Induction of ketosis as a potential therapeutic option to limit hyperglycemia and prevent cytokine storm in COVID-19

Abstract

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 and monocyte-platelet aggregates, which could be responsible for 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 adenosine triphosphate 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, an EKD could be advantageous for the metabolism of anti-inflammatory M2 macrophages because these cells predominantly express oxidative phosphorylation enzymes and are best fed by the oxidation of fatty acids in the mitochondria. An EKD could guarantee the availability of free fatty acids, which are an optimal fuel supply for these cells. Third, an EKD, which could reduce high lactate formation by macrophages due to glycolysis, could favor the production of interferon type 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 an EKD, particularly type 1 or 2 diabetes treated with drugs that can cause hypoglycemia, to avoid the risk for side effects of the diet.

Keywords: Aerobic glycolysis; Alveolar cell type II; COVID-19; Cytokine storm syndrome; Diabetes; Disseminated intravascular coagulation; Hyperglycemia; Interferon type I; Ketogenic diet; Macrophage; Obesity; Warburg effect.

Fig. 1

Possible metabolic pathways during the activation of M1 from AM during COVID-19 infection. AM, alveolar quiescent macrophage; ATP, adenosine triphosphate; IFN, interferon; IL, interleukin; M1, activated macrophage; MCP, monocyte chemoattractant protein; OXPHOS, oxidative phosphorylation; TAC cycle, tricacrboxylic acid cycle; TNF, tumor necrosis factor. This figure was drawn adapting the vector image form the Servier Medical Art bank (http://smart.servier.com/). Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License (https://creativecommons.org/licenses/by/3.0/).

Fig. 2

Hypothetical attenuation of phagocyte hyperactivation by means of an EKD. An EKD could reduce glucose availability for aerobic glycolysis (Warburg-like effect) in M1 macrophages. The main target of this approach is to inhibit M1 phagocyte hyperactivation, which provokes the overproduction of proinflammatory cytokines (IFN-γ, TNF-α, and IL-1 β), leading to excessive accrual of monocytes, neutrophils, and platelets from the blood. AM, alveolar quiescent macrophage; ATP, adenosine triphosphate; EKD, eucaloric ketogenic diet; IFN, interferon; IL, interleukin; M1, activated macrophage; OXPHOS, oxidative phosphorylation; TAC cycle,tricarboxylic acid cycle ; TNF, tumor necrosis factor. This figure was drawn adapting the vector image form the Servier Medical Art bank (http://smart.servier.com/). Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License (https://creativecommons.org/licenses/by/3.0/).