Insulin Use and The Risk of Hepatocellular Carcinoma: Insights and Implications

Juferdy Kurniawan, Maria Teressa

Abstract


In recent years, the incidence of diabetes mellitus and hepatocellular carcinoma (HCC) has been increasing worldwide, in the context of an increasing prevalence of non-alcoholic fatty liver disease (NAFLD). In patients with diabetes mellitus, exogenous insulin is commonly prescribed and used in long-term settings. Recent studies suggest that insulin use may elevate the risk of HCC. A substantial body of work seeks to unpack the association between insulin use and the risk of developing HCC, although there may be conflicting evidence. Further validation is necessary to clarify the true relationship between insulin mechanisms and its hepatocarcinogenic effect. Given the burden of diabetic patients developing HCC, diabetologists and hepatologists must collaborate, particularly regarding the prevention and surveillance of HCC in diabetic patients.


Keywords


hepatocellular carcinoma; insulin; insulin use; risk

References


Villanueva A. Hepatocellular carcinoma. N Engl J Med. 2019;380(15):1452–62.

Wong RJ, Cheung R, Ahmed A. Nonalcoholic steatohepatitis is the most rapidly growing indication for liver transplantation in patients with hepatocellular carcinoma in the U.S. Hepatology. 2014; 59(6):2188-95.

Tsilidis KK, Kasimis JC, Lopez DS, Ntzani EE, Ioannidis JP. Type 2 diabetes and cancer: umbrella review of meta-analyses of observational studies. BMJ. 2015;350:g7607.

Amarapurkar DN, Patel ND, Kamani PM. Impact of diabetes mellitus on outcome of HCC. Ann Hepatol. 2008;7(2):148-51.

Plaz Torres MC, Jaffe A, Perry R, Marabotto E, Strazzabosco M, Giannini EG. Diabetes medications and risk of HCC. Hepatology. 2022;76(6):1880-97.

Perkumpulan Endokrinologi Indonesia. Petunjuk Praktis Terapi Insulin pada Pasien Diabetes Melitus. Jakarta: PB Perkeni; 2021.

Cherrington AD, Moore MC, Sindelar DK, Edgerton DS. Insulin action on the liver in vivo. Biochem Soc Trans. 2007;35(Pt 5):1171-4.

Hopkins BD, Goncalves MD, Cantley LC. Insulin-PI3K signalling: an evolutionarily insulated metabolic driver of cancer. Nat Rev Endocrinol. 2020;16(5):276-83.

Zhang W, Liu HT. MAPK signal pathways in the regulation of cell proliferation in mammalian cells. Cell Res. 2002;12(1):9-18.

Mardilovich K, Pankratz SL, Shaw LM. Expression and function of the insulin receptor substrate proteins in cancer. Cell Commun Signal. 2009;7:14.

Audzeyenka I, Rogacka D, Rachubik P, Typiak M, Rychłowski M, Angielski S, Piwkowska A. The PKGIα–Rac1 pathway is a novel regulator of insulin-dependent glucose uptake in cultured rat podocytes. J Cell Physiol. 2021;236(6):4655-68.

Hers I, Vincent EE, Tavaré JM. Akt signalling in health and disease. Cell Signal. 2011;23(10):1515-27.

Sarbassov DD, Ali SM, Sabatini DM. Growing roles for the mTOR pathway. Curr Opin Cell Biol. 2005;17(6):596-603.

Nagao H, Cai W, Wewer Albrechtsen NJ, et al. Distinct signaling by insulin and IGF-1 receptors and their extra- And intracellular domains. Proc Natl Acad Sci U S A. 2021;118(17): e2019474118.

Chettouh H, Lequoy M, Fartoux L, Vigouroux C, Desbois-Mouthon C. Hyperinsulinaemia and insulin signalling in the pathogenesis and the clinical course of hepatocellular carcinoma. Liver Int. 2015;35(10):2203-17.

Tran TT, Medline A, Bruce WR. Insulin promotion of colon tumors in rats. Cancer Epidemiol Biomarkers Prev. 1996;5(12):1013-5.

Bowker SL, Majumdar SR, Veugelers P, Johnson JA. Increased cancer-related mortality for patients with type 2 diabetes who use sulfonylureas or insulin. Diabetes Care. 2006;29(2):254-8.

