tyrosine kinases (RTKs), primarily through activation of the type 1A PI-3 kinase. |
| 4760 | 14560955 | The amino acid-/rapamycin-sensitive input and the PI-3 kinase input are co-dominant but largely independent, in that deletion of the amino-terminal and carboxy-terminal noncatalytic sequences flanking the p70 S6K catalytic domain renders the kinase insensitive to inhibition by both rapamycin and by withdrawal of amino acids, whereas this p70 S6K mutant remains responsive to activation by RTKs and to inhibition by wortmannin. |
| 4761 | 14560955 | At a molecular level, this dual control of p70 S6K activity is attributable to phosphorylation of the two p70 S6K sites: The Ptd Ins 3,4,5P3-dependent kinasel (PDK1) phosphorylates p70 S6K at a Thr on the activation loop, whereas mTOR phosphorylates a Thr located in a hydrophobic motif carboxyterminal to the catalytic domain. |
| 4762 | 14560955 | Together these two phosphorylations engender a strong, positively cooperative activation of p70 S6K, so that each is indispensable for physiologic regulation. |
| 4763 | 14560955 | Like RTKs, the p70 S6K appears early in metazoan evolution and comes to represent an important site at which the more ancient, nutrient-responsive TOR pathway converges with the RTK/PI-3 kinase pathway in the control of cell growth. |
| 4764 | 14560955 | Dual regulation of p70 S6K is seen in Drosophila; however, this convergence is not yet evident in Caenorhabditis elegans, wherein nutrient activation of the insulin receptor (InsR) pathway negatively regulates dauer development and longevity, whereas the TOR pathway regulates overall mRNA translation through effectors distinct from p70 S6K, as in yeast. |
| 4765 | 14560955 | The C. elegans TOR and InsR pathways show none of the cross- or convergent regulation seen in mammalian cells. |
| 4766 | 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. |
| 4767 | 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. |
| 4768 | 14563700 | PI3-kinase products could induce PLC-gamma activation, whose hydrolytic activity could activate the DAG-dependent isoforms PKC alpha, theta, and epsilon. |
| 4769 | 14568990 | Role of the pleckstrin homology domain of PLCgamma1 in its interaction with the insulin receptor. |
| 4770 | 14568990 | A thiol-reactive membrane-associated protein (TRAP) binds covalently to the cytoplasmic domain of the human insulin receptor (IR) beta-subunit when cells are treated with the homobifunctional cross-linker reagent 1,6-bismaleimidohexane. |
| 4771 | 14568990 | Here, TRAP was found to be phospholipase C gamma1 (PLCgamma1) by mass spectrometry analysis. |
| 4772 | 14568990 | Insulin increased PLCgamma1 tyrosine phosphorylation at Tyr-783 and its colocalization with the IR in punctated structures enriched in cortical actin at the dorsal plasma membrane. |
| 4773 | 14568990 | This association was found to be independent of PLCgamma1 Src homology 2 domains, and instead required the pleckstrin homology (PH)-EF-hand domain. |
| 4774 | 14568990 | Expression of the PH-EF construct blocked endogenous PLCgamma1 binding to the IR and inhibited insulin-dependent phosphorylation of mitogen-activated protein kinase (MAPK), but not AKT. |
| 4775 | 14568990 | Silencing PLCgamma1 expression using small interfering RNA markedly reduced insulin-dependent MAPK regulation in HepG2 cells. |
| 4776 | 14568990 | Conversely, reconstitution of PLCgamma1 in PLCgamma1-/- fibroblasts improved MAPK activation by insulin. |
| 4777 | 14568990 | Our results show that PLCgamma1 is a thiol-reactive protein whose association with the IR could contribute to the activation of MAPK signaling by insulin. |
| 4778 | 14568990 | Role of the pleckstrin homology domain of PLCgamma1 in its interaction with the insulin receptor. |
| 4779 | 14568990 | A thiol-reactive membrane-associated protein (TRAP) binds covalently to the cytoplasmic domain of the human insulin receptor (IR) beta-subunit when cells are treated with the homobifunctional cross-linker reagent 1,6-bismaleimidohexane. |
| 4780 | 14568990 | Here, TRAP was found to be phospholipase C gamma1 (PLCgamma1) by mass spectrometry analysis. |
| 4781 | 14568990 | Insulin increased PLCgamma1 tyrosine phosphorylation at Tyr-783 and its colocalization with the IR in punctated structures enriched in cortical actin at the dorsal plasma membrane. |
| 4782 | 14568990 | This association was found to be independent of PLCgamma1 Src homology 2 domains, and instead required the pleckstrin homology (PH)-EF-hand domain. |
| 4783 | 14568990 | Expression of the PH-EF construct blocked endogenous PLCgamma1 binding to the IR and inhibited insulin-dependent phosphorylation of mitogen-activated protein kinase (MAPK), but not AKT. |
| 4784 | 14568990 | Silencing PLCgamma1 expression using small interfering RNA markedly reduced insulin-dependent MAPK regulation in HepG2 cells. |
| 4785 | 14568990 | Conversely, reconstitution of PLCgamma1 in PLCgamma1-/- fibroblasts improved MAPK activation by insulin. |
| 4786 | 14568990 | Our results show that PLCgamma1 is a thiol-reactive protein whose association with the IR could contribute to the activation of MAPK signaling by insulin. |
| 4787 | 14578283 | Increased insulin sensitivity and hypoinsulinemia in APS knockout mice. |
| 4788 | 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. |
| 4789 | 14578283 | The function of APS in insulin signaling has heretofore remained unknown. |
| 4790 | 14578283 | The blood glucose-lowering effect of insulin, as assessed by the intraperitoneal insulin tolerance test, was increased in APS(-/-) mice. |
| 4791 | 14578283 | Plasma insulin levels during fasting and in the intraperitoneal glucose tolerance test were lower in APS(-/-) mice. |
| 4792 | 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. |
| 4793 | 14578283 | The glucose uptake and GLUT4 translocation were not affected by insulin stimulation in these cells. |
| 4794 | 14578283 | Nevertheless, the insulin-stimulated glucose transport in isolated adipocytes of APS(-/-) mice was increased over that of APS(+/+) mice. |
| 4795 | 14578283 | APS(-/-) mice also showed increased serum levels of leptin and adiponectin, which might explain the increased insulin sensitivity of adipocytes. |
| 4796 | 14578297 | Chronic exposure to interleukin-6 causes hepatic insulin resistance in mice. |
| 4797 | 14578297 | Interleukin (IL)-6 is one of several proinflammatory cytokines associated with the insulin resistance of obesity and type 2 diabetes. |
| 4798 | 14578297 | There is, however, little direct evidence in vivo for a causative role of IL-6 in insulin resistance. |
| 4799 | 14578297 | Here, a 5-day constant subcutaneous infusion of hIL-6 before portal vein insulin challenge resulted in impairment of early insulin receptor signaling in the liver of mice. |
| 4800 | 14578297 | Consistent with an hepatic response to IL-6, STAT3 phosphorylation was increased in livers of IL-6-treated mice at 5 days. |
| 4801 | 14578297 | Chronic infusion of IL-6 also reduced hepatic insulin receptor autophosphorylation by 60% and tyrosine phosphorylation of insulin receptor substrates-1 and -2 by 60 and 40%, respectively. |
| 4802 | 14578297 | IL-6 also decreased refeeding-dependent glucokinase mRNA induction by approximately 40%. |
| 4803 | 14578297 | In contrast to hepatic insulin receptor signal transduction, 5-day IL-6 exposure failed to suppress skeletal muscle insulin receptor signal transduction. |
| 4804 | 14578297 | These data suggest that chronic IL-6 treatment selectively impairs hepatic insulin signaling in vivo, further supporting a role for IL-6 in hepatic insulin resistance of obesity. |
| 4805 | 14578297 | Chronic exposure to interleukin-6 causes hepatic insulin resistance in mice. |
| 4806 | 14578297 | Interleukin (IL)-6 is one of several proinflammatory cytokines associated with the insulin resistance of obesity and type 2 diabetes. |
| 4807 | 14578297 | There is, however, little direct evidence in vivo for a causative role of IL-6 in insulin resistance. |
| 4808 | 14578297 | Here, a 5-day constant subcutaneous infusion of hIL-6 before portal vein insulin challenge resulted in impairment of early insulin receptor signaling in the liver of mice. |
| 4809 | 14578297 | Consistent with an hepatic response to IL-6, STAT3 phosphorylation was increased in livers of IL-6-treated mice at 5 days. |
| 4810 | 14578297 | Chronic infusion of IL-6 also reduced hepatic insulin receptor autophosphorylation by 60% and tyrosine phosphorylation of insulin receptor substrates-1 and -2 by 60 and 40%, respectively. |
| 4811 | 14578297 | IL-6 also decreased refeeding-dependent glucokinase mRNA induction by approximately 40%. |
| 4812 | 14578297 | In contrast to hepatic insulin receptor signal transduction, 5-day IL-6 exposure failed to suppress skeletal muscle insulin receptor signal transduction. |
| 4813 | 14578297 | These data suggest that chronic IL-6 treatment selectively impairs hepatic insulin signaling in vivo, further supporting a role for IL-6 in hepatic insulin resistance of obesity. |
| 4814 | 14578297 | Chronic exposure to interleukin-6 causes hepatic insulin resistance in mice. |
| 4815 | 14578297 | Interleukin (IL)-6 is one of several proinflammatory cytokines associated with the insulin resistance of obesity and type 2 diabetes. |
| 4816 | 14578297 | There is, however, little direct evidence in vivo for a causative role of IL-6 in insulin resistance. |
| 4817 | 14578297 | Here, a 5-day constant subcutaneous infusion of hIL-6 before portal vein insulin challenge resulted in impairment of early insulin receptor signaling in the liver of mice. |
| 4818 | 14578297 | Consistent with an hepatic response to IL-6, STAT3 phosphorylation was increased in livers of IL-6-treated mice at 5 days. |
| 4819 | 14578297 | Chronic infusion of IL-6 also reduced hepatic insulin receptor autophosphorylation by 60% and tyrosine phosphorylation of insulin receptor substrates-1 and -2 by 60 and 40%, respectively. |
| 4820 | 14578297 | IL-6 also decreased refeeding-dependent glucokinase mRNA induction by approximately 40%. |
| 4821 | 14578297 | In contrast to hepatic insulin receptor signal transduction, 5-day IL-6 exposure failed to suppress skeletal muscle insulin receptor signal transduction. |
| 4822 | 14578297 | These data suggest that chronic IL-6 treatment selectively impairs hepatic insulin signaling in vivo, further supporting a role for IL-6 in hepatic insulin resistance of obesity. |
| 4823 | 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. |
| 4824 | 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. |
| 4825 | 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. |
| 4826 | 14596593 | Cellular effects of small molecule PTP1B inhibitors on insulin signaling. |
| 4827 | 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. |
| 4828 | 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. |
| 4829 | 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. |
| 4830 | 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. |
| 4831 | 14596593 | These results indicate that small molecule inhibitors targeted to PTP1B can act as both insulin mimetics and insulin sensitizers. |
| 4832 | 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. |
| 4833 | 14604996 | Role of insulin receptor substrates and protein kinase C-zeta in vascular permeability factor/vascular endothelial growth factor expression in pancreatic cancer cells. |
| 4834 | 14604996 | Previously we have shown that in AsPC-1 pancreatic adenocarcinoma cells, insulin-like growth factor receptor (IGF-IR) regulates VPF/VEGF expression. |
| 4835 | 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. |
| 4836 | 14604996 | The Sp1-dependent VPF/VEGF transcription is regulated mainly by IRS-2. |
| 4837 | 14604996 | Protein kinase C-zeta (PKC-zeta) plays a central role in VPF/VEGF expression and acts as a switching element. |
| 4838 | 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. |
| 4839 | 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. |
| 4840 | 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. |
| 4841 | 14607781 | It has now become apparent that effective insulin signaling in the adipocyte may be strictly dependent on localization of at least two insulin-responsive elements to caveolae (insulin receptor and GLUT4), as well as on a direct functional interaction between caveolin-1 and the insulin receptor. |
| 4842 | 14623899 | Nutrient-dependent and insulin-stimulated phosphorylation of insulin receptor substrate-1 on serine 302 correlates with increased insulin signaling. |
| 4843 | 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. |
| 4844 | 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. |
| 4845 | 14623899 | Insulin or IGF-I stimulated phosphorylation of Ser(302) in various cell backgrounds and in murine muscle. |
| 4846 | 14623899 | The NH(2)-terminal c-Jun kinase did not phosphorylate Ser(302). |
| 4847 | 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. |
| 4848 | 14623899 | Replacing Ser(302) with alanine reduced insulin/IGF-I-stimulated DNA synthesis. |
| 4849 | 14623899 | We conclude that Ser(302) phosphorylation integrates nutrient availability with insulin/IGF-I signaling to promote mitogenesis and cell growth. |
| 4850 | 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. |
| 4851 | 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. |
| 4852 | 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. |
| 4853 | 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. |
| 4854 | 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. |
| 4855 | 14657487 | Drugs that stimulate IRS2 (insulin receptor substrate protein 2) synthesis or signaling might be a good starting point. |
| 4856 | 14691140 | In pancreatic beta-cells, insulin selectively up-regulates the transcription of its own gene and that of the glucokinase gene by signaling through the two isoforms of the insulin receptor, i.e., A-type (Ex11-) and B-type (Ex11+), using different signaling pathways. |
| 4857 | 14691140 | Here we show that activation of the insulin promoter via A-type and of the glucokinase promoter via B-type insulin receptor is not dependent on receptor isoform-specific differences in internalization but on the different localization of the receptor types in the plasma membrane. |
| 4858 | 14691140 | Moreover, our data suggest that selective activation of the insulin and glucokinase promoters occurs by signaling from noncaveolae lipid rafts that are differently sensitive toward cholesterol depletion. |
| 4859 | 14691140 | In pancreatic beta-cells, insulin selectively up-regulates the transcription of its own gene and that of the glucokinase gene by signaling through the two isoforms of the insulin receptor, i.e., A-type (Ex11-) and B-type (Ex11+), using different signaling pathways. |
| 4860 | 14691140 | Here we show that activation of the insulin promoter via A-type and of the glucokinase promoter via B-type insulin receptor is not dependent on receptor isoform-specific differences in internalization but on the different localization of the receptor types in the plasma membrane. |
| 4861 | 14691140 | Moreover, our data suggest that selective activation of the insulin and glucokinase promoters occurs by signaling from noncaveolae lipid rafts that are differently sensitive toward cholesterol depletion. |
| 4862 | 14693412 | The insulin gene (INS), insulin receptor gene (INSR) and insulin receptor substrate 1 gene (IRS1) have been proposed as candidate genes. |
| 4863 | 14693412 | Restriction fragment length polymorphisms in INS, INSR and IRS1 were identified by polymerase chain reaction and digestion with selected restriction enzymes. |
| 4864 | 14693412 | None of the polymorphisms in INSR or IRS1 was associated with any of these traits. |
| 4865 | 14693412 | The insulin gene (INS), insulin receptor gene (INSR) and insulin receptor substrate 1 gene (IRS1) have been proposed as candidate genes. |
| 4866 | 14693412 | Restriction fragment length polymorphisms in INS, INSR and IRS1 were identified by polymerase chain reaction and digestion with selected restriction enzymes. |
| 4867 | 14693412 | None of the polymorphisms in INSR or IRS1 was associated with any of these traits. |
| 4868 | 14693412 | The insulin gene (INS), insulin receptor gene (INSR) and insulin receptor substrate 1 gene (IRS1) have been proposed as candidate genes. |
| 4869 | 14693412 | Restriction fragment length polymorphisms in INS, INSR and IRS1 were identified by polymerase chain reaction and digestion with selected restriction enzymes. |
| 4870 | 14693412 | None of the polymorphisms in INSR or IRS1 was associated with any of these traits. |
| 4871 | 14693696 | Dehydroepiandrosterone stimulates glucose uptake in human and murine adipocytes by inducing GLUT1 and GLUT4 translocation to the plasma membrane. |
| 4872 | 14693696 | Exposure of adipocytes to DHEA does not result in changes of total GLUT4 and GLUT1 protein levels. |
| 4873 | 14693696 | In 3T3-L1 adipocytes, DHEA increases tyrosine phosphorylation of insulin receptor substrate (IRS)-1 and IRS-2 and stimulates IRS-1- and IRS-2-associated phosphatidylinositol (PI) 3-kinase activity with no effects on either insulin receptor or Akt phosphorylation. |
| 4874 | 14693696 | In addition, DHEA causes significant increases of cytosolic Ca(2+) concentrations and a parallel activation of protein kinase C (PKC)-beta(2). |
| 4875 | 14693696 | The effects of DHEA are abrogated by pretreatment of adipocytes with PI 3-kinase and phospholipase C gamma inhibitors, as well as by inhibitors of Ca(2+)-dependent PKC isoforms, including a specific PKC-beta inhibitor. |
| 4876 | 14693696 | Thus, DHEA increases glucose uptake in both human and 3T3-L1 adipocytes by stimulating GLUT4 and GLUT1 translocation to the plasma membrane. |
| 4877 | 14693696 | PI 3-kinase, phospholipase C gamma, and the conventional PKC-beta(2) seem to be involved in DHEA effects. |
| 4878 | 14693698 | Islet-sparing effects of protein tyrosine phosphatase-1b deficiency delays onset of diabetes in IRS2 knockout mice. |
| 4879 | 14693698 | Protein tyrosine phosphatase-1b (Ptp1b) inhibits insulin and leptin signaling by dephosphorylating specific tyrosine residues in their activated receptor complexes. |
| 4880 | 14693698 | Insulin signals are mediated by tyrosine phosphorylation of the insulin receptor and its downstream targets, such as Irs1 and Irs2. |
| 4881 | 14693698 | Irs2 plays an especially important role in glucose homeostasis because it mediates some peripheral actions of insulin and promotes pancreatic beta-cell function. |
| 4882 | 14693698 | To determine whether the deletion of Ptp1b compensates for the absence of Irs2, we analyzed mice deficient in both Ptp1b and Irs2. |
| 4883 | 14693698 | Pancreatic beta-cell area decreased in Ptp1b(-/-) mice, consistent with decreased insulin requirements owing to increased peripheral insulin sensitivity. |
| 4884 | 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. |
| 4885 | 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. |
| 4886 | 14694850 | Major break-throughs in the genetic sciences of type 2 diabetes have been identifications of insulin receptor gene mutations in syndromes of severe insulin resistance and mutations in pancreatic beta-cell genes in the monogenic sub-group of type 2 diabetes: maturity-onset-diabetes-of-the-young, MODY. |
| 4887 | 14694850 | The studies reported in this thesis are excerpts from an extensive strategy of genetically dissecting (mutation analysis) in: 1) patients with the common form of late-onset type 2 diabetes mellitus the pathways that transduce the insulin signals from the plasma membrane to the activation of glycogen synthesis in skeletal muscle, and in 2) patients with either late-onset type diabetes or MODY the pathways involved in normal beta-cell development and beta-cell function (insulin secretion). |
| 4888 | 14694850 | We could not confirm that a Val985Met variant in the insulin receptor is associated with type 2 diabetes or that the Met326Val of the p85 alpha regulatory subunit of the phosphoinositide-3 kinase is associated with insulin resistance. |
| 4889 | 14694850 | We found no coding mutations (missense) in the insulin signalling protein kinases but we confirmed that the 5 bp deletion (PP1ARE) in the 3'-end of the PPP1R3 gene that encodes the glycogen-associated regulatory subunit of protein phosphatase-1 (PP1G) is associated with insulin resistance estimated as insulin mediated glucose uptake. |
| 4890 | 14694850 | In contrast to protein kinases in skeletal muscles the genes encoding beta-cell transcription factors (IPF-1, NeuroD1/BETA2, and Neurogenin 3) are polymorphic but we could not confirm that the Asp76Asn of IPF-1 is a susceptibility gene for late-onset type 2 diabetes. |
| 4891 | 14694850 | On the other hand we confirmed that the Ala45Thr variant in NeuroD1/BETA2 may represent a susceptibility gene for type 1 diabetes but none of these genes revealed any MODY-specific mutations. |
| 4892 | 14694850 | Also the gene encoding the ATP-regulatable potassium channels of the beta-cell (Kir6.2) is polymorphic but none of these polymorphisms associated with changes in glucose-induced insulin secretion. |
| 4893 | 14694850 | Major break-throughs in the genetic sciences of type 2 diabetes have been identifications of insulin receptor gene mutations in syndromes of severe insulin resistance and mutations in pancreatic beta-cell genes in the monogenic sub-group of type 2 diabetes: maturity-onset-diabetes-of-the-young, MODY. |
| 4894 | 14694850 | The studies reported in this thesis are excerpts from an extensive strategy of genetically dissecting (mutation analysis) in: 1) patients with the common form of late-onset type 2 diabetes mellitus the pathways that transduce the insulin signals from the plasma membrane to the activation of glycogen synthesis in skeletal muscle, and in 2) patients with either late-onset type diabetes or MODY the pathways involved in normal beta-cell development and beta-cell function (insulin secretion). |
| 4895 | 14694850 | We could not confirm that a Val985Met variant in the insulin receptor is associated with type 2 diabetes or that the Met326Val of the p85 alpha regulatory subunit of the phosphoinositide-3 kinase is associated with insulin resistance. |
| 4896 | 14694850 | We found no coding mutations (missense) in the insulin signalling protein kinases but we confirmed that the 5 bp deletion (PP1ARE) in the 3'-end of the PPP1R3 gene that encodes the glycogen-associated regulatory subunit of protein phosphatase-1 (PP1G) is associated with insulin resistance estimated as insulin mediated glucose uptake. |
| 4897 | 14694850 | In contrast to protein kinases in skeletal muscles the genes encoding beta-cell transcription factors (IPF-1, NeuroD1/BETA2, and Neurogenin 3) are polymorphic but we could not confirm that the Asp76Asn of IPF-1 is a susceptibility gene for late-onset type 2 diabetes. |
| 4898 | 14694850 | On the other hand we confirmed that the Ala45Thr variant in NeuroD1/BETA2 may represent a susceptibility gene for type 1 diabetes but none of these genes revealed any MODY-specific mutations. |
| 4899 | 14694850 | Also the gene encoding the ATP-regulatable potassium channels of the beta-cell (Kir6.2) is polymorphic but none of these polymorphisms associated with changes in glucose-induced insulin secretion. |
| 4900 | 14704746 | When TNF-alpha activity is blocked in obesity, either biochemically or genetically, the result is improved insulin sensitivity. |
| 4901 | 14704746 | These include the discovery of c-Jun N-terminal kinase (JNK) and I kappa beta kinase (I kappa K) as critical regulators of insulin action activated by TNF-alpha and other inflammatory and stress signals, and the identification of potential targets. |
| 4902 | 14704746 | Here, the role of the JNK pathway in insulin receptor signaling, the impact of blocking this pathway in obesity and the mechanisms underlying JNK-induced insulin resistance will be discussed. |
| 4903 | 14704747 | Recent studies reveal that agents that induce insulin resistance exploit phosphorylation-based negative feedback control mechanisms otherwise utilized by insulin itself, to uncouple the insulin receptor from its downstream effectors and thereby terminate insulin signal transduction. |
| 4904 | 14710358 | The isoforms have different affinities for insulin, IGF-II and IGF-I with the exon 11- isoform binding both insulin and IGF-II with high affinities. |
| 4905 | 14710358 | Activation of the exon 11- insulin receptor by IGF-II and insulin results in mitogenic effects and a potentiation of the cancer phenotype. |
| 4906 | 14722023 | Insulin-like growth factor I receptors are more abundant than insulin receptors in human micro- and macrovascular endothelial cells. |
| 4907 | 14722023 | Our aim was to characterize IGF-I receptor (IGF-IR) and insulin receptor (IR) in human micro- and macrovascular endothelial cells. |
| 4908 | 14722023 | Insulin and the new, long-acting insulin analog glargine interacted with the IGF-IR with thousand- and hundred-fold less potency than IGF-I itself. |
| 4909 | 14722023 | Phosphorylation of the IGF-IR beta-subunit was shown in HAEC for IGF-I (10(-8) M) and insulin (10(-6) M) and in HMVEC for IGF-I and glargine (10(-8) M, 10(-6) M). |
| 4910 | 14722023 | IGF-I 10(-7) M stimulated incorporation of [(3)H]thymidine into DNA, and 10(-9)-10(-7) M also the incorporation of [(3)H]glucose in HMVEC, whereas glargine and insulin had no significant effects at 10(-9)-10(-7) M. |
| 4911 | 14722023 | IGF-I and high concentrations of glargine and insulin activates the IGF-IR. |
| 4912 | 14722023 | Glargine has a higher affinity than insulin for the IGF-IR but probably has no effect on DNA synthesis at concentrations reached in vivo. |
| 4913 | 14737836 | One of the intracellular signal transduction of insulin receptor; MAP kinase may be concerned atherosclerotic mechanisms of insulin resistance. |
| 4914 | 14747278 | Strength training increases insulin-mediated glucose uptake, GLUT4 content, and insulin signaling in skeletal muscle in patients with type 2 diabetes. |
| 4915 | 14747278 | Strength training increased protein content of GLUT4, insulin receptor, protein kinase B-alpha/beta, glycogen synthase (GS), and GS total activity. |
| 4916 | 14747284 | Leptin impairs insulin signaling in rat adipocytes. |
| 4917 | 14747284 | Leptin modulates glucose homeostasis by acting as an insulin-sensitizing factor in most insulin target tissues. |
| 4918 | 14747284 | Moreover, elevated leptin concentrations inhibit insulin metabolic effects in adipocytes. |
| 4919 | 14747284 | Here we studied both, direct and centrally mediated effects of leptin on insulin signaling in rat adipocytes. |
| 4920 | 14747284 | Adipocyte incubation with low leptin concentrations did not modify the insulin stimulation of mitogen-activated protein kinase (MAPK). |
| 4921 | 14747284 | However, at elevated concentrations, leptin impaired insulin-stimulated MAPK activity, glycogen synthase kinase (GSK)3beta phosphorylation, and insulin receptor tyrosine phosphorylation without altering vanadate stimulation. |
| 4922 | 14747284 | Central administration of leptin decreased insulin effects on adipocyte MAPK and GSK3beta phosphorylation. |
| 4923 | 14747284 | In insulin-resistant aged rats with hyperleptinemia and central leptin resistance, insulin poorly stimulated MAPK and central leptin infusion did not further deteriorate adipocyte insulin responsiveness. |
| 4924 | 14747284 | Food restriction increased MAPK stimulation by insulin and restored the ability of centrally infused leptin to attenuate adipocyte insulin signaling in aged rats. |
| 4925 | 14747284 | We conclude that leptin can modulate, in an inhibitory manner, adipocyte insulin signaling by two different ways: as an autocrine signal and, indirectly, through neuroendocrine pathways. |
| 4926 | 14749507 | LRb initiates signaling via three major mechanisms: 1) Tyr(985) of LRb recruits SH2-containing tyrosine phosphatase (SHP-2); 2) Tyr(1138) of LRb recruits signal transducer and activator of transcription 3 (STAT3); and 3) tyrosine phosphorylation sites on the receptor-associated Jak2 likely recruit numerous undefined signaling proteins. |
| 4927 | 14749507 | The Tyr(985) --> SHP-2 pathway is a major regulator of extracellular signal-regulated kinase (ERK) activation during leptin signaling in cultured cells, while the Tyr(1138) --> STAT3 pathway induces the feedback inhibitor, suppressor of cytokine signaling 3 (SOCS3), as well as important positive effectors of leptin action. |
| 4928 | 14749507 | The Jak2-dependent activation of the insulin receptor substrate (IRS) protein --> phosphatidylinositol 3-kinase (PI3'-K) pathway appears to regulate membrane potential in LRb-expressing neurons and contributes to the regulation of feeding. |
| 4929 | 14749507 | Interestingly, the Tyr(1138) --> STAT3 pathway does not strongly regulate neuropeptide Y (NPY) and thus is not required for the control of reproduction and growth. |
| 4930 | 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. |
| 4931 | 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. |
| 4932 | 14749734 | In skeletal muscle, IR tyrosine phosphorylation was normal, but signalling via IRS-1 and PKB was increased. |
| 4933 | 14749734 | Finally, no effect of Grb14 ablation was observed on insulin signalling in white adipose tissue. |
| 4934 | 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. |
| 4935 | 14966267 | The NAD(P)H oxidase homolog Nox4 modulates insulin-stimulated generation of H2O2 and plays an integral role in insulin signal transduction. |
| 4936 | 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. |
| 4937 | 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. |
| 4938 | 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. |
| 4939 | 14966267 | Transfection of specific small interfering RNA oligonucleotides reduced Nox4 protein abundance and also inhibited the insulin signaling cascade. |
| 4940 | 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. |
| 4941 | 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. |
| 4942 | 14966267 | The NAD(P)H oxidase homolog Nox4 modulates insulin-stimulated generation of H2O2 and plays an integral role in insulin signal transduction. |
| 4943 | 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. |
| 4944 | 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. |
| 4945 | 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. |
| 4946 | 14966267 | Transfection of specific small interfering RNA oligonucleotides reduced Nox4 protein abundance and also inhibited the insulin signaling cascade. |
| 4947 | 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. |
| 4948 | 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. |
| 4949 | 14966273 | Differential roles of insulin receptor substrates in brown adipocyte differentiation. |
| 4950 | 14966273 | Insulin promotes adipocyte differentiation via a complex signaling network involving multiple insulin receptor substrates (IRSs). |
| 4951 | 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. |
| 4952 | 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. |
| 4953 | 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. |
| 4954 | 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. |
| 4955 | 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. |
| 4956 | 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. |
| 4957 | 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. |
| 4958 | 14966273 | Differential roles of insulin receptor substrates in brown adipocyte differentiation. |
| 4959 | 14966273 | Insulin promotes adipocyte differentiation via a complex signaling network involving multiple insulin receptor substrates (IRSs). |
| 4960 | 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. |
| 4961 | 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. |
| 4962 | 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. |
| 4963 | 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. |
| 4964 | 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. |
| 4965 | 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. |
| 4966 | 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. |
| 4967 | 14988237 | Insulin receptor and GLUT4 mRNAs were coexpressed in 75% of GE, 60% of GI, and 40% of NG neurons, although there were no statistically significant intergroup differences. |
| 4968 | 14988237 | Hexokinase-I, GLUT3, and lactate dehydrogenase-A and -B were ubiquitous, whereas GLUT2, monocarboxylate transporters-1 and -2, and leptin receptor and GAD mRNAs were expressed less frequently and without apparent relationship to glucosensing capacity. |
| 4969 | 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. |
| 4970 | 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. |
| 4971 | 14998989 | In contrast, rosiglitazone increases the levels of CAP expression and insulin-stimulated c-Cbl phosphorylation without affecting the IRS-1/Akt pathway. |
| 4972 | 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. |
| 4973 | 15010337 | Although a pharmacological dose of insulin produces a dramatic increase in phosphorylation and activity of Akt isoforms 1 and 2 in mammalian skeletal muscle, few studies have examined the effect of physiological concentrations of insulin on the phosphorylation of Akt-1 and -2 in normal and diabetic tissue. |
| 4974 | 15010337 | This study examined the patterns of insulin-stimulated Akt isoform phosphorylation and protein expression in muscle biopsies obtained from obese patients with atypical diabetes immediately after a hyperglycemic crisis and again after near-normoglycemic remission. |
| 4975 | 15010337 | In obese patients with new-onset diabetes mellitus presenting with hyperglycemic crisis (plasma glucose 30.5 +/- 4.8 mM), in vitro stimulation of vastus lateralis muscle biopsies with 100 microU/ml (0.6 nM) insulin increased insulin receptor phosphorylation threefold and Akt-1 phosphorylation on Ser(473) twofold, whereas Akt-2 phosphorylation was not stimulated. |
| 4976 | 15010337 | Hyperglycemic crisis did not affect insulin-stimulated threonine phosphorylation of either Akt-1 or Akt-2. |
| 4977 | 15010337 | The decreased Akt-2 expression at presentation was accompanied by reduced GLUT4 protein expression and increased expression of enzymes counterregulatory to insulin action. |
| 4978 | 15010337 | Thus a physiological concentration of insulin stimulated Akt-1 and Akt-2 phosphorylation in human skeletal muscle in the absence of hyperglycemia, but Akt-2 expression and stimulation appeared to be impaired in muscle of obese patients with atypical diabetes presenting with severe hyperglycemia. |
| 4979 | 15031294 | Transgenic overexpression of protein-tyrosine phosphatase 1B in muscle causes insulin resistance, but overexpression with leukocyte antigen-related phosphatase does not additively impair insulin action. |
| 4980 | 15031294 | Previous studies implicate protein-tyrosine phosphatase 1B (PTP1B) and leukocyte antigen-related phosphatase (LAR) as negative regulators of insulin signaling. |
| 4981 | 15031294 | The expression and/or activity of PTP1B and LAR are increased in muscle of insulin-resistant rodents and humans. |
| 4982 | 15031294 | Overexpression of LAR selectively in muscle of transgenic mice causes whole body insulin resistance. |
| 4983 | 15031294 | To determine whether overexpression of PTP1B also causes insulin resistance, we generated transgenic mice overexpressing human PTP1B selectively in muscle at levels similar to those observed in insulin-resistant humans. |
| 4984 | 15031294 | Insulin-stimulated insulin receptor (IR) tyrosyl phosphorylation and phosphatidylinositol 3'-kinase activity were impaired by 35% and 40-60% in muscle of PTP1B-overexpressing mice compared with controls. |
| 4985 | 15031294 | Insulin stimulation of protein kinase C (PKC)lambda/zeta activity, which is required for glucose transport, was impaired in muscle of PTP1B-overexpressing mice compared with controls, showing that PTP1B overexpression impairs activation of these PKC isoforms. |
| 4986 | 15031294 | Overexpression of PTP1B or LAR alone in muscle caused similar impairments in insulin action; however, compound overexpression achieved by crossing PTP1B- and LAR-overexpressing mice was not additive. |
| 4987 | 15031294 | Antibodies against specific IR phosphotyrosines indicated overlapping sites of action of PTP1B and LAR. |
| 4988 | 15031294 | Thus, overexpression of PTP1B in vivo impairs insulin sensitivity, suggesting that overexpression of PTP1B in muscle of obese humans and rodents may contribute to their insulin resistance. |
| 4989 | 15031294 | Lack of additive impairment of insulin signaling by PTP1B and LAR suggests that these PTPs have overlapping actions in causing insulin resistance in vivo. |
| 4990 | 15033922 | We found that diet-induced insulin resistance promoted amyloidogenic beta-amyloid (Abeta) Abeta1-40 and Abeta1-42 peptide generation in the brain that corresponded with increased gamma-secretase activities and decreased insulin degrading enzyme (IDE) activities. |
| 4991 | 15033922 | Moreover, increased Abeta production also coincided with increased AD-type amyloid plaque burden in the brain and impaired performance in a spatial water maze task. |
| 4992 | 15033922 | Further exploration of the apparent interrelationship of insulin resistance to brain amyloidosis revealed a functional decrease in insulin receptor (IR)-mediated signal transduction in the brain, as suggested by decreased IR beta-subunit (IRbeta) Y1162/1163 autophosphorylation and reduced phosphatidylinositol 3 (PI3)-kinase/pS473-AKT/Protein kinase (PK)-B in these same brain regions. |
| 4993 | 15033922 | This latter finding is of particular interest given the known inhibitory role of AKT/PKB on glycogen synthase kinase (GSK)-3alpha activity, which has previously been shown to promote Abeta peptide generation. |
| 4994 | 15033922 | Most interestingly, we found that decreased pS21-GSK-3alpha and pS9-GSK-3beta phosphorylation, which is an index of GSK activation, positively correlated with the generation of brain C-terminal fragment (CTF)-gamma cleavage product of amyloid precursor protein, an index of gamma-secretase activity, in the brain of insulin-resistant relative to normoglycemic Tg2576 mice. |
| 4995 | 15033922 | Our study is consistent with the hypothesis that insulin resistance may be an underlying mechanism responsible for the observed increased relative risk for AD neuropathology, and presents the first evidence to suggest that IR signaling can influence Abeta production in the brain. |
| 4996 | 15044376 | To examine the effects of genetic background on insulin signaling, we analyzed glucose homeostasis in four inbred strains of mice [C57BL/6 (B6), C57BLKS/6 (KLS), DBA/2 (DBA), and 129X1] and quantitated mRNA content of insulin receptor (IR) and its substrates in insulin-responsive tissues. |
| 4997 | 15044376 | IR substrate (IRS)-1 and IRS-2 mRNA are ubiquitously expressed and IRS-3 and IRS-4 mRNA were detected in significant amounts in fat and brain tissues, respectively. |
| 4998 | 15047622 | Differential effects of interleukin-6 and -10 on skeletal muscle and liver insulin action in vivo. |
| 4999 | 15047622 | The circulating level of the inflammatory cytokine interleukin (IL)-6 is elevated in various insulin-resistant states including type 2 diabetes, obesity, cancer, and HIV-associated lipodystrophy. |
| 5000 | 15047622 | To determine the role of IL-6 in the development of insulin resistance, we examined the effects of IL-6 treatment on whole-body insulin action and glucose metabolism in vivo during hyperinsulinemic-euglycemic clamps in awake mice. |
| 5001 | 15047622 | Pretreatment of IL-6 blunted insulin's ability to suppress hepatic glucose production and insulin-stimulated insulin receptor substrate (IRS)-2-associated phosphatidylinositol (PI) 3-kinase activity in liver. |
| 5002 | 15047622 | Acute IL-6 treatment also reduced insulin-stimulated glucose uptake in skeletal muscle, and this was associated with defects in insulin-stimulated IRS-1-associated PI 3-kinase activity and increases in fatty acyl-CoA levels in skeletal muscle. |
| 5003 | 15047622 | In contrast, we found that co-treatment of IL-10, a predominantly anti-inflammatory cytokine, prevented IL-6-induced defects in hepatic insulin action and signaling activity. |
| 5004 | 15047622 | Additionally, IL-10 co-treatment protected skeletal muscle from IL-6 and lipid-induced defects in insulin action and signaling activity, and these effects were associated with decreases in intramuscular fatty acyl-CoA levels. |
| 5005 | 15047622 | This is the first study to demonstrate that inflammatory cytokines IL-6 and IL-10 alter hepatic and skeletal muscle insulin action in vivo, and the mechanism may involve cytokine-induced alteration in intracellular fat contents. |
| 5006 | 15056942 | On the other hand, PAC1 receptor is expressed in adipocytes. |
| 5007 | 15056942 | PACAP enhances insulin-stimulated glucose uptake in an adipocyte cell-line, 3T3-L1 cells. |
| 5008 | 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. |
| 5009 | 15056942 | These results demonstrate that PACAP enhances glucose-stimulated insulin secretion in islets, enhances insulin action inadipocytes, and prevents hyperglycemia in diabetic animals. |
| 5010 | 15063759 | Mice lacking insulin or insulin-like growth factor 1 receptors in vascular endothelial cells maintain normal blood-brain barrier. |
| 5011 | 15063759 | One of the key tight junction proteins, zona occludens-1 (ZO-1), has been reported to be stimulated in its expression by insulin and IGF-1. |
| 5012 | 15063759 | To assess the role of insulin and IGF-1 in endothelial cells in the BBB we have utilized mice with a vascular endothelial cell-specific knockout of the insulin receptor (VENIRKO) and IGF-1 receptor (VENIFARKO). |
| 5013 | 15063759 | These observations indicate that neither insulin nor IGF-1 signaling in vascular endothelial cells is required for development and maintenance of BBB or BRB. |
| 5014 | 15073413 | The cation [Cr3O(O2CCH2CH3)6(H2O)3]+ has been shown in vitro to mimic to the oligopeptide chromodulin's ability to stimulate the tyrosine kinase activity of insulin receptor and shown in healthy and type 2 diabetic model rats to increase insulin sensitivity and decrease plasma total and low-density lipoprotein cholesterol and triglycerides concentrations. |
| 5015 | 15082116 | Elevated sympathetic activity may promote insulin resistance syndrome by activating alpha-1 adrenergic receptors on adipocytes. |
| 5016 | 15082116 | An excess of free intracellular calcium can reduce the efficiency of insulin-mediated glucose transport by blocking the dephosphorylation of GLUT-4. |
| 5017 | 15082116 | Classical isoforms of protein kinase C (PKC) can interfere with insulin signalling via serine phosphorylation of IRS-1 and the insulin receptor. |
| 5018 | 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. |
| 5019 | 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. |
| 5020 | 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. |
| 5021 | 15082116 | This suggests that, via activation of alpha-1 adrenergic receptors, increased sympathetic activity in adipose tissue may promote insulin resistance syndrome. |
| 5022 | 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. |
| 5023 | 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. |
| 5024 | 15086355 | Insulin-like growth factors and pancreas beta cells. |
| 5025 | 15086355 | Abstract Insulin-like growth factors (IGFs) have been implicated in normal growth, and especially foetal pancreas beta-cell development. |
| 5026 | 15086355 | Insulin-like growth factor-I signalling has a lot in common with insulin signalling, and is involved in diverse cellular effects such as antiapoptosis, protein synthesis, cell growth and mitogenesis. |
| 5027 | 15086355 | Insulin-like growth factor-II can be bound by the insulin receptor A subtype and the IGF-1 receptor, which may explain its antiapoptotic effect. |
| 5028 | 15094073 | Leptin and melanocortins, peptides that down regulate food intake and are largely affected by nutrients, are highly interactive with insulin in the CNS probably via the neurotransmitter serotonin. |
| 5029 | 15094073 | In the hypothalamus, insulin and leptin share a common signaling pathway involved in food intake, namely the insulin receptor substrate, phosphatidylinositol 3-kinase pathway. |
| 5030 | 15094078 | In early-onset familial Alzheimer disease, the inhibition of neuronal insulin receptor function may be due to competitive binding of amyloid beta (Abeta) to the insulin receptor. |
| 5031 | 15094078 | The consequences of the inhibition of neuronal insulin signal transduction may be largely identical to those of disturbances of oxidative energy metabolism and related metabolism, and of hyperphosphorylation of tau-protein. |
| 5032 | 15094078 | As far as the metabolism of amyloid precursor protein (APP) in late-onset sporadic Alzheimer disease is concerned, neuronal insulin receptor dysfunction may result in the intracellular accumulation of Abeta and in subsequent cellular damage. |
| 5033 | 15094078 | In early-onset familial Alzheimer disease, the inhibition of neuronal insulin receptor function may be due to competitive binding of amyloid beta (Abeta) to the insulin receptor. |
| 5034 | 15094078 | The consequences of the inhibition of neuronal insulin signal transduction may be largely identical to those of disturbances of oxidative energy metabolism and related metabolism, and of hyperphosphorylation of tau-protein. |
| 5035 | 15094078 | As far as the metabolism of amyloid precursor protein (APP) in late-onset sporadic Alzheimer disease is concerned, neuronal insulin receptor dysfunction may result in the intracellular accumulation of Abeta and in subsequent cellular damage. |
| 5036 | 15114529 | Myotonic dystrophy (DM) is caused by either an untranslated CTG expansion in the 3' untranslated region of the DMPK gene on chromosome 19 (dystrophia myotonica type 1 [DM1]), or an untranslated CCTG tetranucleotide repeat expansion in intron 1 of the ZNF9 gene on chromosome 3 (dystrophia myotonica type 2 [DM2]). |
| 5037 | 15114529 | In muscle from patients with DM1, altered insulin-receptor splicing to the nonmuscle isoform corresponds to the insulin insensitivity and diabetes that are part of the DM phenotype; because of insulin-receptor species differences, this effect is not seen in mouse models of the disease. |
| 5038 | 15123681 | Insulin receptor substrate-2-dependent interleukin-4 signaling in macrophages is impaired in two models of type 2 diabetes mellitus. |
| 5039 | 15123681 | We have shown previously that hyperinsulinemia inhibits interferon-alpha-dependent activation of phosphatidylinositol 3-kinase (PI3-kinase) through mammalian target of rapamycin (mTOR)-induced serine phosphorylation of insulin receptor substrate (IRS)-1. |
| 5040 | 15123681 | Here we report that chronic insulin and high glucose synergistically inhibit interleukin (IL)-4-dependent activation of PI3-kinase in macrophages via the mTOR pathway. |
| 5041 | 15123681 | Resident peritoneal macrophages (PerMPhis) from diabetic (db/db) mice showed a 44% reduction in IRS-2-associated PI3-kinase activity stimulated by IL-4 compared with PerMPhis from heterozygote (db/+) control mice. |
| 5042 | 15123681 | To investigate the mechanism of this PI3-kinase inhibition, 12-O-tetradecanoylphorbol-13-acetate-matured U937 cells were treated chronically with insulin (1 nm, 18 h) and high glucose (4.5 g/liter, 48 h). |
| 5043 | 15123681 | In these cells, IL-4-stimulated IRS-2-associated PI3-kinase activity was reduced by 37.5%. |
| 5044 | 15123681 | Importantly, chronic insulin or high glucose alone did not impact IL-4-activated IRS-2-associated PI3-kinase. |
| 5045 | 15123681 | Chronic insulin + high glucose did reduce IL-4-dependent IRS-2 tyrosine phosphorylation and p85 association by 54 and 37%, respectively, but did not effect IL-4-activated JAK/STAT signaling. |
| 5046 | 15123681 | When IRS-2 Ser/Thr-Pro motif phosphorylation was examined, chronic insulin + high glucose resulted in a 92% increase in IRS-2 Ser/Thr-Pro motif phosphorylation without a change in IRS-2 mass. |
| 5047 | 15123681 | Pretreatment of matured U937 cells with rapamycin blocked chronic insulin + high glucose-dependent IRS-2 Ser/Thr-Pro motif phosphorylation and restored IL-4-dependent IRS-2-associated PI3-kinase activity. |
| 5048 | 15123681 | Taken together these results indicate that IRS-2-dependent IL-4 signaling in macrophages is impaired in models of type 2 diabetes mellitus through a mechanism that relies on insulin/glucose-dependent Ser/Thr-Pro motif serine phosphorylation mediated by the mTOR pathway. |
| 5049 | 15126519 | The plasma cell glycoprotein 1 (PC-1) gene impairs insulin signaling at the insulin receptor level. |
| 5050 | 15126519 | Therefore, we investigated whether the K121Q polymorphism of the PC-1 gene association with insulin sensitivity, insulin levels, and the prevalence of diabetes and hypertension in adult life depends on size at birth in 489 subjects born in Helsinki during 1924-1933. |
| 5051 | 15126519 | We found that the effect of the PC-1 gene polymorphism on insulin levels and insulin sensitivity, measured as the homeostasis model assessment for insulin resistance, depended on birth length because fasting insulin levels and insulin resistance were highest in subjects carrying the 121Q allele who were small at birth (P for interaction = 0.04 and 0.05). |
| 5052 | 15126519 | We conclude that the interaction between the K121Q polymorphism of the PC-1 gene and birth length affects insulin sensitivity and increases susceptibility to type 2 diabetes and hypertension in adulthood. |
| 5053 | 15131120 | Mice with a fat-specific insulin receptor knock-out (FIRKO) exhibit a polarization of white adipose tissue into two populations of cells, one small (diameter <50 microm) and one large (diameter >100 microm), accompanied by changes in insulin-stimulated glucose uptake, triglyceride synthesis, and lipolysis. |
| 5054 | 15131120 | A total of 27 alterations in protein expression at key steps in lipid and energy metabolism could be defined, which were coordinately regulated by adipocyte cell size, impaired insulin signaling, or both. |
| 5055 | 15131120 | Nine proteins, including vimentin, EH-domain-containing protein 2, elongation factor 2, glucose-regulated protein 78, transketolase, and succinyl-CoA transferase were primarily affected by presence or absence of insulin signaling, whereas 21 proteins, including myosin non-muscle form A, annexin 2, annexin A6, and Hsp47 were regulated in relation to adipocyte size. |
| 5056 | 15134463 | In vitro phosphorylation of insulin receptor substrate 1 by protein kinase C-zeta: functional analysis and identification of novel phosphorylation sites. |
| 5057 | 15134463 | Protein kinase C-zeta (PKC-zeta) participates both in downstream insulin signaling and in the negative feedback control of insulin action. |
| 5058 | 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. |
| 5059 | 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. |
| 5060 | 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. |
| 5061 | 15134463 | Ser(570) was specifically targeted by PKC-zeta, as shown by immunoblotting with a phosphospecific antiserum against Ser(570) of IRS-1. |
| 5062 | 15134463 | Binding of p85alpha to the S570A mutant was less susceptible to inhibition by PKC-zeta, when compared to the S612A mutant. |
| 5063 | 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. |
| 5064 | 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. |
| 5065 | 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. |
| 5066 | 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. |
| 5067 | 15166122 | Increased insulin sensitivity in paternal Gnas knockout mice is associated with increased lipid clearance. |
| 5068 | 15166122 | This was associated with increased phosphorylation of insulin receptor and a downstream effector (Akt kinase) in both liver and muscle in response to insulin. |
| 5069 | 15166122 | Resistin and adiponectin were overexpressed in white adipose tissue of +/p- mice, although there was no difference in serum adiponectin levels. |
| 5070 | 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. |
| 5071 | 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. |
| 5072 | 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. |
| 5073 | 15169905 | Neither affects IR phosphorylation, although both SOCS-1 and SOCS-3 bind to the insulin receptor in vivo in an insulin-dependent fashion. |
| 5074 | 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. |
| 5075 | 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. |
| 5076 | 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. |
| 5077 | 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. |
| 5078 | 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. |
| 5079 | 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. |
| 5080 | 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. |
| 5081 | 15169905 | Neither affects IR phosphorylation, although both SOCS-1 and SOCS-3 bind to the insulin receptor in vivo in an insulin-dependent fashion. |
| 5082 | 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. |
| 5083 | 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. |
| 5084 | 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. |
| 5085 | 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. |
| 5086 | 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. |
| 5087 | 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. |
| 5088 | 15180298 | Dysregulation of IRS2 signaling in mice causes the failure of compensatory hyperinsulinemia during peripheral insulin resistance. |
| 5089 | 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. |
| 5090 | 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. |
| 5091 | 15182363 | Insulin-stimulated phosphorylation of the insulin receptor and IRS1 was not affected, indicating that caveolae integrity is required downstream of IRS1. |
| 5092 | 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. |
| 5093 | 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. |
| 5094 | 15182363 | Insulin-stimulated phosphorylation of the insulin receptor and IRS1 was not affected, indicating that caveolae integrity is required downstream of IRS1. |
| 5095 | 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. |
| 5096 | 15184668 | Development of insulin resistance and obesity in mice overexpressing cellular glutathione peroxidase. |
| 5097 | 15184668 | The objective of our study was to investigate the impact of overexpression of glutathione peroxidase 1 (GPX1), an intracellular selenoprotein that reduces hydrogen peroxide (H(2)O(2)) in vivo, on glucose metabolism and insulin function. |
| 5098 | 15184668 | Their insulin resistance was associated with a 30-70% reduction (P < 0.05) in the insulin-stimulated phosphorylations of insulin receptor (beta-subunit) in liver and Akt (Ser(473) and Thr(308)) in liver and soleus muscle. |
| 5099 | 15184668 | Here we report the development of insulin resistance in mammals with elevated expression of an antioxidant enzyme and suggest that increased GPX1 activity may interfere with insulin function by overquenching intracellular reactive oxygen species required for insulin sensitizing. |
| 5100 | 15196884 | The roles of phospholipase C-gamma 1 and actin-binding protein filamin A in signal transduction of the insulin receptor. |
| 5101 | 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. |
| 5102 | 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. |
| 5103 | 15201286 | On the other hand, protein levels and phosphorylation of PDK1 and Akt were decreased in retina of both mice. |
| 5104 | 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. |
| 5105 | 15201286 | HIF-1alpha and vascular endothelial growth factor were increased and endothelial nitric-oxide synthase was decreased in retina. |
| 5106 | 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. |
| 5107 | 15208455 | Unlike the intensive research in pursuit of understanding the molecular mechanisms of insulin signaling and resistance to its biological action associated most significantly with obesity and type 2 diabetes, the influence of the plasma membrane on insulin sensitivity has been intermittently studied over the years-mainly because it was thought that mediators of insulin action, such as the insulin receptor and the insulin-responsive glucose transporter GLUT4, localize more or less uniformly in the lipids that form cell membranes. |
| 5108 | 15209435 | Plasma cell membrane glycoprotein 1 (PC-1): a marker of insulin resistance in obesity, uremia and diabetes mellitus. |
| 5109 | 15209435 | PC-1 is expressed in many tissues and inhibits insulin signaling either at the level of the insulin receptor or downstream at a postreceptor site. |
| 5110 | 15209435 | An elevated PC-1 content in insulin target tissues may play an important role in the development of insulin resistance in obesity and type 2 diabetes mellitus. |
| 5111 | 15209435 | A polymorphism in PC-1 has been demonstrated to be associated with insulin resistance. |
| 5112 | 15209435 | Women with GDM have an increased PC-1 content and excessive phosphorylation of serine/threonine residues in muscle insulin receptors. |
| 5113 | 15209435 | During the last decade it was found that erythropoietin (EPO) therapy, used for correction of anemia in patients with end stage renal failure, ameliorates insulin resistance. |
| 5114 | 15209435 | A two-month EPO therapy significantly decreased PC-1 activity to the control values, suggesting that an effect on PC-1 expression could be implicated in the amelioration of insulin resistance in uremic patients treated with EPO. |
| 5115 | 15209435 | Current investigations implicate that therapeutic modification of PC-1 expression would be of great benefit for insulin-resistant type 2 diabetics. |
| 5116 | 15209435 | Metformin, a biguanide oral antidiabetic agent, was shown to affect insulin resistance by decreasing enzymatic activity of overexpressed PC-1 molecules in obese type 2 diabetics. |
| 5117 | 15209435 | Although much remains to be learned about PPAR gamma receptor and TZD action, the advent of TZD insulin-sensitizing agents has an enormous impact on our understanding of insulin resistance. |
| 5118 | 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. |
| 5119 | 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. |
| 5120 | 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. |
| 5121 | 15235328 | Hypoxia and AICAR increase glucose transport via an insulin-independent mechanism involving activation of 5'-AMP-activated kinase (AMPK). |
| 5122 | 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. |
| 5123 | 15235328 | Our studies highlight important AMPK-dependent and independent pathways in the regulation of GLUT4 and glucose transport activity in insulin resistant skeletal muscle. |
| 5124 | 15247278 | Differential roles of the insulin and insulin-like growth factor-I (IGF-I) receptors in response to insulin and IGF-I. |
| 5125 | 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. |
| 5126 | 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)). |
| 5127 | 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). |
| 5128 | 15247278 | In these cells, insulin stimulated IR homodimer phosphorylation, whereas IGF-I activated both IGF-I receptor homodimers and hybrid receptors. |
| 5129 | 15247278 | Insulin-stimulated IRS-1 phosphorylation was significantly impaired in IRKO cells but was surprisingly elevated in IGFRKO cells. |
| 5130 | 15247278 | IRS-2 phosphorylation was unchanged in either cell line upon insulin stimulation. |
| 5131 | 15247278 | IGF-I-dependent phosphorylation of IRS-1 and IRS-2 was ablated in IGFRKO cells but not in IRKO cells. |
| 5132 | 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. |
| 5133 | 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. |
| 5134 | 15247278 | Most surprisingly, insulin- or IGF-I-dependent phosphorylation of MAPK was unaltered in either receptor-deficient cell line. |
| 5135 | 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. |
| 5136 | 15247278 | Differential roles of the insulin and insulin-like growth factor-I (IGF-I) receptors in response to insulin and IGF-I. |
| 5137 | 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. |
| 5138 | 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)). |
| 5139 | 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). |
| 5140 | 15247278 | In these cells, insulin stimulated IR homodimer phosphorylation, whereas IGF-I activated both IGF-I receptor homodimers and hybrid receptors. |
| 5141 | 15247278 | Insulin-stimulated IRS-1 phosphorylation was significantly impaired in IRKO cells but was surprisingly elevated in IGFRKO cells. |
| 5142 | 15247278 | IRS-2 phosphorylation was unchanged in either cell line upon insulin stimulation. |
| 5143 | 15247278 | IGF-I-dependent phosphorylation of IRS-1 and IRS-2 was ablated in IGFRKO cells but not in IRKO cells. |
| 5144 | 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. |
| 5145 | 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. |
| 5146 | 15247278 | Most surprisingly, insulin- or IGF-I-dependent phosphorylation of MAPK was unaltered in either receptor-deficient cell line. |
| 5147 | 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. |
| 5148 | 15271787 | Angiotensin II-induced insulin resistance and protein tyrosine phosphatases. |
| 5149 | 15271787 | For example, both angiotensin II (Ang II) and insulin are known to mediate protein tyrosine phosphorylation and dephosphorylation events. |
| 5150 | 15271787 | These apparently paradoxical effects of Ang II and insulin suggest that both convergent and divergent intracellular signaling cascades are stimulated downstream of their respective receptors, producing diverse cellular responses. |
| 5151 | 15271787 | In this review, we discuss the hypothesis that the protein tyrosine phosphatase (PTPase), PTP-1B, plays a central role in Ang II-induced insulin resistance by inhibiting activation of the insulin receptor. |
| 5152 | 15271787 | We hypothesize that Ang II-induced PTP-1B activation leads to dephosphorylation of the insulin receptor and that this signaling pathway underlies the maladaptive responses observed in diabetic vascular and renal tissue during type II diabetes. |
| 5153 | 15271787 | Angiotensin II-induced insulin resistance and protein tyrosine phosphatases. |
| 5154 | 15271787 | For example, both angiotensin II (Ang II) and insulin are known to mediate protein tyrosine phosphorylation and dephosphorylation events. |
| 5155 | 15271787 | These apparently paradoxical effects of Ang II and insulin suggest that both convergent and divergent intracellular signaling cascades are stimulated downstream of their respective receptors, producing diverse cellular responses. |
| 5156 | 15271787 | In this review, we discuss the hypothesis that the protein tyrosine phosphatase (PTPase), PTP-1B, plays a central role in Ang II-induced insulin resistance by inhibiting activation of the insulin receptor. |
| 5157 | 15271787 | We hypothesize that Ang II-induced PTP-1B activation leads to dephosphorylation of the insulin receptor and that this signaling pathway underlies the maladaptive responses observed in diabetic vascular and renal tissue during type II diabetes. |
| 5158 | 15281007 | Type 2 diabetes and the genetics of signal transduction: a study of interaction between adenosine deaminase and acid phosphatase locus 1 polymorphisms. |
| 5159 | 15281007 | Acid phosphatase locus 1 (ACP1) is a highly polymorphic enzyme that has an important role in flavoenzyme activity and in the control of insulin receptor activity and band 3 protein phosphorylation status. |
| 5160 | 15281007 | Based on the hypothesis that ACP1 counteracts insulin signaling by dephosphorylating the insulin receptor and that adenosine has an anti-insulin action, we reasoned that low ACP1 activity (low dephosphorylating action on insulin receptor) when associated with high ADA activity (low adenosine concentration) would result in a cumulative effect towards an increased glucose tolerance. |
| 5161 | 15281007 | On the contrary, high ACP1 activity when associated with low ADA activity would result in a cumulative effect towards a decreased glucose tolerance. |
| 5162 | 15281007 | There was a nonsignificant trend toward an increase in the proportion of subjects with the complex type with high ACP1 activity and low ADA activity (ie, *B/*B; *A/*C; *B/*C; *C/*C//ADA*1/*2 and *2/*2) in type 2 diabetes relative to that observed in newborn infants from the same population. |
| 5163 | 15281007 | High ACP1 activity/low ADA activity joint genotype was positively associated with high glycemic levels and with high body mass index (BMI) values. |
| 5164 | 15281007 | Low ACP1 activity/high ADA activity joint genotype was also positively associated with dyslipidemia. |
| 5165 | 15281007 | These findings suggest that both ACP1 and ADA contribute to the clinical manifestations of type 2 diabetes and probably also have a marginal influence on susceptibility to the disease. |
| 5166 | 15281007 | Type 2 diabetes and the genetics of signal transduction: a study of interaction between adenosine deaminase and acid phosphatase locus 1 polymorphisms. |
| 5167 | 15281007 | Acid phosphatase locus 1 (ACP1) is a highly polymorphic enzyme that has an important role in flavoenzyme activity and in the control of insulin receptor activity and band 3 protein phosphorylation status. |
| 5168 | 15281007 | Based on the hypothesis that ACP1 counteracts insulin signaling by dephosphorylating the insulin receptor and that adenosine has an anti-insulin action, we reasoned that low ACP1 activity (low dephosphorylating action on insulin receptor) when associated with high ADA activity (low adenosine concentration) would result in a cumulative effect towards an increased glucose tolerance. |
| 5169 | 15281007 | On the contrary, high ACP1 activity when associated with low ADA activity would result in a cumulative effect towards a decreased glucose tolerance. |
| 5170 | 15281007 | There was a nonsignificant trend toward an increase in the proportion of subjects with the complex type with high ACP1 activity and low ADA activity (ie, *B/*B; *A/*C; *B/*C; *C/*C//ADA*1/*2 and *2/*2) in type 2 diabetes relative to that observed in newborn infants from the same population. |
