Hepatic steatosis and insulin resistance in hepatitis C infection

Insulin resistance (impaired response to the effect of insulin, a hormone which regulates the body's metabolism of fat and glucose) is associated with a worse outcome and increased risk of death in patients with hepatitis C virus (HCV) infection. The presence of insulin resistance is known to reduce the response to anti-viral treatment in this group of patients.

Due to the lack of understanding of the mechanism of interaction between insulin resistance and HCV infection, we are currently unable to improve treatment response rate in these patients.

The aims of this study are:
1. To develop laboratory-based methods to quantify insulin resistance
2. To study the effect(s) of HCV infection on insulin resistance
3. To determine the effect of drugs modulating insulin resistance on response to anti-viral treatment

Studies in patients and liver cell cultures will be used to determine the precise mechanisms by which HCV causes insulin resistance.

This study will improve our understanding of the effects of HCV infection on insulin resistance which hopefully will ultimately lead to an improvement in the outcome of patients with HCV infection. Furthermore metabolic modifying therapy could represent a major advance in the treatment of patients with HCV infection in the future.

Hepatitis C virus (HCV) is a RNA(ribonucleic acid) virus with diverse genotypes and a broad spectrum of clinical outcomes including hepatic steatosis. Metabolic syndrome is an increasing cause of morbidity and mortality in HCV infection. Several clinical trials have shown that hepatic steatosis impairs anti-viral therapy, suggesting insulin resistance (IR) as an underlying mechanism. Mechanisms of IR in HCV infection are poorly understood due to the use of metabolically inefficient tumour cell lines in the majority of studies. Some studies including our preliminary results, suggest that IR may impair anti-viral therapy in HCV infection and that liver specific glucocorticoid receptor (GC-R) antagonists, glucagon-like peptide (GLP-1) agonists and lipid modifying drugs may improve anti-viral response in HCV infection.

Hypothesis
1.There are genotype and strain specific differences in the ability of HCV to drive IR and lipid accumulation in vitro and in vivo 2.Enhanced GC-R activation contributes to the development of HCV-associated steatosis and represent a novel therapeutic target 3.GLP-1 agonists improve IR and augments response to anti-viral treatment

Objectives (refer to "Objectives")

Methodology
To profile the metabolic pathways that are dysregulated following HCV infection of hepatoma cell lines, primary human hepatocytes and human liver slices that promote lipid accumulation. We will investigate 24 patients with HCV infection with evidence of hepatic steatosis for their pattern(s) of insulin sensitivity in liver, adipose & peripheral muscle. We will quantify hepatic lipogenesis using magnetic resonance spectroscopy, hyperinsulinaemic euglycaemic clamp, adipose microdialysis and biopsy.

Conclusion
In view of the suboptimal response to the current anti-viral treatments, it is imperative that research addresses the molecular mechanisms underlying virus perturbation of lipid metabolism to enable future design of tailored combination therapies.

This study will provide an indepth understanding of the mechanisms of hepatic steatosis and insulin resistance in Hepatits C (HCV) infection. This study will identify the metabolic pathways that are regulated/dys-regulated by HCV which will aid future research into developing potential targets for the treatment of HCV.

HCV is postulated to influence lipid metabolism via the activation of glucocorticoid receptor (GC-R) leading to hepatic steatosis and insulin resistance (also known as metabolic syndrome). Metabolic syndrome is thought to have a major impact on the severity and treatment of HCV infection. If our hypothesis is proven that blockade of the GC-R and activation of glucagon-like peptide (GLP-1) receptor will ameliorate hepatic steatosis, this may have significant future impact on the clinical treatment of

Hepatitis C and may lead to the following patient benefits:
1. Overall improved sustained virological response (SVR) following anti-viral therapy.
2. Improved treatment response in HCV genotype 1 patients (subtype most associated with metabolic syndrome)

In the short term, this would lead be improved quality of life with reduced morbidity and, in the long term, may lead to improved survival.

This study may also lead to the following implications for the further development of clinical practice:
1. Metabolic modifiers for patients undergoing HCV treatment could become standard clinical practice.
2. Initial assessment of insulin resistance could help identify patients at increased risk of having an adverse outcome.

The following potential impact on local policy-making and improvement on NHS service delivery may also apply:
1. Improvements in quality of life and outcome would lead to better delivery of service.
2. Improved SVR in Hepatitis C patients would result in potential cost savings and overall value for money for the service delivered to patients.
3. Improved SVR may also lead to longer survival.