31 Liu, Z. Habener, J. F. 2008 J Biol Chem 283 13 8723-35 Mar 28 0021-9258 (Print) 18216022 beta Catenin/metabolism Wnt Proteins/*metabolism Venoms/pharmacology TCF Transcription Factors/genetics/*metabolism Signal Transduction/*drug effects Receptors, Glucagon/metabolism Rats Glycogen Synthase Kinase 3/metabolism Glucagon-Like Peptide 1/*pharmacology Frizzled Receptors/metabolism Enzyme Activation Cyclin D1/genetics Cyclic AMP-Dependent Protein Kinases/metabolism Cyclic AMP Response Element-Binding Protein/metabolism Cyclic AMP/metabolism Cell Separation Cell Proliferation/drug effects Cell Line Animals Peptides/pharmacology Mice Ligands Insulin-Secreting Cells/*cytology/drug effects/*metabolism Insulin/pharmacology Humans Receptors Glucagon/metabolism 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 GSK3beta 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 GSK3beta. Inhibition of Wnt signaling by small interfering RNAs to beta-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. DK 30834/DK/NIDDK NIH HHS/United StatesDK 55365/DK/NIDDK NIH HHS/United StatesP30 DK 57521/DK/NIDDK NIH HHS/United StatesJournal ArticleResearch Support, N.I.H., ExtramuralUnited States http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18216022