| 5171 | 15281007 | High ACP1 activity/low ADA activity joint genotype was positively associated with high glycemic levels and with high body mass index (BMI) values. |
| 5172 | 15281007 | Low ACP1 activity/high ADA activity joint genotype was also positively associated with dyslipidemia. |
| 5173 | 15281007 | These findings suggest that both ACP1 and ADA contribute to the clinical manifestations of type 2 diabetes and probably also have a marginal influence on susceptibility to the disease. |
| 5174 | 15314154 | Disruption of the SH2-B gene causes age-dependent insulin resistance and glucose intolerance. |
| 5175 | 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. |
| 5176 | 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. |
| 5177 | 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. |
| 5178 | 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. |
| 5179 | 15314154 | Disruption of the SH2-B gene causes age-dependent insulin resistance and glucose intolerance. |
| 5180 | 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. |
| 5181 | 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. |
| 5182 | 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. |
| 5183 | 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. |
| 5184 | 15314154 | Disruption of the SH2-B gene causes age-dependent insulin resistance and glucose intolerance. |
| 5185 | 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. |
| 5186 | 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. |
| 5187 | 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. |
| 5188 | 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. |
| 5189 | 15339744 | Evidence against a role for insulin-signaling proteins PI 3-kinase and Akt in insulin resistance in human skeletal muscle induced by short-term GH infusion. |
| 5190 | 15339744 | GLUT4 content and insulin signaling, as assessed by insulin receptor substrate (IRS)-1-associated phosphatidylinositol 3-kinase and Akt activity were determined. |
| 5191 | 15339744 | GH infusion did not change Akt protein expression, and insulin caused an approximately 13-fold increase in Akt activity (1,309 +/- 327 and 1,287 +/- 173%) after both GH and saline infusion. |
| 5192 | 15339744 | In conclusion, insulin resistance in skeletal muscle induced by short-term GH administration is not associated with detectable changes in the upstream insulin-signaling cascade or reduction in total GLUT4. |
| 5193 | 15339744 | Yet unknown mechanisms in insulin signaling downstream of Akt may be responsible. |
| 5194 | 15372107 | PDX-1 haploinsufficiency limits the compensatory islet hyperplasia that occurs in response to insulin resistance. |
| 5195 | 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. |
| 5196 | 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. |
| 5197 | 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. |
| 5198 | 15378031 | The APS, SH2-B and LNK proteins are adapters that activate and modulate receptor tyrosine kinase and JAK/STAT signaling. |
| 5199 | 15378031 | A newly developed bridging yeast tri-hybrid assay showed that APS dimerizes JAK2, insulin receptor and IGF1 receptor kinases using its SH2 and dimerization domains. |
| 5200 | 15464053 | Kinin B(2) receptor also ameliorates insulin resistance by increasing glucose uptake and supply, and by inducing glucose transporter-4 translocation either directly or through phosphorylation of insulin receptor. |
| 5201 | 15504984 | The PTPN1 gene codes for protein tyrosine phosphatase 1B (PTP1B) (EC 3.1.3.48), which negatively regulates insulin signaling by dephosphorylating the phosphotyrosine residues of the insulin receptor kinase activation segment. |
| 5202 | 15504985 | Association of protein tyrosine phosphatase 1B gene polymorphisms with measures of glucose homeostasis in Hispanic Americans: the insulin resistance atherosclerosis study (IRAS) family study. |
| 5203 | 15504985 | Protein tyrosine phosphatase (PTP)-1B, encoded by the PTPN1 gene, catalyzes the dephosphorylation of proteins at tyrosyl residues. |
| 5204 | 15504985 | PTP-1B has been implicated in negatively regulating insulin signaling by dephosphorylating the phosphotyrosine residues of the insulin receptor. |
| 5205 | 15504985 | The genetic contribution of PTPN1 to measures of glucose homeostasis has been assessed in 811 Hispanic subjects from the Insulin Resistance Atherosclerosis Study Family Study (IRASFS). |
| 5206 | 15504985 | All 20 SNPs with minor allele frequencies >0.1 in a single haplotype block covering the PTPN1 genomic sequence show significant association with the insulin sensitivity index (S(i)) (P = 0.044-0.003) and fasting glucose (P = 0.029 to <0.001). |
| 5207 | 15504985 | In contrast, there is no evidence for association of PTPN1 polymorphisms with acute insulin response (a measure of beta-cell function). |
| 5208 | 15520865 | c-Cbl-deficient mice have reduced adiposity, higher energy expenditure, and improved peripheral insulin action. |
| 5209 | 15520865 | Casitas b-lineage lymphoma (c-Cbl) is an E3 ubiquitin ligase that has an important role in regulating the degradation of cell surface receptors. |
| 5210 | 15520865 | In addition, c-Cbl-/- mice displayed a marked improvement in whole-body insulin action, primarily due to changes in muscle metabolism. |
| 5211 | 15520865 | We observed increased protein levels of the insulin receptor (4-fold) and uncoupling protein-3 (2-fold) in skeletal muscle and a significant increase in the phosphorylation of AMP-activated protein kinase and acetyl-CoA carboxylase. |
| 5212 | 15520865 | These findings suggest that c-Cbl plays an integral role in whole-body fuel homeostasis by regulating whole-body energy expenditure and insulin action. |
| 5213 | 15523593 | Met326Ile aminoacid polymorphism in the human p85 alpha gene has no major impact on early insulin signaling in type 2 diabetes. |
| 5214 | 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. |
| 5215 | 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. |
| 5216 | 15523593 | Furthermore, IRS-1, IRS-2, p85 alpha and MAPK protein contents were not significantly changed, and neither were MAPK or Akt phosphorylation. |
| 5217 | 15534092 | 7-hydroxystaurosporine (UCN-01) inhibition of Akt Thr308 but not Ser473 phosphorylation: a basis for decreased insulin-stimulated glucose transport. |
| 5218 | 15534092 | As Akt is known to mediate in part action initiated at the insulin receptor, we also studied the effect of UCN-01 on Akt activation in whole-cell homogenates of these cells. |
| 5219 | 15534092 | Decreased glucose transport activity directly parallels decreased Akt Thr308 phosphorylation in both an insulin and UCN-01 dose-dependent manner, whereas Akt Ser473 phosphorylation is inhibited only at the lowest insulin concentration, and then, only modestly. |
| 5220 | 15534092 | UCN-01 also inhibits insulin-induced Thr308 but not Ser473 phosphorylation of Akt associated with the plasma membranes and low-density microsomes and inhibits translocation of GLUT4 from low-density microsomes to plasma membranes as expected from the glucose transport activity measurements. |
| 5221 | 15534092 | These data suggest that UCN-01 induces clinical insulin resistance by blocking Akt activation and subsequent GLUT4 translocation in response to insulin, and this effect appears to occur by inhibiting Thr308 phosphorylation even in the face of almost completely unaffected Ser473 phosphorylation. |
| 5222 | 15546994 | To dissect and quantitate these two separate effects, we compared the skeletal muscle gene-expression profiles of muscle insulin receptor knockout (MIRKO) mice and their Lox controls in the basal, streptozotocin-induced diabetic, and insulin-treated diabetic states. |
| 5223 | 15546994 | Pure deficiency of insulin action as present in the MIRKO mouse results in regulation of 130 genes, with down-regulation of NSF (N-ethylmaleimide-sensitive fusion protein) and VAMP-2 (vesicle-associated membrane protein 2), stearoyl CoA desaturase 1, and cAMP-specific phosphodiesterase 4B, as well as up-regulation of some signaling-related genes, such as Akt2, and the fatty-acid transporter CD36. |
| 5224 | 15550505 | Autocrine activation of the local insulin-like growth factor I system is up-regulated by estrogen receptor (ER)-independent estrogen actions and accounts for decreased ER expression in type 2 diabetic mesangial cells. |
| 5225 | 15550505 | We found increased IGF-I receptor (IGFR) expression and activation, including activation of MAPK. |
| 5226 | 15550505 | Surprisingly, estrogens, via an estrogen receptor (ER)-independent mechanism(s), increased IGFR expression, IGFR and insulin receptor substrate phosphorylation, and extracellular signal-regulated kinase activation in db/db MC. |
| 5227 | 15550505 | Treatment with a neutralizing antibody to IGF-I or the MAPK inhibitor PD98059 increased ER expression and transcriptional activity. |
| 5228 | 15561930 | The potential role of SOCS-3 in the interleukin-1beta-induced desensitization of insulin signaling in pancreatic beta-cells. |
| 5229 | 15561930 | Because effective insulin signaling is required for the optimal beta-cell function, we assessed the effect of IL-1beta on the insulin pathway in a rat pancreatic beta-cell line. |
| 5230 | 15561930 | We show that IL-1beta decreases insulin-induced tyrosine phosphorylation of the insulin receptor (IR) and insulin receptor substrate (IRS) proteins as well as phosphatidylinositol 3-kinase (PI3K) activation, and that this action is not due to the IL-1beta-dependent nitric oxide (NO) production in RINm5F cells. |
| 5231 | 15561930 | We next analyzed if suppressor of cytokine signaling (SOCS)-3, which can be induced by multiple cytokines and which we identified as an insulin action inhibitor, was implicated in the IL-1beta inhibitory effect on insulin signaling in these cells. |
| 5232 | 15561930 | We show that IL-1beta increases SOCS-3 expression and induces SOCS-3/IR complex formation in RINm5F cells. |
| 5233 | 15561930 | Moreover, we find that ectopically expressed SOCS-3 associates with the IR and reduces insulin-dependent IR autophosphorylation and IRS/PI3K pathway in a way comparable to IL-1beta treatment in RINm5F cells. |
| 5234 | 15561930 | We propose that IL-1beta decreases insulin action in beta-cells through the induction of SOCS-3 expression, and that this effect potentially alters insulin-induced beta-cell survival. |
| 5235 | 15562822 | Elucidating the intracellular events following activation of the insulin receptor and the interactions between the insulin and IGF-1 signalling systems has been the main focus of a large number of investigators, and for excellent reasons. |
| 5236 | 15562822 | Improved understanding of the signalling pathways involved in insulin action and the impact of IGF-1 on these processes could lead to a better understanding of the pathophysiology of insulin resistance associated with obesity and type 2 diabetes and the identification of key molecules that could lead to newer and more effective therapeutic agents for treating these common disorders that are already an uprising epidemic of the 21st century. |
| 5237 | 15562822 | Then, impairments in insulin signalling pathways and new paradigms regarding the molecular basis of insulin and IGF-1 resistance will be analysed. |
| 5238 | 15564333 | In experimental models, oral salicylates, through their ability to interfere with the nuclear factor-kappa B (NF-kappa B) transcription pathway, have been demonstrated to reverse insulin resistance. |
| 5239 | 15564333 | After an 18-h incubation, the tissues were collected, and NF-kappa B p65 DNA-binding activity and I kappa B kinase (IKK-beta) and insulin receptor-beta protein expression were assessed by ELISA and Western blotting, respectively. |
| 5240 | 15564333 | The incubation medium was collected, and the release of TNF-alpha, IL-6, IL-8, resistin, adiponectin, and leptin was quantified by ELISA. |
| 5241 | 15564333 | Treatment of adipose tissue and skeletal muscle with sulfasalazine and BAY 11-7082 significantly inhibited the release of IL-6, IL-8, and TNF-alpha; NF-kappa B p65 DNA-binding activity; and IKK-beta protein expression (P < 0.05, by Newman-Keuls test). |
| 5242 | 15564333 | There was no effect of sulfasalazine and BAY 11-7082 on resistin, adiponectin, or leptin release. |
| 5243 | 15564333 | The data presented in this study demonstrate that the IKK-beta/NF-kappa B transcription pathway is a key regulator of IL-6, IL-8, and TNF-alpha release from adipose tissue and skeletal muscle. |
| 5244 | 15564333 | Control of the IKK-beta/NF-kappa B pathway may therefore provide an alternative therapeutic strategy for regulating aberrant cytokine release and thereby alleviating insulin resistance in type 2 diabetes mellitus. |
| 5245 | 15570022 | Fibroin did not prevent the insulin-induced downregulation of the insulin receptor or the tyrosine kinase activity associated with the receptor. |
| 5246 | 15570022 | Further, fibroin had no effect on the activity of the insulin-sensitive downstream kinase, Akt. |
| 5247 | 15570022 | In addition, fibroin upregulated glucose transporter (GLUT)1, which increased its expression at the cell surface and enhanced GLUT4 translocation. |
| 5248 | 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. |
| 5249 | 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. |
| 5250 | 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. |
| 5251 | 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. |
| 5252 | 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. |
| 5253 | 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. |
| 5254 | 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. |
| 5255 | 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. |
| 5256 | 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. |
| 5257 | 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. |
| 5258 | 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. |
| 5259 | 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. |
| 5260 | 15590928 | Insulin-degrading enzyme as a downstream target of insulin receptor signaling cascade: implications for Alzheimer's disease intervention. |
| 5261 | 15590928 | Insulin-degrading enzyme (IDE) is one of the proteins that has been demonstrated to play a key role in degrading beta-amyloid (Abeta) monomer in vitro and in vivo, raising the possibility of upregulating IDE as an approach to reduce Abeta. |
| 5262 | 15590928 | Because one of the main functions of IDE is to degrade insulin, we hypothesized that there is a negative feedback mechanism whereby stimulation of insulin receptor-mediated signaling upregulates IDE to prevent chronic activation of the pathway. |
| 5263 | 15590928 | We show that treatment of primary hippocampal neurons with insulin increased IDE protein levels by approximately 25%. |
| 5264 | 15590928 | Insulin treatment also led to phosphatidylinositol-3 (PI3) kinase activation evidenced by Akt phosphorylation, which was blocked by PI3 kinase inhibitors, wortmannin and LY 294002. |
| 5265 | 15590928 | Inhibition of PI3 kinase abolished the IDE upregulation by insulin, indicating a cause-effect relationship between insulin signaling and IDE upregulation. |
| 5266 | 15590928 | Further support for this link was provided by the findings that deficient insulin signaling (decreased PI3 kinase subunit P85) was correlated with reduced IDE in Alzheimer's disease (AD) brains and in Tg2576 Swedish amyloid precursor protein transgenic mice fed a safflower oil-enriched ("Bad") diet used to accelerate pathogenesis. |
| 5267 | 15590928 | Consistent with IDE function in the degradation of Abeta monomer, the IDE decrease in the Bad diet-fed Tg2576 mice was associated with increased Abeta monomer levels. |
| 5268 | 15590928 | These in vitro and in vivo analyses validate the use of enhanced CNS insulin signaling as a potential strategy for AD intervention to correct the IDE defects occurring in AD. |
| 5269 | 15590928 | Insulin-degrading enzyme as a downstream target of insulin receptor signaling cascade: implications for Alzheimer's disease intervention. |
| 5270 | 15590928 | Insulin-degrading enzyme (IDE) is one of the proteins that has been demonstrated to play a key role in degrading beta-amyloid (Abeta) monomer in vitro and in vivo, raising the possibility of upregulating IDE as an approach to reduce Abeta. |
| 5271 | 15590928 | Because one of the main functions of IDE is to degrade insulin, we hypothesized that there is a negative feedback mechanism whereby stimulation of insulin receptor-mediated signaling upregulates IDE to prevent chronic activation of the pathway. |
| 5272 | 15590928 | We show that treatment of primary hippocampal neurons with insulin increased IDE protein levels by approximately 25%. |
| 5273 | 15590928 | Insulin treatment also led to phosphatidylinositol-3 (PI3) kinase activation evidenced by Akt phosphorylation, which was blocked by PI3 kinase inhibitors, wortmannin and LY 294002. |
| 5274 | 15590928 | Inhibition of PI3 kinase abolished the IDE upregulation by insulin, indicating a cause-effect relationship between insulin signaling and IDE upregulation. |
| 5275 | 15590928 | Further support for this link was provided by the findings that deficient insulin signaling (decreased PI3 kinase subunit P85) was correlated with reduced IDE in Alzheimer's disease (AD) brains and in Tg2576 Swedish amyloid precursor protein transgenic mice fed a safflower oil-enriched ("Bad") diet used to accelerate pathogenesis. |
| 5276 | 15590928 | Consistent with IDE function in the degradation of Abeta monomer, the IDE decrease in the Bad diet-fed Tg2576 mice was associated with increased Abeta monomer levels. |
| 5277 | 15590928 | These in vitro and in vivo analyses validate the use of enhanced CNS insulin signaling as a potential strategy for AD intervention to correct the IDE defects occurring in AD. |
| 5278 | 15604363 | Visfatin exerted insulin-mimetic effects in cultured cells and lowered plasma glucose levels in mice. |
| 5279 | 15604363 | Surprisingly, visfatin binds to and activates the insulin receptor. |
| 5280 | 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. |
| 5281 | 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). |
| 5282 | 15613682 | Basal and insulin-stimulated glucose transport and GLUT1 abundance were significantly increased in cultured myotubes from women with PCOS. |
| 5283 | 15613682 | Insulin signaling via IRS-2 was also decreased in myotubes from women with PCOS. |
| 5284 | 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. |
| 5285 | 15632081 | Coordinated regulation of insulin signaling by the protein tyrosine phosphatases PTP1B and TCPTP. |
| 5286 | 15632081 | The protein tyrosine phosphatase PTP1B is a negative regulator of insulin signaling and a therapeutic target for type 2 diabetes. |
| 5287 | 15632081 | Our previous studies have shown that the closely related tyrosine phosphatase TCPTP might also contribute to the regulation of insulin receptor (IR) signaling in vivo (S. |
| 5288 | 15632081 | Here we show that PTP1B and TCPTP function in a coordinated and temporally distinct manner to achieve an overall regulation of IR phosphorylation and signaling. |
| 5289 | 15632081 | Whereas insulin-induced phosphatidylinositol 3-kinase/Akt signaling was prolonged in both TCPTP-/- and PTP1B-/- immortalized mouse embryo fibroblasts (MEFs), mitogen-activated protein kinase ERK1/2 signaling was elevated only in PTP1B-null MEFs. |
| 5290 | 15632081 | By using phosphorylation-specific antibodies, we demonstrate that both IR beta-subunit Y1162/Y1163 and Y972 phosphorylation are elevated in PTP1B-/- MEFs, whereas Y972 phosphorylation was elevated and Y1162/Y1163 phosphorylation was sustained in TCPTP-/- MEFs, indicating that PTP1B and TCPTP differentially contribute to the regulation of IR phosphorylation and signaling. |
| 5291 | 15632081 | Consistent with this, suppression of TCPTP protein levels by RNA interference in PTP1B-/- MEFs resulted in no change in ERK1/2 signaling but caused prolonged Akt activation and Y1162/Y1163 phosphorylation. |
| 5292 | 15632081 | These results demonstrate that PTP1B and TCPTP are not redundant in insulin signaling and that they act to control both common as well as distinct insulin signaling pathways in the same cell. |
| 5293 | 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. |
| 5294 | 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. |
| 5295 | 15634339 | MAP-kinases ERK1/2 and p38 were strongly phosphorylated after surgery, but was dephosphorylated during reversal of insulin resistance. |
| 5296 | 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. |
| 5297 | 15634339 | IRS1, PKB, and downstream metabolic effects, but not insulin-stimulated tyrosine phosphorylation of insulin receptor, exhibited insulin resistance. |
| 5298 | 15634339 | Moreover, we pinpoint the signalling dysregulation in type 2 diabetes to be the insulin-stimulated phosphorylation of IRS1 in human adipocytes. |
| 5299 | 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. |
| 5300 | 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. |
| 5301 | 15634339 | MAP-kinases ERK1/2 and p38 were strongly phosphorylated after surgery, but was dephosphorylated during reversal of insulin resistance. |
| 5302 | 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. |
| 5303 | 15634339 | IRS1, PKB, and downstream metabolic effects, but not insulin-stimulated tyrosine phosphorylation of insulin receptor, exhibited insulin resistance. |
| 5304 | 15634339 | Moreover, we pinpoint the signalling dysregulation in type 2 diabetes to be the insulin-stimulated phosphorylation of IRS1 in human adipocytes. |
| 5305 | 15654920 | The main pathway involved in insulin induction of adipogenic differentiation, monitored by fatty acid synthase expression, is the cascade insulin receptor substrate (IRS)-1/phosphatidylinositol 3-kinase (PI3K)/Akt. |
| 5306 | 15654920 | Acute insulin treatment stimulates glucose transport largely by mediating translocation of GLUT4 to the plasma membrane, involving the activation of IRS-2/PI3K, and the downstream targets Akt and protein kinase C zeta. |
| 5307 | 15654920 | Tumour necrosis factor (TNF-alpha) caused insulin resistance on glucose uptake by impairing insulin signalling at the level of IRS-2. |
| 5308 | 15654920 | Furthermore, brown adipocytes are also target cells for rosiglitazone action since they show a high expression of peroxisome proliferator activated receptor gamma, and rosiglitazone increased the expression of the thermogenic uncoupling protein 1. |
| 5309 | 15654920 | Rosiglitazone ameliorates insulin resistance provoked by TNF-alpha, completely restoring insulin-stimulated glucose uptake in parallel to the insulin signalling cascade. |
| 5310 | 15663202 | Fuji ground water containing natural vanadium (approximately 65 microg/l) at doses of 0.53 microg/kg/day for 12 weeks, blood glucose (BG), serum hemoglobin A1C (HbA1C) levels and insulin secretion from the pancreas of Goto-Kakisaki (GK) rats, a genetic model of Type 2 diabetes, were improved. |
| 5311 | 15663202 | In GK rat liver insulin receptors, the binding properties of [125I] insulin, and the activities of insulin receptor beta subunit and primary insulin-like growth factor-1beta all recovered to normal levels of those found in Wistar rats. |
| 5312 | 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). |
| 5313 | 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. |
| 5314 | 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%). |
| 5315 | 15671208 | We further detected that TA induced phosphorylation of the insulin receptor (IR) and Akt, as well as translocation of glucose transporter 4 (GLUT 4), the protein factors involved in the signaling pathway of insulin-mediated glucose transport. |
| 5316 | 15671481 | S6K1, like other serine and threonine kinases activated by insulin (such as mTOR and PKCzeta), has recently been shown to participate in negative feedback mechanisms aimed at terminating insulin signaling through IRS (insulin receptor substrate) phosphorylation. |
| 5317 | 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. |
| 5318 | 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. |
| 5319 | 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. |
| 5320 | 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. |
| 5321 | 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. |
| 5322 | 15677487 | Propelled by the identification of a small family of NADPH oxidase (Nox) enzyme homologs that produce superoxide in response to cellular stimulation with various growth factors, renewed interest has been generated in characterizing the signaling effects of reactive oxygen species (ROS) in relation to insulin action. |
| 5323 | 15677487 | PTPs normally serve as negative regulators of insulin action via the dephosphorylation of the insulin receptor and its tyrosine-phosphorylated cellular substrates. |
| 5324 | 15677487 | However, ROS can rapidly oxidize the catalytic cysteine of target PTPs, effectively blocking their enzyme activity and reversing their inhibitory effect on insulin signaling. |
| 5325 | 15677487 | Among the cloned Nox homologs, we have recently provided evidence that Nox4 may mediate the insulin-stimulated generation of cellular ROS and is coupled to insulin action via the oxidative inhibition of PTP1B, a PTP known to be a major regulator of the insulin signaling cascade. |
| 5326 | 15677493 | In this study, we determined in vivo the insulin receptor signaling characteristics activated by insulin glulisine (Lys(B3), Glu(B29)) at the level of insulin receptor phosphorylation, insulin receptor substrate phosphorylation, and downstream signaling elements such as phosphatidylinositol (PI) 3-kinase, AKT, and mitogen-activated protein kinase. |
| 5327 | 15677494 | Increased hepatic levels of the insulin receptor inhibitor, PC-1/NPP1, induce insulin resistance and glucose intolerance. |
| 5328 | 15677494 | The ectoenzyme, plasma cell membrane glycoprotein-1 (PC-1), is an insulin receptor (IR) inhibitor that is elevated in cells and tissues of insulin-resistant humans. |
| 5329 | 15677494 | However, the effects of PC-1 overexpression on insulin action have not been studied in animal models. |
| 5330 | 15677494 | In liver of PC-1 animals, insulin-stimulated IR tyrosine kinase and Akt/protein kinase B activation were both decreased. |
| 5331 | 15677494 | The PC-1 animals had 30-40 mg/dl higher glucose levels and twofold higher insulin levels. |
| 5332 | 15677494 | These in vivo data support the concept, therefore, that PC-1 plays a role in insulin resistance and suggest that animals with overexpression of human PC-1 in liver may be interesting models to investigate this pathological process. |
| 5333 | 15677494 | Increased hepatic levels of the insulin receptor inhibitor, PC-1/NPP1, induce insulin resistance and glucose intolerance. |
| 5334 | 15677494 | The ectoenzyme, plasma cell membrane glycoprotein-1 (PC-1), is an insulin receptor (IR) inhibitor that is elevated in cells and tissues of insulin-resistant humans. |
| 5335 | 15677494 | However, the effects of PC-1 overexpression on insulin action have not been studied in animal models. |
| 5336 | 15677494 | In liver of PC-1 animals, insulin-stimulated IR tyrosine kinase and Akt/protein kinase B activation were both decreased. |
| 5337 | 15677494 | The PC-1 animals had 30-40 mg/dl higher glucose levels and twofold higher insulin levels. |
| 5338 | 15677494 | These in vivo data support the concept, therefore, that PC-1 plays a role in insulin resistance and suggest that animals with overexpression of human PC-1 in liver may be interesting models to investigate this pathological process. |
| 5339 | 15689562 | Insulin receptor substrates (Irs-proteins) integrate signals from the insulin and insulin-like growth factor-1 (IGF1) receptors with other processes to control cellular growth, function, and survival. |
| 5340 | 15689562 | However, IGF1-stimulated Akt phosphorylation was barely detected, and cleaved/activated caspase-3 was significantly elevated in isolated retinas of Irs2-/- mice. |
| 5341 | 15711641 | Complementary roles of IRS-1 and IRS-2 in the hepatic regulation of metabolism. |
| 5342 | 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. |
| 5343 | 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. |
| 5344 | 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. |
| 5345 | 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. |
| 5346 | 15711641 | The concomitant injection of IRS-1 and IRS-2 adenoviral shRNAs resulted in systemic insulin resistance, glucose intolerance, and hepatic steatosis. |
| 5347 | 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. |
| 5348 | 15733857 | At the molecular level, Cr(pa)3 enhanced insulin-stimulated phosphorylation of Akt in a time- and concentration-dependent manner without altering the phosphorylation of insulin receptor. |
| 5349 | 15750214 | Review of insulin and insulin-like growth factor expression, signaling, and malfunction in the central nervous system: relevance to Alzheimer's disease. |
| 5350 | 15750214 | This review details what is currently known about insulin, insulin-like growth factor type I (IGF-I) and IGF-II proteins and their corresponding receptors in the brain, and delineates the major controversies pertaining to alterations in the expression and function of these molecules in AD. |
| 5351 | 15750214 | Although no single model was determined to be truly representative of AD, depletion of the neuronal insulin receptor and intracerebroventricular injection of Streptozotocin reproduce a number of important aspects of AD-type neurodegeneration, and therefore provide supportive evidence that AD may be caused in part by neuronal insulin resistance, i.e. brain diabetes. |
| 5352 | 15750215 | Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer's disease--is this type 3 diabetes? |
| 5353 | 15750215 | The present work demonstrates extensive abnormalities in insulin and insulin-like growth factor type I and II (IGF-I and IGF-II) signaling mechanisms in brains with AD, and shows that while each of the corresponding growth factors is normally made in central nervous system (CNS) neurons, the expression levels are markedly reduced in AD. |
| 5354 | 15750215 | These abnormalities were associated with reduced levels of insulin receptor substrate (IRS) mRNA, tau mRNA, IRS-associated phosphotidylinositol 3-kinase, and phospho-Akt (activated), and increased glycogen synthase kinase-3beta activity and amyloid precursor protein mRNA expression. |
| 5355 | 15750215 | The strikingly reduced CNS expression of genes encoding insulin, IGF-I, and IGF-II, as well as the insulin and IGF-I receptors, suggests that AD may represent a neuro-endocrine disorder that resembles, yet is distinct from diabetes mellitus. |
| 5356 | 15752742 | Meg1/Grb10 overexpression causes postnatal growth retardation and insulin resistance via negative modulation of the IGF1R and IR cascades. |
| 5357 | 15752742 | The Meg1/Grb10 protein has been implicated as an adapter protein in the signaling pathways from insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF1R) in vitro. |
| 5358 | 15752742 | All of the Meg1/Grb10 transgenic mice showed growth retardation after weaning (3-4 weeks), which indicates that ectopic overexpression of Meg1/Grb10 inhibits postnatal growth that is mediated by IGF1 via IGF1R. |
| 5359 | 15752742 | In addition, the mice became hyperinsulinemic owing to high levels of insulin resistance, which demonstrates that Meg1/Grb10 also modulates the insulin receptor cascade negatively in vivo. |
| 5360 | 15752742 | These results suggest that Meg1/Grb10 inhibits the function of both insulin and IGF1 receptors in these cells, since a similar phenotype has been reported for Ir and Igf1r double knockout mice. |
| 5361 | 15752742 | Taken together, these results indicate that Meg1/Grb10 interacts with both insulin and IGF1 receptors in vivo, and negatively regulates the IGF growth pathways via these receptors. |
| 5362 | 15752742 | Meg1/Grb10 overexpression causes postnatal growth retardation and insulin resistance via negative modulation of the IGF1R and IR cascades. |
| 5363 | 15752742 | The Meg1/Grb10 protein has been implicated as an adapter protein in the signaling pathways from insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF1R) in vitro. |
| 5364 | 15752742 | All of the Meg1/Grb10 transgenic mice showed growth retardation after weaning (3-4 weeks), which indicates that ectopic overexpression of Meg1/Grb10 inhibits postnatal growth that is mediated by IGF1 via IGF1R. |
| 5365 | 15752742 | In addition, the mice became hyperinsulinemic owing to high levels of insulin resistance, which demonstrates that Meg1/Grb10 also modulates the insulin receptor cascade negatively in vivo. |
| 5366 | 15752742 | These results suggest that Meg1/Grb10 inhibits the function of both insulin and IGF1 receptors in these cells, since a similar phenotype has been reported for Ir and Igf1r double knockout mice. |
| 5367 | 15752742 | Taken together, these results indicate that Meg1/Grb10 interacts with both insulin and IGF1 receptors in vivo, and negatively regulates the IGF growth pathways via these receptors. |
| 5368 | 15772901 | Insulin receptor structure and function as well as major pathways activated by insulin, i.e. phosphatidyl inositol-3 kinase (PI-3 K) cascade or mitogen-activated protein kinase (MAPK) cascades, were functional. |
| 5369 | 15772901 | Abundances of the transcription factors Elk-1 and SRF being major players in coupling of MAPKs to cfos promoter activation were not altered. |
| 5370 | 15787605 | Evidence for impaired activation of the insulin receptor signalling cascade and defective glucose transporter 4 translocation in the skeletal muscle from Type II diabetic patients will be presented. |
| 5371 | 15787606 | It is well documented that insulin sensitizers such as peroxisome-proliferator-activated receptor gamma agonists and aspirin improve insulin action in vivo. |
| 5372 | 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. |
| 5373 | 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. |
| 5374 | 15787606 | Treatment with rosiglitazone for 24 and 48 h increased insulin signalling and decreased IRS1 Ser-307 phosphorylation concomitantly. |
| 5375 | 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. |
| 5376 | 15790685 | In vivo insulin signaling through PI3-kinase is impaired in skeletal muscle of adult rat offspring exposed to ethanol in utero. |
| 5377 | 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. |
| 5378 | 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. |
| 5379 | 15790685 | There was no significant difference in basal or insulin-stimulated Akt activity between EtOH-exposed rats and controls. |
| 5380 | 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. |
| 5381 | 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. |
| 5382 | 15793233 | S-nitrosation of the insulin receptor, insulin receptor substrate 1, and protein kinase B/Akt: a novel mechanism of insulin resistance. |
| 5383 | 15793233 | Evidence demonstrates that exogenous nitric oxide (NO) and the NO produced by inducible nitric oxide synthase (iNOS) can induce insulin resistance in muscle. |
| 5384 | 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. |
| 5385 | 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. |
| 5386 | 15793233 | Reversal of S-nitrosation of these proteins by reducing iNOS expression yielded an improvement in insulin action in both animal models. |
| 5387 | 15793233 | Thus, S-nitrosation of proteins involved in insulin signal transduction is a novel molecular mechanism of iNOS-induced insulin resistance. |
| 5388 | 15793234 | Endoplasmic reticulum stress-induced apoptosis is partly mediated by reduced insulin signaling through phosphatidylinositol 3-kinase/Akt and increased glycogen synthase kinase-3beta in mouse insulinoma cells. |
| 5389 | 15793234 | Because insulin/IGF/Akt signaling has been implicated in beta-cell survival, we sought to determine whether this pathway is involved in ER stress-induced apoptosis. |
| 5390 | 15793234 | Stable cell lines were created by small-interfering RNA (siRNA) with graded reduction of insulin receptor expression, and these cells had enhanced susceptibility to ER stress-induced apoptosis and reduced levels of phospho-glycogen synthase kinase 3beta (GSK3beta). |
| 5391 | 15793234 | These results illustrate that ER stress-induced apoptosis is mediated at least in part by signaling through the phosphatidylinositol 3-kinase/Akt/GSK3beta pathway and that GSK3beta represents a novel target for agents to promote beta-cell survival. |
| 5392 | 15811564 | The haplotypes of the IRS-2 gene affect insulin sensitivity in Japanese patients with type 2 diabetes. |
| 5393 | 15811564 | A commonly occurring nucleotide polymorphism of the insulin-receptor substrate 2 (IRS-2) gene at amino acid 1057 from Glycine to Asparaginic acid (G1057D) was recently shown to be a determinant of insulin sensitivity in both glucose-tolerant individuals and those with type 2 diabetes. |
| 5394 | 15811564 | With respect to the latter, the IRS-2 D1057 allele increase the risk of insulin resistance among obese individuals. |
| 5395 | 15811564 | After we reconstructed haplotypes from the G1057D variant and the -769C/T replacement that was newly identified, we investigated the possibility that the IRS-2 gene affects insulin sensitivity in Japanese glucose-tolerant subjects (n = 260) and type 2 diabetic patients (n = 123). |
| 5396 | 15811564 | This observation raises the possibility that both the IRS-2 D1057 allele and the CA haplotype are useful genetic markers for identifying obese individuals who are particularly susceptible to insulin resistance. |
| 5397 | 15827066 | Insulin and IGF-I activate antiapoptotic pathways via insulin receptor substrate (IRS) proteins in most mammalian cells, including beta-cells. |
| 5398 | 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. |
| 5399 | 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. |
| 5400 | 15827066 | Furthermore, enhanced cytosolic forkhead transcription factor (FoxO1) staining in IRS-1KO grafts suggests intact Akt/PKB activity. |
| 5401 | 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. |
| 5402 | 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. |
| 5403 | 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. |
| 5404 | 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. |
| 5405 | 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. |
| 5406 | 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. |
| 5407 | 15850715 | GLUT-4 (glucose transporter) receptor, tumor necrosis factor-alpha (TNF-alpha), interleukins-6 (IL-6), daf-genes and PPARs (peroxisomal proliferation activator receptors) play a role in the development of insulin resistance syndrome and associated conditions. |
| 5408 | 15850715 | Long chain polyunsaturated fatty acids (LCPUFAs) increase cell membrane fluidity and enhance the number of insulin receptors and the affinity of insulin to its receptors; suppress TNF-alpha, IL-6, macrophage migration inhibitory factor (MIF) and leptin synthesis; increase the number of GLUT-4 receptors, serve as endogenous ligands of PPARs, modify lipolysis, and regulate the balance between pro- and anti-oxidants, and thus, play a critical role in the pathogenesis of insulin resistance. |
| 5409 | 15850715 | In the nematode, Caenorhabditis elegans, the protein encoded by daf-2 is 35% identical to the human insulin receptor; daf-7 codes a transforming growth factor-beta (TGF-beta) type signal and daf-16 enhances superoxide dismutase (SOD) expression. |
| 5410 | 15850715 | Melatonin has anti-oxidant actions similar to daf-16, TGF-beta and SOD. |
| 5411 | 15850715 | These evidences suggest that the activities of Delta6 and Delta5 enzymes play a critical role in the expression and regulation of GLUT-4, TNF-alpha, IL-6, MIF, daf-genes, melatonin, and leptin by modulating the synthesis and tissue concentrations of LCPUFAs. |
| 5412 | 15850715 | Both insulin and insulin-like growth factor-1 (IGF-1) attenuated this response. |
| 5413 | 15850715 | SIRT1 sequesters the proapoptotic factor Bax, prevents stress-induced apoptosis of cells, and thus, prolongs survival. |
| 5414 | 15850715 | In addition, SIRT1 repressed PPAR-gamma, and overexpression of SIRT1 attenuated adipogenesis, and upregulation of SIRT in differentiated fat cells triggered lipolysis and loss of fat, events that are known to attenuate insulin resistance and prolong life span. |
| 5415 | 15855318 | A role for iNOS in fasting hyperglycemia and impaired insulin signaling in the liver of obese diabetic mice. |
| 5416 | 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. |
| 5417 | 15855318 | A role for iNOS in fasting hyperglycemia and hepatic insulin resistance, however, remains to be investigated in obesity-related diabetes. |
| 5418 | 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. |
| 5419 | 15855318 | Exposure to NO donor and ectopically expressed iNOS decreased the protein expression of IRS-1 and -2 in cultured hepatocytes. |
| 5420 | 15855318 | These results suggest that iNOS plays a role in fasting hyperglycemia and contributes to hepatic insulin resistance in ob/ob mice. |
| 5421 | 15864350 | Whereas a liver-specific insulin receptor (IR) knockout (LIRKO) mouse exhibits glucose intolerance as well as insulin resistance, it is unclear whether a more acute decrease in the expression of hepatic IR would be sufficient to induce hepatic insulin resistance. |
| 5422 | 15864351 | Restoration of liver insulin signaling in Insr knockout mice fails to normalize hepatic insulin action. |
| 5423 | 15864351 | Analyses of protein expression indicated that L1 mice had modestly reduced Insr content but normal insulin-stimulated Akt phosphorylation in the liver. |
| 5424 | 15864351 | Conversely, L1 mice had a near complete ablation of Insr protein product in the arcuate and paraventricular nuclei of the hypothalamus, which was associated with a failure to undergo insulin-dependent Akt phosphorylation in the hypothalamus. |
| 5425 | 15864351 | Thus, restoration of hepatic insulin signaling in Insr knockout mice fails to normalize the in vivo response to insulin. |
| 5426 | 15864351 | Restoration of liver insulin signaling in Insr knockout mice fails to normalize hepatic insulin action. |
| 5427 | 15864351 | Analyses of protein expression indicated that L1 mice had modestly reduced Insr content but normal insulin-stimulated Akt phosphorylation in the liver. |
| 5428 | 15864351 | Conversely, L1 mice had a near complete ablation of Insr protein product in the arcuate and paraventricular nuclei of the hypothalamus, which was associated with a failure to undergo insulin-dependent Akt phosphorylation in the hypothalamus. |
| 5429 | 15864351 | Thus, restoration of hepatic insulin signaling in Insr knockout mice fails to normalize the in vivo response to insulin. |
| 5430 | 15864351 | Restoration of liver insulin signaling in Insr knockout mice fails to normalize hepatic insulin action. |
| 5431 | 15864351 | Analyses of protein expression indicated that L1 mice had modestly reduced Insr content but normal insulin-stimulated Akt phosphorylation in the liver. |
| 5432 | 15864351 | Conversely, L1 mice had a near complete ablation of Insr protein product in the arcuate and paraventricular nuclei of the hypothalamus, which was associated with a failure to undergo insulin-dependent Akt phosphorylation in the hypothalamus. |
| 5433 | 15864351 | Thus, restoration of hepatic insulin signaling in Insr knockout mice fails to normalize the in vivo response to insulin. |
| 5434 | 15864351 | Restoration of liver insulin signaling in Insr knockout mice fails to normalize hepatic insulin action. |
| 5435 | 15864351 | Analyses of protein expression indicated that L1 mice had modestly reduced Insr content but normal insulin-stimulated Akt phosphorylation in the liver. |
| 5436 | 15864351 | Conversely, L1 mice had a near complete ablation of Insr protein product in the arcuate and paraventricular nuclei of the hypothalamus, which was associated with a failure to undergo insulin-dependent Akt phosphorylation in the hypothalamus. |
| 5437 | 15864351 | Thus, restoration of hepatic insulin signaling in Insr knockout mice fails to normalize the in vivo response to insulin. |
| 5438 | 15866422 | We have recently shown the co-localization of Rab11 and the glucose transporter GLUT4 in cardiac muscle and an insulin-stimulated increase of Rab11 in GLUT4-containing vesicles in this tissue. |
| 5439 | 15866422 | We now assessed the effect of Rab11 wt and a dominant-negative mutant (N124I) on GLUT4 trafficking in the cardiomyoblast cell line H9c2 stably overexpressing the insulin receptor (H9c2-E2) and in human primary skeletal myotubes. |
| 5440 | 15866422 | However, the dominant-negative mutant reduced the efficiency of insulin to promote glucose uptake and GLUT4 translocation in both cardiac and skeletal muscle cells to about one half. |
| 5441 | 15866422 | The level of Akt phosphorylation does not vary after cotransfection indicating that insulin signalling remained unaffected under these conditions. |
| 5442 | 15866422 | In conclusion, our data show that Rab11 (i) mediates endocytosis of GLUT4 and (ii) plays a pivotal role in insulin-regulated translocation of this transporter to the plasma membrane. |
| 5443 | 15877289 | Analysis of insulin-stimulated insulin receptor activation and glucose transport in cultured skeletal muscle cells from obese subjects. |
| 5444 | 15877289 | In these 2 groups, there was no difference in the ability of insulin to induce autophosphorylation of the IR, phosphorylation of the downstream serine kinase Akt/PKB, or stimulation of glucose transport. |
| 5445 | 15877289 | Moreover, there were no major differences in cultured muscle cell content of either the IR, the IR antagonist PC-1, or GLUT 1 and GLUT 4. |
| 5446 | 15879694 | Insulin resistance and type 2 diabetes mellitus: is there a therapeutic role for IGF-1? |
| 5447 | 15879694 | Its mechanism of action appears to be independent of activation of the insulin receptor although the role of IGF-1 in normal carbohydrate metabolism remains incompletely defined. |
| 5448 | 15879694 | IGF-1 also improves insulin resistance both in type 2 diabetes and in subjects with more severe insulin resistance. |
| 5449 | 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. |
| 5450 | 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. |
| 5451 | 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. |
| 5452 | 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). |
| 5453 | 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. |
| 5454 | 15905322 | Maternal food restriction enhances insulin-induced GLUT-4 translocation and insulin signaling pathway in skeletal muscle from suckling rats. |
| 5455 | 15905322 | The content of the main glucose transporters in muscle, GLUT-4 and GLUT-1, was not affected by undernutrition, but fractionation studies showed an improved insulin-stimulated GLUT-4 translocation. p38MAPK protein, implicated in up-regulation of intrinsic activity of translocated GLUT-4, was increased. |
| 5456 | 15905322 | Surprisingly, protein tyrosine phosphatase-1B association with insulin receptor was also increased by undernutrition. |
| 5457 | 15910615 | Among the many molecules involved in the intracellular processing of the signal provided by insulin, insulin receptor substrate (IRS)-2, the protein kinase B (PKB)-beta isoform and the forkhead transcription factor Foxo1a (FKHR) are of particular interest in this context as recent data have provided strong evidence that dysfunction of these proteins results in insulin resistance in-vivo. |
| 5458 | 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). |
| 5459 | 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). |
| 5460 | 15924147 | Lack of the architectural factor HMGA1 causes insulin resistance and diabetes in humans and mice. |
| 5461 | 15924147 | Here we report a genetic flaw that markedly reduced the intracellular expression of the high mobility group A1 (HMGA1) protein, and adversely affected insulin receptor expression in cells and tissues from four subjects with insulin resistance and type 2 diabetes. |
| 5462 | 15924147 | Restoration of HMGA1 protein expression in subjects' cells enhanced INSR gene transcription, and restored cell-surface insulin receptor protein expression and insulin-binding capacity. |
| 5463 | 15924147 | Loss of Hmga1 expression, induced in mice by disrupting the Hmga1 gene, considerably decreased insulin receptor expression in the major targets of insulin action, largely impaired insulin signaling and severely reduced insulin secretion, causing a phenotype characteristic of human type 2 diabetes. |
| 5464 | 15924147 | Lack of the architectural factor HMGA1 causes insulin resistance and diabetes in humans and mice. |
| 5465 | 15924147 | Here we report a genetic flaw that markedly reduced the intracellular expression of the high mobility group A1 (HMGA1) protein, and adversely affected insulin receptor expression in cells and tissues from four subjects with insulin resistance and type 2 diabetes. |
| 5466 | 15924147 | Restoration of HMGA1 protein expression in subjects' cells enhanced INSR gene transcription, and restored cell-surface insulin receptor protein expression and insulin-binding capacity. |
| 5467 | 15924147 | Loss of Hmga1 expression, induced in mice by disrupting the Hmga1 gene, considerably decreased insulin receptor expression in the major targets of insulin action, largely impaired insulin signaling and severely reduced insulin secretion, causing a phenotype characteristic of human type 2 diabetes. |
| 5468 | 15924147 | Lack of the architectural factor HMGA1 causes insulin resistance and diabetes in humans and mice. |
| 5469 | 15924147 | Here we report a genetic flaw that markedly reduced the intracellular expression of the high mobility group A1 (HMGA1) protein, and adversely affected insulin receptor expression in cells and tissues from four subjects with insulin resistance and type 2 diabetes. |
| 5470 | 15924147 | Restoration of HMGA1 protein expression in subjects' cells enhanced INSR gene transcription, and restored cell-surface insulin receptor protein expression and insulin-binding capacity. |
| 5471 | 15924147 | Loss of Hmga1 expression, induced in mice by disrupting the Hmga1 gene, considerably decreased insulin receptor expression in the major targets of insulin action, largely impaired insulin signaling and severely reduced insulin secretion, causing a phenotype characteristic of human type 2 diabetes. |
| 5472 | 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. |
| 5473 | 15924436 | However, chromium did not inhibit recombinant human PTP1B using either p-nitrophenyl phosphate or the tyrosine-phosphorylated insulin receptor as the substrate. |
| 5474 | 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. |
| 5475 | 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. |
| 5476 | 15924436 | However, chromium did not inhibit recombinant human PTP1B using either p-nitrophenyl phosphate or the tyrosine-phosphorylated insulin receptor as the substrate. |
| 5477 | 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. |
| 5478 | 15928604 | [The role of protein tyrosine phosphatase (PTP-1B) in insulin resistance]. |
| 5479 | 15928604 | The discovery of protein tyrosine phosphatase (PTP-1B) seems to be a milestone in the investigation of insulin signaling transmission. |
| 5480 | 15928604 | PTP-1B is considered a negative regulator of insulin signaling, mainly through insulin receptor dephosphorylation. |
| 5481 | 15928604 | In animal model studies (Elchebly et al.) there was a significant increase in insulin sensitivity of PTP-1B knock-out mice. |
| 5482 | 15928604 | There is also evidence that higher expression of the PTP-1B gene causes insulin resistance in humans. |
| 5483 | 15928604 | PTP-1B inhibitors could thus be promising drugs for insulin resistance therapy. |
| 5484 | 15945346 | White adipose tissue of MIRKO mice have increased the sensitivity to insulin and its glucose uptake is dramatically elevated that activates fat accumulation and induces obesity which results from an increase in adipocyte number (hyperplasia) of the same size as well as individual cells in the control mice. |
| 5485 | 15945346 | MIRKO mouse adipose tissue increased secretion of adiponectin that increases the insulin sensitivity and do not alter the leptin production. |
| 5486 | 15945346 | The beta-cell insulin receptor knockout in combination with the insulin receptor substrates 1 or 2 or both knockouts mice develop beta-cell insensitivity to insulin and the insensitivity to the stimulation of insulin secretion by glucose. |
| 5487 | 15950750 | Early signaling interactions between the insulin and leptin pathways in bovine myogenic cells. |
| 5488 | 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. |
| 5489 | 15950750 | The present study reports early signaling events in the insulin and leptin cascades in primary bovine myogenic cells (BMC). |
| 5490 | 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. |
| 5491 | 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. |
| 5492 | 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. |
| 5493 | 15950750 | JAK-2 association with the ObR and JAK-2 tyrosine phosphorylation were responsive to all three treatments. |
| 5494 | 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. |
| 5495 | 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. |
| 5496 | 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. |
| 5497 | 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. |
| 5498 | 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. |
| 5499 | 15978611 | Activation of IKKbeta by glucose is necessary and sufficient to impair insulin signaling and nitric oxide production in endothelial cells. |
| 5500 | 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. |
| 5501 | 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. |
| 5502 | 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. |
| 5503 | 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. |
| 5504 | 15978611 | Conversely, overexpression of wild-type IKKbeta recapitulated the deleterious effect of high glucose on insulin-mediated activation of eNOS. |
| 5505 | 15989661 | These include influence on insulin receptor kinase activity, control of insulin receptor phosphorylation, change in number of insulin receptors, quantity and activity of GLUT-4, modulation of tumour necrosis factor (TNF) activity, activation of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) and alteration of hepatic glucose metabolism. |
| 5506 | 15997237 | Protein tyrosine phosphatase 1B (PTP1B) acts as a physiological negative regulator of insulin signaling by dephosphorylating the activated insulin receptor (IR). |
| 5507 | 15997237 | Here we examine the role of PTP1B in the insulin-sensitizing action of rosiglitazone (RSG) in skeletal muscle and liver. |
| 5508 | 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. |
| 5509 | 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. |
| 5510 | 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. |
| 5511 | 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. |
| 5512 | 15997237 | These data suggest that RSG enhances insulin activity in skeletal muscle of diabetic rats possibly by ameliorating abnormal levels and activities of PTP1B. |
| 5513 | 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. |
| 5514 | 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. |
| 5515 | 16037382 | The adapter protein GRB10 is an endogenous negative regulator of insulin-like growth factor signaling. |
| 5516 | 16037382 | Growth factor receptor-bound protein (Grb)10 is a protein that interacts with the IGF-I receptor and may thus regulate IGF-I-stimulated growth. |
| 5517 | 16037382 | However, the role of endogenous Grb10 in regulating IGF-I action is not known. |
| 5518 | 16037382 | Using small interfering RNA, we demonstrate that knockdown of Grb10 enhances IGF-I-mediated phosphorylation of insulin receptor substrate proteins, Akt/protein kinase B, and ERK1/2 and leads to a corresponding increase in DNA synthesis. |
| 5519 | 16037382 | Although IGF-I receptor autophosphorylation normally correlates with receptor signaling, we demonstrate a decrease in IGF-I-stimulated receptor phosphorylation in Grb10 knockdown cells. |
| 5520 | 16037382 | Pretreatment of cells with the protein-tyrosine phosphatase inhibitor pervanadate partially reverses this effect of Grb10 knockdown on receptor phosphorylation, indicating that endogenous Grb10 may block phosphatase access to the activated IGF-I receptor. |
| 5521 | 16037382 | Marked small interfering RNA knockdown of Grb10 does not result in increased or decreased expression of the related proteins Grb7 or Grb14. |
| 5522 | 16037382 | As further evidence for Grb10 functional specificity, the recently identified Grb10 interacting GYF proteins are shown to interact specifically with Grb10 and not with Grb7 or Grb14, using yeast two-hybrid assays. |
| 5523 | 16037382 | We conclude that Grb10 functions as a specific endogenous suppressor of IGF-I-stimulated cell signaling and DNA synthesis. |
| 5524 | 16037382 | Modulation of the Grb10-IGF-I receptor pathway may represent a mechanism that regulates IGF-I-responsive cell and tissue growth. |
| 5525 | 16046301 | Increased p85/55/50 expression and decreased phosphotidylinositol 3-kinase activity in insulin-resistant human skeletal muscle. |
| 5526 | 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. |
| 5527 | 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. |
| 5528 | 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. |
| 5529 | 16046317 | AHSG is a natural inhibitor of the insulin receptor tyrosine kinase, and AHSG-null mice exhibit significantly enhanced insulin sensitivity. |
| 5530 | 16054052 | These mice have altered cellular and systemic lipid transport and composition, leading to enhanced insulin receptor signaling, enhanced muscle AMP-activated kinase (AMP-K) activity, and dramatically reduced liver stearoyl-CoA desaturase-1 (SCD-1) activity underlying their phenotype. |
| 5531 | 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. |
| 5532 | 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). |
| 5533 | 16055077 | In addition, greater IRS-1/p85alpha interaction was elicited by the OVC than by VS. |
| 5534 | 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. |
| 5535 | 16087721 | As insulin receptor signaling occurs via protein tyrosine kinase (PTK), we investigated the role of PTK activity in the etiology of beta-cell dysfunction by inhibiting PTK activity in primary cultured mouse pancreatic beta-cells and INS-1 cells with genistein treatment over 24 h. |
| 5536 | 16096055 | Using oligonucleotide microarrays and real-time PCR of pancreatic islets isolated from humans with type 2 diabetes versus normal glucose-tolerant controls, we identified multiple changes in expression of genes known to be important in beta cell function, including major decreases in expression of HNF4alpha, insulin receptor, IRS2, Akt2, and several glucose-metabolic-pathway genes. |
| 5537 | 16105663 | Gastric inhibitory polypeptide modulates adiposity and fat oxidation under diminished insulin action. |
| 5538 | 16105663 | Gut hormone gastric inhibitory polypeptide (GIP) stimulates insulin secretion from pancreatic beta-cells upon ingestion of nutrients. |
| 5539 | 16105663 | Inhibition of GIP signaling prevents the onset of obesity and consequent insulin resistance induced by high-fat diet. |
| 5540 | 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. |
| 5541 | 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. |
| 5542 | 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. |
| 5543 | 16105861 | Decreased insulin-dependent glucose transport by chronic ethanol feeding is associated with dysregulation of the Cbl/TC10 pathway in rat adipocytes. |
| 5544 | 16105861 | Insulin-stimulated glucose disposal in adipocytes is regulated by two separate and independent pathways, the PI3K pathway and the Cbl/TC10 pathway. |
| 5545 | 16105861 | Previous studies suggest that chronic ethanol feeding impairs insulin-stimulated glucose transport in adipocytes in a PI3K-independent manner. |
| 5546 | 16105861 | In search of potential targets of ethanol that would affect insulin-stimulated glucose transport, we investigated the effects of 4-wk ethanol feeding to male Wistar rats on the Cbl/TC10 pathway in isolated adipocytes. |
| 5547 | 16105861 | Insulin receptor and Akt/PKB phosphorylation were not affected by ethanol feeding. |
| 5548 | 16105861 | Chronic ethanol exposure also impaired cCbl and TC10 recruitment to a lipid raft fraction isolated from adipocytes by detergent extraction. |
| 5549 | 16105861 | These results demonstrate that the impairment in insulin-stimulated glucose transport observed in adipocytes after chronic ethanol feeding to rats is associated with a disruption of insulin-mediated Cbl/TC10 signaling and actin polymerization. |
| 5550 | 16114270 | A liver-specific gene-deletion knockout of the IGF-I gene resulted in a mouse model with reduced circulating IGF-I levels, that led to insulin resistance due to the secondary elevation of circulating GH levels. |
| 5551 | 16114270 | A second mouse model, using the transgenic approach, inhibited the IGF-I and insulin receptor function in skeletal muscle, and resulted in severe insulin resistance in muscle followed by insulin resistance in fat and liver and, eventually, beta-cell dysfunction and development of Type 2 diabetes. |
| 5552 | 16114270 | Evidence supporting the hypothesis came from the use of fibrates and leptin injections, each of which enhanced fatty acid (FA) oxidation in liver and muscle and was associated with a reversal of the insulin resistance and diabetes. |
| 5553 | 16123338 | Cardiac-specific overexpression of peroxisome proliferator-activated receptor-alpha causes insulin resistance in heart and liver. |
| 5554 | 16123338 | Mice with heart-specific overexpression of peroxisome proliferator-activated receptor (PPAR)alpha showed a metabolic and cardiomyopathic phenotype similar to the diabetic heart, and we determined tissue-specific glucose metabolism and insulin action in vivo during hyperinsulinemic-euglycemic clamps in awake myosin heavy chain (MHC)-PPARalpha mice (12-14 weeks of age). |
| 5555 | 16123338 | Basal and insulin-stimulated glucose uptake in heart was significantly reduced in the MHC-PPARalpha mice, and cardiac insulin resistance was mostly attributed to defects in insulin-stimulated activities of insulin receptor substrate (IRS)-1-associated phosphatidylinositol (PI) 3-kinase, Akt, and tyrosine phosphorylation of signal transducer and activator of transcription 3 (STAT3). |
| 5556 | 16123338 | Interestingly, MHC-PPARalpha mice developed hepatic insulin resistance associated with defects in insulin-mediated IRS-2-associated PI 3-kinase activity, increased hepatic triglyceride, and circulating interleukin-6 levels. |
| 5557 | 16123338 | Overall, these findings indicate that increased activity of PPARalpha, as occurs in the diabetic heart, leads to cardiac insulin resistance associated with defects in insulin signaling and STAT3 activity, subsequently leading to reduced cardiac function. |
| 5558 | 16127460 | Additionally, SOCS7 associated with the INSR and IRS1--molecules that are essential for normal regulation of insulin action. |
| 5559 | 16137651 | Natural anti-diabetic compound 1,2,3,4,6-penta-O-galloyl-D-glucopyranose binds to insulin receptor and activates insulin-mediated glucose transport signaling pathway. |
| 5560 | 16137651 | Mechanistic studies in adipocytes with alpha-PGG, the more potent of the two anomers, reveal that inhibitors that block the insulin-mediated glucose transport, including one that inhibits the insulin receptor (IR), also completely abolish the glucose transport activated by alpha-PGG. |
| 5561 | 16137651 | In addition, alpha-PGG induces phosphorylation of the IR and Akt, activates PI 3-kinase, and stimulates membrane translocation of GLUT 4. |
| 5562 | 16137651 | Natural anti-diabetic compound 1,2,3,4,6-penta-O-galloyl-D-glucopyranose binds to insulin receptor and activates insulin-mediated glucose transport signaling pathway. |
| 5563 | 16137651 | Mechanistic studies in adipocytes with alpha-PGG, the more potent of the two anomers, reveal that inhibitors that block the insulin-mediated glucose transport, including one that inhibits the insulin receptor (IR), also completely abolish the glucose transport activated by alpha-PGG. |
| 5564 | 16137651 | In addition, alpha-PGG induces phosphorylation of the IR and Akt, activates PI 3-kinase, and stimulates membrane translocation of GLUT 4. |
| 5565 | 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. |
| 5566 | 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. |
| 5567 | 16158225 | A particularly sensitive target of zinc ions is protein tyrosine phosphatase 1B (PTP 1B), a key regulator of the phosphorylation state of the insulin receptor. |
| 5568 | 16198620 | This results in down regulation of insulin receptor substance 1 (IRS-1) signaling by excess free fatty acids. |
| 5569 | 16198620 | In muscle, activated IRS-1 promotes translocation of glucose transporter protein 4 (GLUT4) to cell membrane. |
| 5570 | 16198645 | Involvement of the small protein tyrosine phosphatases TC-PTP and PTP1B in signal transduction and diseases: from diabetes, obesity to cell cycle, and cancer. |
| 5571 | 16198645 | For instance, the phenotypic characterization of knockout mice has been critical in understanding the sites of action of the related PTPs protein tyrosine phosphatase 1B (PTP1B) and T-cell-PTP (TC-PTP). |
| 5572 | 16198645 | By their increased insulin sensitivity and insulin receptor hyperphosphorylation, PTP1B null mice demonstrated a clear function for this enzyme as a negative regulator of insulin signaling. |
| 5573 | 16198645 | As well, TC-PTP has also been recently involved in insulin signaling in vitro. |
| 5574 | 16198645 | Indeed, they possess different as well as overlapping substrates, which suggest complementary and overlapping roles of both TC-PTP and PTP1B. |
| 5575 | 16198645 | Here, we review the function of PTP1B and TC-PTP in diabetes, obesity, and processes related to cancer. |
