Investigation of the mechanism of pancreatic beta-cell death underlying progressive nature of type 2 diabetes mellitus, aiming at the development of treatment strategy for the disease condition.

导致Wolfram综合征的WFS1基因也决定了患2型糖尿病的易感性。WFS1蛋白定位于内质网。WFS1蛋白缺失可诱导β细胞发生内质网应激，β细胞容易发生内质网应激诱导的细胞凋亡。在Wfs1^&lt；-/-&gt；小鼠中，由于内质网应激增加，β-细胞的凋亡加速。吡格列酮通过减轻β-细胞的胰岛素抵抗和内质网应激，保护β细胞免于凋亡。此外，吡格列酮还直接诱导β细胞肾上腺髓质素的表达，参与β细胞的保护作用。在胰腺β细胞中，WFS1蛋白也存在于胰岛素分泌颗粒中，在维持颗粒内的酸性环境中起着关键作用。据报道，颗粒内的酸化对于颗粒的胞吐作用是必要的。在Wfs1^&lt；-/-&gt；小鼠中，葡萄糖诱导的胰岛素分泌在β细胞数量减少之前的早期阶段就受到了损害。WFS1蛋白在分泌颗粒中的作用有待进一步研究。

WFS1 gene, responsible for the Wolfram syndrome, also determines the susceptibility to type 2 diabetes. WFS1 protein localizes to the endoplasmic reticulum. Absence of WFS1 protein induce ER stress in β-cells, and β-cells lacking WFS1 protein is susceptible to the ER stress-induced apoptosis. In Wfs1^<-/-> mice, β-cell apoptosis is accelerated because of increased ER stress. Pioglitazone protects β cell from apoptosis by reducing systemic insulin resistance and ER stress in the β-cells. In addition, pioglitazone directly induced adrenomedullin expression in the β-cells, playing a role in this β-cell protection.In pancreatic β-cells, WFS1 protein also exists in the insulin secretory granules, and play crucial roles in the maintenance of acidic milieu inside the granules. Intra-granular acidification is reported to be necessary for the "priming" of the granule for the exocytosis. In Wfs1^<-/-> mice, glucose-induced insulin secretion is impaired in the early stage before the β cell number is decreased. Roles of WFS1 protein in the secretory granules need to be further investigated.