Gastroenterology
Volume 138, Issue 3 , Pages 932-941.e3 , March 2010

Chronic Hepatitis C Is Associated With Peripheral Rather Than Hepatic Insulin Resistance

  • Kerry–Lee Milner

      Affiliations

    • Garvan Institute for Medical Research, University of New South Wales, Sydney, Australia
    • ,
  • David van der Poorten

      Affiliations

    • Storr Liver Unit, Westmead Millenium Institute, University of Sydney, Sydney, Australia
    • ,
  • Michael Trenell

      Affiliations

    • Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom
    • ,
  • Arthur B. Jenkins

      Affiliations

    • School of Health Sciences, University of Wollongong, Wollongong, Australia
    • ,
  • Aimin Xu

      Affiliations

    • Department of Medicine and Pharmacology and Research Center of Heart, Brain, Hormone and Healthy Ageing, University of Hong Kong, Hong Kong, China
    • ,
  • George Smythe

      Affiliations

    • Bioanalytical Mass Spectrometry Facility, University of New South Wales, Sydney, Australia
    • ,
  • Gregory J. Dore

      Affiliations

    • National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Sydney, Australia
    • ,
  • Amany Zekry

      Affiliations

    • St George Hospital Clinical School, University of New South Wales, Sydney, Australia
    • ,
  • Martin Weltman

      Affiliations

    • Department of Gastroenterology and Hepatology, Nepean Hospital and University of Sydney, Western Clinical School, Sydney, Australia
    • ,
  • Vincent Fragomeli

      Affiliations

    • Department of Gastroenterology and Hepatology, Nepean Hospital and University of Sydney, Western Clinical School, Sydney, Australia
    • ,
  • Jacob George

      Affiliations

    • Storr Liver Unit, Westmead Millenium Institute, University of Sydney, Sydney, Australia
    • ,
  • Donald J. Chisholm

      Affiliations

    • Garvan Institute for Medical Research, University of New South Wales, Sydney, Australia
    • Corresponding Author InformationReprint requests Address requests for reprints to: Donald Chisholm, MBBS, FRACP, Diabetes and Obesity Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, NSW 2010, Australia. fax: (61) 2 9295 8201

Received 4 May 2009 ,Accepted 20 November 2009.