| 5576 | 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. |
| 5577 | 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. |
| 5578 | 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. |
| 5579 | 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. |
| 5580 | 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. |
| 5581 | 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. |
| 5582 | 16226915 | Role of suppressors of cytokine signaling SOCS-1 and SOCS-3 in hepatic steatosis and the metabolic syndrome. |
| 5583 | 16226915 | In this study, we show that expression of suppressor of cytokine signaling SOCS-1 and SOCS-3 is increased in livers of obese insulin-resistant animals, and that adenoviral-mediated overexpression of SOCS-1 or SOCS-3 in liver causes insulin resistance through down-regulation of tyrosine phosphorylation of insulin receptor substrate (IRS) proteins. |
| 5584 | 16226915 | Moreover, the increased SOCS-1 and SOCS-3 also cause a prominent up-regulation of the key regulator of fatty acid synthesis in liver, sterol regulatory element binding protein (SREBP)-1. |
| 5585 | 16226915 | Conversely, inhibition of SOCS-1 and SOCS-3 in livers of obese diabetic db/db mice by antisense treatment modestly improves insulin sensitivity, but completely normalizes the increased expression of SREBP-1. |
| 5586 | 16226915 | Promoter activity analysis reveals that expression of SOCS-1 or SOCS-3 with SOCS-3 being more potent enhances SREBP-1c expression, while it is inhibited by expression of STAT3. |
| 5587 | 16226915 | This STAT3-mediated inhibition of SREBP-1c expression is antagonized by co-expression of SOCS proteins. |
| 5588 | 16226915 | Moreover, db/db mice display decreased STAT3 phosphorylation in liver that is normalized by antisense treatment of SOCS proteins. |
| 5589 | 16226915 | These data suggest that obese subjects in the persistent inflammatory states, such as elevated circulating tumor necrosis factor-alpha, may have down-regulated STAT3-mediated signaling by increased SOCS proteins, leading to up-regulation of SREBP-1c expression and increased fatty acid synthesis in liver. |
| 5590 | 16226915 | Thus, SOCS proteins play an important role in pathogenesis of the metabolic syndrome by concordantly modulating cytokine signaling and insulin signaling. |
| 5591 | 16233930 | Variation of the insulin receptor substrate gene (IRS-1) in African Pygmies and Bantus. |
| 5592 | 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. |
| 5593 | 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. |
| 5594 | 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. |
| 5595 | 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. |
| 5596 | 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. |
| 5597 | 16278247 | Overexpression of the insulin receptor inhibitor PC-1/ENPP1 induces insulin resistance and hyperglycemia. |
| 5598 | 16278247 | The ectoenzyme PC-1 is an insulin receptor inhibitor that is elevated in cells and tissues of humans with type 2 diabetes (T2D). |
| 5599 | 16278247 | We have recently shown that acute PC-1 overexpression in liver causes insulin resistance and glucose intolerance in mice (3), but the chronic effects of PC-1 overexpression on these functions are unknown. |
| 5600 | 16278247 | In the fed state, the PC-1 animals had 100 mg/dl higher glucose levels and sixfold higher insulin levels compared with controls. |
| 5601 | 16278247 | In vivo uptake of 2-deoxy-d-glucose in muscle during insulin infusion was decreased in the PC-1 animals. |
| 5602 | 16278247 | These in vivo data support the concept, therefore, that PC-1 plays a role in insulin resistance and hyperglycemia and suggest that animals with overexpression of human PC-1 in insulin-sensitive tissues may be important models to investigate insulin resistance. |
| 5603 | 16278247 | Overexpression of the insulin receptor inhibitor PC-1/ENPP1 induces insulin resistance and hyperglycemia. |
| 5604 | 16278247 | The ectoenzyme PC-1 is an insulin receptor inhibitor that is elevated in cells and tissues of humans with type 2 diabetes (T2D). |
| 5605 | 16278247 | We have recently shown that acute PC-1 overexpression in liver causes insulin resistance and glucose intolerance in mice (3), but the chronic effects of PC-1 overexpression on these functions are unknown. |
| 5606 | 16278247 | In the fed state, the PC-1 animals had 100 mg/dl higher glucose levels and sixfold higher insulin levels compared with controls. |
| 5607 | 16278247 | In vivo uptake of 2-deoxy-d-glucose in muscle during insulin infusion was decreased in the PC-1 animals. |
| 5608 | 16278247 | These in vivo data support the concept, therefore, that PC-1 plays a role in insulin resistance and hyperglycemia and suggest that animals with overexpression of human PC-1 in insulin-sensitive tissues may be important models to investigate insulin resistance. |
| 5609 | 16294222 | Timp3 deficiency in insulin receptor-haploinsufficient mice promotes diabetes and vascular inflammation via increased TNF-alpha. |
| 5610 | 16294222 | In insulin receptor heterozygous (Insr+/-) mice, we identified the deficiency of tissue inhibitor of metalloproteinase 3 (Timp3, an inhibitor of both TNF-alpha-converting enzyme [TACE] and MMPs) as a common bond between glucose intolerance and vascular inflammation. |
| 5611 | 16294222 | Among Insr+/- mice, those that develop diabetes have reduced Timp3 and increased TACE activity. |
| 5612 | 16294222 | Unchecked TACE activity causes an increase in levels of soluble TNF-alpha, which subsequently promotes diabetes and vascular inflammation. |
| 5613 | 16294222 | A therapeutic role for Timp3/TACE modulation is supported by the observation that pharmacological inhibition of TACE led to marked reduction of hyperglycemia and vascular inflammation in Insr+/- diabetic mice, as well as by the observation of increased insulin sensitivity in Tace+/- mice compared with WT mice. |
| 5614 | 16294222 | Our results suggest that an interplay between reduced insulin action and unchecked TACE activity promotes diabetes and vascular inflammation. |
| 5615 | 16294222 | Timp3 deficiency in insulin receptor-haploinsufficient mice promotes diabetes and vascular inflammation via increased TNF-alpha. |
| 5616 | 16294222 | In insulin receptor heterozygous (Insr+/-) mice, we identified the deficiency of tissue inhibitor of metalloproteinase 3 (Timp3, an inhibitor of both TNF-alpha-converting enzyme [TACE] and MMPs) as a common bond between glucose intolerance and vascular inflammation. |
| 5617 | 16294222 | Among Insr+/- mice, those that develop diabetes have reduced Timp3 and increased TACE activity. |
| 5618 | 16294222 | Unchecked TACE activity causes an increase in levels of soluble TNF-alpha, which subsequently promotes diabetes and vascular inflammation. |
| 5619 | 16294222 | A therapeutic role for Timp3/TACE modulation is supported by the observation that pharmacological inhibition of TACE led to marked reduction of hyperglycemia and vascular inflammation in Insr+/- diabetic mice, as well as by the observation of increased insulin sensitivity in Tace+/- mice compared with WT mice. |
| 5620 | 16294222 | Our results suggest that an interplay between reduced insulin action and unchecked TACE activity promotes diabetes and vascular inflammation. |
| 5621 | 16294222 | Timp3 deficiency in insulin receptor-haploinsufficient mice promotes diabetes and vascular inflammation via increased TNF-alpha. |
| 5622 | 16294222 | In insulin receptor heterozygous (Insr+/-) mice, we identified the deficiency of tissue inhibitor of metalloproteinase 3 (Timp3, an inhibitor of both TNF-alpha-converting enzyme [TACE] and MMPs) as a common bond between glucose intolerance and vascular inflammation. |
| 5623 | 16294222 | Among Insr+/- mice, those that develop diabetes have reduced Timp3 and increased TACE activity. |
| 5624 | 16294222 | Unchecked TACE activity causes an increase in levels of soluble TNF-alpha, which subsequently promotes diabetes and vascular inflammation. |
| 5625 | 16294222 | A therapeutic role for Timp3/TACE modulation is supported by the observation that pharmacological inhibition of TACE led to marked reduction of hyperglycemia and vascular inflammation in Insr+/- diabetic mice, as well as by the observation of increased insulin sensitivity in Tace+/- mice compared with WT mice. |
| 5626 | 16294222 | Our results suggest that an interplay between reduced insulin action and unchecked TACE activity promotes diabetes and vascular inflammation. |
| 5627 | 16294222 | Timp3 deficiency in insulin receptor-haploinsufficient mice promotes diabetes and vascular inflammation via increased TNF-alpha. |
| 5628 | 16294222 | In insulin receptor heterozygous (Insr+/-) mice, we identified the deficiency of tissue inhibitor of metalloproteinase 3 (Timp3, an inhibitor of both TNF-alpha-converting enzyme [TACE] and MMPs) as a common bond between glucose intolerance and vascular inflammation. |
| 5629 | 16294222 | Among Insr+/- mice, those that develop diabetes have reduced Timp3 and increased TACE activity. |
| 5630 | 16294222 | Unchecked TACE activity causes an increase in levels of soluble TNF-alpha, which subsequently promotes diabetes and vascular inflammation. |
| 5631 | 16294222 | A therapeutic role for Timp3/TACE modulation is supported by the observation that pharmacological inhibition of TACE led to marked reduction of hyperglycemia and vascular inflammation in Insr+/- diabetic mice, as well as by the observation of increased insulin sensitivity in Tace+/- mice compared with WT mice. |
| 5632 | 16294222 | Our results suggest that an interplay between reduced insulin action and unchecked TACE activity promotes diabetes and vascular inflammation. |
| 5633 | 16300445 | Plasma membrane association of the insulin sensitive glucose transporter, GLUT4, was reduced in the hippocampus of obese rats in the absence of changes in total GLUT4 and insulin receptor expression. |
| 5634 | 16306344 | Importantly, the inflammatory component in obesity and diabetes is now firmly established with the discovery of causal links between inflammatory mediators, such as tumor necrosis factor (TNF)-alpha and insulin receptor signaling and the elucidation of the underlying molecular mechanisms, such as c-Jun NH2-terminal kinase (JNK)- and inhibitor of nuclear factor-kappaB kinase-mediated transcriptional and posttranslational modifications that inhibit insulin action. |
| 5635 | 16306344 | More recently, obesity-induced endoplasmic reticulum stress has been demonstrated to underlie the initiation of obesity-induced JNK activation, inflammatory responses, and generation of peripheral insulin resistance. |
| 5636 | 16306348 | Here, we directly addressed whether peripheral hyperinsulinemia as one feature of type 2 diabetes can alter in vivo cerebral insulin signaling and tau phosphorylation. |
| 5637 | 16306348 | Peripheral insulin stimulation rapidly increased insulin receptor tyrosine phosphorylation, mitogen-activated protein kinase and phosphatidylinositol (PI) 3-kinase pathway activation, and dose-dependent tau phosphorylation at Ser202 in the central nervous system. |
| 5638 | 16306348 | Importantly, in insulin-stimulated neuronal/brain-specific insulin receptor knockout mice, cerebral insulin receptor signaling and tau phosphorylation were completely abolished. |
| 5639 | 16306348 | Thus, peripherally injected insulin directly targets the brain and causes rapid cerebral insulin receptor signal transduction and site-specific tau phosphorylation in vivo, revealing new insights into the linkage of type 2 diabetes and neurodegeneration. |
| 5640 | 16306348 | Here, we directly addressed whether peripheral hyperinsulinemia as one feature of type 2 diabetes can alter in vivo cerebral insulin signaling and tau phosphorylation. |
| 5641 | 16306348 | Peripheral insulin stimulation rapidly increased insulin receptor tyrosine phosphorylation, mitogen-activated protein kinase and phosphatidylinositol (PI) 3-kinase pathway activation, and dose-dependent tau phosphorylation at Ser202 in the central nervous system. |
| 5642 | 16306348 | Importantly, in insulin-stimulated neuronal/brain-specific insulin receptor knockout mice, cerebral insulin receptor signaling and tau phosphorylation were completely abolished. |
| 5643 | 16306348 | Thus, peripherally injected insulin directly targets the brain and causes rapid cerebral insulin receptor signal transduction and site-specific tau phosphorylation in vivo, revealing new insights into the linkage of type 2 diabetes and neurodegeneration. |
| 5644 | 16306348 | Here, we directly addressed whether peripheral hyperinsulinemia as one feature of type 2 diabetes can alter in vivo cerebral insulin signaling and tau phosphorylation. |
| 5645 | 16306348 | Peripheral insulin stimulation rapidly increased insulin receptor tyrosine phosphorylation, mitogen-activated protein kinase and phosphatidylinositol (PI) 3-kinase pathway activation, and dose-dependent tau phosphorylation at Ser202 in the central nervous system. |
| 5646 | 16306348 | Importantly, in insulin-stimulated neuronal/brain-specific insulin receptor knockout mice, cerebral insulin receptor signaling and tau phosphorylation were completely abolished. |
| 5647 | 16306348 | Thus, peripherally injected insulin directly targets the brain and causes rapid cerebral insulin receptor signal transduction and site-specific tau phosphorylation in vivo, revealing new insights into the linkage of type 2 diabetes and neurodegeneration. |
| 5648 | 16306352 | Whole-body insulin resistance in the absence of obesity in FVB mice with overexpression of Dgat1 in adipose tissue. |
| 5649 | 16306352 | We tested whether augmentation of triglyceride synthesis in adipose tissue by transgenic overexpression of the diacylglycerol aclytransferase-1 (Dgat1) gene causes obesity and/or alters insulin sensitivity. |
| 5650 | 16306352 | Compared with control littermates, Dgat1 transgenic mice were both insulin and leptin resistant and had markedly elevated plasma free fatty acid levels. |
| 5651 | 16306352 | Hepatic insulin signaling was suppressed, as evidenced by decreased phosphorylation of insulin receptor-beta (Tyr(1,131)/Tyr(1,146)) and protein kinase B (Ser473). |
| 5652 | 16306352 | Thus, adipose overexpression of Dgat1 gene in FVB mice leads to diet-inducible insulin resistance, which is secondary to redistribution of fat from adipose tissue to the liver in the absence of obesity. |
| 5653 | 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). |
| 5654 | 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. |
| 5655 | 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. |
| 5656 | 16311104 | Continually high insulin levels impair Akt phosphorylation and glucose transport in human myoblasts. |
| 5657 | 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. |
| 5658 | 16311104 | At the end of the incubation period, IR, IRS1, p85/PI3K, Akt, and GLUT4 protein expression levels were similar in both culture conditions. |
| 5659 | 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. |
| 5660 | 16311104 | Despite increased PI3K activation, Akt-Ser473 phosphorylation was similar in SkMC-L and SkMC-H. |
| 5661 | 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. |
| 5662 | 16311104 | Moreover, in the SkMC-H, insulin stimulation was associated with the inhibition of IRS1 tyrosine dephosphorylation (P < .05). |
| 5663 | 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. |
| 5664 | 16311104 | Moreover, the impairment of the insulin-signaling steps between PI3K and Akt is concomitant with the desensitization of glucose transport. |
| 5665 | 16335791 | Is insulin signaling molecules misguided in diabetes for ubiquitin-proteasome mediated degradation? |
| 5666 | 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). |
| 5667 | 16335791 | It appears that altered ubiquitin-proteasome system might be one of the molecular mechanisms of insulin resistance in many pathological situations. |
| 5668 | 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. |
| 5669 | 16360107 | Protein tyrosine phosphatase 1B (PTP1B) is believed to be one of the enzymes involved in down-regulating the insulin receptor and is a drug target for the treatment of type II diabetes. |
| 5670 | 16360107 | These photoprobes were specific for PTP1B and T-cell protein tyrosine phosphatase over CD45, with the most potent photoprobe having an IC(50) value of 0.2nM for PTP1B. |
| 5671 | 16369209 | Insulin and insulin-like growth factors (IGFs) belong to the most biologically characterized family of peptides involved in metabolism, growth and development. |
| 5672 | 16369209 | The IGF-I receptor is a member of the family of tyrosine kinase growth factor receptors, and is highly homologous (70%) to the insulin receptor, especially in the tyrosine kinase domain (84%) ADDIN. |
| 5673 | 16369209 | However, most of the circulating IGF-I associates with a high molecular weight complex approximately 150 KDa consisting of IGFBP-3 and the acid labile subunit (ALS) ADDIN. |
| 5674 | 16374520 | Irs1 and Irs2 signaling is essential for hepatic glucose homeostasis and systemic growth. |
| 5675 | 16374520 | Insulin receptor substrates, including Irs1 and Irs2, integrate insulin and IGF receptor signals with heterologous pathways to coordinate growth and metabolism. |
| 5676 | 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-/-). |
| 5677 | 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. |
| 5678 | 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. |
| 5679 | 16374520 | Thus, signals delivered by Irs1 or Irs2 regulate hepatic gene expression that coordinates glucose homeostasis and systemic growth. |
| 5680 | 16375695 | Insulin regulation of PEPCK gene expression: a model for rapid and reversible modulation. |
| 5681 | 16375695 | Normally, PEPCK expression is induced by glucagon, catecholamines and glucocorticoids during periods of fasting and in response to stress, but is dominantly inhibited by glucose-induced increases in insulin secretion upon feeding. |
| 5682 | 16375695 | Thus, defining a molecular mechanism for insulin inhibition of PEPCK gene transcription has been a major goal of research in several labs, because it would allow the development of drugs to prevent episodic increases in circulating glucose in diabetics. |
| 5683 | 16375695 | Any mechanism must account for the rapidity, specificity and dominance with which insulin is known to act in regulating PEPCK transcription. |
| 5684 | 16375695 | To date Foxo1 (FKHR) is the only transcription factor for which a complete path from the insulin receptor to gene regulation has been described. |
| 5685 | 16375695 | While this explains the regulation of some genes, such as IGFBP-1, Foxo1 appears not to play a requisite role in regulating PEPCK transcription. |
| 5686 | 16375695 | Investigation of cis-acting elements in the PEPCK promoter has shed considerable light on the mechanisms of activation by cAMP and glucocorticoids but has failed to identify a regulatory element that mediates insulin inhibition of transcription. |
| 5687 | 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. |
| 5688 | 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. |
| 5689 | 16380488 | Adipose triglyceride lipase: function, regulation by insulin, and comparison with adiponutrin. |
| 5690 | 16380488 | ATGL shares the greatest sequence homology with adiponutrin, a nutritionally regulated protein of unclear biological function. |
| 5691 | 16380488 | Here we present a functional analysis of ATGL and adiponutrin and describe their regulation by insulin. |
| 5692 | 16380488 | In mice, both ATGL and adiponutrin are nutritionally regulated in adipose tissue, with ATGL being upregulated and adiponutrin being downregulated by fasting. |
| 5693 | 16380488 | In 3T3-L1 adipocytes, insulin decreased ATGL and increased adiponutrin expression in a dose- and time-dependent manner, suggesting that insulin directly mediates this nutritional regulation. |
| 5694 | 16380488 | In addition, adipose expression of ATGL was increased by insulin deficiency and decreased by insulin replacement in streptozotocin-induced diabetic mice and was increased in fat-specific insulin receptor knockout mice, whereas adiponutrin showed the opposite pattern. |
| 5695 | 16380488 | These data suggest that murine ATGL but not adiponutrin contributes to net adipocyte lipolysis and that ATGL and adiponutrin are oppositely regulated by insulin both in vitro and in vivo. |
| 5696 | 16389895 | Pharmacological studies have shown that reversible albumin binding will protract absorption following subcutaneous injection but still allow the insulin molecule to be recognised by the insulin receptor following dissociation from the carrier protein. |
| 5697 | 16389895 | Together with an important buffering mechanism effected by plasma albumin binding, this explains a highly significant reduction of within-subject variability of pharmacodynamic response observed in repeat isoglycaemic clamp studies where insulin detemir was compared to other basal insulin products. |
| 5698 | 16389895 | No safety considerations have been identified in using albumin as an insulin carrier to protract and buffer insulin action. |
| 5699 | 16399506 | Hypothalamic signaling via the insulin receptor substrate-phosphatidylinositol 3-kinase (IRS-PI3K) pathway, a key intracellular mediator of insulin action, was reduced in rats with uncontrolled diabetes induced by streptozotocin (STZ-DM). |
| 5700 | 16399506 | Further, infusion of a PI3K inhibitor into the third cerebral ventricle of STZ-DM rats prior to peripheral insulin injection attenuated insulin-induced glucose lowering by approximately 35%-40% in both acute and chronic insulin treatment paradigms. |
| 5701 | 16399506 | Conversely, increased PI3K signaling induced by hypothalamic overexpression of either IRS-2 or protein kinase B (PKB, a key downstream mediator of PI3K action) enhanced the glycemic response to insulin by approximately 2-fold in STZ-DM rats. |
| 5702 | 16412093 | Alzheimer-like changes in protein kinase B and glycogen synthase kinase-3 in rat frontal cortex and hippocampus after damage to the insulin signalling pathway. |
| 5703 | 16412093 | The insulin-resistant brain state is related to late-onset sporadic Alzheimer's disease, and alterations in the insulin receptor (IR) and its downstream phosphatidylinositol-3 kinase signalling pathway have been found in human brain. |
| 5704 | 16412093 | In this study, western blot analysis performed 1 month after i.c.v. injection of STZ showed an increase of 63% in the level of phosphorylated glycogen synthase kinase-3alpha/beta (pGSK-3alpha/beta) protein in the rat hippocampus, whereas the levels of the unphosphorylated form (GSK-3alpha/beta) and protein kinase B (Akt/PKB) remained unchanged. |
| 5705 | 16455778 | Insulin effects on both islet cell K(ATP) channels were blocked by wortmannin, indicating that insulin acted on the insulin receptor-phosphatidylinositol 3-kinase signaling pathway. |
| 5706 | 16458527 | IRS1 and IRS2 are the major insulin receptor substrates leading to glucose homeostasis, and have distinct and overlapping roles in diverse organs. |
| 5707 | 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. |
| 5708 | 16460269 | First, studies using tissue-specific knockouts or tissue-specific reconstitution of the insulin receptor in vivo in mice have enabled us to deconstruct the insulin resistance syndromes by dissecting the contributions of different tissues to the insulin-resistant state. |
| 5709 | 16469952 | Regulation of vascular endothelial growth factor expression and vascularization in the myocardium by insulin receptor and PI3K/Akt pathways in insulin resistance and ischemia. |
| 5710 | 16485043 | Role of the forkhead protein FoxO1 in beta cell compensation to insulin resistance. |
| 5711 | 16485043 | We show that the mutant FoxO1 transgene prevents beta cell replication in 2 models of beta cell hyperplasia, 1 due to peripheral insulin resistance (Insulin receptor transgenic knockouts) and 1 due to ectopic local expression of IGF2 (Elastase-IGF2 transgenics), without affecting insulin secretion. |
| 5712 | 16485043 | We propose that beta cell compensation to insulin resistance is a proliferative response of existing beta cells to growth factor signaling and requires FoxO1 nuclear exclusion. |
| 5713 | 16492903 | In metabolic tissues, insulin signaling via the phosphatidylinositol-3-kinase pathway leads to glucose uptake so that in insulin resistance a state of hyperglycemia occurs; other factors such as dyslipidemia and hypertension also arise. |
| 5714 | 16492903 | In cardiovascular tissues there are two pathways of insulin receptor signaling, one that is predominant in metabolic tissues (mediated by phosphatidylinositol-3-kinase) and another being a growth factor-like pathway (mediated by MAPK); the down-regulation of the former and continued activity of the latter pathway leads to atherosclerosis. |
| 5715 | 16505233 | Overexpression of suppressor of cytokine signaling 3 in adipose tissue causes local but not systemic insulin resistance. |
| 5716 | 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. |
| 5717 | 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. |
| 5718 | 16505233 | Whether SOCS3 also inhibits adipocyte insulin signaling in vivo and whether this action further affects systemic insulin sensitivity is not clear. |
| 5719 | 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. |
| 5720 | 16505233 | This impaired insulin signaling in adipose tissue of aP2-SOCS3 mice causes decreased lipogenesis and blocks insulin's antilipolytic action. |
| 5721 | 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. |
| 5722 | 16505233 | Therefore, overexpression of SOCS3 in adipocytes causes local adipocyte insulin resistance, but it is not sufficient to cause systemic insulin resistance. |
| 5723 | 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. |
| 5724 | 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. |
| 5725 | 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. |
| 5726 | 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. |
| 5727 | 16505244 | IRS-1 serine phosphorylation and insulin resistance in skeletal muscle from pancreas transplant recipients. |
| 5728 | 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. |
| 5729 | 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. |
| 5730 | 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. |
| 5731 | 16505244 | Importantly, insulin stimulation of the Akt substrate AS160 was impaired in nondiabetic kidney and pancreas-kidney transplant recipients. |
| 5732 | 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. |
| 5733 | 16507892 | Severely impaired insulin signaling in chronic wounds of diabetic ob/ob mice: a potential role of tumor necrosis factor-alpha. |
| 5734 | 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. |
| 5735 | 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. |
| 5736 | 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. |
| 5737 | 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. |
| 5738 | 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. |
| 5739 | 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. |
| 5740 | 16507892 | Severely impaired insulin signaling in chronic wounds of diabetic ob/ob mice: a potential role of tumor necrosis factor-alpha. |
| 5741 | 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. |
| 5742 | 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. |
| 5743 | 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. |
| 5744 | 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. |
| 5745 | 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. |
| 5746 | 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. |
| 5747 | 16507892 | Severely impaired insulin signaling in chronic wounds of diabetic ob/ob mice: a potential role of tumor necrosis factor-alpha. |
| 5748 | 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. |
| 5749 | 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. |
| 5750 | 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. |
| 5751 | 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. |
| 5752 | 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. |
| 5753 | 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. |
| 5754 | 16507892 | Severely impaired insulin signaling in chronic wounds of diabetic ob/ob mice: a potential role of tumor necrosis factor-alpha. |
| 5755 | 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. |
| 5756 | 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. |
| 5757 | 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. |
| 5758 | 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. |
| 5759 | 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. |
| 5760 | 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. |
| 5761 | 16555000 | Increased phosphorylation of insulin receptor (IR), IRS2 and Akt was prolonged at low bafilomycin concentrations (10 and 50 nmol/L), whereas at high concentrations (100 and 200 nmol/L) phosphorylation rapidly returned to basal levels or below. |
| 5762 | 16555000 | Akt activation was demonstrated by transient increases in phosphorylation of BAD, cytoplasmic retention of FoxO1 and increased preproinsulin mRNA. |
| 5763 | 16557003 | The PI3-K/Akt pathway: roles related to alterations in vasomotor responses in diabetic models. |
| 5764 | 16557003 | The principal mediators of diabetes-associated endothelial dysfunction are (a) increases in oxidized low density lipoprotein, endothelin-1, angiotensin II, oxidative stress, and (b) decreases in the actions of insulin or growth factors in endothelial cells. |
| 5765 | 16557003 | An accumulating body of evidence indicates that abnormal regulation of the phosphatidylinositol 3-kinase (PI3-K)/Akt pathway may be one of several factors contributing to vascular dysfunction in diabetes. |
| 5766 | 16557003 | The PI3-K pathway, which activates serine/threonine protein kinase Akt, enhances NO synthase phosphorylation and NO production. |
| 5767 | 16557003 | Several studies suggest that in diabetes the relative ineffectiveness of insulin and the hyperglycemia act together to reduce activity in the insulin-receptor substrates (IRS)/PI3-K/Akt pathway, resulting in impairments of both IRS/PI3-K/Akt-mediated endothelial function and NO production. |
| 5768 | 16557003 | This article summarizes the PI3-K/Akt pathway-mediated contraction and relaxation responses induced by various agents in the blood vessels of diabetic animals. |
| 5769 | 16563942 | This defect appears to be a result of intracellular lipid-induced inhibition of insulin-stimulated insulin-receptor substrate (IRS)-1 tyrosine phosphorylation resulting in reduced IRS-1-associated phosphatidyl inositol 3 kinase activity. |
| 5770 | 16563942 | Furthermore, the increase in hepatic insulin sensitivity observed in patients with type 2 diabetes following weight loss is also accompanied by a significant reduction in intrahepatic fat without any changes in circulating adipocytokines (interleukin-6, resistin, leptin). |
| 5771 | 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. |
| 5772 | 16567515 | Activated JAK binds to signal transducers and activators of transcription, insulin receptor substrates (IRSs), and Shc. |
| 5773 | 16567515 | Intriguingly, insulin acting through its own receptor kinase also activates JAK2. |
| 5774 | 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%. |
| 5775 | 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. |
| 5776 | 16567515 | Conversely, insulin-stimulated Akt phosphorylation, glucose uptake, and GLUT4 translocation were not affected by siJAK2. |
| 5777 | 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. |
| 5778 | 16567515 | These results suggest that JAK2 may depress the Akt to glucose uptake signaling axis selectively in insulin-resistant states. |
| 5779 | 16567515 | Inhibition of JAK2 may be a useful strategy to relieve insulin resistance of metabolic outcomes. |
| 5780 | 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. |
| 5781 | 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. |
| 5782 | 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. |
| 5783 | 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. |
| 5784 | 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. |
| 5785 | 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. |
| 5786 | 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. |
| 5787 | 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. |
| 5788 | 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. |
| 5789 | 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. |
| 5790 | 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. |
| 5791 | 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. |
| 5792 | 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. |
| 5793 | 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. |
| 5794 | 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. |
| 5795 | 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. |
| 5796 | 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. |
| 5797 | 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. |
| 5798 | 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. |
| 5799 | 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. |
| 5800 | 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. |
| 5801 | 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. |
| 5802 | 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. |
| 5803 | 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. |
| 5804 | 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. |
| 5805 | 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. |
| 5806 | 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. |
| 5807 | 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. |
| 5808 | 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. |
| 5809 | 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. |
| 5810 | 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. |
| 5811 | 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. |
| 5812 | 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. |
| 5813 | 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. |
| 5814 | 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. |
| 5815 | 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. |
| 5816 | 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. |
| 5817 | 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. |
| 5818 | 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. |
| 5819 | 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. |
| 5820 | 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. |
| 5821 | 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. |
| 5822 | 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. |
| 5823 | 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. |
| 5824 | 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. |
| 5825 | 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. |
| 5826 | 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. |
| 5827 | 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. |
| 5828 | 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. |
| 5829 | 16581003 | To evaluate the possibility that decreased insulin signaling in macrophage foam cells might worsen atherosclerosis, Ldlr(-/-) mice were transplanted with insulin receptor Insr(+/+) or Insr(-/-) bone marrow. |
| 5830 | 16581003 | Insr(-/-) macrophages showed diminished Akt phosphorylation and an augmented ER stress response, leading to induction of scavenger receptor A and increased apoptosis when challenged with cholesterol loading or nutrient deprivation. |
| 5831 | 16581003 | These studies suggest that defective insulin signaling and reduced Akt activity impair the ability of macrophages to deal with ER stress-induced apoptosis within atherosclerotic plaques. |
| 5832 | 16581003 | To evaluate the possibility that decreased insulin signaling in macrophage foam cells might worsen atherosclerosis, Ldlr(-/-) mice were transplanted with insulin receptor Insr(+/+) or Insr(-/-) bone marrow. |
| 5833 | 16581003 | Insr(-/-) macrophages showed diminished Akt phosphorylation and an augmented ER stress response, leading to induction of scavenger receptor A and increased apoptosis when challenged with cholesterol loading or nutrient deprivation. |
| 5834 | 16581003 | These studies suggest that defective insulin signaling and reduced Akt activity impair the ability of macrophages to deal with ER stress-induced apoptosis within atherosclerotic plaques. |
| 5835 | 16611137 | We have discussed insulin receptor substrate-family (IRS) related to insulin resistance, detail downstream signaling effects, GLUT4 vesicle translocation and related events, cytokine-mediated insulin resistance, and feedback control mechanisms. |
| 5836 | 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. |
| 5837 | 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. |
| 5838 | 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). |
| 5839 | 16622294 | AMPK activation is also involved in the mechanism of action of metformin and adiponectin. |
| 5840 | 16640344 | Our previous studies indicated that the alpha- and beta-anomers of penta-O-galloyl-D-glucopyranose (PGG), 2 and 3, act as insulin mimetics that bind to and activate the insulin receptor, stimulate glucose transport in adipocytes, and reduce blood glucose and insulin levels in diabetic and obese animals. |
| 5841 | 16642023 | Although the regulation of islet mass is complex, recent studies have suggested the importance of a signaling pathway that includes the insulin or insulin-like growth factor-1 receptors, insulin receptor substrate and phosphatidylinositol (PI) 3-kinase. 3-Phosphoinositide-dependent protein kinase 1 (PDK1) is a serine-threonine kinase that mediates signaling downstream of PI 3-kinase. |
| 5842 | 16644673 | Impact of mitochondrial reactive oxygen species and apoptosis signal-regulating kinase 1 on insulin signaling. |
| 5843 | 16644673 | Tumor necrosis factor (TNF)-alpha inhibits insulin action; however, the precise mechanisms are unknown. |
| 5844 | 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. |
| 5845 | 16644673 | Here, we examined roles of mitochondrial ROS and ASK1 in TNF-alpha-induced impaired insulin signaling in cultured human hepatoma (Huh7) cells. |
| 5846 | 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). |
| 5847 | 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. |
| 5848 | 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. |
| 5849 | 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. |
| 5850 | 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. |
| 5851 | 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. |
| 5852 | 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. |
| 5853 | 16676355 | Recent studies on the role of caveolin-1 in adipocytes showed that caveolin has emerged as an important regulatory element in insulin signaling but little is known on its role in skeletal muscle cells. |
| 5854 | 16676355 | In this study, we demonstrate for the first time that caveolin-1 plays a crucial role in insulin dependent glucose uptake in skeletal muscle cells. |
| 5855 | 16676355 | Differentiation of L6 skeletal muscle cells induce the expression of caveolin-1 and caveolin-3 with partial colocalization. |
| 5856 | 16676355 | However in contrast to adipocytes, phosphorylation of insulin receptor beta (IRbeta) and Akt/Erk was not affected by the respective downregulation of caveolin-1 or caveolin-3 in the muscle cells. |
| 5857 | 16676355 | Moreover, the phosphorylation of IRbeta was detected not only in the caveolae but also in the non-caveolae fractions of the muscle cells despite the interaction of IRbeta with caveolin-1 and caveolin-3. |
| 5858 | 16676355 | However, glucose uptake was reduced specifically by downregulation of caveolin-1, but not that of caveolin-3. |
| 5859 | 16676355 | Taken together, these observations suggest that caveolin-1 plays a crucial role in glucose uptake in differentiated muscle cells and that the regulation of caveolin-1 expression may be an important mechanism for insulin sensitivity, implying the role of muscle cells for type 2 diabetes. |
| 5860 | 16679294 | Identification of the tyrosine phosphatase PTP-MEG2 as an antagonist of hepatic insulin signaling. |
| 5861 | 16679294 | Through the concomitant application of genome-scale functional screening and quantitative image analysis, we have identified PTP-MEG2 as a modulator of insulin-dependent FOXO1 subcellular localization. |
| 5862 | 16679294 | Ectopic expression of PTP-MEG2 in cells inhibited insulin-induced phosphorylation of the insulin receptor, while RNAi-mediated reduction of PTP-MEG2 transcript levels enhanced insulin action. |
| 5863 | 16679294 | Additionally, adenoviral-mediated depletion of PTP-MEG2 in livers of diabetic (db/db) mice resulted in insulin sensitization and normalization of hyperglycemia. |
| 5864 | 16679294 | These data implicate PTP-MEG2 as a mediator of blood glucose homeostasis through antagonism of insulin signaling, and suggest that modulation of PTP-MEG2 activity may be an effective strategy in the treatment of type 2 diabetes. |
| 5865 | 16702017 | The prototypical insulin receptor substrate, IRS-1 plays a central role in insulin signaling. |
| 5866 | 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. |
| 5867 | 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. |
| 5868 | 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. |
| 5869 | 16702017 | In cells lacking intermediate filaments (Vim(-/-)) IRS-1 expression, distribution and insulin-stimulated phosphorylation appeared normal. |
| 5870 | 16702017 | Even after depolymerisation of microfilaments and microtubules, insulin-stimulated phosphorylation of IRS-1 and Akt were maintained in Vim(-/-) cells. |
| 5871 | 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. |
| 5872 | 16733497 | Apelin and visfatin: unique "beneficial" adipokines upregulated in obesity? |
| 5873 | 16733497 | Apelin and visfatin are two recently described adipokines, although they are also synthesized outside adipose tissue. |
| 5874 | 16733497 | Apelin synthesis in adipocytes is stimulated by insulin, and plasma apelin level markedly increases in obesity associated with insulin resistance and hyperinsulinemia. |
| 5875 | 16733497 | Visfatin binds to the insulin receptor at a site distinct from insulin and exerts hypoglycemic effect by reducing glucose release from hepatocytes and stimulating glucose utilization in peripheral tissues. |
| 5876 | 16733497 | Thus, apelin and visfatin are unique among adipose tissue hormones in that they are upregulated in the obese state and both exert primarily beneficial effects. |
| 5877 | 16754202 | Differential phosphorylation of IRS-1 and IRS-2 by insulin and IGF-I receptors. |
| 5878 | 16754202 | The specific contribution of insulin and IGF-I receptors to IRS-protein activation remains elusive. |
| 5879 | 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. |
| 5880 | 16754202 | In myoblasts regular insulin and AspB10-insulin were equipotent in stimulating the IRS cascade, whereas this analog induced a significantly higher Shc phosphorylation. |
| 5881 | 16754202 | Phosphorylation of IRS-1 in response to insulin was inhibited equally by blocking either the insulin or the IGF-I receptor. |
| 5882 | 16754202 | IRS-1 activation by AspB10-insulin was only inhibited by blocking the IGF-I receptor. |
| 5883 | 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. |
| 5884 | 16754202 | We conclude that in myoblasts IRS-2, but not IRS-1, functions as preferred substrate for the IGF-I receptor. |
| 5885 | 16803459 | These caveolae contained caveolin-1 and caveolin-2. |
| 5886 | 16803459 | Another class of high-density caveolae contained caveolin-1, caveolin-2 and specifically fatty acid transport protein-1, fatty acid transport protein-4, fatty acyl-CoA synthetase, hormone-sensitive lipase, perilipin, and insulin-regulated glucose transporter-4. |
| 5887 | 16803459 | A third class of low-density caveolae contained the insulin receptor, class B scavenger receptor-1, and insulin-regulated glucose transporter-4. |
| 5888 | 16803459 | In response to insulin, the insulin receptor autophosphorylation and the amount of insulin-regulated glucose transporter-4 increased in these caveolae. |
| 5889 | 16803459 | These caveolae contained caveolin-1 and caveolin-2. |
| 5890 | 16803459 | Another class of high-density caveolae contained caveolin-1, caveolin-2 and specifically fatty acid transport protein-1, fatty acid transport protein-4, fatty acyl-CoA synthetase, hormone-sensitive lipase, perilipin, and insulin-regulated glucose transporter-4. |
| 5891 | 16803459 | A third class of low-density caveolae contained the insulin receptor, class B scavenger receptor-1, and insulin-regulated glucose transporter-4. |
| 5892 | 16803459 | In response to insulin, the insulin receptor autophosphorylation and the amount of insulin-regulated glucose transporter-4 increased in these caveolae. |
| 5893 | 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? |
| 5894 | 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). |
| 5895 | 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. |
| 5896 | 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. |
| 5897 | 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? |
| 5898 | 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). |
| 5899 | 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. |
| 5900 | 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. |
| 5901 | 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. |
| 5902 | 16814735 | We utilized siRNA to decipher the specific role of predominant insulin receptor substrates and Akt isoforms expressed in human skeletal muscle. |
| 5903 | 16814735 | IRS-1 and Akt2 were required for myoblast differentiation and glucose metabolism, whereas IRS-2 and Akt1 were dispensable. |
| 5904 | 16814735 | A key role of IRS-2 and Akt1 in lipid metabolism was revealed, highlighting reciprocal relationships between metabolic pathways. |
| 5905 | 16828931 | Insulin was perfused with and without an inhibitor for tyrosine kinase or phosphatidylinositol 3-kinase (PI 3-kinase). |
| 5906 | 16828931 | These results suggest that insulin stimulates the release of ANP through PI 3-kinase and tyrosine kinase, and augmentation of insulin-stimulated ANP release in diabetic rat atria may be partly due to an upregulation of insulin receptor. |
| 5907 | 16828971 | Ursolic acid and its derivative inhibit protein tyrosine phosphatase 1B, enhancing insulin receptor phosphorylation and stimulating glucose uptake. |
| 5908 | 16828971 | Protein tyrosine phosphatase 1B (PTP1B) is a key element in the negative regulation of the insulin signaling pathway and may play an important role in diabetes and obesity. |
| 5909 | 16828971 | As competitive inhibitors of PTP1B, ursolic acid and its derivative also inhibit T-cell protein tyrosine phosphatase and src homology phosphatase-2 but not leucocyte antigen-related phosphatase or protein tyrosine phosphatase alpha and epsilon, which are all possibly involved in the insulin pathway. |
| 5910 | 16838191 | Defects in FAT/CD36 have been linked to the hypertriglyceridemia and insulin resistance. |
| 5911 | 16838191 | Expression of FAT/CD36 was reported increase in type 1 diabetes; however, it remains unclear whether serum glucose or insulin plays an important role in this regulation. |
| 5912 | 16838191 | To elucidate the individual contribution of plasma glucose and insulin in the regulation of FAT/CD36 mRNA expression, we induced type 1 diabetes in male Sprague-Dawley rats using streptozotocin (STZ) and compared traditional insulin treatment with administration of the orally absorbed chemical agent vanadate, which reduces blood glucose levels via mechanisms that bypass insulin receptor action. |
| 5913 | 16838191 | Insulin treatment also corrected increased FAT/CD36 mRNA expression at diabetic rats. |
| 5914 | 16838191 | Vanadate significantly reduced serum glucose levels without increasing serum insulin or affecting body weight but reversed increased FAT/CD36 mRNA expression in diabetic rats. |
| 5915 | 16839860 | Insulin mediates its action on target organs through phosphorylation of a transmembrane-spanning tyrosine kinase receptor, the insulin receptor (IR). |
| 5916 | 16839860 | In particular, phosphorylation of IRS-1 on serine Ser612 causes dissociation of the p85 subunit of phosphatidylinositol 3-kinase, inhibiting further signaling. |
| 5917 | 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. |
| 5918 | 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. |
| 5919 | 16873706 | A number of serine kinases that phosphorylate serine residues of IRS-1 and weaken insulin signal transduction have been identified. |
| 5920 | 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. |
| 5921 | 16897338 | The ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) is an inhibitor of the insulin receptor. |
| 5922 | 16897338 | Variants of ENPP1 are associated with infantile arterial calcification, obesity, and insulin resistance. |
| 5923 | 16897338 | We provide further molecular information about ENPP1 as a potential pharmacologic target and characterize its regulation in an insulin-dependent diabetes mellitus animal model. |
| 5924 | 16898568 | The mechanism through which FFA induces insulin resistance involves intramyocellular and intrahepatocellular accumulation of triglycerides and diacylglycerol, activation of several serine/threonine kinases, reduction in tyrosine phosphorylation of the insulin receptor substrate (IRS)-1/2, and impairment of the IRS/phosphatidylinositol 3-kinase pathway of insulin signaling. |
| 5925 | 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. |
| 5926 | 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. |
| 5927 | 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. |
| 5928 | 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. |
| 5929 | 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. |
| 5930 | 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. |
| 5931 | 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. |
| 5932 | 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. |
| 5933 | 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. |
| 5934 | 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. |
| 5935 | 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. |
| 5936 | 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. |
| 5937 | 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. |
| 5938 | 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. |
| 5939 | 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. |
| 5940 | 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. |
| 5941 | 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. |
| 5942 | 16962100 | Acetaldehyde promotes rapamycin-dependent activation of p70(S6K) and glucose uptake despite inhibition of Akt and mTOR in dopaminergic SH-SY5Y human neuroblastoma cells. |
| 5943 | 16962100 | Akt, mammalian target of rapamycin (mTOR), ribosomal-S6 kinase (p70(S6K)), the eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1) and insulin receptor substrate (IRS)-2 were evaluated by Western blot analysis. |
| 5944 | 16962100 | Short-term exposure (12 h) of acetaldehyde (150 muM) facilitated glucose uptake in a rapamycin-dependent manner without affecting apoptosis, IRS-2 expression and insulin-stimulated glucose uptake in SH-SY5Y cells. |
| 5945 | 16962100 | Acetaldehyde suppressed basal and insulin-stimulated Akt phosphorylation without affecting total Akt expression. |
| 5946 | 16962100 | Rapamycin, which inhibits mTOR leading to inactivation of p70(S6K), did not affect acetaldehyde-induced inhibition on phosphorylation of Akt and mTOR. |
| 5947 | 16962100 | Interestingly, acetaldehyde enhanced p70(S6K) activation and depressed 4E-BP1 phosphorylation, the effect of which was blunted and exaggerated, respectively, by rapamycin. |
| 5948 | 16962100 | Collectively, these data suggested that acetaldehyde did not adversely affect glucose uptake despite inhibition of insulin signaling cascade at the levels of Akt and mTOR, possibly due to presence of certain mechanism(s) responsible for enhanced p70(S6K) phosphorylation. |
| 5949 | 16970914 | Among them, VO(3mpa)(2) was found to be the highest potent activator in inducing not only the phosphotyrosine levels of both IRbeta and IRS but also the activation of downstream kinases in the insulin receptor, such as Akt and GSK3beta, which in turn translocated the insulin-dependent GLUT4 to the plasma membrane. |
| 5950 | 16970914 | Our present data indicate that both activation of insulin signaling pathway, which follows the GLUT4 translocation to the plasma membrane, and enhancement of glucose utilization by oxovanadium(IV) complexes cause the hypoglycemic effect in diabetic animals. |
| 5951 | 17003350 | The detection of mRNAs for insulin receptor (IR)A and IRB; insulin receptor substrate (IRS)-1 and IRS-2; phosphoinositide 3-kinase (PI3K) catalytic subunits p110alpha, p110beta, PI3KC2alpha, and PI3KC2gamma; phosphoinositide-dependent protein kinase-1; protein kinase B (PKB)alpha, PKBbeta, and PKBgamma in the beta-cell population suggests the presence of a functional insulin signaling cascade in human beta-cells. |
| 5952 | 17038556 | However, the ability of IL-1beta to alter insulin signaling and action remains to be explored. |
| 5953 | 17038556 | Importantly, we found that prolonged IL-1beta treatment reduced the insulin-induced glucose uptake, whereas an acute treatment had no effect. |
| 5954 | 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. |
| 5955 | 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. |
| 5956 | 17038556 | Pharmacological inhibition of ERK totally inhibited IL-1beta-induced down-regulation of IRS-1 mRNA. |
| 5957 | 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. |
| 5958 | 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. |
| 5959 | 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. |
| 5960 | 17050683 | Saturated fatty acids inhibit induction of insulin gene transcription by JNK-mediated phosphorylation of insulin-receptor substrates. |
| 5961 | 17050683 | A sustained increase in JNK activity was observed in dietary and genetic models of obesity in mice, whereas JNK deficiency prevented obesity-induced insulin resistance. |
| 5962 | 17050683 | A similar insulin-sensitizing effect was seen upon treatment of obese mice with JNK inhibitors. |
| 5963 | 17050683 | We now demonstrate that treatment with the saturated fatty acid palmitic acid results in sustained JNK activation and insulin resistance in primary mouse hepatocytes and pancreatic beta-cells. |
| 5964 | 17050683 | In the latter, palmitic acid treatment inhibits glucose-induced insulin gene transcription, in part, by interfering with autocrine insulin signaling through phosphorylation of insulin-receptor substrates 1 and 2 at sites that interfere with binding to activated insulin receptors. |
| 5965 | 17050683 | Saturated fatty acids inhibit induction of insulin gene transcription by JNK-mediated phosphorylation of insulin-receptor substrates. |
| 5966 | 17050683 | A sustained increase in JNK activity was observed in dietary and genetic models of obesity in mice, whereas JNK deficiency prevented obesity-induced insulin resistance. |
| 5967 | 17050683 | A similar insulin-sensitizing effect was seen upon treatment of obese mice with JNK inhibitors. |
| 5968 | 17050683 | We now demonstrate that treatment with the saturated fatty acid palmitic acid results in sustained JNK activation and insulin resistance in primary mouse hepatocytes and pancreatic beta-cells. |
| 5969 | 17050683 | In the latter, palmitic acid treatment inhibits glucose-induced insulin gene transcription, in part, by interfering with autocrine insulin signaling through phosphorylation of insulin-receptor substrates 1 and 2 at sites that interfere with binding to activated insulin receptors. |
| 5970 | 17065358 | Ectoenzyme nucleotide pyrophosphate phosphodiesterase 1 (ENPP1) is an inhibitor of insulin-induced activation of the insulin receptor. |
| 5971 | 17068109 | In addition, we attempted to demonstrate the role of 17beta-oestradiol and progesterone on insulin sensitivity, focusing on their effects on key proteins of skeletal muscle, insulin receptor (IR) and glucose transporter-4 (Glut-4). |
| 5972 | 17068109 | Our results show that hyperglycaemia could modulate insulin signalling, at the IR and Glut-4 level, in different ways depending on exposure time. 17beta-Oestradiol and progesterone have different effects on insulin signalling. 17beta-Oestradiol treatment improves insulin sensitivity, but its action is dependent on the exposure time and its plasma level. |
| 5973 | 17068109 | By contrast, progesterone only improves insulin sensitivity during the early period of treatment (days 6-11), and this effect is not associated with changes in IR and Glut-4 content. |
| 5974 | 17068137 | Developmental switch from prolonged insulin action to increased insulin sensitivity in protein tyrosine phosphatase 1B-deficient hepatocytes. |
| 5975 | 17068137 | Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of insulin signaling and a therapeutic target for type 2 diabetes. |
| 5976 | 17068137 | The purpose of this study was to evaluate the differences in insulin sensitivity between neonate and adult hepatocytes lacking PTP1B. |
| 5977 | 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. |
| 5978 | 17068137 | Endogenous IR and IRS-2 were down-regulated, whereas IRS-1 was up-regulated in PTP1B(-/-) neonatal hepatocytes and livers of PTP1B(-/-) neonates. |
| 5979 | 17068137 | Insulin-induced activation of phosphatidylinositol 3-kinase/Akt pathway was prolonged in PTP1B(-/-) immortalized neonatal hepatocytes. |
| 5980 | 17068137 | Rescue of PTP1B in deficient cells suppressed the prolonged insulin signaling, whereas RNA interference in wild-type cells promoted prolonged signaling. |
| 5981 | 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. |
| 5982 | 17068137 | By contrast, in adult PTP1B-deficient livers, p85alpha was down-regulated compared with the wild type. |
| 5983 | 17068137 | Moreover, primary hepatocytes from adult PTP1B(-/-) mice displayed enhanced Akt phosphorylation and a more pronounced inhibition of gluconeogenic mRNAs than wild-type cells. |
| 5984 | 17068137 | Hepatic insulin sensitivity due to PTP1B deficiency is acquired through postnatal development. |
| 5985 | 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. |
| 5986 | 17088077 | Effects of small interference RNA against PTP1B and TCPTP on insulin signaling pathway in mouse liver: evidence for non-synergetic cooperation. |
| 5987 | 17088077 | Two closely-related protein tyrosine phosphatases, PTP1B and TCPTP both showed abilities to negatively regulate insulin receptor signaling. |
| 5988 | 17088077 | In order to test whether these two phosphatases can act synergistically, hydrodynamic injection was applied to deliver small interfering RNA (siRNA) of PTP1B and/or TCPTP to mouse liver. |
| 5989 | 17088077 | By measuring insulin-sensitive reporter gene expression and plasma glucose of diabetic mice, we found siRNA of PTP1B or TCPTP alone can sensitize insulin signal transduction, but combined treatment of both siRNAs had no better effects than siRNA of PTP1B. |
| 5990 | 17088077 | These results suggested siRNA of PTP1B and TCPTP can strengthen insulin signaling, but their effects do not appear to be synergistic in mouse liver. |
| 5991 | 17100583 | These studies have demonstrated that selective inhibition of GSK-3 in insulin-resistant skeletal muscle causes improvements in insulin-stimulated glucose transport activity that are likely caused by enhanced post-insulin receptor insulin signaling and GLUT-4 glucose transporter translocation. |
| 5992 | 17106060 | Ghrelin has novel vascular actions that mimic PI 3-kinase-dependent actions of insulin to stimulate production of NO from endothelial cells. |
| 5993 | 17106060 | Therefore, we hypothesized that ghrelin activates endothelial nitric oxide synthase (eNOS) in vascular endothelium, resulting in increased production of nitric oxide (NO) using signaling pathways shared in common with the insulin receptor. |
| 5994 | 17106060 | Similar to insulin, ghrelin acutely stimulated increased production of NO in bovine aortic endothelial cells (BAEC) in primary culture (assessed using NO-specific fluorescent dye 4,5-diaminofluorescein) in a time- and dose-dependent manner. |
| 5995 | 17106060 | Production of NO in response to ghrelin (100 nM, 10 min) in human aortic endothelial cells was blocked by pretreatment of cells with NG-nitro-L-arginine methyl ester (nitric oxide synthase inhibitor), wortmannin [phosphatidylinositol (PI) 3-kinase inhibitor], or (D-Lys3)-GHRP-6 (selective antagonist of ghrelin receptor GHSR-1a), as well as by knockdown of GHSR-1a using small-interfering (si) RNA (but not by mitogen/extracellular signal-regulated kinase inhibitor PD-98059). |
| 5996 | 17106060 | Moreover, ghrelin stimulated increased phosphorylation of Akt (Ser473) and eNOS (Akt phosphorylation site Ser1179) that was inhibitable by knockdown of GHSR-1a using siRNA or by pretreatment of cells with wortmannin but not with PD-98059. |
| 5997 | 17106060 | Ghrelin also stimulated phosphorylation of mitogen-activated protein (MAP) kinase in BAEC. |
| 5998 | 17106060 | However, unlike insulin, ghrelin did not stimulate MAP kinase-dependent secretion of the vasoconstrictor endothelin-1 from BAEC. |
| 5999 | 17106060 | We conclude that ghrelin has novel vascular actions to acutely stimulate production of NO in endothelium using a signaling pathway that involves GHSR-1a, PI 3-kinase, Akt, and eNOS. |
| 6000 | 17109620 | NRF2-dependent glutamate-L-cysteine ligase catalytic subunit expression mediates insulin protection against hyperglycemia- induced brain endothelial cell apoptosis. |
| 6001 | 17109620 | Insulin stimulated glutamate-L-cysteine ligase (GCL) activity by activation of phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR signaling, increased serine phosphorylation and nuclear translocation of nuclear NF-E2-related factor 2 (Nrf2), and upregulation of Nrf2-dependent GCL-catalytic (GCLc) subunit expression. |
| 6002 | 17109620 | Expression of the GCL-modulatory subunit (GCLm) was unchanged. |
| 6003 | 17109620 | Inhibitors of insulin receptor tyrosine kinase, PI3K, Akt and mTOR abrogated insulin-induced Nrf2-mediated GCLc expression, redox balance, and IHEC survival. |
| 6004 | 17109620 | Activation of insulin signaling through PI3K/Akt/mTOR/Nrf2/ GCLc pathway affords significant cell protection by maintaining cellular redox balance. |
| 6005 | 17130472 | We found insulin receptor substrate (IRS)2 and enhanced-activated Akt immunoreactivity in islets and ducts that correlated with increased pancreatic duodenal homeobox (PDX)1 expression. |
| 6006 | 17130472 | In contrast, forkhead box O1 expression was decreased in islets but increased in ducts, suggesting distinct PDX1 regulatory mechanisms in these tissues. |
| 6007 | 17130507 | High-affinity nerve growth factor (NGF) receptor (NGFR-TrkA) expression in DRGs was significantly reduced at 4 months (P < 0.01). |
| 6008 | 17130507 | Insulin receptor and IGF-I receptor (IGF-IR) expressions in DRGs and NGF content in sciatic nerve were significantly decreased in 7-month diabetic rats (P < 0.01, 0.05, and 0.005, respectively). |
| 6009 | 17130507 | Osmopump delivery prevented the decline of NGFR-TrkA, insulin receptor (P < 0.05), and IGF-IR (P < 0.005) expressions in DRGs and improved NGF content (P < 0.05) in sciatic nerve. |
| 6010 | 17130507 | High-affinity nerve growth factor (NGF) receptor (NGFR-TrkA) expression in DRGs was significantly reduced at 4 months (P < 0.01). |
| 6011 | 17130507 | Insulin receptor and IGF-I receptor (IGF-IR) expressions in DRGs and NGF content in sciatic nerve were significantly decreased in 7-month diabetic rats (P < 0.01, 0.05, and 0.005, respectively). |
| 6012 | 17130507 | Osmopump delivery prevented the decline of NGFR-TrkA, insulin receptor (P < 0.05), and IGF-IR (P < 0.005) expressions in DRGs and improved NGF content (P < 0.05) in sciatic nerve. |
| 6013 | 17130651 | The molecular mechanism underlying defective insulin-stimulated glucose transport activity can be attributed to increases in intramyocellular lipid metabolites such as fatty acyl CoAs and diacylglycerol, which in turn activate a serine/threonine kinase cascade, thus leading to defects in insulin signaling through Ser/Thr phosphorylation of insulin receptor substrate (IRS)-1. |
| 6014 | 17130651 | A similar mechanism is also observed in hepatic insulin resistance associated with nonalcoholic fatty liver, which is a common feature of type 2 diabetes, where increases in hepatocellular diacylglycerol content activate protein kinase C-epsilon, leading to reduced insulin-stimulated tyrosine phosphorylation of IRS-2. |
| 6015 | 17135270 | Protein tyrosine phosphatase 1B (PTP-1B) has been implicated in the regulation of the insulin receptor. |
| 6016 | 17135270 | PTP-1B-/- mice have increased insulin sensitivity and are resistant to weight gain when fed a high fat diet, validating PTP-1B as a potential target for the treatment of type 2 diabetes. |
| 6017 | 17135270 | Using two constructs of PTP-1B and a phosphopeptide as substrate, steady state assays showed that the presence of the C-terminal domain decreased both the Km and the k(cat) 2-fold. |
| 6018 | 17143316 | Mechanisms of disease: Ectonucleotide pyrophosphatase phosphodiesterase 1 as a 'gatekeeper' of insulin receptors. |
| 6019 | 17143316 | The transmembrane glycoprotein ectonucleotide pyrophosphatase phosphodiesterase 1 (E-NPP1; also known as plasma cell membrane glycoprotein PC-1) interacts with the insulin receptor and inhibits subsequent signaling by decreasing its beta-subunit autophosphorylation. |
| 6020 | 17143316 | E-NPP1 is overexpressed in skeletal muscle, adipose tissue and cultured skin fibroblasts of insulin-resistant individuals who are not yet obese or diabetic, which indicates that excessive E-NPP1 expression is an early, intrinsic defect in human insulin resistance. |
| 6021 | 17143316 | Genetic studies also support a primary role of E-NPP1 in insulin resistance. |
