Deregulation of Pancreas-Specific Oxidoreductin ERO1β in the Pathogenesis of Diabetes Mellitus

A growing body of evidence has underlined the significance of endoplasmic reticulum (ER) stress in the pathogenesis of diabetes mellitus. ER oxidoreductin 1 beta (ERO1 beta) is a pancreas-specific disulfide oxidase that is known to be upregulated in response to ER stress and to promote protein folding in pancreatic beta cells. It has recently been demonstrated that ERO1 beta promotes insulin biogenesis in beta cells and thus contributes to physiological glucose homeostasis, though it is unknown if ERO1 beta is involved in the pathogenesis of diabetes mellitus. Here we show that in diabetic model mice, ERO1 beta expression is paradoxically decreased in beta cells despite the indications of increased ER stress. However, overexpression of ERO1 beta in beta cells led to the upregulation of unfolded protein response genes and markedly enlarged ER lumens, indicating that ERO1 beta overexpression caused ER stress in the beta cells. Insulin contents were decreased in the beta cells that overexpressed ERO1 beta, leading to impaired insulin secretion in response to glucose stimulation. These data indicate the importance of the fine-tuning of the ER redox state, the disturbance of which would compromise the function of beta cells in insulin synthesis and thus contribute to the pathogenesis of diabetes mellitus.