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

Study Design and Results

Studies in vivo: 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% that progressively increased (P<0.05) from non obese subjects (0.42%) to moderately obese (BMI 30–39.9 kg/m², 1.07%) and severely obese patients (BMIxs40 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 OGTT) 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 6 Gly/Ser than in 12 Gly/Gly carriers.

Studies in vitro: In vitro experiments in HeLa cells co-transfected with aequorin and the mutated Gly/Ser GPR40, indicated that [Ca²⁺]_i increase after oleic acid was significantly lower than in Gly/Gly GRP40 transfected cells. This fact was confirmed using Fura-2/AM.

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