Glucagon-like peptide-1 activation of TCF7L2-dependent Wnt signaling enhances pancreatic beta cell proliferation.
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.
Liu
Zhengyu
Z
Laboratory of Molecular Endocrinology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Habener
Joel F
JF
D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002469:Cell Separation; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D019938:Cyclin D1 / Q000235:genetics; D004789:Enzyme Activation; D000077270:Exenatide; D051157:Frizzled Receptors / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D008024:Ligands; D051379:Mice; D010455:Peptides / Q000494:pharmacology; D051381:Rats; D018027:Receptors, Glucagon / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D051820:TCF Transcription Factors / Q000235:genetics / Q000378:metabolism*; D058118:Transcription Factor 7-Like 2 Protein; D014688:Venoms / Q000494:pharmacology; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism
D017362:Cyclic AMP Response Element-Binding Protein; D051157:Frizzled Receptors; D007328:Insulin; D008024:Ligands; D010455:Peptides; D018027:Receptors, Glucagon; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; C544895:Tcf7l2 protein, mouse; D058118:Transcription Factor 7-Like 2 Protein; D014688:Venoms; D051153:Wnt Proteins; D051176:beta Catenin; D019938:Cyclin D1; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3