权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

A study on the beta-Cell glucose sensors in insulin secretion : The relationship between dysfunction of glucose sensors and development of diabetes mellitus

胰岛素分泌中β细胞葡萄糖传感器的研究：葡萄糖传感器功能障碍与糖尿病发展之间的关系

基本信息

批准号：
07044256
负责人：
SEINO Yutaka
金额：
$ 7.36万
依托单位：
KYOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for international Scientific Research
财政年份：
1995
资助国家：
日本
起止时间：
1995 至 1996
项目状态：
已结题

项目摘要

Genetic factors play important roles in pathogenesis of non-insulin-dependent diabetes mellitus (NIDDM) as well as environmental factors. Recent studies showed that single gene mutation might have a causative effect in pathogenesis of diabetes mellitus. In Japanese patients with NIDDM,the insulin secretion induced by glucose is impaired in early stage of pathogenesis. Here, we report the mutations of candidate genes for glucose sensor in NIDDM subjects.First, we examined the mutations of the GLUT2 gene and found a nucleotide substitution Phe^<479> (TTT->TTC). Although it was a silent mutaion, homozygote of this allele was found only in NIDDM subjects, and allelic frequency of this allele was significantly higher in NIDDM subjects than in controls.Second, the mutations of voltage-dependent calcium channel gene (CACNL1A2) was studied. The PCR-SSCP procedure of exon 1 revealed a change from 7 to 8 ATG trinucleotide repeats in a patient with NIDDM,resulting in an addition of methionine at the amino-terminus. This change was not found in normal controls.Third, we investigated the entire coding region of the gastric inhibitory poltpeptide receptor (GIPR) gene by PCR-SSCP.We identified two missence mutations, Gly^<198>->Cys (Gly198Cys) in exon 7 and Glu^<354>->Gln (Glu354Gln) in exon 12. Functional analysis of the GIPR with either of these mutations revealed that half-maximal stimulation value of GIP-induced cAMP response in Chinese hamster ovary cells expressing the GIPR with Gly198Cys was considerably higher than that of the wild type, whereas that of the GIPR with Glu354Gln was not significantly different from that of wild type. While allelic frequency of Glu354Gln in NIDDM subjects was not different from that in normal control, homozygotes of the Gly198Cys was detected only in NIDDM subjects.Mutations described here might be part of mechanisms which contribute to the pathogenesis of NIDDM,and further studies will reveal the rest.

遗传因素在非胰岛素依赖型糖尿病（NIDDM）的发病机制中起重要作用，环境因素也起重要作用。近年来的研究表明，单基因突变可能在糖尿病的发病机制中起重要作用。在日本NIDDM患者中，葡萄糖诱导的胰岛素分泌在发病早期受损。在此，我们报告了NIDDM患者中葡萄糖传感器候选基因的突变。首先，我们检测了GLUT 2基因的突变，发现了一个核苷酸取代Phe^<479>（TTT->TTC）。虽然该等位基因是一个沉默突变，但仅在NIDDM患者中发现了该等位基因的纯合子，且该等位基因在NIDDM患者中的频率显著高于对照组。PCR-SSCP结果显示，1例NIDDM患者的第1外显子由7个ATG三核苷酸重复变为8个ATG三核苷酸重复，导致氨基末端增加了蛋氨酸。第三，我们采用PCR-SSCP技术对胃抑制多肽受体（GIPR）基因编码区进行了全序列分析，发现了两个缺失突变，即<198>第7外显子的Gly^ ->Cys（Gly 198 Cys）和<354>第12外显子的Glu^ ->Gln（Glu 354 Gln）。功能分析表明，Gly 198 Cys突变的GIPR在中国仓鼠卵巢细胞中诱导cAMP反应的半数最大刺激值显著高于野生型，而Glu 354 Gln突变的GIPR与野生型无显著差异。Glu 354 Gln等位基因频率与正常对照组无差异，Gly 198 Cys纯合子仅见于NIDDM组，本文所述突变可能是NIDDM发病机制的一部分，其余部分有待进一步研究。