De novo COVID-19-associated insulin resistance drives dysregulated neutrophil extracellular trap formation (NETosis) four months after infection

BackgroundGlucose 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.MethodsSixty 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.ResultsAmong 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.