Investigation of insulin resistance-induced endoplasmic reticulum stress in the pancreatic β-cell and development of diabetes mellitus

越来越多的证据表明β-细胞质量的减少在2型糖尿病的发生发展中起着重要的作用。内质网应激最近被认为是β细胞损失的一种候选机制。我们以Wfs1敲除小鼠为模型研究了这一机制。WFS1基因编码一种内质网（ER）膜嵌入蛋白，其纯合突变导致人类选择性β细胞丢失。WFS1蛋白参与内质网应激反应，但缺乏WFS1的β细胞死亡机制尚不完全清楚。有趣的是，Wfs1^<-/->小鼠的表型主要取决于它们的遗传背景。具有C57BL/6J基因背景的Wfs1^<-/->小鼠不会发生显性糖尿病。然而，我们发现，当这些小鼠由于agouti致命黄色突变（Wfs1^<-/-> ^y/ A）而变得轻度肥胖和胰岛素抵抗时，它们早在16周就出现选择性β细胞丢失和严重的胰岛素缺乏性糖尿病。在A^y/ A小鼠胰岛中，ER伴侣Bip/GRP78表达和EIF2□磷酸化升高，提示肥胖诱导β-细胞内质网应激。与Wfs1^<-/->或A^y/ A小鼠相比，Wfs1^<-/->或A^y/ A小鼠中Bip/GRP78蛋白的表达进一步增加。电镜显示β-细胞内质网明显扩张，胰岛素颗粒减少，提示胰岛素抵抗引起内质网应激，缺乏Wfs1的胰腺β-细胞更容易发生内质网应激诱导的凋亡。有趣的是，吡格列酮治疗几乎完全预防糖尿病，并保护β细胞免于凋亡。在胰岛中，尽管ER伴侣表达无差异，但CHOP表达降低。虽然Wolfram综合征是一种独特的疾病，但在2型糖尿病患者中可能存在共同的过程，包括缓慢但进行性的β细胞损失，其中胰岛素需求由于胰岛素抵抗而持续上升。该模型的研究有望为β细胞损失的机制和预防提供见解。少

There are accumulating evidences that decrease in β-cell mass play roles in the development and progression of type 2 diabetes mellitus. Endoplasmic reticulum stress has recently emerged as a candidate mechanism of β-cell loss. We investigated this mechanism using Wfs1 knock-out mouse as a model. The WFS1 gene encodes an endoplasmic reticulum (ER) membrane-embedded protein, homozygous mutations of which cause selective β-cell loss in humans. The WFS1 protein is involved in ER stress responses, but the mechanism of β-cell death in WFS1-deficient β-cells is still not fully understood. Interestingly, the phenotype of Wfs1^<-/-> mice depends mainly on their genetic backgrounds. Wfs1^<-/-> mice with the C57BL/6J background do not develop overt diabetes. However, we found that when these mice become mildly obese and insulin resistant due to the agouti lethal yellow mutation (Wfs1^<-/-> A^y/a), they develop selective β-cell loss and severe insulin-deficient diabetes as early as 16 weeks of ag … More e. This β-cell loss appeared to be due to apoptosis. In A^y/a murine islets, ER chaperone Bip/GRP78 expression and EIF2□ phosphorylation increased, suggesting that obesity induced ER stress in β-cells. Expression of the Bip/GRP78 protein was further increased in Wfs1^<-/-> A^y/a mice as compared to Wfs1^<-/-> or A^y/a mice. Electron micrography revealed markedly dilated ERs and decreased insulin granules in β-cells, suggesting that insulin resistance causes ER stress, and that pancreatic β-cells lacking Wfs1 are more susceptible to ER stress-induced apoptosis. Interestingly, pioglitazone treatment almost completely prevented diabetes, and protected β-cells form apoptosis. In islets, despite no difference in ER chaperone expression, CHOP expression was reduced. Although Wolfram syndrome is a distinct disease, there may be common processes involving slow, but progressive β-cell loss in patients with type 2 diabetes mellitus, in whom insulin demands rise continuously due to insulin resistance. Investigation of this model is anticipated to provide insights into the mechanism and prevention of β-cell loss. Less