Causal inference study on the effect of exogenous insulin on the risk of osteoarthritis

The study explores the previously unexamined link between exogenous insulin treatment for diabetes mellitus and its potential to alter the risk of osteoarthritis (OA) using Mendelian randomization (MR) to investigate a possible causal relationship. By employing a variety of two-sample MR methodologies, including instrumental variable weighting (IVW), weighted median, MR-Egger, weighted mode, simple mode, and conducting multivariate MR (MVMR) Analysis, this research aims to assess the direct effects of exogenous insulin on OA, while also considering the mediating roles of diabetes and smoking status. Our findings through the IVW model reveal a significant causal association, indicating that exogenous insulin use is linked to a decreased risk of OA, evidenced by an odds ratio (OR) of 0.00029 (95% CI: 0-0.694, P = .040158), with no causal effect identified from OA towards exogenous insulin in reverse MR analysis. Further mediation analysis highlights diabetes and smoking as significant mediators of insulin's effect on OA, with diabetes and smoking respectively accounting for 74.26%, 70.11%, and 43.34% of the mediation effect through various indicators. Consequently, this MR study provides substantial evidence of a causal relationship between exogenous insulin use and a reduced OA risk, emphasizing the importance of holistic management for diabetic patients to carefully weigh the benefits of insulin therapy against its potential OA risks.