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J. Biol. Chem., Vol. 280, Issue 45, 37489-37494, November 11, 2005

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Increased P85 Is a Potent Negative Regulator of Skeletal Muscle Insulin Signaling and Induces in Vivo Insulin Resistance Associated with Growth Hormone Excess^*

Linda A. Barbour, Shaikh Mizanoor Rahman¶, Inga Gurevich||, J. Wayne Leitner||, Stephanie J. Fischer¶, Michael D. Roper¶, Trina A. Knotts¶, Yen Vo||, Carrie E. McCurdy¶, Shoshana Yakar**, Derek LeRoith**, C. Ronald Kahn, Lewis C. Cantley, Jacob E. Friedman¶¶¶1, and Boris Draznin||

From the Departments of Medicine, Obstetrics and Gynecology, ^¶Pediatrics, ^¶¶Biochemistry and Molecular Genetics, University Colorado Health Sciences Center, Denver, Colorado 80262, the ^||Veterans Affairs Research Service, Denver Veterans Affairs Medical Center, Denver, Colorado 80220, the ^**Diabetes Branch, NIDDK, National Institutes of Health, Bethesda, Maryland 20892, the Research Division, Joslin Diabetes Center, Children's Hospital, Harvard Medical School, Boston, Massachusetts 02215, and the Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115

Insulin resistance is a cardinal feature of normal pregnancy and excess growth hormone (GH) states, but its underlying mechanism remains enigmatic. We previously found a significant increase in the p85 regulatory subunit of phosphatidylinositol kinase (PI 3-kinase) and striking decrease in IRS-1-associated PI 3-kinase activity in the skeletal muscle of transgenic animals overexpressing human placental growth hormone. Herein, using transgenic mice bearing deletions in p85, p85, or insulin-like growth factor-1, we provide novel evidence suggesting that overexpression of p85 is a primary mechanism for skeletal muscle insulin resistance in response to GH. We found that the excess in total p85 was entirely accounted for by an increase in the free p85-specific isoform. In mice with a liver-specific deletion in insulin-like growth factor-1, excess GH caused insulin resistance and an increase in skeletal muscle p85, which was completely reversible using a GH-releasing hormone antagonist. To understand the role of p85 in GH-induced insulin resistance, we used mice bearing deletions of the genes coding for p85 or p85, respectively (p85 ^+/– and p85^–/–). Wild type and p85^–/– mice developed in vivo insulin resistance and demonstrated overexpression of p85 and reduced insulin-stimulated PI 3-kinase activity in skeletal muscle in response to GH. In contrast, p85^+/–mice retained global insulin sensitivity and PI 3-kinase activity associated with reduced p85 expression. These findings demonstrated the importance of increased p85 in mediating skeletal muscle insulin resistance in response to GH and suggested a potential role for reducing p85 as a therapeutic strategy for enhancing insulin sensitivity in skeletal muscle.

Received for publication, June 27, 2005 , and in revised form, August 29, 2005.

^* This work was supported by a grant from the Veterans Administration Research Service and by the National Institutes of Health Grants DK062155 (to J. E. F.) and GM41890 (to L. C. C.). 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.

¹ To whom correspondence should be addressed: University of Colorado Health Sciences Center, Mail Stop 8106, P. O. Box 6511, Aurora, CO 80045. Tel.: 303-724-3983; Fax: 303-724-3920; E-mail: Jed.Friedman{at}uchsc.edu.

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