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PNAS 103 (32): 12093-12097

Copyright © 2006 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / MEDICAL SCIENCES

Phosphoinositide 3-kinase regulatory subunit p85{alpha} suppresses insulin action via positive regulation of PTEN

Cullen M. Taniguchi*, Thien T. Tran*, Tatsuya Kondo{dagger}, Ji Luo{ddagger},§, Kohjiro Ueki, Lewis C. Cantley{ddagger},§,||, and C. Ronald Kahn*,**

*Cellular and Molecular Physiology, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215; {dagger}Department of Metabolic Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8555, Japan; {ddagger}Department of Systems Biology, Harvard Medical School, Boston, MA 02215; §Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, MA 02115; and Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan

Contributed by Lewis C. Cantley, June 3, 2006

Abstract: The phosphoinositide 3-kinase (PI3K) pathway is central to the metabolic actions of insulin on liver. Here, we show that mice with a liver-specific deletion of the p85{alpha} regulatory subunit of PI3K (L-Pik3r1KO) exhibit a paradoxical improvement of hepatic and peripheral insulin sensitivity. Although PI3K enzymatic activity is diminished in L-Pik3r1KO 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 p85{alpha} 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.

Key Words: conditional gene knockout • diabetes • insulin resistance

Freely available online through the PNAS open access option.

Author contributions: C.M.T., K.U., and L.C.C. designed research; C.M.T., T.T.T., T.K., and J.L. performed research; L.C.C. contributed new reagents/analytic tools; C.M.T., T.K., J.L., and C.R.K. analyzed data; and C.M.T., J.L., L.C.C., and C.R.K. wrote the paper.

Conflict of interest statement: No conflicts declared.

||To whom correspondence may be addressed. E-mail: lcantley{at}hms.harvard.edu

**To whom correspondence may be addressed at: Joslin Diabetes Center, One Joslin Place, Boston, MA 02215. E-mail: c.ronald.kahn{at}joslin.harvard.edu

© 2006 by The National Academy of Sciences of the USA

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