TY - JOUR
T1 - Increased P85α is a potent negative regulator of skeletal muscle insulin signaling and induces in vivo insulin resistance associated with growth hormone excess
AU - Barbour, Linda A.
AU - Rahman, Shaikh Mizanoor
AU - Gurevich, Inga
AU - Leitner, J. Wayne
AU - Fischer, Stephanie J.
AU - Roper, Michael D.
AU - Knotts, Trina A.
AU - Vo, Yen
AU - McCurdy, Carrie E.
AU - Yakar, Shoshana
AU - LeRoith, Derek
AU - Kahn, C. Ronald
AU - Cantley, Lewis C.
AU - Friedman, Jacob E.
AU - Draznin, Boris
PY - 2005/11/11
Y1 - 2005/11/11
N2 - 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.
AB - 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.
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U2 - 10.1074/jbc.M506967200
DO - 10.1074/jbc.M506967200
M3 - Article
C2 - 16166093
AN - SCOPUS:27844460627
SN - 0021-9258
VL - 280
SP - 37489
EP - 37494
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 45
ER -