The Impact of Diabetes Mellitus on Hepatocellular Carcinoma Development
Birupaksha Biswas1, Angel Saluja1, Arohi Singh1, Jotishko Biswas2, Girraj Dhakad3
Clinical Epidemiology & Public Health 3(1) 1-8 https://doi.org/10.25163/health.3110235
Submitted: 01 March 2025 Revised: 06 May 2025 Published: 08 May 2025
Abstract
Background: The metabolic disorder Diabetes mellitus constitutes a steadily increasing global health problem which produces multiple complications during its progressive course. New epidemiological studies indicate that diabetes mellitus (DM) leads to hepatocellular carcinoma (HCC) development which ranks as the sixth most common cancer type and presents as one of the most frequent cancer-related fatalities. HCC development results from three main factors which link diabetes mellitus to the disease including insulin resistance, chronic inflammation, hyperglycemia and obesity. Methods: This evaluation will consider research from several populations using case-control studies and cohort studies as well as meta-analyses to explore the molecular pathways between DM and HCC while determining the impact of drinking alcohol and viral hepatitis risks to DM patients. Results: We will analyze how antidiabetic medications affect the risk of HCC development in the final part. The risk of developing HCC is doubled to tripled for subjects with diabetes mellitus according to epidemiologic research. The combination of high blood sugar levels creates inflammation alongside oxidative stress but elevated insulin levels coupled with long-running triggers of insulin-like growth factor 1 activity stimulates new liver cell growth. Some studies show that diabetes mellitus increases HCC development risk mainly when hepatitis B and C infections simultaneously occur. The independent risk factor status of diabetes mellitus exists for the development of HCC regardless of additional liver diseases. Conclusion: Current research remains limited about the HCC developmental effects of weight variations caused by antidiabetic medications alongside diabetes mellitus history.
Keywords: Hepatocellular carcinoma, diabetes mellitus, hyperglycemia, chronic inflammation, metabolic dysregulation.
References
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Aggarwal, G., Kamada, P., & Chari, S. T. (2012). Prevalence of diabetes mellitus in pancreatic cancer compared to common cancers. Pancreas, 42(2), 198–201. https://doi.org/10.1097/mpa.0b013e3182592c96
Akter, T., Ali, M. R., Faruquee, M. N. A., Bashir, M. S., Rahaman, S., Rahman, M. A., & Islam, S. (2024). A comprehensive study of hepatitis B infections in Bangladesh: Epidemiology, risk factors, and clinical-laboratory correlations. Viral Infections and Cancer Research, 1(1), 8426. https://doi.org/10.59429/vicr.v1i1.8426
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Beasley, P. R. (2006b). Diabetes and hepatocellular carcinoma. Hepatology, 44(6), 1408–1410. https://doi.org/10.1002/hep.21430
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Campbell, C., Wang, T., McNaughton, A. L., Barnes, E., & Matthews, P. C. (2020). Risk factors for the development of hepatocellular carcinoma (HCC) in chronic hepatitis B virus (HBV) infection: a systematic review and meta-analysis. Journal of Viral Hepatitis, 28(3), 493–507. https://doi.org/10.1111/jvh.13452
Das, S. S., Hossain, M. S., Sultana, A., Rana, F. A., Hossen, A., Maowla, M. S., Uddin, M. K. M., Sayem, M. A., Hossian, M., & Bashir, M. S. (2025). The influence of chronic kidney disease on hepatocellular carcinoma. Journal of Primeasia, 6(1), 1–8. https://doi.org/10.25163/primeasia.6110204
