Disruption of the WFS1 gene in mice causes progressive β-cell loss and impaired stimulus-secretion coupling in insulin secretion
Disruption of the WFS1 gene in mice causes progressive β-cell loss and impaired stimulus-secretion coupling in insulin secretion
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DOI：
10.1093/hmg/ddh125
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发表时间：
2004-06-01
影响因子：
3.5
通讯作者：
Oka, Y
中科院分区：
文献类型：
--
作者：
Ishihara, H;Takeda, S;Oka, Y
Wolfram 综合征是一种以青少年发病的糖尿病和视神经萎缩为特征的常染色体隐性遗传疾病，由 WFS1 基因突变引起。为了深入了解这种疾病的病理生理学，我们破坏了小鼠的 wfs1 基因。由于体内胰岛素分泌不足，突变小鼠出现了葡萄糖不耐受或明显的糖尿病。从突变小鼠中分离的胰岛表现出响应葡萄糖的胰岛素分泌减少。胰岛素分泌缺陷伴随着细胞对促分泌剂的钙反应减少。通过形态测量和全胰腺胰岛素含量测量进行的免疫组织化学分析表明，突变小鼠的β细胞进行性丧失，而几乎不表达WFS1蛋白的α细胞被保留。此外，通过 DNA 片段形成评估，在高浓度葡萄糖或暴露于内质网应激诱导剂下，从突变小鼠中分离的胰岛表现出细胞凋亡增加。这些结果强烈表明，WFS1 蛋白在胰岛素胞吐作用的刺激-分泌耦合和 β 细胞质量的维持中发挥着重要作用，β 细胞质量的恶化会导致葡萄糖稳态受损。这些 WFS1 突变小鼠为更好地了解 Wolfram 综合征的病理生理学以及 WFS1 功能提供了宝贵的工具。
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.