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Glucagon-like peptide-1 activation of TCF7L2-dependent Wnt signaling enhances pancreatic beta cell proliferation
| Title | Glucagon-like peptide-1 activation of TCF7L2-dependent Wnt signaling enhances pancreatic beta cell proliferation |
| Publication Type | Journal Article |
| Year of Publication | 2008 |
| Authors | |
| Journal | J Biol Chem |
| Volume | 283 |
| Issue | 13 |
| Pagination | 8723-35 |
| Date Published | Mar 28 |
| Publication Language | eng |
| ISBN Number | 0021-9258 (Print) |
| Accession Number | 18216022 |
| Key Words | Venoms/pharmacology, Receptors, Rats, Enzyme Activation, Cyclic AMP-Dependent Protein Kinases/metabolism, Cell Separation, Cell Line, Animals, Peptides/pharmacology, Mice, Ligands, Insulin/pharmacology, Humans, beta Catenin/metabolism, Wnt Proteins/*metabolism, TCF Transcription Factors/genetics/*metabolism, Signal Transduction/*drug effects, Glucagon/metabolism, Glycogen Synthase Kinase 3/metabolism, Glucagon-Like Peptide 1/*pharmacology, Frizzled Receptors/metabolism, Cyclin D1/genetics, Cyclic AMP Response Element-Binding Protein/metabolism, Cyclic AMP/metabolism, Cell Proliferation/drug effects, Insulin-Secreting Cells/*cytology/drug effects/*metabolism |
| 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. |
| Notes | 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 |
| URL | http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18216022 |
| Citation Key | 433 |
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- Animals
- beta Catenin/metabolism
- Cell Line
- Cell Proliferation/drug effects
- Cell Separation
- Cyclic AMP Response Element-Binding Protein/metabolism
- Cyclic AMP-Dependent Protein Kinases/metabolism
- Cyclic AMP/metabolism
- Cyclin D1/genetics
- Enzyme Activation
- Frizzled Receptors/metabolism
- Glucagon-Like Peptide 1/*pharmacology
- Glycogen Synthase Kinase 3/metabolism
- Humans
- Insulin-Secreting Cells/*cytology/drug effects/*metabolism
- Insulin/pharmacology
- Ligands
- Mice
- Peptides/pharmacology
- Rats
- Receptors, Glucagon/metabolism
- Signal Transduction/*drug effects
- TCF Transcription Factors/genetics/*metabolism
- Venoms/pharmacology
- Wnt Proteins/*metabolism