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Dyal, H. K., Aguilar, M., Bartos, G., Holt, E. W., Bhuket, T., Liu, B., Cheung, R., & Wong, R. J. (2015). Diabetes mellitus increases risk of hepatocellular carcinoma in chronic hepatitis C virus patients: a systematic review. Digestive Diseases and Sciences, 61(2), 636–645. https://doi.org/10.1007/s10620-015-3983-3
El–Serag, H. B., Hampel, H., & Javadi, F. (2006). The association between diabetes and hepatocellular carcinoma: A Systematic Review of Epidemiologic evidence. Clinical Gastroenterology and Hepatology, 4(3), 369–380. https://doi.org/10.1016/j.cgh.2005.12.007
Fujita, K., Iwama, H., Miyoshi, H., Tani, J., Oura, K., Tadokoro, T., Sakamoto, T., Nomura, T., Morishita, A., Yoneyama, H., & Masaki, T. (2016). Diabetes mellitus and metformin in hepatocellular carcinoma. World Journal of Gastroenterology, 22(27), 6100. https://doi.org/10.3748/wjg.v22.i27.6100
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Hossian, M., Hasan, M. M., Sultana, A., Das, S. S., Paul, P., Shamsuzzaman, M., Rahman, M. M., Uddin, M. K. M., Sayem, M. A., & Bashir, M. S. (2024). Potential role of Helicobacter pylori infection in hepatocellular carcinoma: A clinical and laboratory-based study. Journal of Angiotherapy, 8(12), 1–9. https://doi.org/10.25163/angiotherapy.81210217
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Islam, M. R., Yesmin, T., Prapty, A. N., Biswash, M. A. R., Rana, M. S., & Rashid, M. H. O. (2024). Natural environmental sources of resveratrol and its therapeutic role in cancer prevention. Australian Herbal Insight, 7(1), 1–11. https://doi.org/10.25163/ahi.719931
Kuo, C., Grainge, M. J., See, L., Yu, K., Luo, S., Zhang, W., & Doherty, M. (2015). Epidemiology and management of gout in Taiwan: a nationwide population study. Arthritis Research & Therapy, 17(1). https://doi.org/10.1186/s13075-015-0522-8
Kinoshita, Y., Adachi, K., Hongo, M., & Haruma, K. (2011). Systematic review of the epidemiology of gastroesophageal reflux disease in Japan. Journal of Gastroenterology, 46(9), 1092–1103. https://doi.org/10.1007/s00535-011-0429-3
Li, X., Wang, X., & Gao, P. (2017c). Diabetes mellitus and risk of hepatocellular carcinoma. BioMed Research International, 2017, 1–10. https://doi.org/10.1155/2017/5202684
Mekala, K. C., & Bertoni, A. G. (2019). Epidemiology of diabetes mellitus. In Elsevier eBooks (pp. 49–58). https://doi.org/10.1016/b978-0-12-814833-4.00004-6
Mantovani, A., & Targher, G. (2017). Type 2 diabetes mellitus and risk of hepatocellular carcinoma: spotlight on nonalcoholic fatty liver disease. Annals of Translational Medicine, 5(13), 270. https://doi.org/10.21037/atm.2017.04.41
Nawaz, R., Zahid, S., Idrees, M., Rafique, S., Shahid, M., Ahad, A., Amin, I., Almas, I., & Afzal, S. (2017). HCV-induced regulatory alterations of IL-1β, IL-6, TNF-α, and IFN-ϒ operative, leading liver en-route to non-alcoholic steatohepatitis. Inflammation Research, 66(6), 477–486. https://doi.org/10.1007/s00011-017-1029-3
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Reeves, H. L., Zaki, M. Y. W., & Day, C. P. (2016). Hepatocellular carcinoma in obesity, type 2 diabetes, and NAFLD. Digestive Diseases and Sciences, 61(5), 1234–1245. https://doi.org/10.1007/s10620-016-4085-6
Rana, M. S., Bashir, M. S., Das, S. S., Hossain, M., & Barua, S. (2024). Biomarkers for hepatocellular carcinoma: Diagnosis, prognosis, and treatment response assessment – A systematic review. Journal of Primeasia, 5(1), 1–8. https://doi.org/10.25163/primeasia.519784
Ruhl, C. E., & Everhart, J. E. (2003c). Determinants of the association of overweight with elevated serum alanine aminotransferase activity in the United States. Gastroenterology, 124(1), 71–79. https://doi.org/10.1053/gast.2003.50004
Shi, T., Kobara, H., Oura, K., & Masaki, T. (2021). Mechanisms Underlying Hepatocellular Carcinoma Progression in Patients with Type 2 Diabetes. Journal of Hepatocellular Carcinoma, Volume 8, 45–55. https://doi.org/10.2147/jhc.s274933
