Osteoprotegerin lowers type 2 diabetes risk: insights from drug-target Mendelian randomization and mediation analysis

Abstract Background Observational evidence suggests that denosumab, which acts through a mechanism partially analogous to that of the endogenous protein osteoprotegerin (OPG), may be associated with a lower risk of type 2 diabetes (T2D). This raises the possibility that modulation of the OPG pathway may influence diabetes risk. We aim to assess the causal effect of circulating OPG levels on the risk of T2D, glycemic traits, and the mediating effect of pancreatic β-cell function. Methods We conducted a drug-target Mendelian randomization (MR) analysis to evaluate the causal effect of circulating OPG levels on T2D risk. Instrument discovery, exposure effect estimation, and outcome association were performed using separate summary-level data sources. As secondary analyses, we examined the causal effects of circulating OPG levels on glycemic traits. We further performed mediation analysis to quantify the contribution of β-cell function, measured by the homeostasis model assessment of β-cell function. Results Genetically elevated OPG levels were associated with a significantly lowered risk of T2D, with an odds ratio of 0.912 (95% confidence interval (CI) = [0.857, 0.972]; P = 0.004). In secondary analyses, higher OPG levels were nominally associated with lower glycated hemoglobin levels (β = -0.027, 95% CI = [-0.050, -0.004]; P = 0.023). Mediation analysis suggested that enhanced β-cell function may partly mediate the protective association between OPG and T2D. Conclusions These findings provide genetic evidence from a drug-target MR framework that genetically predicted higher OPG levels were associated with lower T2D risk, partly through improvements in β-cell function, and support further investigation of OPG pathway modulation for T2D prevention. Exploratory secondary analyses also suggested a potential association with lower HbA1c levels. Overall, these findings support further investigation of pharmacological modulation of the OPG pathway, including whether RANKL inhibition with denosumab may have implications for T2D risk.