To explore the genetic association between hyperlipidemia and type 2 diabetes mellitus using the Mendelian randomization（MR）method, and to clarify the potential mediating role of circulating inflammatory factors in the relationship between them.

Public Genome-wide association study（GWAS）data was used. The hyperlipidemia data was obtained from GCST90475724（including 436 724 cases, with 17 425 cases of hyperlipidemia）. The T2DM data was from a study by Loh PR and other authors on 468 298 European individuals. The inflammatory factor data was derived from the plasma proteome study by TRAYLOR M（91 analyzable inflammatory factors were screened out）. A two-sample bidirectional MR analysis was conducted to evaluate the total effect between hyperlipidemia and T2DM. A two-step MR method was used for mediation analysis. First, the causal effect of hyperlipidemia on inflammatory factors was determined, and then the impact of inflammatory factors on T2DM was assessed, so as to quantify the direct effect and mediating effect. For the selection of instrumental variables single nucleotide polymorphisms（SNPs）, a significant association criterion of P < 5 × 10^-8 was adopted. Linkage disequilibrium screening（R² < 0.001, threshold of 10 000 kb）and F-statistic（> 10）were used to ensure the validity of instrumental variables. The inverse variance weighting（IVW）was used as the main analysis method, supplemented by sensitivity analyses such as maximum likelihood method, weighted median method, MR-Egger regression and MR-PRESSO to verify the robustness of the results.

There was a significant association between hyperlipidemia and T2DM（OR = 1.748, 95% CI = 1.013-3.015, P = 0.044）, and there was no significant heterogeneity or horizontal pleiotropy. Mediation analysis found that 7 inflammatory factors were associated with T2DM. Among them, fibroblast growth factor 21（FGF21, OR = 1.595, P = 0.009）was a risk factor, and fibroblast growth factor 19（FGF19, OR = 0.807, P = 0.001）was a protective factor. Further analysis showed that interleukin-4（IL-4, OR = 1.089, P = 0.012）and FGF19（OR = 0.863, P = 0.043）might act as mediating factors and participate in the causal pathway from hyperlipidemia to T2DM.

This study reveals the genetic causal relationship between hyperlipidemia and T2DM, confirms the mediating role of specific inflammatory factors in the association between the two. At the same time, traditional Chinese medicine plays an important role in the treatment of both diseases, providing genetic evidence and important means for preventing or treating T2DM by regulating inflammatory factors.