key: cord-0696681-guldy3cq authors: Dalan, Rinkoo title: Metformin, Neutrophils and COVID-19 Infection date: 2020-05-22 journal: Diabetes Res Clin Pract DOI: 10.1016/j.diabres.2020.108230 sha: 0d5afa078cbb277bb9a69070ef66ff84acf99c0a doc_id: 696681 cord_uid: guldy3cq nan In recent commentaries, possible mechanisms of action of metformin which may have conflicting effects in COVID-19 has been proposed [1] [2] [3] . In this commentary, a possible role of metformin in COVID-19 on neutrophils, the first line of defense against microbial, fungal and viral infections is proposed. Although a controlled neutrophilic response is needed to combat infection, uncontrolled neutrophilic response can be deleterious [4] . A longitudinal study in 548 patients from China reported that a progressive increase in neutrophil count or neutrophil lymphocyte ratio was associated with a fatal outcome [5] and a similar report have been published from Poland [6] . In an autopsy study of COVID-19 patients, neutrophil infiltration in pulmonary capillaries, extravasation of neutrophils into the alveolar space, and neutrophilic mucositis has been reported [7] . Neutrophil extracellular traps (NETs) first described in 2004 [8] , are extracellular chromatic webs released from neutrophils and contains deoxyribonucleic acid (DNA), histones, microbicidal proteins, (neutrophil elastase and myeloperoxidase) [9] . Recent reports have shown that that sera from patients with COVID-19 have elevated levels of NETS such as cell-free DNA, myeloperoxidase(MPO)-DNA, and citrullinated histone H3 (Cit-H3), highly specific markers of NETs and these were associated with markers of inflammation [10] . If controlled, NETs are beneficial in the host defence against pathogens [10] . However, if excessive NET formation occurs it has the potential to trigger inflammatory cascade that has been associated with cytokine storm [10] , ARDS [11] and microthrombosis [12] all causes of fatality in COVID- 19. Metformin has been shown to reduce neutrophil count in polycystic ovarian disease [13] and reduce neutrophil lymphocyte ratio in patients with diabetes [14] . It has also been shown to ameliorate NETosis in patients with diabetes [15] and pre-diabetes independent of glucose control [16] . Metformin has been associated with a decrease in neutrophil gelatinase-associated lipocalin (NGAL), an acute phase protein released by neutrophils and is known to be elevated in patients with diabetes [17] . Animal studies have shown that metformin reduces post myocardial infarction injuries by reducing cardiac remodelling and myocardial neutrophil activity [18] . Metformin has also been seen to reduce neutrophil and macrophage infiltration in hyperoxia induced lung injury in neonatal rats [19] . While beneficial mechanistic links through neutrophils can be suggested with the use of metformin, it is important to realise that a relatively high rate of mortality in patients with co-existing diabetes has been reported in COVID-19 [20] . A vast majority of these patients would have been on metformin. Until we have real world data on the effects of metformin use in COVID-19 patients with diabetes, no conclusive judgement with regards to its overall usefulness, neutral or detrimental effects can be made. COVID-19 and diabetes: is metformin a friend or foe? Should anti-diabetic medications be reconsidered amid COVID-19 pandemic? Metformin in COVID-19: A possible role beyond diabetes Update on Neutrophil Function in Severe Inflammation Longitudinal hematologic and immunologic variations associated with the progression of COVID-19 patients in China Can we predict the severity of COVID-19 with a routine blood test? Pol Arch Intern Med Targeting potential drivers of COVID-19: Neutrophil extracellular traps Neutrophil extracellular traps kill bacteria Neutrophil extracellular traps in immunity and disease Neutrophil extracellular traps in COVID-19 Neutrophil extracellular traps are elevated in patients with pneumonia-related acute respiratory distress syndrome Neutrophil Extracellular Traps in Arterial and Venous Thrombosis High neutrophil count in girls and women with hyperinsulinaemic hyperandrogenism: normalization with metformin and flutamide overcomes the aggravation by oral contraception Anti-inflammatory effects of metformin irrespective of diabetes status NETosis before and after hyperglycemic control in type 2 diabetes mellitus patients The antidiabetic drug metformin blunts NETosis in vitro and reduces circulating NETosis biomarkers in vivo Neutrophil gelatinase associated lipocalin (NGAL) is elevated in type 2 diabetics with carotid artery stenosis and reduced under metformin treatment. Cardiovasc Diabetol Metformin attenuates myocardial remodelling and neutrophil recruitment after myocardial infarction in rat Metformin attenuates hyperoxia-induced lung injury in neonatal rats by reducing the inflammatory response Is diabetes mellitus associated with mortality and severity of COVID-19? A meta-analysis