Loss-of-function mutation of the GPR40 gene associates with abnormal stimulated insulin secretion by acting on intracellular calcium mobilization

J Clin Endocrinol Metab. 2008 Sep;93(9):3541-50. doi: 10.1210/jc.2007-2680. Epub 2008 Jun 26.


Background: Free fatty acids (FFAs) acutely stimulate but chronically impair glucose-stimulated insulin secretion from beta-cells. The G protein-coupled transmembrane receptor 40 (GPR40) mediates both acute and chronic effects of FFAs on insulin secretion and plays a role in glucose homeostasis. Limited information is available on the effect of GPR40 genetic abnormalities on insulin secretion and metabolic regulation in human subjects.

Study design and results: For in vivo studies, we screened 734 subjects for the coding region of GPR40 and identified a new single-nucleotide mutation (Gly180Ser). The mean allele frequency was 0.75%, which progressively increased (P < 0.05) from nonobese subjects (0.42%) to moderately obese (body mass index = 30-39.9 kg/m2, 1.07%) and severely obese patients (body mass index > or = 40 kg/m2, 2.60%). The relationship between the GPR40 mutation, insulin secretion, and metabolic alterations was studied in 11 Gly/Ser mutation carriers. In these subjects, insulin secretion (insulinogenic index derived from oral glucose tolerance test) was significantly lower than in 692 Gly/Gly carriers (86.0 +/- 48.2 vs. 183.7 +/- 134.4, P < 0.005). Moreover, a case-control study indicated that plasma insulin and C-peptide responses to a lipid load were significantly (P < 0.05) lower in six Gly/Ser than in 12 Gly/Gly carriers. In vitro experiments in HeLa cells cotransfected with aequorin and the mutated Gly/Ser GPR40 indicated that intracellular Ca2+ concentration increase after oleic acid was significantly lower than in Gly/Gly GPR40-transfected cells. This fact was confirmed using fura-2 acetoxymethyl ester.

Conclusions: This newly identified GPR40 variant results in a loss of function that prevents the beta-cell ability to adequately sense lipids as an insulin secretory stimulus because of impaired intracellular Ca2+ concentration increase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Calcium / metabolism*
  • DNA Mutational Analysis
  • Female
  • Gene Frequency
  • Genetic Linkage*
  • Genotype
  • Glucose Tolerance Test
  • HeLa Cells
  • Humans
  • Insulin / metabolism*
  • Insulin Secretion
  • Insulin-Secreting Cells / metabolism
  • Insulin-Secreting Cells / pathology
  • Intracellular Fluid / metabolism*
  • Male
  • Middle Aged
  • Models, Biological
  • Mutation, Missense / physiology
  • Obesity / genetics
  • Obesity / metabolism
  • Obesity / pathology
  • Receptors, G-Protein-Coupled / genetics*
  • Receptors, G-Protein-Coupled / physiology
  • Transfection


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