title: Specific roles of the p110alpha isoform of phosphatidylinsositol 3-kinase in hepatic insulin signaling and metabolic regulation.
abstract: The class I(A) phosphatidylinsositol 3-kinases (PI3Ks) form a critical node in the insulin metabolic pathway; however, the precise roles of the different isoforms of this enzyme remain elusive. Using tissue-specific gene inactivation, we demonstrate that p110alpha catalytic subunit of PI3K is a key mediator of insulin metabolic actions in the liver. Thus, deletion of p110alpha in liver results in markedly blunted insulin signaling with decreased generation of PIP(3) and loss of insulin activation of Akt, defects that could not be rescued by overexpression of p110beta. As a result, mice with hepatic knockout of p110alpha display reduced insulin sensitivity, impaired glucose tolerance, and increased gluconeogenesis, hypolipidemia, and hyperleptinemia. The diabetic syndrome induced by loss of p110alpha in liver did not respond to metformin treatment. Together, these data indicate that the p110alpha isoform of PI3K plays a fundamental role in insulin signaling and control of hepatic glucose and lipid metabolism.
authors.affiliation: Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Victoria Rotter
authors.initials: VR
authors.lastname: Sopasakis
authors.forename: Pixu
authors.initials: P
authors.lastname: Liu
authors.forename: Ryo
authors.initials: R
authors.lastname: Suzuki
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Kondo
authors.forename: Jonathon
authors.initials: J
authors.lastname: Winnay
authors.forename: Thien T
authors.initials: TT
authors.lastname: Tran
authors.forename: Tomoichiro
authors.initials: T
authors.lastname: Asano
authors.forename: Graham
authors.initials: G
authors.lastname: Smyth
authors.forename: Mini P
authors.initials: MP
authors.lastname: Sajan
authors.forename: Robert V
authors.initials: RV
authors.lastname: Farese
authors.forename: C Ronald
authors.initials: CR
authors.lastname: Kahn
authors.forename: Jean J
authors.initials: JJ
authors.lastname: Zhao
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D058534:Class I Phosphatidylinositol 3-Kinases; D003920:Diabetes Mellitus / Q000188:drug therapy / Q000378:metabolism; D015536:Down-Regulation; D004734:Energy Metabolism; D018149:Glucose Intolerance / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D020738:Leptin / Q000378:metabolism; D008055:Lipids / Q000502:physiology*; D008099:Liver / Q000378:metabolism*; D008687:Metformin / Q000627:therapeutic use; D051379:Mice; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D001786:Blood Glucose; D007328:Insulin; D020738:Leptin; D008055:Lipids; D018129:Phosphatidylinositol Phosphates; C060974:phosphatidylinositol 3,4,5-triphosphate; D008687:Metformin; D019869:Phosphatidylinositol 3-Kinases; C509622:1-phosphatidylinositol 3-kinase p110 subunit, mouse; D058534:Class I Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt