Role of gene mutations in development of diabetes mellitus

基因突变在糖尿病发展中的作用

基本信息

批准号：
04454563
负责人：
KASUGA Masato
金额：
$ 4.35万
依托单位：
Kobe University
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (B)
财政年份：
1992
资助国家：
日本
起止时间：
1992 至 1993
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-04454563/
关键词：
insulin receptor gene glucokinase gene mitochondrial gene IRS-1 gene glucose transporter gene NIDDM インスリン受容体異常症

项目摘要

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.

研究了胰岛素受体基因，葡萄糖动物酶基因，线粒体基因和IRS-1基因在糖尿病疗法中的突变。我们发现一个胰岛素抵抗和糖尿病系列中的胰岛素受体基因突变。我们在培养细胞中表达了这种突变胰岛素受体基因，发现这种突变降低了胰岛素受体和胰岛素作用的激酶活性。我们还发现了一个糖尿病家族中葡萄糖酶基因的突变，但是其他研究者在其他家族成员中对这种突变进行了反应。我们在几名糖尿病患者中发现了线粒体基因的突变（A到G转变）。这些患者具有多种特征，例如母体遗传，耳聋，瘦体构，响应葡萄糖的响应而减少了胰岛素的分泌，并且对精氨酸的分泌减少了。我们发现IRS-1基因的突变，但是糖尿病患者和对照组受试者之间没有改变这种突变的频率，表明这种突变可能与糖尿病的发展可能无关。我们还检查了葡萄糖转运蛋白基因的突变，没有发现任何显着的突变。该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育中的作用，但是我们仅成功地表达了突变胰岛素受体基因在培养的细胞中。必须在培养细胞或小鼠中表达这些基因的突变体，以了解基因突变引起的糖尿病的发病机理。