Neutrophil Extracellular Traps (NETs) Are Associated with Type 2 Diabetes and Diabetic Foot Ulcer Related Amputation: A Prospective Cohort Study

Overview

Journal Diabetes Ther

Specialty Cardiology & Vascular Diseases

Date 2024 Apr 15

PMID 38619692

Authors

Irshat Ibrahim

Yilimire Nuermaimaiti

Gulijianaiti Maimaituxun

Xinling Luo

Mailudemu Maimaituxun

Azimat Akbar

Kahaer Tuerxun

Yuanquan Wu

Affiliations

Soon will be listed here.

Abstract

Introduction: The prevalence of diabetes mellitus and its sequelae has been on the rise, and diabetic foot ulcer (DFU) is the leading cause of non-traumatic lower limb amputation globally. The rising occurrence and financial burden associated with DFU necessitate improved clinical assessment and treatment. Diabetes has been found to enhance the formation of neutrophil extracellular traps (NETs) by neutrophils, and excessive NETs have been implicated in tissue damage and impaired wound healing. However, there is as yet insufficient evidence to clarify the value of NETs in assessing and predicting outcomes of DFU.

Methods: We designed this prospective study with three cohorts formed from type 2 diabetes mellitus (T2DM) patients with DFU (n = 200), newly diagnosed T2DM patients (n = 42), and healthy donors (n = 38). Serum levels of NETs were detected for all groups, and the prognostic value for DFU-related amputation was analyzed.

Results: The results showed that serum NET levels of the DFU group were significantly higher than in the T2DM group (P < 0.05), which also had significantly elevated serum NET levels compared to healthy donors (P < 0.05). Multivariate Cox regression showed that serum NET levels, diabetic foot surgical history, and Wagner grade were the risk factors for amputation (P < 0.05), and these three variables also exhibited the highest coefficient values in additional Lasso Cox regression. For patients with DFU, Kaplan-Meier curves showed that high serum NET levels associated with higher amputation probability (HR = 0.19, P < 0.01) and ROC curve based on NET value showed good validity for amputation (AUC: 0.727, CI 0.651-0.803).

Conclusion: Elevated serum NET levels serve as an easily accessible serological prognostic marker for assessing the risk of DFU-related amputation, thereby offering evaluation metrics for healthcare providers. Further investigations are necessary to understand the mechanisms driving this relationship.

Citing Articles

Trapped in the NETs: Multiple Roles of Platelets in the Vascular Complications Associated with Neutrophil Extracellular Traps.

Sennett C, Pula G Cells. 2025; 14(5).

PMID: 40072064 PMC: 11898727. DOI: 10.3390/cells14050335.

Risk Factors Associated with Amputation for Patients with Diabetic Foot Ulcers: A Retrospective Study.

Yang B, Zha X, Ding Y Diabetes Metab Syndr Obes. 2024; 17:4201-4209.

PMID: 39529615 PMC: 11552380. DOI: 10.2147/DMSO.S490614.

Neutrophil extracellular traps in homeostasis and disease.

Wang H, Kim S, Lei Y, Wang S, Wang H, Huang H Signal Transduct Target Ther. 2024; 9(1):235.

PMID: 39300084 PMC: 11415080. DOI: 10.1038/s41392-024-01933-x.

References

Du F, Ma J, Gong H, Bista R, Zha P, Ren Y . Microbial Infection and Antibiotic Susceptibility of Diabetic Foot Ulcer in China: Literature Review. Front Endocrinol (Lausanne). 2022; 13:881659. PMC: 9161694. DOI: 10.3389/fendo.2022.881659. View

Meloni M, Izzo V, Giurato L, Lazaro-Martinez J, Uccioli L . Prevalence, Clinical Aspects and Outcomes in a Large Cohort of Persons with Diabetic Foot Disease: Comparison between Neuropathic and Ischemic Ulcers. J Clin Med. 2020; 9(6). PMC: 7356179. DOI: 10.3390/jcm9061780. View

Martin P, Leibovich S . Inflammatory cells during wound repair: the good, the bad and the ugly. Trends Cell Biol. 2005; 15(11):599-607. DOI: 10.1016/j.tcb.2005.09.002. View

Njeim R, Azar W, Fares A, Azar S, Kassouf H, Eid A . NETosis contributes to the pathogenesis of diabetes and its complications. J Mol Endocrinol. 2020; 65(4):R65-R76. DOI: 10.1530/JME-20-0128. View

