The role of insulin and incretin-based drugs in biliary tract cancer: epidemiological and experimental evidence

Insulin and incretin-based drugs are important antidiabetic agents with complex effects on cell growth and metabolism. Emerging evidence shows that insulin and incretin-based drugs are associated with altered risk of biliary tract cancer (BTC). Observational study reveals that insulin is associated with an increased risk of extrahepatic cholangiocarcinoma (ECC), but not intrahepatic cholangiocarcinoma (ICC) or gallbladder cancer (GBC). This type-specific effect can be partly explained by the cell of origin and heterogeneous genome landscape of the three subtypes of BTC. Similar to insulin, incretin-based drugs also exhibit very interesting contradictions and inconsistencies in response to different cancer phenotypes, including BTC. Both epidemiological and experimental evidence suggests that incretin-based drugs can be a promoter of some cancers and an inhibitor of others. It is now more apparent that this type of drugs has a broader range of physiological effects on the body, including regulation of endoplasmic reticulum stress, autophagy, metabolic reprogramming, and gene expression. In particular, dipeptidyl peptidase-4 inhibitors (DPP-4i) have a more complex effect on cancer due to the multi-functional nature of DPP-4. DPP-4 exerts both catalytic and non-enzymatic functions to regulate metabolic homeostasis, immune reaction, cell migration, and proliferation. In this review, we collate the epidemiological and experimental evidence regarding the effect of these two classes of drugs on BTC to provide valuable information.