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Molecular and Cellular Biology, January 2004, p. 320-329, Vol. 24, No. 1
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.1.320-329.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

p50{alpha}/p55{alpha} Phosphoinositide 3-Kinase Knockout Mice Exhibit Enhanced Insulin Sensitivity

Dong Chen, Franck Mauvais-Jarvis, Matthias Bluher, Simon J. Fisher, Alison Jozsi, Laurie J. Goodyear, Kohjiro Ueki, and C. Ronald Kahn*

Research Division, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts

Received 23 April 2003/ Returned for modification 25 June 2003/ Accepted 18 September 2003

Class Ia phosphoinositide (PI) 3-kinases are heterodimers composed of a regulatory and a catalytic subunit and are essential for the metabolic actions of insulin. In addition to p85{alpha} and p85ß, insulin-sensitive tissues such as fat, muscle, and liver express the splice variants of the pik3r1 gene, p50{alpha} and p55{alpha}. To define the role of these variants, we have created mice with a deletion of p50{alpha} and p55{alpha} by using homologous recombination. These mice are viable, grow normally, and maintain normal blood glucose levels but have lower fasting insulin levels. Results of an insulin tolerance test indicate that p50{alpha}/p55{alpha} knockout mice have enhanced insulin sensitivity in vivo, and there is an increase in insulin-stimulated glucose transport in isolated extensor digitorum longus muscle tissues and adipocytes. In muscle, loss of p50{alpha}/p55{alpha} results in reduced levels of insulin-stimulated insulin receptor substrate 1 (IRS-1) and phosphotyrosine-associated PI 3-kinase but enhanced levels of IRS-2-associated PI 3-kinase and Akt activation, whereas in adipocytes levels of both insulin-stimulated PI 3-kinase and Akt are unchanged. Despite this, adipocytes of the knockout mice are smaller and have increased glucose uptake with altered glucose metabolic pathways. When treated with gold thioglucose, p50{alpha}/p55{alpha} knockout mice become hyperphagic like their wild-type littermates. However, they accumulate less fat and become mildly less hyperglycemic and markedly less hyperinsulinemic. Taken together, these data indicate that p50{alpha} and p55{alpha} play an important role in insulin signaling and action, especially in lipid and glucose metabolism.

* Corresponding author. Mailing address: Research Division, Joslin Diabetes Center, One Joslin Place, Boston, MA 02215. Phone: (617) 732-2635. Fax: (617) 732-2487. E-mail: c.ronald.kahn{at}joslin.harvard.edu.

Molecular and Cellular Biology, January 2004, p. 320-329, Vol. 24, No. 1
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.1.320-329.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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