Yang S, Wang S, Chen L, Wang Z, Chen J, Ni Q . Neutrophil Extracellular Traps Delay Diabetic Wound Healing by Inducing Endothelial-to-Mesenchymal Transition via the Hippo pathway. Int J Biol Sci. 2023; 19(1):347-361. PMC: 9760440. DOI: 10.7150/ijbs.78046. View

Menegazzo L, Ciciliot S, Poncina N, Mazzucato M, Persano M, Bonora B . NETosis is induced by high glucose and associated with type 2 diabetes. Acta Diabetol. 2014; 52(3):497-503. DOI: 10.1007/s00592-014-0676-x. View

Fadini G, Menegazzo L, Rigato M, Scattolini V, Poncina N, Bruttocao A . NETosis Delays Diabetic Wound Healing in Mice and Humans. Diabetes. 2016; 65(4):1061-71. DOI: 10.2337/db15-0863. View

Yang S, Gu Z, Lu C, Zhang T, Guo X, Xue G . Neutrophil Extracellular Traps Are Markers of Wound Healing Impairment in Patients with Diabetic Foot Ulcers Treated in a Multidisciplinary Setting. Adv Wound Care (New Rochelle). 2019; 9(1):16-27. PMC: 6918858. DOI: 10.1089/wound.2019.0943. View

Armstrong D, Boulton A, Bus S . Diabetic Foot Ulcers and Their Recurrence. N Engl J Med. 2017; 376(24):2367-2375. DOI: 10.1056/NEJMra1615439. View

10.

Armstrong D, Tan T, Boulton A, Bus S . Diabetic Foot Ulcers: A Review. JAMA. 2023; 330(1):62-75. PMC: 10723802. DOI: 10.1001/jama.2023.10578. View

11.

Hurst J, Barn R, Gibson L, Innes H, Bus S, Kennon B . Geospatial mapping and data linkage uncovers variability in outcomes of foot disease according to multiple deprivation: a population cohort study of people with diabetes. Diabetologia. 2019; 63(3):659-667. PMC: 6997267. DOI: 10.1007/s00125-019-05056-9. View

12.

Bus S, van Netten J, Hinchliffe R, Apelqvist J, Lipsky B, Schaper N . Standards for the development and methodology of the 2019 International Working Group on the Diabetic Foot guidelines. Diabetes Metab Res Rev. 2020; 36 Suppl 1:e3267. DOI: 10.1002/dmrr.3267. View

13.

Gao L, Wang J, Yin Y . [Interpretation of 2019 International Working Group on Diabetic Foot guidelines on the prevention and management of diabetic foot disease]. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi. 2020; 34(1):16-20. PMC: 8171829. DOI: 10.7507/1002-1892.201906014. View

14.

Sauerbrei W, Royston P, Binder H . Selection of important variables and determination of functional form for continuous predictors in multivariable model building. Stat Med. 2007; 26(30):5512-28. DOI: 10.1002/sim.3148. View

15.

Nakazawa D, Marschner J, Platen L, Anders H . Extracellular traps in kidney disease. Kidney Int. 2018; 94(6):1087-1098. DOI: 10.1016/j.kint.2018.08.035. View

16.

Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss D . Neutrophil extracellular traps kill bacteria. Science. 2004; 303(5663):1532-5. DOI: 10.1126/science.1092385. View

17.

Yang H, Biermann M, Brauner J, Liu Y, Zhao Y, Herrmann M . New Insights into Neutrophil Extracellular Traps: Mechanisms of Formation and Role in Inflammation. Front Immunol. 2016; 7:302. PMC: 4981595. DOI: 10.3389/fimmu.2016.00302. View

18.

Carminita E, Crescence L, Brouilly N, Altie A, Panicot-Dubois L, Dubois C . DNAse-dependent, NET-independent pathway of thrombus formation in vivo. Proc Natl Acad Sci U S A. 2021; 118(28). PMC: 8285961. DOI: 10.1073/pnas.2100561118. View

19.

Papayannopoulos V . Neutrophil extracellular traps in immunity and disease. Nat Rev Immunol. 2017; 18(2):134-147. DOI: 10.1038/nri.2017.105. View

20.

Denning N, Aziz M, Gurien S, Wang P . DAMPs and NETs in Sepsis. Front Immunol. 2019; 10:2536. PMC: 6831555. DOI: 10.3389/fimmu.2019.02536. View