Komplikasyon gelişmemiş ve komplikasyon gelişmiş Tip 2 DM (Diabetes Mellitus) hastalarında PADI4 (İnsan Peptidil Arjinin Deiminaz Tip 4) düzeylerinin incelenmesi

Abstract

Amaç: İnsan peptidil arjinin deiminaz 4 (PADI4), histon kuyruklarındaki arginin kalıntılarını sitrüline dönüştürür. Son yıllarda araştırmacılar, PADI4'ün inflamasyon, enfeksiyon, kanser ve otoimmün bozukluklardaki rolünü araştırmaktadır. PADI4 ayrıca, disglisemi ile bağlantılı olan NETosis olarak bilinen bir süreç aracılığıyla nötrofil ekstraselüler tuzaklarının (NET) salınımını da düzenler. PADI4'ün tip 2 diyabet mellitustaki (DM) rolü tam olarak anlaşılamamıştır. Bu çalışmanın amacı, henüz diyabetik komplikasyonları olan ve olmayan tip 2 DM hastalarındaki ve sağlıklı kontrol bireylerindeki PADI4 seviyelerini karşılaştırmaktır. Gereç ve yöntem: Bu çalışma 30-65 yaş aralığındaki üç grup gönüllüden oluşmuştur: sağlıklı bir kontrol grubu, diyabetik komplikasyonları olan ve olmayan tip 2 DM hastaları. Kontrol ve tip 2 DM hastalarından alınan serum örneklerinde tam kan sayımı, biyokimya ve PADI4 (ng/ml) tetkikleri çalışılmıştır. Bulgular: Kontrol, komplike ve komplike olmayan tip 2 DM gruplarında serum PADI4 seviyelerinde anlamlı bir farklılık bulunmamıştır (4,94±5,09 ng/ml (orta: 2,62, IQR: 2,34-3,87), 5,06±6,58 ng/ml (orta: 2,59, IQR: 2,19- 2,99) ve 4,51±4,76 (orta: 2,74, IQR: 2,1-3,71). B12 vitamini seviyeleri komplike tip 2 DM grubunda kontrol grubuna göre anlamlı derecede daha yüksek olarak bulunmuştur (647,83±461,37 vs. 357,32±136,15; p=0,03). Komplike tip 2 DM grubunda nefropati, retinopati veya nöropati ile serum PADI4 arasında anlamlı bir korelasyon bulunamamıştır. Komplike olmayan DM grubunda metformin kullanımıyla istatistiksel olarak anlamlı, negatif ve hafif bir korelasyon saptanmıştır (r=-0,325, p=0,05). Sonuç: Sonuç olarak, komplikasyon gelişmiş veya gelişmemiş tip 2 DM hastaları ve sağlıklı kontrol grubu arasında serum PADI4 seviyelerinde istatistiksel olarak anlamlı bir fark saptanmamıştır. PADI4 birçok hastalık tedavisi ve gözetimi için uygulanabilir bir hedef olarak görülmektedir. Bu konuda daha fazla hasta popülasyonlarını içeren prospektif çalışmalara ihtiyaç vardır.

Keywords

• PADI4 protein
• diabetes mellitus
• NETosis
• komplikasyon

Evaluation of PADI4 (Human Peptidyl Arginine Deiminase Type 4) levels in patients with type 2 diabetes mellitus with/without complications

