Increased P85α 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, Boris Draznin

Research output: Contribution to journalArticle

Abstract

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 p85α, p85α, or insulin-like growth factor-1, we provide novel evidence suggesting that overexpression of p85α 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 p85α-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 p85α, which was completely reversible using a GH-releasing hormone antagonist. To understand the role of p85α in GH-induced insulin resistance, we used mice bearing deletions of the genes coding for p85α or p85β, respectively (p85α+/- and p85β-/-). Wild type and p85β-/- mice developed in vivo insulin resistance and demonstrated overexpression of p85α and reduced insulin-stimulated PI 3-kinase activity in skeletal muscle in response to GH. In contrast, p85α+/- mice retained global insulin sensitivity and PI 3-kinase activity associated with reduced p85α expression. These findings demonstrated the importance of increased p85α in mediating skeletal muscle insulin resistance in response to GH and suggested a potential role for reducing p8α as a therapeutic strategy for enhancing insulin sensitivity in skeletal muscle.

Original languageEnglish (US)
Pages (from-to)37489-37494
Number of pages6
JournalJournal of Biological Chemistry
Volume280
Issue number45
DOIs
StatePublished - Nov 11 2005

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Barbour, L. A., Rahman, S. M., Gurevich, I., Leitner, J. W., Fischer, S. J., Roper, M. D., Knotts, T. A., Vo, Y., McCurdy, C. E., Yakar, S., LeRoith, D., Kahn, C. R., Cantley, L. C., Friedman, J. E., & Draznin, B. (2005). Increased P85α is a potent negative regulator of skeletal muscle insulin signaling and induces in vivo insulin resistance associated with growth hormone excess. Journal of Biological Chemistry, 280(45), 37489-37494. https://doi.org/10.1074/jbc.M506967200