Citation: Jizheng Chen, Pan Qiu, Tingfeng Zhao, Haowei Jiang, Kebinur Tursun, Sulaiman Ksimu, Xinwen Chen, Qian Wang. Measures of insulin resistance and beta cell function before and after treatment of HCV infection .VIROLOGICA SINICA, 2024, 39(4) : 667-674.  http://dx.doi.org/10.1016/j.virs.2024.06.007

Measures of insulin resistance and beta cell function before and after treatment of HCV infection

cstr: 32224.14.j.virs.2024.06.007
  • The association between chronic HCV infection and type 2 diabetes mellitus (T2DM) has been established; however, there is limited research on β-cell function particularly in the pre-diabetic population. Here, we evaluated indices of β-cell function and insulin sensitivity across the spectrum from normal glucose tolerance to T2DM in individuals with and without chronic hepatitis C (CHC), and the effects of antiviral treatments on these variables. A total of 153 non-cirrhotic, non-fibrotic CHC patients with a BMI <25 were enrolled in the study. Among them, 119 were successfully treated with either direct acting antiviral (DAA) drugs or pegylated interferon/ribavirin (IFN/RBV) anti-HCV therapy. Fasting state- and oral glucose tolerance test (OGTT)-derived indexes were used to evaluate β-cell function and insulin sensitivity. Among all subjects, 19 (13%) had T2DM and 21% exhibited pre-diabetes including 8% isolated impaired fasting glucose (IFG) and 13% combined IFG and impaired glucose tolerance (IGT). Early and total insulin secretion adjusted for the degree of insulin resistance were decreased in pre-diabetic CHC patients compared to HCV-uninfected individuals. Viral eradication through DAA or IFN/RBV therapy demonstrated positive impacts on insulin sensitivity and β-cell function in CHC patients who achieved sustained virologic response (SVR), regardless of fasting or OGTT state. These findings emphasize the role of HCV in the development of β-cell dysfunction, while also suggesting that viral eradication can improve insulin secretion, reverse insulin resistance, and ameliorate glycemic control. These results have important implications for managing pre-diabetic CHC patients and could prevent diabetes-related clinical manifestations and complications.

  • 加载中
  • 10.1016j.virs.2024.06.007-ESM.docx
    1. AASLD-IDSA HCV Guidance Panel, 2018. Hepatitis C guidance 2018 update: AASLD-IDSA recommendations for testing, managing, and treating hepatitis C virus infection. Clin. Infect. Dis. 67, 1477-1492.

    2. Aghemo, A., Prati, G. M., Rumi, M. G., Soffredini, R., D'Ambrosio, R., Orsi, E., De Nicola, S., Degasperi, E., Grancini, V., & Colombo, M., 2012. Sustained virological response prevents the development of insulin resistance in patients with chronic hepatitis C. Hepatology 56, 1681-1687.

    3. Brandman, D., Bacchetti, P., Ayala, C. E., Maher, J. J., & Khalili, M., 2012. Impact of insulin resistance on HCV treatment response and impact of HCV treatment on insulin sensitivity using direct measurements of insulin action. Diabetes Care 35, 1090-1094.

    4. Cacoub, P., Desbois, A. C., Comarmond, C., & Saadoun, D., 2018. Impact of sustained virological response on the extrahepatic manifestations of chronic hepatitis C: a meta-analysis. Gut 67, 2025-2034.

    5. Carnevale Schianca, G. P., Rossi, A., Sainaghi, P. P., Maduli, E., & Bartoli, E., 2003. The significance of impaired fasting glucose versus impaired glucose tolerance: importance of insulin secretion and resistance. Diabetes Care, 26, 1333-1337.

    6. Carnovale, C., Pozzi, M., Dassano, A., D'Addio, F., Gentili, M., Magni, C., Clementi, E., Radice, S., & Fiorina, P., 2019. The impact of a successful treatment of hepatitis C virus on glyco-metabolic control in diabetic patients: a systematic review and meta-analysis. Acta Diabetol. 56, 341-354.

    7. Caronia, S., Taylor, K., Pagliaro, L., Carr, C., Palazzo, U., Petrik, J., O'Rahilly, S., Shore, S., Tom, B. D., & Alexander, G. J., 1999. Further evidence for an association between non-insulin-dependent diabetes mellitus and chronic hepatitis C virus infection. Hepatology 30, 1059-1063.

    8. Chen, J., Wang, N., Dong, M., Guo, M., Zhao, Y., Zhuo, Z., Zhang, C., Chi, X., Pan, Y., Jiang, J. et al., 2015. The metabolic regulator histone deacetylase 9 contributes to glucose homeostasis abnormality induced by hepatitis C virus infection. Diabetes 64, 4088-4098.

