{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T18:13:27Z","timestamp":1778523207426,"version":"3.51.4"},"reference-count":42,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2026,5,9]],"date-time":"2026-05-09T00:00:00Z","timestamp":1778284800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"European Union-NextGenerationEU","award":["BG-RRP-2.004-0004-C01"],"award-info":[{"award-number":["BG-RRP-2.004-0004-C01"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>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\u2013Sofia, 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 \u00b1 23.1 ng\/mL vs. 21.5 \u00b1 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.<\/jats:p>","DOI":"10.3390\/jcm15103631","type":"journal-article","created":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T17:17:42Z","timestamp":1778519862000},"page":"3631","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Angiopoietin-like Proteins 4 and 8 in Diabetic Complications: Associations with Neuropathy and Metabolic Parameters in Type 2 Diabetes"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-3295-8163","authenticated-orcid":false,"given":"Yuliyan","family":"Naydenov","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Faculty of Medicine, Medical University of Sofia, 1431 Sofia, Bulgaria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vera","family":"Karamfilova","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Faculty of Medicine, Medical University of Sofia, 1431 Sofia, Bulgaria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-2730-0475","authenticated-orcid":false,"given":"Diana","family":"Nikolova","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Faculty of Medicine, Medical University of Sofia, 1431 Sofia, Bulgaria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-3684-9570","authenticated-orcid":false,"given":"Savelia","family":"Yordanova","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Faculty of Medicine, Medical University of Sofia, 1431 Sofia, Bulgaria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4829-9449","authenticated-orcid":false,"given":"Zdravko","family":"Kamenov","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Faculty of Medicine, Medical University of Sofia, 1431 Sofia, Bulgaria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9915-3282","authenticated-orcid":false,"given":"Julieta","family":"Hristova","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, Faculty of Medicine, Medical University of Sofia, 1431 Sofia, Bulgaria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8030-4498","authenticated-orcid":false,"given":"Antoaneta Trifonova","family":"Gateva","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Faculty of Medicine, Medical University of Sofia, 1431 Sofia, Bulgaria"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/S2213-8587(25)00299-2","article-title":"11th Edition of the IDF Diabetes Atlas: Global, Regional, and National Diabetes Prevalence Estimates for 2024 and Projections for 2050","volume":"14","author":"Genitsaridi","year":"2026","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_2","unstructured":"GBD 2021 Diabetes Collaborators (2023). GBD 2021 Diabetes Collaborators Global, Regional, and National Burden of Diabetes from 1990 to 2021, with Projections of Prevalence to 2050: A Systematic Analysis for the Global Burden of Disease Study 2021. Lancet, 402, 203\u2013234."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"TODAY Study Group (2021). Long-Term Complications in Youth-Onset Type 2 Diabetes. N. Engl. J. Med., 385, 416\u2013426.","DOI":"10.1056\/NEJMoa2100165"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1186\/s12933-018-0787-8","article-title":"Vascular Complications in Patients with Type 2 Diabetes: Prevalence and Associated Factors in 38 Countries (the DISCOVER Study Program)","volume":"17","author":"Kosiborod","year":"2018","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"922","DOI":"10.1016\/S1474-4422(22)00188-0","article-title":"Towards Prevention of Diabetic Peripheral Neuropathy: Clinical Presentation, Pathogenesis, and New Treatments","volume":"21","author":"Elafros","year":"2022","journal-title":"Lancet Neurol."},{"key":"ref_6","first-page":"CD012967","article-title":"Alpha-lipoic Acid for Diabetic Peripheral Neuropathy","volume":"1","author":"Baicus","year":"2024","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"American Diabetes Association Professional Practice Committee for Diabetes (2025). 12. Retinopathy, Neuropathy, and Foot Care: Standards of Care in Diabetes\u20142026. Diabetes Care, 49, S261\u2013S276.","DOI":"10.2337\/dc26-S012"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1553","DOI":"10.2337\/diacare.26.5.1553","article-title":"Diabetic Autonomic Neuropathy","volume":"26","author":"Vinik","year":"2003","journal-title":"Diabetes Care"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1162","DOI":"10.1111\/dom.15004","article-title":"Detecting and Treating the Protean Manifestations of Diabetic Autonomic Neuropathy","volume":"25","author":"Bell","year":"2023","journal-title":"Diabetes Obes. Metab."