World J Gastroenterol 12(44): 7075-7080

Insulin resistance and hepatitis C

Manuel Romero-Gómez, Unit for the Clinical Management of Digestive Diseases. Hospital Universitario de Valme. Ctra de Cádiz s/n 41014, Sevilla, Spain

Correspondence to: Manuel Romero-Gómez, MD, Unit for The Clinical Management of Digestive Diseases. Hospital Universitario de Valme. Ctra de Cadiz s/n. Sevilla 41014, Spain. se.elbacrepus@goremorm

Telephone: +34-955-015761 Fax: +34-955-015899

Manuel Romero-Gómez, Unit for the Clinical Management of Digestive Diseases. Hospital Universitario de Valme. Ctra de Cádiz s/n 41014, Sevilla, Spain

Correspondence to: Manuel Romero-Gómez, MD, Unit for The Clinical Management of Digestive Diseases. Hospital Universitario de Valme. Ctra de Cadiz s/n. Sevilla 41014, Spain. se.elbacrepus@goremorm

Telephone: +34-955-015761 Fax: +34-955-015899

Received 2006 Jul 18; Revised 2006 Jul 28; Accepted 2006 Aug 29.

Abstract

Insulin resistance is the major feature of the metabolic syndrome and depends on insulin secretion and insulin sensitivity. In chronic hepatitis C, insulin resistance and type 2 diabetes mellitus are more often seen than in healthy controls or chronic hepatitis B patients. Hepatitis C virus (HCV) infection promotes insulin resistance, mainly by increased TNF production together with enhancement of suppressor of cytokine (SOC-3); both events block PI3K and Akt phosphorylation. Two types of insulin resistance could be found in chronic hepatitis C patients: “viral” and “metabolic” insulin resistance. Insulin resistance in chronic hepatitis C is relevant because it promotes steatosis and fibrosis. The mechanisms by which insulin resistance promotes fibrosis progression include: (1) steatosis, (2) hyperleptinemia, (3) increased TNF production, (4) impaired expression of PPARγ receptors. Lastly, insulin resistance has been found as a common denominator in patients difficult-to-treat like cirrhotics, overweight, HIV coinfected and Afro-American. Insulin resistance together with fibrosis and genotype has been found to be independently associated with impaired response rate to peginterferon plus ribavirin. Indeed, in genotype 1, the sustained response rate was twice (60%) in patients with HOMA ≤ 2 than patients with HOMA > 2. In experiments carried out on Huh-7 cells transfected by full length HCVRNA, interferon alpha blocks HCV replication. However, when insulin (at doses of 128 μU/mL, similar that seen in the hyperinsulinemic state) was added to interferon, the ability to block HCV replication disappeared, and the PKR synthesis was abolished. In summary, hepatitis C promotes insulin resistance and insulin resistance induces interferon resistance, steatosis and fibrosis progression.

Keywords: Diabetes mellitus, Homeostasis model of assessment, Fibrosis, Steatosis, Sustained response, Peginterferon, Ribavirin

