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Impaired Muscle Glycogen Synthase in Type 2 Diabetes Is Associated with Diminished Phosphatidylinositol 3-Kinase Activation

Veterans Affairs San Diego Healthcare System, San Diego, California 92161; and Department of Medicine, University of California, San Diego, La Jolla, California 92093

Address all correspondence and requests for reprints to: R. R. Henry, M.D., Veterans Affairs San Diego Healthcare System (9111G), 3350 La Jolla Village Drive, San Diego, California 92161. E-mail: rrhenry{at}vapop.ucsd.edu

Abstract

Insulin signaling pathways potentially involved in regulation of skeletal muscle glycogen synthase were compared in differentiated human muscle cell cultures from nondiabetic and type 2 diabetic patients. Insulin stimulation of glycogen synthase activity as well as phosphorylation of MAPK, p70 S6 kinase, and protein kinase B (Akt) were blocked by the phosphatidylinositol 3-kinase inhibitors wortmannin (50 nM) and LY294002 (10 µM). In contrast to lean and obese nondiabetic subjects, where there were minimal effects (15–20% inhibition), insulin stimulation of glycogen synthase in muscle cultures from diabetic subjects was greatly diminished (75%) by low concentrations of wortmannin (25 nM) or LY294002 (2 µM). This increased sensitivity of diabetic muscle to impairment of insulin-stimulated glycogen synthase activity occurs together with diminished insulin-stimulation (by 40%) of IRS-1-associated phosphatidylinositol 3-kinase activity in the same cells. Protein expression of IRS-1, p85, p110, Akt, p70 S6 kinase, and MAPK were normal in diabetic cells, as was insulin-stimulated phosphorylation of Akt, p70 S6 kinase, and MAPK. These studies indicate that, despite prolonged growth and differentiation of diabetic muscle under normal metabolic culture conditions, defects of insulin-stimulated phosphatidylinositol 3-kinase and glycogen synthase activity in diabetic muscle persist, consistent with intrinsic (rather than acquired) defects of insulin action.

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