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1097\/MOH.0000000000000580","article-title":"ANGPTL4: A Multifunctional Protein Involved in Metabolism and Vascular Homeostasis","volume":"27","year":"2020","journal-title":"Curr. Opin. Hematol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"100150","DOI":"10.1016\/j.jlr.2021.100150","article-title":"Role and Mechanism of the Action of Angiopoietin-like Protein ANGPTL4 in Plasma Lipid Metabolism","volume":"62","author":"Kersten","year":"2021","journal-title":"J. Lipid Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"120556","DOI":"10.1016\/j.atherosclerosis.2025.120556","article-title":"The Role of ANGPTL8 in Metabolism and Cardiovascular Diseases: Consensus and Controversy","volume":"412","author":"Lin","year":"2026","journal-title":"Atherosclerosis"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"101067","DOI":"10.1016\/j.plipres.2020.101067","article-title":"The Multi-Faces of Angptl8 in Health and Disease: Novel Functions beyond Lipoprotein Lipase Modulation","volume":"80","author":"Ghosh","year":"2020","journal-title":"Prog. Lipid Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1097\/MOL.0000000000000290","article-title":"Regulation of Lipid Metabolism by Angiopoietin-like Proteins","volume":"27","author":"Dijk","year":"2016","journal-title":"Curr. Opin. Lipidol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1097\/MOL.0000000000000910","article-title":"Angiopoietin-like Protein 8: A Multifaceted Protein Instrumental in Regulating Triglyceride Metabolism","volume":"35","author":"Wen","year":"2024","journal-title":"Curr. Opin. Lipidol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1194\/jlr.M088807","article-title":"On the Mechanism of Angiopoietin-like Protein 8 for Control of Lipoprotein Lipase Activity","volume":"60","author":"Kovrov","year":"2019","journal-title":"J. Lipid Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1016\/j.molmed.2019.05.010","article-title":"ANGPTL4 in Metabolic and Cardiovascular Disease","volume":"25","author":"Aryal","year":"2019","journal-title":"Trends Mol. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"938","DOI":"10.1016\/S2213-8587(19)30081-6","article-title":"Diabetic Peripheral Neuropathy: Advances in Diagnosis and Strategies for Screening and Early Intervention","volume":"7","author":"Selvarajah","year":"2019","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1097\/MOL.0000000000000770","article-title":"Lipids and Peripheral Neuropathy","volume":"32","author":"Iqbal","year":"2021","journal-title":"Curr. Opin. Lipidol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1255","DOI":"10.1016\/j.freeradbiomed.2012.01.029","article-title":"Triglyceride, Nonesterified Fatty Acids, and Prediabetic Neuropathy: Role for Oxidative-Nitrosative Stress","volume":"52","author":"Lupachyk","year":"2012","journal-title":"Free Radic. Biol. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1303","DOI":"10.1007\/s00011-023-01753-9","article-title":"Dual Role of ANGPTL4 in Inflammation","volume":"72","author":"Zuo","year":"2023","journal-title":"Inflamm. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1016\/j.ejphar.2013.07.017","article-title":"Pathogenesis of Diabetic Neuropathy: Focus on Neurovascular Mechanisms","volume":"719","author":"Cotter","year":"2013","journal-title":"Eur. J. Pharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1186\/s12974-024-03183-8","article-title":"Inhibition of ANGPTL8 Protects against Diabetes-Associated Cognitive Dysfunction by Reducing Synaptic Loss via the PirB Signaling Pathway","volume":"21","author":"Meng","year":"2024","journal-title":"J. Neuroinflammation"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Harada, M., Yamakawa, T., Kashiwagi, R., Ohira, A., Sugiyama, M., Sugiura, Y., Kondo, Y., and Terauchi, Y. (2021). Association between ANGPTL3, 4, and 8 and Lipid and Glucose Metabolism Markers in Patients with Diabetes. PLoS ONE, 16.","DOI":"10.1371\/journal.pone.0255147"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1007\/BF00400697","article-title":"A Multicentre Study of the Prevalence of Diabetic Peripheral Neuropathy in the United Kingdom Hospital Clinic Population","volume":"36","author":"Young","year":"1993","journal-title":"Diabetologia"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Toshniwal, S.S., Kumar, S., Acharya, S., Ghali, A., Raut, S., Deolikar, V., Reddy, H., Kotak, P., Wanjari, A., and Bawankule, S. (2024). Diagnostic Accuracy of Bellavere\u2019s Score in Cardiac Autonomic Neuropathy among Chronic Kidney Disease Patients: A Study of Prevalence and Dialysis Impact. Front. Med., 11.","DOI":"10.3389\/fmed.2024.1514214"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2285","DOI":"10.2337\/dc10-1303","article-title":"Diabetic Neuropathies: Update on Definitions, Diagnostic Criteria, Estimation of Severity, and Treatments","volume":"33","author":"Tesfaye","year":"2010","journal-title":"Diabetes Care"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1640","DOI":"10.1161\/CIRCULATIONAHA.109.192644","article-title":"Harmonizing the Metabolic Syndrome: A Joint Interim Statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity","volume":"120","author":"Alberti","year":"2009","journal-title":"Circulation"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"101033","DOI":"10.1016\/j.molmet.2020.101033","article-title":"Fasting Induces ANGPTL4 and Reduces LPL Activity in Human Adipose Tissue","volume":"40","author":"Ruppert","year":"2020","journal-title":"Mol. Metab."