Peroxisome Proliferator-activated Receptor Gamma (PPARG) Modulates Free Fatty Acid Receptor 1 (FFAR1) Dependent Insulin Secretion in Humans

Overview

Journal Mol Metab

Specialty Cell Biology

Date 2014 Aug 28

PMID 25161890

Citations 5

Authors

Robert Wagner

Anja Hieronimus

Apostolia Lamprinou

Martin Heni

Erifili Hatziagelaki

Susanne Ullrich

Norbert Stefan

Harald Staiger

Hans-Ulrich Haring

Andreas Fritsche

Affiliations

Soon will be listed here.

Abstract

Genetic variation in FFAR1 modulates insulin secretion dependent on non-esterified fatty acid (NEFA) concentrations. We previously demonstrated lower insulin secretion in minor allele carriers of PPARG Pro12Ala in high-NEFA environment, but the mode of action could not been revealed. We tested if this effect is mediated by FFAR1 in humans. Subjects with increased risk of diabetes who underwent oral glucose tolerance tests were genotyped for 7 tagging SNPs in FFAR1 and PPARG Pro12Ala. The FFAR1 SNPs rs12462800 and rs10422744 demonstrated interactions with PPARG on insulin secretion. FFAR1 rs12462800 (p = 0.0006) and rs10422744 (p = 0.001) were associated with reduced insulin secretion in participants concomitantly carrying the PPARG minor allele and having high fasting FFA. These results suggest that the minor allele of the PPARG SNP exposes its carriers to modulatory effects of FFAR1 on insulin secretion. This subphenotype may define altered responsiveness to FFAR1-agonists, and should be investigated in further studies.

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References

Prentki M, Matschinsky F, Murthy Madiraju S . Metabolic signaling in fuel-induced insulin secretion. Cell Metab. 2013; 18(2):162-85. DOI: 10.1016/j.cmet.2013.05.018. View

Vangipurapu J, Stancakova A, Pihlajamaki J, Kuulasmaa T, Kuulasmaa T, Paananen J . Association of indices of liver and adipocyte insulin resistance with 19 confirmed susceptibility loci for type 2 diabetes in 6,733 non-diabetic Finnish men. Diabetologia. 2010; 54(3):563-71. DOI: 10.1007/s00125-010-1977-4. View

Stumvoll M, Haring H . The peroxisome proliferator-activated receptor-gamma2 Pro12Ala polymorphism. Diabetes. 2002; 51(8):2341-7. DOI: 10.2337/diabetes.51.8.2341. View

Stumvoll M, Haring H . Reduced lipolysis as possible cause for greater weight gain in subjects with the Pro12Ala polymorphism in PPARgamma2?. Diabetologia. 2002; 45(1):152-3. DOI: 10.1007/s125-002-8257-y. View

Nolan C, Madiraju M, Delghingaro-Augusto V, Peyot M, Prentki M . Fatty acid signaling in the beta-cell and insulin secretion. Diabetes. 2006; 55 Suppl 2:S16-23. DOI: 10.2337/db06-s003. View

Albareda M, Rodriguez-Espinosa J, Murugo M, de Leiva A, Corcoy R . Assessment of insulin sensitivity and beta-cell function from measurements in the fasting state and during an oral glucose tolerance test. Diabetologia. 2001; 43(12):1507-11. DOI: 10.1007/s001250051561. View

Kashyap S, Belfort R, Gastaldelli A, Pratipanawatr T, Berria R, Pratipanawatr W . A sustained increase in plasma free fatty acids impairs insulin secretion in nondiabetic subjects genetically predisposed to develop type 2 diabetes. Diabetes. 2003; 52(10):2461-74. DOI: 10.2337/diabetes.52.10.2461. View

SELTZER H, Allen E, Herron Jr A, Brennan M . Insulin secretion in response to glycemic stimulus: relation of delayed initial release to carbohydrate intolerance in mild diabetes mellitus. J Clin Invest. 1967; 46(3):323-35. PMC: 297053. DOI: 10.1172/JCI105534. View

Kim H, Hwang Y, Koo S, Park K, Lee M, Kim K . PPAR-γ activation increases insulin secretion through the up-regulation of the free fatty acid receptor GPR40 in pancreatic β-cells. PLoS One. 2013; 8(1):e50128. PMC: 3553172. DOI: 10.1371/journal.pone.0050128. View

10.

Boden G, Chen X, Rosner J, Barton M . Effects of a 48-h fat infusion on insulin secretion and glucose utilization. Diabetes. 1995; 44(10):1239-42. DOI: 10.2337/diab.44.10.1239. View

11.

Gupta D, Kono T, Evans-Molina C . The role of peroxisome proliferator-activated receptor γ in pancreatic β cell function and survival: therapeutic implications for the treatment of type 2 diabetes mellitus. Diabetes Obes Metab. 2010; 12(12):1036-47. PMC: 3764483. DOI: 10.1111/j.1463-1326.2010.01299.x. View

12.

Poitout V, Lin D . Modulating GPR40: therapeutic promise and potential in diabetes. Drug Discov Today. 2013; 18(23-24):1301-8. DOI: 10.1016/j.drudis.2013.09.003. View

13.

Itoh Y, Kawamata Y, Harada M, Kobayashi M, Fujii R, Fukusumi S . Free fatty acids regulate insulin secretion from pancreatic beta cells through GPR40. Nature. 2003; 422(6928):173-6. DOI: 10.1038/nature01478. View

14.

Stumvoll M, Wahl H, Loblein K, Becker R, Machicao F, Jacob S . Pro12Ala polymorphism in the peroxisome proliferator-activated receptor-gamma2 gene is associated with increased antilipolytic insulin sensitivity. Diabetes. 2001; 50(4):876-81. DOI: 10.2337/diabetes.50.4.876. View

15.

Brisson G, Malaisse-Lagae F, Malaisse W . The stimulus-secretion coupling of glucose-induced insulin release. VII. A proposed site of action for adenosine-3',5'-cyclic monophosphate. J Clin Invest. 1972; 51(2):232-41. PMC: 302121. DOI: 10.1172/JCI106808. View

16.

Kalis M, Leveen P, Lyssenko V, Almgren P, Groop L, Cilio C . Variants in the FFAR1 gene are associated with beta cell function. PLoS One. 2007; 2(11):e1090. PMC: 2042513. DOI: 10.1371/journal.pone.0001090. View

17.

Hanson R, Pratley R, Bogardus C, Narayan K, Roumain J, Imperatore G . Evaluation of simple indices of insulin sensitivity and insulin secretion for use in epidemiologic studies. Am J Epidemiol. 2000; 151(2):190-8. DOI: 10.1093/oxfordjournals.aje.a010187. View

18.

Matsuda M, DeFronzo R . Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. Diabetes Care. 1999; 22(9):1462-70. DOI: 10.2337/diacare.22.9.1462. View

19.

Deeb S, Fajas L, Nemoto M, Pihlajamaki J, Mykkanen L, Kuusisto J . A Pro12Ala substitution in PPARgamma2 associated with decreased receptor activity, lower body mass index and improved insulin sensitivity. Nat Genet. 1998; 20(3):284-7. DOI: 10.1038/3099. View

20.

Wagner R, Staiger H, Ullrich S, Stefan N, Fritsche A, Haring H . Untangling the interplay of genetic and metabolic influences on beta-cell function: Examples of potential therapeutic implications involving TCF7L2 and FFAR1. Mol Metab. 2014; 3(3):261-7. PMC: 3986492. DOI: 10.1016/j.molmet.2014.01.001. View