| 6022 | 17143316 | E-NPP1 is measurable in human serum, where it might represent a valuable biomarker of insulin resistance, but its relationship to tissue and systemic insulin resistance remains to be thoroughly elucidated. |
| 6023 | 17149545 | We then examined insulin signaling pathway where palmitate significantly inhibited insulin stimulated phosphorylation of Insulin receptor tyrosine kinase, IRS 1and PI3 kinase, PDK1 and Akt/PKB. |
| 6024 | 17149545 | LPA(4) rescued this inhibition of signaling molecule by palmitate. |
| 6025 | 17149545 | Insulin mediated translocation of Glut4, the glucose transporter in insulin target cells, was effectively blocked by palmitate while, LPA(4) waived this block. |
| 6026 | 17149545 | Administration of LPA(4) to nutritionally induced diabetic rats significantly reduced the increase in plasma glucose. |
| 6027 | 17149545 | All these indicate LPA(4) to be a potentially therapeutic agent for insulin resistance and type 2 diabetes. |
| 6028 | 17170226 | In addition, visceral fat removal completely reversed the impairment of insulin signal transduction through insulin receptor, insulin receptor substrate (IRS)-1, IRS-2 and Akt in muscle. |
| 6029 | 17170226 | Finally, serum levels of the pro-inflammatory cytokines tumour necrosis factor-alpha, interleukin (IL)-1beta and IL-6 were significantly increased, while adiponectin levels were significantly reduced in DIO mice. |
| 6030 | 17189427 | Essential role of insulin and insulin-like growth factor 1 receptor signaling in cardiac development and function. |
| 6031 | 17189427 | Here we show that mice with combined deficiency of the insulin receptor and insulin-like growth factor 1 (IGF-1) receptor in cardiac and skeletal muscle develop early-onset dilated cardiomyopathy and die from heart failure within the first month of life despite having a normal glucose homeostasis. |
| 6032 | 17189427 | Mice lacking the insulin receptor show impaired cardiac performance at 6 months, and mice lacking the insulin receptor plus one Igf1r allele have slightly increased mortality. |
| 6033 | 17189427 | Morphological characterization and oligonucleotide array analysis of gene expression demonstrate that prior to development of these physiological defects, mice with combined deficiency of both insulin and IGF-1 receptors have a coordinated down-regulation of genes encoding components of the electron transport chain and mitochondrial fatty acid beta-oxidation pathways and altered expression of contractile proteins. |
| 6034 | 17189427 | Thus, while neither the insulin receptor nor IGF-1 receptor in muscle is critical for glucose homeostasis during the first month of life, signaling from these receptors, particularly the insulin receptor, is required for normal cardiac metabolism and function. |
| 6035 | 17189427 | Essential role of insulin and insulin-like growth factor 1 receptor signaling in cardiac development and function. |
| 6036 | 17189427 | Here we show that mice with combined deficiency of the insulin receptor and insulin-like growth factor 1 (IGF-1) receptor in cardiac and skeletal muscle develop early-onset dilated cardiomyopathy and die from heart failure within the first month of life despite having a normal glucose homeostasis. |
| 6037 | 17189427 | Mice lacking the insulin receptor show impaired cardiac performance at 6 months, and mice lacking the insulin receptor plus one Igf1r allele have slightly increased mortality. |
| 6038 | 17189427 | Morphological characterization and oligonucleotide array analysis of gene expression demonstrate that prior to development of these physiological defects, mice with combined deficiency of both insulin and IGF-1 receptors have a coordinated down-regulation of genes encoding components of the electron transport chain and mitochondrial fatty acid beta-oxidation pathways and altered expression of contractile proteins. |
| 6039 | 17189427 | Thus, while neither the insulin receptor nor IGF-1 receptor in muscle is critical for glucose homeostasis during the first month of life, signaling from these receptors, particularly the insulin receptor, is required for normal cardiac metabolism and function. |
| 6040 | 17189427 | Essential role of insulin and insulin-like growth factor 1 receptor signaling in cardiac development and function. |
| 6041 | 17189427 | Here we show that mice with combined deficiency of the insulin receptor and insulin-like growth factor 1 (IGF-1) receptor in cardiac and skeletal muscle develop early-onset dilated cardiomyopathy and die from heart failure within the first month of life despite having a normal glucose homeostasis. |
| 6042 | 17189427 | Mice lacking the insulin receptor show impaired cardiac performance at 6 months, and mice lacking the insulin receptor plus one Igf1r allele have slightly increased mortality. |
| 6043 | 17189427 | Morphological characterization and oligonucleotide array analysis of gene expression demonstrate that prior to development of these physiological defects, mice with combined deficiency of both insulin and IGF-1 receptors have a coordinated down-regulation of genes encoding components of the electron transport chain and mitochondrial fatty acid beta-oxidation pathways and altered expression of contractile proteins. |
| 6044 | 17189427 | Thus, while neither the insulin receptor nor IGF-1 receptor in muscle is critical for glucose homeostasis during the first month of life, signaling from these receptors, particularly the insulin receptor, is required for normal cardiac metabolism and function. |
| 6045 | 17210752 | Bidirectional regulation of upstream IGF-I/insulin receptor signaling and downstream FOXO1 in cardiomyocytes. |
| 6046 | 17210752 | FOXO1 is a member of the forkhead transcriptional factor family, but how insulin and IGF-I receptor signaling regulate FOXO1 in cardiomyocytes is not well understood. |
| 6047 | 17210752 | This study was carried out to elucidate how IGF-I and insulin receptor signaling modulate FOXO1 in cardiomyocytes. |
| 6048 | 17210752 | In cardiomyocytes, activation of IGF-I receptor and insulin receptor lead to rapid phosphorylation of FOXO1. |
| 6049 | 17210752 | Inhibition of phosphatidylinositol 3-kinase/Akt pathway suppressed the effect of insulin and IGF-I on FOXO1 phosphorylation. |
| 6050 | 17210752 | To explore whether FOXO1 could modulate IGF-I and insulin signaling, a constitutively active FOXO1 was overexpressed in cardiomyocytes. |
| 6051 | 17210752 | The abundance of insulin receptor and IGF-I receptor was significantly upregulated in the cells overexpressing active FOXO1, accompanied by increased receptor phosphorylation upon insulin/IGF-I stimulation. |
| 6052 | 17210752 | Interestingly, overexpression of constitutively active FOXO1 also led to activation of MEK and Akt phosphorylation. |
| 6053 | 17210752 | IGF-I-stimulated MEK and Akt phosphorylation were augmented byoverexpression of constitutively active FOXO1. |
| 6054 | 17210752 | These findings indicate bidirectional regulation of insulin/IGF-I receptor signaling and FOXO1 in cardiomyocytes. |
| 6055 | 17210752 | FOXO1 may provide feedback control through upregulation of insulin and IGF-I receptor signaling. |
| 6056 | 17210752 | Bidirectional regulation of upstream IGF-I/insulin receptor signaling and downstream FOXO1 in cardiomyocytes. |
| 6057 | 17210752 | FOXO1 is a member of the forkhead transcriptional factor family, but how insulin and IGF-I receptor signaling regulate FOXO1 in cardiomyocytes is not well understood. |
| 6058 | 17210752 | This study was carried out to elucidate how IGF-I and insulin receptor signaling modulate FOXO1 in cardiomyocytes. |
| 6059 | 17210752 | In cardiomyocytes, activation of IGF-I receptor and insulin receptor lead to rapid phosphorylation of FOXO1. |
| 6060 | 17210752 | Inhibition of phosphatidylinositol 3-kinase/Akt pathway suppressed the effect of insulin and IGF-I on FOXO1 phosphorylation. |
| 6061 | 17210752 | To explore whether FOXO1 could modulate IGF-I and insulin signaling, a constitutively active FOXO1 was overexpressed in cardiomyocytes. |
| 6062 | 17210752 | The abundance of insulin receptor and IGF-I receptor was significantly upregulated in the cells overexpressing active FOXO1, accompanied by increased receptor phosphorylation upon insulin/IGF-I stimulation. |
| 6063 | 17210752 | Interestingly, overexpression of constitutively active FOXO1 also led to activation of MEK and Akt phosphorylation. |
| 6064 | 17210752 | IGF-I-stimulated MEK and Akt phosphorylation were augmented byoverexpression of constitutively active FOXO1. |
| 6065 | 17210752 | These findings indicate bidirectional regulation of insulin/IGF-I receptor signaling and FOXO1 in cardiomyocytes. |
| 6066 | 17210752 | FOXO1 may provide feedback control through upregulation of insulin and IGF-I receptor signaling. |
| 6067 | 17210752 | Bidirectional regulation of upstream IGF-I/insulin receptor signaling and downstream FOXO1 in cardiomyocytes. |
| 6068 | 17210752 | FOXO1 is a member of the forkhead transcriptional factor family, but how insulin and IGF-I receptor signaling regulate FOXO1 in cardiomyocytes is not well understood. |
| 6069 | 17210752 | This study was carried out to elucidate how IGF-I and insulin receptor signaling modulate FOXO1 in cardiomyocytes. |
| 6070 | 17210752 | In cardiomyocytes, activation of IGF-I receptor and insulin receptor lead to rapid phosphorylation of FOXO1. |
| 6071 | 17210752 | Inhibition of phosphatidylinositol 3-kinase/Akt pathway suppressed the effect of insulin and IGF-I on FOXO1 phosphorylation. |
| 6072 | 17210752 | To explore whether FOXO1 could modulate IGF-I and insulin signaling, a constitutively active FOXO1 was overexpressed in cardiomyocytes. |
| 6073 | 17210752 | The abundance of insulin receptor and IGF-I receptor was significantly upregulated in the cells overexpressing active FOXO1, accompanied by increased receptor phosphorylation upon insulin/IGF-I stimulation. |
| 6074 | 17210752 | Interestingly, overexpression of constitutively active FOXO1 also led to activation of MEK and Akt phosphorylation. |
| 6075 | 17210752 | IGF-I-stimulated MEK and Akt phosphorylation were augmented byoverexpression of constitutively active FOXO1. |
| 6076 | 17210752 | These findings indicate bidirectional regulation of insulin/IGF-I receptor signaling and FOXO1 in cardiomyocytes. |
| 6077 | 17210752 | FOXO1 may provide feedback control through upregulation of insulin and IGF-I receptor signaling. |
| 6078 | 17210752 | Bidirectional regulation of upstream IGF-I/insulin receptor signaling and downstream FOXO1 in cardiomyocytes. |
| 6079 | 17210752 | FOXO1 is a member of the forkhead transcriptional factor family, but how insulin and IGF-I receptor signaling regulate FOXO1 in cardiomyocytes is not well understood. |
| 6080 | 17210752 | This study was carried out to elucidate how IGF-I and insulin receptor signaling modulate FOXO1 in cardiomyocytes. |
| 6081 | 17210752 | In cardiomyocytes, activation of IGF-I receptor and insulin receptor lead to rapid phosphorylation of FOXO1. |
| 6082 | 17210752 | Inhibition of phosphatidylinositol 3-kinase/Akt pathway suppressed the effect of insulin and IGF-I on FOXO1 phosphorylation. |
| 6083 | 17210752 | To explore whether FOXO1 could modulate IGF-I and insulin signaling, a constitutively active FOXO1 was overexpressed in cardiomyocytes. |
| 6084 | 17210752 | The abundance of insulin receptor and IGF-I receptor was significantly upregulated in the cells overexpressing active FOXO1, accompanied by increased receptor phosphorylation upon insulin/IGF-I stimulation. |
| 6085 | 17210752 | Interestingly, overexpression of constitutively active FOXO1 also led to activation of MEK and Akt phosphorylation. |
| 6086 | 17210752 | IGF-I-stimulated MEK and Akt phosphorylation were augmented byoverexpression of constitutively active FOXO1. |
| 6087 | 17210752 | These findings indicate bidirectional regulation of insulin/IGF-I receptor signaling and FOXO1 in cardiomyocytes. |
| 6088 | 17210752 | FOXO1 may provide feedback control through upregulation of insulin and IGF-I receptor signaling. |
| 6089 | 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. |
| 6090 | 17222824 | Ligand-activated insulin receptor (IR) attracts and phosphorylates various substrates such as insulin receptor substrates 1-4 (IRS) and Shc. |
| 6091 | 17222824 | We found that the extent of receptor tyrosine phosphorylation positively correlates with binding affinity towards IRS1/2 but not towards Shc. |
| 6092 | 17222824 | Moreover, overexpression of IRS1 or IRS2 but not of Shc increased IR tyrosine phosphorylation in a dose-dependent manner, also independent of insulin. |
| 6093 | 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. |
| 6094 | 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. |
| 6095 | 17222824 | IRS1 and IRS2 could therefore target the activated IR to different cellular compartments. |
| 6096 | 17222824 | Overexpression of IRS1 and IRS2 inhibited insulin-stimulated activation of the MAP kinases Erk1/2 while it increased/induced activation of Akt/PKB. |
| 6097 | 17222824 | Finally, overexpression of IRS1 and IRS2 but not of Shc induced DNA synthesis in starved CHO-IR cells independent of exogenous growth factors. |
| 6098 | 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. |
| 6099 | 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. |
| 6100 | 17222824 | Ligand-activated insulin receptor (IR) attracts and phosphorylates various substrates such as insulin receptor substrates 1-4 (IRS) and Shc. |
| 6101 | 17222824 | We found that the extent of receptor tyrosine phosphorylation positively correlates with binding affinity towards IRS1/2 but not towards Shc. |
| 6102 | 17222824 | Moreover, overexpression of IRS1 or IRS2 but not of Shc increased IR tyrosine phosphorylation in a dose-dependent manner, also independent of insulin. |
| 6103 | 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. |
| 6104 | 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. |
| 6105 | 17222824 | IRS1 and IRS2 could therefore target the activated IR to different cellular compartments. |
| 6106 | 17222824 | Overexpression of IRS1 and IRS2 inhibited insulin-stimulated activation of the MAP kinases Erk1/2 while it increased/induced activation of Akt/PKB. |
| 6107 | 17222824 | Finally, overexpression of IRS1 and IRS2 but not of Shc induced DNA synthesis in starved CHO-IR cells independent of exogenous growth factors. |
| 6108 | 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. |
| 6109 | 17223256 | Regulation of SOCS-3 expression by leptin and its co-localization with insulin receptor in rat skeletal muscle cells. |
| 6110 | 17223256 | Induction of suppressor of cytokine-3 (SOCS-3) protein expression has been implicated as a possible mechanism of leptin-induced insulin resistance. |
| 6111 | 17223256 | Here, we show that treatment of rat skeletal muscle cells with leptin activated the SOCS-3 gene promoter and caused a time-dependent increase in both SOCS-3 mRNA and protein content. |
| 6112 | 17223256 | Confocal microscopy demonstrated increased co-localization of SOCS-3 with insulin receptor in leptin-treated cells and we confirmed a direct interaction between these two proteins by showing increased coimmunoprecipitation of SOCS-3 and insulin receptor after exposure of cells to leptin. |
| 6113 | 17223256 | However, the expected functional consequences were not observed, as we saw no change in basal or insulin-stimulated glucose uptake and phosphorylation of GSK3beta, Akt (T308 and S473) or ERK1/2. |
| 6114 | 17223256 | In summary, leptin induced SOCS-3 expression and its association with the insulin receptor in rat skeletal muscle cells but functional significance of this increase was not apparent upon measuring glucose uptake. |
| 6115 | 17223256 | Regulation of SOCS-3 expression by leptin and its co-localization with insulin receptor in rat skeletal muscle cells. |
| 6116 | 17223256 | Induction of suppressor of cytokine-3 (SOCS-3) protein expression has been implicated as a possible mechanism of leptin-induced insulin resistance. |
| 6117 | 17223256 | Here, we show that treatment of rat skeletal muscle cells with leptin activated the SOCS-3 gene promoter and caused a time-dependent increase in both SOCS-3 mRNA and protein content. |
| 6118 | 17223256 | Confocal microscopy demonstrated increased co-localization of SOCS-3 with insulin receptor in leptin-treated cells and we confirmed a direct interaction between these two proteins by showing increased coimmunoprecipitation of SOCS-3 and insulin receptor after exposure of cells to leptin. |
| 6119 | 17223256 | However, the expected functional consequences were not observed, as we saw no change in basal or insulin-stimulated glucose uptake and phosphorylation of GSK3beta, Akt (T308 and S473) or ERK1/2. |
| 6120 | 17223256 | In summary, leptin induced SOCS-3 expression and its association with the insulin receptor in rat skeletal muscle cells but functional significance of this increase was not apparent upon measuring glucose uptake. |
| 6121 | 17223256 | Regulation of SOCS-3 expression by leptin and its co-localization with insulin receptor in rat skeletal muscle cells. |
| 6122 | 17223256 | Induction of suppressor of cytokine-3 (SOCS-3) protein expression has been implicated as a possible mechanism of leptin-induced insulin resistance. |
| 6123 | 17223256 | Here, we show that treatment of rat skeletal muscle cells with leptin activated the SOCS-3 gene promoter and caused a time-dependent increase in both SOCS-3 mRNA and protein content. |
| 6124 | 17223256 | Confocal microscopy demonstrated increased co-localization of SOCS-3 with insulin receptor in leptin-treated cells and we confirmed a direct interaction between these two proteins by showing increased coimmunoprecipitation of SOCS-3 and insulin receptor after exposure of cells to leptin. |
| 6125 | 17223256 | However, the expected functional consequences were not observed, as we saw no change in basal or insulin-stimulated glucose uptake and phosphorylation of GSK3beta, Akt (T308 and S473) or ERK1/2. |
| 6126 | 17223256 | In summary, leptin induced SOCS-3 expression and its association with the insulin receptor in rat skeletal muscle cells but functional significance of this increase was not apparent upon measuring glucose uptake. |
| 6127 | 17229938 | Defective insulin and acetylcholine induction of endothelial cell-nitric oxide synthase through insulin receptor substrate/Akt signaling pathway in aorta of obese rats. |
| 6128 | 17229938 | Upon JAK2 activation, tyrosine phosphorylation of insulin receptor substrate (IRS)-1 is detected. |
| 6129 | 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. |
| 6130 | 17229938 | The pharmacological blockade of JAK2 or PI 3-kinase reduced ACh-stimulated eNOS phosphorylation, NOS activity, and aorta relaxation. |
| 6131 | 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. |
| 6132 | 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. |
| 6133 | 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. |
| 6134 | 17229938 | Defective insulin and acetylcholine induction of endothelial cell-nitric oxide synthase through insulin receptor substrate/Akt signaling pathway in aorta of obese rats. |
| 6135 | 17229938 | Upon JAK2 activation, tyrosine phosphorylation of insulin receptor substrate (IRS)-1 is detected. |
| 6136 | 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. |
| 6137 | 17229938 | The pharmacological blockade of JAK2 or PI 3-kinase reduced ACh-stimulated eNOS phosphorylation, NOS activity, and aorta relaxation. |
| 6138 | 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. |
| 6139 | 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. |
| 6140 | 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. |
| 6141 | 17237715 | Insulin-like growth factor binding protein-3 induces insulin resistance in adipocytes in vitro and in rats in vivo. |
| 6142 | 17237715 | Insulin-like growth factor binding protein (IGFBP)-3 binds to IGF and modulates their actions and also possesses intrinsic activities. |
| 6143 | 17237715 | We investigated its effects on insulin action and found that when IGFBP-3 was added to fully differentiated 3T3-L1 adipocytes in culture, insulin-stimulated glucose transport was significantly inhibited to 60% of control in a time- and dose-dependent manner. |
| 6144 | 17237715 | Tumor necrosis factor (TNF)-alpha treatment also inhibited glucose transport to the same degree as IGFBP-3 and, in addition, increased IGFBP-3 levels 3-fold. |
| 6145 | 17237715 | Co-treatment with TNF-alpha and IGFBP-3 antisense partially prevented the inhibitory effect of TNF-alpha on glucose transport, indicating a role for IGFBP-3 in cytokine-induced insulin resistance. |
| 6146 | 17237715 | Insulin-stimulated phosphorylation of the insulin receptor was markedly decreased by IGFBP-3 treatment. |
| 6147 | 17237715 | IGFBP-3 treatment suppressed adiponectin expression in 3T3-L1 adipocytes. |
| 6148 | 17237715 | These in vitro and in vivo findings demonstrate that IGFBP-3 has potent insulin-antagonizing capability and suggest a role for IGFBP-3 in cytokine-induced insulin resistance and other mechanisms involved in the development of type-2 diabetes. |
| 6149 | 17259384 | Ceramide- and oxidant-induced insulin resistance involve loss of insulin-dependent Rac-activation and actin remodeling in muscle cells. |
| 6150 | 17259384 | In muscle cells, insulin elicits recruitment of the glucose transporter GLUT4 to the plasma membrane. |
| 6151 | 17259384 | This process engages sequential signaling from insulin receptor substrate (IRS)-1 to phosphatidylinositol (PI) 3-kinase and the serine/threonine kinase Akt. |
| 6152 | 17259384 | GLUT4 translocation also requires an Akt-independent but PI 3-kinase-and Rac-dependent remodeling of filamentous actin. |
| 6153 | 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. |
| 6154 | 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. |
| 6155 | 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. |
| 6156 | 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. |
| 6157 | 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. |
| 6158 | 17259385 | Protein-tyrosine phosphatase 1B-deficient myocytes show increased insulin sensitivity and protection against tumor necrosis factor-alpha-induced insulin resistance. |
| 6159 | 17259385 | Protein-tyrosine phosphatase (PTP)1B is a negative regulator of insulin signaling and a therapeutic target for type 2 diabetes. |
| 6160 | 17259385 | In this study, we have assessed the role of PTP1B in the insulin sensitivity of skeletal muscle under physiological and insulin-resistant conditions. |
| 6161 | 17259385 | PTP1B(-/-) myocytes showed enhanced insulin-dependent activation of insulin receptor autophosphorylation and downstream signaling (tyrosine phosphorylation of insulin receptor substrate [IRS]-1 and IRS-2, activation of phosphatidylinositol 3-kinase, and serine phosphorylation of AKT), compared with wild-type cells. |
| 6162 | 17259385 | Accordingly, PTP1B(-/-) myocytes displayed higher insulin-dependent stimulation of glucose uptake and GLUT4 translocation to the plasma membrane than wild-type cells. |
| 6163 | 17259385 | Treatment with tumor necrosis factor-alpha (TNF-alpha) induced insulin resistance on glucose uptake, impaired insulin signaling, and increased PTP1B activity in wild-type cells. |
| 6164 | 17259385 | Conversely, the lack of PTP1B confers protection against insulin resistance by TNF-alpha in myocyte cell lines and in adult male mice. |
| 6165 | 17259385 | Wild-type mice treated with TNF-alpha developed a pronounced hyperglycemia along the glucose tolerance test, accompanied by an impaired insulin signaling and increased PTP1B activity in muscle. |
| 6166 | 17259385 | However, mice lacking PTP1B maintained a rapid clearance of glucose and insulin sensitivity and displayed normal muscle insulin signaling regardless the presence of TNF-alpha. |
| 6167 | 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. |
| 6168 | 17259395 | These results demonstrate the feasibility of insulin-like regulation in the complete absence of insulin and downstream of the insulin receptor. |
| 6169 | 17272402 | Tissue kallikrein reverses insulin resistance and attenuates nephropathy in diabetic rats by activation of phosphatidylinositol 3-kinase/protein kinase B and adenosine 5'-monophosphate-activated protein kinase signaling pathways. |
| 6170 | 17272402 | We previously reported that iv delivery of the human tissue kallikrein (HK) gene reduced blood pressure and plasma insulin levels in fructose-induced hypertensive rats with insulin resistance. |
| 6171 | 17272402 | The expression of phosphatidylinositol 3-kinase p110 catalytic subunit and the levels of phosphorylation at residue Thr-308 of Akt, insulin receptor B, and AMP-activated protein kinases were significantly decreased in organs from diabetic animals. |
| 6172 | 17292733 | Increased hepatic expression of ganglioside-specific sialidase, NEU3, improves insulin sensitivity and glucose tolerance in mice. |
| 6173 | 17292733 | We previously reported that mice overexpressing NEU3 mainly in muscles developed severe insulin-resistant diabetes. |
| 6174 | 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. |
| 6175 | 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. |
| 6176 | 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. |
| 6177 | 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. |
| 6178 | 17292733 | Insulin-stimulated tyrosine phosphorylations of the insulin receptor were increased in adipose tissues of NEU3 mice. |
| 6179 | 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. |
| 6180 | 17292733 | Our findings also provide further evidence that NEU3 is an important regulator of insulin sensitivity and glucose tolerance. |
| 6181 | 17299086 | Analysis of compensatory beta-cell response in mice with combined mutations of Insr and Irs2. |
| 6182 | 17299086 | To analyze how these two variables contribute to the progressive deterioration of metabolic control seen in diabetes, we asked whether mice with impaired beta-cell growth due to Irs2 ablation would be able to mount a compensatory response in the background of insulin resistance caused by Insr haploinsufficiency. |
| 6183 | 17299086 | As previously reported, approximately 70% of mice with combined Insr and Irs2 mutations developed diabetes as a consequence of markedly decreased beta-cell mass. |
| 6184 | 17299086 | Analysis of compensatory beta-cell response in mice with combined mutations of Insr and Irs2. |
| 6185 | 17299086 | To analyze how these two variables contribute to the progressive deterioration of metabolic control seen in diabetes, we asked whether mice with impaired beta-cell growth due to Irs2 ablation would be able to mount a compensatory response in the background of insulin resistance caused by Insr haploinsufficiency. |
| 6186 | 17299086 | As previously reported, approximately 70% of mice with combined Insr and Irs2 mutations developed diabetes as a consequence of markedly decreased beta-cell mass. |
| 6187 | 17299086 | Analysis of compensatory beta-cell response in mice with combined mutations of Insr and Irs2. |
| 6188 | 17299086 | To analyze how these two variables contribute to the progressive deterioration of metabolic control seen in diabetes, we asked whether mice with impaired beta-cell growth due to Irs2 ablation would be able to mount a compensatory response in the background of insulin resistance caused by Insr haploinsufficiency. |
| 6189 | 17299086 | As previously reported, approximately 70% of mice with combined Insr and Irs2 mutations developed diabetes as a consequence of markedly decreased beta-cell mass. |
| 6190 | 17307054 | The downregulation of the antiatherogenic phosphatidylinositol-3-kinase-mediated insulin receptor-signaling pathway, and maintained activity of the proatherogenic mitogenic-activated protein kinase pathway in insulin-resistant states, leads to accelerated atherosclerosis. |
| 6191 | 17315038 | Mechanisms of disease: metabolic effects of growth hormone and insulin-like growth factor 1. |
| 6192 | 17315038 | Insulin-like growth factor (IGF) 1 is a member of a family that is involved in growth, development, cell differentiation, and metabolism. |
| 6193 | 17315038 | IGF1, IGF2 and insulin act primarily through tyrosine-kinase-linked receptors--the IGF1 receptor (IGF1R) and insulin receptor (IR). |
| 6194 | 17315038 | The IGF1R binds IGF1 and IGF2 with high affinity and the IR binds insulin with high affinity; however, since both receptors share a high degree of structural and functional homology, the IGF1R can bind insulin and the IR can bind the IGFs with reduced affinity. |
| 6195 | 17315038 | The IGF2 receptor is a scavenger receptor, and is, therefore, not involved in mediation of growth or metabolic effects of the IGF family and will not be discussed in the current article. |
| 6196 | 17315038 | For example, excess growth hormone causes insulin resistance and hyperglycemia, whereas IGF1 has insulin-like effects that reduce blood glucose levels and has been used experimentally to treat both type 1 and type 2 diabetes. |
| 6197 | 17316549 | Cinnamon extract and polyphenols affect the expression of tristetraprolin, insulin receptor, and glucose transporter 4 in mouse 3T3-L1 adipocytes. |
| 6198 | 17316549 | The objective of this study was to investigate the effects of cinnamon on the protein and mRNA levels of insulin receptor (IR), glucose transporter 4 (GLUT4), and tristetraprolin (TTP/ZFP36) in mouse 3T3-L1 adipocytes. |
| 6199 | 17316549 | Cinnamon extract and polyphenols affect the expression of tristetraprolin, insulin receptor, and glucose transporter 4 in mouse 3T3-L1 adipocytes. |
| 6200 | 17316549 | The objective of this study was to investigate the effects of cinnamon on the protein and mRNA levels of insulin receptor (IR), glucose transporter 4 (GLUT4), and tristetraprolin (TTP/ZFP36) in mouse 3T3-L1 adipocytes. |
| 6201 | 17325257 | Paradoxical elevation of high-molecular weight adiponectin in acquired extreme insulin resistance due to insulin receptor antibodies. |
| 6202 | 17325257 | Total plasma adiponectin and high-molecular weight (HMW) polymeric adiponectin are strongly positively correlated with insulin sensitivity. |
| 6203 | 17325257 | This implies either that the insulin receptor has a critical physiological role in controlling adiponectin production and/or clearance or that constitutive insulin receptor dysfunction influences adiponectin levels through developmental effects. |
| 6204 | 17325257 | The aim of the current study was to distinguish between these possibilities using a human model of reversible antibody-mediated insulin receptor dysfunction and to refine the previous observations by determining adiponectin complex distribution. |
| 6205 | 17325257 | Cross-sectional and longitudinal determination of fasting plasma adiponectin and adiponectin complex distribution was undertaken in patients with extreme insulin resistance due to insulin receptor mutations, anti-insulin receptor antibodies (type B insulin resistance), or an undefined cause. |
| 6206 | 17325257 | Despite extreme insulin resistance, patients with type B insulin resistance (all women; mean age 42 years [range 12-54]) had dramatically elevated total plasma adiponectin compared with the general population (mean 43.0 mg/l [range 31.3-54.2] vs. 8.9 mg/l [1.5-28.5 for BMI <25 kg/m(2)]), which was accounted for largely by HMW polymers. |
| 6207 | 17325257 | Although the well-established inverse relationship between plasma insulin and adiponectin levels may, in part, reflect positive effects of adiponectin on insulin sensitivity, these data suggest that the magnitude of the effect of insulin action on adiponectin levels may have been underestimated. |
| 6208 | 17325257 | Paradoxical elevation of high-molecular weight adiponectin in acquired extreme insulin resistance due to insulin receptor antibodies. |
| 6209 | 17325257 | Total plasma adiponectin and high-molecular weight (HMW) polymeric adiponectin are strongly positively correlated with insulin sensitivity. |
| 6210 | 17325257 | This implies either that the insulin receptor has a critical physiological role in controlling adiponectin production and/or clearance or that constitutive insulin receptor dysfunction influences adiponectin levels through developmental effects. |
| 6211 | 17325257 | The aim of the current study was to distinguish between these possibilities using a human model of reversible antibody-mediated insulin receptor dysfunction and to refine the previous observations by determining adiponectin complex distribution. |
| 6212 | 17325257 | Cross-sectional and longitudinal determination of fasting plasma adiponectin and adiponectin complex distribution was undertaken in patients with extreme insulin resistance due to insulin receptor mutations, anti-insulin receptor antibodies (type B insulin resistance), or an undefined cause. |
| 6213 | 17325257 | Despite extreme insulin resistance, patients with type B insulin resistance (all women; mean age 42 years [range 12-54]) had dramatically elevated total plasma adiponectin compared with the general population (mean 43.0 mg/l [range 31.3-54.2] vs. 8.9 mg/l [1.5-28.5 for BMI <25 kg/m(2)]), which was accounted for largely by HMW polymers. |
| 6214 | 17325257 | Although the well-established inverse relationship between plasma insulin and adiponectin levels may, in part, reflect positive effects of adiponectin on insulin sensitivity, these data suggest that the magnitude of the effect of insulin action on adiponectin levels may have been underestimated. |
| 6215 | 17325257 | Paradoxical elevation of high-molecular weight adiponectin in acquired extreme insulin resistance due to insulin receptor antibodies. |
| 6216 | 17325257 | Total plasma adiponectin and high-molecular weight (HMW) polymeric adiponectin are strongly positively correlated with insulin sensitivity. |
| 6217 | 17325257 | This implies either that the insulin receptor has a critical physiological role in controlling adiponectin production and/or clearance or that constitutive insulin receptor dysfunction influences adiponectin levels through developmental effects. |
| 6218 | 17325257 | The aim of the current study was to distinguish between these possibilities using a human model of reversible antibody-mediated insulin receptor dysfunction and to refine the previous observations by determining adiponectin complex distribution. |
| 6219 | 17325257 | Cross-sectional and longitudinal determination of fasting plasma adiponectin and adiponectin complex distribution was undertaken in patients with extreme insulin resistance due to insulin receptor mutations, anti-insulin receptor antibodies (type B insulin resistance), or an undefined cause. |
| 6220 | 17325257 | Despite extreme insulin resistance, patients with type B insulin resistance (all women; mean age 42 years [range 12-54]) had dramatically elevated total plasma adiponectin compared with the general population (mean 43.0 mg/l [range 31.3-54.2] vs. 8.9 mg/l [1.5-28.5 for BMI <25 kg/m(2)]), which was accounted for largely by HMW polymers. |
| 6221 | 17325257 | Although the well-established inverse relationship between plasma insulin and adiponectin levels may, in part, reflect positive effects of adiponectin on insulin sensitivity, these data suggest that the magnitude of the effect of insulin action on adiponectin levels may have been underestimated. |
| 6222 | 17325257 | Paradoxical elevation of high-molecular weight adiponectin in acquired extreme insulin resistance due to insulin receptor antibodies. |
| 6223 | 17325257 | Total plasma adiponectin and high-molecular weight (HMW) polymeric adiponectin are strongly positively correlated with insulin sensitivity. |
| 6224 | 17325257 | This implies either that the insulin receptor has a critical physiological role in controlling adiponectin production and/or clearance or that constitutive insulin receptor dysfunction influences adiponectin levels through developmental effects. |
| 6225 | 17325257 | The aim of the current study was to distinguish between these possibilities using a human model of reversible antibody-mediated insulin receptor dysfunction and to refine the previous observations by determining adiponectin complex distribution. |
| 6226 | 17325257 | Cross-sectional and longitudinal determination of fasting plasma adiponectin and adiponectin complex distribution was undertaken in patients with extreme insulin resistance due to insulin receptor mutations, anti-insulin receptor antibodies (type B insulin resistance), or an undefined cause. |
| 6227 | 17325257 | Despite extreme insulin resistance, patients with type B insulin resistance (all women; mean age 42 years [range 12-54]) had dramatically elevated total plasma adiponectin compared with the general population (mean 43.0 mg/l [range 31.3-54.2] vs. 8.9 mg/l [1.5-28.5 for BMI <25 kg/m(2)]), which was accounted for largely by HMW polymers. |
| 6228 | 17325257 | Although the well-established inverse relationship between plasma insulin and adiponectin levels may, in part, reflect positive effects of adiponectin on insulin sensitivity, these data suggest that the magnitude of the effect of insulin action on adiponectin levels may have been underestimated. |
| 6229 | 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. |
| 6230 | 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). |
| 6231 | 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. |
| 6232 | 17328681 | AP20187-mediated activation of a chimeric insulin receptor results in insulin-like actions in skeletal muscle and liver of diabetic mice. |
| 6233 | 17328681 | Systemic AP20187 administration results in time-dependent LFv2IRE tyrosine phosphorylation and activation of the insulin signaling pathway in both liver and muscle of AAV-treated NOD mice. |
| 6234 | 17340225 | Insulin-like effects of visfatin on human osteoblasts. |
| 6235 | 17340225 | Visfatin binds to and activates the insulin receptor (IR), thereby exerting insulin-mimetic effects in various cell lines. |
| 6236 | 17340225 | The expression and tyrosine phosphorylation of IR, IR substrate-1 (IRS-1), and IRS-2 were determined by immunoprecipitation and immunoblotting. |
| 6237 | 17340225 | Real-time quantitative reverse-transcription polymerase chain reaction (PCR) was used for determining alkaline phosphatase (ALP), osteocalcin, and type I collagen mRNA expression. |
| 6238 | 17340225 | Enzyme-linked immunosorbent assay and radioimmunoassay were used for measuring ALP activity, osteocalcin secretion, and type I collagen production. |
| 6239 | 17340225 | We found that visfatin induced tyrosine phosphorylation of IR, IRS-1, and IRS-2. |
| 6240 | 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. |
| 6241 | 17340225 | We also unexpectedly found that visfatin downregulated osteocalcin secretion from human osteoblast-like cells. |
| 6242 | 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. |
| 6243 | 17346204 | This article presents the evidence about FFA-induced insulin secretion in vitro and in vivo, recent advances in the molecular mechanism of FFA action in beta-cells, a role of GPR40 in the development of insulin resistance, and the negative feedback loop of the insulin receptor signal pathway. |
| 6244 | 17347799 | In most models of insulin resistance, there is evidence that this decrement in insulin signaling begins with either the activation or substrate kinase activity of the insulin receptor (IR), which is the only component of the pathway that is unique to insulin action. |
| 6245 | 17353188 | Reduction of LMW-PTP expression with the ASO in cultured mouse hepatocytes and in liver and fat tissues of diet-induced obese (DIO) mice and ob/ob mice led to increased phosphorylation and activity of key insulin signaling intermediates, including insulin receptor-beta subunit, phosphatidylinositol 3-kinase, and Akt in response to insulin stimulation. |
| 6246 | 17363744 | Growth hormone regulation of p85alpha expression and phosphoinositide 3-kinase activity in adipose tissue: mechanism for growth hormone-mediated insulin resistance. |
| 6247 | 17363744 | Phosphoinositide (PI) 3-kinase is involved in insulin-mediated effects on glucose uptake, lipid deposition, and adiponectin secretion from adipocytes. |
| 6248 | 17363744 | Genetic disruption of the p85alpha regulatory subunit of PI 3-kinase increases insulin sensitivity, whereas elevated p85alpha levels are associated with insulin resistance through PI 3-kinase-dependent and -independent mechanisms. |
| 6249 | 17363744 | The objective of this study was to assess the role of the p85alpha subunit of PI 3-kinase and PI 3-kinase signaling in GH-mediated insulin resistance in adipose tissue. |
| 6250 | 17363744 | To do this, p85alpha mRNA and protein expression and insulin receptor substrate (IRS)-1-associated PI 3-kinase activity were measured in white adipose tissue (WAT) of mice with GH excess, deficiency, and sufficiency. |
| 6251 | 17363744 | In conclusion, GH regulates p85alpha expression and PI 3-kinase activity in WAT and provides a potential explanation for 1) the insulin hypersensitivity and associated obesity and hyperadiponectinemia of GH-deficient mice and 2) the insulin resistance and associated reduced fat mass and hypoadiponectinemia of mice with GH excess. |
| 6252 | 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. |
| 6253 | 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. |
| 6254 | 17435330 | Free fatty acids are known to play a key role in promoting loss of insulin sensitivity,thereby causing insulin resistance and type 2 diabetes.However,the underlying mechanism involved is still unclear.In searching for the cause of the mechanism,it has been found that palmitate inhibits insulin receptor (IR)gene expression,leading to a reduced amount of IR protein in insulin target cells. |
| 6255 | 17445543 | We have documented, for the first time, regression of AN in temporal association with disappearance of circulating anti-insulin receptor autoantibodies and achievement of euglycemia in a patient with type B insulin resistance. |
| 6256 | 17446186 | Tumor necrosis factor-alpha induces insulin resistance in endothelial cells via a p38 mitogen-activated protein kinase-dependent pathway. |
| 6257 | 17446186 | Systemic infusion of TNF-alpha abrogates insulin's action to enhance skeletal muscle microvascular perfusion. |
| 6258 | 17446186 | In skeletal muscle TNF-alpha induces insulin resistance via the p38 MAPK pathway. |
| 6259 | 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. |
| 6260 | 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. |
| 6261 | 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. |
| 6262 | 17446186 | TNF-alpha also potently stimulated the phosphorylation of ERK1/2 and AMPK. |
| 6263 | 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. |
| 6264 | 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. |
| 6265 | 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. |
| 6266 | 17467844 | These insulin actions were modestly inhibited by the application of LY294002, the phosphatidylinositol 3-kinase (PI3-kinase) inhibitor, but not completely, suggesting that another mechanism is also involved. |
| 6267 | 17467844 | These results may suggest that the extent of AMPK activation may be a tool for insulin receptors to monitor blood glucose level, with which insulin-induced insulin receptor activation determines the way to go negatively or positively toward [Ca(2+)](c). |
| 6268 | 17469039 | At a molecular level, insulin resistance involves defects of insulin signalling such as reduced insulin receptor tyrosine kinase activity and reduced post-receptor phosphorylation steps that impinge on metabolic and vascular effects of insulin. |
| 6269 | 17475934 | Adiponectin resistance exacerbates insulin resistance in insulin receptor transgenic/knockout mice. |
| 6270 | 17487263 | Effect of type-1 diabetes mellitus on the regulation of insulin and endothelin-1 receptors in rat hearts. |
| 6271 | 17487263 | This project assesses the treatment role with insulin and (or) angiotensin II receptor subtype-1 (AT1-R) blocker (ARB) on insulin receptor and endothelin-1 receptor subtype (ETA-R and ETB-R) regulation in rat hearts suffering from insulin-dependent diabetes mellitus (IDDM). |
| 6272 | 17487263 | However, ETB-R expression was significantly reduced in the diabetic group treated with both insulin and an ARB. |
| 6273 | 17487263 | The changes in the expression of the insulin, the ETA-Rs, and the ETB-Rs at the various sites of the myocardium and the effect of both insulin treatment and blockade of the AT1-R explain the new benefits related to the halting of myocardial remodeling in IDDM rats. |
| 6274 | 17496362 | Between the plasma membrane insulin receptor and the intracellularly sequestered insulin-responsive glucose transporter GLUT4, many events participate in the transduction of the insulin signal. |
| 6275 | 17496362 | In particular, we identify signaling connections spanning the insulin receptor and GLUT4. |
| 6276 | 17496362 | Between the plasma membrane insulin receptor and the intracellularly sequestered insulin-responsive glucose transporter GLUT4, many events participate in the transduction of the insulin signal. |
| 6277 | 17496362 | In particular, we identify signaling connections spanning the insulin receptor and GLUT4. |
| 6278 | 17509747 | Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of the insulin receptor signal transduction pathway. |
| 6279 | 17509747 | The deletion of three possible Sp1 sites in the promoter region of PTP1B significantly reduced the basal promoter activity and transactivation by D-glucose. |
| 6280 | 17509747 | Our data suggested that glucose enhanced PTP1B transcription through Sp1 activation by PKC. |
| 6281 | 17550779 | Insulin action in AgRP-expressing neurons is required for suppression of hepatic glucose production. |
| 6282 | 17550779 | To define the insulin-responsive neurons that mediate these effects, we generated mice with selective inactivation of the insulin receptor (IR) in either pro-opiomelanocortin (POMC)- or agouti-related peptide (AgRP)-expressing neurons of the arcuate nucleus of the hypothalamus. |
| 6283 | 17550779 | While neither POMC- nor AgRP-restricted IR knockout mice exhibited altered energy homeostasis, insulin failed to normally suppress hepatic glucose production during euglycemic-hyperinsulinemic clamps in AgRP-IR knockout (IR(DeltaAgRP)) mice. |
| 6284 | 17550779 | These mice also exhibited reduced insulin-stimulated hepatic interleukin-6 expression and increased hepatic expression of glucose-6-phosphatase. |
| 6285 | 17550779 | These results directly demonstrate that insulin action in POMC and AgRP cells is not required for steady-state regulation of food intake and body weight. |
| 6286 | 17550779 | However, insulin action specifically in AgRP-expressing neurons does play a critical role in controlling hepatic glucose production and may provide a target for the treatment of insulin resistance in type 2 diabetes. |
| 6287 | 17553792 | Disruption of the insulin-like growth factor type 1 receptor in osteoblasts enhances insulin signaling and action. |
| 6288 | 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. |
| 6289 | 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). |
| 6290 | 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. |
| 6291 | 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. |
| 6292 | 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. |
| 6293 | 17553792 | Treatment of osteoblasts with insulin induced Glut-1 mRNA, increased 2-[1,2-(3)H]-deoxy-d-glucose uptake, and enhanced proliferation. |
| 6294 | 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. |
| 6295 | 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. |
| 6296 | 17556363 | High circulating leptin receptors with normal leptin sensitivity in liver-specific insulin receptor knock-out (LIRKO) mice. |
| 6297 | 17556363 | Direct control of leptin receptor expression by insulin could also be demonstrated in isolated hepatocytes from normal mice. |
| 6298 | 17556363 | Despite the markedly increased levels of leptin receptor in their circulation, LIRKO mice exhibit normal or even enhanced leptin sensitivity, as assessed by their physiological and molecular responses to exogenous leptin administration and their lower base-line hypothalamic levels of SOCS3 mRNA. |
| 6299 | 17556363 | Thus, insulin signaling in the liver plays an important role in control of leptin receptor expression and shedding. |
| 6300 | 17556363 | In this manner, insulin signaling in liver plays an important role in leptin homeostasis and fine modulation of leptin action. |
| 6301 | 17567459 | In muscle, lack of exercise, a fat-rich diet, a polymorphism in peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1), and possibly age-related mitochondrial DNA (mtDNA) mutations may variously combine their effects to decrease PGC-1 expression, mitochondrial biogenesis and fat oxidation. |
| 6302 | 17567459 | The activation of Jun N-terminal kinase and protein kinase C-theta triggers the serine phosphorylation and inactivation of the insulin receptor substrate, and hampers the insulin-mediated translocation of glucose transporter-4 to the plasma membrane. |
| 6303 | 17567459 | Eventually, however, increased uncoupling protein-2 expression and possibly acquired mtDNA mutations in pancreatic beta-cells can blunt glucose-mediated adenosine triphosphate (ATP) formation and insulin secretion, to cause diabetes in some patients. |
| 6304 | 17575262 | Retinol-binding protein-4 attenuates insulin-induced phosphorylation of IRS1 and ERK1/2 in primary human adipocytes. |
| 6305 | 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. |
| 6306 | 17575262 | However, little is known about how RBP4 affects insulin signaling. |
| 6307 | 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. |
| 6308 | 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. |
| 6309 | 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. |
| 6310 | 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. |
| 6311 | 17575262 | However, the sensitivity to insulin for downstream signaling to control of protein kinase B and glucose uptake was not affected by RBP4. |
| 6312 | 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. |
| 6313 | 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. |
| 6314 | 17577098 | Effects of PPAR-gamma knock-down and hyperglycemia on insulin signaling in vascular smooth muscle cells from hypertensive rats. |
| 6315 | 17577098 | Peroxisome proliferator-activated receptor (PPAR)-gamma, a target in the treatment of diabetes, improves insulin sensitivity and exerts cardiovascular protective effects by mechanisms that are not completely elucidated. |
| 6316 | 17577098 | To investigate underlying molecular mechanisms responsible for PPAR-gamma-associated vascular insulin signaling in hypertension, we tested whether PPAR-gamma downregulation in vascular smooth muscle cells (VSMC) from WKY and SHRSP rats would decrease insulin signaling and glucose uptake and whether this response would be worsened by hyperglycemia to a greater extent in VSMC of hypertensive origin. |
| 6317 | 17577098 | Passaged mesenteric artery VSMC grown in euglycemic (5.5 mmol/L) or hyperglycemic media (25.0 mmol/L) were treated with PPAR-gamma-siRNA (5 nmol/L), PPAR-gamma antagonist (GW-9662, 10 micromol/L), or PPAR-gamma activator (rosiglitazone, 10 micromol/L) in the presence or absence of insulin (100 nmol/L). |
| 6318 | 17577098 | Immunoblotting revealed that hyperglycemia and PPAR-gamma inhibition significantly (P < 0.001) decreased insulin-stimulated insulin receptor (IR)-beta, Akt, and glycogen synthase kinase (GSK)-3beta phosphorylation, whereas phosphotyrosine phosphatase (PTP)-1B expression was increased in VSMC from both strains. |
| 6319 | 17577098 | Rosiglitazone tended to increase insulin-mediated IR-beta, Akt, and GSK-3beta phosphorylation in VSMC from both strains, whereas insulin-induced PTP-1B expression was reduced by hyperglycemia. |
| 6320 | 17577098 | Insulin-stimulated GLUT-4 expression and glucose transport were attenuated by hyperglycemia in both VSMC. |
| 6321 | 17577098 | These data suggest that PPAR-gamma inhibition results in decreased insulin signaling, particularly in SHR, in an IR-beta phosphorylation-dependent manner. |
| 6322 | 17581838 | Improvement of insulin sensitivity by antagonism of the renin-angiotensin system. |
| 6323 | 17581838 | Although the etiology of this skeletal muscle insulin resistance is multifactorial, there is accumulating evidence that one contributor is overactivity of the renin-angiotensin system (RAS). |
| 6324 | 17581838 | Evidence from animal model and cultured skeletal muscle cell line studies indicates ANG II can induce insulin resistance. |
| 6325 | 17581838 | Chronic ANG II infusion into an insulin-sensitive rat produces a markedly insulin-resistant state that is associated with a negative impact of ROS on the skeletal muscle glucose transport system. |
| 6326 | 17581838 | ANG II treatment of L6 myocytes causes impaired insulin receptor substrate (IRS)-1-dependent insulin signaling that is accompanied by augmentation of NADPH oxidase-mediated ROS production. |
| 6327 | 17581838 | The TG(mREN2)27 rat displays whole body and skeletal muscle insulin resistance that is associated with local oxidative stress and a significant reduction in the functionality of the insulin receptor (IR)/IRS-1-dependent insulin signaling. |
| 6328 | 17581838 | Treatment with a selective ANG II type 1 receptor antagonist leads to improvements in whole body insulin sensitivity, enhanced insulin-stimulated glucose transport in muscle, and reduced local oxidative stress. |
| 6329 | 17581838 | Improvement of insulin sensitivity by antagonism of the renin-angiotensin system. |
| 6330 | 17581838 | Although the etiology of this skeletal muscle insulin resistance is multifactorial, there is accumulating evidence that one contributor is overactivity of the renin-angiotensin system (RAS). |
| 6331 | 17581838 | Evidence from animal model and cultured skeletal muscle cell line studies indicates ANG II can induce insulin resistance. |
| 6332 | 17581838 | Chronic ANG II infusion into an insulin-sensitive rat produces a markedly insulin-resistant state that is associated with a negative impact of ROS on the skeletal muscle glucose transport system. |
| 6333 | 17581838 | ANG II treatment of L6 myocytes causes impaired insulin receptor substrate (IRS)-1-dependent insulin signaling that is accompanied by augmentation of NADPH oxidase-mediated ROS production. |
| 6334 | 17581838 | The TG(mREN2)27 rat displays whole body and skeletal muscle insulin resistance that is associated with local oxidative stress and a significant reduction in the functionality of the insulin receptor (IR)/IRS-1-dependent insulin signaling. |
| 6335 | 17581838 | Treatment with a selective ANG II type 1 receptor antagonist leads to improvements in whole body insulin sensitivity, enhanced insulin-stimulated glucose transport in muscle, and reduced local oxidative stress. |
| 6336 | 17597619 | Resistin down-regulates insulin receptor expression, and modulates cell viability in rodent pancreatic beta-cells. |
| 6337 | 17597619 | The adipokine resistin is known to induce insulin resistance in rodent tissues. |
| 6338 | 17597619 | This study investigated the effects of resistin on insulin secretion, insulin receptor expression and cell viability in pancreatic beta-cells. |
| 6339 | 17597619 | BTC-6 or BRIN-BD11 cells were treated for 24h with resistin, and insulin receptor expression, insulin secretion and cell viability were measured. |
| 6340 | 17597619 | Incubation with 40ng/ml resistin caused significant decreases in insulin receptor mRNA and protein expression, but did not affect insulin secretion. |
| 6341 | 17597619 | Resistin down-regulates insulin receptor expression, and modulates cell viability in rodent pancreatic beta-cells. |
| 6342 | 17597619 | The adipokine resistin is known to induce insulin resistance in rodent tissues. |
| 6343 | 17597619 | This study investigated the effects of resistin on insulin secretion, insulin receptor expression and cell viability in pancreatic beta-cells. |
| 6344 | 17597619 | BTC-6 or BRIN-BD11 cells were treated for 24h with resistin, and insulin receptor expression, insulin secretion and cell viability were measured. |
| 6345 | 17597619 | Incubation with 40ng/ml resistin caused significant decreases in insulin receptor mRNA and protein expression, but did not affect insulin secretion. |
| 6346 | 17597619 | Resistin down-regulates insulin receptor expression, and modulates cell viability in rodent pancreatic beta-cells. |
| 6347 | 17597619 | The adipokine resistin is known to induce insulin resistance in rodent tissues. |
| 6348 | 17597619 | This study investigated the effects of resistin on insulin secretion, insulin receptor expression and cell viability in pancreatic beta-cells. |
| 6349 | 17597619 | BTC-6 or BRIN-BD11 cells were treated for 24h with resistin, and insulin receptor expression, insulin secretion and cell viability were measured. |
| 6350 | 17597619 | Incubation with 40ng/ml resistin caused significant decreases in insulin receptor mRNA and protein expression, but did not affect insulin secretion. |
| 6351 | 17597619 | Resistin down-regulates insulin receptor expression, and modulates cell viability in rodent pancreatic beta-cells. |
| 6352 | 17597619 | The adipokine resistin is known to induce insulin resistance in rodent tissues. |
| 6353 | 17597619 | This study investigated the effects of resistin on insulin secretion, insulin receptor expression and cell viability in pancreatic beta-cells. |
| 6354 | 17597619 | BTC-6 or BRIN-BD11 cells were treated for 24h with resistin, and insulin receptor expression, insulin secretion and cell viability were measured. |
| 6355 | 17597619 | Incubation with 40ng/ml resistin caused significant decreases in insulin receptor mRNA and protein expression, but did not affect insulin secretion. |
| 6356 | 17629673 | At the cellular level, insulin stimulates glucose uptake by inducing the translocation of the glucose transporter 4 (GLUT4) from intracellular storage sites to the plasma membrane, where the transporter facilitates the diffusion of glucose into striated muscle and adipocytes. |
| 6357 | 17629673 | Although the immediate downstream molecules that function proximal to the activated insulin receptor have been relatively well-characterized, it remains unknown how the distal insulin-signaling cascade interfaces with and recruits GLUT4 to the cell surface. |
| 6358 | 17629673 | New biochemical assays and imaging techniques, however, have focused attention on the plasma membrane as a potential target of insulin action leading to GLUT4 translocation. |
| 6359 | 17629673 | Indeed, it now appears that insulin specifically regulates the docking and/or fusion of GLUT4-vesicles with the plasma membrane. |
| 6360 | 17629673 | Future work will focus on identifying the key insulin targets that regulate the GLUT4 docking/fusion processes. |
| 6361 | 17642483 | She had no insulin or insulin receptor antibodies but was positive for islet cell and glutamic acid decarboxylase (GAD) antibodies. |
| 6362 | 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). |
| 6363 | 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. |
| 6364 | 17674807 | Protein tyrosine phosphatase 1B (PTP 1B), a negative regulator of insulin receptor signaling system, has emerged as a highly validated, attractive target for the treatment of non-insulin dependent diabetes mellitus (NIDDM) and obesity. |
| 6365 | 17687071 | Here we report the identification of novel, small-molecule, insulin mimetics that activate the insulin receptor (IR) in vivo and in vitro, stimulate the Akt and extracellular signal-regulated kinase pathways downstream of the IR, and mimic the ability of insulin to stimulate glucose uptake, glycogen synthesis, and lipid synthesis in 3T3-L1 adipocytes. |
| 6366 | 17709881 | Both IGF-I and its receptor (IGF-IR) are specifically expressed in various cell types of the endocrine pancreas. |
| 6367 | 17709881 | For instance, combined inactivation of insulin receptor and IGF-IR or IGF-I and IGF-II genes in early embryos results in no defect on islet cell development; islet beta-cell-specific inactivation of IGF-IR gene causes no change in beta-cell mass; liver- and pancreatic-specific IGF-I gene deficiency (LID and PID mice) suggests that IGF-I exerts an inhibitory effect on islet cell growth albeit indirectly through controlling growth hormone release or expression of Reg family genes. |
| 6368 | 17709881 | Rather, it is probably a negative regulator through controlling growth hormone and insulin release, hyperglycemia, or Reg gene expression. |
| 6369 | 17767907 | Conversely, Foxo1 deletion in liver curtails excessive glucose production caused by generalized ablation of insulin receptors and prevents neonatal diabetes and hepatosteatosis in insulin receptor knockout mice. |
| 6370 | 17785505 | Glucose infusion causes insulin resistance in skeletal muscle of rats without changes in Akt and AS160 phosphorylation. |
| 6371 | 17785505 | Despite these changes, there was no decrease in the phosphorylation state of multiple insulin signaling intermediates [insulin receptor, Akt, AS160 (Akt substrate of 160 kDa), glycogen synthase kinase-3beta] over the same time course. |
| 6372 | 17785698 | IGF-I treatment of insulin resistance. |
| 6373 | 17785698 | Severe insulin resistance resulting from known or putative genetic defects affecting the insulin receptor or post-insulin receptor signalling represents a clinical spectrum ranging from Donohue's and Rabson-Mendenhall syndrome, where the genetic defect is identified, through to the milder phenotype of type A insulin resistance, where a genetic defect can only be detected in around 10% of cases. |
| 6374 | 17785698 | Recombinant human IGF-I alone or combined with its binding protein (IGFBP-3) provides an alternative therapy as IGF-I receptor shares structural and functional homology with the insulin receptor and recombinant human insulin-like growth factor I (rhIGF-I) therapy could improve glucose disposal by signalling through the IGF-I receptor, whilst reducing the adverse effects of high insulin concentrations. |
| 6375 | 17785698 | There are also data which indicate that IGF-I signalling through the IGF-I receptor on the pancreatic beta-cell may be important in maintaining insulin secretion. |
| 6376 | 17785698 | Continued study has confirmed efficacy of rhIGF-I when combined with IGFBP-3 in the treatment of Donohue's and type A insulin resistance subjects. |
| 6377 | 17785698 | IGF-I treatment of insulin resistance. |
| 6378 | 17785698 | Severe insulin resistance resulting from known or putative genetic defects affecting the insulin receptor or post-insulin receptor signalling represents a clinical spectrum ranging from Donohue's and Rabson-Mendenhall syndrome, where the genetic defect is identified, through to the milder phenotype of type A insulin resistance, where a genetic defect can only be detected in around 10% of cases. |
| 6379 | 17785698 | Recombinant human IGF-I alone or combined with its binding protein (IGFBP-3) provides an alternative therapy as IGF-I receptor shares structural and functional homology with the insulin receptor and recombinant human insulin-like growth factor I (rhIGF-I) therapy could improve glucose disposal by signalling through the IGF-I receptor, whilst reducing the adverse effects of high insulin concentrations. |
| 6380 | 17785698 | There are also data which indicate that IGF-I signalling through the IGF-I receptor on the pancreatic beta-cell may be important in maintaining insulin secretion. |
| 6381 | 17785698 | Continued study has confirmed efficacy of rhIGF-I when combined with IGFBP-3 in the treatment of Donohue's and type A insulin resistance subjects. |
| 6382 | 17889958 | AHSG/fetuin-A has diverse biological functions including regulation of calcium homeostasis and inhibition of insulin receptor tyrosine kinase activity. |
| 6383 | 17889958 | The overexpression of c-Fos/c-Jun significantly repressed transcriptional activity and a gel shift assay showed that the -799T DNA fragment had a greater affinity for transcription factor AP-1 than the -799A. |
| 6384 | 17889958 | In conclusion, SNP rs2248690 in the promoter region of the AHSG gene affects the AHSG gene transcription, possibly by producing different association with AP-1. |
| 6385 | 17904393 | IGF-I and INS receptor expression in the salivary glands of diabetic Nod mice submitted to long-term insulin treatment. |
| 6386 | 17904393 | This work aimed to characterize the IGF-I and INS receptor expression in the salivary glands of Nod mice, correlating to therapeutic effects of insulin treatment on these receptors. |
| 6387 | 17904393 | INS receptor expression was gradually decreased. |
| 6388 | 17904393 | It was concluded that not only was the IGF-I receptor expression affected by the diabetic state but also the INS receptor expression. |
| 6389 | 17904393 | IGF-I and INS receptor expression in the salivary glands of diabetic Nod mice submitted to long-term insulin treatment. |
| 6390 | 17904393 | This work aimed to characterize the IGF-I and INS receptor expression in the salivary glands of Nod mice, correlating to therapeutic effects of insulin treatment on these receptors. |
| 6391 | 17904393 | INS receptor expression was gradually decreased. |
| 6392 | 17904393 | It was concluded that not only was the IGF-I receptor expression affected by the diabetic state but also the INS receptor expression. |
| 6393 | 17904393 | IGF-I and INS receptor expression in the salivary glands of diabetic Nod mice submitted to long-term insulin treatment. |
| 6394 | 17904393 | This work aimed to characterize the IGF-I and INS receptor expression in the salivary glands of Nod mice, correlating to therapeutic effects of insulin treatment on these receptors. |
| 6395 | 17904393 | INS receptor expression was gradually decreased. |
| 6396 | 17904393 | It was concluded that not only was the IGF-I receptor expression affected by the diabetic state but also the INS receptor expression. |
| 6397 | 17904393 | IGF-I and INS receptor expression in the salivary glands of diabetic Nod mice submitted to long-term insulin treatment. |
