108
Views
26
CrossRef citations to date
0
Altmetric
Review

Hepatitis C virus-associated insulin resistance: pathogenic mechanisms and clinical implications

, &
Pages 525-533 | Published online: 10 Jan 2014

References

  • World Health Organisation. Weekly epidemiological record. Wkly Epidemiol. Rec.77, 41–48 (2002).
  • Saito I, Miyamura T, Ohbayashi A et al. Hepatitis C virus infection is associated with the development of hepatocellular carcinoma. Proc. Natl Acad. Sci. USA87, 6547–6549 (1990).
  • Seeff LB, Buskell-Bales Z, Wright EC et al. Long-term mortality after transfusion-associated non-A, non-B hepatitis. The National Heart, Lung, and Blood Institute Study Group. N. Engl. J. Med.327, 1906–1911 (1992).
  • Poynard T, Bedossa P, Oplon P, for the OBSTIRC, METAVIR, CLINIVIR, and DOSVIRC groups. Nature history of liver fibrous progression in patients with chronic hepatitis C. Lancet349, 825–832 (1997).
  • Hung CH, Chen CH, Lee CM et al. Association of amino acid variations in the NS5A and E2-PePHD region of hepatitis C virus 1b with hepatocellular carcinoma. J. Viral Hepat.15, 58–65 (2008).
  • Lavanchy D, Mcmahon B. Worldwide prevalence and prevention of hepatitis C. In: Hepatitis C. TJ Liang, HJ Hoofnagle (Eds). Academic Press, San Diego, CA, USA, 185–202 (2000).
  • Gumber SC, Chopra S. Hepatitis C: a multifaceted disease. Review of extrahepatic manifestations. Ann. Intern. Med.123(8), 615–620 (1995).
  • Hadziyannis SJ. The spectrum of extrahepatic manifestations in hepatitis C virus infection. J. Viral Hepat.4, 9–28 (1997).
  • Caronia S, Taylor K, Pagliaro L et al. Further evidence for an association between non-insulin dependent diabetes mellitus and chronic hepatits C virus infection. Hepatology30, 1059–1063 (1999).
  • Mehta SH, Brancati FL, Strathdee SA et al. Hepatitis C virus infection and incident Type 2 diabetes. Hepatology38, 50–56 (2003).
  • Huang JF, Dai CY, Hwang SJ et al. Hepatitis C viremia increases the association with Type 2 diabetes mellitus in a hepatitis B and C endemic area: an epidemiological link with virological implication. Am. J. Gastroenterol.102, 1237–1243 (2007).
  • Petit JM, Bour JB, Galland-Jos C et al. Risk factor for diabetes mellitus and early insulin resistance in chronic hepatitis C. J. Hepatol.35, 279–283 (2001).
  • Hui JM, Sud A, Farrell GC et al. Insulin resistance is associated with chronic hepatitis C virus infection and fibrosis progression. Gastroenterology125, 1695–1704 (2003).
  • Narita R, Abe S, Kihara Y, Akiyama T, Tabaru A, Otsuki M. Insulin resistance and insulin secretion in chronic hepatitis C virus infection. J. Hepatol.41, 132–138 (2004).
  • Warram JH, Martin BC, Krolewski AS, Soeldner JS, Kahn CR. Slow glucose removal rate and hyperinsulinemia precede the development of Type II diabetes in the offspring of diabetic parents. Ann. Intern. Med.113, 909–915 (1990).
  • Martin BC, Warram JH, Krolewski AS, Bergman RN, Soeldner JS, Kahn CR. Role of glucose and insulin resistance in development of Type 2 diabetes mellitus: results of a 25-year follow-up study. Lancet340, 925–929 (1992).
  • DeFronzo RA. Lilly lecture 1987: the triumvirate: β-cell, muscle, liver: a collusion responsible for NIDDM. Diabetes37, 667–687 (1988).
  • Cahill GF Jr. B-cell deficiency, insulin resistance, or both? N. Engl. J. Med.318, 1268–1270 (1988).
