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 [(3)H]-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.
AIMS: Recently, a novel humanG 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 [(3)H]-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 diabeticpatients [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.
Authors: Celia P Briscoe; Andrew J Peat; Stephen C McKeown; David F Corbett; Aaron S Goetz; Thomas R Littleton; David C McCoy; Terry P Kenakin; John L Andrews; Carina Ammala; James A Fornwald; Diane M Ignar; Stephen Jenkinson Journal: Br J Pharmacol Date: 2006-05-15 Impact factor: 8.739
Authors: T Tomita; H Masuzaki; H Iwakura; J Fujikura; M Noguchi; T Tanaka; K Ebihara; J Kawamura; I Komoto; Y Kawaguchi; K Fujimoto; R Doi; Y Shimada; K Hosoda; M Imamura; K Nakao Journal: Diabetologia Date: 2006-03-09 Impact factor: 10.122
Authors: Daniel C-H Lin; Jane Zhang; Run Zhuang; Frank Li; Kathy Nguyen; Michael Chen; Thanhvien Tran; Edwin Lopez; Jenny Ying Lin Lu; Xiaoyan Nina Li; Liang Tang; George R Tonn; Gayathri Swaminath; Jeff D Reagan; Jin-Long Chen; Hui Tian; Yi-Jyun Lin; Jonathan B Houze; Jian Luo Journal: PLoS One Date: 2011-11-08 Impact factor: 3.752