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Background/Objectives: Angiopoietin-like proteins 4 and 8 (ANGPTL4 and ANGPTL8) are key regulators of lipid metabolism and inflammatory processes, with a potential role in the pathogenesis of type 2 diabetes mellitus (T2DM) and its complications. This monocentric observational study evaluated serum levels of ANGPTL4 and ANGPTL8 in 160 participants (93 patients with T2DM and 67 controls without carbohydrate disturbances) and their associations with peripheral and cardiac autonomic neuropathy. Methods: This is a monocentric, cross-sectional, observational study conducted at the Endocrinology and Metabolic Disorders Clinic of Alexandrovska Hospital in Sofia, involving 160 participants and approved by the Ethics Committee of Medical University-Sofia, with all subjects providing written informed consent in accordance with the Declaration of Helsinki. The 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, measurement of serum ANGPTL4 and ANGPTL8 levels by ELISA kits, and statistical analysis performed with IBM SPSS version 25, using parametric and non-parametric tests, correlations, logistic regression, and ROC curves. Results: ANGPTL4 levels were significantly lower in patients with T2DM (12.6 ± 23.1 ng/mL vs. 21.5 ± 29.3 ng/mL; p = 0.033). In a multivariate model, higher values remained associated with lower odds of T2DM (OR per 1 SD = 0.634; p = 0.0424). ANGPTL8 demonstrated moderate discriminatory ability for cardiac autonomic neuropathy (AUC = 0.678; p = 0.007) in unadjusted analysis, but the association did not persist after covariate adjustment. ANGPTL4 showed inverse correlations with body weight, basal metabolic rate, and GGT. Conclusions: The results support the role of ANGPTL4 as a potential biomarker in metabolic disturbances and complications in T2DM, while ANGPTL8 remains mainly insignificant after correction for potential confounding factors.