Glycogen Synthase Kinase-3 and Muscle Insulin Resistance

DESCRIPTION (provided by applicant): 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