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细胞数量减少在2型糖尿病的发生、发展中起重要作用。内质网应激最近已成为β细胞丢失的候选机制。我们使用Wfs 1基因敲除小鼠作为模型研究了这一机制。WFS 1基因编码内质网（ER）膜包埋蛋白，其纯合突变导致人类选择性β细胞丢失。WFS 1蛋白参与ER应激反应，但WFS 1缺陷β细胞中β细胞死亡的机制仍不完全清楚。有趣的是，Wfs 1 ^<-/->小鼠的表型主要取决于它们的遗传背景。具有C57 BL/6 J背景的Wfs 1 ^<-/->小鼠不发展明显的糖尿病。然而，我们发现，当这些小鼠由于agglutinin致死性黄色突变（Wfs 1 ^-/-> A^y/a）而变得轻度肥胖和胰岛素抵抗时，它们早在16周龄时就发生了选择性β细胞丢失和严重的胰岛素缺乏型糖尿病。 ...更多信息 e.这种β细胞损失似乎是由于细胞凋亡。在A^y/a鼠胰岛中，ER伴侣Bip/GRP 78表达和EIF 2 □磷酸化增加，表明肥胖诱导β细胞中的ER应激。与Wfs 1 ^<-/->或A^y/a小鼠相比，Bip/GRP 78蛋白的表达在Wfs 1 ^<-/-> A^y/a小鼠中进一步增加。电子显微镜显示ER显著扩张，β细胞中胰岛素颗粒减少，表明胰岛素抵抗导致ER应激，缺乏Wfs 1的胰腺β细胞更容易受到ER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伴侣蛋白表达没有差异，但CHOP表达减少。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涉及缓慢但进行性β细胞损失的常见过程，其中胰岛素需求由于胰岛素抵抗而持续上升。对该模型的研究预计将为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