Phosphoinositide 3-Kinase Regulatory Subunit p85α Suppresses Insulin Action via Positive Regulation of PTEN

• Published in: Proceedings of the National Academy of Sciences - PNAS 2006-08, Vol.103 (32), p.12093-12097
• Main Authors: Taniguchi, Cullen M., Tran, Thien T., Kondo, Tatsuya, Luo, Ji, Ueki, Kohjiro, Cantley, Lewis C., Kahn, C. Ronald
• Format: Article
• Language: English
• Subjects: Antibodies; Biological Sciences; Diabetes; Insulin; Insulin resistance; Lipids; Liver; Phosphatases; Phosphatidylinositols; Receptors; Type 2 diabetes mellitus
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0604628103

The phosphoinositide 3-kinase (P13K) pathway is central to the metabolic actions of insulin on liver. Here, we show that mice with a liver-specific deletion of the p85α regulatory subunit of P13K (L-Pik3rlKO) exhibit a paradoxical improvement of hepatic and peripheral insulin sensitivity. Although PI3K enzymatic activity is diminished in L-Pik3rlKO livers because of a reduced level of regulatory and catalytic subunits of PI3K, insulin-stimulated Akt activity is actually increased. This increased Akt activity correlates with increased phosphatidylinositol (3,4,5)-trisphosphate levels which are due, at least in part, to diminished activity of the (3,4,5)-trisphosphate phosphatase PTEN. Thus, the regulatory subunit p85α is a critical modulator of insulin sensitivity in vivo not only because of its effects on PI3K activation, but also as a regulator of PTEN activity.