Salam, M. T., Mou, M. A., et al. (2024). Assessment of lipid profile in hepatocellular carcinoma patients: A prospective study in Bangladesh. Journal of Primeasia, 5(1), 1–8. https://doi.org/10.25163/primeasia.519787
Sagnelli, E., Macera, M., Russo, A., Coppola, N., & Sagnelli, C. (2019). Epidemiological and etiological variations in hepatocellular carcinoma. Infection, 48(1), 7–17. https://doi.org/10.1007/s15010-019-01345-y
Singh, M. K., Das, B. K., Choudhary, S., Gupta, D., & Patil, U. K. (2018). Diabetes and hepatocellular carcinoma: A pathophysiological link and pharmacological management. Biomedicine & Pharmacotherapy, 106, 991–1002. https://doi.org/10.1016/j.biopha.2018.06.095
Tufael, M., Rahman, M. M., Upadhye, V. J., Hossain, M. F., & Uddin, N. (2024). Combined biomarkers for early diagnosis of hepatocellular carcinoma. Journal of Angiotherapy, 8(5), 1–12. https://doi.org/10.25163/angiotherapy.859665
Tufael, M., Kar, A., Rashid, M. H. O., Sunny, A. R., Raposo, A., Islam, M. S., Hussain, M. A., Hussen, M. A., Han, H., Coutinho, H. D. M., Ullah, M. S., & Rahman, M. M. (2024). Diagnostic efficacy of tumor markers AFP, CA19-9, and CEA in hepatocellular carcinoma patients. Journal of Angiotherapy, 8(4), 1–10. https://doi.org/10.25163/angiotherapy.849513
Uddin, M. K. M., Sultana, A., Rahman, M. M., Shamsuzzaman, M., Paul, P., Hasan, M. M., Sayem, M. A., Bashir, M. S., Das, S. S., & Hossian, M. (2025). Cardiovascular complications in patients with hepatocellular carcinoma. Journal of Angiotherapy, 9(1), 1–8. https://doi.org/10.25163/angiotherapy.9110218
Yan, L. (2014). Pathogenesis of chronic hyperglycemia: From reductive stress to oxidative stress. Journal of Diabetes Research, 2014, 1–11. https://doi.org/10.1155/2014/137919
Zhang, S., Meng, Y., Zhou, L., Qiu, L., Wang, H., Su, D., Zhang, B., Chan, K., & Han, J. (2022). Targeting epigenetic regulators for inflammation: Mechanisms and intervention therapy. MedComm, 3(4). https://doi.org/10.1002/mco2.173
Aggarwal, G., Kamada, P., & Chari, S. T. (2012). Prevalence of diabetes mellitus in pancreatic cancer compared to common cancers. Pancreas, 42(2), 198–201. https://doi.org/10.1097/mpa.0b013e3182592c96
Akter, T., Ali, M. R., Faruquee, M. N. A., Bashir, M. S., Rahaman, S., Rahman, M. A., & Islam, S. (2024). A comprehensive study of hepatitis B infections in Bangladesh: Epidemiology, risk factors, and clinical-laboratory correlations. Viral Infections and Cancer Research, 1(1), 8426. https://doi.org/10.59429/vicr.v1i1.8426
Arnold, R., Issar, T., Krishnan, A. V., & Pussell, B. A. (2016). Neurological complications in chronic kidney disease. JRSM Cardiovascular Disease, 5. https://doi.org/10.1177/2048004016677687
Bashir, M. S., Hossian, M., Uddin, M. K. M., Sayem, M. A., Sultana, A., Rana, F. A., Akter, T., Das, N., Rana, M. S., & Das, S. S. (2025). Association between hepatocellular carcinoma and diabetes mellitus. Journal of Primeasia, 6(1), 1–7. https://doi.org/10.25163/primeasia.6110193
Bashir, M. S., Sayem, M. A., Das, S. S., Das, N., Sultana, A., Rahman, M. M., Shamsuzzaman, M., Paul, P., Hossian, M., & Uddin, M. K. M. (2025). High viral load is a risk factor for hepatocellular carcinoma: Clinical and laboratory insights from a cross-sectional study. Journal of Angiotherapy, 9(1), 1–8. https://doi.org/10.25163/angiotherapy.9110219
Beasley, P. R. (2006b). Diabetes and hepatocellular carcinoma. Hepatology, 44(6), 1408–1410. https://doi.org/10.1002/hep.21430
Campbell, C., Wang, T., McNaughton, A. L., Barnes, E., & Matthews, P. C. (2020). Risk factors for the development of hepatocellular carcinoma (HCC) in chronic hepatitis B virus (HBV) infection: a systematic review and meta-analysis. Journal of Viral Hepatitis, 28(3), 493–507. https://doi.org/10.1111/jvh.13452
