Department of Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Mol Cell Biol. 2014 Apr;34(7):1290-9. doi: 10.1128/MCB.01647-13. Epub 2014 Jan 27.
A growing body of evidence has underlined the significance of endoplasmic reticulum (ER) stress in the pathogenesis of diabetes mellitus. ER oxidoreductin 1β (ERO1β) is a pancreas-specific disulfide oxidase that is known to be upregulated in response to ER stress and to promote protein folding in pancreatic β cells. It has recently been demonstrated that ERO1β promotes insulin biogenesis in β cells and thus contributes to physiological glucose homeostasis, though it is unknown if ERO1β is involved in the pathogenesis of diabetes mellitus. Here we show that in diabetic model mice, ERO1β expression is paradoxically decreased in β cells despite the indications of increased ER stress. However, overexpression of ERO1β in β cells led to the upregulation of unfolded protein response genes and markedly enlarged ER lumens, indicating that ERO1β overexpression caused ER stress in the β cells. Insulin contents were decreased in the β cells that overexpressed ERO1β, 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 β cells in insulin synthesis and thus contribute to the pathogenesis of diabetes mellitus.
越来越多的证据强调了内质网（ER）应激在糖尿病发病机制中的重要性。ER 氧化还原酶 1β（ERO1β）是一种胰腺特异性二硫键氧化酶，已知其在 ER 应激时上调，并促进胰腺β细胞中的蛋白质折叠。最近的研究表明，ERO1β促进β细胞中的胰岛素生物合成，从而有助于生理葡萄糖稳态，但尚不清楚 ERO1β是否参与糖尿病的发病机制。在这里，我们表明在糖尿病模型小鼠中，尽管 ER 应激增加的迹象，但β细胞中的 ERO1β表达反而降低。然而，在β细胞中过表达 ERO1β会导致未折叠蛋白反应基因的上调，并显著增大 ER 腔，表明 ERO1β过表达导致β细胞中的 ER 应激。过表达 ERO1β的β细胞中的胰岛素含量降低，导致对葡萄糖刺激的胰岛素分泌受损。这些数据表明 ER 氧化还原状态的精细调节的重要性，这种调节的紊乱会损害β细胞在胰岛素合成中的功能，从而有助于糖尿病的发病机制。
