2-deoxy-d-glucose therapy for preventing inflammatory cascade in COVID19 patients

To the Editor,

Researchers have proved beyond doubt that uncontrolled blood sugars in known diabetic patients or patients without diabetes presenting with increased, uncontrolled sugars due to systemic inflammation status per se face adverse outcomes if they have COVID19 disease, due to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2).[1] It has been demonstrated that when human monocytes in patients with COVID19 infection were exposed to high glucose, there was exaggerated viral replication, upregulation of angiotensin-converting enzyme 2 (ACE2), and an increased cytokine production which compromised T-cell response and its overall function in curtailing underlying infection. This led to further damage to lung parenchymal cells which could explain the exaggerated virulence in diabetic patients and in patients with high blood sugars.[2] This leads to the release of proinflammatory cytokines like TNF-α, IL-1β, and IL-6 thus facilitating cytokine storm. This cytokine storm occurs in certain categories of patients due to the hyperactivation of the innate immune system by SARS-CoV-2 and excessive release of proinflammatory cytokines and chemokines.

Otto Warburg described the Warburg effect or the aerobic glycolysis in the year 1920 in which cancer cells utilize excessive glucose levels in presence of oxygen to produce lactate.[3] Researchers had earlier demonstrated in the previous pandemic that in MERS-CoV disease there was aerobic glycolysis which led to the release of proinflammatory cytokines and worsening of the disease. The same is being postulated in COVID19 disease as well. It was observed that by inhibition of glycolysis by using 2-deoxy-d-glucose, glycolytic enzymes 6-phospho-fructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3) which regulated phosphofructokinase-1 (PFK1) and also lactate dehydrogenase A (LDH-A) abolished viral replication and excessive cytokine release.

Glucose homeostasis is impaired in patients with diabetes mellitus, de novo patients, and also in any patient with systemic inflammatory response syndrome due to any bacterial or viral infection. Aerobic glycolysis causes hyperactivation of M1 macrophages that eventually leads to the recruitment of monocytes, neutrophils, and platelets from circulating blood. This leads to the formation of neutrophil extracellular traps and monocyte-platelet aggregates which is supposedly the reason for thrombosis. As accelerated glycolysis is possibly responsible for excessive viral replication and exaggerated severity of the disease, researchers explored agents which could inhibit glycolysis and thus potentially interfere with viral replication during the early stage of the disease.[4] In underlying viral infection, there is a shift from oxidative phosphorylation to aerobic glycolysis in the host cells which facilitates viral replication. Hypoxia-inducible factor-1α (HIF-1α) has been implicated to be an important regulator of glycolysis. HIF-1α levels are induced in SARS-CoV-2 infected monocytes. HIF-1α stabilization or inhibition has important therapeutic effects like reduced replication, reduced release of inflammatory cytokines, restores T-cell function, and improved lung epithelial cell survival [Figure 1].[5]

Figure 1.

(a) Chemical structure of 2-deoxy-d-glucose. (b) Shows the inflammatory cascade as a result of persistent hyperglycemic state in COVID19 patients. Image source: National Center for Biotechnology Information (2021). PubChem Compound Summary for CID 108223, Deoxyglucose. Retrieved June 05, 2021 from https://pubchem.ncbi.nlm.nih.gov/compound/Deoxyglucose

2-deoxy-d-glucose is a glucose molecule in wherein the 2-hydroxyl group is replaced by hydrogen as a result of which it cannot undergo further glycolysis [Figure 1a]. When administered systemically, it competitively inhibits the production of glucose-6-phosphate from glucose at the phosphorglucoisomerase level i.e., at step 2 of glycolysis.[6] It was observed that by inhibition of glycolysis by using 2-deoxy-d-glucose, glycolytic enzymes 6-phospho-fructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3) which regulated phosphofructokinase-1 (PFK1) and also lactate dehydrogenase A (LDH-A) abolished viral replication and excessive cytokine release.

The beneficial effects of 2-deoxy-d-glucose are owing to its anti-glycolytic properties, anti-inflammatory, immune-enhancing properties which can have beneficial effects when used in the acute phase of illness. The immunomodulation properties of 2-deoxy-d-glucose is due to its ability to restore CD/CD8 ratio, enhancing natural killer cells properties, and IFN λ levels.[7] When used in cancer patients, rapid metabolism and short half-life were the problems encountered with the use of 2-deoxy-d-glucose. Safety and efficacy in cardiac, renal, and hepatic ailments has not been validated yet. Fatigue, sweating, dizziness, nausea, symptoms of hypoglycemia are the problems of using 2-deoxy-d-glucose. To address these issues, researchers developed analogues and prodrugs of 2-deoxy-d-glucose. They are 2-halogen substituted d-glucose, fluoro-hexose compounds, and acetates of 2-deoxy monosaccharides as prodrugs. However, these compounds have been used in cancer patients and not in COVID19 patients.[8]

To conclude, providing 2-deoxy-d-glucose as a substrate for inhibiting glycolysis which is a key step in disease progression could have several beneficial effects in patients with COVID19 disease. However, this adjunct therapy needs to validated by conduction well-designed, adequately powered studies. Although the adjunct although appears safe, there is no clarity regarding the dose, timing, and duration of 2-deoxy-d-glucose therapy in COVID19 patients.

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Conflicts of interest

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