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

Abstract

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. The objective of the study was to examine whether salubrinal modulates human islet susceptibility to lipotoxicity. Human islets were treated with oleate or palmitate, alone or in combination with salubrinal, and examined for apoptosis, ultrastructure, and gene expression. 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. 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.