Abstract

Footnotes

Supported by a grant of PAI-CTS-532 from Junta de Andalucía, Andalucía, Spain

S- Editor Liu Y L- Editor Alpini GD E- Editor Liu WF

Footnotes

References

1. Eckel RH, Grundy SM, Zimmet PZThe metabolic syndrome. Lancet. 2005;365:1415–1428.[PubMed][Google Scholar]
2. Kruszynska YT, Home PD, McIntyre NRelationship between insulin sensitivity, insulin secretion and glucose tolerance in cirrhosis. Hepatology. 1991;14:103–111.[PubMed][Google Scholar]
3. Narita R, Abe S, Kihara Y, Akiyama T, Tabaru A, Otsuki MInsulin resistance and insulin secretion in chronic hepatitis C virus infection. J Hepatol. 2004;41:132–138.[PubMed][Google Scholar]
4. Hui JM, Sud A, Farrell GC, Bandara P, Byth K, Kench JG, McCaughan GW, George JInsulin resistance is associated with chronic hepatitis C virus infection and fibrosis progression [corrected] Gastroenterology. 2003;125:1695–1704.[PubMed][Google Scholar]
5. Lecube A, Hernández C, Genescà J, Simó RProinflammatory cytokines, insulin resistance, and insulin secretion in chronic hepatitis C patients: A case-control study. Diabetes Care. 2006;29:1096–1101.[PubMed][Google Scholar]
6. Kawaguchi T, Yoshida T, Harada M, Hisamoto T, Nagao Y, Ide T, Taniguchi E, Kumemura H, Hanada S, Maeyama M, et al Hepatitis C virus down-regulates insulin receptor substrates 1 and 2 through up-regulation of suppressor of cytokine signaling 3. Am J Pathol. 2004;165:1499–1508.[Google Scholar]
7. Wang CS, Wang ST, Yao WJ, Chang TT, Chou PCommunity-based study of hepatitis C virus infection and type 2 diabetes: an association affected by age and hepatitis severity status. Am J Epidemiol. 2003;158:1154–1160.[PubMed][Google Scholar]
8. Zein CO, Levy C, Basu A, Zein NNChronic hepatitis C and type II diabetes mellitus: a prospective cross-sectional study. Am J Gastroenterol. 2005;100:48–55.[PubMed][Google Scholar]
9. Lecube A, Hernández C, Genescà J, Simó RGlucose abnormalities in patients with hepatitis C virus infection: Epidemiology and pathogenesis. Diabetes Care. 2006;29:1140–1149.[PubMed][Google Scholar]
10. Mehta SH, Brancati FL, Sulkowski MS, Strathdee SA, Szklo M, Thomas DLPrevalence of type 2 diabetes mellitus among persons with hepatitis C virus infection in the United States. Hepatology. 2001;33:1554.[PubMed][Google Scholar]
11. Mehta SH, Brancati FL, Strathdee SA, Pankow JS, Netski D, Coresh J, Szklo M, Thomas DLHepatitis C virus infection and incident type 2 diabetes. Hepatology. 2003;38:50–56.[PubMed][Google Scholar]
12. Thuluvath PJ, John PR. Association between hepatitis C, diabetes mellitus, and race. a case-control study. Am J Gastroenterol. 2003;98:438–441.[PubMed]
13. Romero Gómez M, Fernandez-Rodriguez C, Alonso S, Pons JA, López-Serrano P, Gutiérrez ML, Pérez C, Temi-o R, García P, Grande L, et al Sustained response in chronic hepatitis C reduces the risk to develop impaired fasting glucose and/or diabetes type 2. J Hepatol. 2006;44(suppl 2):548A.[PubMed][Google Scholar]
14. Adinolfi LE, Gambardella M, Andreana A, Tripodi MF, Utili R, Ruggiero GSteatosis accelerates the progression of liver damage of chronic hepatitis C patients and correlates with specific HCV genotype and visceral obesity. Hepatology. 2001;33:1358–1364.[PubMed][Google Scholar]
15. Cammà C, Bruno S, Di Marco V, Di Bona D, Rumi M, Vinci M, Rebucci C, Cividini A, Pizzolanti G, Minola E, et al Insulin resistance is associated with steatosis in nondiabetic patients with genotype 1 chronic hepatitis C. Hepatology. 2006;43:64–71.[PubMed][Google Scholar]
16. Ratziu V, Munteanu M, Charlotte F, Bonyhay L, Poynard TFibrogenic impact of high serum glucose in chronic hepatitis C. J Hepatol. 2003;39:1049–1055.[PubMed][Google Scholar]
17. Fartoux L, Poujol-Robert A, Guéchot J, Wendum D, Poupon R, Serfaty LInsulin resistance is a cause of steatosis and fibrosis progression in chronic hepatitis C. Gut. 2005;54:1003–1008.[Google Scholar]
18. Sud A, Hui JM, Farrell GC, Bandara P, Kench JG, Fung C, Lin R, Samarasinghe D, Liddle C, McCaughan GW, et al Improved prediction of fibrosis in chronic hepatitis C using measures of insulin resistance in a probability index. Hepatology. 2004;39:1239–1247.[PubMed][Google Scholar]
19. Ratziu V, Trabut JB, Poynard TFat, diabetes, and liver injury in chronic hepatitis C. Curr Gastroenterol Rep. 2004;6:22–29.[PubMed][Google Scholar]
20. Romero-Gómez M, Castellano-Megias VM, Grande L, Irles JA, Cruz M, Nogales MC, Alcón JC, Robles ASerum leptin levels correlate with hepatic steatosis in chronic hepatitis C. Am J Gastroenterol. 2003;98:1135–1141.[PubMed][Google Scholar]
21. Otte C, Otte JM, Strodthoff D, Bornstein SR, Fölsch UR, Mönig H, Kloehn SExpression of leptin and leptin receptor during the development of liver fibrosis and cirrhosis. Exp Clin Endocrinol Diabetes. 2004;112:10–17.[PubMed][Google Scholar]