  • Moriya K, Yotsuyanagi H, Shintani Y et al. Hepatitis C virus core protein induces hepatic steatosis in transgenic mice. J. Gen. Virol.78, 1527–1531 (1997).
  • 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. Gastroenterology126, 840–848 (2004).
  • Milner KL, van der Poorten D, Trenell M et al. Chronic hepatitis C is associated with peripheral rather than hepatic insulin resistance. Gastroenterology138, 932–941 (2010).
  • Douglas MW, George J. Molecular mechanisms of insulin resistance in chronic hepatitis C. World J. Gastroenterol.15, 4356–4364 (2009).
  • Sesti G. Pathophysiology of insulin resistance. Best Pract. Res. Clin. Endocrinol. Metab.20, 665–679 (2006).
  • Leclercq IA, Da Silva Morais A, Schroyen B, Van Hul N, Geerts A. Insulin resistance in hepatocytes and sinusoidal liver cells: mechanisms and consequences. J. Hepatol.47, 142–156 (2007).
  • Tamemoto H, Kadowaki T, Tobe K et al. Insulin resistance and growth retardation in mice lacking insulin receptor substrate-1. Nature372, 182–186 (1994).
  • Withers DJ, Gutierrez JS, Towery H et al. Disruption of IRS-2 causes Type 2 diabetes in mice. Nature391, 900–904 (1998).
  • Yi Z, Langlais P, De Filippis EA et al. Global assessment of regulation of phosphorylation of insulin receptor substrate (IRS)-1 by insulin in vivo in human muscle. Diabetes56, 1508–1516 (2007).
  • Aytug S, Reich D, Sapiro LE, Bernstein D, Begum N. Impaired IRS-1/PI3-kinase signaling in patients with HCV: a mechanism for increased prevalence of Type 2 diabetes. Hepatology38, 1384–1392 (2003).
  • Bernsmeier C, Duong FH, Christen V et al. Virus-induced over-expression of protein phosphatase 2A inhibits insulin signalling in chronic hepatitis C. J. Hepatol.49, 429–440 (2008).
  • Duong FH, Filipowicz M, Tripodi M, La Monica N, Heim MH. Hepatitis C virus inhibits interferon signaling through up-regulation of protein phosphatase 2A. Gastroenterology126, 263–277 (2004).
  • Christen V, Treves S, Duong FH, Heim MH. Activation of endoplasmic reticulum stress response by hepatitis viruses upregulates protein phosphatase 2A. Hepatology46, 558–565 (2007).
  • Kahn BB, Alquier T, Carling D, Hardie DG. AMP-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism. Cell Metab.1, 15–25 (2005).
  • Hawley SA, Boudeau J, Reid JL et al. Complexes between the LKB1 tumor suppressor, STRAD α/β and MO25 α/β are upstream kinases in the AMP-activated protein kinase cascade. J. Biol.2, 28 (2003).
  • Carling D. AMP-activated protein kinase: balancing the scales. Biochimie87, 87–91 (2005).
  • Shaw RJ, Lamia KA, Vasquez D et al. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science310, 1642–1646 (2005).
  • Mankouri J, Tedbury PR, Gretton S et al. Enhanced hepatitis C virus genome replication and lipid accumulation mediated by inhibition of AMP-activated protein kinase. Proc. Natl Acad. Sci. USA107, 11549–11554 (2010).
  • Kawaguchi T, Yoshida T, Harada M et al. Hepatitis C virus down-regulates insulin receptor substrates 1 and 2 through upregulation of suppressor of cytokine signaling 3. Am. J. Pathol.165, 1499–1508 (2004).
  • Pazienza V, Clement S, Pugnale P et al. The hepatitis C virus core protein of genotypes 3a and 1b downregulates insulin receptor substrate 1 through genotype-specific mechanisms. Hepatology45, 1164–1171 (2007).
