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J. Biol. Chem., Vol. 281, Issue 2, 1159-1168, January 13, 2006
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Exendin-4 Uses Irs2 Signaling to Mediate Pancreatic 
Cell Growth and Function*
1
From the
Howard Hughes Medical Institute, Division of Endocrinology, Department of Medicine, Children's Hospital Boston and Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215
The insulin receptor substrate 2 (Irs2) branch of the insulin/insulin-like growth factor-signaling cascade prevents diabetes in mice because it promotes 
cell replication, function, and survival, especially during metabolic stress. Because exendin-4 (Ex4), a long acting glucagon-like peptide 1 receptor agonist, has similar effects upon cells in rodents and humans, we investigated whether Irs2 signaling was required for Ex4 action in isolated cells and in Irs2-/- mice. Ex4 increased cAMP levels in human islets and Min6 cells, which promoted Irs2 expression and stimulated Akt phosphorylation. In wild type mice Ex4 administered continuously for 28 days increased cell mass 2-fold. By contrast, Ex4 failed to arrest the progressive cell loss in Irs2-/- mice, which culminated in fatal diabetes; however, Ex4 delayed the progression of diabetes by 3 weeks by promoting insulin secretion from the remaining islets. We conclude that some short term therapeutic effects of glucagon-like peptide 1 receptor agonists can be independent of Irs2, but its long term effects upon cell growth and survival are mediated by the Irs2 branch of the insulin/insulin-like growth factor signaling cascade.
Received for publication, July 28, 2005 , and in revised form, November 1, 2005.
* This work was supported by Grant DK55326 from the National Institutes of Health. 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 To whom correspondence should be addressed: Howard Hughes Medical Institute, Division of Endocrinology, Children's Hospital Boston, Karp Research Bldg., 300 Long-wood Ave Boston, MA 02115. Tel.: 617-919-2846; Fax: 617-730-0244; E-mail: morris.white{at}childrens.harvard.edu.
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