Ketogenic diet

The ketogenic diet is a high-fat, medium protein, low carbohydrate diet primarily used for children with treatment-resistant epilepsy. It induces ketosis, a metabolic state in which the body derives most of its energy from ketones rather than glucose. A ketogenic diet increases blood ketone bodies: β-hydroxybutyrate, acetoacetate, and acetone. β-hydroxybutyrate comprises 70% of the ketone bodies produced from a ketogenic diet. The therapeutic benefits of a ketogenic diet are believed to be due to β-hydroxybutyrate which acts as a signalling molecule.

Ketone bodies are a more efficient fuel than glucose. The brain can derive up to 60% of energy from ketones. The metabolic breakdown of ketone bodies produces more ATP per oxygen molecule consumed than other metabolic substrates. The ketone body β-hydroxybutyrate is converted to acetyl-CoA and distributed to metabolically active tissues as a fuel source (e.g. brain, skeletal muscle, heart). This acetyl-CoA is cycled directly into the Kreb’s cycle for energy production thereby bypassing glycolysis and pyruvate dehydrogenase (PDH).

Ketones may enhance antioxidant defenses by multiple mechanisms. β-hydroxybutyrate promotes transcription of genes associated with protective mechanisms including mitochondrial superoxide dismutase (MnSOD), catalase, and metallothionein. The effect is therefore reduced oxidative stress and lipid peroxidation. β-hydroxybutyrate upregulates production of the antioxidant glutathione likely through activation of the nrf2 pathway.

Types of Ketogenic Diets
A ketogenic diet is comprised of a dietary fat to carbohydrate ratio of 3:1 or 4:1. The diet should include <20 grams of carbohydrate per day, or 15-10% of total caloric intake. Ketogenic diets can be less strict if using exogenous ketones.

General Effects
In an animal model, a ketogenic diet was shown to increase mitochondrial biogenesis. A similar result was found in a study of fasting mice. Ketone bodies scavenge free radicals in vivo. Ketogenic diets reduce circulating levels of insulin and insulin-like growth factors. Acute nutritional ketosis is shown to reduce lactate production and improve performance potential in cycling activity. It is shown to prevent muscle wasting.

Epilepsy
Neurotransmitters regulate nerve impulses in the brain by either inhibiting impulse firing or exciting the neuron to fire. A primary inhibitory neurotransmitters is GABA and a primary excitatory neurotransmitters is glutamate. In patients with epilepsy, if the normal balance of inhibition and excitation is disrupted, a seizure can occur.

It is unknown why ketogenic diets are protective against epilepsy. In animal models, the ketone bodies acetoacetate and acetone have anticonvulsant properties through a novel pathway.

The Charlie Foundation supports the use of ketogenic diets with children with severe epilepsy.

Neurodegenerative Disease
There is evidence from uncontrolled clinical trials and animal models that ketogenic diets may be protective in neurodegenerative disorders including Alzheimer's disease and Parkinson's disease.

Mice fed a ketogenic diet had increased activity of dopaminergic neurons. In a rat model of Parkinson's, a ketogenic diet was protective against neurotoxicity by up-regulating glutathione. A clinical trial of Parkinson’s disease compared a ketogenic diet to a low-fat diet with improvement in motor symptoms in both groups after 8 weeks but greater improvement in non-motor symptoms (fatigue, pain, and cognitive impairment) in the ketogenic group. Another study found dietary ketosis enhanced memory in patients with mild cognitive impairment.

Traumatic Brain Injury (TBI)
The ketogenic diet is an effective treatment for TBI recovery in rats and shows potential in humans.

Migraine
A study of 96 migraine patients on a 1-month ketogenic diet experienced up to 80% fewer migraines, less severity, and less reliance on medications.

Multiple Sclerosis
A ketogenic diet reduced the expression of enzymes involved in the biosynthesis of pro-inflammatory eicosanoids and improved quality of life as measured by the Multiple Sclerosis Quality of Life-54 index.

Chronic Fatigue Syndrome
No studies have been done on the effects of ketogenic diets in Chronic fatigue syndrome. Some CFS clinicians recommend ketogenic diets as a management strategy citing mitochondrial dysfunction, immune dysfunction, and neuroinflammation as pathways through which ketogenic diets could confer some benefit.

Risks & Side Effects

 * The ketogenic diet was found to regulate blood sugar but over the long term cause fat to accumulate in the liver in an animal model of Type II Diabetes. An open label, non-randomized, controlled study of the ketogenic diet in Type II Diabetes patients showed sustained long-term beneficial effects on multiple clinical markers of diabetes and cardiometabolic health at 2 years while utilizing less medication.
 * Two children on the diet for refractory epilepsy had selenium deficiency which resulted in sudden cardiac death.
 * Up to 6% of those on a ketogenic diet may experience kidney stones.
 * Ketogenic diets may require additional supplemental nutrition to prevent deficiencies. Common deficiencies include calcium, zinc, selenium, and copper.
 * Ketogenic diets are not recommended for those with genetic primary carnitine deficiencies [including mutations in carnitine palmitoyl transferase (CPT) I or II and mitochondrial translocase] and fatty acid β-oxidation abnormalities (e.g., medium-chain acyl dehydrogenase deficiency).  It is safe for those with mitochondrial defects in complexes I, II, and IV and pyruvate dehydrogenase complex deficiency.

Notable studies

 * Efficacy and Safety of Ketogenic Diet as Adjunctive Treatment in Adults With Refractory Epilepsy (KD) (This study is ongoing, but not recruiting participants.)
 * Long-Term Effects of a Novel Continuous Remote Care Intervention Including Nutritional Ketosis for the Management of Type 2 Diabetes: A 2-Year Non-randomized Clinical Trial.
 * 2019, Potential benefits of a ketogenic diet to improve response and recovery from physical exertion in people with Myalgic encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A feasibility study - (Full text)

Medium chain triglycerides (MCT)
Supplementation with medium-chain triglycerides (MCTs) increases blood levels of ketones. They are often used in ketogenic diets to help maintain ketosis at a lower proportion of fat intake. Regular intake of MCTs can increase expression of ketone transporter MCT1 at the brain, increasing uptake of ketones. A study showed improved cognition in Alzheimer's disease patients taking MCTs.

Exogenous ketones
A challenge of exogenous ketones is in the ability to deliver sufficient β-hydroxybutyrate to the brain and to sustain high levels of β-hydroxybutyrate. Uptake can be increased with a ketogenic diet or regular ingestion of MCT and/or supplemental ketones. Exogenous ketones have been found to increase blood ketone bodies without requiring such strict dietary measures. Exogenous ketones come in esters and salts, both have been found to raise β-hydroxybutyrate to therapeutic levels that can last for hours.

Clinical use
Doctor Sarah Myhill has a page on her web site describing the ketogenic diet. Dr. Courtney Craig has published a hypothesis on the use of ketogenic diets in ME/CFS and offers dietary consulting to patients.

Learn more

 * 2017, Getting Clear on Ketogenic Diets (for Fibromyalgia and ME/CFS): A Review
 * Wikipedia - Ketogenic diet
 * Ketogenic Diet Resource
 * Wikipedia - Fatty acid metabolism