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Rescuing 3T3-L1 Adipocytes from Insulin Resistance Induced by Stimulation of Akt-Mammalian Target of Rapamycin/p70 S6 Kinase (S6K1) Pathway and Serine Phosphorylation of Insulin Receptor Substrate-1: Effect of Reduced Expression of p85 Subunit of Phosphatidylinositol 3-Kinase and S6K1 Kinase

Research Service (R.A., J.W.L., R.H., B.D.), Department of Veterans Affairs, and Department of Medicine (R.A., B.D.), University of Colorado Denver, Aurora, Colorado 80045

Address all correspondence and requests for reprints to: Boris Draznin, M.D., Ph.D., Director, Adult Diabetes Program, Professor of Medicine, Division of Endocrinology, Metabolism and Diabetes, University of Colorado Denver, School of Medicine, Anschutz Medical Campus MS 8106, P.O. Box 6511, 12801 East 17th Avenue, Aurora, Colorado 80045. E-mail: Boris.Draznin{at}UCDenver.edu.

Phosphorylation of insulin receptor substrate-1 (IRS-1) on serine residues has been recognized as a mechanism responsible for a diminution of insulin action and insulin resistance. Potential approaches to improve insulin sensitivity may include interference with and/or reduction in expression of certain signaling intermediates that participate in the pathogenesis of insulin resistance. In this study, we transduced fully differentiated 3T3-L1 adipocytes with a constitutively active myristoylated Akt that led to hyperactivation of mammalian target of rapamycin and p70 S6 kinase (S6K1), increased serine phosphorylation of IRS-1, and reduction in insulin-stimulated phosphatidylinositol (PI) 3-kinase activity and glucose transport. We then reduced expression of the PI 3-kinase regulatory subunit, p85, or expression of S6K1 kinase using small interfering RNA transfections, which led to a reduction in p85 expression of 70% at 48 h (P < 0.05) and S6K1 of 49% (P < 0.05). Reduction in expression of either p85 or S6K1 achieved with small interfering RNA in the presence of myristoylated Akt rescued 3T3-L1 adipocytes from the insulin resistance induced by serine phosphorylation of IRS-1 and completely restored insulin-stimulated activation of PI 3-kinase and glucose uptake. We conclude that reduction in expression of p85 or S6K1 could represent therapeutic targets to mitigate insulin resistance.