Molecular pathways for glucose homeostasis, insulin signaling and autophagy in hepatitis C virus induced insulin resistance in a cellular model

Virology. 2012 Dec 5;434(1):5-17. doi: 10.1016/j.virol.2012.07.003. Epub 2012 Aug 3.


Chronic HCV infection induces insulin resistance (IR). We studied this in a persistently infected cell line with defects in glucose homeostasis resulting from the phosphorylation of glycogen synthase (GS Ser641) and GS kinase isoform 3β (GSK 3βSer9). Reversal of these effects in cells cured of HCV with interferon supports viral specificity. Insulin signaling was disrupted by IRS-1 Ser312 phosphorylation and dysregulation of the Akt pathway. In infected cells, active autophagy was revealed by the formation of LC3 puncta or by increased levels (50-200%) of the markers Beclin 1 and conjugated Atg5/Atg12. Inhibition of autophagy by 3-methyl-adenine (3-MA) reduced Beclin1 levels, inhibited IRS-1 Ser312 or GS Ser641 phosphorylation and decreased viral load. Furthermore, IRS-1 Ser312 and Beclin1 were co-immunoprecipitated suggesting that they interact. It thus appears that HCV infection disturbs glucose homeostasis or insulin signaling to induce IR and also elicits autophagy that may contribute to this process.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • Autophagy*
  • Cell Line
  • Glucose / metabolism*
  • Glycogen Synthase / genetics
  • Glycogen Synthase / metabolism
  • Glycogen Synthase Kinases / genetics
  • Glycogen Synthase Kinases / metabolism
  • Hepacivirus / pathogenicity*
  • Hepatocytes / physiology
  • Hepatocytes / virology
  • Homeostasis*
  • Humans
  • Insulin / metabolism*
  • Insulin Resistance*
  • Models, Biological
  • Mutant Proteins / genetics
  • Mutant Proteins / metabolism
  • Signal Transduction*


  • Insulin
  • Mutant Proteins
  • Glycogen Synthase
  • Glycogen Synthase Kinases
  • Glucose