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 insulinstimulated 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. (HEPATOLOGY 2003;38:1384-1392

Insulin resistance and geographical origin: major predictors of liver fibrosis and response to peginterferon and ribavirin in HCV-4

“…24 25 Interestingly, insulin resistance was associated in multivariate analysis with these classical variables, but the strongest independent predictor was the high viral load (serum HCV-RNA >800 000 IU/ml) suggesting a direct role of the virus in the development of insulin resistance (table 3). 26 27 28 29 30 This hypothesis was reinforced by finding a considerable proportion of patients who showed insulin resistance despite the absence of overweight and cirrhosis (nearly 30%), and the significant correlation of HOMA-IR with serum HCV-RNA levels in these patients (fig 1). …”

Insulin resistance is a cause of steatosis and fibrosis progression in chronic hepatitis C

“…14-20 Impaired IRS-1 signalling could be a possible mechanism, as recently shown in non-obese/non-diabetic patients with chronic HCV infection. 36 In a large cohort study, Hui et al showed a genotype specific association between chronic HCV infection and insulin resistance. 21 The significant link between genotype 1 related steatosis and insulin resistance in our study population tends to support this hypothesis.…”

Insulin resistance and hepatitis C: an evolving story

“…Recent data suggest that HCV core protein reduces IRS-1 and IRS-2 protein levels and inhibits insulin signalling, although differing mechanisms have accounted for this suppression 75 76. It is not completely understood whether altered signalling results from changes in IRS expression, degradation or altered activity 68 75–79.…”

“…Direct effects of HCV in modulating insulin signalling via core protein and NS5A are better understood 75 76 87–89…”