title: Increased P85alpha is a potent negative regulator of skeletal muscle insulin signaling and induces in vivo insulin resistance associated with growth hormone excess.
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 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.
authors.affiliation: Department of Medicine, University Colorado Health Sciences Center, Denver, 80262, USA.
authors.forename: Linda A
authors.initials: LA
authors.lastname: Barbour
authors.forename: Shaikh
authors.initials: S
authors.lastname: Mizanoor Rahman
authors.forename: Inga
authors.initials: I
authors.lastname: Gurevich
authors.forename: J Wayne
authors.initials: JW
authors.lastname: Leitner
authors.forename: Stephanie J
authors.initials: SJ
authors.lastname: Fischer
authors.forename: Michael D
authors.initials: MD
authors.lastname: Roper
authors.forename: Trina A
authors.initials: TA
authors.lastname: Knotts
authors.forename: Yen
authors.initials: Y
authors.lastname: Vo
authors.forename: Carrie E
authors.initials: CE
authors.lastname: McCurdy
authors.forename: Shoshana
authors.initials: S
authors.lastname: Yakar
authors.forename: Derek
authors.initials: D
authors.lastname: Leroith
authors.forename: C Ronald
authors.initials: CR
authors.lastname: Kahn
authors.forename: Lewis C
authors.initials: LC
authors.lastname: Cantley
authors.forename: Jacob E
authors.initials: JE
authors.lastname: Friedman
authors.forename: Boris
authors.initials: B
authors.lastname: Draznin
mesh_terms: D000818:Animals; D015971:Gene Expression Regulation, Enzymologic; D013006:Growth Hormone / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance / Q000502:physiology*; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins; D021122:Protein Subunits / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C526292:IRS1 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; C000608036:PGF protein, human; C000608037:Pgf protein, mouse; D010750:Phosphoproteins; D011257:Pregnancy Proteins; D021122:Protein Subunits; D000072483:Placenta Growth Factor; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; D019869:Phosphatidylinositol 3-Kinases