Hepatitis C Virus Directly Associates With Insulin Resistance Independent of the Visceral Fat Area in Nonobese and Nondiabetic Patients

M. Yoneda; S. Saito; T. Ikeda; K. Fujita; H. Mawatari; H. Kirikoshi; M. Inamori; Y. Nozaki; T. Akiyama; H. Takahashi; Y. Abe; K. Kubota; T. Iwasaki; Y. Terauchi; S. Togo; A. Nakajima

Disclosures

J Viral Hepat. 2007;14(9):600-607. 

In This Article

Summary and Introduction

Summary

Insulin resistance (IR) is known to be associated with the visceral adipose tissue area. Elucidation of the relationship between hepatitis C virus (HCV) and IR is of great clinical relevance, because IR promotes liver fibrosis. In this study, we tested the hypothesis that HCV infection by itself may promote IR. We prospectively evaluated 47 patients with chronic HCV infection who underwent liver biopsy. Patients with obesity, type 2 diabetes mellitus (DM), or a history of alcohol consumption were excluded. IR was estimated by calculation of the modified homeostasis model of insulin resistance (HOMA-IR) index. Abdominal fat distribution was determined by computed tomography. Fasting blood glucose levels were within normal range in all the patients. The results of univariate analysis revealed a significant correlation between the quantity of HCV-RNA and the HOMA-IR (r = 0.368, P = 0.0291). While a significant correlation between the visceral adipose tissue area and the HOMA-IR was also observed in the 97 control, nondiabetic, non-HCV-infected patients (r = 0.398, P < 0.0001), no such significant correlation between the visceral adipose tissue area and the HOMA-IR (r = 0.124, P = 0.496) was observed in the patients with HCV infection. Multiple regression analysis with adjustment for age, gender and visceral adipose tissue area revealed a significant correlation between the HCV-RNA and the HOMA-IR (P = 0.0446). HCV is directly associated with IR in a dose-dependent manner, independent of the visceral adipose tissue area. This is the first report to demonstrate the direct involvement of HCV and IR in patients with chronic HCV infection.

Introduction

Currently, approximately 200 million people around the world are chronically infected with the hepatitis C virus (HCV). Chronic HCV infection often leads to hepatic cirrhosis and hepatocellular carcinoma, thus posing a worldwide problem, both from the medical and the socioeconomical aspect.[1,2] Recent epidemiological studies have suggested that HCV infection is associated with an increased risk of development of type 2 diabetes mellitus (DM), and that type 2 DM is more prevalent among patients with chronic HCV infection than in patients with other liver diseases and in the general population, irrespective of whether or not hepatic cirrhosis is present.[3,4,5,6]

Insulin resistance (IR) plays a primary role in the development of type 2 DM. This is supported by the results of prospective longitudinal studies showing that IR is the best predictor of the development of type 2 DM, preceding its onset by 10-20 years,[7,8,9,10] and the results of cross-sectional studies showing that IR is a consistent finding in patients with type 2 DM.[1,2,11] Recently, visceral adipose tissue has drawn attention as a source of several bioactive substances, known as adipocytokines, such as adiponectin, leptin, plasminogen activator inhibitor-1 and tumour necrosis factor-α, all of which are thought to contribute to IR. It is also well known that IR is strongly associated with the visceral adipose tissue area, and furthermore, that it is a common feature in patients with obesity, type 2 DM and fatty liver.[12] In view of the strong association between HCV infection and the risk of development of DM, it is important to determine whether HCV infection can predispose to the development of IR even before overt diabetes sets in. The effect of HCV infection on IR depends on the viral genotype; patients infected with the genotype 3 virus have a lower prevalence of IR when compared with those infected with the other viral genotypes, even after adjustment for the effects of body mass index (BMI) and other confounders.[13,14] On the other hand, despite the lower prevalence of IR, subjects with HCV genotype 3 infection have more extensive hepatic steatosis.[15,16,17] Animal studies using transgenic mice carrying the core gene of HCV have suggested that HCV-encoded proteins might alter insulin signalling, thereby causing impaired insulin sensitivity and glycaemia dysregulation.[18] However, the pathogenesis of HCV-associated IR in humans remains to be clearly elucidated. None of the epidemiological studies conducted until now have analysed the relationship between HCV infection and the risk of IR independent of the influence of obesity, type 2 diabetes mellitus or alcohol consumption; therefore, the precise relationship between HCV and IR remains unclear in patients with HCV.

In this study, we tested the hypothesis that in Japanese nondiabetic, nonobese patients without a history of alcohol consumption having chronic HCV infection not caused by HCV genotype 3, the HCV infection by itself may promote IR independent of the visceral adipose tissue area, by determining the degree of IR in the subjects based on the fasting blood glucose and plasma insulin levels, and the homeostasis model assessment of IR (HOMA-IR) index.

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