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Molecular and Cellular Biology, March 2005, p. 1596-1607, Vol. 25, No. 5
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.5.1596-1607.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Phosphoinositide 3-Kinase Catalytic Subunit Deletion and Regulatory Subunit Deletion Have Opposite Effects on Insulin Sensitivity in Mice

Saskia M. Brachmann,1,2 Kohjiro Ueki,3 Jeffrey A. Engelman,1 Ronald C. Kahn,3 and Lewis C. Cantley1*

Division of Signal Transduction, Beth Israel Deaconess Medical Center, Department of Systems Biology,1 Research Division, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215,3 Institut fuer Biochemie, Freie Universitaet Berlin, Berlin, Germany2

Received 24 July 2004/ Returned for modification 30 August 2004/ Accepted 29 November 2004

Studies ex vivo have shown that phosphoinositide 3-kinase (PI3K) activity is necessary but not sufficient for insulin-stimulated glucose uptake. Unexpectedly, mice lacking either of the PI3K regulatory subunits p85{alpha} or p85ß exhibit increased insulin sensitivity. The insulin hypersensitivity is particularly unexpected in p85{alpha}–/– p55{alpha}–/– p50{alpha}–/– mice, where a decrease in p110{alpha} and p110ß catalytic subunits was observed in insulin-sensitive tissues. These results raised the possibility that decreasing total PI3K available for stimulation by insulin might circumvent negative feedback loops that ultimately shut off insulin-dependent glucose uptake in vivo. Here we present results arguing against this explanation. We show that p110{alpha}+/– p110ß+/– mice exhibit mild glucose intolerance and hyperinsulinemia in the fasted state. Unexpectedly, p110{alpha}+/– p110ß+/– mice showed a ~50% decrease in p85 expression in liver and muscle. Consistent with this in vivo observation, knockdown of p110 by RNA interference in mammalian cells resulted in loss of p85 proteins due to decreased protein stability. We propose that insulin sensitivity is regulated by a delicate balance between p85 and p110 subunits and that p85 subunits mediate a negative role in insulin signaling independent of their role as mediators of PI3K activation.

* Corresponding author. Mailing address: Beth Israel Hospital, NRB, Division of Signal Transduction, 10th Floor, 330, Brookline, MA 02215. Phone: (617) 667-0947. Fax: (617) 667-0957. E-mail: lewis_cantley{at}hms.harvard.edu.

Molecular and Cellular Biology, March 2005, p. 1596-1607, Vol. 25, No. 5
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.5.1596-1607.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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