1. Increased Hepatic PDGF-AA Signaling Mediates Liver Insulin Resistance in Obesity-Associated Type 2 Diabetes
- Author
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Abderrahmani, A, Yengo, L, Caiazzo, R, Canouil, M, Cauchi, S, Raverdy, V, Plaisance, V, Pawlowski, V, Lobbens, S, Maillet, J, Rolland, L, Boutry, R, Queniat, G, Kwapich, M, Tenenbaum, M, Bricambert, J, Saussenthaler, S, Anthony, E, Jha, P, Derop, J, Sand, O, Rabearivelo, I, Leloire, A, Pigeyre, M, Daujat-Chavanieu, M, Gerbal-Chaloin, S, Dayeh, T, Lassailly, G, Mathurin, P, Staels, B, Auwerx, J, Schurmann, A, Postic, C, Schafmayer, C, Hampe, J, Bonnefond, A, Pattou, F, Froguel, P, Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M)), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Imperial College London, Recherche translationnelle sur le diabète - U 1190 (RTD), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Department of Experimental Diabetology [München-Neuherberg, Germany], German Institute of Human Nutrition Potsdam-Rehbrüecke [München-Neuherberg, Germany] -Nuthetal and German Center for Diabetes Research - DZD [München-Neuherberg, Germany], German Center for Diabetes Diseases [Neuherberg, Germany] (DZD), German Institute of Human Nutrition Potsdam-Rehbrücke (DIfE), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Ecole Polytechnique Fédérale de Lausanne (EPFL), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Skane University Hospital [Malmo], Lund University [Lund], Lille Inflammation Research International Center - U 995 (LIRIC), CHU Lille, Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Laboratory of Integrative and Systems Physiology [Lausanne, Switzerland] (LISP), Kiel University, Technische Universität Dresden = Dresden University of Technology (TU Dresden), This study was supported by nonprofit organizations and public bodies for funding of scientific research conducted in France and within the European Union: 'Centre National de la Recherche Scientifique', 'Université de Lille 2', 'Institut Pasteur de Lille', 'Société Francophone du Diabète', 'Contrat de Plan Etat-Région', 'Agence Nationale de la Recherche', ANR-10-LABX-46, ANR EQUIPEX Ligan MP: ANR-10-EQPX-07-01, European Research Council GEPIDIAB - 294785., ANR-10-LABX-0046,EGID,EGID Diabetes Pole(2010), ANR-10-EQPX-0007,LIGAN PM,Plate forme Lilloise de séquençage du génome humain pour une médecine personnalisée(2010), European Project: 294785,EC:FP7:ERC,ERC-2011-ADG_20110310,GEPIDIAB(2012), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (GI3M), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Philips, Alexandre, EGID Diabetes Pole - - EGID2010 - ANR-10-LABX-0046 - LABX - VALID, Plate forme Lilloise de séquençage du génome humain pour une médecine personnalisée - - LIGAN PM2010 - ANR-10-EQPX-0007 - EQPX - VALID, and Genetics and epigenetics of Type 2 Diabetes physiology - GEPIDIAB - - EC:FP7:ERC2012-11-01 - 2017-10-31 - 294785 - VALID
- Subjects
Adult ,Male ,GENES ,[SDV]Life Sciences [q-bio] ,IMATINIB MESYLATE ,R.C ,DISEASE ,GLUCOSE ,Epigenesis, Genetic ,ALTERED DNA METHYLATION ,ACTIVATION ,PDGFA ,Endocrinology & Metabolism ,Non-alcoholic Fatty Liver Disease ,L.Y ,GLYCEMIC TRAITS ,FIBROSIS ,Humans ,and P.F. contributed equally to the study ,Genetic Predisposition to Disease ,Obesity ,Cells, Cultured ,Platelet-Derived Growth Factor ,M.C ,Science & Technology ,A.A ,FATTY LIVER ,nutritional and metabolic diseases ,Type 2 diabetes ,11 Medical And Health Sciences ,DNA Methylation ,Middle Aged ,Up-Regulation ,[SDV] Life Sciences [q-bio] ,Diabetes Mellitus, Type 2 ,Liver ,Case-Control Studies ,Female ,Epigenetics ,KINASE-C-EPSILON ,Insulin Resistance ,Life Sciences & Biomedicine ,F.P ,Signal Transduction - Abstract
In type 2 diabetes (T2D), hepatic insulin resistance is strongly associated with nonalcoholic fatty liver disease (NAFLD). In this study, we hypothesized that the DNA methylome of livers from patients with T2D compared with livers of individuals with normal plasma glucose levels can unveil some mechanism of hepatic insulin resistance that could link to NAFLD. Using DNA methylome and transcriptome analyses of livers from obese individuals, we found that hypomethylation at a CpG site in PDGFA (encoding platelet-derived growth factor α) and PDGFA overexpression are both associated with increased T2D risk, hyperinsulinemia, increased insulin resistance, and increased steatohepatitis risk. Genetic risk score studies and human cell modeling pointed to a causative effect of high insulin levels on PDGFA CpG site hypomethylation, PDGFA overexpression, and increased PDGF-AA secretion from the liver. We found that PDGF-AA secretion further stimulates its own expression through protein kinase C activity and contributes to insulin resistance through decreased expression of insulin receptor substrate 1 and of insulin receptor. Importantly, hepatocyte insulin sensitivity can be restored by PDGF-AA–blocking antibodies, PDGF receptor inhibitors, and by metformin, opening therapeutic avenues. Therefore, in the liver of obese patients with T2D, the increased PDGF-AA signaling contributes to insulin resistance, opening new therapeutic avenues against T2D and possibly NAFLD.
- Published
- 2018
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