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      Clearance of HCV by Combination Therapy of Pegylated Interferon α-2a and Ribavirin Improves Insulin Resistance

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          Abstract

          Background/Aims

          Chronic hepatitis C virus (HCV) infection is associated with a higher risk of the development of insulin resistance. If HCV is a causal factor for insulin resistance, then clearance of HCV might decrease insulin resistance. The aim of this study was to elucidate the effects of clearance of HCV on insulin resistance.

          Methods

          We analyzed 28 patients with HCV infection who received combination treatment of 180 µg of pegylated interferon α-2a and ribavirin at our institution from May 2004 to November 2006. Insulin resistance was calculated according to the homeostasis model assessment of insulin resistance (HOMA-IR) method.

          Results

          Twenty-two patients (78.6%) achieved sustained virologic response (SVR), where the fasting plasma glucose level significantly decreased after antiviral treatment. Fasting serum insulin and HOMA-IR also significantly decreased after antiviral treatment, whereas the BMI value was not significantly affected. For the nonresponders (n=6), no significant changes were evident in BMI, fasting plasma glucose, fasting serum insulin, and HOMA-IR at 6 months after the end of antiviral treatment. Logistic regression analysis indicated that the only independent factor contributing to the reduction of insulin resistance was the complete disappearance of HCV RNA at 6 months after the end of antiviral treatment (SVR).

          Conclusions

          The clearance of HCV by the combination therapy of pegylated interferon α-2a and ribavirin improves insulin resistance by reducing fasting serum insulin and glucose levels.

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          Most cited references24

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          Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma.

          An association between diabetes and chronic liver disease has been reported. However, the temporal relationship between these conditions remains unknown. We identified all patients with a hospital discharge diagnosis of diabetes between 1985 and 1990 using the computerized records of the Department of Veterans Affairs. We randomly assigned 3 patients without diabetes for every patient with diabetes. We excluded patients with concomitant liver disease. The remaining cohort was followed through 2000 for the occurrence of chronic nonalcoholic liver disease (CNLD) and hepatocellular carcinoma (HCC). Hazard rate ratios (HRR) were determined in Cox proportional hazard survival analysis. The study cohort comprised 173,643 patients with diabetes and 650,620 patients without diabetes. Most were men (98%). Patients with diabetes were older (62 vs. 54 years) than patients without diabetes. The incidence of chronic nonalcoholic liver disease was significantly higher among patients with diabetes (incidence rate: 18.13 vs. 9.55 per 10,000 person-years, respectively, P < 0.0001). Similar results were obtained for HCC (incidence rate: 2.39 vs. 0.87 per 10,000 person-years, respectively, P < 0.0001). Diabetes was associated with an HRR of 1.98 (95% CI: 1.88 to 2.09, P < 0.0001) of CNLD and an HRR of 2.16 (1.86 to 2.52, P < 0.0001) of hepatocellular carcinoma. Diabetes carried the highest risk among patients with longer than 10 years of follow-up. Among men with diabetes, the risk of CNLD and HCC is doubled. This increase in risk is independent of alcoholic liver disease, viral hepatitis, or demographic features.
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            Classification of hepatitis C virus into six major genotypes and a series of subtypes by phylogenetic analysis of the NS-5 region.

            Hepatitis C virus (HCV) showed substantial nucleotide sequence diversity distributed throughout the viral genome, with many variants showing only 68 to 79% overall sequence similarity to one another. Phylogenetic analysis of nucleotide sequences derived from part of the gene encoding a non-structural protein (NS-5) has provided evidence for six major genotypes of HCV amongst a worldwide collection of 76 samples from HCV-infected blood donors and patients with chronic hepatitis. Many of these HCV types comprised a number of more closely related subtypes, leading to a current total of 11 genetically distinct viral populations. Phylogenetic analysis of other regions of the viral genome produced relationships between published sequences equivalent to those found in NS-5, apart from the more highly conserved 5' non-coding region in which only the six major HCV types, but not subtypes, could be differentiated. A new nomenclature for HCV variants is proposed in this communication that reflects the two-tiered nature of sequence differences between different viral isolates. The scheme classifies all known HCV variants to date, and describes criteria that would enable new variants to be assigned within the classification as they are discovered.
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              Hepatitis C virus down-regulates insulin receptor substrates 1 and 2 through up-regulation of suppressor of cytokine signaling 3.

              The pathogenesis of hepatitis C virus (HCV)-associated insulin resistance remains unclear. Therefore, we investigated mechanisms for HCV-associated insulin resistance. Homeostasis model assessment for insulin resistance was increased in patients with HCV infection. An increase in fasting insulin levels was associated with the presence of serum HCV core, the severity of hepatic fibrosis and a decrease in expression of insulin receptor substrate (IRS) 1 and IRS2, central molecules of the insulin-signaling cascade, in patients with HCV infection. Down-regulation of IRS1 and IRS2 was also seen in HCV core-transgenic mice livers and HCV core-transfected human hepatoma cells. Carbobenzoxy-l-leucyl-l-leucyl-l-leucinal, a potent proteosomal proteolysis inhibitor, blocked down-regulation of IRS1 and IRS2 in HCV core-transfected hepatoma cells. In human hepatoma cells, HCV core up-regulated suppressor of cytokine signaling (SOCS) 3 and caused ubiquitination of IRS1 and IRS2. HCV core-induced down-regulation of IRS1 and IRS2 was not seen in SOCS3(-/-) mouse embryonic fibroblast cells. Furthermore, HCV core suppressed insulin-induced phosphorylation of p85 subunit of phosphatidylinositol 3-kinase and Akt, activation of 6-phosphofructo-2-kinase, and glucose uptake. In conclusion, HCV infection changes a subset of hepatic molecules regulating glucose metabolism. A possible mechanism is that HCV core-induced SOCS3 promotes proteosomal degradation of IRS1 and IRS2 through ubiquitination.
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                Author and article information

                Journal
                Gut Liver
                GNL
                Gut and Liver
                The Korean Society of Gastroenterology; the Korean Society of Gastrointestinal Endoscopy; the Korean Association for the Study of the Liver; the Korean Society of Neurogastroenterology and Motility; Korean Association for the Study of Intestinal Diseases; Korean College of Helicobacter and Upper Gastrointestinal Research; Korean Society of Pancreatobiliary Diseases
                1976-2283
                2005-1212
                June 2009
                30 June 2009
                : 3
                : 2
                : 108-115
                Affiliations
                Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea.
                Author notes
                Correspondence to: Hong Joo Kim. Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, 108, Pyeong-dong, Jongno-gu, Seoul 110-746, Korea. Tel: +82-2-2001-2060, Fax: +82-2-2001-2049, hongjoo3.kim@ 123456samsung.com
                Article
                10.5009/gnl.2009.3.2.108
                2852696
                20431732
                c59c4167-4503-449b-8ac6-e86490ca019d
                Copyright © 2009 The Korean Society of Gastroenterology; the Korean Society of Gastrointestinal Endoscopy; the Korean Association for the Study of the Liver; the Korean Society of Neurogastroenterology and Motility; Korean Association for the Study of Intestinal Diseases; Korean College of Helicobacter and Upper Gastrointestinal Research; Korean Society of Pancreatobiliary Diseases
                History
                : 16 July 2008
                : 11 April 2009
                Categories
                Original Article

                Gastroenterology & Hepatology
                insulin resistance,homeostasis model assessment,chronic hepatitis c,pegylated interferon,antiviral treatment

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