Increased hepatic PDGF-AA signaling mediates liver insulin resistance in obesity associated type 2 diabetes

TL;DR

This study reveals that increased PDGF-AA signaling in the liver of obese individuals with T2D promotes insulin resistance and liver disease, and can be mitigated by specific inhibitors and metformin, suggesting new therapeutic strategies.

Contribution

It uncovers a novel mechanism linking PDGF-AA signaling to hepatic insulin resistance in obesity-related T2D, supported by multi-omics and functional studies.

Findings

PDGF-AA overexpression correlates with T2D and NAFLD risk.

High insulin levels cause PDGF-AA overexpression via hypomethylation.

Blocking PDGF-AA improves insulin sensitivity in liver cells.

Abstract

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.