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Diabetes. 2018 Jul;67(7):1310-1321. doi: 10.2337/db17-1539. Epub 2018 May 4.

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

Author information

1
University Lille, Centre National de la Recherche Scientifique, Institut Pasteur de Lille, UMR 8199 - European Genomic Institute for Diabetes, Lille, France p.froguel@imperial.ac.uk amar.abderrahmani@univ-lille2.fr.
2
Section of Genomics of Common Disease, Department of Medicine, Imperial College London, London, U.K.
3
University Lille, Centre National de la Recherche Scientifique, Institut Pasteur de Lille, UMR 8199 - European Genomic Institute for Diabetes, Lille, France.
4
University Lille, INSERM, CHU Lille, U1190 - European Genomic Institute for Diabetes, Lille, France.
5
Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal, and German Center for Diabetes Research (DZD), München-Neuherberg, Germany.
6
Inserm U1016, Institut Cochin, Centre National de la Recherche Scientifique UMR 8104, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
7
Laboratory of Integrative Systems Physiology, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
8
INSERM U1183, University Montpellier, Institute for Regenerative Medicine and Biotherapy, CHU Montpellier, France.
9
Department of Clinical Science, Skane University Hospital Malmö, Malmö, Sweden.
10
University Lille, INSERM, CHU Lille, U995 - Lille Inflammation Research International Center, Lille, France.
11
University Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1011- European Genomic Institute for Diabetes, Lille, France.
12
Department of Visceral and Thoracic Surgery, University Hospital Schleswig-Holstein, Kiel, Germany.
13
Medical Department 1, Technische Universität Dresden, Dresden, Germany.

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.

PMID:
29728363
DOI:
10.2337/db17-1539
[Indexed for MEDLINE]
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