Impaired Irs–1/Pi3–Kinase Signaling in Patients With Hcv: A Mechanism for Increased Prevalence of Type 2 Diabetes

Abstract

Patients with hepatitis C virus (HCV) infection have a greater risk of developing type 2 diabetes mellitus. However, the mechanism of this association is unclear. In this study, we examined the potential defects in upstream insulin signaling pathways in liver specimens obtained from nonobese/nondiabetic subjects with HCV infection. Fasting liver biopsy specimens were obtained from 42 HCV–infected subjects and 10 non–HCV–infected subjects matched for age and body mass index. Liver tissues were exposed to insulin and examined for the contents and phosphorylation/activation status of the upstream insulin signaling molecules by immunoprecipitation and Western blot analysis. HCV infection resulted in a trend toward a 2–fold to 3–fold increase in insulin receptor (IR) and insulin receptor substrate (IRS)–1 contents when compared with non–HCV. In contrast, insulin–stimulated IRS–1 tyrosine phosphorylation was decreased by 2–fold in HCV–infected subjects compared with non–HCV–infected subjects (P < .05). The observed reductions in IRS–1 tyrosine phosphorylation were accompanied by a 3.4–fold decrease in IRS–1/p85 phosphatidylinositol 3–kinase (PI3–kinase) association and a 2.5–fold decrease in IRS–1–associated PI3–kinase enzymatic activity (P < .05 vs. non–HCV). This was accompanied by a marked reduction in insulin–stimulated Akt phosphorylation without any alterations in mitogen–activated protein kinase (MAPK) phosphorylation. Cellular contents of the hepatic p85 subunit of PI3–kinase were comparable between HCV–infected and non–HCV–infected subjects. In conclusion, we found that (1) HCV infection leads to a postreceptor defect in IRS–1 association with the IR and (2) insulin signaling defects in hepatic IRS–1 tyrosine phosphorylation and PI3–kinase association/activation may contribute to insulin resistance, which leads to the development of type 2 diabetes mellitus in patients with HCV infection.