Increased p85α is a potent negative regulator of skeletal muscle insulin signaling and induces in vivo insulin resistance associated with growth hormone excess

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 ( PI3-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 alpha, p85 beta, or insulin-like growth factor-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 insulin-like growth factor-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 alpha expression. These findings demonstrated the importance of increased p85 alpha in mediating skeletal muscle insulin resistance in response to GH and suggested a potential role for reducing p85 alpha as a therapeutic strategy for enhancing insulin sensitivity in skeletal muscle.