Abstract

Objective: Chronic exposure of pancreatic β-cells to saturated free fatty acids (FFAs) causes endoplasmic reticulum (ER) stress and apoptosis, and may contribute to β-cell loss in type 2 diabetes. Here, we evaluated the molecular mechanisms involved in the protection of β-cells from lipotoxic ER stress by GLP-1 agonists, utilized in the treatment of type 2 diabetes.

Research Design and Methods: INS-1E or FACS-purified primary rat β-cells were exposed to oleate or palmitate with or without the GLP-1 agonist exendin-4 or forskolin. CPA was used as a synthetic ER stressor, while the ATF4-CHOP 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 anti-apoptotic GLP-1 effects in the ER stress response and downstream mitochondrial cell death mechanisms.

Results: Exendin-4 and forskolin protected β-cells against FFAs via the induction of the ER chaperone BiP and the anti-apoptotic protein JunB that mediate β-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 XIAP that inhibit mitochondrial apoptosis.

Conclusions: These observations suggest that GLP-1 agonists increase in a context-dependent way β-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 β-cell ER stress in diabetes.