Abstract

Purpose: Human peptidyl arginine deiminase 4 (PADI4) transforms arginine residues on histone tails to citrulline. Recently, researchers have studied PADI4 in inflammation, infection, cancer, and autoimmune disorders. PADI4 also modulates the release of neutrophil extracellular traps (NETs) through a process known as NETosis, which is linked to dysglycemia. PADI4's role in type 2 diabetic mellitus (DM) is not well understood. The goal of this study is to compare PADI4 levels in type 2 DM patients who have not yet experienced diabetic complications, those who have, and a healthy control group. Materials and methods: This research included three groups of volunteers aged 30-65 years old: a healthy control group, a type 2 diabetic with no diabetic complications, and those with diabetic complications. Serum samples from control and type 2 DM patients were analyzed for complete blood count, biochemistry, and PADI4 (ng/ml). Results: The control, complicated, and uncomplicated type 2 DM groups did not differ significantly in their serum PADI4 levels (4.94±5.09 ng/ml (med: 2.62, IQR: 2.34-3.87), 5.06±6.58 ng/ml (med: 2.59, IQR: 2.19-2.99), and 4.51±4.76 (med: 2.74, IQR: 2.1- 3.71). Vitamin B12 levels were significantly higher in the complicated type 2 DM group than in the control group (647.83±461.37 vs. 357.32±136.15; p=0.03). The correlation analysis found no significant relationship between nephropathy, retinopathy, or neuropathy and serum PADI4 in the complicated type 2 DM group. There was a statistically significant, negative, and slight correlation with metformin use in the uncomplicated DM group (r=-0.325, p=0.05). Conclusion: Finally, there was no significant difference in serum PADI4 levels between the type 2 DM groups with complications, those without complications, and the healthy control group. PADI4 is seen as a viable target for illness treatment and surveillance. Prospective studies involving larger patient populations on this subject are needed.

Keywords

• PADI4 protein
• diabetes mellitus
• NETosis
• complication

References

1. Strati M, Moustaki M, Psaltopoulou T, Vryonidou A, Paschou SA. Early onset type 2 diabetes mellitus: an update. Endocrine. 2024;85(3):965-978. doi:10.1007/s12020-024-03772-w
2. International Diabetes Federation. IDF Diabetes Atlas 10th Edition, 2021. https://diabetesatlas.org/. Accessed 29 July, 2025
3. Młynarska E, Czarnik W, Dzieża N, et al. Type 2 Diabetes Mellitus: New Pathogenetic Mechanisms, Treatment and the Most Important Complications. Int J Mol Sci. 2025;26(3):1094. doi:10.3390/ijms26031094
4. Cai Y, Yang Q, Tang X, et al. Baicalin mitigates hyperglycemia-linked intestinal epithelial barrier impairment in part by inhibiting the formation of neutrophil extracellular traps. Front Immunol. 2025;16:1551256. doi:10.3389/fimmu.2025.1551256
5. Karimian M, Mohammadzadeh FZ. Association of PADI4 Gene Polymorphisms With Susceptibility to Rheumatoid Arthritis: Evidence From 24 Case-Control Studies. Int J Immunogenet. 2025;52(1):1-23. doi:10.1111/iji.12701
6. Albiero M, Migliozzi L, Boscaro C, et al. Padi4-Dependent NETosis Enables Diet-Induced Gut Hyperpermeability, Translating Dysbiosis Into Systemic Inflammation and Dysmetabolism. Diabetes. 2025;74(5):705-719. doi:10.2337/db24-0481
7. Rycyk Bojarzynska A, Kasztelan Szczerbinska B, Cichoz Lach H, Surdacka A, Rolinski J. Neutrophil PAD4 Expression and Its Pivotal Role in Assessment of Alcohol-Related Liver Disease. Int J Mol Sci. 2024;25(14):7597. doi:10.3390/ijms25147597
8. Zheng B, Cai P, Chen Y, Wu Y, Liu H. PADI4 and IL-33 gene polymorphisms with susceptibility to systemic lupus erythematosus and juvenile idiopathic arthritis, a systematic review and meta-analysis. Medicine (Baltimore). 2023;102(18):e33700. doi:10.1097/MD.0000000000033700

