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Insulin IR Glucose transport GLUT4 P P IRS PI3K P GLUT4 Akt/PKB GSK-3 P Inactive GSK-3 Active GS Active GS Inactive P Glycogen synthesis 128
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IRS-1 PH PTB 1242 IRS-2 PH PTB NGDY NDQY 1338 IRS-3 PH PTB 495 IRS-4 PH PTB 1257 IRS-5 PH PTB 327 IRS-6 PH PTB 306 PH domain : Pleckstrin homology-like domain PTB domain : Phosphotyrosine-binding domain NXXY motif : calpain cleavage site 130
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Cytokine Insulin IR inos NO S-nitrosylation? IRS-2 GSK-3 Active IRS-2 Ub Ub Ub Ub degradation 134
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Molecular mechanisms of insulin resistance in -cells Toshihiro Tanioka Abstract nsulin resistance is a major causative factor for type 2 diabetes and is associated with increased risk of cardiovascular disease. Inducible nitric oxide synthase (inos), a mediator of inflammation, has emerged as an important player in insulin resistance. Obesity is associated with increased inos expression in insulin-sensitive tissues. Inhibition of inos ameliorates obesity-induced insulin resistance. However, molecular mechanisms by which inos mediates insulin resistance remain largely unknown. This review considers the recent studies which focus on the understanding of molecular mechanisms of insulin resistance in -cells. NO donor or inos caused a reduction in IRS-2 protein expression in a proteasome-dependent manner without altering the mrna level of IRS-2. Furthermore, inhibition of GSK-3 significantly prevented NO donor-induced reduction in IRS-2 protein expression in -cells. These findings suggest that inos-mediated decreased IRS-2 expression, at least in part, through a GSK-3 dependent mechanism may contribute to the progression and/or exacerbation of -cell failure in diabetes. Key WordsiNOS, IRS-2, Proteasome, GSK-3, insulin resistance 138