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细胞质量减少在2型糖尿病的发生发展中起着重要作用。内质网应激最近成为β细胞丢失的一种候选机制。我们以Wfs1基因敲除小鼠为模型，研究了这一机制。Wfs1基因编码一种内质网(ER)膜包埋蛋白，其纯合突变会导致人类选择性的β细胞丢失。Wfs1蛋白参与了内质网应激反应，但Wfs1基因缺陷的β细胞死亡的机制仍不完全清楚。有趣的是，Wfs1^&lt；-/-&gt；小鼠的表型主要取决于它们的遗传背景。具有C57BL/6J背景的Wfs1^&lt；-/-&gt；小鼠不会出现明显的糖尿病。然而，我们发现，当这些小鼠由于刺鼠致死黄色突变(Wfs1^&lt；-/-&gt；A^y/a)而变得轻度肥胖和胰岛素抵抗时，它们早在16周的ag…就会出现选择性β细胞丢失和严重的胰岛素缺乏性糖尿病。更多的e.这种β细胞的丢失似乎是由于细胞凋亡。在A^y/a小鼠胰岛，ER伴侣蛋白Bip/GRP78的表达和eIF2磷酸化增加，提示肥胖诱导了β-细胞的内质网应激。与Wfs1^&lt；-/-&gt；或A^y/a小鼠相比，Wfs1^&lt；-/-&gt；A^y/a小鼠Bip/GRP78蛋白的表达进一步增加。电子显微镜显示β细胞内质网明显扩张，胰岛素颗粒减少，提示胰岛素抵抗导致内质网应激，缺失WFS1的胰腺β细胞更容易发生内质网应激诱导的细胞凋亡。有趣的是，吡格列酮治疗几乎完全预防了糖尿病，并保护β细胞免于凋亡。在胰岛中，尽管ER伴侣的表达没有差异，但CHOP的表达减少了。虽然Wolfram综合征是一种独特的疾病，但在2型糖尿病患者中，由于胰岛素抵抗，胰岛素需求持续增加，可能会有共同的过程，包括缓慢但进行性的β细胞丢失。对这一模型的研究有望为β细胞丢失的机制和预防提供深入的见解。较少

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