References 

  1. Mehta SH, Brancati FL, Sulkowski MS, et al. Prevalence of type 2 diabetes mellitus among persons with hepatitis C virus infection in the United States. Ann Intern Med. 2000;133:592–599
  2. Hui JM, Sud A, Farrell GC, et al. Insulin resistance is associated with chronic hepatitis C virus infection and fibrosis progression. Gastroenterology. 2003;125:1695–1704
  3. Poustchi H, Negro F, Hui J, et al. Insulin resistance and response to therapy in patients infected with chronic hepatitis C virus genotypes 2 and 3. J Hepatol. 2008;48:28–34
  4. Yazicioglu G, Isitan F, Altunbas H, et al. Insulin resistance in chronic hepatitis C. Int J Clin Pract. 2004;58:1020–1022
  5. Vanni E, Abate ML, Gentilcore E, et al. Sites and mechanisms of insulin resistance in nonobese, nondiabetic patients with chronic hepatitis C. Hepatology. 2009;50:697–706
  6. Bonora E, Targher G, Alberiche M, et al. Homeostasis model assessment closely mirrors the glucose clamp technique in the assessment of insulin sensitivity: studies in subjects with various degrees of glucose tolerance and insulin sensitivity. Diabetes Care. 2000;23:57–63
  7. Nelson DR, Lim HL, Marousis CG, et al. Activation of tumor necrosis factor-alpha system in chronic hepatitis C virus infection. Dig Dis Sci. 1997;42:2487–2494
  8. Shintani Y, Fujie H, Miyoshi H, et al. Hepatitis C virus infection and diabetes: direct involvement of the virus in the development of insulin resistance. Gastroenterology. 2004;126:840–848
  9. Cua IH, Hui JM, Bandara P, et al. Insulin resistance and liver injury in hepatitis C is not associated with virus-specific changes in adipocytokines. Hepatology. 2007;46:66–73
  10. Negro F. Insulin resistance and HCV: will new knowledge modify clinical management?. J Hepatol. 2006;45:514–519
  11. Hui JM, Kench J, Farrell GC, et al. Genotype-specific mechanisms for hepatic steatosis in chronic hepatitis C infection. J Gastroenterol Hepatol. 2002;17:873–881
  12. Cheng Y, Dharancy S, Malapel M, et al. Hepatitis C virus infection down-regulates the expression of peroxisome proliferator-activated receptor alpha and carnitine palmitoyl acyl-CoA transferase 1A. World J Gastroenterol. 2005;11:7591–7596
  13. Su AI, Pezacki JP, Wodicka L, et al. Genomic analysis of the host response to hepatitis C virus infection. Proc Natl Acad Sci U S A. 2002;99:15669–15674
  14. Yki-Jarvinen H. Fat in the liver and insulin resistance. Ann Med. 2005;37:347–356
  15. Lara-Castro C, Garvey WT. Intracellular lipid accumulation in liver and muscle and the insulin resistance syndrome. Endocrinol Metab Clin North Am. 2008;37:841–856
  16. Sud A, Hui JM, Farrell GC, et al. Improved prediction of fibrosis in chronic hepatitis C using measures of insulin resistance in a probability index. Hepatology. 2004;39:1239–1247
  17. Forns X, Ampurdanes S, Llovet JM, et al. Identification of chronic hepatitis C patients without hepatic fibrosis by a simple predictive model. Hepatology. 2002;36:986–992
  18. Kannel WB, Sorlie P. Some health benefits of physical activity (The Framingham Study). Arch Intern Med. 1979;139:857–861
  19. Australian Bureau of Statistics. 1995 National Nutrition Survey: User's Guide (4801.0). In: 3) FFQa, ed.
  20. Scheuer PJ. Classification of chronic viral hepatitis: a need for reassessment. J Hepatol. 1991;13:372–374
  21. Szczepaniak LS, Nurenberg P, Leonard D, et al. Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population. Am J Physiol Endocrinol Metab. 2005;288:E462–E468
  22. Szczepaniak LS, Babcock EE, Schick F, et al. Measurement of intracellular triglyceride stores by H spectroscopy: validation in vivo. Am J Physiol. 1999;276:E977–E989
  23. Positano V, Gastaldelli A, Sironi AM, et al. An accurate and robust method for unsupervised assessment of abdominal fat by MRI. J Magn Reson Imaging. 2004;20:684–689
  24. Maggs DG, Buchanan TA, Burant CF, et al. Metabolic effects of troglitazone monotherapy in type 2 diabetes mellitus (A randomized, double-blind, placebo-controlled trial). Ann Intern Med. 1998;128:176–185
  25. Moghetti P, Tosi F, Castello R, et al. The insulin resistance in women with hyperandrogenism is partially reversed by antiandrogen treatment: evidence that androgens impair insulin action in women. J Clin Endocrinol Metab. 1996;81:952–960
  26. Wolfe RR. Radioactive and stable isotope tracers in biomedicine: principles and practice of kinetic analysis. New York, NY: Wiley-Liss; 1992;
  27. Lusk G, Du Bois EF. On the constancy of the basal metabolism. J Physiol. 1924;59:213–216
