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

作     者：Jing Gao Ying Zou Xiao-Yu Lv Li Chen Xin-Guo Hou 

作者机构：Department of EndocrinologyQilu Hospital of Shandong UniversityCheeloo College of MedicineShandong UniversityJinan 250012Shandong ProvinceChina Institute of Endocrine and Metabolic DiseasesShandong UniversityJinan 250012Shandong ProvinceChina Key Laboratory of Endocrine and Metabolic DiseasesShandong Province Medicine&HealthJinan 250012Shandong ProvinceChina Department of EndocrinologyJinan Clinical Research Center for Endocrine and Metabolic DiseaseJinan 250012Shandong ProvinceChina 

出 版 物：《World Journal of Diabetes》 (世界糖尿病杂志（英文版）（电子版）)

年 卷 期：2024年第15卷第4期

页      面：735-757页

核心收录：

学科分类：1002[医学-临床医学] 100205[医学-精神病与精神卫生学] 10[医学] 

基　　金：Supported by National Natural Science Foundation of China No.82270845。 

主　　题：Bioinformatics analysis Type 2 diabetes mellitus Cognitive impairment Hippocampus Immune Microglia 

摘      要：BACKGROUND The cognitive impairment in type 2 diabetes mellitus(T2DM)is a multifaceted and advancing state that requires further exploration to fully comprehend.Neu-roinflammation 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 via receiver operating characteristic curve analysis.Validation experiments including reverse transcription quantitative real-time PCR,Western blotting and immunohistochemistry were conducted both in vivo and in vitro.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(H2-T24,Rac3,and Tfrc).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 in vivo and in vitro,consistent with the bioinformatics analysis.Additionally,11 potential drugs associated with RAC3 and TFRC 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 in vivo and in vitro,consistent with our bioinformatics results.We discovered 11 compounds associated with RAC3 and TFRC.These findings suggest that they are co-regulatory molecules of immunometabolism in diabetic cognitive impairment.