title: Studies of relationships between variation of the human G protein-coupled receptor 40 Gene and Type 2 diabetes and insulin release.
abstract: OBJECTIVE
  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.
authors.affiliation: Steno Diabetes Center, DK-2820 Gentofte, Denmark. yah@steno.dk
authors.forename: Y H
authors.initials: YH
authors.lastname: Hamid
authors.forename: H
authors.initials: H
authors.lastname: Vissing
authors.forename: B
authors.initials: B
authors.lastname: Holst
authors.forename: S A
authors.initials: SA
authors.lastname: Urhammer
authors.forename: C
authors.initials: C
authors.lastname: Pyke
authors.forename: S K
authors.initials: SK
authors.lastname: Hansen
authors.forename: C
authors.initials: C
authors.lastname: Glümer
authors.forename: K
authors.initials: K
authors.lastname: Borch-Johnsen
authors.forename: T
authors.initials: T
authors.lastname: Jørgensen
authors.forename: T W
authors.initials: TW
authors.lastname: Schwartz
authors.forename: O
authors.initials: O
authors.lastname: Pedersen
authors.forename: T
authors.initials: T
authors.lastname: Hansen
mesh_terms: D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*
chemical_list: C473034:FFAR1 protein, human; D007328:Insulin; D043562:Receptors, G-Protein-Coupled