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

Abstract

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.

Keywords: Diabetes; cancer; hepatocellular carcinoma (HCC); nonalcoholic fatty liver disease (NAFLD).

Figure 1

Putative biological mechanisms linking type 2 diabetes mellitus and nonalcoholic fatty liver disease (NAFLD) to the development and progression of hepatocellular carcinoma. The biological mechanisms underlying the association between type 2 diabetes, NAFLD and hepatocellular carcinoma are complex and not entirely understood. Both type 2 diabetes and NAFLD are strongly associated with abdominal obesity, hepatic/peripheral insulin resistance, low-grade chronic inflammation and increased oxidative stress that may contribute to the development and progression of hepatocellular carcinoma, promoting increased cellular growth and proliferation, inhibition of cellular apoptosis, increased angiogenesis and DNA damage. Insulin resistance and coexistent chronic hyperinsulinemia lead to increased production of insulin-like growth factor 1 (IGF-1), which further promotes hepatic cellular growth/proliferation and inhibits cellular apoptosis within the liver. In addition, chronic hyperinsulinemia also activates insulin receptor substrate-1 (IRS-1), which plays a key role in the regulation of multiple cytokine pathways potentially implicated in the pathophysiology of hepatocellular carcinoma. Evidence also suggests that insulin resistance alters gut microbiota (dysbiosis) and increases circulating levels of free fatty acids, which promote hepatic steatosis (NAFLD); both of these pathologic conditions play a part in the development and progression of hepatocellular carcinoma. In particular, clear evidence indicates that NAFLD, especially in its necro-inflammatory form, exacerbates hepatic/peripheral insulin resistance and causes the intrahepatic release of multiple hepatokines and mediators that increase the risk of hepatic carcinogenesis.