期刊
DIABETES
卷 58, 期 12, 页码 2851-2862出版社
AMER DIABETES ASSOC
DOI: 10.2337/db09-0685
关键词
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资金
- European Union [LSHMCT-2006-518153, 036903]
- Belgian Program on Interuniversity Poles of Attraction initiated by the Belgian State [P6/40]
- Fonds National de la Recherche Scientifique
- Fonds de la Recherche Scientifique Medicale
- Actions de Recherche Concertees de la Communaute Francaise, Belgium
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 mid 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. Diabetes 58:2851-2862, 2009
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