Title :

Increased Hepatic PDGF-AA Signaling Mediates Liver Insulin Resistance in Obesity-Associated Type 2 Diabetes

Author(s) :

Abderrahmani, Amar [Auteur correspondant]
Imperial College London
Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 [EGENODIA (GI3M)]
Yengo, Loïc [Auteur]
Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 [EGENODIA (GI3M)]
Caiazzo, Robert [Auteur]
Recherche translationnelle sur le diabète - U 1190 [RTD]
Canouil, Mickael [Auteur]
Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 [EGENODIA (GI3M)]
Cauchi, Stephane [Auteur]
Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 [EGENODIA (GI3M)]
Raverdy, Violeta [Auteur]
Recherche translationnelle sur le diabète - U 1190 [RTD]
Plaisance, Valérie [Auteur]
Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 [EGENODIA (GI3M)]
Pawlowski, Valérie [Auteur]
Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 [EGENODIA (GI3M)]
Lobbens, Stéphane [Auteur]
Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 [EGENODIA (GI3M)]
Maillet, Julie [Auteur]
Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 [EGENODIA (GI3M)]
Rolland, Laure [Auteur]
Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 [EGENODIA (GI3M)]
Boutry, Raphael [Auteur]
Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 [EGENODIA (GI3M)]
Queniat, Gurvan [Auteur]
Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 [EGENODIA (GI3M)]
Kwapich, Maxime [Auteur]
Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 [EGENODIA (GI3M)]
Tenenbaum, Mathie [Auteur]
Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 [EGENODIA (GI3M)]
Bricambert, Julien [Auteur]
Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 [EGENODIA (GI3M)]
Saussenthaler, Sophie [Auteur]
German Institute of Human Nutrition Potsdam-Rehbrücke [DIfE]
Anthony, Elodie [Auteur]
Institut Cochin [IC UM3 (UMR 8104 / U1016)]
Jha, Pooja [Auteur]
Ecole Polytechnique Fédérale de Lausanne [EPFL]
Derop, Julien [Auteur]
Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 [EGENODIA (GI3M)]
Sand, Olivier [Auteur]
Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 [EGENODIA (GI3M)]
Rabearivelo, Iandry [Auteur]
Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 [EGENODIA (GI3M)]
Leloire, Audrey [Auteur]
Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 [EGENODIA (GI3M)]
Pigeyre, Marie [Auteur]
Recherche translationnelle sur le diabète - U 1190 [RTD]
Daujat-Chavanieu, Martine [Auteur]
Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB)
Gerbal-Chaloin, Sabine [Auteur]
Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB)
Dayeh, Tasnim [Auteur]
Lassailly, Guillaume [Auteur]
Lille Inflammation Research International Center - U 995 [LIRIC]
Mathurin, Philippe [Auteur]
Lille Inflammation Research International Center - U 995 [LIRIC]
Staels, Bart [Auteur]
Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 [RNMCD]
Auwerx, Johan [Auteur]
Schürmann, Annette [Auteur]
German Institute of Human Nutrition Potsdam-Rehbrücke [DIfE]
Postic, Catherine [Auteur]
Institut Cochin [IC UM3 (UMR 8104 / U1016)]
Schafmayer, Clemens [Auteur]
Kiel University
Hampe, Jochen [Auteur]
Technische Universität Dresden = Dresden University of Technology [TU Dresden]
Bonnefond, Amélie [Auteur]
Imperial College London
Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 [EGENODIA (GI3M)]
Pattou, François [Auteur]
Recherche translationnelle sur le diabète - U 1190 [RTD]
Froguel, Philippe [Auteur correspondant]
Imperial College London
Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 [EGENODIA (GI3M)]

Journal title :

Diabetes

Pages :

1310 - 1321

Publisher :

American Diabetes Association

Publication date :

2018-07

ISSN :

0012-1797

English keyword(s) :

PDGFA
Type 2 diabetes
Obesity
Liver
Epigenetics
. A.A.
L.Y.
R.C.
M.C.
F.P.
and P.F. contributed equally to the study

HAL domain(s) :

Sciences du Vivant [q-bio]

English abstract : [en]

Type 2 diabetes (T2D) is closely linked with non-alcoholic fatty liver disease (NAFLD) and hepatic insulin resistance, but the involved mechanisms are still elusive. Using DNA methylome and transcriptome analyses of livers ...
Show more >Type 2 diabetes (T2D) is closely linked with non-alcoholic fatty liver disease (NAFLD) and hepatic insulin resistance, but the involved mechanisms are still elusive. Using DNA methylome and transcriptome analyses of livers from obese individuals, we found that both hypomethylation at a CpG site in PDGFA (encoding platelet derived growth factor alpha) and PDGFA overexpression are associated with increased T2D risk, hyperinsulinemia, increased insulin resistance and increased steatohepatitis risk. Both genetic risk score studies and human cell modeling pointed to a causative impact of high insulin levels on PDGFA CpG site hypomethylation, PDGFA overexpression, and increased PDGF-AA secretion from 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 both 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. Conclusion: 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 NAFLD.Show less >

Language :

Anglais

Peer reviewed article :

Oui

Audience :

Internationale

Popular science :

Non

ANR Project :

EGID Diabetes Pole
Plate forme Lilloise de séquençage du génome humain pour une médecine personnalisée

Collections :

• Récepteurs nucléaires, Maladies Cardiovasculaires et Diabète (EGID) - U1011

Source :

Harvested from HAL