Uncovering Comorbid Genes Linking Type 2 Diabetes and Glioblastoma Using Single-Cell Transcriptomics of Peripheral Blood and Mendelian Randomization

Background: Type 2 diabetes mellitus (T2DM) constitutes a prevalent chronic metabolic disturbance driven by defective insulin secretion and systemic insulin resistance. Glioblastoma (GBM), in turn, represents the most malignant and invasive primary neoplasm of the adult central nervous system. Both disorders constitute major threats to global public health and impose substantial clinical and socioeconomic burdens; nevertheless, the overlapping genetic architecture and core molecular regulatory networks connecting these two pathologies remain largely uncharacterized. <div> <br> </div> <div> Objective: This study aims to pinpoint candidate genes implicated in the comorbid pathogenesis of T2DM and GBM, clarify the intrinsic molecular mechanisms that underlie their pathological connection, and establish a robust theoretical framework to guide subsequent mechanistic investigations and translational clinical strategies </div> <div> <br> </div> <div> Methods: First, we analyzed single-cell sequencing(scRNseq) data from patients with T2DM and GBM, identified differentially expressed genes (DEGs) for each disease, and performed cell annotation analysis; we then conducted an intersection analysis of the genes corresponding to the macrophage clusters in both diseases to identify genes common to both conditions; Identify key genes with causal relationships to the two diseases using Mendelian randomization (MR) analysis; further conduct gene-gene interaction (GGI) network analysis, as well as association analyses between key genes and microRNAs (miRNAs), diseases, and drugs; At the same time, we will explore intercellular interactions through cell communication analysis and use Virtual Knockout (vKO) Analysis to validate the roles of key genes in the onset and progression of these two diseases. </div> <div> <br> </div> <div> Results: Analysis of single-cell sequencing data revealed 236 genes shared between T2DM and GBM; meta-replication analysis confirmed that four key genes-MCOLN2, RIN1, ZFP36L1, and ZNF395-all have clear causal associations with both T2DM and GBM.GGI analysis further indicates that the aforementioned key genes are closely associated with genes such as EGFR and signaling pathways such as the MAPK pathway; Analysis of key gene-miRNA associations suggests that these key genes participate in post-transcriptional regulation through miRNAs such as hsa-miR-7-2-3p, hsa-miR-153-5p, hsa-miR-548as-3p, and hsa-miR-4308; Analysis of gene-disease and gene-drug associations indicates that lipopolysaccharides may serve as potential therapeutic agents for both diseases. Analysis of cellular communication reveals that macrophages act as central hub cells within the entire communication network; vKO of key genes shows that these genes are all immune-related transcriptional repressors that regulate the immune microenvironment. </div> <div> <br> </div> <div> Conclusions: This study identifies MCOLN2, RIN1, ZFP36L1, and ZNF395 as key genes underlying the comorbidity of T2DM and GBM. It systematically elucidates the molecular interactions among these key genes and their potential therapeutic implications, thereby providing a foundation for further elucidating the underlying mechanisms linking the two diseases. </div>