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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Abstract
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 [3H]‐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.