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Molecular mechanisms of diabetes in the Mody4 Mutant Akita mouse and their significance in the prevention of human diabetes

Mody4突变秋田小鼠糖尿病的分子机制及其在预防人类糖尿病中的意义

基本信息

批准号：
09470100
负责人：
KOIZUMI Akio
金额：
$ 6.46万
依托单位：
Akita University School of Medicine
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1999
项目状态：
已结题

项目摘要

Animal models have provided useful tools to understand the mechanisms of human diseases. In the present study, we found a mechanism of diabetes in the Akita Mouse on molecular basis. The findings in the preset study may suggest a novel mechanism for diabetes and other diseases.The Akita mouse develops diabetes by 10 weeks of age without insulin resistance or obesity. Pathological investigations have failed to detect autoimmune insulitis at any period in the course of diabetes. Electron microscopic observation revealed proliferation of endplasmic reticulum, vacuolation of cytoplasm, ballooning of mitochondria and scarce of mature insulin granules.The diabetes showed a autosomal dominant mode of inheritance.Linkage analysis of this trait revealed the responsible locus at the telemere portion of chromosome 7. Sequence analyses of one of the candidate genes in this region, insulin, was shown to have a mutation [TGC(Cys)->TAC(Tyr)] and thereby disrupting a disulfide bond between 6 th Cys on the a chain and 6 the Cys on the b chain.Several insulin mutations has been reported and has been known as insulinopathy. Clinical features of insulinopathy is commonly associated with moderate glucose intolerance and hyperinsulinmeia but do not demonstrate Mody phenotype.In the rodents, there are 4 alleles of insulin in the diploid genome. The mutation of one insulin locus, even if it leads to a complete loss of function of insulin, would decrease insulin amounts by only 25%. Thus unless a some type of a "gain of function" mutation is postulated, it is hard to explain an early-onset overt diabetes with an autosomal dominant mode of inheritance.The Akita mouse strain thus may be a very useful tool for investigating the pathological details associated with protein sorting and folding process.

动物模型为理解人类疾病的机制提供了有用的工具。本研究从分子水平上揭示了秋田小鼠糖尿病的发病机制。这项研究的发现可能为糖尿病和其他疾病提出了一种新的机制。秋田小鼠在10周龄时患上糖尿病，而没有胰岛素抵抗或肥胖。病理学检查未能发现自身免疫性胰岛炎在任何时期的过程中的糖尿病。电镜观察显示内质网增生，胞浆空泡化，线粒体气球样变，成熟胰岛素颗粒稀少，糖尿病表现为常染色体显性遗传，连锁分析显示该性状的致病基因位于7号染色体的端粒部分。对该区域中的候选基因之一胰岛素的序列分析显示其具有突变[TGC（Cys）->TAC（Tyr）]，从而破坏了a链上第6个Cys和B链上第6个Cys之间的二硫键。胰岛素病的临床特征通常与中度葡萄糖耐受不良和高胰岛素血症有关，但不表现Mody表型。一个胰岛素位点的突变，即使它导致胰岛素功能的完全丧失，也只会使胰岛素量减少25%。因此，除非假设某种类型的“功能获得”突变，否则很难解释常染色体显性遗传方式的早发显性糖尿病。因此，秋田小鼠品系可能是研究与蛋白质分选和折叠过程相关的病理细节的非常有用的工具。