Anti-diabetic drugs, insulin and metformin, have no direct interaction with hepatitis C virus infection or anti-viral interferon response

Mohamad S. Hakim; Xinying Zhou; Yijin Wang; Maikel P. Peppelenbosch; Qiuwei Pan; Mohamad S. Hakim; Xinying Zhou; Yijin Wang; Maikel P. Peppelenbosch; Qiuwei Pan

doi:10.3934/molsci.2014.1.49

AIMS Molecular Science

2014, Volume 1, Issue 1: 49-58. doi: 10.3934/molsci.2014.1.49

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Research article

Anti-diabetic drugs, insulin and metformin, have no direct interaction with hepatitis C virus infection or anti-viral interferon response

1.
Department of Microbiology, Faculty of Medicine, Universitas Gadjah Mada, Yogyakarta, Indonesia;
2.
Department of Gastroenterology and Hepatology, Erasmus University Medical Center Rotterdam, the Netherlands

Received: 14 November 2013 Accepted: 19 December 2013 Published: 01 January 2014

Hepatitis C virus (HCV) infection is associated with insulin resistance (IR) and type 2 diabetes (T2D). Chronic HCV patients with IR and T2D appear to have a decreased response to the standard pegylated-interferon-alpha and ribavirin (PEG-IFN/RBV) anti-viral therapy. Insulin and metformin are anti-diabetic drugs regularly used in the clinic. A previous in vitro study has shown a negative effect of insulin on interferon signaling. In the clinic, adding metformin to PEG-IFN/RBV therapy was reported to increase the response rate in chronic HCV patients and it has been suggested this effect derives from an improved anti-viral action of interferon. The goal of this study was to further investigate the molecular insight of insulin and metformin interaction with HCV infection and the anti-viral action of interferon. We used two cell culture models of HCV infection. One is a sub-genomic model that assays viral replication through luciferase reporter gene expression. The other one is a full-length infectious model derived from the JFH1 genotype 2a isolate. We found that both insulin and metformin do not affect HCV infection. Insulin and metformin also do not influence the anti-viral potency of interferon. In addition, there is no direct interaction between these two drugs and interferon signaling. Our results do not confirm the previous laboratory observation that insulin interferes with interferon signaling and suggest that classical nutritional signaling through mTOR may be not involved in HCV replication. If metformin indeed can increase the response rate to interferon therapy in patients, our data indicate that this could be mediated via an indirect mechanisms.
- HCV infection,
- insulin,
- metformin,
- interferon
Citation: Mohamad S. Hakim, Xinying Zhou, Yijin Wang, Maikel P. Peppelenbosch, Qiuwei Pan. Anti-diabetic drugs, insulin and metformin, have no direct interaction with hepatitis C virus infection or anti-viral interferon response[J]. AIMS Molecular Science, 2014, 1(1): 49-58. doi: 10.3934/molsci.2014.1.49

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Abstract

Hepatitis C virus (HCV) infection is associated with insulin resistance (IR) and type 2 diabetes (T2D). Chronic HCV patients with IR and T2D appear to have a decreased response to the standard pegylated-interferon-alpha and ribavirin (PEG-IFN/RBV) anti-viral therapy. Insulin and metformin are anti-diabetic drugs regularly used in the clinic. A previous in vitro study has shown a negative effect of insulin on interferon signaling. In the clinic, adding metformin to PEG-IFN/RBV therapy was reported to increase the response rate in chronic HCV patients and it has been suggested this effect derives from an improved anti-viral action of interferon. The goal of this study was to further investigate the molecular insight of insulin and metformin interaction with HCV infection and the anti-viral action of interferon. We used two cell culture models of HCV infection. One is a sub-genomic model that assays viral replication through luciferase reporter gene expression. The other one is a full-length infectious model derived from the JFH1 genotype 2a isolate. We found that both insulin and metformin do not affect HCV infection. Insulin and metformin also do not influence the anti-viral potency of interferon. In addition, there is no direct interaction between these two drugs and interferon signaling. Our results do not confirm the previous laboratory observation that insulin interferes with interferon signaling and suggest that classical nutritional signaling through mTOR may be not involved in HCV replication. If metformin indeed can increase the response rate to interferon therapy in patients, our data indicate that this could be mediated via an indirect mechanisms.

