Integrative Multi-Omics and Machine Learning Reveal Shared Biomarkers in Type 2 Diabetes and Atherosclerosis

Atherosclerosis (AS) is a leading cause of death and disability in type 2 diabetes mellitus (T2DM). However, the shared molecular mechanisms linking T2DM and atherosclerosis have not been fully elucidated. We analyzed AS- and T2DM-related gene expression profiles from the Gene Expression Omnibus (GEO) database to identify overlapping differentially expressed genes and co-expression signatures. Functional enrichment (Gene Ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG)) and protein-protein interaction (PPI) network analyses were then used to describe the pathways and interaction modules associated with these shared signatures, We next applied the cytoHubba algorithm together with several machine learning methods to prioritize hub genes and evaluate their diagnostic potential and combined CIBERSORT-based immune cell infiltration analysis with single-cell RNA sequencing data to examine cell types and the expression patterns of the shared genes in specific cell populations. We identified 72 shared feature genes. Functional enrichment analysis of these genes revealed significant enrichment of inflammatory- and metabolism-related pathways. Three genes-IL1B, MMP9, and P2RY13-emerged as shared hub genes and yielded robust ANN-based predictive performance across datasets. Immune deconvolution and single-cell analyses consistently indicated inflammatory amplification and an imbalance of macrophage polarization in both conditions. Biology mapped to the hubs suggests IL1B drives inflammatory signaling, MMP9 reflects extracellular-matrix remodeling, and P2RY13 implicates cholesterol transport. Collectively, these findings indicate that T2DM and AS converge on immune and inflammatory processes with macrophage dysregulation as a central axis; IL1B, MMP9, and P2RY13 represent potential biomarkers and therapeutic targets and may influence disease progression by regulating macrophage states, supporting translational application to diagnosis and treatment of T2DM-related atherosclerosis. These findings are preliminary. Further experimental and clinical studies are needed to confirm their validity, given the limitations of the present study.