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

Diabet Med. 2005 Jan;22(1):74-80. doi: 10.1111/j.1464-5491.2005.01505.x.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Case-Control Studies
  • Diabetes Mellitus, Type 2 / genetics*
  • Diabetes Mellitus, Type 2 / metabolism
  • Humans
  • Insulin / metabolism*
  • Middle Aged
  • Mutation / genetics*
  • Pedigree
  • Polymorphism, Single Nucleotide / genetics*
  • Receptors, G-Protein-Coupled / genetics*


  • FFAR1 protein, human
  • Insulin
  • Receptors, G-Protein-Coupled