Enhanced Signaling Downstream of Ribonucleic Acid-Activated Protein Kinase-Like Endoplasmic Reticulum Kinase Potentiates Lipotoxic Endoplasmic Reticulum Stress in Human Islets

Background: Free fatty acids cause pancreatic β-cell apoptosis and may contribute to β-cell loss in type 2 diabetes via the induction of endoplasmic reticulum (ER) stress. Eukaryotic translation initiation factor 2α (eIF2α) phosphorylation is an adaptive response to ER stress, and reductions in eIF2α phosphorylation trigger β-cell failure. Salubrinal inhibits eIF2α dephosphorylation and has been proposed as a novel therapy for diabetes. Objective: The objective of the study was to examine whether salubrinal modulates human islet susceptibility to lipotoxicity. Study Design: Human islets were treated with oleate or palmitate, alone or in combination with salubrinal, and examined for apoptosis, ultrastructure, and gene expression. Results: Salubrinal enhanced signaling downstream of eIF2α and markedly induced the proapoptotic transcription factor CCAAT/enhancer-binding protein homologous protein, but it did not induce the inositol requiring-1α or activating transcription factor 6 ER stress pathways. Salubrinal potentiated the deleterious effects of oleate and palmitate in human islets. This proapoptotic effect involved ER dilation and mitochondrial rounding and fragmentation. Conclusions: Excessive eIF2α phosphorylation is poorly tolerated by human islets and exacerbates fatty acid-induced apoptosis through ER and mitochondrial mechanisms. This should be taken into consideration when designing approaches to pharmacologically modulate the β-cell ER stress response in type 2 diabetes. Excessive eIF2α phosphorylation by salubrinal is poorly tolerated by human islets and exacerbates free fatty acid-induced apoptosis through endoplasmic reticulum stress and mitochondrial mechanisms.