par Ladrière, Laurence ;Igoillo Esteve, Mariana ;Andrade Da Cunha, Daniel ;Brion, Jean Pierre ;Bugliani, Marco;Marchetti, Piero;Eizirik, Decio L. ;Cnop, Miriam
Référence The Journal of clinical endocrinology and metabolism, 95, 3, page (1442-1449)
Publication Publié, 2010
Article révisé par les pairs
Résumé : Background: 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 (ER) stress. Eukaryotic translation initiation factor 2alpha (eIF2alpha) phosphorylation is an adaptive response to ER stress, and reductions in eIF2alpha phosphorylation trigger beta-cell failure. Salubrinal inhibits eIF2alpha 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 eIF2alpha and markedly induced the proapoptotic transcription factor CCAAT/enhancer-binding protein homologous protein, but it did not induce the inositol requiring-1alpha 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 eIF2alpha 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 beta-cell ER stress response in type 2 diabetes.

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