Molecular insights into Parkinson's disease and type 2 diabetes mellitus: Metformin's role and genetic pathways explored.

Background To explore whether there is a bidirectional relationship between Parkinson's disease (PD) and type 2 diabetes mellitus (T2DM), study the common pathogenic mechanisms, screen relevant genes involved in the pathological process, and predict the potential targets of metformin (Met), so as to develop new therapeutic strategies. Method A two-sample Mendelian randomization (MR) analysis was conducted to analyze the correlation between PD and T2DM. Common confounding genes identified in both PD and T2DM datasets were subjected to GO and KEGG analysis, PPI network analysis, and Hub gene identification. qPCR was used to verify the expression of hub genes in an animal model of T2DM complicated with PD. Subsequently, the analysis focused on whether metformin alleviates the behavioral and pathological manifestations of PD aggravated by T2DM. The intersection of metformin with T2DM and PD targets was identified, and the core targets and signaling pathways were analyzed. Finally, molecular docking analysis was performed between metformin and core proteins to identify the docking sites. Result Through MR analysis, a positive correlation between PD and T2DM was identified, indicating a mutual causal relationship. The hub genes RAC1, TPM2, MGA, and DENND3 are up-regulated in animal models of T2DM with PD. Met targets intersecting with T2DM and PD were analyzed, revealing 17 and 21 intersecting genes respectively, involved in various pathways related to oxidative stress, immune, and inflammation. PPI analysis identified hub genes for T2DM (MMP9, NCF1, CYCS, EIF4E, SOD2) and PD (GFAP, VIM, MOCOS, EIF1, TH, ACTA2, CDC42). Animal models validated the expression of these genes and pathways. Molecular docking analysis explored Met's binding sites on proteins, with lower binding energies indicating greater stability. Conclusion This study contributes to a deeper understanding of the co pathogenesis of PD and T2DM, and provides new insights into the role of metformin in this disease.