Studies of relationships between variation of the human G protein-coupled receptor 40 gene and Type 2 diabetes and insulin release

Yasmin H. Hamid, H. Vissing, B. Holst, S. A. Urhammer, C. Pyke, S. K. Hansen, C. Glümer, K. Borch-Johnsen, T. Jørgensen, T. W. Schwartz, O. Pedersen, T. Hansen

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    Abstrakt

    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 EC 50 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.

    OriginalsprogEngelsk
    Sider (fra-til)74-80
    Antal sider7
    TidsskriftDiabetic Medicine
    Vol/bind22
    Udgave nummer1
    DOI
    StatusUdgivet - 1 jan. 2005

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