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

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.

Expert Opinion on Managing Chronic HCV Infection in Patients with Type 2 Diabetes Mellitus

“…In humans, liver biopsy specimens taken from non-diabetic, HCV-infected patients showed inhibition of insulin-stimulated tyrosine phosphorylation of hepatic insulin receptor substrate-1 (IRS-1), leading to inhibition of the PI3-kinase/Akt insulin signalling pathway [31]. In a recent study using a mouse model of HCV-induced IR, HCV proteins directly impaired Glut2-mediated hepatic glucose intake and gluconeogenesis by downregulating IRS-2 and altering FoxO1 phosphorylation and nuclear exclusion insulin in hepatocytes [32]. In addition to HCV-induced hepatic IR, there is evidence of HCV-induced peripheral IR, predominantly in skeletal muscle [33,34].…”

Dietary Energy Levels from Middle to Late Gestation of Guangdong Small-Ear Spotted Pig: Effects on Body Weight, Muscle Development, and Glucose Metabolism of its Newborn Piglets

“…Skeletal muscle consumes nearly 80% of glucose [10], and liver regulates glycogen storage, glucose uptake and output [11], indicating skeletal muscle and liver play an important role in glucose homeostasis. Glucose homeostasis is disrupted when the insulin signal pathway is suppressed in liver and muscle [12,13].…”

Clinical outcomes in chronic hepatitis C long-term responders to pre-direct antiviral agents: a single-center retrospective study

“…[21][22][23][24][25][26] Particularly, HCV genotypes 1 and 4 infection is associated to the development of IR regardless of the presence of steatosis. 23,[27][28] Recently, Lerat et al demonstrated that in HCV transgenic mice, the development of IR and glucose intolerance are supported by HCV per se through the expression of viral proteins in the hepatocytes which negatively act on the glucose uptake by the liver through the down-regulation of Glut2 and IRS-2 expression via SOCS3-dependent mechanisms. 28 Unfortunately, in our population we did not have data on homeostasis model of assessment (HOMA)-IR, but we showed that in HCV patients infected with HCV genotype non-3, baseline BMI was significantly higher compared to those infected with HCV genotype 3a indicating that in the first group, steatosis was mainly driven by metabolic rather than viral derangements.…”