| 6398 | 17904393 | This work aimed to characterize the IGF-I and INS receptor expression in the salivary glands of Nod mice, correlating to therapeutic effects of insulin treatment on these receptors. |
| 6399 | 17904393 | INS receptor expression was gradually decreased. |
| 6400 | 17904393 | It was concluded that not only was the IGF-I receptor expression affected by the diabetic state but also the INS receptor expression. |
| 6401 | 17914103 | Insulin pathway related genes and risk of colorectal cancer: INSR promoter polymorphism shows a protective effect. |
| 6402 | 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. |
| 6403 | 17914103 | SNPs in the INS, IGFBPI, and IRS2 genes did not affect the risk of CRC. |
| 6404 | 17914103 | Insulin pathway related genes and risk of colorectal cancer: INSR promoter polymorphism shows a protective effect. |
| 6405 | 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. |
| 6406 | 17914103 | SNPs in the INS, IGFBPI, and IRS2 genes did not affect the risk of CRC. |
| 6407 | 17983584 | JNK1 in hematopoietically derived cells contributes to diet-induced inflammation and insulin resistance without affecting obesity. |
| 6408 | 17983584 | Obesity-induced insulin resistance is a major factor in the etiology of type 2 diabetes, and Jun kinases (JNKs) are key negative regulators of insulin sensitivity in the obese state. |
| 6409 | 17983584 | Activation of JNKs (mainly JNK1) in insulin target cells results in phosphorylation of insulin receptor substrates (IRSs) at serine and threonine residues that inhibit insulin signaling. |
| 6410 | 17983584 | Here we used reciprocal adoptive transfer experiments to determine whether JNK1 in myeloid cells, such as macrophages, also contributes to insulin resistance and central adiposity. |
| 6411 | 17983584 | Our results show that deletion of Jnk1 in the nonhematopoietic compartment protects mice from high-fat diet (HFD)-induced insulin resistance, in part through decreased adiposity. |
| 6412 | 17983584 | By contrast, Jnk1 removal from hematopoietic cells has no effect on adiposity but confers protection against HFD-induced insulin resistance by decreasing obesity-induced inflammation. |
| 6413 | 18056790 | Chromosomal assignment of the causative mutation and subsequent candidate gene analysis led to the detection of the mutations that resulted in novel alleles of genes already known to be involved in glucose homeostasis, like glucokinase, insulin 2, and insulin receptor. |
| 6414 | 18171427 | SOCS proteins causing trouble in insulin action. |
| 6415 | 18171427 | SOCS-1 and SOCS-3 have been extensively studied both in vitro and in vivo in the context of insulin action. |
| 6416 | 18171427 | It has been shown that these two SOCS members are able to inhibit the insulin signalling pathway by three different mechanisms: (1) inhibition of tyrosine phosphorylation of insulin receptor substrate (IRS) proteins because of competition at the docking site on the insulin receptor (IR), (2) induction of the proteasomal degradation of the IRS and (3) inhibition of the IR kinase. |
| 6417 | 18171427 | A significant correlation between SOCS-3 expression and insulin resistance has been demonstrated in vivo. |
| 6418 | 18171427 | Interestingly, the level of SOCS-3 expression is strikingly enhanced in insulin-sensitive tissues from both patients and animal models with type 2 diabetes and insulin resistance. |
| 6419 | 18171427 | While it remains to be established whether the increased expression of SOCS is a cause or a consequence of insulin resistance, a large body of observations supports a role for SOCS proteins in the disease process found in states with insulin resistance. |
| 6420 | 18199690 | The role of membrane glycoprotein plasma cell antigen 1/ectonucleotide pyrophosphatase phosphodiesterase 1 in the pathogenesis of insulin resistance and related abnormalities. |
| 6421 | 18199690 | A number of laboratories have observed that PC-1 (membrane [corrected] glycoprotein plasma cell antigen 1; also termed [corrected] ectonucleotide pyrophosphatase phosphodiesterase 1 or ENPP1) [corrected] is either overexpressed or overactive in muscle, adipose tissue, fibroblasts, and other tissues of insulin-resistant individuals, both nondiabetic and diabetic. |
| 6422 | 18199690 | Moreover, PC-1 (ENPP1) overexpression [corrected] in cultured cells in vitro and in transgenic mice in vivo, [corrected] impairs insulin stimulation of insulin receptor (IR) activation and downstream signaling. |
| 6423 | 18199690 | When PC-1 is overexpressed, it inhibits insulin [corrected]induced IR beta-subunit tyrosine kinase activity. |
| 6424 | 18199690 | In addition, a polymorphism of PC-1 (K121Q) in various ethnic populations is closely associated with insulin resistance, T2D, and cardio [corrected] and nephrovascular diseases. |
| 6425 | 18199690 | These data suggest therefore that PC-1 is a candidate protein that may play a role in human insulin resistance and T2D by its overexpression, its overactivity, or both. |
| 6426 | 18202124 | Protein kinase C-zeta phosphorylates insulin receptor substrate-1, -3, and -4 but not -2: isoform specific determinants of specificity in insulin signaling. |
| 6427 | 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. |
| 6428 | 18202124 | Because IRS-1 is upstream from PI3K, this represents a negative feedback mechanism that may contribute to signal specificity in insulin action. |
| 6429 | 18202124 | To determine whether similar feedback pathways exist for other IRS isoforms, we evaluated IRS-2, -3, and -4 as substrates for PKC-zeta. |
| 6430 | 18202124 | In an in vitro kinase assay, purified recombinant PKC-zeta phosphorylated IRS-1, -3 and -4 but not IRS-2. |
| 6431 | 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. |
| 6432 | 18202124 | Insulin-stimulated IRS tyrosine phosphorylation was impaired by overepxression of PKC-zeta for IRS-1, -3, and -4 but not IRS-2. |
| 6433 | 18202124 | Significant insulin-stimulated increases in PI3K activity was coimmunoprecipitated with all IRS isoforms. |
| 6434 | 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. |
| 6435 | 18202124 | That is, PI3K activity associated with IRS-2 in response to insulin was similar in control cells and cells overexpressing PKC-zeta. |
| 6436 | 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. |
| 6437 | 18202124 | The inability of PKC-zeta to phosphorylate IRS-2 may help determine specific functional roles for IRS-2. |
| 6438 | 18204460 | Dok1 mediates high-fat diet-induced adipocyte hypertrophy and obesity through modulation of PPAR-gamma phosphorylation. |
| 6439 | 18204460 | Insulin receptor substrate (IRS)-1 and IRS-2 have dominant roles in the action of insulin, but other substrates of the insulin receptor kinase, such as Gab1, c-Cbl, SH2-B and APS, are also of physiological relevance. |
| 6440 | 18204460 | Embryonic fibroblasts from Dok1-deficient mice were impaired in adipogenic differentiation, and this defect was accompanied by an increased activity of the protein kinase ERK and a consequent increase in the phosphorylation of peroxisome proliferator-activated receptor (PPAR)-gamma on Ser112. |
| 6441 | 18204460 | These results indicate that Dok1 promotes adipocyte hypertrophy by counteracting the inhibitory effect of ERK on PPAR-gamma and may thus confer predisposition to diet-induced obesity. |
| 6442 | 18220662 | "Actin"g on GLUT4: membrane & cytoskeletal components of insulin action. |
| 6443 | 18220662 | The dissection of mechanisms that regulate glucose transport by insulin has revealed an intricate network of signaling molecules scattered from the insulin receptor to the intracellular glucose transporter GLUT4. |
| 6444 | 18220662 | It is also appreciated that some insulin receptor signals jaunt in different directions to regulate events essential for the efficient redistribution of GLUT4 to the plasma membrane. |
| 6445 | 18220662 | Following current considerations of insulin signals regulating GLUT4, this review will focus on in vitro and in vivo evidence that supports an essential role for phosphoinositides and actin filaments in the control of glucose transport. |
| 6446 | 18220662 | "Actin"g on GLUT4: membrane & cytoskeletal components of insulin action. |
| 6447 | 18220662 | The dissection of mechanisms that regulate glucose transport by insulin has revealed an intricate network of signaling molecules scattered from the insulin receptor to the intracellular glucose transporter GLUT4. |
| 6448 | 18220662 | It is also appreciated that some insulin receptor signals jaunt in different directions to regulate events essential for the efficient redistribution of GLUT4 to the plasma membrane. |
| 6449 | 18220662 | Following current considerations of insulin signals regulating GLUT4, this review will focus on in vitro and in vivo evidence that supports an essential role for phosphoinositides and actin filaments in the control of glucose transport. |
| 6450 | 18220968 | Protein tyrosine phosphatase 1B (PTP1B) is an enzyme that plays a critical role in down-regulating insulin signaling through dephosphorylation of the insulin receptor. |
| 6451 | 18220968 | Inhibitors of PTP1B showed increased insulin sensitivity and normalize plasma glucose level and thus are useful therapeutic agents for the treatment of diabetes. |
| 6452 | 18237751 | Both exendin-4 and exercise enhanced insulin receptor substrate (IRS)-2 expression through the activation of cAMP responding element binding protein in the islets, which potentiated their insulin/insulin like growth factor-1 signaling. |
| 6453 | 18245813 | Iron depletion improves insulin resistance in patients with nonalcoholic fatty liver disease and diabetes and also stabilizes the hypoxia-inducible factor (HIF)-1, resulting in increased glucose uptake in vitro. |
| 6454 | 18245813 | In HepG2 cells, deferoxamine stabilized HIF-1alpha and induced the constitutive glucose transporter Glut1 and the insulin receptor. |
| 6455 | 18245813 | Up-regulation of insulin receptor by deferoxamine was mimicked by the intracellular iron chelator deferasirox and the hypoxia inducer CoCl2 and required the HIF-1 obligate partner ARNT/HIF-1beta. |
| 6456 | 18245813 | Deferoxamine consistently increased the phosphorylation status of Akt/PKB and its targets FoxO1 and Gsk3beta, which mediate the effect of insulin on gluconeogenesis and glycogen synthesis, and up-regulated genes involved in glucose uptake and utilization. |
| 6457 | 18245813 | Iron depletion of Sprague-Dawley rats increased HIF-1alpha expression, improved glucose clearance, and was associated with up-regulation of insulin receptor and Akt/PKB levels and of glucose transport in hepatic tissue. |
| 6458 | 18245813 | Iron depletion improves insulin resistance in patients with nonalcoholic fatty liver disease and diabetes and also stabilizes the hypoxia-inducible factor (HIF)-1, resulting in increased glucose uptake in vitro. |
| 6459 | 18245813 | In HepG2 cells, deferoxamine stabilized HIF-1alpha and induced the constitutive glucose transporter Glut1 and the insulin receptor. |
| 6460 | 18245813 | Up-regulation of insulin receptor by deferoxamine was mimicked by the intracellular iron chelator deferasirox and the hypoxia inducer CoCl2 and required the HIF-1 obligate partner ARNT/HIF-1beta. |
| 6461 | 18245813 | Deferoxamine consistently increased the phosphorylation status of Akt/PKB and its targets FoxO1 and Gsk3beta, which mediate the effect of insulin on gluconeogenesis and glycogen synthesis, and up-regulated genes involved in glucose uptake and utilization. |
| 6462 | 18245813 | Iron depletion of Sprague-Dawley rats increased HIF-1alpha expression, improved glucose clearance, and was associated with up-regulation of insulin receptor and Akt/PKB levels and of glucose transport in hepatic tissue. |
| 6463 | 18245813 | Iron depletion improves insulin resistance in patients with nonalcoholic fatty liver disease and diabetes and also stabilizes the hypoxia-inducible factor (HIF)-1, resulting in increased glucose uptake in vitro. |
| 6464 | 18245813 | In HepG2 cells, deferoxamine stabilized HIF-1alpha and induced the constitutive glucose transporter Glut1 and the insulin receptor. |
| 6465 | 18245813 | Up-regulation of insulin receptor by deferoxamine was mimicked by the intracellular iron chelator deferasirox and the hypoxia inducer CoCl2 and required the HIF-1 obligate partner ARNT/HIF-1beta. |
| 6466 | 18245813 | Deferoxamine consistently increased the phosphorylation status of Akt/PKB and its targets FoxO1 and Gsk3beta, which mediate the effect of insulin on gluconeogenesis and glycogen synthesis, and up-regulated genes involved in glucose uptake and utilization. |
| 6467 | 18245813 | Iron depletion of Sprague-Dawley rats increased HIF-1alpha expression, improved glucose clearance, and was associated with up-regulation of insulin receptor and Akt/PKB levels and of glucose transport in hepatic tissue. |
| 6468 | 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. |
| 6469 | 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. |
| 6470 | 18267303 | The gene silencing for INSR or TNFalpha resulted in the inhibition or stimulation of GLUT4, respectively. |
| 6471 | 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. |
| 6472 | 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. |
| 6473 | 18267303 | The gene silencing for INSR or TNFalpha resulted in the inhibition or stimulation of GLUT4, respectively. |
| 6474 | 18288891 | Insulin resistance is characterized by impaired signaling through the insulin/insulin receptor/insulin receptor substrate/PI-3K/Akt pathway, leading to elevation of negatively regulated substrates such as glycogen synthase kinase-3beta (Gsk-3beta). |
| 6475 | 18288891 | In these studies, we designed experiments to determine the contribution of Gsk-3beta to regulation of beta-cell mass in two mouse models of insulin resistance. |
| 6476 | 18288891 | Crossing these mice with those having haploinsufficiency for Gsk-3beta (Gsk-3beta+/-) reduced insulin resistance by augmenting whole-body glucose disposal, and significantly reduced beta-cell mass. |
| 6477 | 18288891 | Preservation of beta-cell mass in Gsk-3beta+/- Irs2-/- mice was accompanied by suppressed p27(kip1) levels and increased Pdx1 levels. |
| 6478 | 18288891 | To separate peripheral versus beta-cell-specific effects of reduction of Gsk3beta activity on preservation of beta-cell mass, mice homozygous for a floxed Gsk-3beta allele (Gsk-3(F/F)) were then crossed with rat insulin promoter-Cre (RIP-Cre) mice to produce beta-cell-specific knockout of Gsk-3beta (betaGsk-3beta-/-). |
| 6479 | 18299442 | Plasma adiponectin as a marker of insulin receptor dysfunction: clinical utility in severe insulin resistance. |
| 6480 | 18309377 | Insulin stimulates the clonogenic potential of angiogenic endothelial progenitor cells by IGF-1 receptor-dependent signaling. |
| 6481 | 18309377 | Inhibiting the insulin receptor with neutralizing antibodies or antisense oligonucleotides had no effect on EPC outgrowth.(1) In contrast, targeting the human insulin-like growth factor 1 (IGF-1) receptor with neutralizing antibodies significantly suppressed insulin-induced outgrowth of EPCs from both healthy controls and patients with type 2 diabetes. |
| 6482 | 18309377 | This IGF-1 receptor-mediated insulin effect on EPC growth was at least in part dependent on MAP kinases(2) and was abrogated when extracellular signal-regulated kinase 1/2 (Erk1/2) and protein kinase 38 (p38) activity was inhibited. |
| 6483 | 18309377 | In conclusion, this is the first study showing an insulin-mediated activation of the IGF-1 receptor leading to an increased clonogenic and angiogenic potential of EPCs in vitro. |
| 6484 | 18321395 | Momordica charantia (bitter melon) reduces plasma apolipoprotein B-100 and increases hepatic insulin receptor substrate and phosphoinositide-3 kinase interactions. |
| 6485 | 18321395 | Insulin resistance is characterized by significant down-regulation of hepatic insulin signalling as documented by attenuated phosphorylation of insulin receptor (IR), IR substrates 1 and 2, phosphoinositide-3 kinase, protein kinase B, and over-expression of phosphotyrosine phosphatase 1B. |
| 6486 | 18321395 | The aim of this study was to evaluate the effects of BMJ on plasma apoB levels and hepatic insulin signalling cascade in mice fed high-fat diet (HFD). |
| 6487 | 18321395 | The data indicate that BMJ not only improves glucose and insulin tolerance but also lowers plasma apoB-100 and apoB-48 in HFD-fed mice as well as modulates the phosphorylation status of IR and its downstream signalling molecules. |
| 6488 | 18321395 | Momordica charantia (bitter melon) reduces plasma apolipoprotein B-100 and increases hepatic insulin receptor substrate and phosphoinositide-3 kinase interactions. |
| 6489 | 18321395 | Insulin resistance is characterized by significant down-regulation of hepatic insulin signalling as documented by attenuated phosphorylation of insulin receptor (IR), IR substrates 1 and 2, phosphoinositide-3 kinase, protein kinase B, and over-expression of phosphotyrosine phosphatase 1B. |
| 6490 | 18321395 | The aim of this study was to evaluate the effects of BMJ on plasma apoB levels and hepatic insulin signalling cascade in mice fed high-fat diet (HFD). |
| 6491 | 18321395 | The data indicate that BMJ not only improves glucose and insulin tolerance but also lowers plasma apoB-100 and apoB-48 in HFD-fed mice as well as modulates the phosphorylation status of IR and its downstream signalling molecules. |
| 6492 | 18376848 | Conjointly, the solvent-exposed residues of the central alpha-helix of the B chain form a well-defined ridge, which is flanked and partly overlapped by the two described insulin receptor binding surfaces on either side of the insulin molecule. |
| 6493 | 18376848 | To evaluate the importance of this interface in insulin receptor binding, we developed a new powerful method that allows us to introduce all the naturally occurring amino acids into a given position and subsequently determine the receptor binding affinities of the resulting insulin analogues. |
| 6494 | 18376848 | Conjointly, the solvent-exposed residues of the central alpha-helix of the B chain form a well-defined ridge, which is flanked and partly overlapped by the two described insulin receptor binding surfaces on either side of the insulin molecule. |
| 6495 | 18376848 | To evaluate the importance of this interface in insulin receptor binding, we developed a new powerful method that allows us to introduce all the naturally occurring amino acids into a given position and subsequently determine the receptor binding affinities of the resulting insulin analogues. |
| 6496 | 18393172 | Mitogenic effect of the insulin analogue glargine in malignant cells in comparison with insulin and IGF-I. |
| 6497 | 18393172 | The aim of the study was to investigate if the insulin analogue glargine, with an increased affinity for the IGF-I receptor (IGF-IR), affects the cell growth to a larger extent than human insulin in malignant cells expressing IGF-IRs. |
| 6498 | 18393172 | The gene expression of insulin receptor (IR) varied between 4.3-7.5 x 10(-3) and the expression of IGF-IR between 7.7-147.7 x 10(-3) in relation to GAPDH (glyceraldehyde-3-phosphate dehydrogenase). |
| 6499 | 18393172 | Insulin receptor and IGF-IR protein varied between 2.0-4.1 ng/mg protein and 2.0-40.4 ng/mg protein, respectively. |
| 6500 | 18393172 | The IGF-IR was phosphorylated by IGF-I at a concentration of 10(-10)-10(-9) M. |
| 6501 | 18393172 | SaOS-2 cells were more sensitive to IGF-I than to insulin and glargine. |
| 6502 | 18393172 | MCF-7 cells were more sensitive to des(1-3)IGF-I than to IGF-I. |
| 6503 | 18393172 | Mitogenic effect of the insulin analogue glargine in malignant cells in comparison with insulin and IGF-I. |
| 6504 | 18393172 | The aim of the study was to investigate if the insulin analogue glargine, with an increased affinity for the IGF-I receptor (IGF-IR), affects the cell growth to a larger extent than human insulin in malignant cells expressing IGF-IRs. |
| 6505 | 18393172 | The gene expression of insulin receptor (IR) varied between 4.3-7.5 x 10(-3) and the expression of IGF-IR between 7.7-147.7 x 10(-3) in relation to GAPDH (glyceraldehyde-3-phosphate dehydrogenase). |
| 6506 | 18393172 | Insulin receptor and IGF-IR protein varied between 2.0-4.1 ng/mg protein and 2.0-40.4 ng/mg protein, respectively. |
| 6507 | 18393172 | The IGF-IR was phosphorylated by IGF-I at a concentration of 10(-10)-10(-9) M. |
| 6508 | 18393172 | SaOS-2 cells were more sensitive to IGF-I than to insulin and glargine. |
| 6509 | 18393172 | MCF-7 cells were more sensitive to des(1-3)IGF-I than to IGF-I. |
| 6510 | 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. |
| 6511 | 18407262 | The anorexic peptides insulin, leptin and the neurotransmitter serotonin share common signalling pathways involved in food intake, in particular the insulin receptor substrate, phosphatidylinositol-3-kinase (PI3K) pathway. |
| 6512 | 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. |
| 6513 | 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. |
| 6514 | 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. |
| 6515 | 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. |
| 6516 | 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. |
| 6517 | 18516099 | Impaired insulin-mediated vasorelaxation in a nonobese model of type 2 diabetes: role of endothelin-1. |
| 6518 | 18516099 | Insulin resistance involves decreased phosphorylation of insulin receptor substrate (IRS) proteins and (or) Akt. |
| 6519 | 18516099 | Diet-induced insulin resistance enhances endothelin-1(ET-1)-mediated vasoconstriction and prevents vasodilatation to insulin. |
| 6520 | 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. |
| 6521 | 18516099 | Preincubation with 1 micromol/L BQ-123 or BQ-788 for ETA- and ETB-receptor blockade, respectively, resulted in improved insulin sensitivity. |
| 6522 | 18516099 | Immunoblotting for native and phosphorylated Akt and IRS-1 revealed a decrease in Akt activation in the GK group. |
| 6523 | 18535100 | Placental restriction increased pancreatic expression of IGF-II and IGF-I but decreased that of voltage-gated calcium channel, alpha1D subunit (CACNA1D) in lambs. |
| 6524 | 18535100 | In male lambs, pancreatic IGF-II and insulin receptor expression correlated strongly and positively with beta-cell mass and CACNA1D expression with glucose-stimulated insulin disposition. |
| 6525 | 18535100 | IGF-II and insulin receptor are implicated as key molecular regulators of beta-cell mass compensation, whereas impaired expression of the voltage-gated calcium channel may underlie impaired beta-cell function after intrauterine growth restriction. |
| 6526 | 18535100 | Placental restriction increased pancreatic expression of IGF-II and IGF-I but decreased that of voltage-gated calcium channel, alpha1D subunit (CACNA1D) in lambs. |
| 6527 | 18535100 | In male lambs, pancreatic IGF-II and insulin receptor expression correlated strongly and positively with beta-cell mass and CACNA1D expression with glucose-stimulated insulin disposition. |
| 6528 | 18535100 | IGF-II and insulin receptor are implicated as key molecular regulators of beta-cell mass compensation, whereas impaired expression of the voltage-gated calcium channel may underlie impaired beta-cell function after intrauterine growth restriction. |
| 6529 | 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. |
| 6530 | 18555856 | We also analyzed the abundance of insulin receptor signaling proteins, for example, IRS-1, IRS-2, and PI-3 kinase. |
| 6531 | 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. |
| 6532 | 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. |
| 6533 | 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. |
| 6534 | 18555856 | We also analyzed the abundance of insulin receptor signaling proteins, for example, IRS-1, IRS-2, and PI-3 kinase. |
| 6535 | 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. |
| 6536 | 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. |
| 6537 | 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. |
| 6538 | 18555856 | We also analyzed the abundance of insulin receptor signaling proteins, for example, IRS-1, IRS-2, and PI-3 kinase. |
| 6539 | 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. |
| 6540 | 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. |
| 6541 | 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. |
| 6542 | 18585815 | Concerning the mitogenic properties, glargine and insulin-induced comparable dose-dependent phosphorylation of MAP kinase (MAPK) and 5-bromo-2'-deoxyuridine (BrdU) incorporation. |
| 6543 | 18585970 | Recent research revealed several molecules, including tumor necrosis factor alpha, suppressor of cytokine signaling 1 and 3 proteins, insulin-receptor substrates 1 and 2, and other adipocytokines, potentially are involved in the development of insulin resistance in patients with chronic hepatitis C. |
| 6544 | 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. |
| 6545 | 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. |
| 6546 | 18669627 | Inhibition of ADRP prevents diet-induced insulin resistance. |
| 6547 | 18669627 | The lipid droplet protein adipose differentiation-related protein (ADRP) mediates hepatic steatosis, but whether this affects insulin action in the liver or peripheral organs in diet-induced obesity is uncertain. |
| 6548 | 18669627 | Insulin action in the liver was enhanced after ADRP ASO treatment, whereas muscle and adipose tissue were not affected. |
| 6549 | 18669627 | ADRP ASO increased the phosphorylation of insulin receptor substrate (IRS)1, IRS2, and Akt, and decreased gluconeogenic enzymes and PKCepsilon, consistent with its insulin-sensitizing action. |
| 6550 | 18669627 | These results demonstrate an important role for ADRP in the pathogenesis of diet-induced insulin resistance. |
| 6551 | 18707891 | Protein tyrosine phosphatase 1B is a key factor in the negative regulation of insulin pathway and a promising target for treatment of diabetes and obesity. |
| 6552 | 18707891 | Modifying at 3 and 28 positions, we obtained compound 13 with a K(i) of 130 nM, which exhibited good selectivity between other phosphatases involved in insulin pathway except T-cell protein tyrosine phosphatase. |
| 6553 | 18707891 | Further evaluation in cell models illustrated that the derivatives enhanced insulin receptor phosphorylation in CHO/hIR cells and also stimulated glucose uptake in L6 myotubes with or addition of without insulin. |
| 6554 | 18719658 | The ectoenzyme ENPP1 (also termed membrane glycoprotein PC-1 or ENPP1/PC-1) is an inhibitor of insulin-induced activation of the insulin receptor. |
| 6555 | 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. |
| 6556 | 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. |
| 6557 | 18840478 | Calreticulin regulates insulin receptor expression and its downstream PI3 Kinase/Akt signalling pathway. |
| 6558 | 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. |
| 6559 | 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. |
| 6560 | 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. |
| 6561 | 18840478 | Intriguingly, the increased expression of insulin receptor beta in the crt-/- was due to decreased levels of p53 protein. |
| 6562 | 18840478 | Calreticulin regulates insulin receptor expression and its downstream PI3 Kinase/Akt signalling pathway. |
| 6563 | 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. |
| 6564 | 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. |
| 6565 | 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. |
| 6566 | 18840478 | Intriguingly, the increased expression of insulin receptor beta in the crt-/- was due to decreased levels of p53 protein. |
| 6567 | 18855718 | The crosstalk between insulin and renin-angiotensin-aldosterone signaling systems and its effect on glucose metabolism and diabetes prevention. |
| 6568 | 18855718 | Early insulin signaling steps are impaired in essential hypertension and a large body of data suggests that there is a crosstalk at multiple levels between the signal transduction pathways that mediate insulin and angiotensin II actions. |
| 6569 | 18855718 | At the extracellular level the angiotensin converting enzyme (ACE) regulates the synthesis of angiotensin II and bradykinin that is a powerful vasodilator. |
| 6570 | 18855718 | At early intracellular level angiotensin II acts on JAK-2/IRS1-IRS2/PI3-kinase, JNK and ERK to phosphorylate serine residues of key elements of insulin signaling pathway therefore inhibiting signaling by the insulin receptor. |
| 6571 | 18855718 | On another level angiotensin II inhibits the insulin signaling inducing the regulatory protein SOCS 3. |
| 6572 | 18855718 | Angiotensin II acting through the AT1 receptor can inhibit insulin-induced nitric oxide (NO) production by activating ERK 1/2 and JNK and enhances the activity of NADPH oxidase that leads to an increased reactive oxygen species generation. |
| 6573 | 18855718 | From the clinical standpoint, the inhibition of the renin angiotensin system improves insulin sensitivity and decreases the incidence of Type 2 Diabetes Mellitus (T2DM). |
| 6574 | 18855718 | This review will discuss: a) the molecular mechanisms of the crosstalk between the insulin and angiotensin II signaling systems b) the results of clinical studies employing drugs targeting the renin-angiotensin II-aldosterone systems and their role in glucose metabolism and diabetes prevention. |
| 6575 | 18925540 | Protein tyrosine phosphatase 1B (PTP1B) and leukocyte antigen-related PTPase (LAR) are the PTPases implicated most frequently in insulin resistance and diabetes mellitus. |
| 6576 | 18925540 | Here, we show that PTP1B and LAR are expressed in human fibroblasts, and we examine the regulation of PTPase activity in fibroblasts from patients with an insulin receptor gene mutation as an in vitro model of insulin resistance. |
| 6577 | 18925540 | Insulin stimulation of fibroblasts with mutations resulted in a significantly smaller increase in PTP1B activity compared with stimulation of wild-type fibroblasts (p<0.05). |
| 6578 | 18942491 | Impact of rosiglitazone on visfatin and adiponectin plasma concentrations in patients with type 2 diabetes and coronary artery disease. |
| 6579 | 18942491 | Visfatin is a recently described new adipokine that is considered to bind to the insulin receptor and induce insulin action via signal transduction pathways distinct from those of insulin. |
| 6580 | 18942491 | This study investigated whether circulating plasma visfatin levels may be influenced by PPARy activation, as shown for adiponectin and other adipokines. |
| 6581 | 18942491 | Laboratory measurements for lipids, adiponectin, and visfatin were performed with validated tests. |
| 6582 | 18942491 | Visfatin secretion is not regulated by PPARgamma and further research is required to investigate its role in insulin resistance. |
| 6583 | 18981591 | The anti-diabetic effect was examined by glucose transport activity, glucose transporter 4 (Glut4) expression in myotubes, and the level of insulin receptor (IR) tyrosine phosphorylation as influenced by tyrosine phosphatase 1B, each of which is a major target of diabetes treatment. |
| 6584 | 18991599 | Second, exercise improves blood glucose clearance via enhanced GLUT 4 translocation and protein content, as well as enhanced insulin-insulin receptor binding and post-receptor signaling. |
| 6585 | 19001411 | The phosphotyrosine interactome of the insulin receptor family and its substrates IRS-1 and IRS-2. |
| 6586 | 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. |
| 6587 | 19001411 | Our results retrieve known interactions and substantially broaden the spectrum of potential interaction partners of IRS-1 and IRS-2. |
| 6588 | 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. |
| 6589 | 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. |
| 6590 | 19001411 | The phosphotyrosine interactome of the insulin receptor family and its substrates IRS-1 and IRS-2. |
| 6591 | 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. |
| 6592 | 19001411 | Our results retrieve known interactions and substantially broaden the spectrum of potential interaction partners of IRS-1 and IRS-2. |
| 6593 | 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. |
| 6594 | 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. |
| 6595 | 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). |
| 6596 | 19007436 | In addition, a defect in insulin secretion could occur due to UPS-mediated degradation of IRS2 in the beta-cells of the pancreas. |
| 6597 | 19013138 | Coexistences of insulin signaling-related proteins and choline acetyltransferase in neurons. |
| 6598 | 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. |
| 6599 | 19026743 | For instance, in AD the accumulation of the amyloid-beta peptide (Abeta), which characterizes the disease and is thought to participate in the neurodegenerative process, may also induce neuronal insulin resistance. |
| 6600 | 19026743 | Conversely, disrupting normal glucose metabolism in transgenic animal models of AD that over-express the human amyloid precursor protein (hAPP) promotes amyloid-peptide aggregation and accelerates the disease progression. |
| 6601 | 19026743 | Studying these processes at a cellular level suggests that insulin resistance and Abeta aggregation may not only be the consequence of excitotoxicity, aberrant Ca(2+) signals, and proinflammatory cytokines such as TNF-alpha, but may also promote these pathological effectors. |
| 6602 | 19026743 | At the molecular level, insulin resistance and Abeta disrupt common signal transduction cascades including the insulin receptor family/PI3 kinase/Akt/GSK3 pathway. |
| 6603 | 19029027 | Diabetes reduces autophosphorylation of retinal insulin receptor and increases protein-tyrosine phosphatase-1B activity. |
| 6604 | 19049803 | Insulin regulates P-glycoprotein in rat brain microvessel endothelial cells via an insulin receptor-mediated PKC/NF-kappaB pathway but not a PI3K/Akt pathway. |
| 6605 | 19049803 | This induced effect was blocked by insulin receptor antibody, insulin receptor tyrosine kinase inhibitor I-OMe-AG538, PKC inhibitor chelerythrine and NF-kappaB inhibitor pyrrolidine dithiocarbamate ammonium (PDTC). |
| 6606 | 19049803 | But this induced effect was not inhibited by phosphatidylinositol 3-kinase (PI3K)/Akt inhibitor LY294002. |
| 6607 | 19049803 | These results indicated that insulin regulated P-glycoprotein function and expression through signal transduction pathways involving activation of PKC/NF-kappaB but not PI3K/Akt pathway. |
| 6608 | 19049803 | Insulin regulates P-glycoprotein in rat brain microvessel endothelial cells via an insulin receptor-mediated PKC/NF-kappaB pathway but not a PI3K/Akt pathway. |
| 6609 | 19049803 | This induced effect was blocked by insulin receptor antibody, insulin receptor tyrosine kinase inhibitor I-OMe-AG538, PKC inhibitor chelerythrine and NF-kappaB inhibitor pyrrolidine dithiocarbamate ammonium (PDTC). |
| 6610 | 19049803 | But this induced effect was not inhibited by phosphatidylinositol 3-kinase (PI3K)/Akt inhibitor LY294002. |
| 6611 | 19049803 | These results indicated that insulin regulated P-glycoprotein function and expression through signal transduction pathways involving activation of PKC/NF-kappaB but not PI3K/Akt pathway. |
| 6612 | 19051206 | Autoreactive T-cell receptor (Vbeta/D/Jbeta) sequences in diabetes are homologous to insulin, glucagon, the insulin receptor, and the glucagon receptor. |
| 6613 | 19051206 | An analysis of some of these sequences shows that TCR from both human diabetics and NOD mice mimic insulin, glucagon, the insulin receptor, and the glucagon receptor. |
| 6614 | 19051206 | Autoreactive T-cell receptor (Vbeta/D/Jbeta) sequences in diabetes are homologous to insulin, glucagon, the insulin receptor, and the glucagon receptor. |
| 6615 | 19051206 | An analysis of some of these sequences shows that TCR from both human diabetics and NOD mice mimic insulin, glucagon, the insulin receptor, and the glucagon receptor. |
| 6616 | 19059538 | Berberine reduces insulin resistance through protein kinase C-dependent up-regulation of insulin receptor expression. |
| 6617 | 19059538 | Berberine induced InsR gene expression through a protein kinase C (PKC)-dependent activation of its promoter. |
| 6618 | 19059538 | In animal models, treatment of type 2 diabetes mellitus rats with BBR lowered fasting blood glucose and fasting serum insulin, increased insulin sensitivity, and elevated InsR mRNA as well as PKC activity in the liver. |
| 6619 | 19059538 | Berberine reduces insulin resistance through protein kinase C-dependent up-regulation of insulin receptor expression. |
| 6620 | 19059538 | Berberine induced InsR gene expression through a protein kinase C (PKC)-dependent activation of its promoter. |
| 6621 | 19059538 | In animal models, treatment of type 2 diabetes mellitus rats with BBR lowered fasting blood glucose and fasting serum insulin, increased insulin sensitivity, and elevated InsR mRNA as well as PKC activity in the liver. |
| 6622 | 19059538 | Berberine reduces insulin resistance through protein kinase C-dependent up-regulation of insulin receptor expression. |
| 6623 | 19059538 | Berberine induced InsR gene expression through a protein kinase C (PKC)-dependent activation of its promoter. |
| 6624 | 19059538 | In animal models, treatment of type 2 diabetes mellitus rats with BBR lowered fasting blood glucose and fasting serum insulin, increased insulin sensitivity, and elevated InsR mRNA as well as PKC activity in the liver. |
| 6625 | 19083193 | The role of HSP70 on ENPP1 expression and insulin-receptor activation. |
| 6626 | 19083193 | Ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1) inhibits insulin-receptor (IR) signaling and, when over-expressed, induces insulin resistance in vitro and in vivo. |
| 6627 | 19083193 | Understanding the regulation of ENPP1 expression may, thus, unravel new molecular mechanisms of insulin resistance. |
| 6628 | 19083193 | Through this binding, HSP70 stabilizes ENPP1 mRNA and increases ENPP1 transcript and protein levels. |
| 6629 | 19083193 | This positive modulation of ENPP1 expression is paralleled by a reduced insulin-induced IR and IRS-1 phosphorylation. |
| 6630 | 19083193 | Taken together these data suggest that HSP70, by affecting ENPP1 expression, may be a novel mediator of altered insulin signaling. |
| 6631 | 19083193 | The role of HSP70 on ENPP1 expression and insulin-receptor activation. |
| 6632 | 19083193 | Ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1) inhibits insulin-receptor (IR) signaling and, when over-expressed, induces insulin resistance in vitro and in vivo. |
| 6633 | 19083193 | Understanding the regulation of ENPP1 expression may, thus, unravel new molecular mechanisms of insulin resistance. |
| 6634 | 19083193 | Through this binding, HSP70 stabilizes ENPP1 mRNA and increases ENPP1 transcript and protein levels. |
| 6635 | 19083193 | This positive modulation of ENPP1 expression is paralleled by a reduced insulin-induced IR and IRS-1 phosphorylation. |
| 6636 | 19083193 | Taken together these data suggest that HSP70, by affecting ENPP1 expression, may be a novel mediator of altered insulin signaling. |
| 6637 | 19122674 | Further investigation reveals that insulin stimulates the formation of a new beta-arrestin-2 signal complex, in which beta-arrestin-2 scaffolds Akt and Src to insulin receptor. |
| 6638 | 19136667 | Oxidized LDL impair adipocyte response to insulin by activating serine/threonine kinases. |
| 6639 | 19136667 | Specifically, in oxLDL-treated cells insulin receptor (IR) substrate-1 (IRS-1) was highly degraded likely because of the enhanced Ser(307)phosphorylation. |
| 6640 | 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). |
| 6641 | 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). |
| 6642 | 19136667 | The activated NF-kappaB further impaired per se GLUT4 functionality. |
| 6643 | 19136667 | Specific inhibitors of IKKbeta, JNK, and NF-kappaB restored insulin sensitivity in adipocytes treated with oxLDL. |
| 6644 | 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). |
| 6645 | 19195868 | Effects of chromium picolinate on glucose uptake in insulin-resistant 3T3-L1 adipocytes involve activation of p38 MAPK. |
| 6646 | 19195868 | In addition, its effects on insulin signaling pathways and mitogen-activated protein kinase (MAPK) signaling cascades were assessed by immunoblotting analysis and real-time PCR. |
| 6647 | 19195868 | The results showed that CrPic induced glucose metabolism and uptake, as well as GLUT4 translocation to plasma membrane (PM) in both control and insulin-resistant 3T3-L1 adipocytes without any changes in insulin receptor beta (IR-beta), protein kinase B (AKt), c-Cbl, extracellular signal-regulated kinase (ERK), c-Jun phosphorylation and c-Cbl-associated protein (CAP) mRNA levels. |
| 6648 | 19195868 | Interestingly, CrPic was able to increase the basal and insulin-stimulated levels of p38 MAPK activation in the control and insulin-resistant cells. |
| 6649 | 19195868 | Pretreatment with the specific p38 MAPK inhibitor SB203580 partially inhibited the CrPic-induced glucose transport, but CrPic-activated translocation of GLUT4 was not inhibited by SB203580. |
| 6650 | 19195868 | This study provides an experimental evidence of the effects of CrPic on glucose uptake through the activation of p38 MAPK and it is independent of the effect on GLUT4 translocation. |
| 6651 | 19195868 | The findings also suggest exciting new insights into the role of p38 MAPK in glucose uptake and GLUT4 translocation. |
| 6652 | 19213832 | Recent evidence supports the idea that insulin signaling through the insulin receptor substrate/phosphatidyl-inositol 3-kinase/Akt pathway is involved in the maintenance of beta-cell mass and function. |
| 6653 | 19213832 | We previously identified the insulin-response element binding protein-1 (IRE-BP1) as an effector of insulin-induced Akt signaling in the liver, and showed that the 50-kDa carboxyl fragment confers the transcriptional activity of this factor. |
| 6654 | 19213832 | To test whether IRE-BP1 modulates beta-cell function and insulin secretion, we used the rat insulin II promoter to drive expression of the carboxyl fragment in beta-cells. |
| 6655 | 19213832 | Our findings suggest that increased gene transcription mediated through IRE-BP1 may contribute to beta-cell dysfunction in insulin resistance, and allow for the hypothesis that IRE-BP1 plays a role in the pathophysiology of type 2 diabetes. |
| 6656 | 19224872 | The L-4F mimetic peptide prevents insulin resistance through increased levels of HO-1, pAMPK, and pAKT in obese mice. |
| 6657 | 19224872 | We hypothesized that L-4F reduces adiposity via increased pAMPK, pAKT, HO-1, and increased insulin receptor phosphorylation in ob mice. |
| 6658 | 19224872 | Food intake, insulin, glucose adipocyte stem cells, pAMPK, pAKT, CB1, and insulin receptor phosphorylation were determined. |
| 6659 | 19224872 | The anti-obesity effects of L-4F are manifested by a decrease in visceral fat content with reciprocal increases in adiponectin, pAMPK, pAKT, and phosphorylation of insulin receptors with improved insulin sensitivity. |
| 6660 | 19224872 | The L-4F mimetic peptide prevents insulin resistance through increased levels of HO-1, pAMPK, and pAKT in obese mice. |
| 6661 | 19224872 | We hypothesized that L-4F reduces adiposity via increased pAMPK, pAKT, HO-1, and increased insulin receptor phosphorylation in ob mice. |
| 6662 | 19224872 | Food intake, insulin, glucose adipocyte stem cells, pAMPK, pAKT, CB1, and insulin receptor phosphorylation were determined. |
| 6663 | 19224872 | The anti-obesity effects of L-4F are manifested by a decrease in visceral fat content with reciprocal increases in adiponectin, pAMPK, pAKT, and phosphorylation of insulin receptors with improved insulin sensitivity. |
| 6664 | 19237574 | Antidiabetic drug metformin (GlucophageR) increases biogenesis of Alzheimer's amyloid peptides via up-regulating BACE1 transcription. |
| 6665 | 19237574 | Insulin modulates metabolism of beta-amyloid precursor protein (APP) in neurons, decreasing the intracellular accumulation of beta-amyloid (Abeta) peptides, which are pivotal in AD pathogenesis. |
| 6666 | 19237574 | The present study investigates whether the widely prescribed insulin-sensitizing drug, metformin (Glucophage(R)), affects APP metabolism and Abeta generation in various cell models. |
| 6667 | 19237574 | We demonstrate that metformin, at doses that lead to activation of the AMP-activated protein kinase (AMPK), significantly increases the generation of both intracellular and extracellular Abeta species. |
| 6668 | 19237574 | Furthermore, the effect of metformin on Abeta generation is mediated by transcriptional up-regulation of beta-secretase (BACE1), which results in an elevated protein level and increased enzymatic activity. |
| 6669 | 19237574 | Unlike insulin, metformin exerts no effect on Abeta degradation. |
| 6670 | 19237574 | In addition, we found that glucose deprivation and various tyrphostins, known inhibitors of insulin-like growth factors/insulin receptor tyrosine kinases, do not modulate the effect of metformin on Abeta. |
| 6671 | 19237574 | Finally, inhibition of AMP-activated protein kinase (AMPK) by the pharmacological inhibitor Compound C largely suppresses metformin's effect on Abeta generation and BACE1 transcription, suggesting an AMPK-dependent mechanism. |
| 6672 | 19237574 | Although insulin and metformin display opposing effects on Abeta generation, in combined use, metformin enhances insulin's effect in reducing Abeta levels. |
| 6673 | 19251743 | TANK-binding kinase 1 mediates phosphorylation of insulin receptor at serine residue 994: a potential link between inflammation and insulin resistance. |
| 6674 | 19251743 | The I kappaB kinase-beta (IKK-beta)/nuclear factor-kappaB signaling pathway has been suggested to link inflammation with obesity and insulin resistance. |
| 6675 | 19251743 | In addition, angiotensin (Ang) II is able to induce insulin resistance and an inflammatory state through Ang II receptor type 1 (AT1R). |
| 6676 | 19251743 | Accordingly, we examined whether inhibition of AT1R with irbesartan (IRB) can protect against the development of insulin resistance in obese Zucker rats (OZRs). |
| 6677 | 19251743 | IRB-treatment improved the insulin-stimulated insulin receptor (IR) phosphorylation at tyrosine (Tyr) residues 1158, 1162, 1163 (involved in activation of the IR kinase) and at Tyr972 (involved in substrate recognition). |
| 6678 | 19251743 | AT1R blockade also originated a dramatic increase in the phosphorylation of Akt and glycogen synthase kinase-3beta. |
| 6679 | 19251743 | In this study, we demonstrated that Ser994 of IR is a direct substrate for TANK-binding kinase 1 (TBK1), a new member of the IKK-related kinase family. |
| 6680 | 19251743 | Interestingly, a marked increase in the association between TBK1 and the IR was found in the liver of OZR as well as in other models of insulin resistance/diabetes. |
| 6681 | 19251743 | Taken together, these findings suggest that TBK1 could be involved in the insulin resistance mechanism related with IR Ser994 phosphorylation in a genetic model of diabetes. |
| 6682 | 19251743 | TANK-binding kinase 1 mediates phosphorylation of insulin receptor at serine residue 994: a potential link between inflammation and insulin resistance. |
| 6683 | 19251743 | The I kappaB kinase-beta (IKK-beta)/nuclear factor-kappaB signaling pathway has been suggested to link inflammation with obesity and insulin resistance. |
| 6684 | 19251743 | In addition, angiotensin (Ang) II is able to induce insulin resistance and an inflammatory state through Ang II receptor type 1 (AT1R). |
| 6685 | 19251743 | Accordingly, we examined whether inhibition of AT1R with irbesartan (IRB) can protect against the development of insulin resistance in obese Zucker rats (OZRs). |
| 6686 | 19251743 | IRB-treatment improved the insulin-stimulated insulin receptor (IR) phosphorylation at tyrosine (Tyr) residues 1158, 1162, 1163 (involved in activation of the IR kinase) and at Tyr972 (involved in substrate recognition). |
| 6687 | 19251743 | AT1R blockade also originated a dramatic increase in the phosphorylation of Akt and glycogen synthase kinase-3beta. |
| 6688 | 19251743 | In this study, we demonstrated that Ser994 of IR is a direct substrate for TANK-binding kinase 1 (TBK1), a new member of the IKK-related kinase family. |
| 6689 | 19251743 | Interestingly, a marked increase in the association between TBK1 and the IR was found in the liver of OZR as well as in other models of insulin resistance/diabetes. |
| 6690 | 19251743 | Taken together, these findings suggest that TBK1 could be involved in the insulin resistance mechanism related with IR Ser994 phosphorylation in a genetic model of diabetes. |
| 6691 | 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. |
| 6692 | 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. |
| 6693 | 19275676 | Role of resistin in insulin sensitivity in rodents and humans. |
| 6694 | 19275676 | Resistin is a potential link between obesity and insulin resistance or type 2 diabetes. |
| 6695 | 19275676 | This is likely in part due to an up-regulation of suppressor of cytokine signaling (SOCS)-3, which interferes with the activation of insulin receptor substrate (IRS)-1. |
| 6696 | 19275676 | However, in humans resistin is expressed primarily by macrophages and seems to be involved in the recruitment of other immune cells and the secretion of pro-inflammatory factors, including tumor necrosis factor (TNF)alpha. |
| 6697 | 19275676 | Human resistin may interfere with insulin signaling by stimulating the expression of phosphatase and tensin homolog deleted on chromosome ten (PTEN), which dephosphorylates 3-phosphorylated phosphoinositide (PIP(3)). |
| 6698 | 19276091 | Targeted disruption of ROCK1 causes insulin resistance in vivo. |
| 6699 | 19276091 | Rho-kinase (ROCK) isoforms have been shown to participate in insulin signaling and glucose metabolism in cultured cell lines. |
| 6700 | 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. |
| 6701 | 19276091 | Interestingly, ROCK1 gene ablation caused a significant increase in glucose-induced insulin secretion, leading to hyperinsulinemia. |
| 6702 | 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. |
| 6703 | 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. |
| 6704 | 19276091 | Insulin-induced phosphorylation of Akt, AS160, S6K, and S6 was also decreased in skeletal muscle. |
| 6705 | 19276091 | These data suggest that ROCK1 deficiency causes systemic insulin resistance by impairing insulin signaling in skeletal muscle. |
| 6706 | 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. |
| 6707 | 19337956 | In addition to stimulating insulin secretion, 4-hydroxyisoleucine reduced insulin resistance in muscle and/or liver by activating insulin receptor substrate-associated phosphoinositide 3 (PI3) kinase activity. 4-Hydroxyisoleucine also reduced body weight in diet-induced obese mice. |
| 6708 | 19362933 | Several cytokines, tumor necrosis factor-alpha and its soluble receptor forms, sTNFR1 and sTNFR2, resistin, retinol-binding protein 4, plasminogen activator inhibitor, lipocain 1 inhibit the signalization of insulin receptor causing insulin resistance in target tissues, mainly in adipose, liver and muscle, brain, endothelial as well as in pancreatic beta-cells. |
| 6709 | 19362933 | However, many other proteins produced by the fat tissue, such as adiponectin, visfatin, vaspin, apelin, omentin and chemerin enhance the signal transmission of the receptor. |
| 6710 | 19362933 | Recently discovered common mechanisms leading to insulin and cytokine resistance in obesity and type 2 diabetes mellitus, e.g. protein family of suppressor of cytokine signaling (SOCS) are also discussed. |
| 6711 | 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. |
| 6712 | 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. |
| 6713 | 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. |
| 6714 | 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. |
| 6715 | 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. |
| 6716 | 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. |
| 6717 | 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. |
| 6718 | 19381127 | HCV infection promotes IR mainly through increased TNF-a and cytokine suppressor (SOCS-3) production. |
| 6719 | 19381127 | Both events inhibit insulin receptor and IRS-1 (insulin receptor substrate) tyrosine phosphorylation. |
| 6720 | 19423756 | Insulin and insulin-like growth factor-I receptors differentially mediate insulin-stimulated adhesion molecule production by endothelial cells. |
| 6721 | 19423756 | ECs express abundant IGF-I receptors as well as insulin receptors. |
| 6722 | 19423756 | Whether IGF-I receptors contribute to insulin-induced endothelial production of adhesion molecules is unknown. |
| 6723 | 19423756 | The cellular content of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) was measured, and monocyte adhesion to ECs was quantified. |
| 6724 | 19423756 | Insulin increased both VCAM-1 (P < 0.001) and ICAM-1 (P < 0.0002) content, which was accompanied by an increased number of monocytes adherent to BAECs (P = 0.0001). |
| 6725 | 19423756 | Inhibition of either MAPK kinase-1 or p38 MAPK but not phosphatidylinositol 3-kinase abolished insulin-mediated production of adhesion molecules. |
| 6726 | 19423756 | Insulin receptor small interfering RNA knockdown abolished insulin-stimulated increases of ICAM-1 but not VCAM-1. |
| 6727 | 19423756 | Conversely, IGF-I receptor blockade with either a neutralizing antibody or specific small interfering RNA eliminated insulin-induced VCAM-1 but not ICAM-1 production. |
| 6728 | 19423756 | Blockade of signaling via either the insulin or IGF-I receptors decreased monocyte adherence to BAECs (P < 0.01 for each). |
| 6729 | 19423756 | We conclude that insulin and IGF-I receptors differentially mediate the production of adhesion molecules by ECs and monocyte adhesion onto the vascular endothelium in response to the hyperinsulinemic state. |
| 6730 | 19436651 | Arterial stiffness in insulin resistance: the role of nitric oxide and angiotensin II receptors. |
| 6731 | 19436651 | The insulin resistance syndrome (INSR) is associated with increased cardiovascular risk, and affects up to 25% of the Australian population aged >20 years. |
| 6732 | 19436651 | We have reviewed the role of nitric oxide (NO) and angiotensin II receptors in the modulation of arterial stiffness in the setting of insulin resistance. |
| 6733 | 19436651 | The renin-angiotensin system is activated in diseased vascular beds, with up regulation of the two known angiotensin II receptors: the angiotensin II type 1 receptor (AT1R) and the angiotensin II type 2 receptor (AT2R). |
| 6734 | 19436651 | Increased AT1R mediated activity in the vasculature is central to the development of increased arterial stiffness and is enhanced in INSR states. |
| 6735 | 19436651 | AT1R blockade may therefore be valuable treatment for early INSR as antagonism of AT1 receptors would allow angiotensin II to act unopposed at AT2 receptors. |
| 6736 | 19436651 | Arterial stiffness in insulin resistance: the role of nitric oxide and angiotensin II receptors. |
| 6737 | 19436651 | The insulin resistance syndrome (INSR) is associated with increased cardiovascular risk, and affects up to 25% of the Australian population aged >20 years. |
| 6738 | 19436651 | We have reviewed the role of nitric oxide (NO) and angiotensin II receptors in the modulation of arterial stiffness in the setting of insulin resistance. |
| 6739 | 19436651 | The renin-angiotensin system is activated in diseased vascular beds, with up regulation of the two known angiotensin II receptors: the angiotensin II type 1 receptor (AT1R) and the angiotensin II type 2 receptor (AT2R). |
| 6740 | 19436651 | Increased AT1R mediated activity in the vasculature is central to the development of increased arterial stiffness and is enhanced in INSR states. |
| 6741 | 19436651 | AT1R blockade may therefore be valuable treatment for early INSR as antagonism of AT1 receptors would allow angiotensin II to act unopposed at AT2 receptors. |
| 6742 | 19436651 | Arterial stiffness in insulin resistance: the role of nitric oxide and angiotensin II receptors. |
| 6743 | 19436651 | The insulin resistance syndrome (INSR) is associated with increased cardiovascular risk, and affects up to 25% of the Australian population aged >20 years. |
| 6744 | 19436651 | We have reviewed the role of nitric oxide (NO) and angiotensin II receptors in the modulation of arterial stiffness in the setting of insulin resistance. |
| 6745 | 19436651 | The renin-angiotensin system is activated in diseased vascular beds, with up regulation of the two known angiotensin II receptors: the angiotensin II type 1 receptor (AT1R) and the angiotensin II type 2 receptor (AT2R). |
| 6746 | 19436651 | Increased AT1R mediated activity in the vasculature is central to the development of increased arterial stiffness and is enhanced in INSR states. |
| 6747 | 19436651 | AT1R blockade may therefore be valuable treatment for early INSR as antagonism of AT1 receptors would allow angiotensin II to act unopposed at AT2 receptors. |
| 6748 | 19440117 | Autoimmune syndromes are a rare cause of hypoglycemia characterized by elevated levels of insulin in the presence of either anti-insulin antibodies (insulin autoimmune syndrome) or anti-insulin receptor antibodies (type B insulin resistance). |
| 6749 | 19458242 | The insulin receptor (IR) kinase is expressed at high levels in the olfactory bulb, in which it suppresses a dominant Shaker ion channel (Kv1.3) via tyrosine phosphorylation of critical N- and C-terminal residues. |
| 6750 | 19458242 | We optimized a 7 d intranasal insulin delivery (IND) in awake mice to ascertain the biochemical and behavioral effects of insulin to this brain region, given that nasal sprays for insulin have been marketed notwithstanding our knowledge of the role of Kv1.3 in olfaction, metabolism, and axon targeting. |
| 6751 | 19467150 | In maternal diabetes, components of this system including insulin, IGF1, IGF2 and various IGF-binding proteins are deregulated in the maternal or fetal circulation, or in the placenta. |
| 6752 | 19467150 | The placenta expresses considerable amounts of insulin and IGF1 receptors at distinct locations on both placental surfaces. |
| 6753 | 19467150 | This makes the insulin and the IGF1 receptor accessible to fetal and/or maternal insulin, IGF1 and IGF2. |
| 6754 | 19467150 | Unlike the receptor for IGF1, the insulin receptor undergoes a gestational change in expression site from the trophoblast at the beginning of pregnancy to the endothelium at term. |
| 6755 | 19467325 | 17beta-estradiol treatment is unable to reproduce p85 alpha redistribution associated with gestational insulin resistance in rats. |
| 6756 | 19467325 | The results support the conclusion that retroperitoneal adipose tissue plays a pivotal role in the decrease in insulin sensitivity during pregnancy, through a mechanism that involves p85 alpha redistribution to the insulin receptor and impairment of Glut4 translocation to the plasma membrane. |
| 6757 | 19467325 | Treatment with 17beta-estradiol did not reproduce the molecular adaptations that occur during pregnancy, suggesting that other hormonal factors presents in gestation but absent in our experimental model are responsible for p85 alpha redistribution to the insulin receptor. |
| 6758 | 19467325 | 17beta-estradiol treatment is unable to reproduce p85 alpha redistribution associated with gestational insulin resistance in rats. |
| 6759 | 19467325 | The results support the conclusion that retroperitoneal adipose tissue plays a pivotal role in the decrease in insulin sensitivity during pregnancy, through a mechanism that involves p85 alpha redistribution to the insulin receptor and impairment of Glut4 translocation to the plasma membrane. |
| 6760 | 19467325 | Treatment with 17beta-estradiol did not reproduce the molecular adaptations that occur during pregnancy, suggesting that other hormonal factors presents in gestation but absent in our experimental model are responsible for p85 alpha redistribution to the insulin receptor. |
| 6761 | 19472218 | Phospholipid transfer protein reduces phosphorylation of tau in human neuronal cells. |
| 6762 | 19472218 | In this study we provide evidence that phospholipid transfer protein (PLTP), one of the main lipid transfer proteins in the brain, significantly reduces levels of phosphorylated tau and increases levels of the inactive form of glycogen synthase kinase-3beta (GSK3 beta) in HCN2 cells. |
| 6763 | 19472218 | Furthermore, inhibition of phosphatidylinositol-3 kinase (PI3K) reversed the PLTP-induced increase in levels of GSK3 beta phosphorylated at serine 9 (pGSK3 beta(Ser9)) and partially reversed the PLTP-induced reduction in tau phosphorylation. |
| 6764 | 19472218 | We provide evidence that the PLTP-induced changes are not due to activation of Disabled-1 (Dab1), insofar as PLTP reduced levels of total and phosphorylated Dab1 in HCN2 cells. |
| 6765 | 19472218 | We have also shown that inhibition of tyrosine kinase activity of insulin receptor (IR) and/or insulin-like growth factor 1 (IGF1) receptor (IGFR) reverses the PLTP-induced increase in levels of phosphorylated Akt (pAkt(Thr308) and pAkt(Ser473)), suggesting that PLTP-mediated activation of the PI3K/Akt pathway is dependent on IR/IGFR receptor tyrosine kinase activity. |
| 6766 | 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. |
| 6767 | 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. |
| 6768 | 19519303 | The role of IGF-1 receptor and insulin receptor signaling for the pathogenesis of Alzheimer's disease: from model organisms to human disease. |
| 6769 | 19519303 | Alternatively, the mechanism might be directly related to insulin and insulin-like growth factor(IGF)-1 signaling, leading to the proposal that AD is a "brain-type diabetes". |
| 6770 | 19519303 | Furthermore, postmortem analyses of brains from patients with AD revealed a markedly downregulated expression of insulin receptor (IR), IGF-1 receptor (IGF-1R), insulin receptor substrate (IRS)-1 and IRS-2, and these changes progress with severity of neurodegeneration. |
| 6771 | 19519303 | Recently, Cohen and coworkers have show that knocking down DAF-2 in C. elegans, the homolog of the mammalian IR/IGF-1R, reduces beta-amyloid(Abeta)(1-42) toxicity. |
| 6772 | 19519303 | Cell based experiments suggest a specific role for the IGF 1/IRS-2 signaling pathway in regulating alpha-/beta-secretase activity. |
| 6773 | 19519303 | Moreover circulating IGF-1 might influence Abeta clearance from the brain by promoting Abeta transport over the blood brain barrier. |
| 6774 | 19519303 | Interestingly, brain specific deletion of IRS-2 increases life span, suggesting that long term neuronal IGF-1R signaling might be harmful. |
| 6775 | 19519303 | Taken together, the data from humans and different model organisms indicate a role of IR/IGF-1R signaling in Abeta metabolism, and clearance as well as longevity. |
| 6776 | 19519303 | Since more studies are needed to elucidate the impact of insulin and/or IGF-1 treatment in AD, the time to propose these hormones as a potential treatment option for AD has not come yet. |
| 6777 | 19519303 | The role of IGF-1 receptor and insulin receptor signaling for the pathogenesis of Alzheimer's disease: from model organisms to human disease. |
| 6778 | 19519303 | Alternatively, the mechanism might be directly related to insulin and insulin-like growth factor(IGF)-1 signaling, leading to the proposal that AD is a "brain-type diabetes". |
| 6779 | 19519303 | Furthermore, postmortem analyses of brains from patients with AD revealed a markedly downregulated expression of insulin receptor (IR), IGF-1 receptor (IGF-1R), insulin receptor substrate (IRS)-1 and IRS-2, and these changes progress with severity of neurodegeneration. |
| 6780 | 19519303 | Recently, Cohen and coworkers have show that knocking down DAF-2 in C. elegans, the homolog of the mammalian IR/IGF-1R, reduces beta-amyloid(Abeta)(1-42) toxicity. |
| 6781 | 19519303 | Cell based experiments suggest a specific role for the IGF 1/IRS-2 signaling pathway in regulating alpha-/beta-secretase activity. |
| 6782 | 19519303 | Moreover circulating IGF-1 might influence Abeta clearance from the brain by promoting Abeta transport over the blood brain barrier. |
| 6783 | 19519303 | Interestingly, brain specific deletion of IRS-2 increases life span, suggesting that long term neuronal IGF-1R signaling might be harmful. |
| 6784 | 19519303 | Taken together, the data from humans and different model organisms indicate a role of IR/IGF-1R signaling in Abeta metabolism, and clearance as well as longevity. |
| 6785 | 19519303 | Since more studies are needed to elucidate the impact of insulin and/or IGF-1 treatment in AD, the time to propose these hormones as a potential treatment option for AD has not come yet. |
| 6786 | 19541499 | Akt and PTEN: beta-cell mass and pancreas plasticity. |
| 6787 | 19541499 | The insulin receptor substrate (insulin receptor 2/phosphoinositide 3-kinase [PI3K]) pathway plays a crucial part in regulating beta-cell mass and function. |
| 6788 | 19541499 | The serine-threonine kinase Akt, also known as protein kinase B, is one of the major downstream targets of the PI3K pathway and is negatively regulated by phosphatase and tensin homologue deleted on chromosome 10. |
| 6789 | 19541746 | Dual ablation of Grb10 and Grb14 in mice reveals their combined role in regulation of insulin signaling and glucose homeostasis. |
| 6790 | 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. |
| 6791 | 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. |
| 6792 | 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. |
| 6793 | 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. |
| 6794 | 19543529 | Rapid insulin-dependent endocytosis of the insulin receptor by caveolae in primary adipocytes. |
| 6795 | 19577557 | Suppression of PC-1/ENPP-1 expression improves insulin sensitivity in vitro and in vivo. |
