Specific Roles of the p110α Isoform of Phosphatidylinsositol 3-Kinase in Hepatic Insulin Signaling and Metabolic Regulation

SummaryThe class IA 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 p110α catalytic subunit of PI3K is a key mediator of insulin metabolic actions in the liver. Thus, deletion of p110α in liver results in markedly blunted insulin signaling with decreased generation of PIP3 and loss of insulin activation of Akt, defects that could not be rescued by overexpression of p110β. As a result, mice with hepatic knockout of p110α display reduced insulin sensitivity, impaired glucose tolerance, and increased gluconeogenesis, hypolipidemia, and hyperleptinemia. The diabetic syndrome induced by loss of p110α in liver did not respond to metformin treatment. Together, these data indicate that the p110α isoform of PI3K plays a fundamental role in insulin signaling and control of hepatic glucose and lipid metabolism.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (274 K)Download as PowerPoint slideHighlights► Liver-specific deletion of the p110α catalytic subunit of PI3K ► Disruption of p110α results in impaired insulin action and glucose homeostasis ► Disruption of p110α cannot be rescued by p110β or ameliorated by metformin ► Liver p110α is necessary for the action of the antidiabetic drug metformin