The unfolded protein response is required to maintain the integrity of the endoplasmic reticulum, prevent oxidative stress and preserve differentiation in beta-cells

Diabetes is an epidemic of worldwide proportions caused by beta-cell failure. Nutrient fluctuations and insulin resistance drive beta-cells to synthesize insulin beyond their capacity for protein folding and secretion and thereby activate the unfolded protein response (UPR), an adaptive signalling pathway to promote cell survival upon accumulation of unfolded protein in the endoplasmic reticulum (ER). Protein kinase-like endoplasmic reticulum kinase (PERK) signals one component of the UPR through phosphorylation of eukaryotic initiation factor 2 on the alpha-subunit (eIF2 alpha) to attenuate protein synthesis, thereby reducing the biosynthetic burden. beta-Cells uniquely require PERK-mediated phosphorylation of eIF2 alpha to preserve cell function. Unabated protein synthesis in beta-cells is sufficient to initiate a cascade of events, including oxidative stress, that are characteristic of beta-cell failure observed in type 2 diabetes. In contrast to acute adaptive UPR activation, chronic activation increases expression of the proapoptotic transcription factor CAAT/enhancer-binding protein homologous protein (CHOP). Chop deletion in insulin-resistant mice profoundly increases beta-cell mass and prevents beta-cell failure to forestall the progression of diabetes. The findings suggest an unprecedented link by which protein synthesis and/or misfolding in the ER causes oxidative stress and should encourage the development of novel strategies to treat diabetes.