Endoplasmic reticulum stress and eIF2α phosphorylation: The Achilles heel of pancreatic β cells

Background: Pancreatic beta cell dysfunction and death are central in the pathogenesis of most if not all forms of diabetes. Understanding the molecular mechanisms underlying beta cell failure is important to develop beta cell protective approaches. Scope of review: Here we review the role of endoplasmic reticulum stress and dysregulated endoplasmic reticulum stress signaling in beta cell,failure in monogenic and polygenic forms of diabetes. There is substantial evidence for the presence of endoplasmic reticulum stress in beta cells in type 1 and type 2 diabetes. Direct evidence for the importance of this stress response is provided by an increasing number of monogenic forms of diabetes. In particular, mutations in the PERK branch of the unfolded protein response provide insight into its importance for human beta cell function and survival. The knowledge gained from different rodent models is reviewed. More disease- and patient-relevant models, using human induced pluripotent stem cells differentiated into beta cells, will further advance our understanding of pathogenic mechanisms. Finally, we review the therapeutic modulation of endoplasmic reticulum stress and signaling in beta cells. Major conclusions: Pancreatic beta cells are sensitive to excessive endoplasmic reticulum stress and dysregulated eIF2 alpha phosphorylation, as indicated by transcriptome data, monogenic forms of diabetes and pharmacological studies. This should be taken into consideration when devising new therapeutic approaches for diabetes. (C) 2017 The Authors, Published by Elsevier GmbH.