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Rosiglitazone, Insulin Treatment, and Fasting Correct Defective Activation of Protein Kinase C-/ by Insulin in Vastus Lateralis Muscles and Adipocytes of Diabetic Rats¹

J. A. Haley Veterans Hospital Research Service and Department of Internal Medicine, University of South Florida College of Medicine Tampa, Florida 33612

Address all correspondence and requests for reprints to: Robert V. Farese, M.D., Research Service (VAR 151), J. A. Haley Veterans Hospital, 13000 Bruce B. Downs Boulevard, Tampa, Florida 33612. E-mail: rfarese{at}com1.med.usf.edu

Atypical protein kinases C (PKCs), and , and protein kinase B (PKB) are thought to function downstream of phosphatidylinositol 3-kinase (PI 3-kinase) and regulate glucose transport during insulin action in skeletal muscle and adipocytes. Insulin-stimulated glucose transport is defective in type II diabetes mellitus, and this defect is ameliorated by thiazolidinediones and lowering of blood glucose by chronic insulin therapy or short-term fasting. Presently, we evaluated the effects of these insulin-sensitizing modalities on the activation of insulin receptor substrate-1 (IRS-1)-dependent PI 3-kinase, PKC-/, and PKB in vastus lateralis skeletal muscles and adipocytes of nondiabetic and Goto-Kakizaki (GK) diabetic rats. Insulin provoked rapid increases in the activity of PI 3-kinase, PKC-/, and PKB in muscles and adipocytes of nondiabetic rats, but increases in IRS-1-dependent PI 3-kinase and PKC-/, but not PKB, activity were substantially diminished in GK muscles and adipocytes. Rosiglitazone treatment for 10–14 days, 10-day insulin treatment, and 60-h fasting reversed defects in PKC-/ activation in GK muscles and adipocytes and increased glucose transport in GK adipocytes, without necessarily increasing IRS-1-dependent PI 3-kinase or PKB activation. Our findings suggest that insulin-sensitizing modalities, viz. thiazolidinediones, chronic insulin treatment, and short-term fasting, similarly improve defects in insulin-stimulated glucose transport at least partly by correcting defects in insulin-induced activation of PKC-/.