Abstract
OBJECTIVE: Whether fasting insulin (FI) plays a role in cancer risk remains unclear. This study aimed to investigate the association between FI and cancer risk and to explore its potential mediator role in the association between type 2 diabetes mellitus (T2DM) and cancer. METHODS: Two-sample Mendelian randomization (TSMR) analysis was performed to evaluate the effect of FI on overall and 14 site-specific cancers using genome-wide association study (GWAS) summary-level data from Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) and consortia of 14 site-specific cancers. The primary MR approach was conducted by using the random-effect inverse-variance weighted (IVW) method, and sensitivity analyses were implemented by adopting weighted-median, weighted-mode, MR-Egger, and MR-PRESSO tests. Polygenic risk score analysis was executed by using individual-level data from UK Biobank to validate the findings from TSMR analyses. Multivariable Mendelian randomization (MVMR) was carried out to estimate the mediation effect of FI on the association between T2DM and cancer. RESULTS: TSMR study suggested that genetically determined high FI levels were associated with increased risk of colorectal cancer (odds ratio (OR) = 1.87, 95% CI: 1.23-2.84, p = 0.003) and endometrial cancer (OR = 1.89, 95% CI: 1.08-3.01, p = 0.008), but not associated with overall cancer risk or the other 12 studied cancer sites. Polygenic risk score analysis successfully replicated the association between genetic liability to high FI levels and the increased risk of colorectal and endometrial cancers. MVMR and MR mediation analyses detected an intermediary effect of FI and quantified that FI mediated 21.3% of the association between T2DM and endometrial cancer. CONCLUSIONS: This study demonstrated that FI levels are associated with the risk of colorectal and endometrial cancers, and FI was found to play an intermediary role in the association between T2DM and endometrial cancer. The associations between FI and other cancers need to be further studied.