| 6796 | 19577557 | Plasma cell membrane glycoprotein-1, or ectonucleotide pyrophosphatase/phosphodieterase (PC-1/ENPP1) has been shown to inhibit insulin signaling in cultured cells in vitro and in transgenic mice in vivo when overexpressed. |
| 6797 | 19577557 | However, it has not been proven that suppression of PC-1 expression or inhibition of its function will actually improve insulin sensitivity. |
| 6798 | 19577557 | We show in the current study that transient overexpression of PC-1 inhibits insulin-stimulated insulin receptor tyrosine phosphorylation in HEK293 cells, while knockdown of PC-1 with siRNA significantly increases insulin-stimulated Akt phosphorylation in HuH7 human hepatoma cells. |
| 6799 | 19577557 | Taken together, these results demonstrate that suppression of PC-1 expression improves insulin sensitivity in vitro and in an animal model of diabetes, supporting the proposition that PC-1 inhibition is a potential therapeutic approach for the treatment of type 2 diabetes. |
| 6800 | 19589910 | Human aortic smooth muscle cells are insulin resistant at the receptor level but sensitive to IGF1 and IGF2. |
| 6801 | 19589910 | For comparison, the effects of IGF1 and IGF2 were also studied. |
| 6802 | 19589910 | In HASMC, both mRNA and protein expression of IGF1 receptors (IGF1R) were fivefold higher compared to insulin receptor (IR). |
| 6803 | 19589910 | IGF1 stimulated IR substrate-1 and AKT at 10(-8) mol/l and extracellular signal-regulated kinases 1 and 2 at 10(-9)-10(-8) mol/l respectively. |
| 6804 | 19589910 | IGF1 and 2 at a concentration of 10(-8)-10(-7) mol/l significantly stimulated (3)H-thymidine incorporation, whereas insulin did not. (14)C-Glucose accumulation was stimulated by IGF1 or IGF2 10(-8)-10(-7) mol/l, and also by insulin 10(-7) mol/l. |
| 6805 | 19589910 | Our results suggest that IGF1R and hybrid IR/IGF1R are activated by physiological concentrations of IGF1 and 2 in HASMC and this propagates downstream signaling and biological effects, while insulin has no effect on its receptor or downstream signaling probably due to a preponderance of IGF1R and incorporation of IR into hybrid IR/IGF1R. |
| 6806 | 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. |
| 6807 | 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. |
| 6808 | 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. |
| 6809 | 19605645 | Both insulin resistance (type II diabetes) and beta-amyloid (Abeta) oligomers are implicated in Alzheimer's disease (AD). |
| 6810 | 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). |
| 6811 | 19605645 | IRS-1 couples insulin and other trophic factor receptors to downstream kinases and neuroprotective signaling. |
| 6812 | 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. |
| 6813 | 19605645 | The omega-3 fatty acid docosahexaenoic acid (DHA) similarly inhibited JNK and the phosphorylation of IRS-1 and tau in cultured hippocampal neurons. |
| 6814 | 19605645 | Feeding 3xTg-AD transgenic mice a diet high in saturated and omega-6 fat increased active JNK and phosphorylated IRS-1 and tau. |
| 6815 | 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. |
| 6816 | 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. |
| 6817 | 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. |
| 6818 | 19617901 | Physical and functional interaction between polyoma virus middle T antigen and insulin and IGF-I receptors is required for oncogene activation and tumour initiation. |
| 6819 | 19617901 | The insulin-like growth factor I receptor (IGF-IR) and the insulin receptor (IR) are known to be implicated in the development of many cancers. |
| 6820 | 19617901 | Insulin and IGF-I increase association of the IR and IGF-IR with PyVmT, enhance tyrosine phosphorylation of PyVmT and augment the recruitment of Src and PLCgamma(1) to PyVmT. |
| 6821 | 19617901 | This is accompanied by robust and sustained phosphorylation of Akt and ERK1/2, which are implicated in both PyVmT and IGF-IR/IR signalling. |
| 6822 | 19649881 | Protein tyrosine phosphatases (PTPs) as drug targets: inhibitors of PTP-1B for the treatment of diabetes. |
| 6823 | 19649881 | In the case of the signaling cascade initiated by the activation of the insulin receptor, an important gene knockout study in mice has identified PTP-1B as a potential target for anti-diabetes therapy, and has thus made it a focus of attention for several groups. |
| 6824 | 19662499 | In skeletal muscle cells S1P, through engagement of its S1P(2) receptor, is found to produce a transient burst of reactive oxygen species through a calcium-dependent activation of the small GTPase Rac1. |
| 6825 | 19662499 | S1P-induced redox-signaling is sensed by protein tyrosine phosphatase-1B, the main negative regulator of insulin receptor phosphorylation, which undergoes oxidation and enzymatic inhibition. |
| 6826 | 19679549 | Recently, we identified a novel crosstalk between insulin and G protein-coupled receptor (GPCR) signaling pathways in human pancreatic cancer cells. |
| 6827 | 19679549 | Insulin enhanced GPCR signaling through a rapamycin-sensitive mTOR-dependent pathway. |
| 6828 | 19679549 | Here, we determined whether metformin disrupts the crosstalk between insulin receptor and GPCR signaling in pancreatic cancer cells. |
| 6829 | 19679549 | Treatment of human pancreatic cancer cells (PANC-1, MIAPaCa-2, and BxPC-3) with insulin (10 ng/mL) for 5 minutes markedly enhanced the increase in intracellular [Ca(2+)] induced by GPCR agonists (e.g., neurotensin, bradykinin, and angiotensin II). |
| 6830 | 19679549 | Metformin pretreatment completely abrogated insulin-induced potentiation of Ca(2+) signaling but did not interfere with the effect of GPCR agonists alone. |
| 6831 | 19679549 | Insulin also enhanced GPCR agonist-induced growth, measured by DNA synthesis, and the number of cells cultured in adherent or nonadherent conditions. |
| 6832 | 19679549 | Low doses of metformin (0.1-0.5 mmol/L) blocked the stimulation of DNA synthesis, and the anchorage-dependent and anchorage-independent growth induced by insulin and GPCR agonists. |
| 6833 | 19690174 | Silencing mitogen-activated protein 4 kinase 4 (MAP4K4) protects beta cells from tumor necrosis factor-alpha-induced decrease of IRS-2 and inhibition of glucose-stimulated insulin secretion. |
| 6834 | 19690174 | In healthy humans, TNF-alpha infusion induces skeletal muscle insulin resistance. |
| 6835 | 19690174 | Human and rat primary beta cells were sorted by FACS and cultured for 24 h +/- 20 ng/ml TNF-alpha to explore the impact on apoptosis, proliferation, and short-term insulin secretion (1 h, 2.8 mm glucose followed by 1 h, 16.7 mm glucose at the end of the 24-h culture period) as well as key signaling protein phosphorylation and expression. |
| 6836 | 19690174 | Prior exposure to TNF-alpha for 24 h inhibits glucose-stimulated insulin secretion from primary beta cells. |
| 6837 | 19690174 | This is associated with a decrease in glucose-stimulated phosphorylation of key proteins in the insulin signaling pathway including Akt, AS160, and other Akt substrates, ERK as well as the insulin receptor. |
| 6838 | 19690174 | Strikingly, TNF-alpha treatment decreased IRS-2 protein level by 46 +/- 7% versus control, although mRNA expression was unchanged. |
| 6839 | 19690174 | While TNF-alpha treatment increased MAP4K4 mRNA expression by 33 +/- 5%, knockdown of MAP4K4 by siRNA-protected beta cells against the detrimental effects of TNF-alpha on both insulin secretion and signaling. |
| 6840 | 19690174 | We thus identify MAP4K4 as a key upstream mediator of TNF-alpha action on the beta cell, making it a potential therapeutic target for preservation of beta cell function in type 2 diabetes. |
| 6841 | 19720790 | Severe insulin resistance and intrauterine growth deficiency associated with haploinsufficiency for INSR and CHN2: new insights into synergistic pathways involved in growth and metabolism. |
| 6842 | 19721352 | In addition, quantitative RT-PCR was used to determine changes in insulin signaling gene (insulin receptor substrate (IRS)-1, IRS-2 and phosphatidylinositol 3-kinase (PI3-K) P85alpha) mRNA levels in peripheral leukocytes. |
| 6843 | 19721352 | In peripheral leukocytes, the IRS-2 and PI3-K p85alpha mRNA levels significantly increased, and a significant increase in pyruvate kinase and pyruvate carboxylase activity, two enzymes involved in cellular energy metabolism, was also observed post treatment. |
| 6844 | 19752219 | Insulin receptor isoforms and insulin receptor/insulin-like growth factor receptor hybrids in physiology and disease. |
| 6845 | 19752219 | IR-A is often aberrantly expressed in cancer cells, thus increasing their responsiveness to IGF-II and to insulin and explaining the cancer-promoting effect of hyperinsulinemia observed in obese and type 2 diabetic patients. |
| 6846 | 19769946 | DHPO (20mg/kg/d i.p. for 21 days) attenuated fasting blood glucose, improved glucose disposal and corrected dyslipidemia in genetic (leptin deficient, ob/ob) and dietary (high-fat-fed) mouse models of insulin resistance. |
| 6847 | 19769946 | The increase in 2DG-uptake was associated with an increase in the phosphorylation of AMPK (thr-172) and its downstream effector acetyl-CoA carboxylase without any changes in the phosphorylation of Akt of insulin receptor. |
| 6848 | 19769946 | The AMPK inhibitor, compound C attenuated DHPO-induced glucose-uptake whereas the PI3-kinase inhibitor Wortmannin was less effective. |
| 6849 | 19773552 | Insulin binds with high affinity to the insulin receptor (IR) and with low affinity to the type 1 insulin-like growth factor (IGF) receptor (IGFR). |
| 6850 | 19773552 | The nonstandard side chains project into solvent at the edge of a conserved receptor-binding surface shared by insulin and IGF-I. |
| 6851 | 19785000 | The anti-diabetic effect of anthocyanins in streptozotocin-induced diabetic rats through glucose transporter 4 regulation and prevention of insulin resistance and pancreatic apoptosis. |
| 6852 | 19785000 | ANT not only enhanced STZ-mediated insulin level decreases, but also decreased the triglyceride levels induced by STZ injection in serum. |
| 6853 | 19785000 | Diabetic rats exhibited a lower expression of glucose transporter 4 proteins in the membrane fractions of heart and skeletal muscle tissues, which was enhanced by ANT. |
| 6854 | 19785000 | In addition, ANT activated insulin receptor phosphorylation, suggesting an increased utilization of glucose by tissues. |
| 6855 | 19785000 | Moreover, ANT protected pancreatic tissue from STZ-induced apoptosis through regulation of caspase-3, Bax, and Bcl-2 proteins. |
| 6856 | 19785000 | Furthermore, ANT significantly suppressed malondialdehyde levels and restored superoxide dismutase and catalase activities in diabetic rats. |
| 6857 | 19785000 | Taken together, ANT from black soybean seed coat have anti-diabetic effects that are due, in part, to the regulation of glucose transporter 4 and prevention of insulin resistance and pancreatic apoptosis, suggesting a possible use as a drug to regulate diabetes. |
| 6858 | 19800084 | Accordingly, insulin-stimulated phosphorylations of InsR beta-subunit and Akt were increased after BBR treatment in cultured cells. |
| 6859 | 19800084 | In the clinical study, BBR significantly lowered fasting blood glucose (FBG), hemoglobin A(1c), triglyceride, and insulin levels in patients with type 2 diabetes mellitus (T2DM). |
| 6860 | 19822665 | Analogous to the actions of insulin in higher vertebrates, those in Drosophila include expansion of the insect fat cell mass both by increasing the adipocyte number and by promoting lipid accumulation. |
| 6861 | 19822665 | The ability of insulin to accomplish the former depends on its capacity to bring about phosphorylation and inhibition of the transcription factor Drosophila FOXO (dFOXO) and the serine/threonine protein kinase shaggy, the fly ortholog of glycogen synthase kinase 3 (GSK3). |
| 6862 | 19822665 | Thus, the findings of this study provide evidence that the control of fat mass by insulin is a conserved process and place dFOXO and shaggy/GSK3 downstream of the insulin receptor in controlling adipocyte cell number and triglyceride storage, respectively. |
| 6863 | 19841616 | We report that curcumin dose-dependently eliminates insulin-induced HSC activation by suppressing expression of type I collagen gene and other key genes relevant to HSC activation. |
| 6864 | 19841616 | Furthermore, curcumin attenuates insulin-induced oxidative stress in HSCs by inducing gene expression of glutamate-cysteine ligase (GCL), leading to de novo synthesis of glutathione and the suppression of gene expression of InsR. |
| 6865 | 19862665 | Insulin in combination with glucose activates protein kinase B (PKB or Akt) phosphorylation via phosphoinositide 3-kinase (PI3-kinase). |
| 6866 | 19862665 | Long-term (48 h) stimulation of HUVECs with high glucose augmented expression of the insulin receptor and E-selectin, but downregulated COUP-TFII protein expression. |
| 6867 | 19906834 | Visfatin regulates insulin secretion, insulin receptor signalling and mRNA expression of diabetes-related genes in mouse pancreatic beta-cells. |
| 6868 | 19906834 | This study investigated the effects of visfatin upon insulin secretion, insulin receptor activation and mRNA expression of key diabetes-related genes in clonal mouse pancreatic beta-cells. beta-TC6 cells were cultured in RPMI 1640 and were subsequently treated with recombinant visfatin. |
| 6869 | 19906834 | Incubation with visfatin caused significant changes in the mRNA expression of several key diabetes-related genes, including marked up-regulation of insulin (9-fold increase), hepatocyte nuclear factor (HNF)1beta (32-fold increase), HNF4alpha (16-fold increase) and nuclear factor kappaB (40-fold increase). |
| 6870 | 19906834 | Significant down-regulation was seen in angiotensin-converting enzyme (-3.73-fold) and UCP2 (-1.3-fold). |
| 6871 | 19906834 | Visfatin also caused a significant 46% increase in insulin secretion compared to control (P<0.003) at low glucose, and this increase was blocked by co-incubation with the specific nicotinamide phosphoribosyltransferase inhibitor FK866. |
| 6872 | 19906834 | Both visfatin and nicotinamide mononucleotide induced activation of both insulin receptor and extracellular signal-regulated kinase (ERK)1/2, with visfatin-induced insulin receptor/ERK1/2 activation being inhibited by FK866. |
| 6873 | 19906834 | We conclude that visfatin can significantly regulate insulin secretion, insulin receptor phosphorylation and intracellular signalling and the expression of a number of beta-cell function-associated genes in mouse beta-cells. |
| 6874 | 19906834 | Visfatin regulates insulin secretion, insulin receptor signalling and mRNA expression of diabetes-related genes in mouse pancreatic beta-cells. |
| 6875 | 19906834 | This study investigated the effects of visfatin upon insulin secretion, insulin receptor activation and mRNA expression of key diabetes-related genes in clonal mouse pancreatic beta-cells. beta-TC6 cells were cultured in RPMI 1640 and were subsequently treated with recombinant visfatin. |
| 6876 | 19906834 | Incubation with visfatin caused significant changes in the mRNA expression of several key diabetes-related genes, including marked up-regulation of insulin (9-fold increase), hepatocyte nuclear factor (HNF)1beta (32-fold increase), HNF4alpha (16-fold increase) and nuclear factor kappaB (40-fold increase). |
| 6877 | 19906834 | Significant down-regulation was seen in angiotensin-converting enzyme (-3.73-fold) and UCP2 (-1.3-fold). |
| 6878 | 19906834 | Visfatin also caused a significant 46% increase in insulin secretion compared to control (P<0.003) at low glucose, and this increase was blocked by co-incubation with the specific nicotinamide phosphoribosyltransferase inhibitor FK866. |
| 6879 | 19906834 | Both visfatin and nicotinamide mononucleotide induced activation of both insulin receptor and extracellular signal-regulated kinase (ERK)1/2, with visfatin-induced insulin receptor/ERK1/2 activation being inhibited by FK866. |
| 6880 | 19906834 | We conclude that visfatin can significantly regulate insulin secretion, insulin receptor phosphorylation and intracellular signalling and the expression of a number of beta-cell function-associated genes in mouse beta-cells. |
| 6881 | 19906834 | Visfatin regulates insulin secretion, insulin receptor signalling and mRNA expression of diabetes-related genes in mouse pancreatic beta-cells. |
| 6882 | 19906834 | This study investigated the effects of visfatin upon insulin secretion, insulin receptor activation and mRNA expression of key diabetes-related genes in clonal mouse pancreatic beta-cells. beta-TC6 cells were cultured in RPMI 1640 and were subsequently treated with recombinant visfatin. |
| 6883 | 19906834 | Incubation with visfatin caused significant changes in the mRNA expression of several key diabetes-related genes, including marked up-regulation of insulin (9-fold increase), hepatocyte nuclear factor (HNF)1beta (32-fold increase), HNF4alpha (16-fold increase) and nuclear factor kappaB (40-fold increase). |
| 6884 | 19906834 | Significant down-regulation was seen in angiotensin-converting enzyme (-3.73-fold) and UCP2 (-1.3-fold). |
| 6885 | 19906834 | Visfatin also caused a significant 46% increase in insulin secretion compared to control (P<0.003) at low glucose, and this increase was blocked by co-incubation with the specific nicotinamide phosphoribosyltransferase inhibitor FK866. |
| 6886 | 19906834 | Both visfatin and nicotinamide mononucleotide induced activation of both insulin receptor and extracellular signal-regulated kinase (ERK)1/2, with visfatin-induced insulin receptor/ERK1/2 activation being inhibited by FK866. |
| 6887 | 19906834 | We conclude that visfatin can significantly regulate insulin secretion, insulin receptor phosphorylation and intracellular signalling and the expression of a number of beta-cell function-associated genes in mouse beta-cells. |
| 6888 | 19906834 | Visfatin regulates insulin secretion, insulin receptor signalling and mRNA expression of diabetes-related genes in mouse pancreatic beta-cells. |
| 6889 | 19906834 | This study investigated the effects of visfatin upon insulin secretion, insulin receptor activation and mRNA expression of key diabetes-related genes in clonal mouse pancreatic beta-cells. beta-TC6 cells were cultured in RPMI 1640 and were subsequently treated with recombinant visfatin. |
| 6890 | 19906834 | Incubation with visfatin caused significant changes in the mRNA expression of several key diabetes-related genes, including marked up-regulation of insulin (9-fold increase), hepatocyte nuclear factor (HNF)1beta (32-fold increase), HNF4alpha (16-fold increase) and nuclear factor kappaB (40-fold increase). |
| 6891 | 19906834 | Significant down-regulation was seen in angiotensin-converting enzyme (-3.73-fold) and UCP2 (-1.3-fold). |
| 6892 | 19906834 | Visfatin also caused a significant 46% increase in insulin secretion compared to control (P<0.003) at low glucose, and this increase was blocked by co-incubation with the specific nicotinamide phosphoribosyltransferase inhibitor FK866. |
| 6893 | 19906834 | Both visfatin and nicotinamide mononucleotide induced activation of both insulin receptor and extracellular signal-regulated kinase (ERK)1/2, with visfatin-induced insulin receptor/ERK1/2 activation being inhibited by FK866. |
| 6894 | 19906834 | We conclude that visfatin can significantly regulate insulin secretion, insulin receptor phosphorylation and intracellular signalling and the expression of a number of beta-cell function-associated genes in mouse beta-cells. |
| 6895 | 19923424 | Adenovirus-mediated overexpression of caveolin-3 in hepatic cells also enhanced IR signaling, as shown by increased phosphorylation of IR in response to insulin stimulation and higher glycogen synthesis at baseline. |
| 6896 | 19923424 | These effects were attributed mostly to increased insulin receptor activity and caveolin-mediated, direct inhibition of protein tyrosine phosphatase 1B, which was increased in obese mouse livers. |
| 6897 | 19929783 | Branched-chain amino acids and pigment epithelium-derived factor: novel therapeutic agents for hepatitis c virus-associated insulin resistance. |
| 6898 | 19929783 | HCV directly causes insulin resistance through HCV core protein-elicited proteasomal degradation of insulin receptor substrates and subsequent inactivation of intracellular insulin signaling molecules such as Akt. |
| 6899 | 19929783 | Furthermore, tumor necrosis factor-alpha (TNF-alpha) and/or triglyceride accumulation-induced nuclear factor-kappaB (NF-kappaB) activation in the liver is shown to play a role in insulin resistance in patients with HCV-related chronic liver disease as well. |
| 6900 | 19929783 | We, along with others, have recently found that branched-chain amino acids (BCAAs) and pigment epithelium-derived factor (PEDF) could improve the HCV-associated insulin resistance via suppression of NF-kappaB and preservation of insulin signaling pathway. |
| 6901 | 19929783 | In this review, we discuss the mechanisms for the actions of BCAAs and PEDF, and their clinical implications in insulin resistance of chronic liver disease in patients with HCV infection. |
| 6902 | 19933998 | Divergent regulation of energy expenditure and hepatic glucose production by insulin receptor in agouti-related protein and POMC neurons. |
| 6903 | 19946718 | Cell-type-specific roles of IGF-1R and EGFR in mediating Zn2+-induced ERK1/2 and PKB phosphorylation. |
| 6904 | 19946718 | Zn(2+) exerts insulin-mimetic and antidiabetic effects in rodent models of insulin resistance, and activates extracellular-signal-regulated kinases 1 and 2 (ERK1/2) and protein kinase B (PKB), key components of the insulin signaling pathway. |
| 6905 | 19946718 | Zn(2+)-induced signaling has been shown to be associated with an increase in the tyrosine phosphorylation of insulin receptor (IR), as well as of insulin-like growth factor 1 receptor (IGF-1R) and epidermal growth factor receptor (EGFR) in several cell types. |
| 6906 | 19946718 | Therefore, using a series of pharmacological inhibitors and genetically engineered cells, we have investigated the roles of various R-PTKs in Zn(2+)-induced ERK1/2 and PKB phosphorylation. |
| 6907 | 19946718 | Pretreatment of Chinese hamster ovary (CHO) cells overexpressing a human IR (CHO-HIR cells) with AG1024, an inhibitor for IR protein tyrosine kinase (PTK) and IGF-1R-PTK, blocked Zn(2+)-induced ERK1/2 and PKB phosphorylation, but AG1478, an inhibitor for EGFR, was without effect in CHO cells. |
| 6908 | 19946718 | On the other hand, both of these inhibitors were able to attenuate Zn(2+)-induced phosphorylation of ERK1/2 and PKB in A10 vascular smooth muscle cells. |
| 6909 | 19946718 | Furthermore, both Zn(2+) and insulin-like growth factor 1 failed to stimulate ERK1/2 and PKB phosphorylation in IGF-1R knockout cells. |
| 6910 | 19946718 | Taken together, these data suggest that distinct R-PTKs mediate Zn(2+)-evoked ERK1/2 and PKB phosphorylation in a cell-specific manner. |
| 6911 | 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. |
| 6912 | 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. |
| 6913 | 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. |
| 6914 | 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. |
| 6915 | 19956695 | To dissect the mechanisms linking insulin signaling with mitochondrial function, we first identified a mitochondria-tethering complex in beta-cells that included glucokinase (GK), and the pro-apoptotic protein, BAD(S). |
| 6916 | 19956695 | Mitochondria isolated from beta-cells derived from beta-cell specific insulin receptor knockout (betaIRKO) mice exhibited reduced BAD(S), GK and protein kinase A in the complex, and attenuated function. |
| 6917 | 20061534 | Insulin-feedback via PI3K-C2alpha activated PKBalpha/Akt1 is required for glucose-stimulated insulin secretion. |
| 6918 | 20061534 | Phosphatidylinositide 3-kinases (PI3Ks) play central roles in insulin signal transduction. |
| 6919 | 20061534 | By applying pharmacological inhibitors, transient overexpression and small-interfering RNA-based knockdown of PI3K and PKB/Akt isoforms, together with PI-lipid profiling and live-cell confocal and total internal reflection fluorescence microscopy, we now demonstrate that in response to insulin, PI3K-C2alpha generates PI(3,4)P(2), which allows the selective activation of PKBalpha/Akt1. |
| 6920 | 20061534 | Knockdown of PI3K-C2alpha expression and subsequent reduction of PKBalpha/Akt1 activity in the pancreatic beta-cell impaired glucose-stimulated insulin release, at least in part, due to reduced glucokinase expression and increased AS160 activity. |
| 6921 | 20061534 | Hence, our results identify signal transduction via PI3K-C2alpha as a novel pathway whereby insulin activates PKB/Akt and thus discloses PI3K-C2alpha as a potential drugable target in type 2 diabetes. |
| 6922 | 20061534 | The high degree of codistribution of PI3K-C2alpha and PKBalpha/Akt1 with insulin receptor B type, but not A type, in the same plasma membrane microdomains lends further support to the concept that selectivity in insulin signaling is achieved by the spatial segregation of signaling events. |
| 6923 | 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. |
| 6924 | 20064934 | We hypothesized that NO-induced inactivation of endogenous protein-tyrosine phosphatases (PTPs) would enhance insulin receptor-mediated signaling. |
| 6925 | 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. |
| 6926 | 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. |
| 6927 | 20064934 | We have shown that eNOS-dependent NO production is essential for the activation of insulin signaling. |
| 6928 | 20068149 | MKR mice harbor a transgene encoding a dominant-negative, kinase-dead human insulin-like growth factor-I receptor (IGF-IR) that is expressed exclusively in skeletal muscle, where it acts to inactivate endogenous insulin receptor (IR) and IGF-IR. |
| 6929 | 20068149 | Although lean female MKR mice are insulin resistant and glucose intolerant, displaying accelerated mammary gland development and enhanced phosphorylation of IR/IGF-IR and Akt in mammary tissue, in the context of three different mouse models of breast cancer, these metabolic abnormalities were found to accelerate the development of hyperplastic precancerous lesions. |
| 6930 | 20068149 | Normal or malignant mammary tissue isolated from these mice exhibited increased phosphorylation of IR/IGF-IR and Akt, whereas extracellular signal-regulated kinase 1/2 phosphorylation was largely unaffected. |
| 6931 | 20085539 | Insulin stimulates glucose transport in fat and skeletal muscle cells primarily by inducing the translocation of GLUT4 (glucose transporter isoform 4) to the PM (plasma membrane) from specialized GSVs (GLUT4 storage vesicles). |
| 6932 | 20085539 | In fully differentiated adipocytes, depletion of glycosphingolipids dramatically accelerated insulin-stimulated GLUT4 translocation. |
| 6933 | 20085539 | Although insulin-induced phosphorylation of IRS (insulin receptor substrate) and Akt remained intact in glycosphingolipid-depleted cells, both in vitro budding of GLUT4 vesicles and FRAP of GLUT4-GFP on GSVs were stimulated. |
| 6934 | 20085539 | Glycosphingolipid depletion also enhanced the insulin-induced translocation of VAMP2 (vesicle-associated membrane protein 2), but not the transferrin receptor or cellubrevin, indicating that the effect of glycosphingolipids was specific to VAMP2-positive GSVs. |
| 6935 | 20130739 | Role of glucagon-like peptide-1 analogues on insulin receptor regulation in diabetic rat hearts. |
| 6936 | 20130739 | Male rats were divided into the following 9 groups: nondiabetic (N), nondiabetic treated with exendin-4 (NE), nondiabetic treated with dipeptidyl peptidase IV (DPP-IV) inhibitor (NDp), diabetic (D), diabetic treated with insulin (DI), diabetic treated with exendin-4 (DE), diabetic co-treated with insulin and exendin-4 (DIE), diabetic treated with DPP-IV inhibitor (DDp), and diabetic co-treated with insulin and DPP-IV inhibitor (DIDp). |
| 6937 | 20130739 | After the rats were treated for 1 month, a first-order Bessel function was employed to estimate the insulin binding affinity (with time constant tau = 1/k-n) to its receptors on the coronary endothelium and cardiomyocytes using CHAPS-untreated and CHAPS-treated heart perfusion, respectively. |
| 6938 | 20130739 | Treatment with insulin and (or) exendin-4, a glucagon-like peptide-1 (GLP-1) analogue, increased tau on the coronary endothelium only. |
| 6939 | 20130739 | Therefore, negative myocardial effects related to the insulin receptor were diminished in diabetic rats treated with DPP-IV inhibitor and, more efficiently, by exendin-4. |
| 6940 | 20130739 | Role of glucagon-like peptide-1 analogues on insulin receptor regulation in diabetic rat hearts. |
| 6941 | 20130739 | Male rats were divided into the following 9 groups: nondiabetic (N), nondiabetic treated with exendin-4 (NE), nondiabetic treated with dipeptidyl peptidase IV (DPP-IV) inhibitor (NDp), diabetic (D), diabetic treated with insulin (DI), diabetic treated with exendin-4 (DE), diabetic co-treated with insulin and exendin-4 (DIE), diabetic treated with DPP-IV inhibitor (DDp), and diabetic co-treated with insulin and DPP-IV inhibitor (DIDp). |
| 6942 | 20130739 | After the rats were treated for 1 month, a first-order Bessel function was employed to estimate the insulin binding affinity (with time constant tau = 1/k-n) to its receptors on the coronary endothelium and cardiomyocytes using CHAPS-untreated and CHAPS-treated heart perfusion, respectively. |
| 6943 | 20130739 | Treatment with insulin and (or) exendin-4, a glucagon-like peptide-1 (GLP-1) analogue, increased tau on the coronary endothelium only. |
| 6944 | 20130739 | Therefore, negative myocardial effects related to the insulin receptor were diminished in diabetic rats treated with DPP-IV inhibitor and, more efficiently, by exendin-4. |
| 6945 | 20144759 | Here, we provide evidence that double-stranded RNA-dependent protein kinase (PKR) can respond to nutrient signals as well as endoplasmic reticulum (ER) stress and coordinate the activity of other critical inflammatory kinases such as the c-Jun N-terminal kinase (JNK) to regulate insulin action and metabolism. |
| 6946 | 20144759 | PKR also directly targets and modifies insulin receptor substrate and hence integrates nutrients and insulin action with a defined pathogen response system. |
| 6947 | 20157388 | On immunohistochemistry analysis for the Kir6.2 subunit of K(ATP) channels, insulin receptor beta-subunits, and glucose transporters (GLUT) type 2 and 4 in liver, fat and skeletal muscle tissues, the sulfonylurea drugs (glimepiride and gliclazide) were more effective than repaglinide in recovery from their decreased expressions in OLETF rats. |
| 6948 | 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. |
| 6949 | 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. |
| 6950 | 20354158 | Hypothalamic inflammation induced by high-fat feeding causes insulin and leptin resistance and contributes to the pathogenesis of obesity. |
| 6951 | 20354158 | Insulin-treated cells were evaluated for induction of markers of insulin receptor signaling (p-IRS, p-Akt). |
| 6952 | 20354158 | In both hypothalamic cell lines, inflammation was induced by prototypical inflammatory mediators LPS and TNFalpha, as judged by induction of IkappaBalpha (3- to 5-fold) and IL-6 (3- to 7-fold) mRNA and p-IkappaBalpha protein, and TNFalpha pretreatment reduced insulin-mediated p-Akt activation by 30% (P < 0.05). |
| 6953 | 20360006 | Insulin and insulin-like growth factor-1 receptors act as ligand-specific amplitude modulators of a common pathway regulating gene transcription. |
| 6954 | 20360006 | Insulin and insulin-like growth factor-1 (IGF-1) act on highly homologous receptors, yet in vivo elicit distinct effects on metabolism and growth. |
| 6955 | 20360006 | To investigate how the insulin and IGF-1 receptors exert specificity in their biological responses, we assessed their role in the regulation of gene expression using three experimental paradigms: 1) preadipocytes before and after differentiation into adipocytes that express both receptors, but at different ratios; 2) insulin receptor (IR) or IGF1R knock-out preadipocytes that only express the complimentary receptor; and 3) IR/IGF1R double knock-out (DKO) cells reconstituted with the IR, IGF1R, or both. |
| 6956 | 20360006 | In wild-type preadipocytes, which express predominantly IGF1R, microarray analysis revealed approximately 500 IGF-1 regulated genes (p < 0.05). |
| 6957 | 20360006 | After differentiation, when IR levels increase and IGF1R decrease, insulin became the dominant regulator of each of these genes. |
| 6958 | 20360006 | Measurement of the 50 most highly regulated genes by quantitative PCR did not reveal a single gene regulated uniquely via the IR or IGF1R using cells expressing exclusively IGF-1 or insulin receptors. |
| 6959 | 20360006 | Insulin and IGF-1 dose responses from 1 to 100 nm in WT, IRKO, IGFRKO, and DKO cells re-expressing IR, IGF1R, or both showed that insulin and IGF-1 produced effects in proportion to the concentration of ligand and the specific receptor on which they act. |
| 6960 | 20360006 | Thus, IR and IGF1R act as identical portals to the regulation of gene expression, with differences between insulin and IGF-1 effects due to a modulation of the amplitude of the signal created by the specific ligand-receptor interaction. |
| 6961 | 20371624 | FOXO3a mediates signaling crosstalk that coordinates ubiquitin and atrogin-1/MAFbx expression during glucocorticoid-induced skeletal muscle atrophy. |
| 6962 | 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. |
| 6963 | 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. |
| 6964 | 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. |
| 6965 | 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. |
| 6966 | 20371624 | IRS-2 protein, MEK/ERK signaling, Sp1 phosphorylation, and UbC transcription were simultaneously increased. |
| 6967 | 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. |
| 6968 | 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. |
| 6969 | 20371624 | IRS-1 and Akt phosphorylation were decreased, whereas MEK/ERK signaling and expression of IRS-2, UbC and AT-1 were increased. |
| 6970 | 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. |
| 6971 | 20375985 | Visfatin (also known as pre-B cell colony-enhancing factor) is a newly discovered adipocytokine that is preferentially produced by visceral fat and regulated by cytokines promoting insulin resistance. |
| 6972 | 20375985 | Further, in both renal cells, visfatin synthesis was significantly increased by high glucose in the media but not by angiotensin II. |
| 6973 | 20375985 | Additionally, visfatin treatment induced rapid uptake of glucose and was associated with increased translocation of GLUT-1 to the cellular membrane of both renal cell types. |
| 6974 | 20375985 | Furthermore, visfatin induced tyrosine phosphorylation of the insulin receptor, activated downstream insulin signaling pathways such as Erk-1, Akt, and p38 MAPK, and markedly increased the levels of TGFbeta1, PAI-1, type I collagen, and MCP-1 in both renal cells. |
| 6975 | 20392809 | Insulin-like growth factor-I regulation of immune function: a potential therapeutic target in autoimmune diseases? |
| 6976 | 20392809 | This topically limited review explores the relationship between the immune system and insulin-like growth factors (IGF-I and IGF-II) and the proteins through which they act, including IGF-I receptor (IGF-IR) and the IGF-I binding proteins. |
| 6977 | 20392809 | Many of the consequences ascribed to IGF-IR activation result from its association with several accessory proteins that are either identical or closely related to those involved in insulin receptor signaling. |
| 6978 | 20392809 | Relatively recent awareness that IGF-I and IGF-IR regulate immune function has cast this pathway in an unexpected light; it may represent an important switch governing the quality and amplitude of immune responses. |
| 6979 | 20392809 | IGF-I/IGF-IR signaling may also participate in the pathogenesis of autoimmune diseases, although its relationship with these processes seems complex and relatively unexplored. |
| 6980 | 20392809 | On the one hand, IGF-I seems to protect experimental animals from developing insulin-deficient diabetes mellitus. |
| 6981 | 20392809 | Potential involvement of IGF-I and IGF-IR in the pathogenesis of autoimmune diseases suggests that this pathway might constitute an attractive therapeutic target. |
| 6982 | 20393162 | Lipid-induced insulin resistance is prevented in lean and obese myotubes by AICAR treatment. |
| 6983 | 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. |
| 6984 | 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. |
| 6985 | 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). |
| 6986 | 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). |
| 6987 | 20393162 | Despite a divergent response to lipid between lean and obese myotubes, AICAR inclusion improved insulin signaling in all myotubes. |
| 6988 | 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. |
| 6989 | 20457905 | Insulin receptor functionally enhances multistage tumor progression and conveys intrinsic resistance to IGF-1R targeted therapy. |
| 6990 | 20457905 | The type 1 insulin-like growth factor receptor (IGF-1R) tyrosine kinase is an important mediator of the protumorigenic effects of IGF-I/II, and inhibitors of IGF-1R signaling are currently being tested in clinical cancer trials aiming to assess the utility of this receptor as a therapeutic target. |
| 6991 | 20457905 | Despite mounting evidence that the highly homologous insulin receptor (IR) can also convey protumorigenic signals, its direct role in cancer progression has not been genetically defined in vivo, and it remains unclear whether such a role for IR signaling could compromise the efficacy of selective IGF-1R targeting strategies. |
| 6992 | 20457905 | A transgenic mouse model of pancreatic neuroendocrine carcinogenesis engages the IGF signaling pathway, as revealed by its dependence on IGF-II and by accelerated malignant progression upon IGF-1R overexpression. |
| 6993 | 20457905 | Insulin receptor functionally enhances multistage tumor progression and conveys intrinsic resistance to IGF-1R targeted therapy. |
| 6994 | 20457905 | The type 1 insulin-like growth factor receptor (IGF-1R) tyrosine kinase is an important mediator of the protumorigenic effects of IGF-I/II, and inhibitors of IGF-1R signaling are currently being tested in clinical cancer trials aiming to assess the utility of this receptor as a therapeutic target. |
| 6995 | 20457905 | Despite mounting evidence that the highly homologous insulin receptor (IR) can also convey protumorigenic signals, its direct role in cancer progression has not been genetically defined in vivo, and it remains unclear whether such a role for IR signaling could compromise the efficacy of selective IGF-1R targeting strategies. |
| 6996 | 20457905 | A transgenic mouse model of pancreatic neuroendocrine carcinogenesis engages the IGF signaling pathway, as revealed by its dependence on IGF-II and by accelerated malignant progression upon IGF-1R overexpression. |
| 6997 | 20484460 | Single-nucleotide polymorphisms in the SH2B1 loci and chromosomal deletions of the SH2B1 loci associate with obesity and insulin resistance in humans. |
| 6998 | 20484460 | In cultured cells, SH2B1 promotes leptin and insulin signaling by binding via its SH2 domain to phosphorylated tyrosines in Janus kinase 2 and the insulin receptor, respectively. |
| 6999 | 20484460 | Neuron-specific expression of recombinant SH2B1, but not R555E or DeltaN503, corrected hyperphagia, obesity, glucose intolerance, and insulin resistance in SH2B1 null mice. |
| 7000 | 20493839 | Western blotting was done for insulin receptor signaling and Akt and ELISA analyses for TNFalpha concentration and cleavage of caspase 3 at 2- and 8-months of diabetes. |
| 7001 | 20501674 | FoxO1 links hepatic insulin action to endoplasmic reticulum stress. |
| 7002 | 20501674 | Forkhead box O1 (FoxO1) is a transcription factor that mediates the inhibitory effect of insulin on target genes in hepatic metabolism. |
| 7003 | 20501674 | Increased FoxO1 activity augments the expression of insulin receptor (IR) and IR substrate (IRS)2, which in turn inhibits FoxO1 activity in response to reduced insulin action. |
| 7004 | 20501674 | FoxO1-ADA is a constitutively active allele that is refractory to insulin inhibition, allowing us to determine the metabolic effect of a dislodged FoxO1 feedback loop in mice. |
| 7005 | 20501674 | Unexpectedly, hepatic FoxO1-ADA production elicited a profound unfolded protein response, culminating in the induction of hepatic glucose-regulated protein 78 (GRP78) expression. |
| 7006 | 20501674 | FoxO1 targeted GRP78 gene for trans-activation via selective binding to an insulin responsive element in the GRP78 promoter. |
| 7007 | 20501674 | Our studies underscore the importance of an IR and IRS2-dependent feedback loop to keep FoxO1 activity in check for maintaining hepatic glycogen homeostasis and promoting adaptive unfolded protein response in response to altered metabolism and insulin action. |
| 7008 | 20501674 | Excessive FoxO1 activity, resulting from a dislodged FoxO1 feedback loop in insulin resistant liver, is attributable to hepatic endoplasmic reticulum stress and metabolic abnormalities in diabetes. |
| 7009 | 20506299 | PTP1B deficiency enhances liver growth during suckling by increasing the expression of insulin-like growth factor-I. |
| 7010 | 20506299 | Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of insulin and tyrosine kinase growth factor signaling. |
| 7011 | 20506299 | We have recently demonstrated that PTP1B deficiency increases GLUT2/insulin receptor (IR) A complexes and glucose uptake in suckling, but not adult, primary hepatocytes. |
| 7012 | 20506299 | Conversely, the activity of glucose 6-phosphate dehydrogenase (G6PD), the rate limiting enzyme of the pentose phosphate cycle (PPC) which provides substrates for DNA synthesis, was enhanced in the liver of PTP1B(-/-) animals. |
| 7013 | 20506299 | At the molecular level, STAT 5B phosphorylation, IGF-I mRNA, and protein levels as well as IGF-IR tyrosine phosphorylation were increased in the livers of PTP1B-deficient neonates. |
| 7014 | 20506299 | The effects of PTP1B deficiency on G6PD activity, STAT 5B/IGF-I/IGF-IR axis, PCNA expression and liver growth during suckling were maintained by transferring PTP1B(-/-) embryos (PTP1B(-/-T)) to a wild-type female. |
| 7015 | 20517721 | The Insulin Receptor/PI 3-kinase (INSR/PI3K) signalling pathway is a key regulator of cell and organismal metabolism. |
| 7016 | 20535861 | The synergistic action of unopposed oestrogen and leptin, compounded by increasing insulin, cortisol and xeno-oestrogen exposure directly initiate, promote and exacerbate obesity, type 2 diabetes, uterine overgrowth, prostatic enlargement, prostate cancer and breast cancer. |
| 7017 | 20535861 | This review, in collaboration with hundreds of evidence-based clinical researchers, correlates the significant interactions these hormones exert upon the upregulation of p450 aromatase, oestrogen, leptin and insulin receptor function; the normal status quo of their binding globulins; and how adduct formation alters DNA sequencing to ultimately produce an array of metabolic conditions ranging from menopausal symptoms and obesity to Alzheimer's disease and breast and prostate cancer. |
| 7018 | 20535861 | It reveals the way that poor diet, increased stress, unopposed endogenous oestrogens, exogenous oestrogens, pesticides, xeno-oestrogens and leptin are associated with increased aromatase activity, and how its products, increased endogenous oestrogen and lowered testosterone, are associated with obesity, type 2 diabetes, Alzheimer's disease and oestrogenic disease. |
| 7019 | 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. |
| 7020 | 20560104 | Concomitantly, insulin-induced activation of Akt/PKB and of ERK1/2 was strongly inhibited. |
| 7021 | 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. |
| 7022 | 20560104 | ER stress decreased the secretion of the adipokines adiponectin and leptin, but strongly increased secretion of IL-6. |
| 7023 | 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. |
| 7024 | 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. |
| 7025 | 20573722 | Insulin-stimulated insulin receptor phosphorylation was greatly reduced by exposure to palmitate. |
| 7026 | 20573722 | Similar results were observed with IRS-1-P, PI3K (p85 alpha), and Akt-P. |
| 7027 | 20573722 | In these cells cultured, specifics MAPKs inhibitors were able to reduce both Pax6 and glucagon gene and protein expression. |
| 7028 | 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. |
| 7029 | 20573722 | In contrast, the IRS-2/MAPKs pathway is stimulated, through an activation of the IGF-IR, leading to increased Pax6 and glucagon expression. |
| 7030 | 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. |
| 7031 | 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. |
| 7032 | 20573722 | Insulin-stimulated insulin receptor phosphorylation was greatly reduced by exposure to palmitate. |
| 7033 | 20573722 | Similar results were observed with IRS-1-P, PI3K (p85 alpha), and Akt-P. |
| 7034 | 20573722 | In these cells cultured, specifics MAPKs inhibitors were able to reduce both Pax6 and glucagon gene and protein expression. |
| 7035 | 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. |
| 7036 | 20573722 | In contrast, the IRS-2/MAPKs pathway is stimulated, through an activation of the IGF-IR, leading to increased Pax6 and glucagon expression. |
| 7037 | 20585550 | Akt represents a nodal point between the Insulin receptor and TOR signaling, and its activation by phosphorylation controls cell proliferation, cell size, and metabolism. |
| 7038 | 20585550 | This feedback inhibition is switched from TORC1 to S6K only in the context of enhanced TORC1 activity, as triggered by mutations in tsc2. |
| 7039 | 20621572 | The mechanism of increased tumor activity of insulin analogues is explained by the fact that they act through insulin receptors (IR) and insulin-like growth factor-1 (IGF-1R), stimulating cell growth and inhibiting apoptosis. |
| 7040 | 20621572 | There are two major mechanisms: an increase in the binding time of insulin to IR and increased activation of IGF-1R. |
| 7041 | 20621572 | Therefore, to evaluate the safety of an analogue, the slower dissociation rate from its insulin receptor must be excluded, as well as the increased affinity for the IGF-1 receptor. |
| 7042 | 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. |
| 7043 | 20663687 | The proliferating role of insulin and insulin-like growth factors in cancer. |
| 7044 | 20663687 | Hyperinsulinemia leads to increased expression of insulin-like growth factor (IGF)-I expression. |
| 7045 | 20663687 | In fact, increased insulin, IGF-I and IGF-II levels are associated with tumor growth in vitro, in animal models, and in epidemiological studies in humans. |
| 7046 | 20663687 | In this paper, we discuss the roles of insulin, IGF-I and IGF-II, their interaction with the insulin receptor (IR) and IGF-I receptor (IGF-IR), and their signaling pathways and regulation as these pertain to tumor growth. |
| 7047 | 20717964 | NT-S100A8 did not counteract insulin induced phosphorylation of the insulin receptor, Akt and IκB-α, but it independently activated Akt and NF-κB signaling in PC cells. |
| 7048 | 20717964 | In conclusion, NT-S100A8 exerts a mild effect on PC cell growth, while it reduces PC cell invasion, possibly by Akt and NF-κB signaling, NT-S100A8 enhances [Ca(2+)](i) oscillations and insulin release, probably by inducing Ca(2+) influx from the extracellular space, but it does not interfere with insulin signaling. |
| 7049 | 20730455 | The interaction of insulin analogs with the insulin receptor isoforms (IR-A and IR-B) and with the IGF-I receptor (IGF-IR) is similar but not identical to that of insulin, and therefore, their biological effects do not always reproduce insulin actions in terms of quantity, quality and timing. |
| 7050 | 20730455 | Also, intracellular signaling is different with respect to insulin, with a prevalent activation of the ERK rather than the AKT pathway. |
| 7051 | 20810672 | In lung tissue, metformin did not activate AMPK but inhibited phosphorylation of insulin-like growth factor-I receptor/insulin receptor (IGF-1R/IR), Akt, extracellular signal-regulated kinase (ERK), and mTOR. |
| 7052 | 20810672 | This suggested that metformin indirectly inhibited mTOR in lung tissue by decreasing activation of insulin-like growth factor-I receptor/insulin receptor and Akt upstream of mTOR. |
| 7053 | 20810672 | In lung tissue, metformin did not activate AMPK but inhibited phosphorylation of insulin-like growth factor-I receptor/insulin receptor (IGF-1R/IR), Akt, extracellular signal-regulated kinase (ERK), and mTOR. |
| 7054 | 20810672 | This suggested that metformin indirectly inhibited mTOR in lung tissue by decreasing activation of insulin-like growth factor-I receptor/insulin receptor and Akt upstream of mTOR. |
| 7055 | 20829623 | In particular, glucocorticoid excess stimulates the expression of several key enzymes involved in the process of gluconeogenesis, with a consequent increase of glucose production, and induces an impairment of insulin sensitivity either directly by interfering with the insulin receptor signaling pathway or indirectly, through the stimulation of lipolysis and proteolysis and the consequent increase of fatty acids and amino acids, which contribute to the development of insulin resistance. |
| 7056 | 20835859 | Long-acting insulin analogues elicit atypical signalling events mediated by the insulin receptor and insulin-like growth factor-I receptor. |
| 7057 | 20844837 | Modulation of insulin sensitivity and caveolin-1 expression by orchidectomy in a nonobese type 2 diabetes animal model. |
| 7058 | 20844837 | Therefore, we hypothesized that sex hormones affect the expression of caveolin-1 and contribute to the development of insulin resistance and hyperglycemia in JYD mice. |
| 7059 | 20844837 | Expression of insulin-signaling molecules such as insulin receptor, protein kinase B, and glucose transporter-4 were decreased in male JYD mice compared with female mice. |
| 7060 | 20844837 | Orchidectomized JYD male mice showed improved glucose and insulin tolerance with a concomitant increase in the expression of insulin-signaling molecules and caveolin-1 in adipose tissue and skeletal muscle. |
| 7061 | 20844837 | We conclude that sex hormones modulate the expression of caveolin-1 and insulin-signaling molecules, subsequently affecting insulin sensitivity and the development of type 2 diabetes in JYD mice. |
| 7062 | 20879971 | These genes include glucokinase (GCK), HLA antigens, insulin receptor (INSR), insulin-like growth factor-2 (IGF2), HNF4A, insulin gene (INS-VNTR), plasminogen activator inhibitor 1 (PAI-1), potassium inwardly rectifying channel subfamily J, member 11 (KCNJ11), hepatocyte nuclear factor-4a (HNF4A). |
| 7063 | 20889126 | Examination of "normal" insulin-responsive podocytes in vivo and in vitro demonstrates that insulin signals through the MAPK and PI3K pathways via the insulin receptor and directly remodels the actin cytoskeleton of this cell. |
| 7064 | 20929976 | Direct recruitment of insulin receptor and ERK signaling cascade to insulin-inducible gene loci. |
| 7065 | 20947509 | Genetic analysis of type-1 insulin-like growth factor receptor signaling through insulin receptor substrate-1 and -2 in pancreatic beta cells. |
| 7066 | 20947509 | Inactivation of insulin receptor (InsR), IGF1 receptor (Igf1r), or Irs1 in β cells impairs insulin secretion. |
| 7067 | 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. |
| 7068 | 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. |
| 7069 | 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. |
| 7070 | 20947509 | This additivity of phenotypic manifestations indicates that Irs2 serves a pathway that is largely independent of Igf1r signaling. |
| 7071 | 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. |
| 7072 | 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. |
| 7073 | 20947509 | Genetic analysis of type-1 insulin-like growth factor receptor signaling through insulin receptor substrate-1 and -2 in pancreatic beta cells. |
| 7074 | 20947509 | Inactivation of insulin receptor (InsR), IGF1 receptor (Igf1r), or Irs1 in β cells impairs insulin secretion. |
| 7075 | 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. |
| 7076 | 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. |
| 7077 | 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. |
| 7078 | 20947509 | This additivity of phenotypic manifestations indicates that Irs2 serves a pathway that is largely independent of Igf1r signaling. |
| 7079 | 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. |
| 7080 | 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. |
| 7081 | 20947509 | Genetic analysis of type-1 insulin-like growth factor receptor signaling through insulin receptor substrate-1 and -2 in pancreatic beta cells. |
| 7082 | 20947509 | Inactivation of insulin receptor (InsR), IGF1 receptor (Igf1r), or Irs1 in β cells impairs insulin secretion. |
| 7083 | 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. |
| 7084 | 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. |
| 7085 | 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. |
| 7086 | 20947509 | This additivity of phenotypic manifestations indicates that Irs2 serves a pathway that is largely independent of Igf1r signaling. |
| 7087 | 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. |
| 7088 | 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. |
| 7089 | 20957214 | Chimeric design, synthesis, and biological assays of a new nonpeptide insulin-mimetic vanadium compound to inhibit protein tyrosine phosphatase 1B. |
| 7090 | 20957214 | The PTP1B acts as a negative regulator of insulin signaling by blocking the active site where phosphate hydrolysis of the insulin receptor takes place. |
| 7091 | 20957214 | Due to its nonsubstituted, small-sized scaffold design, its remarkable complex stability, and low toxicity; TSAG0101 should be considered as an innovative insulin-mimetic principle with promising properties and, therefore, could become a new lead compound for potential nonpeptide PTP1B inhibitors in antidiabetic drug research. |
| 7092 | 20975707 | Pseudogene-mediated posttranscriptional silencing of HMGA1 can result in insulin resistance and type 2 diabetes. |
| 7093 | 20975707 | Previously, we demonstrated that high mobility group A1 (HMGA1) protein regulates the insulin receptor (INSR) gene and that two diabetic patients demonstrated a marked destabilization of HMGA1 mRNA. |
| 7094 | 20975707 | Targeted knockdown of HMGA1-p mRNA in patient cells results in a reciprocal increase in HMGA1 mRNA stability and expression levels with a parallel correction in cell-surface INSR expression and insulin binding. |
| 7095 | 20975707 | Pseudogene-mediated posttranscriptional silencing of HMGA1 can result in insulin resistance and type 2 diabetes. |
| 7096 | 20975707 | Previously, we demonstrated that high mobility group A1 (HMGA1) protein regulates the insulin receptor (INSR) gene and that two diabetic patients demonstrated a marked destabilization of HMGA1 mRNA. |
| 7097 | 20975707 | Targeted knockdown of HMGA1-p mRNA in patient cells results in a reciprocal increase in HMGA1 mRNA stability and expression levels with a parallel correction in cell-surface INSR expression and insulin binding. |
| 7098 | 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. |
| 7099 | 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. |
| 7100 | 21072680 | Over-expression of LYRM1 inhibits glucose transport in rat skeletal muscles via attenuated phosphorylation of PI3K (p85) and Akt. |
| 7101 | 21072680 | Western blotting was performed to assess the translocation of insulin-sensitive glucose transporter 4 (GLUT4). |
| 7102 | 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. |
| 7103 | 21072680 | LYRM1 over-expression in L6 myotubes reduced insulin-stimulated glucose uptake and impaired insulin-stimulated GLUT4 translocation. |
| 7104 | 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. |
| 7105 | 21072680 | LYRM1 regulates the function of IRS-1, PI3K, and Akt, and decreases GLUT4 translocation and glucose uptake in response to insulin. |
| 7106 | 21113646 | Present study concentrated on the search for correlation between single nucleotides polymorphisms in UTRs of the INSR, PIK3R1, PTPN1, and SLC2A4 genes and IR. 130 unrelated diabetic patients and 98 healthy controls were analyzed in present study. |
| 7107 | 21113646 | Statistical significance was received for rs3745551 located in 3'-UTR of the INSR and rs3756668 located in 3'-UTR of the PIK3R1 gene with higher number of G/G genotype in insulin resistant subjects. |
| 7108 | 21113646 | Present study provides evidence for association between SNPs in UTRs of the INSR and PIK3R1 genes and insulin resistant phenotype. |
| 7109 | 21113646 | Present study concentrated on the search for correlation between single nucleotides polymorphisms in UTRs of the INSR, PIK3R1, PTPN1, and SLC2A4 genes and IR. 130 unrelated diabetic patients and 98 healthy controls were analyzed in present study. |
| 7110 | 21113646 | Statistical significance was received for rs3745551 located in 3'-UTR of the INSR and rs3756668 located in 3'-UTR of the PIK3R1 gene with higher number of G/G genotype in insulin resistant subjects. |
| 7111 | 21113646 | Present study provides evidence for association between SNPs in UTRs of the INSR and PIK3R1 genes and insulin resistant phenotype. |
| 7112 | 21113646 | Present study concentrated on the search for correlation between single nucleotides polymorphisms in UTRs of the INSR, PIK3R1, PTPN1, and SLC2A4 genes and IR. 130 unrelated diabetic patients and 98 healthy controls were analyzed in present study. |
| 7113 | 21113646 | Statistical significance was received for rs3745551 located in 3'-UTR of the INSR and rs3756668 located in 3'-UTR of the PIK3R1 gene with higher number of G/G genotype in insulin resistant subjects. |
| 7114 | 21113646 | Present study provides evidence for association between SNPs in UTRs of the INSR and PIK3R1 genes and insulin resistant phenotype. |
| 7115 | 21132054 | CONCLUSION: These results suggest that cleavage of the extracellular domain of the insulin receptor, a situation that interferes with the ability for insulin to bind and provide an intracellular signal for glucose transport, may be involved in insulin resistance. |
| 7116 | 21239487 | Using GLUT4-Cre mice, we restored InsR expression in muscle, fat, and brain of Insr(-/-) mice (GIRKI (Glut4-insulin receptor knock-in line 1) mice). |
| 7117 | 21289434 | Insulin-stimulated translocation of glucose transporter 4 (GLUT4) to cell membrane leading to glucose uptake is the rate-limiting step in diabetes. |
| 7118 | 21289434 | We describe a real-time, visual, cell-based qualitative GLUT4 translocation assay using CHO-HIRc-myc-GLUT4eGFP cells that stably express myc- and eGFP-tagged GLUT4 in addition to human insulin receptor (HIRc). |
| 7119 | 21305025 | The signaling mechanisms involved several proteins that include 7 major functional proteins such as INS, INSR, IRS1, IRS2, PIK3CA, Akt2, and GLUT4. |
| 7120 | 21330367 | Insulin-like growth factor 1-mediated hyperthermia involves anterior hypothalamic insulin receptors. |
| 7121 | 21330367 | The objective is to investigate the role of insulin-like growth factor 1 (IGF-1) in the regulation of core body temperature. |
| 7122 | 21330367 | Sequencing cDNA libraries from individual warm-sensitive neurons from the preoptic area (POA) of the hypothalamus, a region involved in the central control of thermoregulation, identified neurons that express both IGF-1 receptor (IGF-1R) and insulin receptor transcripts. |
| 7123 | 21330367 | IGF-1 injection into the POA caused dose-dependent hyperthermia that could be blocked by pretreatment with the IGF-1R tyrosine kinase inhibitor, PQ401. |
| 7124 | 21330367 | Transgenic mice that lack neuronal insulin receptor expression in the brain (NIRKO mice) were unable to mount the full hyperthermic response to IGF-1, suggesting that the IGF-1 mediated hyperthermia is partly dependent on expression of functional neuronal insulin receptors. |
| 7125 | 21330367 | These data indicate a novel thermoregulatory role for both IGF-1R and neuronal insulin receptors in IGF-1 activation of BAT and hyperthermia. |
| 7126 | 21330367 | Insulin-like growth factor 1-mediated hyperthermia involves anterior hypothalamic insulin receptors. |
| 7127 | 21330367 | The objective is to investigate the role of insulin-like growth factor 1 (IGF-1) in the regulation of core body temperature. |
| 7128 | 21330367 | Sequencing cDNA libraries from individual warm-sensitive neurons from the preoptic area (POA) of the hypothalamus, a region involved in the central control of thermoregulation, identified neurons that express both IGF-1 receptor (IGF-1R) and insulin receptor transcripts. |
| 7129 | 21330367 | IGF-1 injection into the POA caused dose-dependent hyperthermia that could be blocked by pretreatment with the IGF-1R tyrosine kinase inhibitor, PQ401. |
| 7130 | 21330367 | Transgenic mice that lack neuronal insulin receptor expression in the brain (NIRKO mice) were unable to mount the full hyperthermic response to IGF-1, suggesting that the IGF-1 mediated hyperthermia is partly dependent on expression of functional neuronal insulin receptors. |
| 7131 | 21330367 | These data indicate a novel thermoregulatory role for both IGF-1R and neuronal insulin receptors in IGF-1 activation of BAT and hyperthermia. |
| 7132 | 21406565 | It is known that elevated PAI-1 plasma levels are correlated with the occurrence of the metabolic syndrome and type 2 diabetes, and we show that PAI-1 reduces the furin-dependent maturation and activity of the insulin receptor and ADAM17: two proteins involved in the onset of these metabolic disorders. |
| 7133 | 21435176 | Insulin and insulin-like growth factor-1 (IGF-1) also have intense effects in the central nervous system (CNS), regulating key processes such as neuronal survival and longevity, as well as learning and memory. |
| 7134 | 21435176 | Whereas the density of brain insulin receptor decreases during age, IGF-1 receptor increases, suggesting that specific insulin-mediated signals is involved in aging and possibly in cognitive decline. |
| 7135 | 21437903 | PA treatment provoked release of cytochrome c from the inner mitochondrial membrane to the cytosol, activated members of the MAPK protein family JNK, p38, ERK, activated caspases 3/9, and increased oxidative/nitrosative stress. |
| 7136 | 21437903 | Exposure of cells to PA for 12 h increased insulin receptor (IR) and GLUT-4 levels in the plasma membrane. |
| 7137 | 21437903 | Insulin treatment (10 mU/ml/30 min) increased the phosphorylation of the IR β-subunit and Akt. |
| 7138 | 21474992 | Epigenetic DNA methylation in the promoters of the Igf1 receptor and insulin receptor genes in db/db mice. |
| 7139 | 21474992 | We have investigated promoter methylation of the Insr, Igf1 and Igf1r genes in skeletal and cardiac muscles of normal and diabetic db/db mice. |
| 7140 | 21474992 | Epigenetic DNA methylation in the promoters of the Igf1 receptor and insulin receptor genes in db/db mice. |
| 7141 | 21474992 | We have investigated promoter methylation of the Insr, Igf1 and Igf1r genes in skeletal and cardiac muscles of normal and diabetic db/db mice. |
| 7142 | 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. |
| 7143 | 21478152 | Resistin has been suggested to be involved in the development of diabetes and insulin resistance. |
| 7144 | 21478152 | Therefore, we wanted to elucidate the mechanisms associated with resistin-induced cardiac hypertrophy and myocardial insulin resistance. |
| 7145 | 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. |
| 7146 | 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. |
| 7147 | 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. |
| 7148 | 21478152 | Inhibition of JNK (with JNK inhibitor SP600125 or using dominant-negative JNK) reduced serine 307 phosphorylation of IRS1. |
| 7149 | 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. |
| 7150 | 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. |
| 7151 | 21519329 | Oncostatin M produced in Kupffer cells in response to PGE2: possible contributor to hepatic insulin resistance and steatosis. |
| 7152 | 21519329 | In a recent study, PGE(2) produced in Kupffer cells attenuated insulin-dependent glucose utilization by interrupting the intracellular signal chain downstream of the insulin receptor in hepatocytes. |
| 7153 | 21519329 | OSM in turn attenuated insulin-dependent Akt activation and, as a downstream target, glucokinase induction in hepatocytes, most likely by inducing suppressor of cytokine signaling 3 (SOCS3). |
| 7154 | 21519329 | COX-2 and OSM mRNA were induced early in the course of the development of non-alcoholic steatohepatitis (NASH) in mice. |
| 7155 | 21519329 | Thus, induction of OSM production in Kupffer cells by an autocrine PGE(2)-dependent feed-forward loop may be an additional, thus far unrecognized, mechanism contributing to hepatic insulin resistance and the development of NASH. |
| 7156 | 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. |
| 7157 | 21520470 | These findings demonstrate that ginsenosides Rg3 and Re may stimulate glucose uptake via the PI3K pathways involving IRS-1. |
| 7158 | 21536370 | Hyperinsulinemia stimulates the liver to produce more insulin-like growth factor (IGF), another mitogen and an anti-apoptotic agent which binds insulin receptor/IGF receptor and stimulates prostate growth. |
| 7159 | 21536370 | Previously, we have shown that the expression of c-Jun in the fibroblastic stroma can promote secretion of IGF-I, which stimulates prostate epithelial cell proliferation through activating specific target genes. |
