The effectiveness of calorie restriction or a ketogenic diet can be understood through analysis of its biochemistry. A landmark study by Nobel laureate Otto Warburg demonstrated neoplastic metabolic dependence on aerobic glycolysis for energy production 1).
A high-fat, low-carbohydrate diet, often referred to as a ketogenic diet (KD), has been suggested to reduce frequency and severity of chronic pediatric and adult seizures. A hypoglycemic state, perpetuated by administration of a KD, has been hypothesized as a potential aid to the current standard treatments of high-grade gliomas.
The ketogenic diet is the treatment of choice for epilepsy related to glucose transporter 1 deficiency syndrome and pyruvate dehydrogenase deficiency (expert opinion, level U recommendation) 2).
Treatment with KD resulted in a marked improvement in seizures and cognitive functions but its effect appeared to be less striking on the other neurological disorders of the patients. When the classic KD is not tolerated, an alternative to KD may be helpful 3).
The effectiveness is based on the “Warburg Effect” of cancer metabolism and the microenvironment of glioblastoma (GBM) tumors.
A consumed fat molecule (triacylglycerol) is catabolized into free fatty acids and eventually Acetyl-CoA. If increased fatty acid oxidation elevates the levels of Acetyl-CoA to surpass the capacity of the citric acid cycle, excessive levels of ketone bodies accumulate (Beta hydroxybutyrate (BHB) and acetoacetate (ACA)). Normal neurons and glial cells are able to metabolize BHB and ACA; however, neoplastic cells appear less able to utilize these sources for energy derivation. Cancer (CP1) cells also have markedly elevated levels of reactive oxygen species (ROS) that have been associated with angiogenesis and cell proliferation through mediation of vascular endothelial growth factor (VEGF) and hypoxia inducible factor 1 (HIF-1). Ketone bodies have been linked to ROS reduction in vivo. Due to tumor cells’ metabolic dependence on glucose and glutamate, elevated levels of ketone bodies in the intracranial region diminish glycolytic levels and inhibit angiogenesis.
A calorically-restricted diet administered to mice infused with a malignant mouse astrocytoma (CT-2A) or a human glioma (U87-MG) was effective in decreasing vascularity, increasing programmed cell death, and was associated with diminished levels of insulin-like growth factors 4).
Recent clinical findings have demonstrated that induced hypoglycemia and ketogenic diet are tolerable and can potentially be an adjuvant to standard treatments, such as surgery and chemoradiation. Other findings have advocated for KD as a malignant cell growth inhibitor, and indicate that further studies analyzing larger cohorts of GBM patients treated with a KD are needed to determine the breadth of impact a KD can have on GBM treatment 5)
The KD directly or indirectly alters the expression of several proteins involved in malignant progression and may be a useful tool for the treatment of gliomas 6).