title: Peroxisome proliferator-activated receptor gamma (PPARG) modulates free fatty acid receptor 1 (FFAR1) dependent insulin secretion in humans.
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.
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, Diabetology, Nephrology, Vascular Disease and Clinical Chemistry, University Hospital of the Eberhard Karls University, Tübingen, Germany ; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen (IDM), Tübingen, Germany ; German Center for Diabetes Research (DZD), Neuherberg, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Wagner
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, Diabetology, Nephrology, Vascular Disease and Clinical Chemistry, University Hospital of the Eberhard Karls University, Tübingen, Germany ; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen (IDM), Tübingen, Germany ; German Center for Diabetes Research (DZD), Neuherberg, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Hieronimus
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, Diabetology, Nephrology, Vascular Disease and Clinical Chemistry, University Hospital of the Eberhard Karls University, Tübingen, Germany ; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen (IDM), Tübingen, Germany ; German Center for Diabetes Research (DZD), Neuherberg, Germany.
authors.forename: Apostolia
authors.initials: A
authors.lastname: Lamprinou
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, Diabetology, Nephrology, Vascular Disease and Clinical Chemistry, University Hospital of the Eberhard Karls University, Tübingen, Germany ; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen (IDM), Tübingen, Germany ; German Center for Diabetes Research (DZD), Neuherberg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Heni
authors.affiliation: 2nd Department of Internal Medicine, Research Institute and Diabetes Center, Athens University Medical School, "Attikon" University Hospital, Athens, Greece.
authors.forename: Erifili
authors.initials: E
authors.lastname: Hatziagelaki
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, Diabetology, Nephrology, Vascular Disease and Clinical Chemistry, University Hospital of the Eberhard Karls University, Tübingen, Germany ; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen (IDM), Tübingen, Germany ; German Center for Diabetes Research (DZD), Neuherberg, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Ullrich
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, Diabetology, Nephrology, Vascular Disease and Clinical Chemistry, University Hospital of the Eberhard Karls University, Tübingen, Germany ; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen (IDM), Tübingen, Germany ; German Center for Diabetes Research (DZD), Neuherberg, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Stefan
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, Diabetology, Nephrology, Vascular Disease and Clinical Chemistry, University Hospital of the Eberhard Karls University, Tübingen, Germany ; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen (IDM), Tübingen, Germany ; German Center for Diabetes Research (DZD), Neuherberg, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Staiger
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, Diabetology, Nephrology, Vascular Disease and Clinical Chemistry, University Hospital of the Eberhard Karls University, Tübingen, Germany ; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen (IDM), Tübingen, Germany ; German Center for Diabetes Research (DZD), Neuherberg, Germany.
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Häring
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, Diabetology, Nephrology, Vascular Disease and Clinical Chemistry, University Hospital of the Eberhard Karls University, Tübingen, Germany ; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen (IDM), Tübingen, Germany ; German Center for Diabetes Research (DZD), Neuherberg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Fritsche
keywords: FFAR1; FFAR1, free fatty acid receptor 1; Free fatty acid receptor 1; G-protein coupled receptor 40; GPR40; GPR40, G-protein coupled receptor 40; Insulin secretion; NEFA, non-esterified fatty acids; OGTT, oral glucose tolerance test; PPARG; TUEF, Tuebingen Family Study