Hepatitis C Virus Infection Is Associated With Hepatic and Adipose Tissue Insulin Resistance That Improves After Viral Cure

Teegan R. Lim; Jonathan M. Hazlehurst; Andrei I. Oprescu; Matthew J. Armstrong; Sewa F. Abdullah; Nigel P. Davies; Robert Flintham; Peter Balfe; David J. Mutimer; Jane A. McKeating; Jeremy W. Tomlinson

Disclosures

Clin Endocrinol. 2019;90(3):440-448. 

In This Article

Abstract and Introduction

Summary

Background: Chronic hepatitis C (CHC) is associated with systemic insulin resistance, yet there are limited data on the tissue-specific contribution in vivo to this adverse metabolic phenotype, and the effect of HCV cure.

Methods: We examined tissue-specific insulin sensitivity in a cohort study involving 13 patients with CHC compared to 12 BMI-matched healthy control subjects. All subjects underwent a two-step clamp incorporating the use of stable isotopes to measure carbohydrate and lipid flux (hepatic and global insulin sensitivity) with concomitant subcutaneous adipose tissue microdialysis and biopsy (subcutaneous adipose tissue insulin sensitivity). Investigations were repeated in seven patients with CHC following antiviral therapy with a documented sustained virological response.

Results: Adipose tissue was more insulin resistant in patients with CHC compared to healthy controls, as evidence by elevated glycerol production rate and impaired insulin-mediated suppression of both circulating nonesterified fatty acids (NEFA) and adipose interstitial fluid glycerol release during the hyperinsulinaemic euglycaemic clamp. Hepatic and muscle insulin sensitivity were similar between patients with CHC and controls. Following viral eradication, hepatic insulin sensitivity improved as demonstrated by a reduction in endogenous glucose production rate. In addition, circulating NEFA decreased with sustained virological response (SVR) and insulin was more effective at suppressing adipose tissue interstitial glycerol release with a parallel increase in the expression of insulin signalling cascade genes in adipose tissue consistent with enhanced adipose tissue insulin sensitivity.

Conclusion: Chronic hepatitis C patients have profound subcutaneous adipose tissue insulin resistance in comparison with BMI-matched controls. For the first time, we have demonstrated that viral eradication improves global, hepatic and adipose tissue insulin sensitivity.

Introduction

Hepatitis C virus (HCV) infection is a global health problem affecting 170 million people that leads to progressive liver disease including cirrhosis and hepatocellular carcinoma (HCC). Chronic hepatitis C (CHC) is also associated with metabolic syndrome.[1,2] Type 2 diabetes mellitus (T2DM) is more prevalent in patients with CHC-associated cirrhosis compared to other causes of cirrhosis.[3] Metabolic syndrome in CHC is associated with an increased risk of progressive liver diseases[4] and population-based studies link T2DM to fibrosis and highlight its role as a risk factor for developing HCC.[5]

Hepatitis C virus replicates within hepatocytes in the liver and yet the sites of insulin resistance in patients with CHC remain elusive, with some studies reporting the liver as the primary site[6,7] and others suggest extra-hepatic sites, namely adipose tissue and skeletal muscle.[8] Most of the current evidence studying insulin resistance in CHC is based on homoeostatic model assessment of insulin resistance (HOMA-IR) which cannot distinguish sites of IR.[9] Hepatic steatosis and insulin resistance can limit treatment response to interferon-based therapies.[10,11,12] Directly acting antiviral agents (DAAs) have recently become the standard of care with high rates of cure >90%.[13,14,15] Curing HCV infection with DAA or interferon-based therapies improves the metabolic profile;[16,17,18] however, none of these studies investigated the tissue-specific effects of HCV infection on IR.

Based upon the premise that CHC is a multisystem disease with a significant metabolic burden, we investigated the tissue-specific contributions to the adverse metabolic phenotype in CHC using state-of-the-art metabolic phenotyping techniques. Secondly, we assessed the impact of curative treatments on liver function and the adverse metabolic features associated with CHC. Our underpinning hypothesis is that adipose tissue insulin resistance is the cardinal feature of the metabolic abnormalities associated with chronic hepatitis C and this improves with viral eradication.

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