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The ketogenic diet initially was developed in the 1920s in response to the observation that fasting had antiseizure properties . During fasting, the body metabolizes fat stores via lipolysis and then the fatty acids undergo beta-oxidation into acetoacetate, β-hydroxybutyrate, and acetone—ketone bodies the cell can then use as precursors to generate adenosine triphosphate (ATP). The ketogenic diet, which is very high in fat and low in carbohydrates, is thought to simulate the metabolic effects of starvation by forcing the body to use primarily fat as a fuel source. The ketogenic diet fell out of favor with the development of new anticonvulsant agents, starting with phenytoin in 1938, but it has experienced a resurgence in use over the past 20 years, particularly in the treatment of refractory epilepsy.
Ketone bodies, especially β-hydroxybutyrate, can be measured easily, so much work has centered on determining how these molecules may have anticonvulsant effects. Inconsistencies in studies attempting to correlate seizure protection with levels of ketone bodies suggest that another mechanism may be involved in the diet’s beneficial effects on seizures [2–5, Class III]. Several mechanisms have been proposed, including changes in ATP production making neurons more resilient in the face of metabolic demands during seizures; altered brain pH affecting neuronal excitability; direct inhibitory effects of ketone bodies or fatty acids on ion channels; and shifts in amino acid metabolism to favor the synthesis of the inhibitory neurotransmitter GABA [6,7].
With renewed use of the ketogenic diet has come heightened interest in its potential use for other conditions (Table 1). Over the past few years, there has been an explosion in speculation about the diet’s potential applications in a variety of metabolic, oncologic, neurodegenerative, and psychiatric disorders. This review examines data supporting the potential use of the ketogenic diet in each disorder and considers potential mechanisms of action in each disorder, using these data to shed light on the diet’s disease-modifying effects. Both the human and animal studies discussed used standard ketogenic diets unless otherwise specified.
The ketogenic diet has many potential effects and is likely to have different mechanisms in different diseases . In metabolic conditions, cancer, trauma, and ischemia, the ketogenic diet may confer a protective effect by providing an additional energy substrate to tissue at risk of cell death. However, ketosis may have more complicated effects. In one model, rats fed the ketogenic diet show marked upregulation of both the ketone transporter and the glucose transporter type 1 (GLUT-1), promoting the influx of nutrients into the brain . These authors provided evidence that the ketogenic diet increases capillary density without increasing overall blood flow, providing a way that the diet may help nourish tissue at risk. This finding is particularly interesting in light of findings in animals with tumors, in which the diet is associated with an anti-angiogenic effect [10,11]. These discordant results eventually will need to be reconciled; they may be due to differences in angiogenic stimuli in normal cells versus malignant cells.
It is possible to discuss two aspects of the diet: known or “direct” properties (high ketone-body levels, high fat, and restriction of calories from carbohydrate) and potential indirect effects (eg, effects on neurotransmitters, ion channels, or mitochondrial biogenesis) (Table 2). Ketone bodies provide alternative substrates for use in the tricarboxylic acid cycle and enhance mitochondrial function (evidenced by increased ATP production and decreased effects of reactive oxygen species). Fatty acids and calorie restriction may have beneficial effects by themselves. The potential indirect effects have been studied in epilepsy but have not been investigated to the same degree in other illnesses. Formal studies of the efficacy of the ketogenic diet in epilepsy should serve as a model for future clinical investigations in other diseases [12••].
The ketogenic diet is well established as therapy for intractable epilepsy. It should be considered first-line therapy in glucose transporter type 1 and pyruvate dehydrogenase deficiency. It should be considered early in the treatment of Dravet syndrome and myoclonic-astatic epilepsy (Doose syndrome).
Initial studies indicate that the ketogenic diet appears effective in other metabolic conditions, including phosphofructokinase deficiency and glycogenosis type V (McArdle disease). It appears to function in these disorders by providing an alternative fuel source. A growing body of literature suggests the ketogenic diet may be beneficial in certain neurodegenerative diseases, including Alzheimer disease, Parkinson’s disease, and amyotrophic lateral sclerosis. In these disorders, the ketogenic diet appears to be neuroprotective, promoting enhanced mitochondrial function and rescuing adenosine triphosphate production.
Dietary therapy is a promising intervention for cancer, given that it may target the relative inefficiency of tumors in using ketone bodies as an alternative fuel source. The ketogenic diet also may have a role in improving outcomes in trauma and hypoxic injuries.
Dr. Hartman was supported by a Neurological Sciences Academic Development Award (K12NS001696). The authors gratefully acknowledge Max Wiznitzer, MD, for helpful comments regarding some of the trials discussed here.
No potential conflicts of interest relevant to this article were reported.
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