| Sumario: | Vascular complications of Type 2 diabetes (T2D) significantly contribute to its morbidity and mortality. Identifying robust biomarkers is critical for improving risk prediction, understanding disease mechanisms, and guiding targeted therapies. Fasting plasma samples from a subset of 542 participants in the FIELD (Fenofibrate Intervention and Event Lowering in Diabetes) trial were subjected to mass spectrometry. Participants were divided into groups for analysis based on presence of microvascular and/or macrovascular complications, and time of its occurrence (history of at baseline or during trial follow-up). Random Forest algorithm was applied to identify potential novel protein biomarkers. Gene ontology analysis was performed to determine the biological pathways and processes linked to these proteins. Fifty proteins associated with type 2 diabetes vascular complications were identified with 14 uniquely associated with microvascular complications, 13 with macrovascular and 23 common for both. Pathway analysis revealed seven main pathways underlying type 2 diabetes vascular complications including platelet degranulation and extracellular matrix interactions. Gene ontology analysis showed that these proteins functioned predominantly in the extracellular matrix and were involved in biological processes related to blood coagulation and lipoproteins remodelling. This study provides insights into the molecular mechanisms underlying type 2 diabetes vascular complications, highlighting novel protein biomarkers and their key biological pathways. These findings support the development of precision medicine strategies for risk prediction and targeted interventions in type 2 diabetes management. Further clinical validation of these biomarkers is warranted to confirm their potential utility in improving patient outcomes. • Proteomics coupled with machine learning uncovered high-confidence biomarkers. • Shared biomarkers were identified for microvascular and macrovascular complications. • Seven key pathways drive the development and progression of diabetes complications.
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