The ketogenic diet (KD) is a high-fat, adequate-protein, and very-low-carbohydrate diet regimen that mimic the metabolism of the fasting state to induce the production of ketone bodies. The KD has long been established as a remarkably successful dietary approach for the treatment of intractable epilepsy and has increasingly garnered research attention rapidly in the past decade, subject to emerging evidence of the promising therapeutic potential of the KD for various diseases, besides epilepsy, from obesity to malignancies.
In particular, the KD can mimic the metabolic effects of fasting without significant calorie deprivation.
In the past few decades, the KD has received extensive interest because of its beneficial effects in a number of diseases, such as neurological disorders, obesity, type 2 diabetes mellitus (T2DM), cancer, intestinal disorders, and respiratory compromise
Ketogenic process
In the liver, excessive production of acetyl coenzyme A (acetyl-CoA) and oxidation of fatty acids leads to the production of Ketone Bodies (KBs). The acetyl-CoA molecule can be utilized in the Krebs cycle or to produce acetoacetate, which is then spontaneously converted to acetone or 3-β-hydroxybutyrate by 3-β-hydroxybutyrate dehydrogenase. The KBs then enter the bloodstream and can be utilized by the brain, heart, and muscle, where they produce cellular energy in mitochondria. Higher circulating KB levels lead to ketonemia and ketonuria.
Under physiological conditions, the blood concentration of KBs during prolonged fasting usually is 5–7 mM, while the glucose concentration could be lowered to below 1 mM without either convulsions or any impairment of cognitive function. In diabetic ketoacidosis, the plasma KB levels can increase up to 25 mM due to insulin deficiency, with a consequent increase in the plasma glucose concentration and decreased blood pH. The KBs constitute a more efficient energy source than glucose, metabolize faster than glucose, and can bypass the glycolytic pathway by directly entering the Krebs cycle, whereas glucose needs to undergo glycolysis. Moreover, KBs cause fatty acid-mediated activation of peroxisome proliferator-activated receptor α as well as the inhibition of glycolysis and fatty acids. Therefore, KBs reduce the production of glycolytic adenosine triphosphate (ATP) and increase mitochondrial oxidation-induced ATP generation, thereby promoting mitochondrial oxidative metabolism, with resultant beneficial downstream metabolic changes.
Effects against COVID- 19
Human SARS-CoV-2 infection is characterized by a high mortality rate due to some patients developing a large innate immune response associated with a cytokine storm and acute respiratory distress syndrome (ARDS). This is characterized at the molecular level by decreased energy metabolism, altered redox state, oxidative damage, and cell death.
Central metabolism is controlled by four major nucleotide coenzyme couples: ADP/ATP, NAD+/NADH, NADP+/NADPH, and acetyl-CoA/CoA]. The prominent role these couples play in central metabolism is highlighted. Metabolic therapy aimed at restoring these ratios is often used as an adjunct to more targeted therapies. The ketogenic diet as a treatment for childhood epilepsy has drawn focus to (R)-beta-hydroxybutyrate (R-BHB) as a metabolic therapy. Recently, exogenous ketones, which are various formulations of BHB, acetoacetate, or their precursors, have made it possible to raise blood R-BHB levels and alter the ratios of the controlling coenzyme couples without implementing a ketogenic diet. (R)-3-Hydroxybutyl (R)-3-hydroxybutyrate, a type of ketone ester, is one of the several forms of exogenous ketones that increase systemic R-BHB levels. R-BHB-derived metabolites restore flux through the citric acid (Krebs) cycle and oxidative phosphorylation when viral-induced changes in enzyme activity prevent glucose or fatty acids from fueling these pathways. Increasing R-BHB levels has been shown to normalize ADP/ATP, NAD+/NADH, NADP+/NADPH, and acetyl-CoA/CoA ratios in diseased tissue. R-BHB has multiple anti-inflammatory signaling roles and functions as an epigenetic modifier to stimulate a program of gene expression that alters metabolism to restore cellular redox function. The focus of metabolic therapy is on the restoration of the coenzyme ratios that largely control metabolic flux through central metabolic pathways.
The covid-19 pandemic is now a global threat. Especially, severe covid-19 with cytokine storm syndrome is desperately lethal and a main cause of mortality. The KD has been proposed as an adjunct therapy for covid-19 patients due to its contribution to the reduction of critical risk factors such as obesity, type 2 diabetes and hypertension, anti-inflammation, and metabolism modulation. It is proposed that switching lipid metabolism, which can be achieved by a ketogenic diet rich in MCTs or by intermittent fasting, may disfavor viral replication and infection and inhibit cytokine storm. Importantly, it is also believed that the induction of ketosis may help to prevent the cytokine storm. A recent retrospective analysis of 34 covid-19 patients receiving an eucaloric KD in comparison to 68 who received a eucaloric standard diet showed that the former might have a lower risk in motility and ICU admission. Thus, the KD could be a theoretical preventive and supportive care option for patients with covid-19. But clinical evidence are needed.