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Endocrinology Vol. 144, No. 3 947-954
Copyright © 2003 by The Endocrine Society

ARTICLE

Defective Activation of Atypical Protein Kinase C {zeta} and {lambda} by Insulin and Phosphatidylinositol-3,4,5-(PO4)3 in Skeletal Muscle of Rats Following High-Fat Feeding and Streptozotocin-Induced Diabetes

Yoshinori Kanoh, Mini P. Sajan, Gautam Bandyopadhyay, Atsushi Miura, Mary L. Standaert and Robert V. Farese

Research Service, James A. Haley Veterans Administration Medical Center 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., ACOS-151, James A. Haley Veterans Administration Hospital, 13000 Bruce B. Downs Boulevard, Tampa, Florida 33612. E-mail: rfarese{at}hsc.med.usf.edu.

Insulin-stimulated glucose transport in skeletal muscle is thought to be effected at least partly through atypical protein kinase C isoforms (aPKCs) operating downstream of phosphatidylinositol (PI) 3-kinase and 3-phosphoinositide-dependent protein kinase-1 (PDK-1). However, relatively little is known about the activation of aPKCs in physiological conditions or insulin-resistant states. Presently, we studied aPKC activation in vastus lateralis muscles of normal chow-fed and high-fat-fed rats and after streptozotocin (STZ)-induced diabetes. In normal chow-fed rats, dose-dependent increases in aPKC activity approached maximal levels after 15–30 min of stimulation by relatively high and lower, presumably more physiological, insulin concentrations, achieved by im insulin or ip glucose administration. Insulin-induced activation of aPKCs was impaired in both high-fat-fed and STZ-diabetic rats, but, surprisingly, IRS-1-dependent and IRS-2-dependent PI 3-kinase activation was not appreciably compromised. Most interestingly, direct in vitro activation of aPKCs by PI-3,4,5-(PO4)3, the lipid product of PI 3-kinase, was impaired in both high-fat-fed and STZ-diabetic rats. Defects in activation of aPKCs by insulin and PI-3,4,5-(PO4)3 could not be explained by diminished PDK-1-dependent phosphorylation of threonine-410 in the PKC-{zeta} activation loop, as this phosphorylation was increased even in the absence of insulin treatment in high-fat-fed rats. Conclusions: 1) muscle aPKCs are activated at relatively low, presumably physiological, as well as higher supraphysiological, insulin concentrations; 2) aPKC activation is defective in muscles of high-fat-fed and STZ-diabetic rats; and 3) defective aPKC activation in these states is at least partly due to impaired responsiveness to PI-3,4,5-(PO4)3, apparently at activation steps distal to PDK-1-dependent loop phosphorylation.




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