Studies of relationships between variation of the human G protein-coupled receptor 40 Gene and Type 2 diabetes and insulin release
Studies of relationships between variation of the human G protein-coupled receptor 40 Gene and Type 2 diabetes and insulin release
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DOI：
10.1111/j.1464-5491.2005.01505.x
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发表时间：
2005-01-01
影响因子：
3.5
通讯作者：
Hansen, T
中科院分区：
文献类型：
--
作者：
Hamid, YH;Vissing, H;Hansen, T
目的最近发现一种新的人类G蛋白偶联受体40(GPR40)，它主要表达于胰岛，可介导长链脂肪酸对葡萄糖诱导的胰岛素分泌的放大作用。本研究的目的是检测GPR40编码区的变异，并评估已识别的变异是否会增加2型糖尿病或胰岛素释放的风险。方法采用直接测序的方法对43例2型糖尿病患者、18例正常糖耐量受试者和3例青年(MODY)X期糖尿病患者进行突变分析。用高通量芯片质谱仪(MALDI-TOF)分析聚合酶链式反应(PCR)产生的引物延伸产物，进行基因分型。用不同浓度的5，8，11-二十碳三磷酸刺激COS-7细胞，观察GPR40突变对[H-3]-肌醇代谢的影响。结果发现两个核苷酸突变：Arg211His多态和罕见的Asp175Asn突变。两个变异体的EC50值与野生型相似。然而，稀有的Asp175Asn的最大疗效比野生型低39%(P=0.01)。在1384例2型糖尿病患者[MAF%；23.4(95%CI：21.8-25.0)]和4424例中年糖耐量受试者[24.1%(23.2-25.0)]中，Arg211His基因多态性具有相似的等位基因频率。对来自Inter99队列的5597名非糖尿病中年人进行的一项基因-数量性状研究显示，不同GPR40基因携带者之间口服葡萄糖耐量试验(OGTT)得出的胰岛素释放估计值没有显著差异。结论GPR40编码区的变异似乎与2型糖尿病或胰岛素释放改变无关。
Aims Recently, a novel human G protein-coupled receptor 40 (GPR40), which is predominantly expressed in pancreatic islets, was shown to mediate an amplifying effect of long-chain fatty acids on glucose-induced insulin secretion. The present aim was to examine the coding region of GPR40 for variation and to assess whether identified variants confer an increased risk of Type 2 diabetes or altered insulin release.Methods Mutation analysis was performed in 43 patients with Type 2 diabetes, 18 normal glucose-tolerant subjects, and 3 maturity-onset of diabetes in the young (MODY) X patients using direct sequencing. Genotyping was performed using polymerase chain reaction (PCR)-generated primer extension products analysis by high throughput chip-based mass spectrometry (MALDI-TOF). The potential impact of GPR40 mutations on [H-3]-myo-inositol turnover was estimated in COS-7 cells after stimulation with various concentrations of 5,8,11-eicosatriynoic acid.Results Two nucleotide substitutions, an Arg211His polymorphism and a rare Asp175Asn mutation, were identified. Both variants showed EC50 values similar to the wild type. However, the maximal efficacy of the rare Asp175Asn was 39% lower compared with the wild type (P = 0.01). The Arg211His polymorphism had a similar allele frequency among 1384 Type 2 diabetic patients [MAF%; 23.4 (95% CI: 21.8-25.0)] and 4424 middle-aged glucose-tolerant subjects [24.1% (23.2-25.0)]. A genotype-quantitative trait study of 5597 non-diabetic, middle-aged subjects from the Inter99 cohort showed no significant differences in oral glucose tolerance test (OGTT)-derived estimates of insulin release between carriers of various GPR40 genotypes.Conclusions Variations in the coding region of GPR40 do not appear to be associated with Type 2 diabetes or insulin release alterations.