Type 2 diabetes mellitus and risk of hepatocellular carcinoma: spotlight on nonalcoholic fatty liver disease

The incidence of both type 2 diabetes mellitus (T2DM) and multiple cancer types are rapidly increasing worldwide. Several studies documented that T2DM is closely associated with an increased incidence of cancer. However, while some methodological considerations preclude a definitive association between T2DM and the risk of certain cancers, the relationship between T2DM and increased risk of incident hepatocellular carcinoma (HCC) remains significant even after adjustment for detection bias and reverse causation, indicating that such association is clinically reliable and robust. In addition, a number of observational studies also showed that T2DM is associated with higher mortality among persons with HCC. Some recent meta-analyses suggested that treatment with metformin may be associated with a lower risk of HCC, and may also beneficially influence HCC prognosis, whereas treatment with sulphonylureas or insulin seems to be related to a higher HCC risk. The underlying biological mechanisms linking T2DM and HCC are complex and difficult to elucidate, but the existence of close inter-connections among T2DM, obesity and nonalcoholic fatty liver disease (NAFLD) induces hepatic/systemic insulin resistance and causes the release of multiple pro-inflammatory cytokines, vasoactive factors and pro-oxidant molecules, which are all potentially implicated in the development and progression of HCC. In this clinical review, we discuss the epidemiological evidence linking T2DM to the risk of HCC. Moreover, we also briefly discuss the putative underlying mechanisms linking T2DM, NAFLD and HCC, and the potential effect of certain hypoglycemic agents on the risk of developing HCC.