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

动物模型为理解人类疾病的机制提供了有用的工具。在本研究中，我们从分子基础上发现了秋田小鼠糖尿病的发病机制。这项预先设定的研究结果可能会为糖尿病和其他疾病提供一种新的机制。秋田鼠在10周大时患上糖尿病，没有胰岛素抵抗或肥胖。病理检查未能发现糖尿病病程中任何时期的自身免疫性胰岛素炎。电子显微镜观察发现内质网增多，细胞质空泡化，线粒体肿胀，成熟胰岛素颗粒稀少。糖尿病表现为常染色体显性遗传模式。连锁分析揭示了7号染色体端粒部分的责任基因。该区域候选基因之一的序列分析显示，胰岛素存在突变[TGC(Cys)-&Gt；Tac(Tyr)]，从而破坏了a链上6个Cys和B链上6个Cys之间的二硫键。已有报道了几个胰岛素突变，被称为胰岛素病。胰岛素病的临床特征通常与中度糖耐量异常和高胰岛素血症有关，但不表现为Mody表型。在啮齿动物中，二倍体基因组中有4个胰岛素等位基因。一个胰岛素基因的突变，即使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，除非假设了某种类型的“功能获得”突变，否则很难解释具有常染色体显性遗传模式的早发性显性糖尿病。因此，秋田鼠品系可能是一个非常有用的工具，可以研究与蛋白质分类和折叠过程相关的病理细节。

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.