Novel insights into immune-related genes associated with type 2 diabetes mellitus-related cognitive impairment.

Background: The cognitive impairment in type 2 diabetes mellitus (T2DM) is a multifaceted and advancing state that requires further exploration to fully comprehend. Neuroinflammation is considered to be one of the main mechanisms and the immune system has played a vital role in the progression of the disease.

Aim: To identify and validate the immune-related genes in the hippocampus associated with T2DM-related cognitive impairment.

Methods: To identify differentially expressed genes (DEGs) between T2DM and controls, we used data from the Gene Expression Omnibus database GSE125387. To identify T2DM module genes, we used Weighted Gene Co-Expression Network Analysis. All the genes were subject to Gene Set Enrichment Analysis. Protein-protein interaction network construction and machine learning were utilized to identify three hub genes. Immune cell infiltration analysis was performed. The three hub genes were validated in GSE152539 receiver operating characteristic curve analysis. Validation experiments including reverse transcription quantitative real-time PCR, Western blotting and immunohistochemistry were conducted both and . To identify potential drugs associated with hub genes, we used the Comparative Toxicogenomics Database (CTD).

Results: A total of 576 DEGs were identified using GSE125387. By taking the intersection of DEGs, T2DM module genes, and immune-related genes, a total of 59 genes associated with the immune system were identified. Afterward, machine learning was utilized to identify three hub genes (, , and ). The hub genes were associated with a variety of immune cells. The three hub genes were validated in GSE152539. Validation experiments were conducted at the mRNA and protein levels both and , consistent with the bioinformatics analysis. Additionally, 11 potential drugs associated with and were identified based on the CTD.

Conclusion: Immune-related genes that differ in expression in the hippocampus are closely linked to microglia. We validated the expression of three hub genes both and , consistent with our bioinformatics results. We discovered 11 compounds associated with and . These findings suggest that they are co-regulatory molecules of immunometabolism in diabetic cognitive impairment.