  • Banks AS, Li J, McKeag L et al. Deletion of SOCS7 leads to enhanced insulin action and enlarged islets of Langerhans. J. Clin. Invest.115, 2462–2471 (2005).
  • Persico M, Capasso M, Persico E et al. Suppressor of cytokine signaling 3 (SOCS3) expression and hepatitis C virus-related chronic hepatitis: insulin resistance and response to antiviral therapy. Hepatology46, 1009–1015 (2007).
  • Festa A, D’Agostino R Jr, Tracy RP, Haffner SM. Insulin resistance atherosclerosis study. Elevated levels of acute phase proteins and plasminogen activator inhibitor-1 predict the development of Type 2 diabetes: the insulin resistance atherosclerosis study. Diabetes51, 1131–1137 (2002).
  • Spranger J, Kroke A, Mohlig M et al. Inflammatory cytokines and the risk to develop Type 2 diabetes: results of the prospective population-based European prospective investigation into cancer and nutrition (EPIC)-potsdam study. Diabetes52, 812–817 (2003).
  • Senn JJ, Klover PJ, Nowak IA, Mooney RA. Interleukin-6 induces cellular insulin resistance in hepatocytes. Diabetes51, 3391–3399 (2002).
  • Klover PJ, Zimmers TA, Koniaris LG, Mooney RA. Chronic exposure to interleukin-6 causes hepatic insulin resistance in mice. Diabetes52, 2784–2789 (2003).
  • Gupta D, Varma S, Khandelwal RL. Long-term effects of tumor necrosis factor-α treatment on insulin signaling pathway in HepG2 cells and HepG2 cells overexpressing constitutively active Akt/PKB. J. Cell. Biochem.100, 593–607 (2007).
  • 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. Hepatology46, 66–73 (2007).
  • Hung CH, Lee CM, Chen CH et al. Association of inflammatory and anti-inflammatory cytokines with insulin resistance in chronic hepatitis C. Liver Int.29, 1086–1093 (2009).
  • Evans JL, Goldfine ID, Maddux BA, Grodsky GM. Are oxidative stress activated signaling pathways mediators of insulin resistance and β-cell dysfunction? Diabetes52, 1–8 (2003).
  • Jacob S, Ruus P, Hermann R et al. Oral administration of RAC-α-lipoic acid modulates insulin sensitivity in patients with Type 2 diabetes mellitus: a placebo-controlled pilot trial. Free Radic. Biol. Med.27, 309–314 (1999).
  • Hirai N, Kawano H, Hirashima O et al. Insulin resistance and endothelial dysfunction in smokers: effects of vitamin C. Am. J. Physiol. Heart Circ. Physiol.279, H1172–H1178 (2000).
  • Okuda M, Li K, Beard MR et al. Mitochondrial injury, oxidative stress, and antioxidant gene expression are induced by hepatitis C virus core protein. Gastroenterology122, 366–375 (2002).
  • Korenaga M, Wang T, Li Y et al. Hepatitis C virus core protein inhibits mitochondrial electron transport and increases reactive oxygen species (ROS) production. J. Biol. Chem.280, 37481–37488 (2005).
  • Mitsuyoshi H, Itoh Y, Sumida Y et al. Evidence of oxidative stress as a cofactor in the development of insulin resistance in patients with chronic hepatitis C. Hepatol. Res.38, 348–353 (2008).
  • Levent G, Ali A, Ahmet A et al. Oxidative stress and antioxidant defense in patients with chronic hepatitis C patients before and after pegylated interferon α-2b plus ribavirin therapy. J. Transl. Med.4, 25 (2006).
  • Vidali M, Tripodi MF, Ivaldi A et al. Interplay between oxidative stress and hepatic steatosis in the progression of chronic hepatitis C. J. Hepatol.48, 399–406 (2008).
  • Bianchi G, Marchesini G, Zoli M, Bugianesi E, Fabbri A, Pisi E. Prognostic signifcance of diabetes in patients with cirrhosis. Hepatology20, 119–125 (1994).
