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

Hervé Lerat,Mohamed Rabah Imache,Jacqueline Polyte,Aurore Gaudin,Marion Mercey,Flora Donati,Camille Baudesson,Martin R Higgs,Alexandre Picard,Christophe Magnan,Fabienne Foufelle,Jean-Michel Pawlotsky

doi:10.1074/jbc.m117.785030

Abstract

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.

Highlights

Virus-related type 2 diabetes is commonly observed in individuals infected with the hepatitis C virus (HCV); the underlying molecular mechanisms remain unknown
We studied the impact of the HCV proteins on the prevalence of insulin resistance in our murine model
Because orally administered glucose can induce secretion of glucagon-like peptide 1 (GLP-1) by the gut, which increases insulin secretion by pancreatic ␤ cells, mice were subjected to intraperitoneal glucose tolerance tests (IPGTT), which bypass the effect of GLP-1 and are associated with lower glucose-stimulated insulin secretion than oral glucose tolerance tests

Summary

Introduction

Virus-related type 2 diabetes is commonly observed in individuals infected with the hepatitis C virus (HCV); the underlying molecular mechanisms remain unknown. A correlation between IR and the HCV RNA level, a surrogate marker of viral replication, has been reported [17], and the incidence of IR is higher in patients infected with genotypes 1 and 4 than in those infected with genotypes 2 or 3 [18, 19] This genotype specificity of HCVinduced IR could result from amino acid sequence differences across genotypes in the core sequence [20, 21] and HCV corecose infusion rate; GUR, glucose utilization rate; GK, glucokinase; PFKFB3, fructose 1,6-bisphosphatase; PEPCK, phosphoenolpyruvate carboxykinase; Glc-6-PC, glucose-6-phosphatase; RT-qPCR, quantitative real-time PCR; HBSS, Hanks’ buffered salt solution; tg, transgenic; UPR, unfolded protein response. The cure of infection is often associated with IR reduction, in particular in patients infected with genotype 1 [25,26,27,28]

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