22. Ding X, Saxena NK, Lin S, Xu A, Srinivasan S, Anania FAThe roles of leptin and adiponectin: a novel paradigm in adipocytokine regulation of liver fibrosis and stellate cell biology. Am J Pathol. 2005;166:1655–1669.[Google Scholar]
23. Sung CK, She H, Xiong S, Tsukamoto HTumor necrosis factor-alpha inhibits peroxisome proliferator-activated receptor gamma activity at a posttranslational level in hepatic stellate cells. Am J Physiol Gastrointest Liver Physiol. 2004;286:G722–G729.[PubMed][Google Scholar]
24. Dharancy S, Malapel M, Perlemuter G, Roskams T, Cheng Y, Dubuquoy L, Podevin P, Conti F, Canva V, Philippe D, et al Impaired expression of the peroxisome proliferator-activated receptor alpha during hepatitis C virus infection. Gastroenterology. 2005;128:334–342.[PubMed][Google Scholar]
25. Burgess HA, Daugherty LE, Thatcher TH, Lakatos HF, Ray DM, Redonnet M, Phipps RP, Sime PJPPARgamma agonists inhibit TGF-beta induced pulmonary myofibroblast differentiation and collagen production: implications for therapy of lung fibrosis. Am J Physiol Lung Cell Mol Physiol. 2005;288:L1146–L1153.[PubMed][Google Scholar]
26. Taiwo BOInsulin resistance, HIV infection, and anti-HIV therapies. AIDS Read. 2005;15:171–176, 179-180.[PubMed][Google Scholar]
27. Shikuma CM, Day LJ, Gerschenson MInsulin resistance in the HIV-infected population: the potential role of mitochondrial dysfunction. Curr Drug Targets Infect Disord. 2005;5:255–262.[PubMed][Google Scholar]
28. Visnegarwala F, Chen L, Raghavan S, Tedaldi EPrevalence of diabetes mellitus and dyslipidemia among antiretroviral naive patients co-infected with hepatitis C virus (HCV) and HIV-1 compared to patients without co-infection. J Infect. 2005;50:331–337.[PubMed][Google Scholar]
29. Duong M, Petit JM, Piroth L, Grappin M, Buisson M, Chavanet P, Hillon P, Portier HAssociation between insulin resistance and hepatitis C virus chronic infection in HIV-hepatitis C virus-coinfected patients undergoing antiretroviral therapy. J Acquir Immune Defic Syndr. 2001;27:245–250.[PubMed][Google Scholar]
30. Romero Gómez M, Tural C, Sola R, Martínez-Sierra MC, Viloria MM, Jiménez MD, Arizcorreta A, Trabadela C, Clotet B, Planas RInsulin resistance in co-infected HCV/HIV patients: A negative factor influencing sustained response to peginterferon plus ribavirin. J Hepatol. 2006;44 suppl 2:603A.[PubMed][Google Scholar]
31. Koivisto VA, Pelkonen R, Cantell KEffect of interferon on glucose tolerance and insulin sensitivity. Diabetes. 1989;38:641–647.[PubMed][Google Scholar]
32. Imano E, Kanda T, Ishigami Y, Kubota M, Ikeda M, Matsuhisa M, Kawamori R, Yamasaki YInterferon induces insulin resistance in patients with chronic active hepatitis C. J Hepatol. 1998;28:189–193.[PubMed][Google Scholar]
33. Ito Y, Takeda N, Ishimori M, Akai A, Miura K, Yasuda KEffects of long-term interferon-alpha treatment on glucose tolerance in patients with chronic hepatitis C. J Hepatol. 1999;31:215–220.[PubMed][Google Scholar]
34. Tai TY, Lu JY, Chen CL, Lai MY, Chen PJ, Kao JH, Lee CZ, Lee HS, Chuang LM, Jeng YMInterferon-alpha reduces insulin resistance and beta-cell secretion in responders among patients with chronic hepatitis B and C. J Endocrinol. 2003;178:457–465.[PubMed][Google Scholar]
35. Romero-Gómez M, González-Escribano MF, Torres B, Barroso N, Montes-Cano MA, Sánchez-Muñoz D, Núñez-Roldan A, Aguilar-Reina JHLA class I B44 is associated with sustained response to interferon + ribavirin therapy in patients with chronic hepatitis C. Am J Gastroenterol. 2003;98:1621–1626.[PubMed][Google Scholar]
36. Romero-Gómez M, Del Mar Viloria M, Andrade RJ, Salmerón J, Diago M, Fernández-Rodríguez CM, Corpas R, Cruz M, Grande L, Vázquez L, et al Insulin resistance impairs sustained response rate to peginterferon plus ribavirin in chronic hepatitis C patients. Gastroenterology. 2005;128:636–641.[PubMed][Google Scholar]
37. D'Souza R, Sabin CA, Foster GRInsulin resistance plays a significant role in liver fibrosis in chronic hepatitis C and in the response to antiviral therapy. Am J Gastroenterol. 2005;100:1509–1515.[PubMed][Google Scholar]
38. Grace MJ, Cutler DPegylating IFNs at his-34 improves the in vitro antiviral activity through the JAK/STAT pathway. Antivir Chem Chemother. 2004;15:287–297.[PubMed][Google Scholar]
39. Sanyal AJ, Chand N, Comar K, Mirshahi FHyperinsulinemia block the inhibition of HCV replication by interferon: A potential mechanism for failure of interferon therapy in subjects with HCV and NASH. Hepatology. 2004;40:179A.[PubMed][Google Scholar]
40. Walsh MJ, Jonsson JR, Richardson MM, Lipka GM, Purdie DM, Clouston AD, Powell EENon-response to antiviral therapy is associated with obesity and increased hepatic expression of suppressor of cytokine signalling 3 (SOCS-3) in patients with chronic hepatitis C, viral genotype 1. Gut. 2006;55:529–535.[Google Scholar]