  • Aslam F, Alam M, Lakkis NM. Hepatitis C and carotid atherosclerosis: a retrospective analysis. Atherosclerosis209, 340–343 (2010).
  • Marchesini G, Ronchi M, Forlani G et al. Cardiovascular disease in cirrhosis – a point-prevalence study in relation to glucose tolerance. Am. J. Gastroenterol.94, 655–662 (1999).
  • Fartoux L, Poujol-Robert A, Guéchot J, Wendum D, Poupon R, Serfaty L. Insulin resistance is a cause of steatosis and fibrosis progression in chronic hepatitis C. Gut54, 1003–1008 (2005).
  • Camma C, Bruno S, Di Marco V et al. Insulin resistance is associated with steatosis in nondiabetic patients with genotype 1 chronic hepatitis C. Hepatology43, 64–71 (2006).
  • Ding X, Saxena NK, Lin S, Xu A, Srinivasan S, Anania FA. The roles of leptin and adiponectin: a novel paradigm in adipocytokine regulation of liver fibrosis and stellate cell biology. Am. J. Pathol.166, 1655–1669 (2005).
  • Dharancy S, Malapel M, Perlemuter G et al. Impaired expression of the peroxisome proliferator-activated receptor α during hepatitis C virus infection. Gastroenterology128, 334–342 (2005).
  • Cua IH, Hui JM, Kench JG, George J. Genotype-specific interactions of insulin resistance, steatosis, and fibrosis in chronic hepatitis C. Hepatology48, 723–731 (2008).
  • Hung CH, Lee CM, Kuo FY et al. Steatosis correlates with hepatic expression of death receptors and activation of nuclear factor-κ B in chronic hepatitis C. Liver Int.28, 339–346 (2008).
  • Paradis V, Perlemuter G, Bonvoust F et al. High glucose and hyperinsulinemia stimulate connective tissue growth factor expression: a potential mechanism involved in progression to fibrosis in nonalcoholic steatohepatitis. Hepatology34, 738–744 (2001).
  • Piodi A, Chouteau P, Lerat H, Hézode C, Pawlotsky JM. Morphological changes in intracellular lipid droplets induced by different hepatitis C virus genotype core sequences and relationship with steatosis. Hepatology48, 16–27 (2008).
  • Cammà C, Petta S, Di Marco V et al. Insulin resistance is a risk factor for esophageal varices in hepatitis C virus cirrhosis. Hepatology49, 195–203 (2009).
  • Vincent MA, Montagnani M, Quon MJ. Molecular and physiologic actions of insulin related to production of nitric oxide in vascular endothelium. Curr. Diab. Rep.3, 279–288 (2003).
  • Yu ML, Dai CY, Huang JF et al. Rapid virological response and treatment duration for chronic hepatitis C genotype 1 patients: a randomized trial. Hepatology47, 1884–1893 (2008).
  • Yu ML, Dai CY, Huang JF et al. A randomised study of peginterferon and ribavirin for 16 versus 24 weeks in patients with genotype 2 chronic hepatitis C. Gut56, 553–559 (2007).
  • Dai CY, Huang JF, Hsieh MY et al. Insulin resistance predicts response to peginterferon-α/ribavirin combination therapy in chronic hepatitis C patients. J. Hepatol.50, 712–718 (2009).
  • Fried MW, Shiffman ML, Reddy KR et al. Peginterferon α-2a plus ribavirin for chronic hepatitis C virus infection. N. Engl. J. Med.347, 975–982 (2002).
  • Hadziyannis SJ, Sette H Jr, Morgan TR et al. Peginterferon-α2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann. Intern. Med.140, 346–355 (2004).
  • von Wagner M, Huber M, Berg T et al. Peginterferon-α-2a (40KD) and ribavirin for 16 or 24 weeks in patients with genotype 2 or 3 chronic hepatitis C. Gastroenterology129, 522–527 (2005).
