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

• Published in: The Journal of biological chemistry 2005-11, Vol.280 (45), p.37489-37494
• Main Authors: Barbour, Linda A, Mizanoor Rahman, Shaikh, Gurevich, Inga, Leitner, J Wayne, Fischer, Stephanie J, Roper, Michael D, Knotts, Trina A, Vo, Yen, McCurdy, Carrie E, Yakar, Shoshana, Leroith, Derek, Kahn, C Ronald, Cantley, Lewis C, Friedman, Jacob E, Draznin, Boris
• Format: Article
• Language: English
• Subjects: Animals; Gene Expression Regulation, Enzymologic; Growth Hormone - metabolism; Humans; Insulin - metabolism; Insulin Receptor Substrate Proteins; Insulin Resistance - physiology; Insulin-Like Growth Factor I - genetics; Insulin-Like Growth Factor I - metabolism; Mice; Mice, Knockout; Mice, Transgenic; Muscle, Skeletal - metabolism; Phosphatidylinositol 3-Kinases - chemistry; Phosphatidylinositol 3-Kinases - metabolism; Phosphoproteins - metabolism; Placenta Growth Factor; Pregnancy Proteins; Protein Subunits - chemistry; Protein Subunits - metabolism; Signal Transduction
• ISSN: 0021-9258

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 p85alpha, p85beta, or insulin-like growth factor-1, we provide novel evidence suggesting that overexpression of p85alpha 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 p85alpha-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 p85alpha, which was completely reversible using a GH-releasing hormone antagonist. To understand the role of p85alpha in GH-induced insulin resistance, we used mice bearing deletions of the genes coding for p85alpha or p85beta, respectively (p85alpha (+/-) and p85beta(-/-)). Wild type and p85beta(-/-) mice developed in vivo insulin resistance and demonstrated overexpression of p85alpha and reduced insulin-stimulated PI 3-kinase activity in skeletal muscle in response to GH. In contrast, p85alpha(+/-)mice retained global insulin sensitivity and PI 3-kinase activity associated with reduced p85alpha expression. These findings demonstrated the importance of increased p85alpha in mediating skeletal muscle insulin resistance in response to GH and suggested a potential role for reducing p85alpha as a therapeutic strategy for enhancing insulin sensitivity in skeletal muscle.