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

doi:10.4239/wjd.v15.i4.735

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Apr 15, 2024 (publication date) through Mar 2, 2026

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World Journal of Diabetes

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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 by National 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.

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

ARTICLE HIGHLIGHTS

Research background

Cognitive decline in type 2 diabetes mellitus (T2DM) is a complex and progressive condition that demands additional research for complete understanding. Neuroinflammation is seen as a primary mechanism, with the immune system significantly influencing the disease's advancement.

Research motivation

Cognitive impairment in T2DM is complex and evolving, necessitating deeper research. The immune system significantly impacts its progression.

Research objectives

To pinpoint and confirm hippocampus immune-related genes linked to cognitive impairment in T2DM.

Research methods

Using the Gene Expression Omnibus database GSE125387, we pinpointed genes differentially expressed between T2DM and control mice, and identified key module genes related to T2DM through Weighted Gene Co-Expression Network Analysis. We conducted Gene Set Enrichment Analysis for these genes and built a protein-protein interaction network, employing Lasso regression and Random Forest to identify three hub genes. These genes underwent immune cell infiltration analysis and were validated in GSE152539 using receiver operating characteristic curve analysis. Validation included RT-qPCR, Western blotting, and immunohistochemistry at mRNA and protein levels, both in vivo and in vitro. Furthermore, we discovered 11 potential drugs linked to these genes using the Comparative Toxicogenomics Database.

Research results

We identified 576 DEGs from GSE125387 and intersected them with T2DM module and immune-related genes, finding 59 immune system-related genes. Machine learning pinpointed three hub genes (H2-T24, Rac3, Tfrc), linked to various immune cells. These genes were validated in GSE152539, with experiments at mRNA and protein levels in vivo and in vitro, aligning with our bioinformatics analysis. Additionally, 11 potential drugs related to RAC3 and TFRC were identified using the Comparative Toxicogenomics Database.

Research conclusions

The immune system plays a significant role in cognitive impairment in T2DM. The immune-related differently expressed genes in hippocampus were closely related to microglia. We confirmed the expression of three such genes both in vivo and in vitro, in line with our bioinformatics findings. Three hub genes screened were associated with a variety of immune cells. Moreover, 11 drugs related to RAC3 and TFRC were identified.

Research perspectives

These genes are as co-regulatory molecules in the immunometabolism of diabetic cognitive impairment, offering new perspectives for its treatment.