  • Bortoletto G, Scribano L, Realdon S et al. Hyperinsulinaemia reduces the 24-h virological response to PEG-interferon therapy in patients with chronic hepatitis C and insulin resistance. J. Viral Hepat.17, 475–480 (2010).
  • Romero-Gómez M, Del Mar Viloria M, Andrade RJ et al. Insulin resistance impairs sustained response rate to peginterferon plus ribavirin in chronic hepatitis C patients. Gastroenterology128, 636–641 (2005).
  • 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.48, 28–34 (2008).
  • Vlotides G, Sörensen AS, Kopp F et al. SOCS-1 and SOCS-3 inhibit IFN-α-induced expression of the antiviral proteins 2,5-OAS and MxA. Biochem. Biophys. Res. Commun.320, 1007–1014 (2004).
  • Davila JA, Morgan RO, Shaib Y, McGlynn KA, El-Serag HB. Diabetes increases the risk of hepatocellular carcinoma in the United States: a population based case control study. Gut54, 533–539 (2005).
  • Veldt BJ, Chen W, Heathcote EJ et al. Increased risk of hepatocellular carcinoma among patients with hepatitis C cirrhosis and diabetes mellitus. Hepatology47, 1856–1862 (2008).
  • Hung CH, Lee CM, Wang JH et al. Impact of diabetes mellitus on incidence of hepatocellular carcinoma in chronic hepatitis C patients treated with interferon-based antiviral therapy. Int. J. Cancer128(10), 2344–2352 (2010).
  • Tung HD, Wang JH, Tseng PL et al. Neither diabetes mellitus nor overweight was a risk factor for hepatocellular carcinoma in a dual HBV and HCV endemic area: community cross-sectional and case-control studies. Am. J. Gastroenterol.105, 624–631 (2010).
  • Ikeda K, Saitoh S, Koida I et al. A multivariate analysis of risk factors for hepatocellular carcinogenesis – a prospective observation of 795 cases with viral and alcoholic cirrhosis. Hepatology18, 47–53 (1993).
  • Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of US adults. N. Engl. J. Med.348, 1625–1638 (2003).
  • Wolk A, Gridley G, Svensson M et al. A prospective study of obesity and cancer risk (Sweden). Cancer Causes Control12, 13–21 (2001).
  • Moller H, Mellemgaard A, Lindvig K, Olsen JH. Obesity and cancer risk: a Danish record-linkage study. Eur. J. Cancer.30A(3), 344–350 (1994).
  • Hung CH, Wang JH, Hu TH et al. Insulin resistance is associated with hepatocellular carcinoma in chronic hepatitis C infection. World J. Gastroenterol.16, 2265–2271 (2010).
  • Nkontchou G, Bastard JP, Ziol M et al. Insulin resistance, serum leptin, and adiponectin levels and outcomes of viral hepatitis C cirrhosis. J. Hepatol.53, 827–833 (2010).
  • Bugianesi E, McCullough AJ, Marchesini G. Insulin resistance: a metabolic pathway to chronic liver disease. Hepatology42, 987–1000 (2005).
  • Le Roith D. Seminars in medicine of the Beth Israel Deaconess Medical Center. Insulin-like growth factors. N. Engl. J. Med.336, 633–640 (1997).
  • El-Serag HB. Epidemiology of hepatocellular carcinoma in USA. Hepatol. Res.37(Suppl. 2), S88–S94 (2007).
  • Pagadala M, Dasarathy S, Eghtesad B, McCullough AJ. Posttransplant metabolic syndrome: an epidemic waiting to happen. Liver Transpl.15, 1662–1670 (2009).
  • Yoo HY, Thuluvath PJ. The effect of insulin-dependent diabetes mellitus on outcome of liver transplantation. Transplantation74, 1007–1012 (2002).
  • Velidedeoglu E, Mange KC, Frank A et al. Factors differentially correlated with the outcome of liver transplantation in HCV+ and HCV- recipients. Transplantation77, 1834–1842 (2004).