Chen, C., Yu, M., & Liaw, Y. (1997). Epidemiological characteristics and risk factors of hepatocellular carcinoma. Journal of Gastroenterology and Hepatology, 12(9–10). https://doi.org/10.1111/j.1440-1746.1997.tb00513.x
Das, S. S., Hossain, M. S., Sultana, A., Rana, F. A., Hossen, A., Maowla, M. S., Uddin, M. K. M., Sayem, M. A., Hossian, M., & Bashir, M. S. (2025). The influence of chronic kidney disease on hepatocellular carcinoma. Journal of Primeasia, 6(1), 1–8. https://doi.org/10.25163/primeasia.6110204
De Cól, J. P., De Lima, E. P., Pompeu, F. M., Araújo, A. C., De Alvares Goulart, R., Bechara, M. D., Laurindo, L. F., Méndez-Sánchez, N., & Barbalho, S. M. (2024). Underlying Mechanisms behind the Brain–Gut–Liver Axis and Metabolic-Associated Fatty Liver Disease (MAFLD): An Update. International Journal of Molecular Sciences, 25(7), 3694. https://doi.org/10.3390/ijms25073694
Dyal, H. K., Aguilar, M., Bartos, G., Holt, E. W., Bhuket, T., Liu, B., Cheung, R., & Wong, R. J. (2015). Diabetes mellitus increases risk of hepatocellular carcinoma in chronic hepatitis C virus patients: a systematic review. Digestive Diseases and Sciences, 61(2), 636–645. https://doi.org/10.1007/s10620-015-3983-3
El–Serag, H. B., Hampel, H., & Javadi, F. (2006). The association between diabetes and hepatocellular carcinoma: A Systematic Review of Epidemiologic evidence. Clinical Gastroenterology and Hepatology, 4(3), 369–380. https://doi.org/10.1016/j.cgh.2005.12.007
Fujita, K., Iwama, H., Miyoshi, H., Tani, J., Oura, K., Tadokoro, T., Sakamoto, T., Nomura, T., Morishita, A., Yoneyama, H., & Masaki, T. (2016). Diabetes mellitus and metformin in hepatocellular carcinoma. World Journal of Gastroenterology, 22(27), 6100. https://doi.org/10.3748/wjg.v22.i27.6100
Harding, J. L., Weber, M. B., & Shaw, J. E. (2024). The Global Burden of Diabetes. Textbook of Diabetes, 28–40. https://doi.org/10.1002/9781119697473.ch3
Hassan, M. M., Hwang, L., Hatten, C. J., Swaim, M., Li, D., Abbruzzese, J. L., Beasley, P., & Patt, Y. Z. (2002c). Risk factors for hepatocellular carcinoma: Synergism of alcohol with viral hepatitis and diabetes mellitus. Hepatology, 36(5), 1206–1213. https://doi.org/10.1053/jhep.2002.36780
Hassan, M. M., Hwang, L., Hatten, C. J., Swaim, M., Li, D., Abbruzzese, J. L., Beasley, P., & Patt, Y. Z. (2002b). Risk factors for hepatocellular carcinoma: Synergism of alcohol with viral hepatitis and diabetes mellitus. Hepatology, 36(5), 1206–1213. https://doi.org/10.1053/jhep.2002.36780
Hossian, M., Hasan, M. M., Sultana, A., Das, S. S., Paul, P., Shamsuzzaman, M., Rahman, M. M., Uddin, M. K. M., Sayem, M. A., & Bashir, M. S. (2024). Potential role of Helicobacter pylori infection in hepatocellular carcinoma: A clinical and laboratory-based study. Journal of Angiotherapy, 8(12), 1–9. https://doi.org/10.25163/angiotherapy.81210217
Islam, M. R., Yesmin, T., Prapty, A. N., Biswash, M. A. R., Rana, M. S., & Rashid, M. H. O. (2024). Natural environmental sources of resveratrol and its therapeutic role in cancer prevention. Australian Herbal Insight, 7(1), 1–11. https://doi.org/10.25163/ahi.719931
Kinoshita, Y., Adachi, K., Hongo, M., & Haruma, K. (2011). Systematic review of the epidemiology of gastroesophageal reflux disease in Japan. Journal of Gastroenterology, 46(9), 1092–1103. https://doi.org/10.1007/s00535-011-0429-3
Kuo, C., Grainge, M. J., See, L., Yu, K., Luo, S., Zhang, W., & Doherty, M. (2015). Epidemiology and management of gout in Taiwan: a nationwide population study. Arthritis Research & Therapy, 17(1). https://doi.org/10.1186/s13075-015-0522-8
Li, X., Wang, X., & Gao, P. (2017c). Diabetes mellitus and risk of hepatocellular carcinoma. BioMed Research International, 2017, 1–10. https://doi.org/10.1155/2017/5202684
