Comprehensive Analysis Reveals Biomarkers Related to Diabetic Peripheral Neuropathy and Its Molecular Mechanism

Diabetic peripheral neuropathy (DPN) is a common complication of both type 1 and 2 diabetes. DPN lacks accurate early diagnostic indicators, prompting united identification of biomarkers through transcriptomics and Mendelian randomization (MR) to inform DPN prevention and treatment strategies.

Differential expression analysis pinpointed DPN-related genes (DE-DPN-RGs) by screening differentially expressed genes (DEGs) across GSE95849 and GSE185011 datasets. MR approach validated DE-DPN-RGs causally linked to DPN as potential biomarkers, with sensitivity analysis and Steiger test reinforcing the findings. These biomarkers' expressions were verified via RT-qPCR, while their biological roles, pathways influencing DPN progression, and possible therapeutic targets were comprehensively investigated.

124 DE-DPN-RGs were identified from 5340 DEGs1 and 896 DEGs2, among them, TNF, OSBPL8, IER3, SLC16A3, CREB5, and LRWD1, showing significant causal relationships with DPN. Sensitivity analysis along with the Steiger test validated the reliability of the results, demonstrating their resilience against reverse causation. Furthermore, OSBPL8, SLC16A3, CREB5, and LRWD1 demonstrated significant differential expression between DPN and control groups in both the GSE95849 and GSE185011 datasets, with consistent expression trends across both datasets, thereby warranting their designation as biomarkers. Biomarkers functioned in metabolic reactions of amino acids, rRNA processing, and translation, with potential therapeutic candidates including rosuvastatin, nitrofurfurylhydrazide, and neostigmine bromide. All four biomarkers exhibited significant upregulation in the DPN group as confirmed by RT-qPCR analysis, with the exception of OSBPL8, which displayed a non-significant difference between the groups.

In conclusion, SLC16A3, CREB5, and LRWD1 emerge as promising biomarkers, elucidating roles in DPN pathogenesis and offering potential therapeutic targets.