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Persistent Activation of Phosphatidylinositol 3-Kinase Causes Insulin Resistance Due to Accelerated Insulin-Induced Insulin Receptor Substrate-1 Degradation in 3T3-L1 Adipocytes¹

Department of Medicine (K.E., N.N., P.M.S., J.M.O.), Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, California 92093; Veterans Administration Research Service (J.M.O.), San Diego, La Jolla, California 92161; The Whittier Diabetes Institute (J.M.O.), University of California, San Diego, La Jolla, California 92093; and the Third Department of Medicine (K.E., H.M., Y.N., A.K., R.K.), Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan

Address all correspondence and requests for reprints to: Jerrold M. Olefsky, Department of Medicine (0673), University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0673.

Recently, we have reported that the overexpression of a membrane-targeted phosphatidylinositol (PI) 3-kinase (p110CAAX) stimulated p70S6 kinase, Akt, glucose transport, and Ras activation in the absence of insulin but inhibited insulin-stimulated glycogen synthase activation and MAP kinase phosphorylation in 3T3-L1 adipocytes. To investigate the mechanism of p110CAAX-induced cellular insulin resistance, we have now studied the effect of p110CAAX on insulin receptor substrate (IRS)-1 protein. Overexpression of p110CAAX alone decreased IRS-1 protein levels to 63 ± 10% of control values. Insulin treatment led to an IRS-1 gel mobility shift (most likely caused by serine/threonine phosphorylation), with subsequent IRS-1 degradation. Moreover, insulin-induced IRS-1 degradation was enhanced by expression of p110CAAX (61 ± 16% vs. 13 ± 15% at 20 min, and 80 ± 8% vs. 41 ± 12% at 60 min, after insulin stimulation with or without p110CAAX expression, respectively). In accordance with the decreased IRS-1 protein, the insulin-stimulated association between IRS-1 and the p85 subunit of PI 3-kinase was also decreased in the p110CAAX-expressing cells, and IRS-1-associated PI 3-kinase activity was decreased despite the fact that total PI 3-kinase activity was increased. Five hours of wortmannin pretreatment inhibited both serine/threonine phosphorylation and degradation of IRS-1 protein. These results indicate that insulin treatment leads to serine/threonine phosphorylation of IRS-1, with subsequent IRS-1 degradation, through a PI 3-kinase-sensitive mechanism. Consistent with this, activated PI 3-kinase phosphorylates IRS-1 on serine/threonine residues, leading to IRS-1 degradation. The similar finding was observed in IRS-2 as well as IRS-1. These results may also explain the cellular insulin-resistant state induced by chronic p110CAAX expression.

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