Metformin treatment is better than a prescriptive diet or vitamin E in the therapy of NAFLD patients receiving nutritional counseling. Limited histological data support an association between improved aminotransferases and biopsy findings, which require confirmation in a double-blind trial with appropriate statistical power based on liver histology.

Plasma levels of adiponectin are decreased in patients with nonalcoholic fatty liver disease (NAFLD), but the relationship among plasma adiponectin, insulin sensitivity, and histological features is unclear. In 174 NAFLD patients and 42 controls, we examined plasma adiponectin concentrations in relation to 1) lipid profile, indices of insulin resistance, and features of the metabolic syndrome (n = 174); 2) hepatic insulin resistance (clamp technique with tracer infusion) (10 patients); and 3) histological features at liver biopsy (n = 116). When the data from all subjects were combined, plasma adiponectin levels were positively associated with increased age, female gender, and plasma high-density lipoprotein levels, and negatively associated with waist circumference, body mass index, triglycerides, indices of insulin resistance, and aminotransferase levels, and also predicted the presence of the metabolic syndrome. In step-wise regression, increased age, female gender, waist circumference, triglyceride levels, and homeostasis model assessment independently associated with adiponectin (adjusted R(2), 0.329). In NAFLD, adiponectin was only associated with increased age, female gender, and triglycerides (adjusted R(2), 0.245). When the measured histological parameters were included in the model, plasma adiponectin levels were also inversely proportional to the percentage of hepatic fat content (adjusted R(2), 0.221), whereas necroinflammation and fibrosis did not fit in the model. Adiponectin was negatively correlated with insulin-suppressed endogenous glucose production during the clamp (P = 0.011). The results demonstrate that decreased levels of circulating adiponectin in NAFLD are related to hepatic insulin sensitivity and to the amount of hepatic fat content. Hypoadiponectinemia in NAFLD is part of a metabolic disturbance characterized by ectopic fat accumulation in the central compartment.

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Chronic hepatitis C (CHC) has been associated with type 2 diabetes and insulin resistance, but the extent of impairment in insulin action, the target pathways involved, and the role of the virus per se have not been defined. In this study, we performed a euglycemic hyperinsulinemic clamp (1 mU ⅐ minute ؊1 ⅐ kg ؊1 ) coupled with infusion of tracers ([6,6-2 H 2 ]glucose, [ 2 H 5 ]glycerol) and indirect calorimetry in 14 patients with biopsy-proven CHC, who were selected not to have any features of the metabolic syndrome, and in seven healthy controls. We also measured liver expression of inflammatory cytokines/mediators and tested their association with the metabolic parameters. Compared to controls, in patients with CHC: (1) total glucose disposal (TGD) during the clamp was 25% lower (P ‫؍‬ 0.003) due to impaired glucose oxidation (P ‫؍‬ 0.0002), (2) basal endogenous glucose production (EGP) was 20% higher (P ‫؍‬ 0.011) and its suppression during the clamp was markedly reduced (P ‫؍‬ 0.007), and (3) glycerol appearance was not different in the basal state or during the clamp, but lipid oxidation was less suppressed by insulin (P ‫؍‬ 0.004). Lipid oxidation was higher in patients with CHC who had more steatosis and was directly related to EGP, TGD, and glucose oxidation. The decreased insulin-stimulated suppression of EGP was associated with increased hepatic suppressor of cytokine signaling 3 (SOCS3; P < 0.05) and interleukin-18 (P < 0.05) expression. T ype 2 diabetes (T2DM) is a frequent complication of hepatitis C virus (HCV) infection, second in prevalence only to cryoglobulinemia. The first report by Allison et al. 1 of an increased prevalence of T2DM in HCV-positive subjects with cirrhosis has been repeatedly confirmed also at earlier stages of liver disease. 2,3 In a large survey study, 3 HCV-positive subjects older than 40 years were three times more likely than HCV-negative controls to have diabetes. In a longitudinal study, the risk of developing diabetes was up to 12 times higher in patients who were HCV-positive than in the general population. 4 HCV is associated with insulin resistance (IR) also in nondiabetic patients. In a prospective study including 600 consecutive patients with chronic hepatitis C (CHC), 5 IR assessed using the Homeostasis Model Assessment of IR (HOMA-IR) was found in 32% of patients without diabetes and was associated with both the metabolic syndrome (MS) and with high serum HCV RNA levels, suggesting a possible interaction of viral replication with insulin action. The improvement of IR in

Hepatic steatosis has been associated with fibrosis, but it is unknown whether the latter is independent of the etiology of fat infiltration. We analyzed the relationship between clinical characteristics, insulin resistance (HOMA-R) and histological parameters in 132 patients with "viral" steatosis caused by genotype 3 chronic hepatitis C (CHC-3) and 132 patients with "metabolic" steatosis caused by nonalcoholic fatty liver disease (NAFLD), matched by age, BMI, and degree of liver fat accumulation. Tests of liver function were comparable in the two study populations. The prevalence of features of insulin resistance was higher in NAFLD, as was HOMA-R (P ‫؍‬ .008). Logistic regression analysis confirmed that steatosis was associated with a high viral load and low serum cholesterol in CHC-3, and with high aminotransferase, glucose, ferritin and hypertriglyceridemia in NAFLD. At univariate analysis, advanced fibrosis was associated with steatosis in NAFLD, but not in CHC-3. Other parameters related to fibrosis severity were HOMA-R and a low platelet count in CHC-3, and high aminotransferases, HOMA-R, ferritin and low HDLcholesterol in NAFLD. On multivariate analysis, only low platelet count (OR ‫؍‬ 0.78; 95% CI, 0.67-0.92) and HOMA-R (OR ‫؍‬ 2.98; 1.13-7.89) were independent predictors of advanced fibrosis in CHC-3. In NAFLD, severe fibrosis was predicted by fat grading (OR ‫؍‬ 3.03; 1.41-6.53), ferritin (OR ‫؍‬ 1.13; 1.03-1.25) and HOMA-R (OR ‫؍‬ 1.16; 1.02-1.31). In conclusion, insulin resistance is an independent predictor of advanced fibrosis in both NAFLD and CHC-3, but the extent of steatosis contributes to advanced disease only in NAFLD. Virus-induced hepatic steatosis as seen in CHC-3 does not contribute significantly to liver fibrosis. (HEPATOLOGY 2006;44:1648-1655

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S133 minimal reduction of HCV RNA synthesis, suggesting that inhibition of replication is not due to a direct suppression of replicase activity. Conclusions: The intracellular expression of antibodies that target HCV proteins and inhibit important viral functions may represent a promising new direction for therapy of HCV infection.