| 7160 | 21537430 | Among the many molecules involved in the intracellular processing of the signal provided by insulin, the insulin receptor substrate-2, the protein kinase B and the forkhead transcription factor Foxo 1a are of particular interest, as recent data has provided strong evidence that dysfunction of these proteins results in insulin resistance in vivo. |
| 7161 | 21537430 | Recently, studies have revealed that phosphoinositidedependent kinase 1-independent phosphorylation of protein kinase Cε causes a reduction in insulin receptor gene expression. |
| 7162 | 21540285 | Conversely, those with low insulin, IGF-I and IGF-II levels appear to be relatively protected from cancer development. |
| 7163 | 21540285 | Some studies suggest that targeting insulin receptor signaling may be an important alternative or adjunct to targeting IGF-I receptor signaling. |
| 7164 | 21602604 | Insulin suppresses the expression and function of breast cancer resistance protein in primary cultures of rat brain microvessel endothelial cells. |
| 7165 | 21602604 | The aim of this study was to investigate the role of insulin in the regulation of breast cancer resistance protein (BCRP) function and expression using primary cultured rat brain microvessel endothelial cells (rBMECs) as an in vitro model of the blood brain barrier (BBB). |
| 7166 | 21602604 | Further results showed that insulin down-regulated the function and expression of BCRP in rBMECs in a concentration-dependent manner. |
| 7167 | 21602604 | Treatment with an antibody against the insulin receptor abolished the down-regulation of BCRP function and expression that was induced by insulin. |
| 7168 | 21602604 | These results indicate that insulin suppressed the function and expression of BCRPs in rBMEC primary cultures. |
| 7169 | 21633908 | The molecular characteristics of insulin X10, along with its interaction at both the IGF-1 receptor and the insulin receptor, have provided us with important insights into mechanisms implicated in metabolic and mitogenic signalling of insulin analogues. |
| 7170 | 21654750 | We identify caveolin-1, a critical regulator of the insulin receptor, as a direct target gene of miR-103/107. |
| 7171 | 21654750 | We demonstrate that caveolin-1 is upregulated upon miR-103/107 inactivation in adipocytes and that this is concomitant with stabilization of the insulin receptor, enhanced insulin signalling, decreased adipocyte size and enhanced insulin-stimulated glucose uptake. |
| 7172 | 21654750 | We identify caveolin-1, a critical regulator of the insulin receptor, as a direct target gene of miR-103/107. |
| 7173 | 21654750 | We demonstrate that caveolin-1 is upregulated upon miR-103/107 inactivation in adipocytes and that this is concomitant with stabilization of the insulin receptor, enhanced insulin signalling, decreased adipocyte size and enhanced insulin-stimulated glucose uptake. |
| 7174 | 21686432 | She had no insulin or insulin receptor antibodies but was positive for islet cell and glutamic acid decarboxylase (GAD) antibodies. |
| 7175 | 21705841 | In the present study, we investigated the effects of berberine on fasting blood glucose, liver glycogen, Akt, Glycogen synthase kinase-3, glucokinase and insulin receptor substrate (IRS) in alloxan-induced diabetic mice, exploring its possible hypoglycemic mechanism. |
| 7176 | 21705841 | Liver glycogen content, the expression and activity of glucokinase and the phosphorylated Akt and IRS were all significantly reduced in diabetic mice whereas berberine blocked these changes. |
| 7177 | 21705841 | Collectively, Berberine upregulates the activity of Akt possibly via insulin signaling pathway, eventually lowering high blood glucose in alloxan-induced diabetic mice. |
| 7178 | 21720388 | The association of phosphoinositide 3-kinase enhancer A with hepatic insulin receptor enhances its kinase activity. |
| 7179 | 21720388 | Here, we show that phosphoinositide 3-kinase enhancer A (PIKE-A) is a new insulin-dependent enhancer of hepatic IRTK. |
| 7180 | 21720388 | Specifically, insulin-provoked phosphoinositide 3-kinase/Akt signalling is diminished in the liver of LPKO mice, leading to the failure of insulin-suppressed gluconeogenesis and hyperglycaemia. |
| 7181 | 21728966 | In lipopolysaccharide (LPS)-stimulated macrophages, SF23 decreased nitrite production and attenuated the mRNA expression of both iNOS and COX-2. |
| 7182 | 21728966 | Interestingly, SF23, but not rosiglitazone, prevented LPS-induced mitochondrial membrane hyperpolarization, apoptosis, reactive oxygen species (ROS) generation, and the expression of NADPH oxidase subunits, Nox1 and Nox2. |
| 7183 | 21728966 | Finally, in macrophages exposed to high concentrations of glucose, SF23 induced significant increases in the mRNA expression of glucose transporters, insulin receptor substrate and mitoNEET. |
| 7184 | 21742034 | Adult rat models of streptozotocin-induced DM1 and genetic strains of DM2 and HTN were used to investigate relative contributions of DM and HTN for alterations in cerebral structure and function as well as insulin receptor biology using cognitive testing, magnetic resonance imaging (MRI), and histological and molecular methods. |
| 7185 | 21776823 | Molecular and cellular studies indicated that metformin significantly elevated p53 and Bax levels and reduced STAT3 and Bcl-2. |
| 7186 | 21776823 | Receptor inhibitor studies indicated that p53 activation was mediated through insulin receptor (IR), not insulin-like growth factor-1 receptor (IGF-IR). |
| 7187 | 21776823 | Furthermore, MEK inhibitor significantly suppressed metformin-induced p53 and Bax elevation while ERK inhibitor generated a slight reduction in p53 levels. |
| 7188 | 21776823 | In contrast, PI3K inhibitor did not produce any effect on the metformin-elevated p53 levels. |
| 7189 | 21776823 | Finally, SAPK/JNK, known to be involved in apoptosis, was activated in cells treated with metformin and the activation appeared to occur downstream of ERK. |
| 7190 | 21776823 | All these results suggested that metformin activated p53, Bax, and induced tumor cell apoptosis through the ERK signaling pathway. |
| 7191 | 21776823 | This pathway has not been previously described for IR, p53, Bax activation, or apoptosis. |
| 7192 | 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. |
| 7193 | 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. |
| 7194 | 21810948 | Acute insulin treatment resulted in time- and concentration-dependent activation of the signaling cascade, including phosphorylation of the insulin receptor, Akt, p70S6K, and glycogen synthase kinase-3β. |
| 7195 | 21810948 | Chronic insulin treatment resulted in increased basal Akt phosphorylation. |
| 7196 | 21810948 | More importantly, acute insulin stimulation after chronic insulin treatment resulted in blunted phosphorylation of Akt, p70S6K, and glycogen synthase kinase-3β. |
| 7197 | 21810948 | Interestingly, when the cells were treated with phosphatidylinositol 3-kinase pathway inhibitor, but not MAPK pathway inhibitor, chronic insulin treatment did not block acute insulin treatment-induced Akt phosphorylation. |
| 7198 | 21810948 | Insulin-induced Akt phosphorylation was lower in dorsal root ganglion neurons from BKS-db/db compared with control BKS-db+ mice. |
| 7199 | 21841811 | Activating transcription factor 6 protects insulin receptor from ER stress-stimulated desensitization via p42/44 ERK pathway. |
| 7200 | 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. |
| 7201 | 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. |
| 7202 | 21913804 | We showed that when insulin-like growth factor II (IGF-II) is highly expressed in breast tissues and cell lines, the IGF-I receptor signaling pathway is highly activated. |
| 7203 | 21913804 | Since IGF-II activates the insulin receptor (INSR), we propose that the INSR signaling is also activated in this system. |
| 7204 | 21926342 | Losartan improves aortic endothelium-dependent relaxation via proline-rich tyrosine kinase 2/Src/Akt pathway in type 2 diabetic Goto-Kakizaki rats. |
| 7205 | 21926342 | We hypothesized that insulin-induced relaxation and the associated proline-rich tyrosine kinase 2 (Pyk2)/Src/Akt pathway would be abnormal in aortas from the Goto-Kakizaki (GK) type 2 diabetic rat, which exhibits hyperglycemia/insulin resistance, and that losartan treatment of such rats (25 mg·kg(-1)·day(-1) for 2 wk) would correct these abnormalities. |
| 7206 | 21926342 | Pyk2, Src, and Akt/endothelial nitric oxide synthase (eNOS) signaling-pathway protein levels and activities were assayed mainly by Western blotting and partly by immunohistochemistry. |
| 7207 | 21926342 | In GK (vs. age-matched control) aortas, various insulin-stimulated levels [nitric oxide production and the phosphorylations of eNOS at Ser(1177), of Akt at Thr(308), of phosphoinositide-dependent kinase-1 (PDK1) at Ser(241), of Src at Tyr(416), and of Pyk2 at Tyr(579)] were all significantly decreased and unaffected by either Src inhibitor (PP2) or Pyk2 inhibitor (AG17), while the insulin-stimulated levels of insulin receptor substrate (IRS)-1 phosphorylation at Ser(307), total-eNOS, and total-Akt were significantly increased. |
| 7208 | 21926342 | The insulin-stimulated phosphorylation levels of Src/PDK1/Akt/eNOS, but not of Pyk2, were decreased by PP2 in control and losartan-treated GK, but not in GK, aortas. |
| 7209 | 21926342 | These results suggest that in the GK diabetic aorta increased phospho-IRS-1 (at Ser(307)) and decreased Pyk2/Src activity inhibit insulin-induced stimulation of the PDK/Akt/eNOS pathway. |
| 7210 | 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. |
| 7211 | 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. |
| 7212 | 21966329 | It has been shown that the naturally occurring gut hormones incretins, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) can preserve the morphology and function of pancreatic beta cell. |
| 7213 | 21966329 | In addition, GIP and GLP-1 act on insulin receptors to facilitate insulin-receptor binding, resulting in optimal glucose metabolism. |
| 7214 | 21966329 | The paper also identified and reviewed a number of inhibitors, which can block dipeptidyl peptidase 4 (DPP-4), the enzyme responsible for the rapid degradation of GLP-1. |
| 7215 | 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. |
| 7216 | 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. |
| 7217 | 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. |
| 7218 | 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. |
| 7219 | 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. |
| 7220 | 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. |
| 7221 | 22055502 | In contrast, mice homozygous for a constitutively deacetylated Foxo1 allele (Foxo1(KR/KR)) display a unique metabolic phenotype of impaired insulin action on hepatic glucose metabolism but decreased plasma lipid levels and low respiratory quotient that are consistent with a state of preferential lipid usage. |
| 7222 | 22055502 | Moreover, Foxo1(KR/KR) mice show a dissociation between weight gain and insulin resistance in predisposing conditions (high fat diet, diabetes, and insulin receptor mutations), possibly due to decreased cytokine production in adipose tissue. |
| 7223 | 22057897 | Insulin receptor signaling mediates APP processing and β-amyloid accumulation without altering survival in a transgenic mouse model of Alzheimer's disease. |
| 7224 | 22057897 | In brains from patients with Alzheimer's disease (AD), expression of insulin receptor (IR), insulin-like growth factor-1 receptor (IGF-1R), and insulin receptor substrate proteins is downregulated. |
| 7225 | 22057897 | A key step in the pathogenesis of AD is the accumulation of amyloid precursor protein (APP) cleavage products, β-amyloid (Aβ)(1-42) and Aβ(1-40). |
| 7226 | 22057897 | Analyzing APP C-terminal fragments (CTF) revealed decreased α-/β-CTFs in the brains of nIR(-/-)Tg2576 mice suggesting decreased APP processing. |
| 7227 | 22057897 | Cell based experiments showed that inhibition of the PI3-kinase pathway suppresses endosomal APP cleavage and decreases α- as well as β-secretase activity. |
| 7228 | 22057897 | Deletion of only one copy of the neuronal IGF-1R partially rescues the premature mortality of Tg2576 mice without altering total amyloid load. |
| 7229 | 22057897 | Analysis of Tg2576 mice expressing either a dominant negative or constitutively active form of forkhead box-O (FoxO)1 did not reveal any alteration of amyloid burden, APP processing and did not rescue premature mortality in these mice. |
| 7230 | 22057897 | But exclusively decreased IGF-1R expression reduces AD-associated mortality independent of β-amyloid accumulation and FoxO1-mediated transcription. |
| 7231 | 22057897 | Insulin receptor signaling mediates APP processing and β-amyloid accumulation without altering survival in a transgenic mouse model of Alzheimer's disease. |
| 7232 | 22057897 | In brains from patients with Alzheimer's disease (AD), expression of insulin receptor (IR), insulin-like growth factor-1 receptor (IGF-1R), and insulin receptor substrate proteins is downregulated. |
| 7233 | 22057897 | A key step in the pathogenesis of AD is the accumulation of amyloid precursor protein (APP) cleavage products, β-amyloid (Aβ)(1-42) and Aβ(1-40). |
| 7234 | 22057897 | Analyzing APP C-terminal fragments (CTF) revealed decreased α-/β-CTFs in the brains of nIR(-/-)Tg2576 mice suggesting decreased APP processing. |
| 7235 | 22057897 | Cell based experiments showed that inhibition of the PI3-kinase pathway suppresses endosomal APP cleavage and decreases α- as well as β-secretase activity. |
| 7236 | 22057897 | Deletion of only one copy of the neuronal IGF-1R partially rescues the premature mortality of Tg2576 mice without altering total amyloid load. |
| 7237 | 22057897 | Analysis of Tg2576 mice expressing either a dominant negative or constitutively active form of forkhead box-O (FoxO)1 did not reveal any alteration of amyloid burden, APP processing and did not rescue premature mortality in these mice. |
| 7238 | 22057897 | But exclusively decreased IGF-1R expression reduces AD-associated mortality independent of β-amyloid accumulation and FoxO1-mediated transcription. |
| 7239 | 22073309 | In both cultured human umbilical vein endothelial cells and rat microvascular preparations, visfatin (50 ng/mL) stimulated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity, as determined by lucigenin-derived chemiluminiscence. |
| 7240 | 22073309 | The relaxation to ACh impaired by visfatin was restored by the NADPH oxidase inhibitor apocynin (10 µmol/L). |
| 7241 | 22073309 | Additionally, the Nampt inhibitor APO866 (10 mmol/L to 10 µmol/L), but not an insulin receptor-blocking antibody, also prevented the stimulation of NADPH oxidase and the relaxation impairment elicited by visfatin. |
| 7242 | 22073309 | Accordingly, the product of Nampt activity nicotinamide mononucleotide (100 nmol/L to 1 mmol/L) stimulated endothelial NADPH oxidase activity and concentration-dependently impaired ACh-induced vasorelaxation. |
| 7243 | 22073309 | In conclusion, visfatin impairs endothelium-dependent relaxation through a mechanism involving NADPH oxidase stimulation and relying on Nampt enzymatic activity, and therefore arises as a potential new player in the development of endothelial dysfunction. |
| 7244 | 22081023 | A hepatocyte growth factor receptor (Met)-insulin receptor hybrid governs hepatic glucose metabolism. |
| 7245 | 22081023 | Met is the transmembrane tyrosine kinase cell surface receptor for hepatocyte growth factor (HGF) and is structurally related to the insulin receptor (INSR) tyrosine kinase. |
| 7246 | 22081023 | We show that Met is essential for an optimal hepatic insulin response by directly engaging INSR to form a Met-INSR hybrid complex, which culminates in a robust signal output. |
| 7247 | 22081023 | These results provide new insights into the molecular basis of hepatic insulin resistance and suggest that HGF may have therapeutic potential for type 2 diabetes in the clinical setting. |
| 7248 | 22081023 | A hepatocyte growth factor receptor (Met)-insulin receptor hybrid governs hepatic glucose metabolism. |
| 7249 | 22081023 | Met is the transmembrane tyrosine kinase cell surface receptor for hepatocyte growth factor (HGF) and is structurally related to the insulin receptor (INSR) tyrosine kinase. |
| 7250 | 22081023 | We show that Met is essential for an optimal hepatic insulin response by directly engaging INSR to form a Met-INSR hybrid complex, which culminates in a robust signal output. |
| 7251 | 22081023 | These results provide new insights into the molecular basis of hepatic insulin resistance and suggest that HGF may have therapeutic potential for type 2 diabetes in the clinical setting. |
| 7252 | 22081023 | A hepatocyte growth factor receptor (Met)-insulin receptor hybrid governs hepatic glucose metabolism. |
| 7253 | 22081023 | Met is the transmembrane tyrosine kinase cell surface receptor for hepatocyte growth factor (HGF) and is structurally related to the insulin receptor (INSR) tyrosine kinase. |
| 7254 | 22081023 | We show that Met is essential for an optimal hepatic insulin response by directly engaging INSR to form a Met-INSR hybrid complex, which culminates in a robust signal output. |
| 7255 | 22081023 | These results provide new insights into the molecular basis of hepatic insulin resistance and suggest that HGF may have therapeutic potential for type 2 diabetes in the clinical setting. |
| 7256 | 22087313 | Free fatty acid-induced PP2A hyperactivity selectively impairs hepatic insulin action on glucose metabolism. |
| 7257 | 22087313 | While insulin-receptor phosphorylation was unaffected, activation of Akt and inactivation of the downstream targets Glycogen synthase kinase 3α (Gsk3α and Forkhead box O1 (FoxO1) was inhibited in palmitate-exposed cells. |
| 7258 | 22087313 | Accordingly, dose-response curves for insulin-mediated suppression of the FoxO1-induced gluconeogenic genes and for de novo glucose production were right shifted, and insulin-stimulated glucose oxidation and glycogen synthesis were impaired. |
| 7259 | 22087313 | The activity of the Akt-inactivating Protein Phosphatase 2A (PP2A) was increased in the insulin-resistant cells. |
| 7260 | 22087313 | Furthermore, inhibition of PP2A by specific inhibitors increased insulin-stimulated activation of Akt and phosphorylation of FoxO1 and Gsk3α. |
| 7261 | 22087313 | Finally, PP2A mRNA levels were increased in liver, muscle and adipose tissue, while PP2A activity was increased in liver and muscle tissue in insulin-resistant ZDF rats. |
| 7262 | 22087313 | In conclusion, our findings indicate that FFAs may cause a selective impairment of insulin action upon hepatic glucose metabolism by increasing PP2A activity. |
| 7263 | 22158866 | Inhibition of insulin signaling in endothelial cells by protein kinase C-induced phosphorylation of p85 subunit of phosphatidylinositol 3-kinase (PI3K). |
| 7264 | 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). |
| 7265 | 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. |
| 7266 | 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. |
| 7267 | 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. |
| 7268 | 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. |
| 7269 | 22160220 | Insulin receptor substrate 2 (IRS2)-deficient mice show sensorineural hearing loss that is delayed by concomitant protein tyrosine phosphatase 1B (PTP1B) loss of function. |
| 7270 | 22160220 | The insulin receptor substrate (IRS) proteins are key mediators of insulin and insulinlike growth factor 1 (IGF-1) signaling. |
| 7271 | 22160220 | Protein tyrosine phosphatase (PTP)-1B dephosphorylates and inactivates both insulin and IGF-1 receptors. |
| 7272 | 22160220 | IRS2-deficient mice present altered hepatic insulin signaling and β-cell failure and develop type 2-like diabetes. |
| 7273 | 22160220 | However, the involvement of IRS2 and PTP1B, two IGF-1 downstream signaling mediators, in hearing onset and loss has not been studied. |
| 7274 | 22160220 | We show for the first time that IRS2 is essential for hearing and that PTP1B inhibition may be useful for treating deafness associated with hyperglycemia and type 2 diabetes. |
| 7275 | 22178988 | In this study, we compared indexes of peripheral neuropathy and investigated insulin signaling in the sciatic nerve of insulin-deficient mice and amyloid precursor protein (APP) overexpressing transgenic mice. |
| 7276 | 22178988 | Insulin-deficient and APP transgenic mice displayed similar patterns of peripheral neuropathy with decreased motor nerve conduction velocity, thermal hypoalgesia, and loss of tactile sensitivity. |
| 7277 | 22178988 | Phosphorylation of the insulin receptor and glycogen synthase kinase 3β (GSK3β) was similarly affected in insulin-deficient and APP transgenic mice despite significantly different blood glucose and plasma insulin levels, and nerve of both models showed accumulation of Aβ-immunoreactive protein. |
| 7278 | 22202099 | In this review, we discuss the association between IR, metabolic stress, and atherosclerosis with focus on 1) tissue and cell distribution of insulin receptor and its differential signaling transduction and 2) potential mechanism of insulin signaling impairment and its role in the development of atherosclerosis and vascular function in metabolic disorders including hyperglycemia, hypertension, dyslipidemia, and hyperhomocysteinemia. |
| 7279 | 22209745 | We used a diabetic model, the Goto Kakizaki (GK) rats, to explore insulin receptor expression, insulin and serotonin efficiency in the hypothalamus and liver by means of Akt phosphorylation. |
| 7280 | 22209745 | Insulin or dexfenfluramine (stimulator of serotonin) treatment induced Akt phosphorylation in Wistar rats but not in GK rats that exhibit down-regulated insulin receptor. |
| 7281 | 22209745 | Studies in a neuroblastoma cell line showed that serotonin-induced Akt phosphorylation is PI3-kinase dependent. |
| 7282 | 22209745 | We used a diabetic model, the Goto Kakizaki (GK) rats, to explore insulin receptor expression, insulin and serotonin efficiency in the hypothalamus and liver by means of Akt phosphorylation. |
| 7283 | 22209745 | Insulin or dexfenfluramine (stimulator of serotonin) treatment induced Akt phosphorylation in Wistar rats but not in GK rats that exhibit down-regulated insulin receptor. |
| 7284 | 22209745 | Studies in a neuroblastoma cell line showed that serotonin-induced Akt phosphorylation is PI3-kinase dependent. |
| 7285 | 22210315 | It has recently been suggested that the low-frequency c.136-14_136-13insC variant in high-mobility group A1 (HMGA1) may strongly contribute to insulin resistance and type 2 diabetes risk. |
| 7286 | 22210315 | Finally, this variant had no effects on metabolic traits and was not involved in variations of HMGA1 and insulin receptor (INSR) expressions. |
| 7287 | 22231969 | Ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) is expressed in several tissues, including the kidneys. |
| 7288 | 22231969 | Increased levels of ENPP1 expression inhibit tyrosine-kinase activity of the insulin receptor in several cell types, leading to insulin resistance. |
| 7289 | 22231969 | K121Q polymorphism of the ENPP1 gene seems to be associated with insulin resistance and DN development. |
| 7290 | 22278734 | The insulin receptor (IR) and low-density lipoprotein receptor (LDLR) maintain glucose and lipid metabolism, respectively. |
| 7291 | 22278734 | A short 10 min exposure of cells to insulin disrupts the association between the two receptors and generates LDLR with higher LDL clearing activity without any change in protein expression. |
| 7292 | 22278734 | This co-association of LDLR with IR and their dissociation by insulin may be an important part of the regulatory mechanism of the normal physiological receptor function in a biological system. |
| 7293 | 22306989 | ApoA1: mimetic peptide reverses adipocyte dysfunction in vivo and in vitro via an increase in heme oxygenase (HO-1) and Wnt10b. |
| 7294 | 22306989 | Reduction in heme oxygenase (HO-1) has been shown to exacerbate vascular dysfunction and insulin resistance in obese mice and involves a decrease in adiponectin levels. |
| 7295 | 22306989 | We hypothesized that the apoA1 mimetic peptide, L-4F, will target the expression of the HO-1-adiponectin axis and reverse adipocyte dysfunction both in vivo and in vitro. |
| 7296 | 22306989 | The administration of L-4F [2 mg/Kg/daily (i.p.) for 4-week to 8-week-old obese (ob) mice restored adipocyte function, increased adiponectin release (p < 0.05) and decreased the levels of IL-1 and IL-6 (p < 0.05)]. |
| 7297 | 22306989 | Treatment of both mesenchymal stem cell (MSC)-derived adipocytes with L-4F (50 μg/ml) increased adiponectin (p < 0.05), decreased IL-1 and IL-6 (p < 0.05) levels and increased MSC-derived adipocyte cell numbers by 50% in S phase (p < 0.05). |
| 7298 | 22306989 | An increase of HO-1 expression by L-4F increased insulin-receptor phosphorylation. |
| 7299 | 22306989 | These findings support the hypothesis that L-4F increases early adipocyte markers, HO-1-adiponectin, WNT10b and decreases Peg1/Mest, negative regulators of adipocyte differentiation. |
| 7300 | 22307937 | The inhibition of protein tyrosine phosphatase 1B (PTP1B) is considered a valid strategy to combat insulin resistance and type II diabetes. |
| 7301 | 22307937 | We show here that a dichloromethane extract of Ratanhiae radix ( RR_EX) dose-dependently inhibits human recombinant PTP1B in vitro and enhances insulin-stimulated glucose uptake in murine myocytes. |
| 7302 | 22307937 | This compound inhibited PTP1B in vitro with an IC (50) of 20.2 µM and dose-dependently increased insulin receptor phosphorylation as well as insulin-stimulated glucose uptake in cultured myotubes. |
| 7303 | 22319636 | InsR/FoxO1 signaling curtails hypothalamic POMC neuron number. |
| 7304 | 22319636 | To investigate the role of InsR/FoxO1 signaling in the development and maintenance of these circuits, we surveyed the pool of hypothalamic neurons expressing Pomc mRNA in different mouse models of impaired hypothalamic InsR signaling. |
| 7305 | 22319636 | To establish whether FoxO1 signaling plays a role in this process, we examined POMC neuron number in mice with POMC-specific deletion of FoxO1, and detected a 23% decrease in age-matched animals, consistent with a cell-autonomous role of InsR/FoxO1 signaling in regulating POMC neuron number, distinct from its established role to activate Pomc transcription. |
| 7306 | 22319636 | InsR/FoxO1 signaling curtails hypothalamic POMC neuron number. |
| 7307 | 22319636 | To investigate the role of InsR/FoxO1 signaling in the development and maintenance of these circuits, we surveyed the pool of hypothalamic neurons expressing Pomc mRNA in different mouse models of impaired hypothalamic InsR signaling. |
| 7308 | 22319636 | To establish whether FoxO1 signaling plays a role in this process, we examined POMC neuron number in mice with POMC-specific deletion of FoxO1, and detected a 23% decrease in age-matched animals, consistent with a cell-autonomous role of InsR/FoxO1 signaling in regulating POMC neuron number, distinct from its established role to activate Pomc transcription. |
| 7309 | 22319636 | InsR/FoxO1 signaling curtails hypothalamic POMC neuron number. |
| 7310 | 22319636 | To investigate the role of InsR/FoxO1 signaling in the development and maintenance of these circuits, we surveyed the pool of hypothalamic neurons expressing Pomc mRNA in different mouse models of impaired hypothalamic InsR signaling. |
| 7311 | 22319636 | To establish whether FoxO1 signaling plays a role in this process, we examined POMC neuron number in mice with POMC-specific deletion of FoxO1, and detected a 23% decrease in age-matched animals, consistent with a cell-autonomous role of InsR/FoxO1 signaling in regulating POMC neuron number, distinct from its established role to activate Pomc transcription. |
| 7312 | 22342226 | Adiponectin and leptin in human severe insulin resistance - diagnostic utility and biological insights. |
| 7313 | 22342226 | There is an intimate interplay between systemic insulin action and the actions of the adipocyte-derived proteins leptin and adiponectin. |
| 7314 | 22342226 | Concordant findings in humans and rodents demonstrate that leptin gates critical physiological functions to the prevailing nutritional state, however the physiological functions of adiponectin are less convincingly established. |
| 7315 | 22342226 | Murine evidence suggests that adiponectin can exert insulin-sensitising effects, plasma concentrations of adiponectin in humans correlate in most populations with insulin sensitivity, and increasingly strong evidence suggests an association between common genetic variation around the adiponectin gene and diabetes. |
| 7316 | 22342226 | However rare and severe genetic variants lowering adiponectin levels have not been convincingly associated with insulin resistance, and the discordant and sometimes extreme hyperadiponectinaemia seen in patients with severe insulin resistance due to loss of insulin receptor function poses a challenge to the widely held view that low adiponectin in humans plays a role in causing prevalent insulin resistance. |
| 7317 | 22342226 | The mechanism underlying this phenomenon remains to be elucidated, but the best available evidence implicates increased production of adiponectin in states of insulin receptor dysfunction, attributable at least in part to increased transcription of the ADIPOQ gene. |
| 7318 | 22342226 | Adiponectin and leptin in human severe insulin resistance - diagnostic utility and biological insights. |
| 7319 | 22342226 | There is an intimate interplay between systemic insulin action and the actions of the adipocyte-derived proteins leptin and adiponectin. |
| 7320 | 22342226 | Concordant findings in humans and rodents demonstrate that leptin gates critical physiological functions to the prevailing nutritional state, however the physiological functions of adiponectin are less convincingly established. |
| 7321 | 22342226 | Murine evidence suggests that adiponectin can exert insulin-sensitising effects, plasma concentrations of adiponectin in humans correlate in most populations with insulin sensitivity, and increasingly strong evidence suggests an association between common genetic variation around the adiponectin gene and diabetes. |
| 7322 | 22342226 | However rare and severe genetic variants lowering adiponectin levels have not been convincingly associated with insulin resistance, and the discordant and sometimes extreme hyperadiponectinaemia seen in patients with severe insulin resistance due to loss of insulin receptor function poses a challenge to the widely held view that low adiponectin in humans plays a role in causing prevalent insulin resistance. |
| 7323 | 22342226 | The mechanism underlying this phenomenon remains to be elucidated, but the best available evidence implicates increased production of adiponectin in states of insulin receptor dysfunction, attributable at least in part to increased transcription of the ADIPOQ gene. |
| 7324 | 22344624 | Acute treatment with candesartan cilexetil, an angiotensin II type 1 receptor blocker, improves insulin sensitivity in high-fructose-diet-fed rats. |
| 7325 | 22344624 | We aimed to determine whether acute treatment with candesartan cilexetil (CV-11974), an angiotensin II type 1 receptor blocker (ARB) can improve insulin sensitivity in high-fructose-diet (HFD)-fed rats. |
| 7326 | 22344624 | Furthermore, restoration of impaired tyrosine phosphorylation of insulin receptor (IR) β, Akt phosphorylation at Ser⁴⁷³ and Thr³⁰⁸, and phosphorylation of the 160-kDa Akt substrate (AS160) in the skeletal muscles of HFD-fed rats were achieved by this treatment. |
| 7327 | 22387882 | Alterations in insulin signaling in primary mammalian adipocytes were determined by the phosphorylation of Akt, a critical insulin signaling intermediate. |
| 7328 | 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. |
| 7329 | 22387882 | A similar TF-induced reduction in insulin-stimulated Akt phosphorylation was observed in primary human subcutaneous adipose tissue. |
| 7330 | 22387882 | In contrast, insulin receptor-β, phosphatidylinositol 3-kinase, and Akt expression were unchanged, indicating a specific abrogation of insulin signaling. |
| 7331 | 22387882 | Additionally, TF-treated adipocytes exhibited altered endocrine function with a reduction in both basal and insulin-stimulated leptin secretion. |
| 7332 | 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. |
| 7333 | 22403294 | To develop a novel treatment for these individuals, we used phage display technology to target the insulin receptor (INSR) complexed with insulin and identified a high affinity, allosteric, human monoclonal antibody, XMetA, which mimicked the glucoregulatory, but not the mitogenic, actions of insulin. |
| 7334 | 22403294 | Biophysical studies with cultured cells expressing human INSR demonstrated that XMetA acted allosterically and did not compete with insulin for binding to its receptor. |
| 7335 | 22403294 | To develop a novel treatment for these individuals, we used phage display technology to target the insulin receptor (INSR) complexed with insulin and identified a high affinity, allosteric, human monoclonal antibody, XMetA, which mimicked the glucoregulatory, but not the mitogenic, actions of insulin. |
| 7336 | 22403294 | Biophysical studies with cultured cells expressing human INSR demonstrated that XMetA acted allosterically and did not compete with insulin for binding to its receptor. |
| 7337 | 22426206 | Regulation of hepatic LDL receptors by mTORC1 and PCSK9 in mice. |
| 7338 | 22426206 | Recent studies have also suggested that hepatic insulin signaling sustains LDLR levels. |
| 7339 | 22426206 | We therefore sought to elucidate the mechanisms linking hepatic insulin signaling to regulation of LDLR levels. |
| 7340 | 22426206 | In WT mice, insulin receptor knockdown by shRNA resulted in decreased hepatic mTORC1 signaling and LDLR protein levels. |
| 7341 | 22426206 | It also led to increased expression of PCSK9, a known post-transcriptional regulator of LDLR expression. |
| 7342 | 22426206 | Administration of the mTORC1 inhibitor rapamycin caused increased expression of PCSK9, decreased levels of hepatic LDLR protein, and increased levels of VLDL/LDL cholesterol in WT but not Pcsk9-/- mice. |
| 7343 | 22426206 | Conversely, mice with increased hepatic mTORC1 activity exhibited decreased expression of PCSK9 and increased levels of hepatic LDLR protein levels. |
| 7344 | 22426206 | Pcsk9 is regulated by the transcription factor HNF1α, and our further detailed analyses suggest that increased mTORC1 activity leads to activation of PKCδ, reduced activity of HNF4α and HNF1α, decreased PCSK9 expression, and ultimately increased hepatic LDLR protein levels, which result in decreased circulating LDL levels. |
| 7345 | 22446839 | In vivo studies demonstrated that M30 administration (1 mg/kg, P.O. three times a week) reduced hepatic ferritin levels; increased hepatic insulin receptor and glucose transporter-1 levels and improved glucose tolerance in C57BL/6 mice and in a mouse model of type-2 diabetes, the ob/ob (leptin(-/-)). |
| 7346 | 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. |
| 7347 | 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. |
| 7348 | 22470480 | Mice treated with BPA were insulin resistant and had increased glucose-stimulated insulin release. |
| 7349 | 22470480 | In skeletal muscle, insulin-stimulated tyrosine phosphorylation of the insulin receptor β subunit was impaired in BPA-treated mice. |
| 7350 | 22470480 | This impairment was associated with a reduced insulin-stimulated Akt phosphorylation in the Thr(308) residue. |
| 7351 | 22470480 | Both skeletal muscle and liver displayed an upregulation of IRS-1 protein by BPA. |
| 7352 | 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. |
| 7353 | 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. |
| 7354 | 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. |
| 7355 | 22470480 | Mice treated with BPA were insulin resistant and had increased glucose-stimulated insulin release. |
| 7356 | 22470480 | In skeletal muscle, insulin-stimulated tyrosine phosphorylation of the insulin receptor β subunit was impaired in BPA-treated mice. |
| 7357 | 22470480 | This impairment was associated with a reduced insulin-stimulated Akt phosphorylation in the Thr(308) residue. |
| 7358 | 22470480 | Both skeletal muscle and liver displayed an upregulation of IRS-1 protein by BPA. |
| 7359 | 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. |
| 7360 | 22474028 | Skeletal muscle protein tyrosine phosphatase 1B regulates insulin sensitivity in African Americans. |
| 7361 | 22474028 | Protein tyrosine phosphatase 1B (PTP1B) is postulated to modulate insulin action by dephosphorylating the insulin receptor signaling proteins and attenuating insulin signaling. |
| 7362 | 22474028 | We sought to determine the relationship of skeletal muscle PTP1B to whole-body insulin sensitivity. |
| 7363 | 22474028 | PTP1B gene expression was significantly higher in subjects with T2DM versus control (P < 0.0001) and remained significantly different after adjusting for age and insulin sensitivity (P = 0.05). |
| 7364 | 22474028 | PTP1B gene expression was positively related to protein abundance (r(s) = 0.39; P = 0.03; adjusted for age and insulin sensitivity) and negatively related to insulin sensitivity (r(s) = -0.52; P = 0.002; adjusted for age). |
| 7365 | 22474028 | PTP1B overexpression resulted in reduction of Akt phosphorylation in the control subjects. |
| 7366 | 22474028 | Moreover, interference RNA transfection downregulated PTP1B expression and enhanced Akt phosphorylation in subjects with T2DM. |
| 7367 | 22474028 | These data show that skeletal muscle PTP1B gene expression is increased in African American subjects with T2DM, is negatively associated with whole-body insulin sensitivity, and contributes to modulation of insulin signaling. |
| 7368 | 22521314 | Aim of the present study was to analyze the influence of obesity-associated hyperinsulinemia on tau phosphorylation without changes in glucose homeostasis. 15% high fat diet fed over 12-16 weeks induced 2.4-fold increased plasma insulin levels without changing glucose tolerance. |
| 7369 | 22521314 | Additionally, chronic hyperinsulinemia did not influence downstream insulin receptor signaling and the expression of the tau kinases (e.g. |
| 7370 | 22521314 | ERK-1/-2, Akt, GSK-3β, CDK5 or JNK) and tau phosphatases (e.g. |
| 7371 | 22521314 | Thus, we successfully induced hyperinsulinemia without causing glucose intolerance in our experimental animals but this did not influence central insulin receptor signaling or tau phosphorylation. |
| 7372 | 22521314 | Aim of the present study was to analyze the influence of obesity-associated hyperinsulinemia on tau phosphorylation without changes in glucose homeostasis. 15% high fat diet fed over 12-16 weeks induced 2.4-fold increased plasma insulin levels without changing glucose tolerance. |
| 7373 | 22521314 | Additionally, chronic hyperinsulinemia did not influence downstream insulin receptor signaling and the expression of the tau kinases (e.g. |
| 7374 | 22521314 | ERK-1/-2, Akt, GSK-3β, CDK5 or JNK) and tau phosphatases (e.g. |
| 7375 | 22521314 | Thus, we successfully induced hyperinsulinemia without causing glucose intolerance in our experimental animals but this did not influence central insulin receptor signaling or tau phosphorylation. |
| 7376 | 22523330 | The insulin receptor isoform A: a mitogenic proinsulin receptor? |
| 7377 | 22542614 | Insulin receptor β (IRβ) expression was lower in the livers of the aged animals, whereas IRβ and Akt(1/2/3) protein expressions were higher in the muscles. |
| 7378 | 22542614 | The expressions of protein kinase C, protein kinase A and exocytotic proteins, such as syntaxin 1 and synaptosomal-associated protein 25 kDa (SNAP-25), were similar in islets from aged and control rats. |
| 7379 | 22542614 | Furthermore, the expression of proteins of the insulin transduction cascade showed an adaptive profile, with a compensatory increase in IRβ and Akt(1/2/3) in gastrocnemius muscles, which may maintain normal glucose homeostasis in 24-month-old rats. |
| 7380 | 22579212 | Continuous treatment with 5mg/kg borapetoside C (twice daily) for 7 days increased phosphorylation of insulin receptor (IR) and protein kinase B (Akt) as well as the expression of glucose transporter-2 (GLUT2) in T1DM mice. |
| 7381 | 22579212 | Combined treatment of a low dose borapetoside C (0.1mg/kg, twice daily) plus insulin for 7 days enhanced insulin-induced IR and Akt phosphorylation and GLUT2 expression in the liver of T1DM mice. |
| 7382 | 22579915 | The current study was designed to investigate the therapeutic effect of vitamin D₃ and curcumin treatment on β₂-adrenoceptors, transcription factor CREB, insulin receptors, protein kinase B (Akt) and malate dehydrogenase activity in the skeletal muscle of diabetic rats. |
| 7383 | 22579915 | Radioreceptor binding assay was done for β₂-adrenoceptors using specific ligand, [³H] propranolol and gene expression studies of β₂-adrenoceptors, transcription factor CREB, insulin receptors and Akt were also done using specific probes. |
| 7384 | 22579915 | Similarly, an up regulation of β₂-adrenoceptor and CREB gene expression was observed in the diabetic group whereas the insulin receptor expression was down regulated which signifies the increased glycogenolysis, gluconeogenesis and decreased glycogenesis in the muscles. |
| 7385 | 22609131 | Hypertrophic adipocytes begin to secrete low levels of TNF-α, which stimulate preadipocytes and endothelial cells to produce MCP-1, in turn responsible for attracting macrophages to the adipose tissue, thus developing a state of chronic low-grade inflammation which is causally linked to insulin resistance. |
| 7386 | 22609131 | FFA cause insulin resistance by inhibiting insulin signaling through the activation of serin-kinases, i.e. protein kinase C-Θ, and the kinases JNK and IKK, which promote a mechanism of serine phosphorylation of Insulin Receptor Substrates (IRS), leading to interruption of the downstream insulin receptor (IR) signaling. |
| 7387 | 22617042 | The Gly(972)Arg variant of human IRS1 gene is associated with variation in glomerular filtration rate likely through impaired insulin receptor signaling. |
| 7388 | 22617042 | Expression of IRS1 mutant Arg972 in human mesangial cells significantly reduced the insulin-stimulated phosphorylation of IRS1 and Akt kinase. |
| 7389 | 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. |
| 7390 | 22617042 | The Gly(972)Arg variant of human IRS1 gene is associated with variation in glomerular filtration rate likely through impaired insulin receptor signaling. |
| 7391 | 22617042 | Expression of IRS1 mutant Arg972 in human mesangial cells significantly reduced the insulin-stimulated phosphorylation of IRS1 and Akt kinase. |
| 7392 | 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. |
| 7393 | 22617471 | Regulation of glucose transport by insulin: traffic control of GLUT4. |
| 7394 | 22617471 | Insulin increases glucose uptake into fat and muscle cells through the regulated trafficking of vesicles that contain glucose transporter type 4 (GLUT4). |
| 7395 | 22617471 | New insights into insulin signalling reveal that phosphorylation events initiated by the insulin receptor regulate key GLUT4 trafficking proteins, including small GTPases, tethering complexes and the vesicle fusion machinery. |
| 7396 | 22649556 | Topiramate, on the hepatic molecular level, has opposed the high fat/high fructose diet effect, where it significantly increased adiponectin receptors, GLUT2, and tyrosine kinase activity, while decreased insulin receptor isoforms. |
| 7397 | 22649556 | The study proved that insulin-resistance has an effect on hepatic molecular level and that the topiramate-mediated insulin sensitivity is ensued partly by modulation of hepatic insulin receptor isoforms, activation of tyrosine kinase, induction of GLUT2 and elevation of adiponectin receptors, as well as their ligand, adiponectin, besides its known improving effect on glucose tolerance and lipid homeostasis. |
| 7398 | 22649556 | Topiramate, on the hepatic molecular level, has opposed the high fat/high fructose diet effect, where it significantly increased adiponectin receptors, GLUT2, and tyrosine kinase activity, while decreased insulin receptor isoforms. |
| 7399 | 22649556 | The study proved that insulin-resistance has an effect on hepatic molecular level and that the topiramate-mediated insulin sensitivity is ensued partly by modulation of hepatic insulin receptor isoforms, activation of tyrosine kinase, induction of GLUT2 and elevation of adiponectin receptors, as well as their ligand, adiponectin, besides its known improving effect on glucose tolerance and lipid homeostasis. |
| 7400 | 22654904 | Interestingly, studies in rodents suggest that reduced insulin receptor (IR) and insulin-like growth factor-1 receptor (IGF-1R) signaling decrease AD pathology, that is, β-amyloid toxicity. |
| 7401 | 22654904 | In the mammalian brain, there are FoxO1, FoxO3a, and FoxO6 expressed. |
| 7402 | 22654904 | Surprisingly, high-fat diet specifically reduces the expression of FoxO3a and FoxO6 suggesting that IR/IGF-1 → FoxO-mediated transcription is involved in the pathogenesis of obesity-associated cognitive impairment. |
| 7403 | 22654904 | Therefore, the function of FoxO1 and FoxO3a has been investigated in animal models of Alzheimer's disease in detail. |
| 7404 | 22688332 | Nesfatin-1 action in the brain increases insulin sensitivity through Akt/AMPK/TORC2 pathway in diet-induced insulin resistance. |
| 7405 | 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. |
| 7406 | 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. |
| 7407 | 22688332 | Nesfatin-1 action in the brain increases insulin sensitivity through Akt/AMPK/TORC2 pathway in diet-induced insulin resistance. |
| 7408 | 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. |
| 7409 | 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. |
| 7410 | 22688333 | Intraportal delivery of insulin in a constant versus pulsatile pattern led to delayed and impaired activation of hepatic insulin receptor substrate (IRS)-1 and IRS-2 signaling, impaired activation of downstream insulin signaling effector molecules AKT and Foxo1, and decreased expression of glucokinase (Gck). |
| 7411 | 22688333 | We further established that hepatic Gck expression is decreased in the HIP rat model of T2DM, a defect that correlated with a progressive defect of pulsatile insulin secretion. |
| 7412 | 22778220 | We identified in Pax6 knockdown model that genes involved in glucagon secretion such as the glucokinase (GCK), G protein-coupled receptor (GPR40), and GIP receptor (GIPR) as well as the corresponding proteins were significantly decreased whereas the insulin receptor (IR) Kir6.2/Sur1, and glucose transporter 1 genes were not affected. |
| 7413 | 22778220 | We demonstrated that Pax6 directly binds and activates specific elements on the promoter region of the GPR40, GCK, and GIPR genes. |
| 7414 | 22778220 | Finally, through site-directed mutagenesis experiments, we showed that disruption of Pax6 binding on the GCK, GPR40, and GIPR gene promoters led to specific decreases of their activities in the αTC1.9 glucagon-producing cell line. |
| 7415 | 22778220 | Hence our results indicate that Pax6 acts on the regulation of glucagon secretion at least through the transcriptional control of GCK, GPR40, and GIPR. |
| 7416 | 22808485 | We studied reactivity of insulin signal pathway elements, insulin receptor and insulin receptor substrate protein-2 (IRS2 protein), in rat brain in response to insulin insufficiency and insulin resistance during the development of experimental type 1 or type 2 diabetes mellitus. |
| 7417 | 22854958 | Znt7-null mice are more susceptible to diet-induced glucose intolerance and insulin resistance. |
| 7418 | 22854958 | The Znt7 gene encodes a ubiquitously expressed zinc transporter that is involved in transporting cytoplasmic zinc into the Golgi apparatus and a ZnT7-containing vesicular compartment. |
| 7419 | 22854958 | Overexpression of ZnT7 in the pancreatic β-cell stimulates insulin synthesis and secretion through regulation of insulin gene transcription. |
| 7420 | 22854958 | The activity of the insulin signaling pathway was down-regulated in myocytes isolated from the femoral muscle of Znt7 knock-out (KO) mice. |
| 7421 | 22854958 | Insulin tolerance tests showed that male Znt7 KO mice were insulin-resistant. |
| 7422 | 22854958 | Diet-induced insulin resistance in male Znt7 KO mice was paralleled by a reduction in mRNA expression of Insr, Irs2, and Akt1 in the primary skeletal myotubes isolated from the KO mice. |
| 7423 | 22854958 | Overexpression of ZnT7 in a rat skeletal muscle cell line (L6) increased Irs2 mRNA expression, Irs2 and Akt phosphorylation, and glucose uptake. |
| 7424 | 22854958 | We conclude that a combination of decreased insulin secretion and increased insulin resistance accounts for the glucose intolerance observed in Znt7 KO mice. |
| 7425 | 22869320 | Regulation of insulin sensitivity by serine/threonine phosphorylation of insulin receptor substrate proteins IRS1 and IRS2. |
| 7426 | 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. |
| 7427 | 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. |
| 7428 | 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. |
| 7429 | 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). |
| 7430 | 22869320 | Regulation of insulin sensitivity by serine/threonine phosphorylation of insulin receptor substrate proteins IRS1 and IRS2. |
| 7431 | 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. |
| 7432 | 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. |
| 7433 | 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. |
| 7434 | 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). |
| 7435 | 22884029 | The unique signaling roles of PI3K pathways instituted by the engagement of the insulin receptor in an autocrine, positive feed-back loop. |
| 7436 | 22908267 | Oral advanced glycation endproducts (AGEs) promote insulin resistance and diabetes by depleting the antioxidant defenses AGE receptor-1 and sirtuin 1. |
| 7437 | 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. |
| 7438 | 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. |
| 7439 | 22908267 | Oral advanced glycation endproducts (AGEs) promote insulin resistance and diabetes by depleting the antioxidant defenses AGE receptor-1 and sirtuin 1. |
| 7440 | 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. |
| 7441 | 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. |
| 7442 | 22915345 | Retinopathy, a common complication of diabetes, is characterized by an unbalanced production of nitric oxide (NO), a process regulated by nitric oxide synthase (NOS). |
| 7443 | 22915345 | We hypothesized that retinopathy might stem from changes in the insulin receptor substrate (IRS)/PI3K/AKT pathway and/or expression of NOS isoforms. |
| 7444 | 22915345 | Immunoblotting analysis revealed that the retinal tissue of HFD rats had lower levels of AKT(1) , eNOS and nNOS protein than those of samples taken from control animals. |
| 7445 | 22919275 | Systemic inflammation, oxidative stress, elevated serum adipokines and fetuin-A, metabolic acidosis, vitamin D deficiency, depressed serum erythropoietin, endoplasmic reticulum stress, and suppressors of cytokine signaling all cause IR by suppressing insulin receptor-PI3K-Akt pathways in CKD. |
| 7446 | 22961082 | Central resistin overexposure induces insulin resistance through Toll-like receptor 4. |
| 7447 | 22961082 | Resistin promotes both inflammation and insulin resistance associated with energy homeostasis impairment. |
| 7448 | 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. |
| 7449 | 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. |
| 7450 | 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. |
| 7451 | 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. |
| 7452 | 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. |
| 7453 | 22966070 | Tub has a key role in insulin and leptin signaling and action in vivo in hypothalamic nuclei. |
| 7454 | 22966070 | In the current study, we investigated whether insulin, leptin, and obesity can modulate Tub in vivo in hypothalamic nuclei, and we investigated possible consequences on energy balance, neuropeptide expression, and hepatic glucose metabolism. |
| 7455 | 22966070 | Food intake, metabolic characteristics, signaling proteins, and neuropeptide expression were measured in response to fasting and refeeding, intracerebroventricular insulin and leptin, and Tub antisense oligonucleotide (ASO). |
| 7456 | 22966070 | Tub is a substrate of insulin receptor tyrosine kinase (IRTK) and leptin receptor (LEPR)-Janus kinase 2 (JAK2) in hypothalamic nuclei. |
| 7457 | 22966070 | After leptin or insulin stimulation, Tub translocates to the nucleus. |
| 7458 | 22966070 | Inhibition of Tub expression in hypothalamus by ASO increased food intake, fasting blood glucose, and hepatic glucose output, decreased O(2) consumption, and blunted the effect of insulin or leptin on proopiomelanocortin, thyroid-releasing hormone, melanin-concentrating hormone, and orexin expression. |
| 7459 | 22966070 | In hypothalamus of mice administered a high-fat diet, there is a reduction in leptin and insulin-induced Tub-p-tyr and nuclear translocation, which is reversed by reducing protein tyrosine phosphatase 1B expression. |
| 7460 | 22966070 | These results indicate that Tub has a key role in the control of insulin and leptin effects on food intake, and the modulation of Tub may contribute to insulin and leptin resistance in DIO mice. |
| 7461 | 22974639 | The type II diacylglycerol kinases (DGKs) contain several functional domains such as a pleckstrin homology (PH) domain, two C1 domains and a sterile α-motif (SAM) domain. |
| 7462 | 22974639 | Moreover, a high extracellular concentration of glucose activated DGKδ in skeletal muscle cells, which was followed by a reduction in the intracellular diacylglycerol levels and the inactivation of protein kinase Cα, the enzyme that phosphorylates and inactivates the insulin receptor. |
| 7463 | 23001013 | Striatal dopamine receptors modulate the expression of insulin receptor, IGF-1 and GLUT-3 in diabetic rats: effect of pyridoxine treatment. |
| 7464 | 23001013 | Gene expressions were done using fluorescently labeled Taqman probes of dopamine D(1), D(2) receptor, Insulin receptor, Insulin like growth factor-1(IGF-1) and Glucose transporter-3 (GLUT-3). |
| 7465 | 23001013 | Our results showed decreased gene expression of Insulin receptor, IGF-1 and increased gene expression of GLUT-3 in diabetic rats compared to control. |
| 7466 | 23001013 | Pyridoxine treatment restored diabetes induced alterations in dopamine D(1), D(2) receptors, Insulin receptor, IGF-1, GLUT-3 gene expressions in striatum compared to diabetic rats. |
| 7467 | 23001013 | Insulin treatment reversed dopamine D(1), D(2) receptor, GLUT-3 mRNA expression, D(2) receptor binding parameters in the striatum compared to diabetic group. |
| 7468 | 23001013 | Striatal dopamine receptors modulate the expression of insulin receptor, IGF-1 and GLUT-3 in diabetic rats: effect of pyridoxine treatment. |
| 7469 | 23001013 | Gene expressions were done using fluorescently labeled Taqman probes of dopamine D(1), D(2) receptor, Insulin receptor, Insulin like growth factor-1(IGF-1) and Glucose transporter-3 (GLUT-3). |
| 7470 | 23001013 | Our results showed decreased gene expression of Insulin receptor, IGF-1 and increased gene expression of GLUT-3 in diabetic rats compared to control. |
| 7471 | 23001013 | Pyridoxine treatment restored diabetes induced alterations in dopamine D(1), D(2) receptors, Insulin receptor, IGF-1, GLUT-3 gene expressions in striatum compared to diabetic rats. |
| 7472 | 23001013 | Insulin treatment reversed dopamine D(1), D(2) receptor, GLUT-3 mRNA expression, D(2) receptor binding parameters in the striatum compared to diabetic group. |
| 7473 | 23001013 | Striatal dopamine receptors modulate the expression of insulin receptor, IGF-1 and GLUT-3 in diabetic rats: effect of pyridoxine treatment. |
| 7474 | 23001013 | Gene expressions were done using fluorescently labeled Taqman probes of dopamine D(1), D(2) receptor, Insulin receptor, Insulin like growth factor-1(IGF-1) and Glucose transporter-3 (GLUT-3). |
| 7475 | 23001013 | Our results showed decreased gene expression of Insulin receptor, IGF-1 and increased gene expression of GLUT-3 in diabetic rats compared to control. |
| 7476 | 23001013 | Pyridoxine treatment restored diabetes induced alterations in dopamine D(1), D(2) receptors, Insulin receptor, IGF-1, GLUT-3 gene expressions in striatum compared to diabetic rats. |
| 7477 | 23001013 | Insulin treatment reversed dopamine D(1), D(2) receptor, GLUT-3 mRNA expression, D(2) receptor binding parameters in the striatum compared to diabetic group. |
| 7478 | 23001013 | Striatal dopamine receptors modulate the expression of insulin receptor, IGF-1 and GLUT-3 in diabetic rats: effect of pyridoxine treatment. |
| 7479 | 23001013 | Gene expressions were done using fluorescently labeled Taqman probes of dopamine D(1), D(2) receptor, Insulin receptor, Insulin like growth factor-1(IGF-1) and Glucose transporter-3 (GLUT-3). |
| 7480 | 23001013 | Our results showed decreased gene expression of Insulin receptor, IGF-1 and increased gene expression of GLUT-3 in diabetic rats compared to control. |
| 7481 | 23001013 | Pyridoxine treatment restored diabetes induced alterations in dopamine D(1), D(2) receptors, Insulin receptor, IGF-1, GLUT-3 gene expressions in striatum compared to diabetic rats. |
| 7482 | 23001013 | Insulin treatment reversed dopamine D(1), D(2) receptor, GLUT-3 mRNA expression, D(2) receptor binding parameters in the striatum compared to diabetic group. |
| 7483 | 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. |
| 7484 | 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. |
| 7485 | 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). |
| 7486 | 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. |
| 7487 | 23018458 | Insulin modulates the inflammatory granulocyte response to streptococci via phosphatidylinositol 3-kinase. |
| 7488 | 23018458 | We found that GBS-induced, MyD88-dependent chemokine formation of PML was specifically downmodulated by insulin via insulin receptor-mediated induction of PI3K. |
| 7489 | 23018458 | The targeted modulation of bacteria-induced chemokine formation by insulin via PI3K may form a basis for the development of novel targets of adjunctive sepsis therapy. |
| 7490 | 23039274 | These studies indicate, therefore, that monoclonal antibodies that allosterically activate the INSR, such as XMetA, have the potential to be novel agents for the treatment of hyperglycaemia in conditions associated with the insulin resistance of obesity. |
| 7491 | 23085227 | Pyrroloquinoline quinone, a novel protein tyrosine phosphatase 1B inhibitor, activates insulin signaling in C2C12 myotubes and improves impaired glucose tolerance in diabetic KK-A(y) mice. |
| 7492 | 23085227 | Protein tyrosine phosphatase 1B (PTP1B) negatively regulates insulin signaling by tyrosine dephosphorylation of insulin receptor, and increased activity and expression of PTP1B is implicated in the pathogenesis of insulin resistance. |
| 7493 | 23085227 | Therefore, inhibition of PTP1B is anticipated to improve insulin resistance in type 2 diabetic subjects. |
| 7494 | 23085227 | Here, we report that PQQ induces the ligand-independent activation of insulin signaling by inhibiting cellular PTP1B and enhances glucose uptake through the translocation of glucose transporter 4 in mouse C2C12 myotubes. |
| 7495 | 23085254 | Our results showed that with the development of a liver GCK deficiency, significant decreases in the mRNA levels for insulin receptor and Glut2 were observed in the liver, and HkII in muscle, while glucagon mRNA increased markedly in the pancreas. |
| 7496 | 23093779 | Osteoblast-targeted disruption of glucocorticoid signaling significantly attenuated the suppression of osteocalcin synthesis and prevented the development of insulin resistance, glucose intolerance, and abnormal weight gain in corticosterone-treated mice. |
| 7497 | 23093779 | Nearly identical effects were observed in glucocorticoid-treated animals following heterotopic (hepatic) expression of both carboxylated and uncarboxylated osteocalcin through gene therapy, which additionally led to a reduction in hepatic lipid deposition and improved phosphorylation of the insulin receptor. |
| 7498 | 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. |
| 7499 | 23226034 | Results showed that the NsiI polymorphism in INSR and BstnI polymorphism of IRS1 were significantly associated with T2DM only among the Berber group. |
| 7500 | 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. |
| 7501 | 23226034 | Results showed that the NsiI polymorphism in INSR and BstnI polymorphism of IRS1 were significantly associated with T2DM only among the Berber group. |
| 7502 | 23251042 | Therefore it is need of the hour to explore the recombinant insulin- insulin receptor interaction by all possible means. |
| 7503 | 23314177 | We previously have shown that Ahsg, a liver glycoprotein, inhibits insulin receptor (InsR) tyrosine kinase (TK) activity and the ERK1/2 mitogenic signaling arm of insulin signaling. |
| 7504 | 23314177 | Here we show that Ahsg blocks insulin-stimulated GLUT4 translocation and Akt activation in intact cells (mouse myoblasts). |
| 7505 | 23314177 | Furthermore, Ahsg inhibits InsR autophosphorylation of highly-purified insulin holoreceptors in a cell-free, ATP-dependent system, with an IC50 within the range of single-chain Ahsg concentrations in human serum. |
| 7506 | 23314177 | Binding of (125)I-insulin to living cells overexpressing the InsR shows a dissociation constant (KD) of 250pM, unaltered in the presence of 300 nM Ahsg. |
| 7507 | 23314177 | Treatment of myogenic cells with Ahsg blunts insulin-stimulated InsR autophosphorylation and AKT phosphorylation. |
| 7508 | 23314177 | Taken together, we show that Ahsg antagonizes the metabolic functions initiated by InsR activation without interference in insulin binding. |
| 7509 | 23314177 | The experiments suggest a direct interaction of Ahsg with the InsR ectodomain β-subunit in a mode that does not significantly alter the high-affinity binding of insulin to the holoreceptor's two complementing α-subunits. |
| 7510 | 23314177 | We previously have shown that Ahsg, a liver glycoprotein, inhibits insulin receptor (InsR) tyrosine kinase (TK) activity and the ERK1/2 mitogenic signaling arm of insulin signaling. |
| 7511 | 23314177 | Here we show that Ahsg blocks insulin-stimulated GLUT4 translocation and Akt activation in intact cells (mouse myoblasts). |
| 7512 | 23314177 | Furthermore, Ahsg inhibits InsR autophosphorylation of highly-purified insulin holoreceptors in a cell-free, ATP-dependent system, with an IC50 within the range of single-chain Ahsg concentrations in human serum. |
| 7513 | 23314177 | Binding of (125)I-insulin to living cells overexpressing the InsR shows a dissociation constant (KD) of 250pM, unaltered in the presence of 300 nM Ahsg. |
| 7514 | 23314177 | Treatment of myogenic cells with Ahsg blunts insulin-stimulated InsR autophosphorylation and AKT phosphorylation. |
| 7515 | 23314177 | Taken together, we show that Ahsg antagonizes the metabolic functions initiated by InsR activation without interference in insulin binding. |
| 7516 | 23314177 | The experiments suggest a direct interaction of Ahsg with the InsR ectodomain β-subunit in a mode that does not significantly alter the high-affinity binding of insulin to the holoreceptor's two complementing α-subunits. |
| 7517 | 23314177 | We previously have shown that Ahsg, a liver glycoprotein, inhibits insulin receptor (InsR) tyrosine kinase (TK) activity and the ERK1/2 mitogenic signaling arm of insulin signaling. |
| 7518 | 23314177 | Here we show that Ahsg blocks insulin-stimulated GLUT4 translocation and Akt activation in intact cells (mouse myoblasts). |
| 7519 | 23314177 | Furthermore, Ahsg inhibits InsR autophosphorylation of highly-purified insulin holoreceptors in a cell-free, ATP-dependent system, with an IC50 within the range of single-chain Ahsg concentrations in human serum. |
| 7520 | 23314177 | Binding of (125)I-insulin to living cells overexpressing the InsR shows a dissociation constant (KD) of 250pM, unaltered in the presence of 300 nM Ahsg. |
| 7521 | 23314177 | Treatment of myogenic cells with Ahsg blunts insulin-stimulated InsR autophosphorylation and AKT phosphorylation. |
| 7522 | 23314177 | Taken together, we show that Ahsg antagonizes the metabolic functions initiated by InsR activation without interference in insulin binding. |
| 7523 | 23314177 | The experiments suggest a direct interaction of Ahsg with the InsR ectodomain β-subunit in a mode that does not significantly alter the high-affinity binding of insulin to the holoreceptor's two complementing α-subunits. |
| 7524 | 23314177 | We previously have shown that Ahsg, a liver glycoprotein, inhibits insulin receptor (InsR) tyrosine kinase (TK) activity and the ERK1/2 mitogenic signaling arm of insulin signaling. |
| 7525 | 23314177 | Here we show that Ahsg blocks insulin-stimulated GLUT4 translocation and Akt activation in intact cells (mouse myoblasts). |
| 7526 | 23314177 | Furthermore, Ahsg inhibits InsR autophosphorylation of highly-purified insulin holoreceptors in a cell-free, ATP-dependent system, with an IC50 within the range of single-chain Ahsg concentrations in human serum. |
| 7527 | 23314177 | Binding of (125)I-insulin to living cells overexpressing the InsR shows a dissociation constant (KD) of 250pM, unaltered in the presence of 300 nM Ahsg. |
| 7528 | 23314177 | Treatment of myogenic cells with Ahsg blunts insulin-stimulated InsR autophosphorylation and AKT phosphorylation. |
| 7529 | 23314177 | Taken together, we show that Ahsg antagonizes the metabolic functions initiated by InsR activation without interference in insulin binding. |
