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Non-alcoholic fatty liver disease (NAFLD) and chronic hepatitis C (CHC), the two most common chronic liver diseases, are associated with liver steatosis, insulin resistance (IR) and type 2 diabetes. These distinct diseases can induce advanced liver fibrosis, end stage liver disease and hepatocellular cancer, which are influenced by increased IR and steatosis. The pathogenic mechanisms contributing to liver disease progression remain elusive and include an interplay between IR, excess fat, lipotoxicity, inflammation and adipokine disturbances which, in NAFLD, occur together with overnutrition and dysregulated energy balance. This thesis, using data from NAFLD and CHC subjects, explores the pathogenesis of IR in CHC and the interaction between IR, fat depots and circulating adipokines in disease progression in NAFLD; this has important implications for arresting long term metabolic and liver complications. CHC infection is associated with IR, demonstrated to be predominantly peripheral (in muscle and fat) and independent of liver steatosis. Despite higher liver steatosis in genotype 3, IR was similar to genotype 1; IR was associated with viral load and subcutaneous (not visceral) fat, suggesting interplay between the virus and peripheral adipocytes. Despite higher TNF-alpha and lipocalin-2 levels in CHC, adipocytokines do not appear to contribute to CHC IR. Antiviral eradication of CHC improves IR independent of changes in fat depots and adipokine levels, supporting a direct role of the virus inducing IR. In NAFLD visceral fat correlates with liver inflammation and fibrosis independent of IR and steatosis, and also with components of the metabolic syndrome. Adipokines, Adipocycte fatty acid-binding protein (AFABP) and Lipocalin-2, produced in adipocytes, macrophages and other tissues are elevated in NAFLD, with AFABP predicting liver inflammation and fibrosis independent of IR, liver steatosis and visceral adiposity. Conclusion: Here we demonstrated that in NAFLD, adi

Chronic hepatitis C (CHC) is associated with lipid-related changes and insulin resistance; the latter predicts response to antiviral therapy, liver disease progression and the risk of diabetes. We sought to determine whether insulin sensitivity improves following CHC viral eradication after antiviral therapy and whether this is accompanied by changes in fat depots or adipokine levels. We compared 8 normoglycaemic men with CHC (genotype 1 or 3) before and at least 6 months post viral eradication and 15 hepatitis C antibody negative controls using an intravenous glucose tolerance test and two-step hyperinsulinaemic–euglycaemic clamp with [6,6-2H2] glucose to assess peripheral and hepatic insulin sensitivity. Magnetic resonance imaging and spectroscopy quantified abdominal fat compartments, liver and intramyocellular lipid. Peripheral insulin sensitivity improved (glucose infusion rate during high-dose insulin increased from 10.1 ± 1.6 to 12 ± 2.1 mg/kg/min/, P = 0.025), with no change in hepatic insulin response following successful viral eradication, without any accompanying change in muscle, liver or abdominal fat depots. There was corresponding improvement in incremental glycaemic response to intravenous glucose (pretreatment: 62.1 ± 8.3 vs post-treatment: 56.1 ± 8.5 mm, P = 0.008). Insulin sensitivity after viral clearance was comparable to matched controls without CHC. Post therapy, liver enzyme levels decreased but, interestingly, levels of glucagon, fatty acid–binding protein and lipocalin-2 remained elevated. Eradication of the hepatitis C virus improves insulin sensitivity without alteration in fat depots, adipokine or glucagon levels, consistent with a direct link of the virus with insulin resistance.