INDUCTION OF KETOSIS AS A POTENTIAL THERAPEUTIC OPTION TO LIMIT HYPERGLYCEMIA AND PREVENT CYTOKINE STORM IN COVID-19

Sukkar, Samir Giuseppe; Bassetti, Matteo

The severe form of Coronavirus Disease 19 (COVID-19) is characterized by "cytokine storm syndrome" (CSS) and disseminated intravascular coagulation (DIC). Diabetes, obesity and hypertension have, as minor common denominators, chronic low-grade inflammation and high plasma myeloperoxidase levels, which could be linked to pulmonary phagocytic hyperactivation and CSS. The hyperactivation of M1 macrophages with a proinflammatory phenotype, which is linked to aerobic glycolysis, leads to the recruitment of monocytes, neutrophils and platelets from circulating blood and plays a crucial role in thrombo-inflammation (as recently demonstrated in COVID- 19) through the formation of neutrophil extracellular traps (NETs) and monocyte-platelet aggregates, which could be responsible for disseminated intravascular coagulation (DIC). The modulation of glucose availability for activated M1 macrophages by means of a eucaloric ketogenic diet (EKD) could represent a possible metabolic tool for reducing ATP production from aerobic glycolysis in the M1 macrophage phenotype during the exudative phase. This approach could reduce the overproduction of cytokines and, consequently, the accumulation of neutrophils, monocytes and platelets from the blood. Second, a EKD could be advantageous for the metabolism of anti-inflammatory M2 macrophages because these cells predominantly express OXPHOS enzymes and are best fed by the oxidation of fatty acids in the mitochondria. A EKD could guarantee the availability of free fatty acids, which are an optimal fuel supply for these cells. Third, a EKD, which could reduce high lactate formation by macrophages due to glycolysis, could favor the production of interferons type I (IFNs I), which are inhibited by excessive lactate production. From a practical point of view, the hypothesis, in addition to being proven in clinical studies, must obviously take into account the contraindications of a EKD, particularly type I diabetes and type II diabetes treated with drugs that can cause hypoglycemia, to avoid the risk of side effects of the diet.