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

Amar Abderrahmani, Loïc Yengo, Robert Caiazzo, Mickaël Canouil, Stéphane Cauchi, Violeta Raverdy, Valérie Plaisance, Valérie Pawlowski, Stéphane Lobbens, Julie Maillet, Laure Rolland, Raphael Boutry, Gurvan Queniat, Maxime Kwapich, Mathie Tenenbaum, Julien Bricambert, Sophie Saussenthaler, Elodie Anthony, Pooja Jha, Julien DeropOlivier Sand, Iandry Rabearivelo, Audrey Leloire, Marie Pigeyre, Martine Daujat-Chavanieu, Sabine Gerbal-Chaloin, Tasnim Dayeh, Guillaume Lassailly, Philippe Mathurin, Bart Staels, Johan Auwerx, Annette Schürmann, Catherine Postic, Clemens Schafmayer, Jochen Hampe, Amélie Bonnefond, François Pattou, Philippe Froguel

Research output: Contribution to journalArticlepeer-review

34 Citations (SciVal)

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.

Original languageEnglish
Pages (from-to)1310-1321
Number of pages12
JournalDiabetes
Volume67
Issue number7
DOIs
Publication statusPublished - 2018 Jul 1
Externally publishedYes

Subject classification (UKÄ)

  • Endocrinology and Diabetes

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