Hepatitis C virus induces a prediabetic state by directly impairing hepatic glucose metabolism in mice

J Biol Chem. 2017 Aug 4;292(31):12860-12873. doi: 10.1074/jbc.M117.785030. Epub 2017 May 30.


Virus-related type 2 diabetes is commonly observed in individuals infected with the hepatitis C virus (HCV); however, the underlying molecular mechanisms remain unknown. Our aim was to unravel these mechanisms using FL-N/35 transgenic mice expressing the full HCV ORF. We observed that these mice displayed glucose intolerance and insulin resistance. We also found that Glut-2 membrane expression was reduced in FL-N/35 mice and that hepatocyte glucose uptake was perturbed, partly accounting for the HCV-induced glucose intolerance in these mice. Early steps of the hepatic insulin signaling pathway, from IRS2 to PDK1 phosphorylation, were constitutively impaired in FL-N/35 primary hepatocytes via deregulation of TNFα/SOCS3. Higher hepatic glucose production was observed in the HCV mice, despite higher fasting insulinemia, concomitant with decreased expression of hepatic gluconeogenic genes. Akt kinase activity was higher in HCV mice than in WT mice, but Akt-dependent phosphorylation of the forkhead transcription factor FoxO1 at serine 256, which triggers its nuclear exclusion, was lower in HCV mouse livers. These findings indicate an uncoupling of the canonical Akt/FoxO1 pathway in HCV protein-expressing hepatocytes. Thus, the expression of HCV proteins in the liver is sufficient to induce insulin resistance by impairing insulin signaling and glucose uptake. In conclusion, we observed a complete set of events leading to a prediabetic state in HCV-transgenic mice, providing a valuable mechanistic explanation for HCV-induced diabetes in humans.

Keywords: glucose metabolism; hepatitis C virus (HCV); insulin resistance; transgenic mice; type 2 diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Absorption, Physiological
  • Animals
  • Cell Line, Tumor
  • Cells, Cultured
  • Gene Expression Regulation
  • Gluconeogenesis
  • Glucose / metabolism
  • Glucose Transporter Type 2 / genetics
  • Glucose Transporter Type 2 / metabolism
  • Hepacivirus / genetics
  • Hepacivirus / metabolism
  • Hepacivirus / pathogenicity*
  • Hepatitis C / metabolism
  • Hepatitis C / pathology
  • Hepatitis C / physiopathology*
  • Hepatitis C / virology
  • Hepatocytes / metabolism
  • Hepatocytes / pathology
  • Hepatocytes / virology*
  • Insulin Resistance*
  • Male
  • Mice, Transgenic
  • Muscle, Striated / metabolism
  • Muscle, Striated / virology
  • Open Reading Frames
  • Phosphorylation
  • Prediabetic State / etiology*
  • Prediabetic State / virology
  • Protein Processing, Post-Translational
  • RNA / metabolism
  • Specific Pathogen-Free Organisms
  • Viral Proteins / genetics
  • Viral Proteins / metabolism


  • Glucose Transporter Type 2
  • RNA, recombinant
  • Slc2a2 protein, mouse
  • Viral Proteins
  • RNA
  • Glucose