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J. Biol. Chem., Vol. 279, Issue 38, 39705-39709, September 17, 2004

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Protective Effect of Phosphatidylinositol 4,5-Bisphosphate against Cortical Filamentous Actin Loss and Insulin Resistance Induced by Sustained Exposure of 3T3-L1 Adipocytes to Insulin^*

Guoli Chen, Priya Raman¶, Padma Bhonagiri, Andrew B. Strawbridge, Guruprasad R. Pattar, and Jeffrey S. Elmendorf||**

From the Departments of Cellular & Integrative Physiology and ^||Biochemistry & Molecular Biology, Indiana University School of Medicine, Center for Diabetes Research, Indianapolis, Indiana 46202

Muscle and fat cells develop insulin resistance when cultured under hyperinsulinemic conditions for sustained periods. Recent data indicate that early insulin signaling defects do not fully account for the loss of insulin action. Given that cortical filamentous actin (F-actin) represents an essential aspect of insulin regulated glucose transport, we tested to see whether cortical F-actin structure was compromised during chronic insulin treatment. The acute effect of insulin on GLUT4 translocation and glucose uptake was diminished in 3T3-L1 adipocytes exposed to a physiological level of insulin (5 nM) for 12 h. This insulin-induced loss of insulin responsiveness was apparent under both low (5.5 mM) and high (25 mM) glucose concentrations. Microscopic and biochemical analyses revealed that the hyperinsulinemic state caused a marked loss of cortical F-actin. Since recent data link phosphatidylinositol 4,5-bisphosphate (PIP₂) to actin cytoskeletal mechanics, we tested to see whether the insulin-resistant condition affected PIP₂ and found a noticeable loss of this lipid from the plasma membrane. Using a PIP₂ delivery system, we replenished plasma membrane PIP₂ in cells following the sustained insulin treatment and observed a restoration in cortical F-actin and insulin responsiveness. These data reveal a novel molecular aspect of insulin-induced insulin resistance involving defects in PIP₂/actin regulation.

Received for publication, April 16, 2004 , and in revised form, July 8, 2004.

^* This work was supported in part by National Center for Complementary and Alternative Medicine Grant R01-AT001846 (to J. S. E.), American Diabetes Foundation Career Development Award 60779 (to J. S. E.), and by two American Heart Association Midwest Affiliate Predoctoral Fellowships (to G. C. and A. B. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Both authors made substantial and equal contributions to this work.

^¶ Current address: Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Dept. of Molecular Cardiology, Cleveland Clinic Foundation, Cleveland, OH 44195.

^** To whom correspondence should be addressed: Dept. of Cellular & Integrative Physiology, Indiana University School of Medicine, Center for Diabetes Research, Indianapolis, IN 46202. Tel.: 317-274-7852; Fax: 317-274-3318; E-mail: jelmendo{at}iupui.edu.

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