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

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title = "Increased Hepatic PDGF-AA Signaling Mediates Liver Insulin Resistance in Obesity-Associated Type 2 Diabetes",
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.",
author = "Amar Abderrahmani and Lo{\"i}c Yengo and Robert Caiazzo and Micka{\"e}l Canouil and St{\'e}phane Cauchi and Violeta Raverdy and Val{\'e}rie Plaisance and Val{\'e}rie Pawlowski and St{\'e}phane Lobbens and Julie Maillet and Laure Rolland and Raphael Boutry and Gurvan Queniat and Maxime Kwapich and Mathie Tenenbaum and Julien Bricambert and Sophie Saussenthaler and Elodie Anthony and Pooja Jha and Julien Derop and Olivier Sand and Iandry Rabearivelo and Audrey Leloire and Marie Pigeyre and Martine Daujat-Chavanieu and Sabine Gerbal-Chaloin and Tasnim Dayeh and Guillaume Lassailly and Philippe Mathurin and Bart Staels and Johan Auwerx and Annette Sch{\"u}rmann and Catherine Postic and Clemens Schafmayer and Jochen Hampe and Am{\'e}lie Bonnefond and Fran{\c c}ois Pattou and Philippe Froguel",
year = "2018",
month = jul,
day = "1",
doi = "10.2337/db17-1539",
language = "English",
volume = "67",
pages = "1310--1321",
journal = "Diabetes",
issn = "1939-327X",
publisher = "American Diabetes Association Inc.",
number = "7",