  • Veldt BJ, Poterucha JJ, Watt KD et al. Insulin resistance, serum adipokines and risk of fibrosis progression in patients transplanted for hepatitis C. Am. J. Transplant.9, 1406–1413 (2009).
  • Nagao Y, Kawaguchi T, Tanaka K, Kumashiro R, Sata M. Extrahepatic manifestations and insulin resistance in an HCV hyperendemic area. Int. J. Mol. Med.16, 291–296 (2005).
  • Nagao Y, Kawasaki K, Sata M. Insulin resistance and lichen planus in patients with HCV-infectious liver diseases. J. Gastroenterol. Hepatol.23, 580–585 (2008).
  • Nagao Y, Sata M. High incidence of multiple primary carcinomas in HCV-infected patients with oral squamous cell carcinoma. Med. Sci. Monit.15, CR453–CR459 (2009).
  • Hickman IJ, Clouston AD, Macdonald GA et al. Effect of weight reduction on liver histology and biochemistry in patients with chronic hepatitis C. Gut51, 89–94 (2002).
  • Orchard TJ, Temprosa M, Goldberg R et al. Diabetes Prevention Program Research Group. The effect of metformin and intensive lifestyle intervention on the metabolic syndrome: the Diabetes Prevention Program randomized trial. Ann. Intern. Med.142, 611–619 (2005).
  • Arase Y, Suzuki F, Suzuki Y et al. Sustained virological response reduces incidence of onset of Type 2 diabetes in chronic hepatitis C. Hepatology49, 739–744 (2009).
  • Hung CH, Kuo FY, Wang JH et al. Impact of steatosis on long-term histological outcome in chronic hepatitis C after antiviral therapy. Antivir. Ther.11, 483–489 (2006).
  • Kim YD, Park KG, Lee YS et al. Metformin inhibits hepatic gluconeogenesis through AMP activated protein kinase-dependent regulation of the orphan nuclear receptor SHP. Diabetes57, 306–314 (2008).
  • Overbeck K, Genne D, Golay A, Negro F. Pioglitazone in chronic hepatitis C not responding to pegylated interferon-α and ribavirin. J. Hepatol.49, 295–298 (2008).
  • Serfaty L, Fartoux L, Poupon R. Pioglitazone as adjuvant therapy in chronic hepatitis C: sequential rather than concomitant administration with pegylated interferon and ribavirin? J. Hepatol.50, 1269–1271 (2009).
  • Khattab M, Emad M, Abdelaleem A et al. Pioglitazone improves virological response to peginterferon α-2b/ribavirin combination therapy in hepatitis C genotype 4 patients with insulin resistance. Liver Int.30, 447–454 (2010).
  • Romero-Gómez M, Diago M, Andrade RJ et al; Spanish Treatment of Resistance to Insulin in Hepatitis C Genotype 1 Group. Treatment of insulin resistance with metformin in naive genotype 1 chronic hepatitis C patients receiving peginterferon α-2a plus ribavirin. Hepatology50, 1702–1708 (2009).
  • Currie CJ, Poole CD, Gale EA. The influence of glucose-lowering therapies on cancer risk in Type 2 diabetes. Diabetologia52, 1766–1777 (2009).
  • Hede K. Doctors seek to prevent breast cancer recurrence by lowering insulin levels. J. Natl Cancer Inst.100, 530–532 (2008).
  • Li D, Yeung SC, Hassan MM, Konopleva M, Abbruzzese JL. Antidiabetic therapies affect risk of pancreatic cancer. Gastroenterology137, 482–488 (2009).
  • Donadon V, Balbi M, Mas MD, Casarin P, Zanette G. Metformin and reduced risk of hepatocellular carcinoma in diabetic patients with chronic liver disease. Liver Int.30, 750–758 (2010).
  • Ge D, Fellay J, Thompson AJ et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature461, 399–401 (2009).
  • Balagopal A, Thomas DL, Thio CL. IL28B and the control of hepatitis C virus infection. Gastroenterology139, 1865–1876 (2010).

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.