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

Abderrahmani, Amar; Yengo, Loïc; Caiazzo, Robert; Canouil, Mickaël; Cauchi, Stéphane; Raverdy, Violeta; Plaisance, Valérie; Pawlowski, Valérie; Lobbens, Stéphane and Maillet, Julie, et al. (2018) In Diabetes 67(7). p.1310-1321
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... (More)

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.

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@article{75aa807f-1d08-404b-9af4-53b16f003988,
  abstract     = {<p>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.</p>},
  author       = {Abderrahmani, Amar and Yengo, Loïc and Caiazzo, Robert and Canouil, Mickaël and Cauchi, Stéphane and Raverdy, Violeta and Plaisance, Valérie and Pawlowski, Valérie and Lobbens, Stéphane and Maillet, Julie and Rolland, Laure and Boutry, Raphael and Queniat, Gurvan and Kwapich, Maxime and Tenenbaum, Mathie and Bricambert, Julien and Saussenthaler, Sophie and Anthony, Elodie and Jha, Pooja and Derop, Julien and Sand, Olivier and Rabearivelo, Iandry and Leloire, Audrey and Pigeyre, Marie and Daujat-Chavanieu, Martine and Gerbal-Chaloin, Sabine and Dayeh, Tasnim and Lassailly, Guillaume and Mathurin, Philippe and Staels, Bart and Auwerx, Johan and Schürmann, Annette and Postic, Catherine and Schafmayer, Clemens and Hampe, Jochen and Bonnefond, Amélie and Pattou, François and Froguel, Philippe},
  issn         = {1939-327X},
  language     = {eng},
  month        = {07},
  number       = {7},
  pages        = {1310--1321},
  publisher    = {American Diabetes Association Inc.},
  series       = {Diabetes},
  title        = {Increased Hepatic PDGF-AA Signaling Mediates Liver Insulin Resistance in Obesity-Associated Type 2 Diabetes},
  url          = {http://dx.doi.org/10.2337/db17-1539},
  volume       = {67},
  year         = {2018},
}