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J. Biol. Chem., Vol. 283, Issue 13, 8723-8735, March 28, 2008

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Glucagon-like Peptide-1 Activation of TCF7L2-dependent Wnt Signaling Enhances Pancreatic Beta Cell Proliferation^*

From the Laboratory of Molecular Endocrinology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114

The insulinotropic hormone GLP-1 (glucagon-like peptide-1) is a new therapeutic agent that preserves or restores pancreatic beta cell mass. We report that GLP-1 and its agonist, exendin-4 (Exd4), induce Wnt signaling in pancreatic beta cells, both isolated islets, and in INS-1 cells. Basal and GLP-1 agonist-induced proliferation of beta cells requires active Wnt signaling. Cyclin D1 and c-Myc, determinants of cell proliferation, are up-regulated by Exd4. Basal endogenous Wnt signaling activity depends on Wnt frizzled receptors and the protein kinases Akt and GSK3β but not cAMP-dependent protein kinase. In contrast, GLP-1 agonists enhance Wnt signaling via GLP-1 receptor-mediated activation of Akt and beta cell independent of GSK3β. Inhibition of Wnt signaling by small interfering RNAs to β-catenin or a dominant-negative TCF7L2 decreases both basal and Exd4-induced beta cell proliferation. Wnt signaling appears to mediate GLP-1-induced beta cell proliferation raising possibilities for novel treatments of diabetes.

Received for publication, July 25, 2007 , and in revised form, January 18, 2008.

^* This work was supported in part by United States Public Health Service Grants DK55365 and DK30834 (to J. F. H.) and National Institutes of Health Pilot and Feasibility Award P30 DK57521 (to Z. L.). 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 Table S1 and Figs. 1-3.

¹ To whom correspondence should be addressed: Laboratory of Molecular Endocrinology, 55 Fruit St., Thier 306, Massachusetts General Hospital, Boston, MA 02114. E-mail: jhabener{at}partners.org.

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