Identification of Key lncRNAs and ceRNA Regulatory Networks in Diabetes-Associated Cognitive Dysfunction

Introduction: Diabetes clinical guidelines have begun to emphasize the management of cognitive dysfunction in diabetes. Moreover, several studies have shown that long non-coding RNAs (lncRNAs) play critical roles in human diseases. However, no studies have elucidated whether lncRNAs are involved in the pathogenesis of diabetes-associated cognitive dysfunction (DACD). Methods: The hippocampi of male mice with homozygous leptin receptor-deficient T2DM and their littermates were analyzed via high-throughput sequencing. RNA and protein sequencing data were utilized to identify differentially expressed (DE) mRNAs, lncRNAs, and proteins between diabetes mellitus and control groups. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed for DE-mRNAs-DE-proteins. Subsequently, lncRNA-mRNA-pathway and lncRNA-miRNA-mRNA networks were constructed. Quantitative real-time PCR (qRT-PCR) was conducted to verify the expression trends of key lncRNAs in DACD. Results: We identified upregulated and downregulated mRNAs, lncRNAs, and proteins in the diabetes group. Eleven DE-mRNAs-DE-proteins were associated with inflammatory response, lipid/ steroid metabolism, and cell growth. The lncRNA-mRNA-pathway network contained 36 lncRNA-mRNA pairs linked to 8 KEGG pathways. Twenty-five lncRNAs corresponding to Apoa1 were identified as key candidates. Subcellular localization and ceRNA network analyses suggested that lncRNA 3110039I08Rik and lncRNA Gm36445 may regulate DACD. qRT-PCR confirmed their increased expression in diabetic mice. Conclusion: Our results identified two novel lncRNAs that may play critical roles in DACD.