Early proteomic and metabolomic signatures in diabetes associated with progression to diabetic retinopathy over 1–2 years

Background The progression from diabetes mellitus (DM) to diabetic retinopathy (DR) represents a dynamic pathological process in which vascular and metabolic alterations gradually lead to retinal damage. Understanding the molecular changes during this transition is critical for timely identification and intervention. Methods We performed DIA-based proteomics and untargeted metabolomics on longitudinal paired plasma samples from 15 DM patients who developed DR during 1–2 years. Differential expression, pathway enrichment, and protein–metabolite correlation analyses were performed. Key proteins were validated by ELISA in an independent cohort of 22 DM patients without DR and 22 NPDR patients, and their predictive performance for DR progression was assessed using receiver operating characteristic (ROC) curve analysis. Results Proteomic analysis identified 57 differentially expressed proteins enriched in energy metabolism, detoxification, and cellular defense responses. Metabolomic profiling revealed 168 differential metabolites, primarily involved in taurine and hypotaurine metabolism, neuroactive ligand–receptor interaction, and tyrosine metabolism. Integrated proteomic–metabolomic analysis revealed significant correlations between proteins and metabolites. Eight candidate proteins were validated by ELISA, including three previously reported in DR (Annexin A1 (ANXA1), Glutathione Peroxidase 1 (GPX1), Glutathione S-transferase Mu 1 (GSTM1)) and five newly identified candidates (Aldehyde Dehydrogenase 18 family member A1 (ALDH18A1), Galactose-1-Phosphate Uridylyltransferase (GALT), Proteoglycan 2 (PRG2), Ubiquitin-activating Enzyme E1 (UBA1), Glucagon (GCG)). ROC analysis demonstrated strong discriminative performance for these proteins, with area under the curve (AUC) values ranging from 0.853 to 0.945. Conclusions Our study reveals coordinated alterations in plasma proteins and metabolites during the progression from DM to DR. Integrated multi-omics analysis identified five novel candidate biomarkers, which may serve as potential targets for early detection and risk stratification of DR.