Insulin resistance of skeletal muscle glucose transport activity is considered a primary defect in the development of type 2 diabetes. While the etiology of skeletal muscle insulin resistance is certainly multifactorial, there is emerging evidence that elevated glycogen synthase kinase-3 (GSK3), a serine/threonine kinase existing as alpha- and beta-isoforms, is associated with decreased insulin action on glucose transport, GS activity, and glycogen synthesis. Moreover, recent evidence indicates that selective GSK3 inhibition in skeletal muscle of insulin-resistant rodents causes enhanced insulin-stimulated glucose transport activity and GS activity. However, it remains unclear if the metabolic effects of GSK3 inhibition are mediated by alterations in the functionality of specific insulin signaling elements in insulin-resistant skeletal muscle. We therefore propose to use two independent models of obesity-associated insulin resistance, the Zucker Diabetic Fatty (ZDF) rat and the high fat-fed Wistar rat, to determine if selective GSK3 inhibition using novel substituted aminopyrimidine compounds (with Ki of <10 nM for both GSK3alpha and GSK3beta) and arylindolemaleimeide compounds (with Ki of<10 nM for GSK3alpha and <30 nM for GSK3 Beta) can increase insulin stimulation of insulin receptor, insulin receptor substrate- 1 (IRS- 1), phosphatidylinositol-3-kinase (PI3-kinase), Akt, and GSK3 in skeletal muscle, and to assess whether these alterations in insulin signaling are associated with enhanced GLUT-4 translocation and glucose transport activity. The GSK3 inhibitors will be administered acutely (1 hr) in vitro, or acutely (4 hr) and chronically (14 days) in vivo. We hypothesize that the beneficial effects of this selective GSK3 inhibition in obesity-associated insulin resistance will be associated with decreased serine phosphorylation of IRS-1, increased tyrosine phosphorylation of IRS-1, and with upregulation of insulin-stimulated PI3-kinase activity, serine phosphorylation of Akt and GSK3, and cell-surface GLUT-4 in skeletal muscle. The results of this study will provide novel insights into the specific role of GSK3 in the modulation of insulin action on glucose transport activity in skeletal muscle in conditions of obesity-associated insulin resistance.
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