Pisani P. Hyper-insulinaemia and cancer, meta-analyses of epidemiological studies. Arch Physiol Biochem. 2008;114(1):63-70.

Chettouh H, Fartoux L, Aoudjehane L, et al. Mitogenic insulin receptor-A is overexpressed in human hepatocellular carcinoma due to EGFR-mediated dysregulation of RNA splicing factors. Cancer Res. 2013;73(13):3974-86.

Tanaka S, Wands JR. Insulin receptor substrate 1 overexpression in human hepatocellular carcinoma cells prevents transforming growth factor β1-induced apoptosis. Cancer Res. 1996;56(15):3391-4.

Boissan M, Beurel E, Wendum D, et al. Overexpression of insulin receptor substrate-2 in human and murine hepatocellular carcinoma. Am J Pathol. 167(3):869-77.

Pollak M. Insulin and insulin-like growth factor signalling in neoplasia. Nat Rev Cancer. 2008;8(12):915-28.

Gu Y, Wang C, Zheng Y, et al. Cancer incidence and mortality in patients with type 2 diabetes treated with human insulin: A cohort study in Shanghai. PLoS One. 2013;8(1):e53411.

Kasmari AJ, Welch A, Liu G, Leslie D, McGarrity T, Riley T. Independent of cirrhosis, hepatocellular carcinoma risk is increased with diabetes and metabolic syndrome. Am J Med. 2017;130(6):746.e1-746.e7.

Schlesinger S, Aleksandrova K, Pischon T, et al. Diabetes mellitus, insulin treatment, diabetes duration, and risk of biliary tract cancer and hepatocellular carcinoma in a European Cohort. Ann Oncol. 2013; 24(9):2449-55.

Bosetti C, Franchi M, Nicotra F, et al. Insulin and other antidiabetic drugs and hepatocellular carcinoma risk: a nested case-control study based on Italian healthcare utilization databases. Pharmacoepidemiol Drug Saf. 2015;24(7):771-8.

Singh S, Singh PP, Singh AG, Murad MH, Sanchez W. Anti-diabetic medications and the risk of hepatocellular cancer: a systematic review and meta-analysis. Am J Gastroenterol. 2013;108(6):881-91; quiz 892

Mannucci E, Monami M, Balzi D, et al. Doses of insulin and its analogues and cancer occurrence in insulin-treated type 2 diabetic patients. Diabetes Care. 33(9):1997-2003.

Oliveria SA, Koro CE, Ulcickas Yood M, Sowell M. Cancer incidence among patients treated with antidiabetic pharmacotherapy. Diabetes Metab Syndr Clin Res Rev. 2008;2(1):45-57.

Simon TG, King LY, Chong DQ, et al. Diabetes, metabolic comorbidities, and risk of hepatocellular carcinoma: results from two prospective cohort studies. Hepatology. 2018;67(5):1797-806.

Lai SW, Chen PC, Liao KF, Muo CH, Lin CC, Sung FC. Risk of hepatocellular carcinoma in diabetic patients and risk reduction associated with anti-diabetic therapy: a population-based cohort study. Am J Gastroenterol. 2012;107(1):46-52.

Kementerian Kesehatan Republik Indonesia. Pedoman nasional pelayanan kedokteran tata laksana karsinoma sel hati pada dewasa Indonesia. 2022;39–97. Available from: jdih.kemkes.go.id

Nakatsuka T, Tateishi R. Nakatsuka T, Tateishi R. Development and prognosis of hepatocellular carcinoma in patients with diabetes. Clin Mol Hepatol. 2023;29(1):51-64.

Tateishi R, Matsumura T, Okanoue T, et al. Hepatocellular carcinoma development in diabetic patients: a nationwide survey in Japan. J Gastroenterol. 2021;56(3):261-73.

Kawaguchi T, Taniguchi E, Morita Y, et al. Association of exogenous insulin or sulphonylurea treatment with an increased incidence of hepatoma in patients with hepatitis C virus infection. Liver Int. 2010; 30(3):479-86.

Kramer JR, Natarajan Y, Dai J, et al. Effect of diabetes medications and glycemic control on risk of hepatocellular cancer in patients with nonalcoholic fatty liver disease. Hepatology. 2022;75(6):1420-8.


Full Text: PDF

Refbacks

  • There are currently no refbacks.


Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.