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Front Immunol
. 2026 May 4:17:1787799.
doi: 10.3389/fimmu.2026.1787799. eCollection 2026.
De novo COVID-19-associated insulin resistance drives dysregulated neutrophil extracellular trap formation (NETosis) four months after infection
Sergio Sanhueza # 1 , Camilo Cabrera # 1 , Romina Quiroga 1 , Bárbara Antilef 1 , Camila Muñoz 1 2 , Agustín Vera 1 , Ricardo Cartes 1 3 , Liliana Lamperti 1 , Enrique Guzmán-Gutiérrez 1 , Claudio Aguayo 1 , Valeska Ormazábal 1 , Mauricio Alejandro Hernández 4 , Jaime Lastra 5 , Benilde Riffo 6 , Gustavo Cerda 7 , Luciano Ferrada 7 , David De Gonzalo-Calvo 8 9 , María C García-Hidalgo 8 9 , Mario Henríquez 10 11 12 , María Inés Barría 13 , Ricardo A Verdugo 14 , Alicia Colombo 15 , Gonzalo Labarca 1 12 16 17 , Estefanía Nova-Lamperti 1
Affiliations
Background: Glucose metabolism disorders (GMDs) are established risk factors for severe COVID-19, but increasing evidence indicates that they may also develop de novo after SARS-CoV-2 infection. Neutrophil extracellular trap formation (NETosis) plays a central role in immunothrombosis, and because neutrophils rely predominantly on glycolysis, they are particularly sensitive to systemic metabolic disturbances. However, the impact of post-COVID-19 GMDs on NETosis remains poorly understood. This study aimed to characterize the emergence of GMDs after COVID-19 and to determine their effect on neutrophil NETosis.
Methods: Sixty COVID-19 patients were stratified according to the presence or absence of GMDs before infection and at four months post-infection. Demographic, clinical, metabolic, and inflammatory parameters were assessed. Vital NETosis was quantified by flow cytometry. In addition, the capacity of patient plasma to induce NETosis was evaluated using live-cell imaging of healthy neutrophils as biosensors.
Results: Among patients without pre-existing GMDs, 24 of 36 developed insulin resistance (IR) four months after COVID-19. Neutrophils from these patients exhibited increased basal NETosis but showed impaired NETosis in response to TLR7/8 agonists, key sensors of viral single-stranded RNA, compared with control groups. In contrast, NETosis responses to IL-6 and TNF-α were preserved, excluding an intrinsic neutrophil defect. Plasma from IR patients significantly enhanced NETosis, and in vitro experiments demonstrated that insulin enhances NETosis independently of glucose concentrations.
Discussion: De novo IR following COVID-19 dysregulates NETosis primarily through an insulin-enhancing effect. Post-viral control of glucose metabolism disorders may be critical to limit pathological NETosis and its thrombo-inflammatory consequences.
Keywords: COVID-19; NETosis; insulin resistance; long-covid; neutrophil.
. 2026 May 4:17:1787799.
doi: 10.3389/fimmu.2026.1787799. eCollection 2026.
De novo COVID-19-associated insulin resistance drives dysregulated neutrophil extracellular trap formation (NETosis) four months after infection
Sergio Sanhueza # 1 , Camilo Cabrera # 1 , Romina Quiroga 1 , Bárbara Antilef 1 , Camila Muñoz 1 2 , Agustín Vera 1 , Ricardo Cartes 1 3 , Liliana Lamperti 1 , Enrique Guzmán-Gutiérrez 1 , Claudio Aguayo 1 , Valeska Ormazábal 1 , Mauricio Alejandro Hernández 4 , Jaime Lastra 5 , Benilde Riffo 6 , Gustavo Cerda 7 , Luciano Ferrada 7 , David De Gonzalo-Calvo 8 9 , María C García-Hidalgo 8 9 , Mario Henríquez 10 11 12 , María Inés Barría 13 , Ricardo A Verdugo 14 , Alicia Colombo 15 , Gonzalo Labarca 1 12 16 17 , Estefanía Nova-Lamperti 1
Affiliations
- PMID: 42158877
- PMCID: PMC13182236
- DOI: 10.3389/fimmu.2026.1787799
Background: Glucose metabolism disorders (GMDs) are established risk factors for severe COVID-19, but increasing evidence indicates that they may also develop de novo after SARS-CoV-2 infection. Neutrophil extracellular trap formation (NETosis) plays a central role in immunothrombosis, and because neutrophils rely predominantly on glycolysis, they are particularly sensitive to systemic metabolic disturbances. However, the impact of post-COVID-19 GMDs on NETosis remains poorly understood. This study aimed to characterize the emergence of GMDs after COVID-19 and to determine their effect on neutrophil NETosis.
Methods: Sixty COVID-19 patients were stratified according to the presence or absence of GMDs before infection and at four months post-infection. Demographic, clinical, metabolic, and inflammatory parameters were assessed. Vital NETosis was quantified by flow cytometry. In addition, the capacity of patient plasma to induce NETosis was evaluated using live-cell imaging of healthy neutrophils as biosensors.
Results: Among patients without pre-existing GMDs, 24 of 36 developed insulin resistance (IR) four months after COVID-19. Neutrophils from these patients exhibited increased basal NETosis but showed impaired NETosis in response to TLR7/8 agonists, key sensors of viral single-stranded RNA, compared with control groups. In contrast, NETosis responses to IL-6 and TNF-α were preserved, excluding an intrinsic neutrophil defect. Plasma from IR patients significantly enhanced NETosis, and in vitro experiments demonstrated that insulin enhances NETosis independently of glucose concentrations.
Discussion: De novo IR following COVID-19 dysregulates NETosis primarily through an insulin-enhancing effect. Post-viral control of glucose metabolism disorders may be critical to limit pathological NETosis and its thrombo-inflammatory consequences.
Keywords: COVID-19; NETosis; insulin resistance; long-covid; neutrophil.