Specific roles of the p110alpha isoform of phosphatidylinsositol 3-kinase in hepatic insulin signaling and metabolic regulation.
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.
Sopasakis
Victoria Rotter
VR
Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA.
Liu
Pixu
P
Suzuki
Ryo
R
Kondo
Tatsuya
T
Winnay
Jonathon
J
Tran
Thien T
TT
Asano
Tomoichiro
T
Smyth
Graham
G
Sajan
Mini P
MP
Farese
Robert V
RV
Kahn
C Ronald
CR
Zhao
Jean J
JJ
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
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