Gao J, Zou Y, Lv XY, Chen L, Hou XG. Novel insights into immune-related genes associated with type 2 diabetes mellitus-related cognitive impairment. World J Diabetes 2024; 15(4): 735-757 [PMID: 38680704 DOI: 10.4239/wjd.v15.i4.735]
Corresponding Author of This Article
Xin-Guo Hou, MD, PhD, Chief, Chief Doctor, Department of Endocrinology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, No. 107 Wenhua Xilu, Jinan 250012, Shandong Province, China. houxinguo@sdu.edu.cn
Research Domain of This Article
Endocrinology & Metabolism
Article-Type of This Article
Basic Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
World J Diabetes. Apr 15, 2024; 15(4): 735-757 Published online Apr 15, 2024. doi: 10.4239/wjd.v15.i4.735
Novel insights into immune-related genes associated with type 2 diabetes mellitus-related cognitive impairment
Jing Gao, Ying Zou, Xiao-Yu Lv, Li Chen, Xin-Guo Hou
Jing Gao, Ying Zou, Xiao-Yu Lv, Li Chen, Xin-Guo Hou, Department of Endocrinology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong Province, China
Xin-Guo Hou, Institute of Endocrine and Metabolic Diseases, Shandong University, Jinan 250012, Shandong Province, China
Xin-Guo Hou, Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan 250012, Shandong Province, China
Xin-Guo Hou, Department of Endocrinology, Jinan Clinical Research Center for Endocrine and Metabolic Disease, Jinan 250012, Shandong Province, China
Author contributions: The design of this study was carried out by Hou XG; the collection and analysis of bioinformatics data, experimental validation, and writing of the manuscript were carried out by Gao J; Zou Y took on the task of conducting statistical analysis on the experimental data; Lv XY was responsible for animal modeling; Chen L contributed to the literature research; the final manuscript was read and approved by all the authors.
Supported byNational Natural Science Foundation of China, No. 82270845.
Institutional review board statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of the Qilu Medical College of Shandong University (IACUC protocol number: 23001).
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of the Qilu Medical College of Shandong University (IACUC protocol number: 23001).
Conflict-of-interest statement: The authors assert that there are no conflicting interests.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE Guidelines, and the manuscript was prepared and revised according to the ARRIVE Guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Xin-Guo Hou, MD, PhD, Chief, Chief Doctor, Department of Endocrinology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, No. 107 Wenhua Xilu, Jinan 250012, Shandong Province, China. houxinguo@sdu.edu.cn
Received: November 11, 2023 Peer-review started: November 11, 2023 First decision: January 15, 2024 Revised: January 21, 2024 Accepted: March 4, 2024 Article in press: March 4, 2024 Published online: April 15, 2024 Processing time: 152 Days and 8.4 Hours
Abstract
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 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.
Core Tip: Using GSE125387, we identified differentially expressed genes in the hippocampus of T2DM mice and controls. Fifty-nine genes were identified through functional enrichment analysis and protein-protein interactions analysis. Machine learning was utilized to identify three hub genes (H2-T24, Rac3, and Tfrc). And the three hub genes were validated in GSE152539. Validation experiments were conducted at the mRNA and protein levels both in vivo and in vitro. Additionally, 11 potential compands associated with RAC3 and TFRC were identified based on the Comparative Toxicogenomics Database. The findings provide new insights into the treatment of T2DM-related cognitive impairment.
