生物
内科学
内分泌学
Wolfram综合征
胰岛素
未折叠蛋白反应
β细胞
胰岛素振荡
糖耐量受损
葡萄糖稳态
糖尿病
内质网
胰岛素抵抗
细胞生物学
小岛
医学
作者
Hisamitsu Ishihara,Satoshi Takeda,Akira Tamura,Rui Takahashi,Suguru Yamaguchi,Daisuke Takei,Takahiro Yamada,Hiroshi Inoue,Hiroyuki Soga,Hideki Katagiri,Yukio Tanizawa,Yoshitomo Oka
摘要
Wolfram syndrome, an autosomal recessive disorder characterized by juvenile-onset diabetes mellitus and optic atrophy, is caused by mutations in the WFS1 gene. In order to gain insight into the pathophysiology of this disease, we disrupted the wfs1 gene in mice. The mutant mice developed glucose intolerance or overt diabetes due to insufficient insulin secretion in vivo. Islets isolated from mutant mice exhibited a decrease in insulin secretion in response to glucose. The defective insulin secretion was accompanied by reduced cellular calcium responses to the secretagogue. Immunohistochemical analyses with morphometry and measurement of whole-pancreas insulin content demonstrated progressive beta-cell loss in mutant mice, while the alpha-cell, which barely expresses WFS1 protein, was preserved. Furthermore, isolated islets from mutant mice exhibited increased apoptosis, as assessed by DNA fragment formation, at high concentration of glucose or with exposure to endoplasmic reticulum-stress inducers. These results strongly suggest that WFS1 protein plays an important role in both stimulus-secretion coupling for insulin exocytosis and maintenance of beta-cell mass, deterioration of which leads to impaired glucose homeostasis. These WFS1 mutant mice provide a valuable tool for understanding better the pathophysiology of Wolfram syndrome as well as WFS1 function.
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