sanjaykumar wrote:Glucose analogues may be important in modifying protein glycosylation which may impact cellular receptor binding or immunological vulnerability.
I’m not dismissing such results however, these matters are not about opinion but facts. Let’s leave opinion to Rana Ayub and genocide Susie.
2DG is proposed to work by a mechanism of action detailed here: https://www.nature.com/articles/s41392-021-00532-4
Abnormal glucose metabolism primarily caused by impaired insulin secretion and/or action is a characteristic feature of T2D and affects several tissues highly important for the regulation of whole body metabolism, such as liver, adipocytes, muscle, pancreatic islets, and immune cells. The increased glucose metabolism imposed by sustained hyperglycemia may enhance SARS-CoV-2’s entry and subsequent replication, as well as an exacerbated immune response in individuals with diabetes. Thus, a disrupted glucose metabolism and metabolic derangement in diabetes may be an intrinsic cellular strategy that favors SARS-CoV-2 pathogenesis. In this context, Codo et al.1 explored the molecular response of SARS-CoV-2 infected human monocytes under diabetic condition. The authors initially show that SARS-CoV-2 efficiently infects peripheral blood monocytes, upregulates angiotensin-converting enzyme 2 (ACE2), a key SARS-CoV-2’s receptor and highly induced proinflammatory cytokines such as TNF-α, IL-1β, and IL-6. This is consistent with the altered innate immune response and excessive inflammatory cytokine production, the so-called “cytokine storm” observed in severe COVID-19.1 Notably, dose-dependent increase in glucose concentrations potentiate SARS-CoV-2 replication as well as ACE2 upregulation and cytokine production in monocytes suggesting elevated glucose as a principal promoter of virus replication and inflammatory response. SARS-CoV-2 directly induces glycolysis in monocytes, which is in line with the enrichment of glycolytic genes and metabolic remodeling observed by single-cell RNA sequencing (RNA-seq) of lung monocyte from COVID-19 patients.1
To understand the biochemical mechanism required for SARS-CoV-2’ replication and its impact in monocytes, Codo et al.1 provided conclusive evidences that glycolytic flux is indispensable for SARS-CoV-2’s impact. Through well-designed experiments, the authors show that inhibition of glycolysis by 2-deoxy-D-glucose (2-DG) as well as inhibition of glycolytic enzymes 6-phospho-fructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3), a positive regulator of phosphofructokinase-1 (PFK1) as well as lactate dehydrogenase A (LDH-A) abolishes viral replication and cytokine response placing glycolysis as a key upstream event during SARS-CoV-2 pathogenesis, although critical glycolytic intermediate/final product(s) mediating such effect was not determined. Similarly, 2-DG blocks SARS-CoV-2 replication in a colon epithelial carcinoma cell line.3 The metabolic transcription factor hypoxia-inducible factor-1α (HIF-1α) is a master regulator of glycolysis and HIF-1α levels and activity as well as target genes are strongly induced in SARS-CoV-2 infected monocytes consistent with elevated HIF-1α in blood monocytes isolated from critical COVID-19 patients.1 Codo et al. further identified that HIF-1α inhibition or stabilization blocks or exacerbates HIF-1α target genes, viral replication and ACE2 and cytokine expression, indicating that HIF-1α is essential for elevated glycolysis and subsequent inflammatory responses. The authors further offer mechanistic insight into how HIF-1α is stabilized under increased glucose condition. Through a series of biochemical experiments, they show that an increase in mitochondrial reactive oxygen species (ROS) due to impaired oxidative metabolism is responsible for HIF-1α stabilization and the proinflammatory state in SARS-CoV-2 infected monocytes1
Finally, the authors investigated whether metabolic remodeling and altered immune state of monocytes potentiated by high glucose during SARS-CoV-2 infection impairs T cell function and response. Conditioned media obtained from metabolically primed SARS-CoV-2 infected monocytes compromise CD4 or CD8 T-cell proliferation and also induce lung epithelial cell death.1 Inhibition of HIF-1α, as well as neutralization of ROS or IL-1β antagonize such effects and restore T-cell function or lung epithelial cell survival, which suggests that increased glucose metabolism through aerobic glycolysis and subsequent cytokine production in monocytes could further deteriorate neighboring cells in a paracrine fashion under pro-diabetic conditions in COVID-19 patients
The cellular energy status is instrumental for coordinating inflammatory responses as the host cellular metabolism is critical for anti-virulence during infection. For example, the proinflammatory cytokine IL-1β is increased in people with COVID-19. IL-1β processing is regulated through generation of 3-phosphoglycerate, a by-product of glycolysis suggesting a direct link to glucose metabolism. Furthermore, the inhibition of glycolysis with 2-DG was shown to halt IL-1β induction and to protect against LPS-induced sepsis in mice.4 This together with Codo et al.‘s findings indicate that SARS-CoV-2 replication and cellular host response are promoted by metabolic rewiring including a shift to aerobic glycolysis. Similarly, proinflammatory cytokines induced by Influenza A virus (IAV) infection is regulated by glucose metabolism reprogramming5 emphasizing the importance of glucose metabolism in virus-induced cytokine storm.
Layperson summary: Cells can use sugar to make energy in two broad ways. The first way is complex and takes longer but is ultimately more efficient in how much energy is generated per sugar (glucose) molecule. The second way is simple and quick but not efficient; cells need a lot more glucose to generate a given amount of energy, compared to the first way.
When COVID infects cells it alters them to prefer the second way over the first way... because doing so creates more favourable conditions for COVID to replicate. As a result, COVID-infected cells hog a lot of glucose. Moreover, as an effect of switching over to this second way of metabolizing glucose, other things also happen to the COVID-infected cells. One of these things is that they overproduce cellular signaling molecules that promote inflammation and ultimately result in tissue damage.
One way to break this circuit is to give COVID-infected cells 2DG. The cells will hungrily ingest it, mistaking it for glucose. But they won't be able to use it to generate energy. Thus we hope all the ill-effects of cells overusing glucose to sustain the second pathway of energy metabolism can be curtailed, and less inflammation and damage will occur.