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1123","DOI":"10.1056\/NEJMoa1510926","article-title":"Inactivating Variants in ANGPTL4 and Risk of Coronary Artery Disease","volume":"374","author":"Dewey","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1111\/liv.15099","article-title":"Gamma-Glutamyl Transferase (\u03b3-GT)-an Old Dog with New Tricks?","volume":"42","author":"Brennan","year":"2022","journal-title":"Liver Int."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1186\/s12944-021-01577-8","article-title":"Elevated Gamma-Glutamyl Transferase Has a Non-Linear Association with Incident Non-Alcoholic Fatty Liver Disease in the Non-Obese Chinese Population: A Secondary Retrospective Study","volume":"20","author":"Wu","year":"2021","journal-title":"Lipids Health Dis."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1111\/hepr.13603","article-title":"Angiopoietin-like Protein 4 Deficiency Augments Liver Fibrosis in Liver Diseases Such as Nonalcoholic Steatohepatitis in Mice through Enhanced Free Cholesterol Accumulation in Hepatic Stellate Cells","volume":"51","author":"Teratani","year":"2021","journal-title":"Hepatol. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"4436","DOI":"10.1038\/s41467-023-40183-3","article-title":"LILRB2\/PirB Mediates Macrophage Recruitment in Fibrogenesis of Nonalcoholic Steatohepatitis","volume":"14","author":"Li","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Morinaga, J., Zhao, J., Endo, M., Kadomatsu, T., Miyata, K., Sugizaki, T., Okadome, Y., Tian, Z., Horiguchi, H., and Miyashita, K. (2018). Association of Circulating ANGPTL 3, 4, and 8 Levels with Medical Status in a Population Undergoing Routine Medical Checkups: A Cross-Sectional Study. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0193731"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"968","DOI":"10.1016\/j.ophtha.2015.01.007","article-title":"Aqueous Levels of Angiopoietin-like 4 and Semaphorin 3E Correlate with Nonperfusion Area and Macular Volume in Diabetic Retinopathy","volume":"122","author":"Kwon","year":"2015","journal-title":"Ophthalmology"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"34411","DOI":"10.1074\/jbc.M403058200","article-title":"The Direct Peroxisome Proliferator-Activated Receptor Target Fasting-Induced Adipose Factor (FIAF\/PGAR\/ANGPTL4) Is Present in Blood Plasma as a Truncated Protein That Is Increased by Fenofibrate Treatment","volume":"279","author":"Mandard","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Yang, Y., Smith, S., Chen, Y.Q., Li, H., Zhen, E.Y., Sloan, J.H., Siegel, R.W., Qian, Y., Wen, Y., and Jung, H. (2026). Effects of Fenofibrate on Angiopoietin-like 3\/4\/8 Proteins and Apolipoprotein A5. J. Lipid Res., 101050.","DOI":"10.1016\/j.jlr.2026.101050"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1549","DOI":"10.1161\/ATVBAHA.122.318880","article-title":"Plasma ANGPTL8 Levels and Risk for Secondary Cardiovascular Events in Japanese Patients with Stable Coronary Artery Disease Receiving Statin Therapy","volume":"43","author":"Morinaga","year":"2023","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1923","DOI":"10.1016\/S0140-6736(25)00825-6","article-title":"Safety and Efficacy of a Novel ANGPTL4 Inhibitory Antibody for Lipid Lowering: Results from Phase 1 and Phase 1b\/2a Clinical Studies","volume":"405","author":"Cummings","year":"2025","journal-title":"Lancet"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2632","DOI":"10.1038\/s41591-025-03830-4","article-title":"Targeting the Angiopoietin-like Protein 3\/8 Complex with a Monoclonal Antibody in Patients with Mixed Hyperlipidemia: A Phase 1 Trial","volume":"31","author":"Gaudet","year":"2025","journal-title":"Nat. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"117558","DOI":"10.1016\/j.atherosclerosis.2024.117558","article-title":"Impact of Loss-of-Function in Angiopoietin-like 4 on the Human Phenome","volume":"393","author":"Gagnon","year":"2024","journal-title":"Atherosclerosis"}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/10\/3631\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T17:38:58Z","timestamp":1778521138000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/10\/3631"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,9]]},"references-count":42,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["jcm15103631"],"URL":"https:\/\/doi.org\/10.3390\/jcm15103631","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,9]]}}}