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，WFS1基因发生突变。WFS1基因也是一种2型糖尿病基因。我们对日本的沃尔夫拉姆综合症进行了一项全国性的调查。在患者中，胰腺b细胞死亡是由内质网应激引起的。此外，β细胞在功能上也是不正常的。这种功能衰竭至少部分是由于分泌颗粒内部的酸化缺陷造成的。WFS1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，它维持着颗粒内的酸性环境，这对颗粒胞吐的“启动”很重要。我们还研究了内质网应激导致b细胞凋亡的机制。我们发现，过高的GSK-3b活性会促进ATF4的降解，从而导致细胞凋亡。我们还研究了时钟基因与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.