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生机制。这项预先研究的发现可能为糖尿病和其他疾病提供了一种新的机制。秋田鼠在10周龄时患上糖尿病，但没有胰岛素抵抗或肥胖。病理检查未能在糖尿病病程的任何时期发现自身免疫性胰岛素炎。电镜观察显示内质网增生，细胞质空泡化，线粒体鼓泡化，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。连锁分析表明，该性状的致病位点位于7号染色体远端部分。该区域的候选基因之一胰岛素的序列分析显示有一个突变[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。一些胰岛素突变已被报道，并已被称为胰岛素病。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相关，但不表现出Mody表型。在啮齿类动物中，二倍体基因组中有4个胰岛素等位基因。一个胰岛素位点的突变，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，除非假定存在某种类型的“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显性糖尿病。因此，秋田小鼠品系可能是研究与蛋白质分类和折叠过程相关的病理细节的非常有用的工具。

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.