Role of Alpha-Defensins 3 and 5 in Diabetic Complications: Associations with Nephropathy and Metabolic Parameters in Type 2 Diabetes

Background/Objectives: DEFA3 and DEFA5 are alpha-defensins, which are small cationic antimicrobial peptides that are part of the innate immune system. DEFA3 encodes human neutrophil peptide-3 (HNP-3), primarily expressed in neutrophils, while DEFA5 encodes human defensin-5 (HD-5), predominantly expressed in Paneth cells of the small intestine. Both defensins show elevated levels in diabetes and are strongly associated with diabetic nephropathy, with the highest concentrations found in patients with this complication. We evaluated serum levels of DEFA3 and DEFA5 in 160 participants (93 patients with T2DM and 67 controls without carbohydrate disturbances) and their associations with diabetic nephropathy, as well as peripheral and cardiac autonomic neuropathy and anthropometric and metabolic parameters. Methods: This was a monocentric, cross-sectional, observational study conducted at the Endocrinology and Metabolic Disorders Clinic of Alexandrovska Hospital in Sofia. Main methods included detailed clinical and anthropometric assessments, diagnosis of peripheral neuropathy via the Neuropathy Disability Score (NDS), evaluation of cardiac autonomic neuropathy using heart rate variability analysis and Ewing cardiovascular reflex tests, comprehensive laboratory investigations with fasting blood samples, and measurement of serum DEFA3 and DEFA5 levels by ELISA kits. Results: Serum DEFA3 and DEFA5 levels did not differ significantly between patients with T2DM and controls without carbohydrate disturbances, nor by sex or menopausal status. Patients with diabetic nephropathy showed significantly higher levels of both DEFA3 (345.7 ± 77.9 pg/mL vs. 299.2 ± 100.3 pg/mL; p = 0.042) and DEFA5 (5.3 ± 10.1 pg/mL vs. 2.9 ± 2.9 pg/mL; p = 0.044). DEFA5 levels were also elevated in participants with increased albumin-to-creatinine ratio (4.9 ± 9.9 pg/mL vs. 2.2 ± 1.5 pg/mL; p = 0.043). No significant differences were observed in patients with peripheral neuropathy, cardiac autonomic neuropathy, retinopathy, or macroangiopathy, although a non-significant trend toward higher values was noted. DEFA3 demonstrated moderate discriminatory ability for diabetic nephropathy (AUC = 0.641; p = 0.037), superior to DEFA5 (AUC = 0.570; p = 0.303). DEFA3 showed multiple weak positive correlations with diabetes duration, body weight, BMI, total and LDL-cholesterol, serum creatinine, and uric acid, while DEFA5 correlated only with total cholesterol. Conclusions: Circulating DEFA3 and DEFA5 are associated with diabetic nephropathy and selected metabolic and renal parameters in patients with type 2 diabetes, with DEFA3 showing moderate discriminatory capacity. The associations were largely attenuated after covariate adjustment, suggesting that these alpha-defensins likely reflect downstream innate immune activation and renal stress rather than acting as independent drivers of complications.