Abstract
Free fatty acids cause pancreatic beta-cell apoptosis and may contribute to beta-cell loss in type 2 diabetes via the induction of endoplasmic reticulum stress. Reductions in eukaryotic translation initiation factor (eIF) 2alpha phosphorylation trigger beta-cell failure and diabetes. Salubrinal selectively inhibits eIF2alpha dephosphorylation, protects other cells against endoplasmic reticulum stress-mediated apoptosis, and has been proposed as a beta-cell protector. Unexpectedly, salubrinal induced apoptosis in primary beta-cells, and it potentiated the deleterious effects of oleate and palmitate. Salubrinal induced a marked eIF2alpha phosphorylation and potentiated the inhibitory effects of free fatty acids on protein synthesis and insulin release. The synergistic activation of the PERK-eIF2alpha branch of the endoplasmic reticulum stress response, but not of the IRE1 and activating transcription factor-6 pathways, led to a marked induction of activating transcription factor-4 and the pro-apoptotic transcription factor CHOP. Our findings demonstrate that excessive eIF2alpha phosphorylation is poorly tolerated by beta-cells and exacerbates free fatty acid-induced apoptosis. This modifies the present paradigm regarding the beneficial role of eIF2alpha phosphorylation in beta-cells and must be taken into consideration when designing therapies to protect beta-cells in type 2 diabetes.
Highlights
Type 2 diabetes develops in individuals who fail to compensate for insulin resistance by increasing pancreatic insulin output
Salubrinal Synergizes with free fatty acids (FFA) to Activate the eIF2␣ Branch of the UPR in -Cells—Sal is a selective inhibitor of eIF2␣ dephosphorylation [18] and thereby engages only the PERK-eIF2␣ branch of the UPR
Following our observation that FFA cause ER dilation and apoptosis in pancreatic -cells [29], we demonstrated that FFA induce an ER stress response in -cells [5]
Summary
Type 2 diabetes develops in individuals who fail to compensate for insulin resistance by increasing pancreatic insulin output. Sal-induced eIF2␣ phosphorylation was proapoptotic in pancreatic -cells, and it potentiated the deleterious effects of the FFA oleate and palmitate. Exposure of INS-1E (Fig. 1C) or primary -cells (Fig. 1D) to oleate or palmitate in the presence of sal unexpectedly potentiated the pro-apoptotic effect of the FFA.
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