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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
/p55
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
and p85ß, insulin-sensitive tissues such as fat, muscle, and liver express the splice variants of the pik3r1 gene, p50
and p55
. To define the role of these variants, we have created mice with a deletion of p50
and p55
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
/p55
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
/p55
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
/p55
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
and p55
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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Copyright © 2004 by the American Society for Microbiology. All rights reserved.