Abstract
BACKGROUND: Diabetes mellitus (DM) is the common comorbidity with lung cancer (LC), and metabolic disorders have been identified as significant contributors to the pathogenesis of both DM and LC. The causality between diabetes mellitus and lung cancer is still controversial. Hence, the causal effects of DM on the risk of LC was systemically investigated, and the mediating role of blood metabolites in this relationship was further explored. METHODS: This study utilized a comprehensive Mendelian randomization (MR) analysis to investigate the association between diabetes mellitus and lung cancer. The inverse variance weighted method was employed as the principle approach. MR Egger and weighted median were complementary calculations for MR assessment. A two-step MR analysis was performed to evaluate the mediating effects of blood metabolites as potential intermediate factors. Simultaneously, sensitivity analyses were performed to confirm the lack of horizontal pleiotropy and heterogeneity. RESULTS: The two-sample MR analysis illustrated the overall effect of type 1 diabetes mellitus (T1DM) on lung squamous cell carcinoma (LUSC) (OR: 1.040, 95% CI: 1.010-1.072, p = 0.009). No causal connection was found between T2DM and the subtypes of lung cancer. Two-step MR identified two candidate mediators partially mediating the total effect of T1DM on LUSC, including glutamine conjugate of C6H10O2 levels (17.22%) and 2-hydroxyoctanoate levels (5.85%). CONCLUSION: Our findings supported a potentially causal effect of T1DM against LUSC, and shed light on the importance of metabolites as risk factors in understanding this relationship.