Role of gene mutations in development of diabetes mellitus

检测糖尿病患者胰岛素受体基因、葡萄糖激酶基因、线粒体基因和胰岛素受体1基因的突变情况。我们在一个胰岛素抵抗和糖尿病家系中发现了一个胰岛素受体基因突变。我们在培养的细胞中表达了这种突变的胰岛素受体基因，发现这种突变降低了胰岛素受体的激酶活性和胰岛素作用。我们还在一个糖尿病家族中发现了葡萄糖激酶基因突变，但其他研究人员已经在其他家族成员中报告了这种突变。我们在几例糖尿病患者中发现了线粒体基因3243位A → G突变。这些患者具有几个特征，例如母体遗传、耳聋、瘦体质、响应于葡萄糖的胰岛素分泌减少和响应于精氨酸的胰高血糖素分泌减少。我们发现IRS-1基因存在突变，但该突变频率在糖尿病患者和对照组之间没有改变，提示该突变可能与糖尿病的发生无关。我们还检查了葡萄糖转运蛋白基因的突变，没有发现任何显著的突变。本项目的目的之一是通过在培养细胞中表达突变基因来阐明突变在糖尿病发展中的作用，然而我们只成功地将突变胰岛素受体基因表达到培养细胞中。在培养细胞或小鼠中表达这些基因突变体对于理解基因突变引起的糖尿病的发病机制是必要的。

Mutations of insulin receptor gene, glucokinase gene, mitochaondrial gene and IRS-1 gene in diabetic parients were investigated. We found a mutation of insulin receptor gene in one family of insulin resistance and diabetes mellitus. We expressed this mutant insulin receptor gene in cultured cells and found that this mutation decreased kinase activity of insulin receptors and insulin action. We also found a mutation of glucokinase gene in one family of diabetes mellitus, however this mutation was aleady reportred in other family member by other investigators. We found a mutation (A to G transition at position 3243) of mitochondrial gene in several diabetic patients. These patients had several characteristics such as maternal inheritance, deafness, lean body constitutions, decreased insulin secretion in response to glucose and decreased glucagon secretion in response to arginine. We found a mutation of IRS-1 gene, however the frequency of this mutation was not changed between diabetic patients and control subjects suggesting this mutation may not be involved in the development of diabetes mellitus. We also examined mutations of glucose transporter genes and did not find any significant mutations. One purpose of this project is to clarify a role of mutation in the development of diabetes mellitus by expressing the mutant gene in cultured cells, however we only succeeded in expressing of the mutant insulin receptor gene into cultured cells. It will be necessary to express these mutants of genes in cultured cells or mice for understanding the pathogenesis of diabetes mellitus caused by gene mutations.