Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Cell Line
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Cell Proliferation / drug effects
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Cell Separation
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Cyclic AMP / metabolism
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Cyclic AMP Response Element-Binding Protein / metabolism
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Cyclic AMP-Dependent Protein Kinases / metabolism
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Cyclin D1 / genetics
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Enzyme Activation
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Exenatide
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Frizzled Receptors / metabolism
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Glucagon-Like Peptide 1 / pharmacology*
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Glycogen Synthase Kinase 3 / metabolism
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Humans
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Insulin / pharmacology
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Insulin-Secreting Cells / cytology*
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Insulin-Secreting Cells / drug effects
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Insulin-Secreting Cells / metabolism*
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Ligands
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Mice
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Peptides / pharmacology
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Rats
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Receptors, Glucagon / metabolism
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Signal Transduction / drug effects*
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TCF Transcription Factors / genetics
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TCF Transcription Factors / metabolism*
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Transcription Factor 7-Like 2 Protein
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Venoms / pharmacology
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Wnt Proteins / metabolism*
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beta Catenin / metabolism
Substances
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Cyclic AMP Response Element-Binding Protein
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Frizzled Receptors
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Insulin
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Ligands
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Peptides
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Receptors, Glucagon
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TCF Transcription Factors
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TCF7L2 protein, human
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Tcf7l2 protein, mouse
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Transcription Factor 7-Like 2 Protein
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Venoms
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Wnt Proteins
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beta Catenin
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Cyclin D1
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Glucagon-Like Peptide 1
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Exenatide
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Cyclic AMP
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Cyclic AMP-Dependent Protein Kinases
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Glycogen Synthase Kinase 3