jci.org
J Clin Invest, January 2002, Volume 109, Number 1, 141-149
Copyright ©2002 by the American Society for Clinical Investigation
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Article
Reduced expression of the murine p85 subunit of phosphoinositide 3-kinase improves insulin signaling and ameliorates diabetes
Franck Mauvais-Jarvis1, Kohjiro Ueki1, David A. Fruman2, Michael F. Hirshman1, Kei Sakamoto1, Laurie J. Goodyear1, Matteo Iannacone1, Domenico Accili3, Lewis C. Cantley2 and C. Ronald Kahn1
1 Research Division, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA 2 Division of Signal Transduction, Beth Israel Deaconess Medical Center, Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA 3 Diabetes Research Unit, Columbia University, New York, New York, USA
Address correspondence to: C. Ronald Kahn, Research Division, Joslin Diabetes Center, One Joslin Place, Boston, Massachusetts 02215, USA. Phone: (617) 732-2635; Fax: (617) 732-2487; E-mail: c.ronald.kahn@joslin.harvard.edu.
Received for publication May 18, 2001, and accepted in revised form October 29, 2001.
A critical component of insulin action is the enzyme phosphoinositide (PI) 3-kinase. The major regulatory subunits of PI 3-kinase, p85 and its splice variants, are encoded by the Pik3r1 gene. Heterozygous disruption of Pik3r1 improves insulin signaling and glucose homeostasis in normal mice and mice made insulin-resistant by heterozygous deletion of the Insulin receptor and/or insulin receptor substrate-1 (IRS1) genes. Reduced expression of p85 modulates the molecular balance between this protein, the p110 catalytic subunit of PI 3-kinase, and the IRS proteins. Thus, despite the decrease in p85, PI 3-kinase activation is normal, insulin-stimulated Akt activity is increased, and glucose tolerance and insulin sensitivity are improved. Furthermore, Pik3r1 heterozygosity protects mice with genetic insulin resistance from developing diabetes. These data suggest that regulation of p85 levels may provide a novel therapeutic target for the treatment of type 2 diabetes. |
