Diabetes and Hepatocellular Carcinoma Risk Factors

Diabetes mellitus, particularly type 2, has emerged as a significant contributor to the global burden of hepatocellular carcinoma (HCC). Chronic hyperglycaemia and compensatory hyperinsulinaemia promote hepatocyte proliferation, oxidative stress and pro-inflammatory signalling, creating a milieu favourable to oncogenesis. Insulin resistance often coexists with obesity, dyslipidaemia and nonalcoholic fatty liver disease (NAFLD), which may progress to nonalcoholic steatohepatitis (NASH) and cirrhosis—key precursors of HCC. Antidiabetic therapies further modulate risk: some agents appear to confer protection, while exogenous insulin may enhance mitogenic pathways. Interactions with viral hepatitis, alcohol intake and genetic susceptibility add complexity. Early identification of high-risk individuals via metabolic and fibrosis biomarkers enables targeted surveillance and preventive interventions, underscoring the global importance of integrated metabolic and liver health management.

Research from Nature Portfolio

Recent analyses comparing antidiabetic regimens have revealed differential effects on HCC incidence. A comprehensive network meta-analysis across observational and trial data showed that metformin use was associated with the greatest reduction in HCC risk, roughly halving incidence compared with insulin and sulphonylureas, while insulin therapy corresponded to a two- to threefold increase in risk. These findings support prioritising insulin-sensitising strategies in patients with diabetes at elevated HCC risk. In parallel, mechanistic work in murine models demonstrated that insulin receptor substrate-1 (Irs1) is upregulated in chemically induced HCC lesions and that hepatocyte-specific deletion of Irs1 markedly attenuates tumour development. This study also linked Wnt/β-catenin signalling to Irs1 induction, implicating a convergence of growth factor and developmental pathways in diabetes-associated hepatocarcinogenesis.

Diabetes and Hepatocellular Carcinoma Risk Factors publication trend

The graph below shows the total number of articles in diabetes and hepatocellular carcinoma risk factors across all publications each year (not limited to Nature Index journals).

Technical terms

Hyperglycaemia: Elevated blood glucose concentration over prolonged periods.

Hyperinsulinaemia: Chronically increased circulating insulin, often secondary to insulin resistance.

Insulin resistance: Reduced sensitivity of target tissues to insulin’s actions, promoting compensatory insulin secretion.

Nonalcoholic steatohepatitis (NASH): Advanced form of NAFLD characterised by hepatic inflammation and fibrosis.

Network meta-analysis: Statistical method comparing multiple interventions using direct and indirect evidence.

Insulin receptor substrate (Irs1): Intracellular adaptor protein mediating insulin and IGF signalling in hepatocytes.

FIB-4 index: Fibrosis-4 score calculated from age, liver enzymes and platelets to estimate hepatic fibrosis.

References

1. The association between alcohol consumption and the risk of hepatocellular carcinoma according to glycemic status in Korea: A nationwide population-based study. PLOS Medicine (2023).
2. Systematic Review with Network Meta-Analysis: Antidiabetic Medication and Risk of Hepatocellular Carcinoma. Scientific Reports (2016).
3. Hepatocellular carcinoma development in diabetic patients: a nationwide survey in Japan. Journal of Gastroenterology (2021).
4. Role of insulin receptor substrates in the progression of hepatocellular carcinoma. Scientific Reports (2017).
5. Metformin Actions on the Liver: Protection Mechanisms Emerging in Hepatocytes and Immune Cells against NASH-Related HCC. International Journal of Molecular Sciences (2021).