  28. Finegood DT, Bergman RN. Optimal segments: a method for smoothing tracer data to calculate metabolic fluxes. Am J Physiol. 1983;244:E472–E479
  29. Steele R, Wall JS, De Bodo RC, et al. Measurement of size and turnover rate of body glucose pool by the isotope dilution method. Am J Physiol. 1956;187:15–24
  30. Finegood DT, Bergman RN, Vranic M. Estimation of endogenous glucose production during hyperinsulinemic-euglycemic glucose clamps (Comparison of unlabeled and labeled exogenous glucose infusates). Diabetes. 1987;36:914–924
  31. Hofer H, Bankl HC, Wrba F, et al. Hepatocellular fat accumulation and low serum cholesterol in patients infected with HCV-3a. Am J Gastroenterol. 2002;97:2880–2885
  32. Hume R. Prediction of lean body mass from height and weight. J Clin Pathol. 1966;19:389–391
  33. Aytug S, Reich D, Sapiro LE, et al. Impaired IRS-1/PI3-kinase signaling in patients with HCV: a mechanism for increased prevalence of type 2 diabetes. Hepatology. 2003;38:1384–1392
  34. Kotronen A, Juurinen L, Tiikkainen M, et al. Increased liver fat, impaired insulin clearance, and hepatic and adipose tissue insulin resistance in type 2 diabetes. Gastroenterology. 2008;135:122–130
  35. Mirandola S, Realdon S, Iqbal J, et al. Liver microsomal triglyceride transfer protein is involved in hepatitis C liver steatosis. Gastroenterology. 2006;130:1661–1669
  36. Kraegen EW, Cooney GJ. Free fatty acids and skeletal muscle insulin resistance. Curr Opin Lipidol. 2008;19:235–241
  37. Laskus T, Radkowski M, Wang LF, et al. Search for hepatitis C virus extrahepatic replication sites in patients with acquired immunodeficiency syndrome: specific detection of negative-strand viral RNA in various tissues. Hepatology. 1998;28:1398–1401
  38. Kawaguchi T, Ide T, Taniguchi E, et al. Clearance of HCV improves insulin resistance, beta-cell function, and hepatic expression of insulin receptor substrate 1 and 2. Am J Gastroenterol. 2007;102:570–576
  39. Moucari R, Asselah T, Cazals-Hatem D, et al. Insulin resistance in chronic hepatitis C: association with genotypes 1 and 4, serum HCV RNA level, and liver fibrosis. Gastroenterology. 2008;134:416–423
  40. Gan SK, Kriketos AD, Poynten AM, et al. Insulin action, regional fat, and myocyte lipid: altered relationships with increased adiposity. Obes Res. 2003;11:1295–1305
  41. Pittas AG, Joseph NA, Greenberg AS. Adipocytokines and insulin resistance. J Clin Endocrinol Metab. 2004;89:447–452
  42. Whitehead JP, Richards AA, Hickman IJ, et al. Adiponectin—a key adipokine in the metabolic syndrome. Diabetes Obes Metab. 2006;8:264–280
  43. Uysal KT, Wiesbrock SM, Marino MW, et al. Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function. Nature. 1997;389:610–614
  44. Hotamisligil GS. The role of TNFalpha and TNF receptors in obesity and insulin resistance. J Intern Med. 1999;245:621–625
  45. Hoo RL, Yeung DC, Lam KS, et al. Inflammatory biomarkers associated with obesity and insulin resistance: a focus on Lipocalin-2 and adipocyte fatty acid-binding protein. Expert Rev Endocrinol Metab. 2008;3:29–41
  46. Fisher RM, Thorne A, Hamsten A, et al. Fatty acid binding protein expression in different human adipose tissue depots in relation to rates of lipolysis and insulin concentration in obese individuals. Mol Cell Biochem. 2002;239:95–100
  47. Furuhashi M, Hotamisligil GS. Fatty acid-binding proteins: role in metabolic diseases and potential as drug targets. Nat Rev Drug Discov. 2008;7:489–503
  48. Milner KL, van der Poorten D, Xu A, et al. Adipocyte fatty acid binding protein levels relate to inflammation and fibrosis in nonalcoholic fatty liver disease. Hepatology. 2009;49:1926–1934
  49. Ferrannini E, Muscelli E, Natali A, et al. Association of fasting glucagon and proinsulin concentrations with insulin resistance. Diabetologia. 2007;50:2342–2347

 View this article's video abstract at www.gastrojournal.org.

 Conflicts of interest The authors disclose no conflicts.

 Funding Supported by grants from the National Health and Medical Research Council of Australia (Grant 358398), GESA postgraduate medical research scholarship, Robert W. Storr Bequest to the University of Sydney, a University of Sydney Grant and Hong Kong Research Council CRF (HKU 2/07C to A.X.). K.M. is supported by a National Health and Medical Research Council Postgraduate scholarship. M.T. is supported by a Diabetes UK RD Lawrence Fellowship.

PII: S0016-5085(09)02102-7

doi: 10.1053/j.gastro.2009.11.050

Gastroenterology
Volume 138, Issue 3 , Pages 932-941.e3 , March 2010

Article Tools

* Image Usage & Resolution