Glucagon-Like Peptide-1 Agonists Protect Pancreatic β-Cells From Lipotoxic Endoplasmic Reticulum Stress Through Upregulation of BiP and JunB

• DOI: 10.2337/db09-0685
• Publication Date: 2009-09-01T01:06:51Z
• Authors: Daniel A. Cunha; Laurence Ladrière; Fernanda Ortis; Mariana Igoillo-E...; Esteban N. Gurzov; Roberto Lupi; Piero Marchetti; Décio L. Eizirik; Miriam Cnop
• Keywords: JUNB; Lipotoxicity

OBJECTIVE Chronic exposure of pancreatic β-cells to saturated free fatty acids (FFAs) causes endoplasmic reticulum (ER) stress and apoptosis may contribute β-cell loss in type 2 diabetes. Here, we evaluated the molecular mechanisms involved protection from lipotoxic ER by glucagon-like peptide (GLP)-1 agonists utilized treatment RESEARCH DESIGN AND METHODS INS-1E or fluorescence-activated cell sorter–purified primary rat were exposed oleate palmitate with without GLP-1 agonist exendin-4 forskolin. Cyclopiazonic acid was used as a synthetic stressor, while activating transcription factor 4–C/EBP homologous protein branch selectively activated salubrinal. The signaling pathways modulated studied real-time PCR Western blot. Knockdown RNA interference identify mediators antiapoptotic effects response downstream mitochondrial death mechanisms. RESULTS Exendin-4 forskolin protected against FFAs via induction chaperone BiP JunB that mediate survival under conditions. On other hand, stressors inactivating caspase 12 upregulating Bcl-2 X-chromosome–linked inhibitor inhibit apoptosis. CONCLUSIONS These observations suggest increase context-dependent way defense different stress–induced identification allows for targeted approaches alleviate