| Glucagon-like peptide-1 agonists protect pancreatic beta-cells from lipotoxic endoplasmic reticulum stress through upregulation of BiP and JunB. | |
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MedLine Citation:
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PMID: 19720788 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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OBJECTIVE: Chronic exposure of pancreatic beta-cells to saturated free fatty acids (FFAs) causes endoplasmic reticulum (ER) stress and apoptosis and may contribute to beta-cell loss in type 2 diabetes. Here, we evaluated the molecular mechanisms involved in the protection of beta-cells from lipotoxic ER stress by glucagon-like peptide (GLP)-1 agonists utilized in the treatment of type 2 diabetes. RESEARCH DESIGN AND METHODS: INS-1E or fluorescence-activated cell sorter-purified primary rat beta-cells were exposed to oleate or palmitate with or without the GLP-1 agonist exendin-4 or forskolin. Cyclopiazonic acid was used as a synthetic ER stressor, while the activating transcription factor 4-C/EBP homologous protein branch was selectively activated with salubrinal. The ER stress signaling pathways modulated by GLP-1 agonists were studied by real-time PCR and Western blot. Knockdown by RNA interference was used to identify mediators of the antiapoptotic GLP-1 effects in the ER stress response and downstream mitochondrial cell death mechanisms. RESULTS: Exendin-4 and forskolin protected beta-cells against FFAs via the induction of the ER chaperone BiP and the antiapoptotic protein JunB that mediate beta-cell survival under lipotoxic conditions. On the other hand, exendin-4 and forskolin protected against synthetic ER stressors by inactivating caspase 12 and upregulating Bcl-2 and X-chromosome-linked inhibitor of apoptosis protein that inhibit mitochondrial apoptosis. CONCLUSIONS: These observations suggest that GLP-1 agonists increase in a context-dependent way the beta-cell defense mechanisms against different pathways involved in ER stress-induced apoptosis. The identification of the pathways modulated by GLP-1 agonists allows for targeted approaches to alleviate beta-cell ER stress in diabetes. |
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Authors:
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Daniel A Cunha; Laurence Ladrière; Fernanda Ortis; Mariana Igoillo-Esteve; Esteban N Gurzov; Roberto Lupi; Piero Marchetti; Décio L Eizirik; Miriam Cnop |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2009-08-31 |
Journal Detail:
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Title: Diabetes Volume: 58 ISSN: 1939-327X ISO Abbreviation: Diabetes Publication Date: 2009 Dec |
Date Detail:
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Created Date: 2009-11-26 Completed Date: 2009-12-14 Revised Date: 2013-03-19 |
Medline Journal Info:
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Nlm Unique ID: 0372763 Medline TA: Diabetes Country: United States |
Other Details:
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Languages: eng Pagination: 2851-62 Citation Subset: AIM; IM |
Affiliation:
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Laboratory of Experimental Medicine, Université Libre de Bruxelles, Brussels, Belgium. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Antigens, Differentiation / metabolism Apoptosis Blotting, Western Cell Survival DNA-Binding Proteins / metabolism Diabetes Mellitus, Type 2 / metabolism*, prevention & control Endoplasmic Reticulum / metabolism* Forskolin / pharmacology Glucagon-Like Peptide 1 / agonists*, metabolism* Heat-Shock Proteins / genetics, metabolism* Hypoglycemic Agents / pharmacology Insulin-Secreting Cells / metabolism* Lipid Metabolism* / drug effects Male Peptides / pharmacology Polymerase Chain Reaction Proto-Oncogene Proteins / metabolism Proto-Oncogene Proteins c-jun / genetics, metabolism* RNA Interference Rats Rats, Wistar Receptors, Glucagon / metabolism Transcription Factors / metabolism Up-Regulation Venoms / pharmacology |
| Chemical | |
Reg. No./Substance:
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0/Antigens, Differentiation; 0/DNA-Binding Proteins; 0/Heat-Shock Proteins; 0/Hspa5 protein, rat; 0/Hypoglycemic Agents; 0/Myd116 protein, rat; 0/Peptides; 0/Proto-Oncogene Proteins; 0/Proto-Oncogene Proteins c-jun; 0/Receptors, Glucagon; 0/Transcription Factors; 0/Venoms; 0/glucagon-like peptide-1 receptor; 0/regulatory factor X transcription factors; 141732-76-5/exenatide; 66428-89-5/Forskolin; 89750-14-1/Glucagon-Like Peptide 1 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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