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J. Biol. Chem., Vol. 280, Issue 47, 39388-39393, November 25, 2005

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Phosphatase and Tensin Homolog Regulation of Islet Growth and Glucose Homeostasis^*

Jake A. Kushner1, Laura Simpson, Lynn M. Wartschow¶, Shaodong Guo¶, Matthew M. Rankin, Ramon Parsons, and Morris F. White¶2

From the Division of Endocrinology, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania 19104, Institute for Cancer Genetics, College of Physicians and Surgeons, Columbia University, New York, New York 10032, and ^¶Howard Hughes Medical Institute, Division of Endocrinology, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts 02115

The Irs2 branch of the insulin/insulin-like growth factor signaling cascade activates the phosphatidylinositol 3-kinase Akt Foxo1 cascade in many tissues, including hepatocytes and pancreatic -cells. The 3'-lipid phosphatase Pten ordinarily attenuates this cascade; however, its influence on -cell growth or function is unknown. To determine whether decreased Pten expression could restore -cell function and prevent diabetes in Irs2^-/- mice, we generated wild type or Irs2 knock-out mice that were haploinsufficient for Pten (Irs2^-/-::Pten^+/-). Irs2^-/- mice develop diabetes by 3 months of age as -cell mass declined progressively until insulin production was lost. Pten insufficiency increased peripheral insulin sensitivity in wild type and Irs2^-/- mice and increased Akt and Foxo1 phosphorylation in the islets. Glucose tolerance improved in the Pten^+/- mice, although -cell mass and circulating insulin levels decreased. Compared with Irs2^-/- mice, the Irs2^-/-::Pten^+/- mice displayed nearly normal glucose tolerance and survived without diabetes, because normal but small islets produced sufficient insulin until the mice died of lymphoproliferative disease at 12 months age. Thus, steps to enhance phosphatidylinositol 3-kinase signaling can promote -cell growth, function, and survival without the Irs2 branch of the insulin/insulin-like growth factor signaling cascade.

Received for publication, April 15, 2005 , and in revised form, August 26, 2005.

^* This work was supported in part by National Institutes of Health Grants DK55326, DK43808, DK38712 (to M. F. W.), and CA82783 (to R. P.) and Howard Hughes Medical Institute funds (to M. F. W.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by National Institutes of Health Institutional Training Grant DK02024, National Institutes of Health Training Grant DK064101, a Charles H. Hood Foundation Child Health Research grant, a Lawson Wilkins Pediatric Endocrine Society clinical scholar award, and a March of Dimes Basil O'Connor career development award.

² To whom correspondence should be addressed: Howard Hughes Medical Institute, Division of Endocrinology, Children's Hospital Boston, Dept. of Medicine, Harvard Medical School, Karp Research Bldg., Rm. 04210, 300 Longwood Ave., Boston, MA 02115. Tel.: 617-919-2846; Fax: 617-730-0244; E-mail: morris.white{at}childrens.harvard.edu.

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