No abstract

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