| 7530 | 23314177 | The experiments suggest a direct interaction of Ahsg with the InsR ectodomain β-subunit in a mode that does not significantly alter the high-affinity binding of insulin to the holoreceptor's two complementing α-subunits. |
| 7531 | 23314177 | We previously have shown that Ahsg, a liver glycoprotein, inhibits insulin receptor (InsR) tyrosine kinase (TK) activity and the ERK1/2 mitogenic signaling arm of insulin signaling. |
| 7532 | 23314177 | Here we show that Ahsg blocks insulin-stimulated GLUT4 translocation and Akt activation in intact cells (mouse myoblasts). |
| 7533 | 23314177 | Furthermore, Ahsg inhibits InsR autophosphorylation of highly-purified insulin holoreceptors in a cell-free, ATP-dependent system, with an IC50 within the range of single-chain Ahsg concentrations in human serum. |
| 7534 | 23314177 | Binding of (125)I-insulin to living cells overexpressing the InsR shows a dissociation constant (KD) of 250pM, unaltered in the presence of 300 nM Ahsg. |
| 7535 | 23314177 | Treatment of myogenic cells with Ahsg blunts insulin-stimulated InsR autophosphorylation and AKT phosphorylation. |
| 7536 | 23314177 | Taken together, we show that Ahsg antagonizes the metabolic functions initiated by InsR activation without interference in insulin binding. |
| 7537 | 23314177 | The experiments suggest a direct interaction of Ahsg with the InsR ectodomain β-subunit in a mode that does not significantly alter the high-affinity binding of insulin to the holoreceptor's two complementing α-subunits. |
| 7538 | 23314177 | We previously have shown that Ahsg, a liver glycoprotein, inhibits insulin receptor (InsR) tyrosine kinase (TK) activity and the ERK1/2 mitogenic signaling arm of insulin signaling. |
| 7539 | 23314177 | Here we show that Ahsg blocks insulin-stimulated GLUT4 translocation and Akt activation in intact cells (mouse myoblasts). |
| 7540 | 23314177 | Furthermore, Ahsg inhibits InsR autophosphorylation of highly-purified insulin holoreceptors in a cell-free, ATP-dependent system, with an IC50 within the range of single-chain Ahsg concentrations in human serum. |
| 7541 | 23314177 | Binding of (125)I-insulin to living cells overexpressing the InsR shows a dissociation constant (KD) of 250pM, unaltered in the presence of 300 nM Ahsg. |
| 7542 | 23314177 | Treatment of myogenic cells with Ahsg blunts insulin-stimulated InsR autophosphorylation and AKT phosphorylation. |
| 7543 | 23314177 | Taken together, we show that Ahsg antagonizes the metabolic functions initiated by InsR activation without interference in insulin binding. |
| 7544 | 23314177 | The experiments suggest a direct interaction of Ahsg with the InsR ectodomain β-subunit in a mode that does not significantly alter the high-affinity binding of insulin to the holoreceptor's two complementing α-subunits. |
| 7545 | 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. |
| 7546 | 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. |
| 7547 | 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. |
| 7548 | 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. |
| 7549 | 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. |
| 7550 | 23335325 | Most of the known SOCS proteins are involved in the modulation of the development of insulin resistance, β-cell failure and eventually T1D and T2D. |
| 7551 | 23335325 | Regarding insulin resistance and T2D, SOCS proteins take part in mediating signals produced by diabetogenic substances and regulate insulin receptor functioning, affecting insulin sensitivity. |
| 7552 | 23338941 | The IGF-1 receptor and regulation of nitric oxide bioavailability and insulin signalling in the endothelium. |
| 7553 | 23338941 | The insulin-like growth factor-1 receptor (IGF-1R), like the insulin receptor (IR), plays a significant role in determining bioavailability of the critical signalling molecule nitric oxide (NO) and hence, modulates endothelial cell function, particularly in response to stimulation with insulin. |
| 7554 | 23349480 | Thus, insulin receptor inactivation in ECs does not impair insulin action, whereas inactivation of Irs2 does. |
| 7555 | 23349535 | Mineralocorticoid receptor-mediated vascular insulin resistance: an early contributor to diabetes-related vascular disease? |
| 7556 | 23349535 | Conversely, renin-angiotensin-aldosterone system and mineralocorticoid receptor (MR) antagonism reduces cardiovascular risk in these patient populations. |
| 7557 | 23349535 | Recent and accumulating evidence in this area has implicated excessive Ser phosphorylation and proteosomal degradation of the docking protein, insulin receptor substrate, and enhanced signaling through hybrid insulin/IGF-1 receptor as important mechanisms underlying aldosterone-mediated interruption of downstream vascular insulin signaling. |
| 7558 | 23354051 | Central role of E3 ubiquitin ligase MG53 in insulin resistance and metabolic disorders. |
| 7559 | 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. |
| 7560 | 23354051 | Conversely, ablation of MG53 prevents diet-induced metabolic syndrome by preserving the insulin receptor, IRS1 and insulin signalling integrity. |
| 7561 | 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. |
| 7562 | 23354051 | Central role of E3 ubiquitin ligase MG53 in insulin resistance and metabolic disorders. |
| 7563 | 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. |
| 7564 | 23354051 | Conversely, ablation of MG53 prevents diet-induced metabolic syndrome by preserving the insulin receptor, IRS1 and insulin signalling integrity. |
| 7565 | 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. |
| 7566 | 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. |
| 7567 | 23363978 | Insulin signaling in the hypothalamus, as assessed by insulin receptor and AKT phosphorylation, decreased after binge drinking. |
| 7568 | 23363978 | Quantitative polymerase chain reaction showed increased hypothalamic inflammation and expression of protein tyrosine phosphatase 1B (PTP1B), a negative regulator of insulin signaling. |
| 7569 | 23363978 | These results show that, in rats, binge drinking induces systemic insulin resistance by impairing hypothalamic insulin action and that this effect can be prevented by inhibition of brain PTP1B. |
| 7570 | 23380686 | Expression analysis of cholinergic, insulin receptor and GLUT-3 in the brainstem of streptozotocin (STZ) induced diabetic rats were studied. |
| 7571 | 23380686 | Our result showed that Bmax of total muscarinic and muscarinic M3 receptors were increased and muscarinic M1 receptor was decreased in diabetic rats compared to control. mRNA level of muscarinic M3, α7-nicotinic acetylcholine, insulin receptors, acetylcholine esterase, choline acetyltransferase and GLUT-3 significantly increased and M1 receptor decreased in the brainstem of diabetic rats. |
| 7572 | 23380686 | The results show that diabetes is associated with significant reduction in brainstem function coupled with altered cholinergic, insulin receptor and GLUT-3 gene expression. |
| 7573 | 23380686 | The present study indicates beneficial effect of curcumin in diabetic rats by regulating the cholinergic, insulin receptor and GLUT-3 in the brainstem similar to the responses obtained with insulin therapy. |
| 7574 | 23380686 | Expression analysis of cholinergic, insulin receptor and GLUT-3 in the brainstem of streptozotocin (STZ) induced diabetic rats were studied. |
| 7575 | 23380686 | Our result showed that Bmax of total muscarinic and muscarinic M3 receptors were increased and muscarinic M1 receptor was decreased in diabetic rats compared to control. mRNA level of muscarinic M3, α7-nicotinic acetylcholine, insulin receptors, acetylcholine esterase, choline acetyltransferase and GLUT-3 significantly increased and M1 receptor decreased in the brainstem of diabetic rats. |
| 7576 | 23380686 | The results show that diabetes is associated with significant reduction in brainstem function coupled with altered cholinergic, insulin receptor and GLUT-3 gene expression. |
| 7577 | 23380686 | The present study indicates beneficial effect of curcumin in diabetic rats by regulating the cholinergic, insulin receptor and GLUT-3 in the brainstem similar to the responses obtained with insulin therapy. |
| 7578 | 23380686 | Expression analysis of cholinergic, insulin receptor and GLUT-3 in the brainstem of streptozotocin (STZ) induced diabetic rats were studied. |
| 7579 | 23380686 | Our result showed that Bmax of total muscarinic and muscarinic M3 receptors were increased and muscarinic M1 receptor was decreased in diabetic rats compared to control. mRNA level of muscarinic M3, α7-nicotinic acetylcholine, insulin receptors, acetylcholine esterase, choline acetyltransferase and GLUT-3 significantly increased and M1 receptor decreased in the brainstem of diabetic rats. |
| 7580 | 23380686 | The results show that diabetes is associated with significant reduction in brainstem function coupled with altered cholinergic, insulin receptor and GLUT-3 gene expression. |
| 7581 | 23380686 | The present study indicates beneficial effect of curcumin in diabetic rats by regulating the cholinergic, insulin receptor and GLUT-3 in the brainstem similar to the responses obtained with insulin therapy. |
| 7582 | 23395167 | LRP6 enhances glucose metabolism by promoting TCF7L2-dependent insulin receptor expression and IGF receptor stabilization in humans. |
| 7583 | 23395167 | Further investigations showed that the LRP6(R611C) mutation diminishes TCF7L2-dependent transcription of the IR while it increases the stability of IGFR and enhances mTORC1 activity. |
| 7584 | 23395167 | These findings identify the Wnt/LRP6/TCF7L2 axis as a regulator of glucose metabolism and a potential therapeutic target for insulin resistance. |
| 7585 | 23397157 | Insulin and insulin-like growth factor-1 (IGF-1) are important regulators of developmental and cognitive functions in the central nervous system. |
| 7586 | 23397157 | Aim of the present study was to examine the effects of maternal diabetes on insulin receptor (InsR) and IGF-1 receptor (IGF-1R) expression in the developing rat cerebellum. |
| 7587 | 23397157 | The expression of InsR and IGF-1R in cerebelli was evaluated using real-time PCR and western blot analysis. |
| 7588 | 23397157 | We found a significant upregulation of both IGF-1R and InsR transcripts in cerebellum of pups born to diabetic mothers at P0, compared to controls. |
| 7589 | 23397157 | In contrast to InsR, which does not show any difference, there was a markedly reduction in cerebellar expression of IGF-1R mRNA and protein level in the diabetic group of newborns at P7. |
| 7590 | 23397157 | Moreover, 2 weeks after birth, mRNA expression and protein levels of both InsR and IGF-1R in cerebellum of the diabetic group was significantly downregulated. |
| 7591 | 23397157 | Compared to controls, we did not find any difference in cerebellar InsR or IGF-1R mRNA and protein levels in the insulin treated group. |
| 7592 | 23397157 | The present study revealed that diabetes during pregnancy strongly influences the regulation of both InsR and IGF-1R in the developing cerebellum. |
| 7593 | 23397157 | Insulin and insulin-like growth factor-1 (IGF-1) are important regulators of developmental and cognitive functions in the central nervous system. |
| 7594 | 23397157 | Aim of the present study was to examine the effects of maternal diabetes on insulin receptor (InsR) and IGF-1 receptor (IGF-1R) expression in the developing rat cerebellum. |
| 7595 | 23397157 | The expression of InsR and IGF-1R in cerebelli was evaluated using real-time PCR and western blot analysis. |
| 7596 | 23397157 | We found a significant upregulation of both IGF-1R and InsR transcripts in cerebellum of pups born to diabetic mothers at P0, compared to controls. |
| 7597 | 23397157 | In contrast to InsR, which does not show any difference, there was a markedly reduction in cerebellar expression of IGF-1R mRNA and protein level in the diabetic group of newborns at P7. |
| 7598 | 23397157 | Moreover, 2 weeks after birth, mRNA expression and protein levels of both InsR and IGF-1R in cerebellum of the diabetic group was significantly downregulated. |
| 7599 | 23397157 | Compared to controls, we did not find any difference in cerebellar InsR or IGF-1R mRNA and protein levels in the insulin treated group. |
| 7600 | 23397157 | The present study revealed that diabetes during pregnancy strongly influences the regulation of both InsR and IGF-1R in the developing cerebellum. |
| 7601 | 23397157 | Insulin and insulin-like growth factor-1 (IGF-1) are important regulators of developmental and cognitive functions in the central nervous system. |
| 7602 | 23397157 | Aim of the present study was to examine the effects of maternal diabetes on insulin receptor (InsR) and IGF-1 receptor (IGF-1R) expression in the developing rat cerebellum. |
| 7603 | 23397157 | The expression of InsR and IGF-1R in cerebelli was evaluated using real-time PCR and western blot analysis. |
| 7604 | 23397157 | We found a significant upregulation of both IGF-1R and InsR transcripts in cerebellum of pups born to diabetic mothers at P0, compared to controls. |
| 7605 | 23397157 | In contrast to InsR, which does not show any difference, there was a markedly reduction in cerebellar expression of IGF-1R mRNA and protein level in the diabetic group of newborns at P7. |
| 7606 | 23397157 | Moreover, 2 weeks after birth, mRNA expression and protein levels of both InsR and IGF-1R in cerebellum of the diabetic group was significantly downregulated. |
| 7607 | 23397157 | Compared to controls, we did not find any difference in cerebellar InsR or IGF-1R mRNA and protein levels in the insulin treated group. |
| 7608 | 23397157 | The present study revealed that diabetes during pregnancy strongly influences the regulation of both InsR and IGF-1R in the developing cerebellum. |
| 7609 | 23397157 | Insulin and insulin-like growth factor-1 (IGF-1) are important regulators of developmental and cognitive functions in the central nervous system. |
| 7610 | 23397157 | Aim of the present study was to examine the effects of maternal diabetes on insulin receptor (InsR) and IGF-1 receptor (IGF-1R) expression in the developing rat cerebellum. |
| 7611 | 23397157 | The expression of InsR and IGF-1R in cerebelli was evaluated using real-time PCR and western blot analysis. |
| 7612 | 23397157 | We found a significant upregulation of both IGF-1R and InsR transcripts in cerebellum of pups born to diabetic mothers at P0, compared to controls. |
| 7613 | 23397157 | In contrast to InsR, which does not show any difference, there was a markedly reduction in cerebellar expression of IGF-1R mRNA and protein level in the diabetic group of newborns at P7. |
| 7614 | 23397157 | Moreover, 2 weeks after birth, mRNA expression and protein levels of both InsR and IGF-1R in cerebellum of the diabetic group was significantly downregulated. |
| 7615 | 23397157 | Compared to controls, we did not find any difference in cerebellar InsR or IGF-1R mRNA and protein levels in the insulin treated group. |
| 7616 | 23397157 | The present study revealed that diabetes during pregnancy strongly influences the regulation of both InsR and IGF-1R in the developing cerebellum. |
| 7617 | 23397157 | Insulin and insulin-like growth factor-1 (IGF-1) are important regulators of developmental and cognitive functions in the central nervous system. |
| 7618 | 23397157 | Aim of the present study was to examine the effects of maternal diabetes on insulin receptor (InsR) and IGF-1 receptor (IGF-1R) expression in the developing rat cerebellum. |
| 7619 | 23397157 | The expression of InsR and IGF-1R in cerebelli was evaluated using real-time PCR and western blot analysis. |
| 7620 | 23397157 | We found a significant upregulation of both IGF-1R and InsR transcripts in cerebellum of pups born to diabetic mothers at P0, compared to controls. |
| 7621 | 23397157 | In contrast to InsR, which does not show any difference, there was a markedly reduction in cerebellar expression of IGF-1R mRNA and protein level in the diabetic group of newborns at P7. |
| 7622 | 23397157 | Moreover, 2 weeks after birth, mRNA expression and protein levels of both InsR and IGF-1R in cerebellum of the diabetic group was significantly downregulated. |
| 7623 | 23397157 | Compared to controls, we did not find any difference in cerebellar InsR or IGF-1R mRNA and protein levels in the insulin treated group. |
| 7624 | 23397157 | The present study revealed that diabetes during pregnancy strongly influences the regulation of both InsR and IGF-1R in the developing cerebellum. |
| 7625 | 23397157 | Insulin and insulin-like growth factor-1 (IGF-1) are important regulators of developmental and cognitive functions in the central nervous system. |
| 7626 | 23397157 | Aim of the present study was to examine the effects of maternal diabetes on insulin receptor (InsR) and IGF-1 receptor (IGF-1R) expression in the developing rat cerebellum. |
| 7627 | 23397157 | The expression of InsR and IGF-1R in cerebelli was evaluated using real-time PCR and western blot analysis. |
| 7628 | 23397157 | We found a significant upregulation of both IGF-1R and InsR transcripts in cerebellum of pups born to diabetic mothers at P0, compared to controls. |
| 7629 | 23397157 | In contrast to InsR, which does not show any difference, there was a markedly reduction in cerebellar expression of IGF-1R mRNA and protein level in the diabetic group of newborns at P7. |
| 7630 | 23397157 | Moreover, 2 weeks after birth, mRNA expression and protein levels of both InsR and IGF-1R in cerebellum of the diabetic group was significantly downregulated. |
| 7631 | 23397157 | Compared to controls, we did not find any difference in cerebellar InsR or IGF-1R mRNA and protein levels in the insulin treated group. |
| 7632 | 23397157 | The present study revealed that diabetes during pregnancy strongly influences the regulation of both InsR and IGF-1R in the developing cerebellum. |
| 7633 | 23397157 | Insulin and insulin-like growth factor-1 (IGF-1) are important regulators of developmental and cognitive functions in the central nervous system. |
| 7634 | 23397157 | Aim of the present study was to examine the effects of maternal diabetes on insulin receptor (InsR) and IGF-1 receptor (IGF-1R) expression in the developing rat cerebellum. |
| 7635 | 23397157 | The expression of InsR and IGF-1R in cerebelli was evaluated using real-time PCR and western blot analysis. |
| 7636 | 23397157 | We found a significant upregulation of both IGF-1R and InsR transcripts in cerebellum of pups born to diabetic mothers at P0, compared to controls. |
| 7637 | 23397157 | In contrast to InsR, which does not show any difference, there was a markedly reduction in cerebellar expression of IGF-1R mRNA and protein level in the diabetic group of newborns at P7. |
| 7638 | 23397157 | Moreover, 2 weeks after birth, mRNA expression and protein levels of both InsR and IGF-1R in cerebellum of the diabetic group was significantly downregulated. |
| 7639 | 23397157 | Compared to controls, we did not find any difference in cerebellar InsR or IGF-1R mRNA and protein levels in the insulin treated group. |
| 7640 | 23397157 | The present study revealed that diabetes during pregnancy strongly influences the regulation of both InsR and IGF-1R in the developing cerebellum. |
| 7641 | 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). |
| 7642 | 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. |
| 7643 | 23419399 | Coffee improves insulin-stimulated Akt phosphorylation in liver and skeletal muscle in diabetic KK-A(y) mice. |
| 7644 | 23419399 | To investigate coffee's effect on insulin signaling in liver, skeletal muscle, and adipose tissue (epididymal fat), we assayed the tyrosine phosphorylation of insulin receptor (IR) and serine phosphorylation of Akt. |
| 7645 | 23419399 | Coffee ingestion significantly increased the insulin-induced serine phosphorylation of Akt in liver and skeletal muscle, but not in epididymal fat, of KK-A(y) mice. |
| 7646 | 23419399 | Our results also indicated that coffee ingestion may contribute to the improvement of insulin resistance and hyperglycemia in KK-A(y) mice via the activation of Akt in insulin signaling in liver and skeletal muscle. |
| 7647 | 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. |
| 7648 | 23463119 | HCV-nonstructural protein could increase protein phosphatase 2A which has been shown to inactivate the key enzyme Akt by dephosphorylating it. |
| 7649 | 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. |
| 7650 | 23463119 | PPARα upregulates glycerol-3-phosphate dehydrogenase, glycerol kinase, and glycerol transport proteins, which allows for glucose synthesis during fasting states. |
| 7651 | 23463119 | It is speculated that TNF-alpha plays a major role in the pathogenesis of IR through lowering IRS1/2. |
| 7652 | 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. |
| 7653 | 23469261 | Protein kinase Cε modulates insulin receptor localization and trafficking in mouse embryonic fibroblasts. |
| 7654 | 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. |
| 7655 | 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. |
| 7656 | 23469261 | These alterations in insulin receptor trafficking were associated with reduced expression of CEACAM1, a receptor substrate previously shown to modulate insulin clearance. |
| 7657 | 23469261 | Virally-mediated reconstitution of PKCε in MEFs increased CEACAM1 expression and partly restored the sensitivity of the receptor to insulin-stimulated redistribution. |
| 7658 | 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. |
| 7659 | 23469261 | Protein kinase Cε modulates insulin receptor localization and trafficking in mouse embryonic fibroblasts. |
| 7660 | 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. |
| 7661 | 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. |
| 7662 | 23469261 | These alterations in insulin receptor trafficking were associated with reduced expression of CEACAM1, a receptor substrate previously shown to modulate insulin clearance. |
| 7663 | 23469261 | Virally-mediated reconstitution of PKCε in MEFs increased CEACAM1 expression and partly restored the sensitivity of the receptor to insulin-stimulated redistribution. |
| 7664 | 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. |
| 7665 | 23469261 | Protein kinase Cε modulates insulin receptor localization and trafficking in mouse embryonic fibroblasts. |
| 7666 | 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. |
| 7667 | 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. |
| 7668 | 23469261 | These alterations in insulin receptor trafficking were associated with reduced expression of CEACAM1, a receptor substrate previously shown to modulate insulin clearance. |
| 7669 | 23469261 | Virally-mediated reconstitution of PKCε in MEFs increased CEACAM1 expression and partly restored the sensitivity of the receptor to insulin-stimulated redistribution. |
| 7670 | 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. |
| 7671 | 23469261 | Protein kinase Cε modulates insulin receptor localization and trafficking in mouse embryonic fibroblasts. |
| 7672 | 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. |
| 7673 | 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. |
| 7674 | 23469261 | These alterations in insulin receptor trafficking were associated with reduced expression of CEACAM1, a receptor substrate previously shown to modulate insulin clearance. |
| 7675 | 23469261 | Virally-mediated reconstitution of PKCε in MEFs increased CEACAM1 expression and partly restored the sensitivity of the receptor to insulin-stimulated redistribution. |
| 7676 | 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. |
| 7677 | 23474485 | Hepatic STAT3 phosphorylation after histidine ICV administration was attenuated in histamine H1 receptor knockout (Hrh1KO) mice but not in neuron-specific insulin receptor knockout (NIRKO) mice. |
| 7678 | 23474485 | Conversely, hepatic STAT3 phosphorylation after insulin ICV administration was attenuated in NIRKO but not in Hrh1KO mice. |
| 7679 | 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. |
| 7680 | 23493758 | However, therapies with monoclonal antibodies targeting the IGF1 receptor (IGF1R) have been largely unsuccessful. |
| 7681 | 23493758 | One of the potential reasons for this failure is the existence of the highly homologous insulin receptor (IR), which appears to be at least equally efficient as the IGF1R in the transition of mitogenic signals to the nucleus and promotion of cell growth. |
| 7682 | 23493758 | Furthermore, IGF1 and insulin receptors can form hybrid receptors sensitive to stimulation of all three ligands of the system: insulin, IGF1, and IGF2. |
| 7683 | 23493758 | Although the connection between insulin, diabetes, and cancer has been established for years now, clear evidence that demonstrate the redundancy of insulin and insulin receptors and insulin-like growth factors and their receptors in cancer is missing. |
| 7684 | 23507573 | Minireview: nuclear insulin and insulin-like growth factor-1 receptors: a novel paradigm in signal transduction. |
| 7685 | 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. |
| 7686 | 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. |
| 7687 | 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. |
| 7688 | 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). |
| 7689 | 23507573 | The ability of InsR and IGF1R to function as transcription factors, although poorly understood, constitutes a new paradigm in signal transduction. |
| 7690 | 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. |
| 7691 | 23507573 | Minireview: nuclear insulin and insulin-like growth factor-1 receptors: a novel paradigm in signal transduction. |
| 7692 | 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. |
| 7693 | 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. |
| 7694 | 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. |
| 7695 | 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). |
| 7696 | 23507573 | The ability of InsR and IGF1R to function as transcription factors, although poorly understood, constitutes a new paradigm in signal transduction. |
| 7697 | 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. |
| 7698 | 23507573 | Minireview: nuclear insulin and insulin-like growth factor-1 receptors: a novel paradigm in signal transduction. |
| 7699 | 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. |
| 7700 | 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. |
| 7701 | 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. |
| 7702 | 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). |
| 7703 | 23507573 | The ability of InsR and IGF1R to function as transcription factors, although poorly understood, constitutes a new paradigm in signal transduction. |
| 7704 | 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. |
| 7705 | 23507573 | Minireview: nuclear insulin and insulin-like growth factor-1 receptors: a novel paradigm in signal transduction. |
| 7706 | 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. |
| 7707 | 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. |
| 7708 | 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. |
| 7709 | 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). |
| 7710 | 23507573 | The ability of InsR and IGF1R to function as transcription factors, although poorly understood, constitutes a new paradigm in signal transduction. |
| 7711 | 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. |
| 7712 | 23507573 | Minireview: nuclear insulin and insulin-like growth factor-1 receptors: a novel paradigm in signal transduction. |
| 7713 | 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. |
| 7714 | 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. |
| 7715 | 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. |
| 7716 | 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). |
| 7717 | 23507573 | The ability of InsR and IGF1R to function as transcription factors, although poorly understood, constitutes a new paradigm in signal transduction. |
| 7718 | 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. |
| 7719 | 23507573 | Minireview: nuclear insulin and insulin-like growth factor-1 receptors: a novel paradigm in signal transduction. |
| 7720 | 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. |
| 7721 | 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. |
| 7722 | 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. |
| 7723 | 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). |
| 7724 | 23507573 | The ability of InsR and IGF1R to function as transcription factors, although poorly understood, constitutes a new paradigm in signal transduction. |
| 7725 | 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. |
| 7726 | 23515289 | Recently it was demonstrated that both the insulin receptor (IR) and the IGF-IR mediate hyperinsulinemia's mitogenic effect in several breast cancer models. |
| 7727 | 23531619 | Expression of SHP-1 induced by hyperglycemia prevents insulin actions in podocytes. |
| 7728 | 23531619 | Previous studies demonstrated that Src homology-2 domain-containing phosphatase-1 (SHP-1) is elevated in renal cortex of type 1 diabetic mice; we hypothesized that hyperglycemia-induced SHP-1 expression may affect insulin actions in podocytes. |
| 7729 | 23531619 | In contrast to Ins2(+/+) mice, insulin-stimulated protein kinase B (Akt) and extracellular signal-regulated kinase (ERK) phosphorylation were remarkably reduced in renal podocytes of Akita mice. |
| 7730 | 23531619 | This renal insulin resistance was associated with elevated SHP-1 expression in the glomeruli. |
| 7731 | 23531619 | HG exposure raised mRNA and protein levels of SHP-1 and reduced the insulin-signaling pathway in podocytes. |
| 7732 | 23531619 | Overexpression of dominant-negative SHP-1 in podocytes prevented HG effects and restored insulin actions. |
| 7733 | 23531619 | Elevated SHP-1 expression induced by high glucose levels was directly associated with insulin receptor-β in vitro and in vivo to prevent insulin-stimulated Akt and ERK phosphorylation. |
| 7734 | 23531619 | In conclusion, our results showed that high levels of SHP-1 expression in glomeruli cause insulin resistance and podocyte loss, thereby contributing to diabetic nephropathy. |
| 7735 | 23538787 | Vesiculin, a novel IGF-II-like protein was recently isolated from the secretory granules of murine β-cells, and preliminary studies indicate it is capable of signalling via the insulin receptor (IR)/insulin-like growth factor receptor 1(IGF1R) family giving it the potential to elicit both metabolic and mitogenic responses in the beta-cell. |
| 7736 | 23560040 | Insulin-receptor substrate-2 (irs-2) is required for maintaining glucokinase and glucokinase regulatory protein expression in mouse liver. |
| 7737 | 23560040 | Since glucokinase (GK) and glucokinase regulatory protein (GKRP) function as key glucose sensors, we have investigated the expression of GK and GKRP in liver of Irs-2 deficient mice and Irs2(-/-) mice where Irs2 was reintroduced specifically into pancreatic β-cells [RIP-Irs-2/IRS-2(-/-)]. |
| 7738 | 23560040 | GK and GKRP mRNA levels in liver of IRS-2(-/-) were significantly lower, whereas in RIP-Irs-2/IRS-2(-/-) mice, both GK and GKRP mRNAs levels were comparable to wild-type animals. |
| 7739 | 23560040 | At the protein level, the liver content of GK was reduced in IRS-2(-/-) mice as compared with controls, although GKRP levels were similar between these experimental models. |
| 7740 | 23560040 | Both GK and GKRP levels were lower in RIP-Irs-2/IRS-2(-/-) mice. |
| 7741 | 23560040 | Interestingly, GK and GKRP protein expression remained low in RIP-Irs-2/IRS-2(-/-) mice, perhaps reflecting different mRNA half-lives or alterations in the process of translation and post-translational regulation. |
| 7742 | 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. |
| 7743 | 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. |
| 7744 | 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. |
| 7745 | 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. |
| 7746 | 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. |
| 7747 | 23569175 | We investigated 1) the ability of purified glargine (GLA), metabolites 1 (M1) and 2 (M2), IGF-I, and NPH insulin to activate the insulin receptor (IR)-A and IR-B and IGF-I receptor (IGF-IR) in vitro; 2) plasma concentrations of GLA, M1, and M2 during long-term insulin therapy in type 2 diabetic patients; and 3) IR-A and IR-B activation in vitro induced by serum from patients treated with GLA or NPH insulin. |
| 7748 | 23572162 | Here, we use a mouse model of Her2-mediated breast cancer on a background of hyperinsulinemia to determine how elevated circulating insulin levels affect Her2-mediated primary tumor growth and lung metastasis. |
| 7749 | 23572162 | In tumor tissues removed at 2, 4, and 6 weeks of Neu-NT overexpression, we observed increased tumor mass and higher phosphorylation of the insulin receptor/IGF1 receptor, suggesting that activation of these receptors in conditions of hyperinsulinemia could contribute to the increased growth of mammary tumors. |
| 7750 | 23574745 | Insulin-like growth factor (IGF)-1, IGF-2, IGF-1 receptors, insulin, and the insulin receptor play roles in the development and progression of cancers. |
| 7751 | 23577003 | We have provided an overview of functional BRET studies associated with the RTK superfamily involving: neurotrophic receptors [e.g., tropomyosin-related kinase (Trk) and p75 neurotrophin receptor (p75NTR)]; insulinotropic receptors [e.g., insulin receptor (IR) and insulin-like growth factor receptor (IGFR)] and growth factor receptors [e.g., ErbB receptors including the EGFR, the fibroblast growth factor receptor (FGFR), the vascular endothelial growth factor receptor (VEGFR) and the c-kit and platelet-derived growth factor receptor (PDGFR)]. |
| 7752 | 23577003 | In addition, we review BRET-mediated studies of other tyrosine kinase-associated receptors including cytokine receptors, i.e., leptin receptor (OB-R) and the growth hormone receptor (GHR). |
| 7753 | 23579487 | Cellular insulin resistance disrupts leptin-mediated control of neuronal signaling and transcription. |
| 7754 | 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. |
| 7755 | 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. |
| 7756 | 23579487 | Prolonged insulin exposure was used to induce cellular insulin resistance, and thereafter leptin-mediated regulation of signal transduction and gene expression was assessed. |
| 7757 | 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. |
| 7758 | 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. |
| 7759 | 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. |
| 7760 | 23579487 | Cellular insulin resistance may cause or exacerbate neuronal leptin resistance and, by extension, obesity. |
| 7761 | 23579487 | This study provides improved understanding of the complex cellular crosstalk between insulin-leptin signal transduction that is disrupted during neuronal insulin resistance. |
| 7762 | 23579487 | Cellular insulin resistance disrupts leptin-mediated control of neuronal signaling and transcription. |
| 7763 | 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. |
| 7764 | 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. |
| 7765 | 23579487 | Prolonged insulin exposure was used to induce cellular insulin resistance, and thereafter leptin-mediated regulation of signal transduction and gene expression was assessed. |
| 7766 | 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. |
| 7767 | 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. |
| 7768 | 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. |
| 7769 | 23579487 | Cellular insulin resistance may cause or exacerbate neuronal leptin resistance and, by extension, obesity. |
| 7770 | 23579487 | This study provides improved understanding of the complex cellular crosstalk between insulin-leptin signal transduction that is disrupted during neuronal insulin resistance. |
| 7771 | 23579487 | Cellular insulin resistance disrupts leptin-mediated control of neuronal signaling and transcription. |
| 7772 | 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. |
| 7773 | 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. |
| 7774 | 23579487 | Prolonged insulin exposure was used to induce cellular insulin resistance, and thereafter leptin-mediated regulation of signal transduction and gene expression was assessed. |
| 7775 | 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. |
| 7776 | 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. |
| 7777 | 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. |
| 7778 | 23579487 | Cellular insulin resistance may cause or exacerbate neuronal leptin resistance and, by extension, obesity. |
| 7779 | 23579487 | This study provides improved understanding of the complex cellular crosstalk between insulin-leptin signal transduction that is disrupted during neuronal insulin resistance. |
| 7780 | 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. |
| 7781 | 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). |
| 7782 | 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. |
| 7783 | 23589295 | Insulin directly regulates steroidogenesis via induction of the orphan nuclear receptor DAX-1 in testicular Leydig cells. |
| 7784 | 23589295 | In this study, we found that insulin directly binds to insulin receptors in Leydig cell membranes and activates phospho-insulin receptor-β (phospho-IR-β), phospho-IRS1, and phospho-AKT, leading to up-regulation of DAX-1 (dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1) gene expression in the MA-10 mouse Leydig cell line. |
| 7785 | 23589295 | Insulin also inhibits cAMP-induced and liver receptor homolog-1 (LRH-1)-induced steroidogenic enzyme gene expression and steroidogenesis. |
| 7786 | 23589295 | In contrast, knockdown of DAX-1 reversed insulin-mediated inhibition of steroidogenesis. |
| 7787 | 23589295 | In insulin-injected mouse models, insulin receptor signal pathway was activated and subsequently inhibited steroidogenesis via induction of DAX-1 without significant change of luteinizing hormone or FSH levels. |
| 7788 | 23589295 | Insulin-mediated induction of DAX-1 in Leydig cells of testis may be a key regulatory step of serum sex hormone level in insulin-resistant states. |
| 7789 | 23589295 | Insulin directly regulates steroidogenesis via induction of the orphan nuclear receptor DAX-1 in testicular Leydig cells. |
| 7790 | 23589295 | In this study, we found that insulin directly binds to insulin receptors in Leydig cell membranes and activates phospho-insulin receptor-β (phospho-IR-β), phospho-IRS1, and phospho-AKT, leading to up-regulation of DAX-1 (dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1) gene expression in the MA-10 mouse Leydig cell line. |
| 7791 | 23589295 | Insulin also inhibits cAMP-induced and liver receptor homolog-1 (LRH-1)-induced steroidogenic enzyme gene expression and steroidogenesis. |
| 7792 | 23589295 | In contrast, knockdown of DAX-1 reversed insulin-mediated inhibition of steroidogenesis. |
| 7793 | 23589295 | In insulin-injected mouse models, insulin receptor signal pathway was activated and subsequently inhibited steroidogenesis via induction of DAX-1 without significant change of luteinizing hormone or FSH levels. |
| 7794 | 23589295 | Insulin-mediated induction of DAX-1 in Leydig cells of testis may be a key regulatory step of serum sex hormone level in insulin-resistant states. |
| 7795 | 23603635 | Different categories of compounds including mono and di substituted benzoquinones, vanadium based compounds and natural products have been reported to cause insulin-like effects either by increasing phosphorylation of insulin receptor (IR) or inhibiting the protein tyrosine phosphatases. |
| 7796 | 23604820 | Since insulin sensitivity to cells is attributed to phosphorylation of the insulin receptor (IR), protein tyrosine phosphatase 1B (PTP1B), which dephosphorylates the tyrosine residues of IR proteins, is primarily responsible for insulin resistance in type 2 diabetes. |
| 7797 | 23604820 | Therefore, PTP1B inhibitors ameliorating the insulin-dependent signaling pathway are potential therapeutic candidates for the treatment and prevention of diabetes. |
| 7798 | 23614367 | Growth factor receptor-bound protein 10-mediated negative regulation of the insulin-like growth factor-1 receptor-activated signalling pathway results in cognitive disorder in diabetic rats. |
| 7799 | 23614367 | Growth factor receptor-bound protein 10 (Grb10) is a Src homology 2 domain-containing protein and one of the binding partners for several transmembrane tyrosine kinase receptors, including insulin receptor (IR) and insulin-like growth factor-1 receptor (IGF1-R). |
| 7800 | 23637016 | De novo 19p13.2 microdeletion encompassing the insulin receptor and resistin genes in a patient with obesity and learning disability. |
| 7801 | 23637016 | The deletion encompasses several genes, including resistin and the first part of the insulin receptor, genes that are relevant for obesity. |
| 7802 | 23637016 | Plasma analyses and gene expression demonstrated that the deletion resulted in haploinsufficiency for resistin and insulin receptor in the patient compared to controls. |
| 7803 | 23637016 | Thus, haploinsufficiency of insulin receptor and resistin does not appear to influence glucose and lipid metabolism. |
| 7804 | 23637016 | In conclusion, we identified a 19p13.2 microdeletion encompassing the insulin receptor and resistin genes resulting in haploinsufficiency in an obese, but otherwise healthy patient. |
| 7805 | 23637016 | De novo 19p13.2 microdeletion encompassing the insulin receptor and resistin genes in a patient with obesity and learning disability. |
| 7806 | 23637016 | The deletion encompasses several genes, including resistin and the first part of the insulin receptor, genes that are relevant for obesity. |
| 7807 | 23637016 | Plasma analyses and gene expression demonstrated that the deletion resulted in haploinsufficiency for resistin and insulin receptor in the patient compared to controls. |
| 7808 | 23637016 | Thus, haploinsufficiency of insulin receptor and resistin does not appear to influence glucose and lipid metabolism. |
| 7809 | 23637016 | In conclusion, we identified a 19p13.2 microdeletion encompassing the insulin receptor and resistin genes resulting in haploinsufficiency in an obese, but otherwise healthy patient. |
| 7810 | 23637016 | De novo 19p13.2 microdeletion encompassing the insulin receptor and resistin genes in a patient with obesity and learning disability. |
| 7811 | 23637016 | The deletion encompasses several genes, including resistin and the first part of the insulin receptor, genes that are relevant for obesity. |
| 7812 | 23637016 | Plasma analyses and gene expression demonstrated that the deletion resulted in haploinsufficiency for resistin and insulin receptor in the patient compared to controls. |
| 7813 | 23637016 | Thus, haploinsufficiency of insulin receptor and resistin does not appear to influence glucose and lipid metabolism. |
| 7814 | 23637016 | In conclusion, we identified a 19p13.2 microdeletion encompassing the insulin receptor and resistin genes resulting in haploinsufficiency in an obese, but otherwise healthy patient. |
| 7815 | 23637016 | De novo 19p13.2 microdeletion encompassing the insulin receptor and resistin genes in a patient with obesity and learning disability. |
| 7816 | 23637016 | The deletion encompasses several genes, including resistin and the first part of the insulin receptor, genes that are relevant for obesity. |
| 7817 | 23637016 | Plasma analyses and gene expression demonstrated that the deletion resulted in haploinsufficiency for resistin and insulin receptor in the patient compared to controls. |
| 7818 | 23637016 | Thus, haploinsufficiency of insulin receptor and resistin does not appear to influence glucose and lipid metabolism. |
| 7819 | 23637016 | In conclusion, we identified a 19p13.2 microdeletion encompassing the insulin receptor and resistin genes resulting in haploinsufficiency in an obese, but otherwise healthy patient. |
| 7820 | 23637016 | De novo 19p13.2 microdeletion encompassing the insulin receptor and resistin genes in a patient with obesity and learning disability. |
| 7821 | 23637016 | The deletion encompasses several genes, including resistin and the first part of the insulin receptor, genes that are relevant for obesity. |
| 7822 | 23637016 | Plasma analyses and gene expression demonstrated that the deletion resulted in haploinsufficiency for resistin and insulin receptor in the patient compared to controls. |
| 7823 | 23637016 | Thus, haploinsufficiency of insulin receptor and resistin does not appear to influence glucose and lipid metabolism. |
| 7824 | 23637016 | In conclusion, we identified a 19p13.2 microdeletion encompassing the insulin receptor and resistin genes resulting in haploinsufficiency in an obese, but otherwise healthy patient. |
| 7825 | 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. |
| 7826 | 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. |
| 7827 | 23677929 | Implication of insulin receptor A isoform and IRA/IGF-IR hybrid receptors in the aortic vascular smooth muscle cell proliferation: role of TNF-α and IGF-II. |
| 7828 | 23677929 | Moreover, insulin, through ERK signaling, and the proatherogenic stimuli, through ERK and p38 signaling, induced a higher proliferation in IRA than IRB VSMCs. |
| 7829 | 23677929 | The latter effect might be due to IRA cells showing a higher expression of angiotensin II, endothelin 1, and thromboxane 2 receptors and basal association between IRA and these receptors. |
| 7830 | 23677929 | More importantly, we observed a significant increase of IRA, TNF-R1, and IGF-IR expression as well as higher association of IRA with TNF-R1 or IGF-IR in the aorta from ApoE(-/-) and BATIRKO mice, 2 models showing vascular damage. |
| 7831 | 23677929 | Finally, our data suggest that the IRA isoform and its association with TNF-R1 or IGF-IR confers proliferative advantage to VSMCs, mainly in response to TNF-α or IGF-II, which might be of significance in the early atherosclerotic process. |
| 7832 | 23688574 | Activation of μ-opioid receptor (MOR) could result in reversal of the impairment of insulin-stimulated glucose disposal in genetically obese Zucker rats via exercise training. |
| 7833 | 23688574 | This improvement of insulin resistance was associated with an elevation of circulating β-endorphin to ameliorate the post-receptor insulin signaling cascade, including downstream effectors of the phosphatidylinositol 3-kinase (PI3-kinase) signaling pathway. |
| 7834 | 23688574 | In insulin resistant rats, Loperamide treatment effected on the insulin receptor substrate (IRS)-1/PI3-kinase/Akt signaling cascade and subsequent insulin-stimulated glucose transport trafficking on skeletal muscle, which were all suppressed by MOR antagonism. |
| 7835 | 23688574 | In addition, induction of insulin resistance by the intake of high fructose is more rapid in MOR knockout mice than in wild-type mice. |
| 7836 | 23688574 | Improvements in insulin sensitivity through the peripheral MOR activation overcoming defects related to the post-receptor in IRS-1-associated PI3-kinase step have been defined. |
| 7837 | 23688574 | Opioid receptor activation, especially of the μ-subtype, may provide merits in the amelioration of defective insulin action. |
| 7838 | 23688574 | Atypical zeta (ζ) isoform of protein kinase C serves as a factor that integrates with peripheral MOR pathway and insulin signals for glucose utilization. |
| 7839 | 23688574 | The developments call new insights into the chemical compounds and/or herbal products that might enhance opioid peptide secretion and/or stimulate MOR in peripheral insulin-sensitive tissues to serve as potential agents or adjuvants for helping the glucose metabolism. |
| 7840 | 23688574 | In the present review, we update these topics and discuss the concept of targeting peripheral MOR pathway for the treatment of insulin resistance. |
| 7841 | 23690773 | To investigate the mechanism of action in peripheral tissues of novel complex drug containing release-active dilutions of antibodies to the beta subunit of the insulin receptor and antibodies to endothelial nitric oxide synthase (Subetta), which has shown efficacy in animal models of diabetes. |
| 7842 | 23690773 | Increasing adiponectin production in absence of insulin by Subetta probably via modulating effect on the beta subunit of the insulin receptor might serve as one of the mechanisms of the antidiabetic effect of this drug. |
| 7843 | 23690773 | To investigate the mechanism of action in peripheral tissues of novel complex drug containing release-active dilutions of antibodies to the beta subunit of the insulin receptor and antibodies to endothelial nitric oxide synthase (Subetta), which has shown efficacy in animal models of diabetes. |
| 7844 | 23690773 | Increasing adiponectin production in absence of insulin by Subetta probably via modulating effect on the beta subunit of the insulin receptor might serve as one of the mechanisms of the antidiabetic effect of this drug. |
| 7845 | 23696562 | Cytochrome P450 (CYP) epoxygenases metabolize arachidonic acid to biologically active cis-epoxyeicosatrienoic acids, which have potent vasodilatory, antiinflammatory, antiapoptotic, and antidiabetes properties. |
| 7846 | 23696562 | Here, we showed the effects of cardiac-specific overexpression of CYP epoxygenase 2J2 (CYP2J2) on diabetic cardiomyopathy and insulin resistance in high-fat (HF) diet fed, low-dose streptozotocin-treated mice. |
| 7847 | 23696562 | We conclude that cardiac-specific overexpression of CYP2J2 significantly protects against diabetic cardiomyopathy, which may be due to improved cardiac insulin resistance, glucose uptake, and reversal of cardiac hypertrophy. |
| 7848 | 23696562 | Relevant mechanisms may include up-regulation of peroxisome proliferator-activated receptor γ, activation of insulin receptor and AMP-activated protein kinase signaling pathways, and inhibition of nuclear factor of activated T cells c3 signal by enhanced atrial natriuretic peptide production. |
| 7849 | 23702602 | The association of adipose-derived dimethylarginine dimethylaminohydrolase-2 with insulin sensitivity in experimental type 2 diabetes mellitus. |
| 7850 | 23702602 | Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase (NOS), which can be hydrolyzed by dimethylarginine-dimethylaminohydrolase (DDAH). |
| 7851 | 23702602 | In the present study, we examined the effects of adipocyte-derived DDAH/ADMA on insulin sensitivity using animal and cell models. |
| 7852 | 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. |
| 7853 | 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. |
| 7854 | 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. |
| 7855 | 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. |
| 7856 | 23705494 | Obesity and diabetes mellitus are associated with low or elevated serum leptin and insulin levels (U-like relation). |
| 7857 | 23705494 | Mutations in LEP and INS are linked to leptin and insulin decrease while mutations in LEPR and INSR to their increase. |
| 7858 | 23705494 | Mutations of INSR induce insulin resistance, lipodystrophy, other pathology, and suggest an important role of insulin in glucose level regulation and in stimulation of fat accumulation as well. |
| 7859 | 23705494 | Obesity and diabetes mellitus are associated with low or elevated serum leptin and insulin levels (U-like relation). |
| 7860 | 23705494 | Mutations in LEP and INS are linked to leptin and insulin decrease while mutations in LEPR and INSR to their increase. |
| 7861 | 23705494 | Mutations of INSR induce insulin resistance, lipodystrophy, other pathology, and suggest an important role of insulin in glucose level regulation and in stimulation of fat accumulation as well. |
| 7862 | 23741292 | Insulin receptor substrate (IRS) proteins are key mediators of insulin and insulin-like growth factor (IGF) signalling. |
| 7863 | 23741292 | In mice, deletion of Irs1 is associated with profound growth retardation and increased longevity whereas Irs2-deficiency causes diabetes and female infertility. |
| 7864 | 23741292 | Expression of Irs1, Irs3, and Irs4 was comparable between experimental groups. |
| 7865 | 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. |
| 7866 | 23743798 | Liver glucose-6-phosphatase proteins in suckling and weaned grey seal pups: structural similarities to other mammals and relationship to nutrition, insulin signalling and metabolite levels. |
| 7867 | 23743798 | G6Pase comprises a translocase (SLC37A4) and a catalytic subunit (G6PC). |
| 7868 | 23743798 | G6PC and SLC37A4 expression and activity are normally regulated by nutritional state and glucostatic hormones, particularly insulin, and are elevated in diabetes. |
| 7869 | 23743798 | We tested the hypotheses that (1) grey seal G6PC and SLC37A4 cDNA and predicted protein sequences differ from other species' at functional sites, (2) relative G6Pase protein abundances are lower during feeding than fasting and (3) relative G6Pase protein abundances are related to insulin, insulin receptor phosphorylation and key metabolite levels. |
| 7870 | 23743798 | We show that G6PC and partial SLC37A4 cDNA sequences encode proteins sharing 82-95 % identity with other mammals. |
| 7871 | 23748282 | Fetuin-A is an endogenous inhibitor of the insulin-stimulated insulin receptor tyrosine kinase recently shown that high levels of circulating fetuin-A are associated with insulin resistance in humans suggesting that fetuin-A may represent a novel mechanism involved in the pathophysiology of type 2 diabetes (T2DM). |
| 7872 | 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. |
| 7873 | 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. |
| 7874 | 23762123 | Further experiments suggested that TLSP, LSP1, and LSP2 effectively inhibited hepatic gluconeogenesis and increased hepatic glycolysis and hepatic glycogen content. |
| 7875 | 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 . |
| 7876 | 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. |
| 7877 | 23762820 | These proteins interfere with different steps in insulin-signaling: ENPP1/PC-1 and the phosphatases PTP1B and PTPRF/LAR inhibit the insulin receptor activation; INPPL1/SHIP-2 hydrolyzes PI3-kinase products, hampering the phosphoinositide-mediated downstream signaling; and TRIB3 binds the serine-threonine kinase Akt, reducing its phosphorylation levels. |
| 7878 | 23762820 | While several variants have been described over the years for all these genes, solid evidence of an association with type 2 diabetes and related diseases seems to exist only for rs1044498 of the ENPP1 gene and for rs2295490 of the TRIB3 gene. |
| 7879 | 23762875 | The aim of the present study was to evaluate the potential antidiabetic effects of two-component drug Subetta and its components (release-active dilutions of antibodies to β -subunit insulin receptor (RAD of Abs to β -InsR) and to endothelial nitric oxide synthase (RAD of Abs to eNOS)) in Goto-Kakizaki (Paris colony) (GK/Par) diabetic rats. |
| 7880 | 23765754 | Fetuin A is inhibitor of insulin receptor which belongs the family of receptor tyrosine kinase. |
| 7881 | 23765754 | In the present study; measurement of serum levels of fetuin A and 8-hydroxydeoxyguanosine in obese subjects (n=46) and healthy controls (n=22), and examination of the relations between these parameters and insulin resistance have been purposed. |
| 7882 | 23765754 | Fetuin A may be a promising link between insulin resistance and obesity as well its comorbidities. |
| 7883 | 23771523 | Previously, we showed that metformin prevented tobacco carcinogen (NNK)-induced lung tumorigenesis in a non-diabetic mouse model, which was associated with decreased IGF-I/insulin receptor signaling but not activation of AMPK in lung tissues, as well as decreased circulating levels of IGF-I and insulin. |
| 7884 | 23772224 | These adipokines including leptin, visfatin, resistin, apelin, vaspin, and retinol binding protein-4 can regulate inflammatory responses and contribute to the pathogenesis of diabetes. |
| 7885 | 23772224 | These effects are mediated by key inflammatory signaling molecules including activated serine kinases such as c-Jun N-terminal kinase and serine kinases inhibitor κB kinase and insulin signaling molecules including insulin receptor substrates, protein kinase B (PKB, also known as Akt), and nuclear factor kappa B. |
| 7886 | 23773625 | We also analyzed the expression of enzymes involved in gluconeogenesis and lipogenesis, phosphoenolpyruvate carboxykinase (PEPCK) and lipin-1. |
| 7887 | 23773625 | The observed increase of insulin receptor supstrate-1 phosphorylation on Ser(307) represents a hallmark of impaired insulin signaling in the liver of fructose-fed rat and probably is a consequence of the alterations in 11βHSD1 and lipin-1 levels. |
| 7888 | 23835113 | Ceramide induces β-cell apoptosis by multiple mechanisms namely; activation of extrinsic apoptotic pathway, increasing cytochrome c release, free radical generation, induction of endoplasmic reticulum stress and inhibition of Akt. |
| 7889 | 23835113 | Ceramide also modulates many of the insulin signaling intermediates such as insulin receptor substrate, Akt, Glut-4, and it causes insulin resistance. |
| 7890 | 23835331 | Insulin receptor phosphorylation by endogenous insulin or the insulin analog AspB10 promotes mammary tumor growth independent of the IGF-I receptor. |
| 7891 | 23835331 | Endogenous hyperinsulinemia and insulin receptor (IR)/IGF-I receptor (IGF-IR) phosphorylation in tumors are associated with a worse prognosis in women with breast cancer. |
| 7892 | 23835331 | We aimed to determine whether stimulating the IR with the insulin analog AspB10 could increase tumor growth independently of IGF-IR signaling. |
| 7893 | 23835331 | We induced orthotopic mammary tumors in control FVB/n and hyperinsulinemic MKR mice, and treated them with the insulin analog AspB10, recombinant human IGF-I, or vehicle. |
| 7894 | 23835331 | IGF-I led to activation of both the IGF-IR and IR and probably hybrid receptors. |
| 7895 | 23835331 | Insulin receptor phosphorylation by endogenous insulin or the insulin analog AspB10 promotes mammary tumor growth independent of the IGF-I receptor. |
| 7896 | 23835331 | Endogenous hyperinsulinemia and insulin receptor (IR)/IGF-I receptor (IGF-IR) phosphorylation in tumors are associated with a worse prognosis in women with breast cancer. |
| 7897 | 23835331 | We aimed to determine whether stimulating the IR with the insulin analog AspB10 could increase tumor growth independently of IGF-IR signaling. |
| 7898 | 23835331 | We induced orthotopic mammary tumors in control FVB/n and hyperinsulinemic MKR mice, and treated them with the insulin analog AspB10, recombinant human IGF-I, or vehicle. |
| 7899 | 23835331 | IGF-I led to activation of both the IGF-IR and IR and probably hybrid receptors. |
| 7900 | 23861377 | In this study, we investigated whether loss of GH receptor (GHR) signaling in postnatal skeletal muscle alters muscle mass and regenerative ability in adult mice and whether this was dependent on IGF-1 receptor (IGF-1R) signaling. |
| 7901 | 23861377 | To do so, we used mouse models with skeletal muscle-specific loss of GHR signaling (mGHRKO), IGF-1R and insulin receptor signaling (MKR), or both GHR and IGF-1R/insulin receptor signaling (mGHRKO/MKR). |
| 7902 | 23861377 | Additionally, in our model, muscle Igf-1 expression is not dependent on GHR signaling in postnatal skeletal muscle. |
| 7903 | 23865415 | Emerging role of JNK in insulin resistance. |
| 7904 | 23865415 | The stress-activated c-Jun N-terminal kinase (JNK) has been increasingly recognized as a central mediator of insulin resistance. |
| 7905 | 23865415 | JNK mediates many of the effects of stress on insulin resistance through inhibitory phosphorylation of insulin receptor substrate, and suppression of the JNK pathway has been shown to improve insulin resistance and glucose tolerance. |
| 7906 | 23865415 | This review focuses on recent findings that support a critical role for JNK in the development of insulin resistance associated with inflammation, endoplasmic reticulum stress, oxidative stress and mitochondrial dysfunction. |
| 7907 | 23865415 | JNK regulation of autophagy and its implications in insulin resistance also will be discussed. |
| 7908 | 23874448 | These results were attributed to the increase of β-catenin/PPARγ complex bindings to peroxisome proliferator response elements in rat glucokinase (GK) promoter and the prolongation of S-phase of cell cycle by cyclin D1. |
| 7909 | 23874448 | These events resulted from more rapid and higher phosphorylation levels of insulin-signaling intermediates, including insulin receptor substrate (IRS)-1/IRS-2/phosphotylinositol 3 kinase/v-akt murine thymoma viral oncogene homolog (AKT) 1, and the consequent enhancement of β-catenin nuclear translocation and Wnt responsive genes including GK and cyclin D1. |
| 7910 | 23874448 | Indeed, the higher functionality and proliferation shown in INS-IR cells were offset by β-catenin, cyclin D1, GK, AKT1, and IRS-2 gene depletion. |
| 7911 | 23899607 | SNAP-P.g. was also internalized into the human hepatoma cell line HepG2, and this attenuated the phosphorylation of insulin receptor substrate (IRS)-1, Akt and glycogen synthase kinase-3β induced by insulin. |
| 7912 | 23908801 | The Role of Insulin and Insulin-like Growth Factors in the Increased Risk of Cancer in Diabetes. |
| 7913 | 23908801 | Candidates include hyperinsulinemia, insulin-like growth factor-1 (IGF-1), and insulin-like growth factor-2 (IGF-2) signaling. |
| 7914 | 23908801 | These studies demonstrated that increased insulin, IGF-1, and IGF-2 signaling through the insulin receptor and IGF-1 receptor can induce cancer development and progression. |
| 7915 | 23919962 | Elastin-derived peptides are new regulators of insulin resistance development in mice. |
| 7916 | 23919962 | In the current study, we show that elastin-derived peptides (EDPs) may be involved in the development of insulin resistance (IRES) in mice. |
| 7917 | 23919962 | Based on in vivo, in vitro, and in silico approaches, we propose that this IRES is due to interaction between the insulin receptor (IR) and the neuraminidase-1 subunit of the elastin receptor complex triggered by EDPs. |
| 7918 | 23923576 | Since insulin signaling pathway has been shown to be regulated by nutritional supplements, in the present study, we investigated the possible effects of free amino acids, such as lysine, arginine and alanine and their mixture in modulating the insulin receptor tyrosine kinase (IRTK) and phosphatidyl inositol-3-OH-kinase (PI3K) activities and on the changes in actin dynamics in monocytes (MC), exposed to high glucose concentration (25 mM). |
| 7919 | 23937793 | Growth receptor binding protein 10 (Grb10) is an adaptor protein that interacts with the insulin receptor and insulin-like growth factor (IGF)-1 receptor. |
| 7920 | 23937793 | Overexpression of Grb10 in muscle cells and adipocytes inhibits insulin signalling, and transgenic mice overexpressing Grb10 exhibit impaired glucose tolerance. |
| 7921 | 23937793 | The effects of Grb10 on glucose-stimulated insulin secretion (GSIS) and the insulin/IGF-1 signalling pathway were investigated in rat islets and/or dispersed islet cells with Grb10 overexpresion by adenovirus transfection. |
| 7922 | 23937793 | Expression of Grb10 was increased in islets isolated from rats fed a high-fat plus high-sugar diet compared with islets isolated from rats fed normal chow diet, as well as in INS 832/13 cells exposed to high levels of glucose (20 mmol/L), palmitate (1 mmol/L) and interleukin-1β (50 U/mL). |
| 7923 | 23937793 | Overexpression of Grb10 in INS 832/13 cells or rat islets impaired GSIS compared with the respective control (all P < 0.05). |
| 7924 | 23937793 | Moreover, inhibition of GSIS by Grb10 overexpression was associated with a decrease in insulin- and IGF-1-induced Akt and extracellular signal-regulated kinase 1/2 phosphorylation. |
| 7925 | 23937793 | The results of the present study demonstrate that Grb10 is an important negative regulator of insulin/IGF-1 signalling in pancreatic β-cells and a potential target to improve β-cell function. |
| 7926 | 23940800 | Genetic inactivation of pyruvate dehydrogenase kinases improves hepatic insulin resistance induced diabetes. |
| 7927 | 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. |
| 7928 | 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). |
| 7929 | 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. |
| 7930 | 23940800 | To examine the specific hepatic effects of Pdks on diabetes, we also knocked down the Pdk2 or Pdk4 gene using specific shRNAs. |
| 7931 | 23940800 | The data also indicate that the Pdk4 gene knockdown led to better glucose tolerance than the Pdk2 gene knockdown. |
| 7932 | 23983688 | A twenty-first century cancer epidemic caused by obesity: the involvement of insulin, diabetes, and insulin-like growth factors. |
| 7933 | 23983688 | We review the molecular basis of the involvement of morbidly high concentrations of endogenous or therapeutic insulin and of insulin-like growth factors in the progression from obesity to diabetes and finally to cancer. |
| 7934 | 23983688 | Insulin-like growth factors, IGF-1 and IGF-2, secreted by visceral or mammary adipose tissue have significant paracrine and endocrine effects. |
| 7935 | 23983688 | Structural studies elucidate how each of the three ligands, insulin, IGF-1, and IGF-2, interacts differently with isoforms A and B of the insulin receptor and with type I IGF receptor and explain how these protagonists contribute to diabetes-associated cancer. |
| 7936 | 23983688 | Novel drugs that target the insulin and insulin-like growth factor signal transduction pathways are in clinical trial and should be effective if appropriate biomarker-informed patient stratification is implemented. |
| 7937 | 24015152 | Insulin/IGF-1 signaling plays a central role in control of cellular metabolism and survival, while insulin receptor substrate (IRS) protein -1 and -2 and downstream PI-3 kinase→Akt→Foxo1 signaling cascade play key roles in many functions of insulin/IGF-1. |