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J. Biol. Chem., Vol. 282, Issue 33, 23829-23840, August 17, 2007

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Protein-tyrosine Phosphatase 1B Deficiency Reduces Insulin Resistance and the Diabetic Phenotype in Mice with Polygenic Insulin Resistance^*

Bingzhong Xue, Young-Bum Kim, Anna Lee, Elena Toschi, Susan Bonner-Weir, C. Ronald Kahn, Benjamin G. Neel^¶1, and Barbara B. Kahn²

From the Division of Endocrinology, Diabetes, and Metabolism and the ^¶Cancer Biology Program, Division of Hematology-Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, and the Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215

Mice heterozygous for insulin receptor (IR) and IR substrate (IRS)-1 deficiency provide a model of polygenic type 2 diabetes in which early-onset, genetically programmed insulin resistance leads to diabetes. Protein-tyrosine phosphatase 1B (PTP1B) dephosphorylates tyrosine residues in IR and possibly IRS proteins, thereby inhibiting insulin signaling. Mice lacking PTP1B are lean and have increased insulin sensitivity. To determine whether PTP1B can modify polygenic insulin resistance, we crossed PTP1B^–/– mice with mice with a double heterozygous deficiency of IR and IRS-1 alleles (DHet). DHet mice weighed slightly less than wild-type mice and exhibited severe insulin resistance and hyperglycemia, with 35% of DHet males developing diabetes by 9–10 weeks of age. Body weight in DHet mice with PTP1B deficiency was similar to that in DHet mice. However, absence of PTP1B in DHet mice markedly improved glucose tolerance and insulin sensitivity at 10–11 weeks of age and reduced the incidence of diabetes and hyperplastic pancreatic islets at 6 months of age. Insulin-stimulated phosphorylation of IR, IRS proteins, Akt/protein kinase B, glycogen synthase kinase 3, and p70^S6K was impaired in DHet mouse muscle and liver and was differentially improved by PTP1B deficiency. In addition, increased phosphoenolpyruvate carboxykinase expression in DHet mouse liver was reversed by PTP1B deficiency. In summary, PTP1B deficiency reduces insulin resistance and hyperglycemia without altering body weight in a model of polygenic type 2 diabetes. Thus, even in the setting of high genetic risk for diabetes, reducing PTP1B is partially protective, further demonstrating its attractiveness as a target for prevention and treatment of type 2 diabetes.

Received for publication, October 13, 2006 , and in revised form, May 1, 2007.

^* This work was supported by National Institutes of Health Grants DK60839 (to B. B. K.), DK60838 (to B. G. N.), DK31036 and DK33201 (to C. R. K.), and Grant DK66056 (to S. B.-W.); Boston Area Diabetes Endocrinology Research Center Metabolic Physiology Core Grant DK57521 (to B. B. K.); and American Diabetes Association Grant 7-05-PPG-02 (to Y. B.-K.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1–4.

¹ To whom correspondence may be addressed. E-mail: bneel{at}bidmc.harvard.edu. ² To whom correspondence may be addressed: Div. of Endocrinology, Beth Israel Deaconess Medical Center, 330 Brookline Ave., Boston, MA 02215. E-mail: bkahn{at}bidmc.harvard.edu.

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