References

[1]	Rosen HR (2011) Clinical practice. Chronic hepatitis C infection. N Engl J Med 364: 2429-2438
[2]	Heim MH (2013) 25 years of interferon-based treatment of chronic hepatitis C: an epoch coming to an end. Nat Rev Immunol 13: 535-542. doi: 10.1038/nri3463
[3]	Pan Q, Peppelenbosch MP, Janssen HL, et al. (2012) Telaprevir/boceprevir era: from bench to bed and back. World J Gastroenterol 18: 6183-6188. doi: 10.3748/wjg.v18.i43.6183
[4]	Alberti A (2009) What are the comorbidities influencing the management of patients and the response to therapy in chronic hepatitis C? Liver Int 29 Suppl 1: 15-18.
[5]	Sheikh MY, Choi J, Qadri I, et al. (2008) Hepatitis C virus infection: molecular pathways to metabolic syndrome. Hepatology 47: 2127-2133. doi: 10.1002/hep.22269
[6]	Naing C, Mak JW, Ahmed SI, et al. (2012) Relationship between hepatitis C virus infection and type 2 diabetes mellitus: meta-analysis. World J Gastroenterol 18: 1642-1651. doi: 10.3748/wjg.v18.i14.1642
[7]	White DL, Ratziu V, El-Serag HB (2008) Hepatitis C infection and risk of diabetes: a systematic review and meta-analysis. J Hepatol 49: 831-844. doi: 10.1016/j.jhep.2008.08.006
[8]	Dai CY, Huang JF, Hsieh MY, et al. (2009) Insulin resistance predicts response to peginterferon-alpha/ribavirin combination therapy in chronic hepatitis C patients. J Hepatol 50: 712-718. doi: 10.1016/j.jhep.2008.12.017
[9]	Elgouhari HM, Zein CO, Hanouneh I, et al. (2009) Diabetes mellitus is associated with impaired response to antiviral therapy in chronic hepatitis C infection. Dig Dis Sci 54: 2699-2705. doi: 10.1007/s10620-008-0683-2
[10]	Chu CJ, Lee SD, Hung TH, et al. (2009) Insulin resistance is a major determinant of sustained virological response in genotype 1 chronic hepatitis C patients receiving peginterferon alpha-2b plus ribavirin. Aliment Pharmacol Ther 29: 46-54. doi: 10.1111/j.1365-2036.2008.03823.x
[11]	Romero-Gomez M, Del Mar Viloria M, Andrade RJ, et al. (2005) Insulin resistance impairs sustained response rate to peginterferon plus ribavirin in chronic hepatitis C patients. Gastroenterology 128: 636-641. doi: 10.1053/j.gastro.2004.12.049
[12]	Romero-Gomez M, Diago M, Andrade RJ, et al. (2009) Treatment of insulin resistance with metformin in naive genotype 1 chronic hepatitis C patients receiving peginterferon alfa-2a plus ribavirin. Hepatology 50: 1702-1708. doi: 10.1002/hep.23206
[13]	Yu JW, Sun LJ, Zhao YH, et al. (2012) The effect of metformin on the efficacy of antiviral therapy in patients with genotype 1 chronic hepatitis C and insulin resistance. Int J Infect Dis 16: e436-441.
[14]	Franceschini L, Realdon S, Marcolongo M, et al. (2011) Reciprocal interference between insulin and interferon-alpha signaling in hepatic cells: a vicious circle of clinical significance? Hepatology 54: 484-494. doi: 10.1002/hep.24394
[15]	van Veelen W, Korsse SE, van de Laar L, et al. (2011) The long and winding road to rational treatment of cancer associated with LKB1/AMPK/TSC/mTORC1 signaling. Oncogene 30: 2289-2303. doi: 10.1038/onc.2010.630
[16]	Korsse SE, Peppelenbosch MP, van Veelen W (2013) Targeting LKB1 signaling in cancer. Biochim Biophys Acta 1835: 194-210.
[17]	Viollet B, Guigas B, Sanz Garcia N, et al. (2012) Cellular and molecular mechanisms of metformin: an overview. Clin Sci (Lond) 122: 253-270. doi: 10.1042/CS20110386
[18]	Frese M, Schwarzle V, Barth K, et al. (2002) Interferon-gamma inhibits replication of subgenomic and genomic hepatitis C virus RNAs. Hepatology 35: 694-703. doi: 10.1053/jhep.2002.31770
[19]	Wakita T, Pietschmann T, Kato T, et al. (2005) Production of infectious hepatitis C virus in tissue culture from a cloned viral genome. Nat Med 11: 791-796. doi: 10.1038/nm1268
[20]	Platanias LC (2005) Mechanisms of type-I- and type-II-interferon-mediated signalling. Nat Rev Immunol 5: 375-386. doi: 10.1038/nri1604
[21]	Samuel VT, Shulman GI (2012) Mechanisms for insulin resistance: common threads and missing links. Cell 148: 852-871. doi: 10.1016/j.cell.2012.02.017
[22]	Tripathy D, Chavez AO (2010) Defects in insulin secretion and action in the pathogenesis of type 2 diabetes mellitus. Curr Diab Rep 10: 184-191. doi: 10.1007/s11892-010-0115-5
[23]	Pazienza V, Clement S, Pugnale P, et al. (2007) The hepatitis C virus core protein of genotypes 3a and 1b downregulates insulin receptor substrate 1 through genotype-specific mechanisms. Hepatology 45: 1164-1171. doi: 10.1002/hep.21634
[24]	Tsatsoulis A, Mantzaris MD, Bellou S, et al. (2013) Insulin resistance: an adaptive mechanism becomes maladaptive in the current environment - an evolutionary perspective. Metabolism 62: 622-633. doi: 10.1016/j.metabol.2012.11.004
[25]	Bortoletto G, Scribano L, Realdon S, et al. (2010) 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.
[26]	Bonjardim CA, Ferreira PC, Kroon EG (2009) Interferons: signaling, antiviral and viral evasion. Immunol Lett 122: 1-11. doi: 10.1016/j.imlet.2008.11.002
[27]	Bartenschlager R (2002) Hepatitis C virus replicons: potential role for drug development. Nat Rev Drug Discov 1: 911-916. doi: 10.1038/nrd942
[28]	Schott S, Bierhaus A, Schuetz F, et al. (2011) Therapeutic effects of metformin in breast cancer: involvement of the immune system? Cancer Immunol Immunother 60: 1221-1225. doi: 10.1007/s00262-011-1062-y
[29]	Shrivastava S, Bhanja Chowdhury J, Steele R, et al. (2012) Hepatitis C virus upregulates Beclin1 for induction of autophagy and activates mTOR signaling. J Virol 86: 8705-8712. doi: 10.1128/JVI.00616-12
[30]	Bose SK, Shrivastava S, Meyer K, et al. (2012) Hepatitis C virus activates the mTOR/S6K1 signaling pathway in inhibiting IRS-1 function for insulin resistance. J Virol 86:6315-6322. doi: 10.1128/JVI.00050-12

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