Identification of circulating miRNA alterations in diabetes patients excluding periodontitis effects: insights into target gene downregulation in diabetic complications.

BACKGROUND

Diabetes mellitus (DM) induces systemic complications through chronic metabolic dysregulation. Circulating exosomal microRNAs (miRNAs) are emerging as key regulators of post-transcriptional gene expression and may drive diabetes-associated pathologies. Although miRNAs have been widely studied in diabetes, the characterization of PD-independent miRNA signatures across tissues remains limited. This study aimed to identify DM-specific miRNA alterations and their contribution to systemic metabolic dysfunction independent of PD.

METHODS

Exosomes were isolated from plasma samples, and small RNA sequencing was performed to identify differentially expressed miRNAs (DE-miRs) using the limma R package. Predicted target genes were identified using TargetScan and validated through bulk RNA sequencing datasets from four tissues-foot, kidney, pancreas, and retina. Differentially expressed genes (DEGs) were analyzed, followed by Gene Ontology Biological Process (GOBP) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment to elucidate diabetes-related mechanisms.

RESULTS

We identified 9 upregulated and 6 downregulated DE-miRs specific to the diabetic group. TargetScan predicted 216 upregulated and 64 downregulated target genes. Functional validation revealed that these genes were enriched in pathways related to glucose metabolism, cellular stress response, and tissue repair. Notably, SREK1 and GLIPR1 were commonly detected across all four tissues, suggesting potential systemic regulators of diabetes-related complications.

CONCLUSION

This study suggests that circulating exosomal miRNAs, independent of periodontitis, may function as systemic regulators in diabetes. Unlike previous studies, which did not distinguish co-morbid periodontitis, we specifically defined PD-independent miRNA signatures and validated their cross-organ regulatory effects on target genes. Our results revealed a cross-organ miRNA-mRNA regulatory network and identified common regulatory targets. These findings provide insights into both systemic and organ-specific mechanisms underlying diabetic complications and highlight the potential of miRNAs as biomarkers and therapeutic targets.