Loss-of-function mutation of the GPR40 gene associates with abnormal stimulated insulin secretion by acting on intracellular calcium mobilization(695 views) Vettor R, Granzotto M, De Stefani D, Trevellin E, Rossato M, Farina MG, Milan G, Pilon C, Nigro A, Federspil G, Vigneri R, Vitiello L, Rizzuto R, Baratta R, Frittitta L
Keywords: Aequorin, C Peptide, Calcium, Fura 2 Acetoxymethyl Ester, G Protein Coupled Receptor, G Protein Coupled Receptor 40, Glycine, Insulin, Oleic Acid, Serine, Unclassified Drug, Adult, Article, Body Mass, Calcium Cell Level, Calcium Mobilization, Controlled Study, Female, Gene Frequency, Genetic Association, Genetic Transfection, Hela Cell, Heterozygote, Human, Human Cell, In Vivo Study, Insulin Blood Level, Insulin Release, Major Clinical Study, Metabolic Disorder, Obesity, Oral Glucose Tolerance Test, Priority Journal, Single Nucleotide Polymorphism, Dna Mutational Analysis, Genotype, Insulin-Secreting Cells, Intracellular Fluid, Linkage (genetics), Middle Aged, Models, Biological, Missense, G-Protein-Coupled,
Affiliations: *** IBB - CNR ***
Endocrine-Metabolic Laboratory, Department of Medical and Surgical Sciences, University of Padova, I-35128 Padova, Italy
Department of Biology, University of Padova, I-35121 Padova, Italy
Department of Internal and Specialist Medicine, University of Catania Medical School, Garibaldi Hospital, I-95122 Catania, Italy
Department of Experimental and Diagnostic Medicine, Interdisciplinary Center for the Study of Inflammation (ICSI), University of Ferrara, I-44100 Ferrara, Italy
Emilia Romagna Laboratory for Genomics and Biotechnology (ER-Gentech), University of Ferrara, I-44100 Ferrara, Italy
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Briscoe, C. P., Tadayyon, M., Andrews, J. L., Benson, W. G., Chambers, J. K., Eilert, M. M., Ellis, C., Muir, A. I., The orphan G protein-coupled receptor GPR40 is activated by medium and long chain fatty acids (2003) J Biol Chem, 278, pp. 11303-11311
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Lam, T. K., Schwartz, G. J., Rossetti, L., Hypothalamic sensing of fatty acids (2005) Nat Neurosci, 8, pp. 579-584
Pocai, A., Lam, T. K., Obici, S., Gutierrez-Juarez, R., Muse, E. D., Arduini, A., Rossetti, L., Restoration of hypothalamic lipid sensing normalizes energy and glucose homeostasis in overfed rats (2006) J Clin Invest, 116, pp. 1081-1091
Arias-Montano, J. A., Young, J. M., Characteristics of histamine H1 receptors on HeLa cells (1993) Eur J Pharmacol, 245, pp. 291-295
Covington, D. K., Briscoe, C. A., Brown, A. J., Jayawickreme, C. K., The G-protein-coupled receptor 40 family (GPR40-GPR43) and its role in nutrient sensing (2006) Biochem Soc Trans, 34, pp. 770-773
Latour, M. G., Alquier, T., Oseid, E., Tremblay, C., Jetton, T. L., Luo, J., Lin, D. C., Poitout, V., GPR40 is necessary but not sufficient for fatty acid stimulation of insulin secretion in vivo (2007) Diabetes, 56, pp. 1087-1094
Lee, D. K., George, S. R., O'Dowd, B. F., Continued discovery of ligands for G protein-coupled receptors (2003) Life Sci, 74, pp. 293-297
Brown, A. J., Goldsworthy, S. M., Barnes, A. A., Eilert, M. M., Tcheang, L., Daniels, D., Muir, A. I., Dowell, S. J., The orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids (2003) J Biol Chem, 278, pp. 11312-11319
Feng, D. D., Luo, Z., Roh, S. G., Hernandez, M., Tawadros, N., Keating, D. J., Chen, C., Reduction in voltage-gated K+ currents in primary cultured rat pancreatic -cells by linoleic acids (2006) Endocrinology, 147, pp. 674-682
Abdul-Ghani, M. A., Williams, K., DeFronzo, R. A., Stern, M., What is the best predictor of future type 2 diabetes? (2007) Diabetes Care, 30, pp. 1544-1548
Nolan, C. J., Leahy, J. L., Delghingaro-Augusto, V., Moibi, J., Soni, K., Peyot, M. L., Fortier, M., Prentki, M., -Cell compensation for insulin resistance in Zucker fatty rats: Increased lipolysis and fatty acid signalling (2006) Diabetologia, 49, pp. 2120-2130
Loss-of-function mutation of the GPR40 gene associates with abnormal stimulated insulin secretion by acting on intracellular calcium mobilization
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.
Loss-of-function mutation of the GPR40 gene associates with abnormal stimulated insulin secretion by acting on intracellular calcium mobilization
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Loss-of-function mutation of the GPR40 gene associates with abnormal stimulated insulin secretion by acting on intracellular calcium mobilization
Petraglia F, Singh AA, Carafa V, Nebbioso A, Conte M, Scisciola L, Valente S, Baldi A, Mandoli A, Petrizzi VB, Ingenito C, De Falco S, Cicatiello V, Apicella I, Janssen-megens EM, Kim B, Yi G, Logie C, Heath S, Ruvo M, Wierenga ATJ, Flicek P, Yaspo ML, Della Valle V, Bernard O, Tomassi S, Novellino E, Feoli A, Sbardella G, Gut I, Vellenga E, Stunnenberg HG, Mai A, Martens JHA, Altucci L * Combined HAT/EZH2 modulation leads to cancer-selective cell death(289 views) Oncotarget (ISSN: 1949-2553electronic, 1949-2553linking), 2018 May 22; 9(39): 25630-25646. Impact Factor:5.008 ViewExport to BibTeXExport to EndNote