    9. Defronzo, R. A., 2009. Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes 58, 773-795.

    10. Dong, T. S., Aby, E. S., Benhammou, J. N., Kawamoto, J., Han, S. H., May, F. P., & Pisegna, J. R., 2018. Metabolic syndrome does not affect sustained virologic response of direct-acting antivirals while hepatitis C clearance improves hemoglobin A1c. World J. Hepatol. 10, 612-621.

    11. Dreux, M., Garaigorta, U., Boyd, B., Decembre, E., Chung, J., Whitten-Bauer, C., Wieland, S., & Chisari, F. V., 2012. Short-range exosomal transfer of viral RNA from infected cells to plasmacytoid dendritic cells triggers innate immunity. Cell Host Microbe 12, 558-570.

    12. Dyal, H. K., Aguilar, M., Bartos, G., Holt, E. W., Bhuket, T., Liu, B., Cheung, R., & Wong, R. J., 2016. Diabetes mellitus increases risk of hepatocellular carcinoma in chronic hepatitis C virus patients: a systematic review. Dig. Dis. Sci. 61, 636-645.

    13. Fletcher, N. F., Yang, J. P., Farquhar, M. J., Hu, K., Davis, C., He, Q., Dowd, K., Ray, S. C., Krieger, S. E., Neyts, J. et al., 2010. Hepatitis C virus infection of neuroepithelioma cell lines. Gastroenterology 139, 1365-1374.

    14. Genuth, S., Alberti, K. G., Bennett, P., Buse, J., Defronzo, R., Kahn, R., Kitzmiller, J., Knowler, W. C., Lebovitz, H., Lernmark, A. et al., 2003. Follow-up report on the diagnosis of diabetes mellitus. Diabetes Care 26, 3160-3167.

    15. Herzberg-Schafer, S. A., Staiger, H., Heni, M., Ketterer, C., Guthoff, M., Kantartzis, K., Machicao, F., Stefan, N., Haring, H. U., & Fritsche, A., 2010. Evaluation of fasting state-/oral glucose tolerance test-derived measures of insulin release for the detection of genetically impaired β-cell function. PLoS One 5, e14194.

    16. Hsu, C. S., Liu, C. J., Liu, C. H., Wang, C. C., Chen, C. L., Lai, M. Y., Chen, P. J., Kao, J. H., & Chen, D. S., 2008. High hepatitis C viral load is associated with insulin resistance in patients with chronic hepatitis C. Liver Int. 28, 271-277.

    17. Iwasaki, Y., Ohkubo, A., Kajinuma, H., Akanuma, Y., & Kosaka, K., 1978. Degradation and secretion of insulin in hepatic cirrhosis. J. Clin. Endocrinol. Metab. 47, 774-779.

    18. Kosaka, K., Kuzuya, T., Hagura, R., & Yoshinaga, H., 1996. Insulin response to oral glucose load is consistently decreased in established non-insulin-dependent diabetes mellitus: the usefulness of decreased early insulin response as a predictor of non-insulin-dependent diabetes mellitus. Diabet. Med. 13, S109-S119.

    19. Lecube, A., Hernandez, C., Genesca, J., & Simo, R., 2006. Glucose abnormalities in patients with hepatitis C virus infection: epidemiology and pathogenesis. Diabetes Care 29, 1140-1149.

    20. Lorenzo, C., Wagenknecht, L. E., Rewers, M. J., Karter, A. J., Bergman, R. N., Hanley, A. J., & Haffner, S. M., 2010. Disposition index, glucose effectiveness, and conversion to type 2 diabetes: the Insulin Resistance Atherosclerosis Study (IRAS). Diabetes Care 33, 2098-2103.

    21. Mahale, P., Engels, E. A., Li, R., Torres, H. A., Hwang, L. Y., Brown, E. L., & Kramer, J. R., 2018. The effect of sustained virological response on the risk of extrahepatic manifestations of hepatitis C virus infection. Gut 67, 553-561.

    22. Masini, M., Campani, D., Boggi, U., Menicagli, M., Funel, N., Pollera, M., Lupi, R., Del Guerra, S., Bugliani, M., Torri, S. et al., 2005. Hepatitis C virus infection and human pancreatic beta-cell dysfunction. Diabetes Care 28, 940-941.

    23. Mason, A. L., Lau, J. Y., Hoang, N., Qian, K., Alexander, G. J., Xu, L., Guo, L., Jacob, S., Regenstein, F. G., Zimmerman, R. et al., 1999. Association of diabetes mellitus and chronic hepatitis C virus infection. Hepatology, 29, 328-333.

    24. Matsuda, M., & DeFronzo, R. A., 1999. Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. Diabetes Care 22, 1462-1470.

    25. Naing, C., Mak, J. W., Ahmed, S. I., & Maung, M., 2012. Relationship between hepatitis C virus infection and type 2 diabetes mellitus: meta-analysis. World J. Gastroenterol. 18, 1642-1651.

