Adropin and Endothelin-1 as Complementary Signals Associated with Early Vascular Aging in Middle-Aged Type 2 Diabetes

Background: Early vascular aging (EVA) is a common complication of type 2 diabetes mellitus. Early identification is crucial in middle-aged individuals with T2DM, as vascular stiffness can occur gradually for years before cardiovascular disease. However, EVA is rarely considered in routine care. Adropin is a vasoprotective peptide that may counter-regulate endothelin-1 (ET-1). Therefore, this study aims to examine the association between circulating adropin, ET-1, oxLDL, MMP-2, VEGFA, and EVA. Methods: This observational study included 300 adults aged 25-55 years (150 T2DM; 150 age/sex-matched controls). ePWV was calculated from age and mean blood pressure. EVA was classified using a residual-based, age-specific ePWV threshold derived from controls. Associations were tested using correlation and logistic regression. ROC and decision curve analyses were performed to evaluate diagnostic performance and clinical utility. Results: EVA prevalence was 38.6% overall, occurring in 7.3% of controls and increasing across T2DM with good and poor glycemic control (56.1% and 80.95%, respectively, p < 0.001). Compared with normal vascular aging, EVA showed lower adropin and higher ET-1, oxLDL and MMP-2, with lower VEGFA (all p < 0.05). In fully adjusted models, adropin (OR 0.991 per pg/mL; p < 0.001) and ET-1 (OR 1.017 per pg/mL, p = 0.005) remained independently associated with EVA. A combined adropin + ET-1 predictor improved discrimination (AUC 0.901, 95% CI 0.868-0.934), at a predicted-probability cutoff of 0.607, 78.7% sensitivity and 87.0% specificity. Conclusions: In middle-aged T2DM, EVA was associated with lower adropin and higher ET-1 in T2DM. These findings support an association between these biomarkers and the EVA phenotype.