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- Title
Glucagon-like peptide-1 agonists protect pancreatic beta-cells from lipotoxic endoplasmic reticulum stress through upregulation of BiP and JunB.
- Authors
Cunha DA; Ladrière L; Ortis F; Igoillo-Esteve M; Gurzov EN; Lupi R; Marchetti P; Eizirik DL; Cnop M; Cunha, Daniel A; Ladrière, Laurence; Ortis, Fernanda; Igoillo-Esteve, Mariana; Gurzov, Esteban N; Lupi, Roberto; Marchetti, Piero; Eizirik, Décio L; Cnop, Miriam
- Abstract
<bold>Objective: </bold>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.<bold>Research Design and Methods: </bold>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.<bold>Results: </bold>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.<bold>Conclusions: </bold>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.
- Publication
Diabetes, 2009, Vol 58, Issue 12, p2851
- ISSN
0012-1797
- Publication type
journal article
- DOI
10.2337/db09-0685