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

被引:51
作者
Vettor, Roberto [1 ]
Granzotto, Marnie [1 ]
De Stefani, Diego [4 ,5 ]
Trevellin, Elisabetta [2 ]
Rossato, Marco [1 ]
Farina, Maria Grazia [3 ]
Milan, Gabriella [1 ]
Pilon, Catia [1 ]
Nigro, Angela [3 ]
Federspil, Giovanni [1 ]
Vigneri, Riccardo [3 ]
Vitiello, Libero [2 ]
Rizzuto, Rosario [4 ,5 ]
Baratta, Roberto [3 ]
Frittitta, Lucia [3 ]
机构
[1] Univ Padua, Dept Med & Surg Sci, Endocrine Metab Lab, I-35128 Padua, Italy
[2] Univ Padua, Dept Biol, I-35121 Padua, Italy
[3] Univ Catania, Sch Med, Garibaldi Hosp, Dept Internal & Specialist Med,Div Endocrinol, I-95122 Catania, Italy
[4] Univ Ferrara, Sect Gen Pathol, Dept Expt & Diagnost Med, ICSI, I-44100 Ferrara, Italy
[5] Univ Ferrara, Emilia Romagna Lab Genom & Biotechnol ER Gentech, I-44100 Ferrara, Italy
关键词
D O I
10.1210/jc.2007-2680
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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/m(2), 1.07%) and severely obese patients (body mass index >= 40 kg/m(2), 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.
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收藏
页码:3541 / 3550
页数:10
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