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Loss-of-Function Mutation of the GPR40 Gene Associates with Abnormal Stimulated Insulin Secretion by Acting on Intracellular Calcium Mobilization

Endocrine-Metabolic Laboratory (R.Ve., M.G., M.R., G.M., C.P., G.F.), Internal Medicine, Department of Medical and Surgical Sciences, University of Padova, I-35128 Padova, Italy; Department of Biology (E.T., L.V.), University of Padova, I-35121 Padova, Italy; Division of Endocrinology (M.G.F., A.N., R.Vi., R.B., L.F.), Department of Internal and Specialist Medicine, University of Catania Medical School, Garibaldi Hospital, I-95122 Catania, Italy; and Department of Experimental and Diagnostic Medicine (D.D.S., R.R.), Section of General Pathology, Interdisciplinary Center for the Study of Inflammation (ICSI) and Emilia Romagna Laboratory for Genomics and Biotechnology (ER-Gentech), University of Ferrara, I-44100 Ferrara, Italy

Address all correspondence and requests for reprints to: Roberto Vettor, M.D., Department of Medical and Surgical Sciences, University of Padova, via Ospedale, 105, I-35128 Padova, Italy. E-mail: roberto.vettor{at}unipd.it; or Lucia Frittitta, M.D., Division of Endocrinology, Department of Internal and Specialist Medicine, University of Catania Medical School, Garibaldi Hospital, Via Palermo 636, I-95122 Catania, Italy. E-mail: lfritti{at}unict.it.

Background: Free fatty acids (FFAs) acutely stimulate but chronically impair glucose-stimulated insulin secretion from β-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 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 β-cell ability to adequately sense lipids as an insulin secretory stimulus because of impaired intracellular Ca²⁺ concentration increase.

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