9. American Diabetes Association Professional Practice Committee. 2. Diagnosis and Classification of Diabetes: Standards of Care in Diabetes-2024. Diabetes Care. 2024;47(Suppl 1):S20-S42. doi:10.2337/dc24-S002
10. Aukrust SG, Holte KB, Opstad TB, Seljeflot I, Berg TJ, Helseth R. NETosis in Long-Term Type 1 Diabetes Mellitus and Its Link to Coronary Artery Disease. Front Immunol. 2022;12:799539. doi:10.3389/fimmu.2021.799539
11. Rodríguez Espinosa O, Rojas Espinosa O, Moreno Altamirano MM, López Villegas EO, Sánchez García FJ. Metabolic requirements for neutrophil extracellular traps formation. Immunology. 2015;145(2):213-224. doi:10.1111/imm.12437
12. Njeim R, Azar WS, Fares AH, Azar ST, Kfoury Kassouf H, Eid AA. NETosis contributes to the pathogenesis of diabetes and its complications. J Mol Endocrinol. 2020;65(4):R65-R76. doi:10.1530/JME-20-0128
13. Smyth DJ, Howson JM, Payne F, et al. Analysis of polymorphisms in 16 genes in type 1 diabetes that have been associated with other immune-mediated diseases. BMC Med Genet. 2006;7:20. doi:10.1186/1471-2350-7-20
14. Aiken SG, Grimes T, Munro S, Zarganes Tzitzikas T, La Thangue NB, Brennan PE. A patent review of peptidylarginine deiminase 4 (PAD4) inhibitors (2014-present). Expert Opin Ther Pat. 2025;35(6):611-621. doi:10.1080/13543776.2025.2484366
15. Costa NA, Gut AL, Azevedo PS, et al. Peptidylarginine deiminase 4 concentration, but not PADI4 polymorphisms, is associated with ICU mortality in septic shock patients. J Cell Mol Med. 2018;22(10):4732-4737. doi:10.1111/jcmm.13717
16. Su X, Li L, Dai J, Xiao B, Jin Z, Liu B. GSK484, a PAD4 inhibitor, improves endothelial dysfunction in mice with sepsis-induced lung injury by inhibiting H3Cit expression. Nan Fang Yi Ke Da Xue Xue Bao. 2024;44(12):2396-2403. doi:10.12122/j.issn.1673-4254.2024.12.16
17. Ünlü A, Ünver Koluman B, Hacıoğlu S, Akgün Çağlıyan G, Güler N. Predictive value of serum vitamin B12 elevation in acute leukemia. Pam Tıp Derg 2023;16(2):230-236. doi:10.31362/patd.1210492
18. Pardo Cabello AJ, Manzano Gamero V, Puche Cañas E. Vitamin B12: For more than just the treatment of megaloblastic anemia? Rev Clin Esp (Barc). 2023;223(2):114-119. doi:10.1016/j.rceng.2022.11.004
19. Amado Garzon SB, Molina Pimienta L, Vejarano Pombo A, Vélez Bonilla M, Moreno Chaparro J, Buitrago Lopez A. Elevated Vitamin B12, Risk of Cancer, and Mortality: A Systematic Review. Cancer Invest. 2024;42(6):515-526. doi:10.1080/07357907.2024.2366907
20. Yang CW, Hsu HY, Lee YZ, Lee SJ. Vitamin B12 inhibits peptidylarginine deiminases and ameliorates rheumatoid arthritis in CAIA mice. Biochem Biophys Res Commun. 2024;704:149668. doi:10.1016/j.bbrc.2024.149668
21. Ramzan NUH, Shahjahan K, Dhillon RA, et al. Vitamin B12 Deficiency in Patients Taking Metformin: Pathogenesis and Recommendations. Cureus. 2024;16(9):e68550. doi:10.7759/cureus.68550
22. Shivaprasad C, Gautham K, Ramdas B, Gopaldatta KS, Nishchitha K. Metformin Usage Index and assessment of vitamin B12 deficiency among metformin and non-metformin users with type 2 diabetes mellitus. Acta Diabetol. 2020;57(9):1073-1080. doi:10.1007/s00592-020-01526-4
23. Hurley Kim K, Vu CH, Dao NM, et al. Effect of Metformin Use on Vitamin B12 Deficiency Over Time (EMBER): A Real-World Evidence Database Study Endocr Pract. 2023;29(11):862-867. doi:10.1016/j.eprac.2023.06.013
24. Al Fawaeir S, Al Odat I. Influence of metformin intake on serum vitamin B12 levels in patients with type 2 diabetes mellitus. PLoS One. 2022;17(12):e0279740. doi:10.1371/journal.pone.0279740