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PKC- Mediates Insulin Effects on Glucose Transport in Cultured Preadipocyte-Derived Human Adipocytes

J. A. Haley Veterans’ Hospital Research Service and Department of Internal Medicine, University of South Florida College of Medicine (G.B., M.P.S., Y.K., M.L.S., R.V.F.), Tampa, Florida 33612; Hypertension-Endocrine Branch, National Heart, Lung and Blood Institute, National Institutes of Health (M.J.Q.), Bethesda, Maryland 20892; and Zen-Bio, Inc. (R.L.-C., A.S.), Research Triangle Park, North Carolina 27709

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

Abstract

Insulin-stimulated glucose transport is impaired in the early phases of type 2 diabetes mellitus. Studies in rodent cells suggest that atypical PKC (aPKC) isoforms (, , and ) and PKB, and their upstream activators, PI3K and 3-phosphoinositide-dependent protein kinase-1 (PDK-1), play important roles in insulin-stimulated glucose transport. However, there is no information on requirements for aPKCs, PKB, or PDK-1 during insulin action in human cell types. Presently, by using preadipocyte-derived adipocytes, we were able to employ adenoviral gene transfer methods to critically examine these requirements in a human cell type. These adipocytes were found to contain PKC-, rather than PKC-/, as their major aPKC. Expression of kinase-inactive forms of PDK-1, PKC-, and PKC- (which functions interchangeably with PKC-) as well as chemical inhibitors of PI 3-kinase and PKC-/, wortmannin and the cell-permeable myristoylated PKC- pseudosubstrate, respectively, effectively inhibited insulin-stimulated glucose transport. In contrast, expression of a kinase-inactive, activation-resistant, triple alanine mutant form of PKB- had little or no effect, and expression of wild-type and constitutively active PKC- or PKC- increased glucose transport. Our findings provide convincing evidence that aPKCs and upstream activators, PI 3-kinase and PDK-1, play important roles in insulin-stimulated glucose transport in preadipocyte-derived human adipocytes.

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