Investigation of the mechanism of beta-cell failure in diabetes using Wolfram Syndrome as a model

Wolfram综合征是一种常染色体隐性遗传疾病，以胰岛素缺乏性糖尿病和视神经萎缩为特征。糖尿病是由胰腺b细胞凋亡引起的。在大多数患者中，WFS 1基因发生突变。WFS 1基因也是2型糖尿病的一个基因。我们在日本进行了一项关于Wolfram综合征的全国性调查。在患者中，胰腺B细胞死亡是由ER应激引起的。此外，β细胞功能异常。这种功能衰竭至少部分是由于分泌颗粒内的酸化缺陷。WFS 1蛋白除存在于ER膜外，还存在于分泌颗粒膜上。在分泌颗粒中，它维持颗粒内酸性环境，这对于颗粒胞吐的“启动”是重要的。我们还研究了ER应激引起B细胞凋亡的机制。我们发现，过度的GSK-3b活性增强ATF 4降解，导致细胞凋亡。我们还研究了生物钟基因与b细胞功能的关系。

Wolfram syndrome is an autosomal recessive disorder characterized by insulin deficient diabetes and optic atrophy. Diabetes is caused by pancreatic b-cell apoptosis. In most patients, WFS1 gene is mutated. WFS1 gene is also a type 2 diabetes gene. We conducted a nation-wide survey for the Wolfram syndrome in Japan. In the patients, pancreatic b-cell death is caused by ER stress. In addition, beta-cells are functionally abnormal. That functional failure is at least in part, due to acidification defects inside the secretory granules. WFS1 protein exists on the secretory granule membrane, in addition to the ER membrane. In the secretory granule, it maintains intra-granular acidic milieu, that is important for "priming" of the granule exocytosis. We also studied the mechanism whereby ER stress causes b-cell apoptosis. We found that excessive Gsk-3b activity enhances ATF4 degradation leading to the apoptosis. We also studied relationship between clock genes and b-cell function.