Proteomics and metabolomics biomarkers for predicting the onset and progression of diabetic complications: A systematic review and bioinformatics integration.

Diabetic complications are major drivers of morbidity and mortality, leading to progressive cardiovascular, renal, retinal, and neurological damage. Early intervention is hindered by the lack of reliable biomarkers for prediction and disease staging. Advances in proteomics and metabolomics provide powerful tools to elucidate molecular mechanisms and identify clinically actionable signatures. This systematic review included 67 cohort and 41 cross-sectional studies published between 2012 and August 2025, comprising 73,580 participants. Most studies involved type 2 diabetes (T2D) populations (n = 71), followed by type 1 diabetes (T1D) (n = 16), as well as mixed T1D and T2D cohorts (n = 8). Most investigations analyzed serum or plasma, with additional studies examining urine and other matrices. Proteomic profiling was primarily conducted using mass spectrometry (MS)-based platforms, alongside several affinity-based technologies. Metabolomic analyses were largely MS-based, with a minority employing nuclear magnetic resonance spectroscopy. Overall, 275 metabolites and 363 proteins demonstrated predictive relevance. Pathway enrichment implicated lipoprotein metabolism in macrovascular complications, complement/coagulation and inflammatory signaling in nephropathy, VEGFA-VEGFR2 signaling in retinopathy, and receptor-mediated endocytosis in neuropathy, while amino acid metabolism was consistently disrupted. These molecular signatures show promise for early detection and risk stratification but require standardized prospective validation before clinical translation. PROSPERO registration number: CRD420250656551 Name of the registration: Metabolomics and proteomics-based biomarkers for chronic complications of diabetes: A comprehensive systematic review and meta-analysis. URL: https://www.crd.york.ac.uk/PROSPERO/view/CRD420250656551.