Obesity has consistently been shown to be associated with a higher risk of prostate cancer (PCa) death. Insulin resistance is a hypothesized biological mechanism in this association; however, data in support of this hypothesis is limited. We investigated mediation of the triglyceride-glucose (TyG) index, an indicator of insulin resistance, in the association of body mass index (BMI) with PCa death. The study included 259,884 men from eight European cohorts, with 11,760 incident PCa’s and 1784 PCa deaths during follow-up. We analysed PCa cases with follow-up from PCa diagnosis, as well as the full cohort with follow-up from the baseline cancer-free state, thus incorporating both PCa incidence and death. We calculated hazard ratios (HR) and the proportion of the total effect of body mass index (BMI) on PCa death mediated through TyG index. In the PCa-case-only analysis, TyG index was positively associated with PCa death (HR per 1-standard deviation: 1.11, 95% confidence interval (CI); 1.01–1.22), and mediated a substantial proportion of the baseline BMI effect on PCa death (HRtotal effect per 5-kg/m2 BMI: 1.24; 1.14–1.35, of which 28%; 4%–52%, mediated). In contrast, in the full cohort, the TyG index was not associated with PCa death (HR: 1.03; 0.94-1.13), hence did not substantially mediate the effect of BMI on PCa death. We conclude that insulin resistance could be an important pathway through which obesity accelerates PCa progression to death. The study has been published in the British Journal of Cancer.
