Selective Inhibition of Eukaryotic Translation Initiation Factor 2 Dephosphorylation Potentiates Fatty Acid-induced Endoplasmic Reticulum Stress and Causes Pancreatic

Free fatty acids cause pancreatic Type 2 diabetes develops in individuals who fail to compen--cell apoptosis and maycontributeto -celllossintype2diabetesviatheinductionofendoplasmic reticulum stress. Reductions in eukaryotictranslation initiation factor (eIF) 2 phosphorylation triggerdisposition to the disease is an important risk factor, the rapid-cell failure and diabetes. Salubrinal selectively inhibitseIF2 dephosphorylation, protects other cells against endo-plasmic reticulum stress-mediated apoptosis, and has beenproposed as a -cell protector. Unexpectedly, salubrinalinduced apoptosis in primary -cells, and it potentiated thedeleterious effects of oleate and palmitate. Salubrinalinduced a marked eIF2 phosphorylation and potentiatedthe inhibitory effects of free fatty acids on protein synthesisand insulin release. The synergistic activation of the PERK-eIF2 branch of the endoplasmic reticulum stress response,but not of the IRE1 and activating transcription factor-6pathways, led to a marked induction of activating transcrip-tion factor-4 and the pro-apoptotic transcription factorCHOP. Our findings demonstrate that excessive eIF2 phos-phorylation is poorly tolerated by -cells and exacerbatesfree fatty acid-induced apoptosis. This modifies the presentparadigm regarding the beneficial role of eIF2 phosphoryl-ation in -cells and must be taken into consideration whendesigning therapies to protect -cells in type 2 diabetes.sate for insulin resistance by increasing pancreatic insulin out-put. This relative insulin deficiency results from pancreatic