Impact of IL-6 receptor inhibitors on cerebrospinal fluid metabolites in type 2 diabetes patients

This study aimed to investigate whether interleukin-6 (IL-6) receptor inhibitors affect cerebrospinal fluid (CSF) metabolites in type 2 diabetes (T2D) patients. The initial phase employed drug-targeted Mendelian randomization to investigate the association between IL-6 receptor inhibitors and T2D across diverse populations. Subsequently, variables related to T2D were utilized as mediators in the relationship between IL-6 receptor inhibitors and CSF metabolites. Finally, the mediating effect of T2D was evaluated using mediation analysis. In the European cohort, the use of IL-6 receptor inhibitors was associated with a 25.3% reduction in the risk of T2D, as indicated by an odds ratio of 0.747 with a 95% confidence interval ranging from 0.556 to 0.938 ( P = .003). In the East Asian cohort, IL-6 receptor inhibitors were associated with a 1.188-fold increase in the risk of elevated fasting insulin levels, with an odds ratio of 1.188 and a 95% confidence interval of 1.034 to 1.343 ( P = .029). Mediation analysis revealed that IL-6 receptor inhibitors significantly elevated the levels of galacto-glycero-lipid (GG) in CSF, with 3.06% of the effect attributable to the reduced risk of T2D, and 96.94% directly resulting from the action of the IL-6 receptor inhibitors. The findings preliminarily indicated that race constituted a variable potentially influencing the differential effects of IL-6 receptor inhibitors among patients with type 2 diabetes (T2D) across various regions. While the administration of IL-6 receptor inhibitors might impact glucose concentrations in CSF, the role of T2D as a mediator in CSF metabolites was weak. The predominant determinant appeared to be the administration of IL-6 receptor inhibitors.