    26. Narita, R., Abe, S., Kihara, Y., Akiyama, T., Tabaru, A., & Otsuki, M., 2004. Insulin resistance and insulin secretion in chronic hepatitis C virus infection. J. Hepatol. 41, 132-138.

    27. Nathan, D. M., Davidson, M. B., DeFronzo, R. A., Heine, R. J., Henry, R. R., Pratley, R., Zinman, B., & American Diabetes, A., 2007. Impaired fasting glucose and impaired glucose tolerance: implications for care. Diabetes Care 30, 753-759.

    28. Ohn, J. H., Kwak, S. H., Cho, Y. M., Lim, S., Jang, H. C., Park, K. S., & Cho, N. H., 2016. 10-year trajectory of β-cell function and insulin sensitivity in the development of type 2 diabetes: a community-based prospective cohort study. Lancet Diabetes Endocrinol. 4, 27-34.

    29. Retnakaran, R., Shen, S., Hanley, A. J., Vuksan, V., Hamilton, J. K., & Zinman, B., 2008. Hyperbolic relationship between insulin secretion and sensitivity on oral glucose tolerance test. Obesity (Silver Spring) 16, 1901-1907.

    30. Schlesinger, S., Neuenschwander, M., Barbaresko, J., Lang, A., Maalmi, H., Rathmann, W., Roden, M., & Herder, C., 2022. Prediabetes and risk of mortality, diabetes-related complications and comorbidities: umbrella review of meta-analyses of prospective studies. Diabetologia. 65, 275-285.

    31. Seltzer, H. S., Allen, E. W., Herron, A. L., Jr., & Brennan, M. T., 1967. Insulin secretion in response to glycemic stimulus: relation of delayed initial release to carbohydrate intolerance in mild diabetes mellitus. J. Clin. Invest. 46, 323-335.

    32. Shintani, Y., Fujie, H., Miyoshi, H., Tsutsumi, T., Tsukamoto, K., Kimura, S., Moriya, K., & Koike, K., 2004. Hepatitis C virus infection and diabetes: direct involvement of the virus in the development of insulin resistance. Gastroenterology 126, 840-848.

    33. Stancakova, A., Javorsky, M., Kuulasmaa, T., Haffner, S. M., Kuusisto, J., & Laakso, M., 2009. Changes in insulin sensitivity and insulin release in relation to glycemia and glucose tolerance in 6,414 Finnish men. Diabetes 58, 1212-1221.

  • 加载中

Figures(1)

Article Metrics

Article views(903) PDF downloads(2) Cited by()

Related
Proportional views

    Measures of insulin resistance and beta cell function before and after treatment of HCV infection

      Corresponding author: Jizheng Chen, chen_jizheng@gzlab.ac.cn
      Corresponding author: Xinwen Chen, chen_xinwen@gzlab.ac.cn
      Corresponding author: Qian Wang, wqian@njmu.edu.cn
    • a. State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510182, China;
    • b. Jiangsu Province Key Lab of Human Functional Genomics, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, 210029, China;
    • c. State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, 430071, China;
    • d. Guangzhou Laboratory, Guangzhou, 510005, China;
    • e. The First Affiliated Hospital of Xinjiang Medical University, Urumchi, 830054, China

    Abstract: The association between chronic HCV infection and type 2 diabetes mellitus (T2DM) has been established; however, there is limited research on β-cell function particularly in the pre-diabetic population. Here, we evaluated indices of β-cell function and insulin sensitivity across the spectrum from normal glucose tolerance to T2DM in individuals with and without chronic hepatitis C (CHC), and the effects of antiviral treatments on these variables. A total of 153 non-cirrhotic, non-fibrotic CHC patients with a BMI <25 were enrolled in the study. Among them, 119 were successfully treated with either direct acting antiviral (DAA) drugs or pegylated interferon/ribavirin (IFN/RBV) anti-HCV therapy. Fasting state- and oral glucose tolerance test (OGTT)-derived indexes were used to evaluate β-cell function and insulin sensitivity. Among all subjects, 19 (13%) had T2DM and 21% exhibited pre-diabetes including 8% isolated impaired fasting glucose (IFG) and 13% combined IFG and impaired glucose tolerance (IGT). Early and total insulin secretion adjusted for the degree of insulin resistance were decreased in pre-diabetic CHC patients compared to HCV-uninfected individuals. Viral eradication through DAA or IFN/RBV therapy demonstrated positive impacts on insulin sensitivity and β-cell function in CHC patients who achieved sustained virologic response (SVR), regardless of fasting or OGTT state. These findings emphasize the role of HCV in the development of β-cell dysfunction, while also suggesting that viral eradication can improve insulin secretion, reverse insulin resistance, and ameliorate glycemic control. These results have important implications for managing pre-diabetic CHC patients and could prevent diabetes-related clinical manifestations and complications.

    Figure (1)  Reference (33) Relative (20)

    目录

    /

    DownLoad:  Full-Size Img  PowerPoint
    Return
    Return