Mantovani, A., & Targher, G. (2017). Type 2 diabetes mellitus and risk of hepatocellular carcinoma: spotlight on nonalcoholic fatty liver disease. Annals of Translational Medicine, 5(13), 270. https://doi.org/10.21037/atm.2017.04.41
Mekala, K. C., & Bertoni, A. G. (2019). Epidemiology of diabetes mellitus. In Elsevier eBooks (pp. 49–58). https://doi.org/10.1016/b978-0-12-814833-4.00004-6
Nawaz, R., Zahid, S., Idrees, M., Rafique, S., Shahid, M., Ahad, A., Amin, I., Almas, I., & Afzal, S. (2017). HCV-induced regulatory alterations of IL-1β, IL-6, TNF-α, and IFN-ϒ operative, leading liver en-route to non-alcoholic steatohepatitis. Inflammation Research, 66(6), 477–486. https://doi.org/10.1007/s00011-017-1029-3
Ozakyol, A. (2017). Global Epidemiology of Hepatocellular Carcinoma (HCC Epidemiology). Journal of Gastrointestinal Cancer, 48(3), 238–240. https://doi.org/10.1007/s12029-017-9959-0
Rana, M. S., Bashir, M. S., Das, S. S., Hossain, M., & Barua, S. (2024). Biomarkers for hepatocellular carcinoma: Diagnosis, prognosis, and treatment response assessment – A systematic review. Journal of Primeasia, 5(1), 1–8. https://doi.org/10.25163/primeasia.519784
Reeves, H. L., Zaki, M. Y. W., & Day, C. P. (2016). Hepatocellular carcinoma in obesity, type 2 diabetes, and NAFLD. Digestive Diseases and Sciences, 61(5), 1234–1245. https://doi.org/10.1007/s10620-016-4085-6
Ruhl, C. E., & Everhart, J. E. (2003c). Determinants of the association of overweight with elevated serum alanine aminotransferase activity in the United States. Gastroenterology, 124(1), 71–79. https://doi.org/10.1053/gast.2003.50004
Sagnelli, E., Macera, M., Russo, A., Coppola, N., & Sagnelli, C. (2019). Epidemiological and etiological variations in hepatocellular carcinoma. Infection, 48(1), 7–17. https://doi.org/10.1007/s15010-019-01345-y
Salam, M. T., Mou, M. A., et al. (2024). Assessment of lipid profile in hepatocellular carcinoma patients: A prospective study in Bangladesh. Journal of Primeasia, 5(1), 1–8. https://doi.org/10.25163/primeasia.519787
Shi, T., Kobara, H., Oura, K., & Masaki, T. (2021). Mechanisms Underlying Hepatocellular Carcinoma Progression in Patients with Type 2 Diabetes. Journal of Hepatocellular Carcinoma, Volume 8, 45–55. https://doi.org/10.2147/jhc.s274933
Singh, M. K., Das, B. K., Choudhary, S., Gupta, D., & Patil, U. K. (2018). Diabetes and hepatocellular carcinoma: A pathophysiological link and pharmacological management. Biomedicine & Pharmacotherapy, 106, 991–1002. https://doi.org/10.1016/j.biopha.2018.06.095
Tufael, M., Kar, A., Rashid, M. H. O., Sunny, A. R., Raposo, A., Islam, M. S., Hussain, M. A., Hussen, M. A., Han, H., Coutinho, H. D. M., Ullah, M. S., & Rahman, M. M. (2024). Diagnostic efficacy of tumor markers AFP, CA19-9, and CEA in hepatocellular carcinoma patients. Journal of Angiotherapy, 8(4), 1–10. https://doi.org/10.25163/angiotherapy.849513
Tufael, M., Rahman, M. M., Upadhye, V. J., Hossain, M. F., & Uddin, N. (2024). Combined biomarkers for early diagnosis of hepatocellular carcinoma. Journal of Angiotherapy, 8(5), 1–12. https://doi.org/10.25163/angiotherapy.859665
Uddin, M. K. M., Sultana, A., Rahman, M. M., Shamsuzzaman, M., Paul, P., Hasan, M. M., Sayem, M. A., Bashir, M. S., Das, S. S., & Hossian, M. (2025). Cardiovascular complications in patients with hepatocellular carcinoma. Journal of Angiotherapy, 9(1), 1–8. https://doi.org/10.25163/angiotherapy.9110218
Yan, L. (2014). Pathogenesis of chronic hyperglycemia: From reductive stress to oxidative stress. Journal of Diabetes Research, 2014, 1–11. https://doi.org/10.1155/2014/137919
Zhang, S., Meng, Y., Zhou, L., Qiu, L., Wang, H., Su, D., Zhang, B., Chan, K., & Han, J. (2022). Targeting epigenetic regulators for inflammation: Mechanisms and intervention therapy. MedComm, 3(4). https://doi.org/10.1002/mco2.173
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