Increased P85alpha is a potent negative regulator of skeletal muscle insulin signaling and induces in vivo insulin resistance associated with growth hormone excess

doi:10.1074/jbc.M506967200

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Increased P85alpha 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, and Boris Draznin

Department of Pediatrics, University of Colorado Health Science Center at Fitzsimons, Aurora, CO 80045

Corresponding Author: Jed.Friedman{at}UCHSC.edu

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 (hPGH). Herein, using transgenic mice bearing deletions in p85 $alpha$ , p85 $beta$ , or IGF-1, we provide novel evidence suggesting that overexpression of p85 $alpha$ 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 $alpha$ specific isoform. In mice with a liver-specific deletion in IGF-1, excess GH caused insulin resistance and an increase in skeletal muscle p85 $alpha$ which was completely reversible using a GH releasing hormone antagonist. To understand the role of p85 $alpha$ in GH-induced insulin resistance, we used mice bearing deletions of the genes coding for p85 $alpha$ or p85 $beta$ , respectively (p85 $alpha$ +/- and p85 $beta$ -/-). Wild type and p85 $beta$ -/- mice developed in vivo insulin resistance and demonstrated overexpression of p85 $alpha$ and reduced insulin-stimulated PI 3-kinase activity in skeletal muscle in response to GH. In contrast, p85 $alpha$ +/- mice retained global insulin sensitivity and PI 3-kinase activity associated with reduced p85 expression. These findings demonstrate the importance of increased p85 $alpha$ in mediating skeletal muscle insulin resistance in response to GH, and suggest a potential role for reducing p85 $alpha$ as a therapeutic strategy for enhancing insulin sensitivity in skeletal muscle.

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