Overview and potential therapeutic applications of the ketogenic diet

Ketones are organic molecules produced by liver. Three main ketone bodies are produced in the body; acetone, acetoacetic acid, beta-hydroxybutyric acid. When the body produces ketones in a sufficient amount one is said to be in a state of ‘ketosis’.

The body needs constant energy production to maintain life. Adenosine triphosphate (ATP) is the currency the body uses for energy. The brain accounts for about 20% of all energy needs, which is relatively high percent given its small size. While the neurons in the brain can utilize same amounts other energy sources (i.e. lactate and fatty acids), it primarily relies on glucose as its major source of energy. The main source of glucose is from the intake of dietary carbohydrates. Below is a diagram showing where glucose funnels into the Kreb’s cycle which is the major energy-producing pathway in the body. The process occurs in the mitochondria, which is the ‘powerhouse’ of the cell.

















In periods of starvation or severe glucose restriction, a temporary source of glucose can be found in the liver as stored glycogen. The length of time this glycogen will last depends on how big the storage is and the energy expenditure demands. It is certainly known that even periods of extreme starvation do not cause death, therefore the brain must be utilizing an alternative energy source to maintain normal function. During periods when glucose is not readily available in sufficient amounts the body can produce Kreb’s cycle substrates, mainly Acetyl CoA, by two sources, free fatty acids, and ketone bodies. The liver can produce a ketone body called beta-hydroxybutyrate (B-OHB) from long and medium chain triglycerides. B-OHB can then be converted in the Acetyl CoA and enter the Kreb’s cycle for energy production. Ketones can readily cross the blood-brain-barrier and be used as fuel by mitochondria of neurons. The process explains why animals (including humans) can go prolonged periods without any intake of glucose and still survive. To demonstrate that the brain can effectively utilize ketones as a fuel source an old study was performed where patients with high levels of circulating B-OHB were injected with insulin to lower their glucose to dangerous levels, yet patients remained symptom-free with normal neurologic function. In a normal state of ketosis without exogenous insulin, glucose levels will stabilize around 65-70 mg/dL. This occurs because the backbone of triglycerides, glycerol, is cleaved during the process of ketone production in the liver and is then converted to glycogen, which can be used to make a steady state of glucose. The ability for the body to produce ketones is the explanation why one can not only survive, but even thrive in the absence of glucose intake.

It is also worth discussing the difference between nutritional ketosis and diabetic ketoacidosis (DKA). Nutritional ketosis is a normal physiologic response to low carbohydrate (glucose) intake. DKA occurs in patients with either a complete absence of insulin (Type I) or severe insulin resistance (Type II). With a normally functioning pancreas, enough insulin is produced so that B-OHB levels can’t rise above about 7-8 mMol, which is well below the level to induce a pathologic acidotic state. These two metabolic states are completely separate from each other and the word ‘ketosis’ should not be automatically associated with a dangerous state, as it often is in the medical community.

While the utility and benefits of being in a ketogenic state are growing rapidly, historically the best example of its use is in refractory seizure patients. This treatment strategy is not new and its use can be found as far back as 500 BC. Dietary management of epilepsy started to fall out of favor as antiepileptic drugs became available. While the exact mechanism of how the ketogenic diet helps prevent seizure is unknown, it’s clear that the ketones do possess anti-epileptic properties. Mechanistic theories include direct and indirect anticonvulsant properties of ketones themselves, decreased production of reactive oxygen species, increased synthesis of GABA (a neurotransmitter in the brain and reduces excitability of the cells), and boosting of the production of energy in the brain’s tissue via mitochondrial biogenesis.

The major hurdle to overcome when initiating a ketogenic diet, especially in animals, is the inconvenience. You will not find a ketogenic diet on the shelves of the pet food stores. Feeding a ketogenic diet requires very precise macronutrient calculations and is rather limited in ingredients used. If not formulated correctly, micronutrient deficiencies may occur. A state of ketosis will only occur if dietary carbohydrates (in addition to avoiding excess protein) are kept below a certain threshold. Even one lapse in the strict diet may prevent a state of ketosis from being achieved. Despite the limited room for error in the development of the ketogenic diet, it can be appropriately formulated to be nutritionally complete.  Certain foods which contain medium train-triglycerides (MCT’s) are more ‘ketogenic’ than those that contain more long-chain triglycerides.  Tropical oil, especially coconut oil, is particularly high in MCT. MCT’s are types of fatty acids containing 6–12 carbons. They include caproic acid (C6), caprylic acid (C8), capric or decanoic acid (C10) and lauric acid (C12). Because of the shorter chain length of the fatty acids, MCTs are rapidly broken down and absorbed into the body and unlike longer-chain fatty acids, MCTs go straight to the liver. There they can be used as an instant energy source or turned directly into ketones.

A recent study randomly evaluated the use of a MCT diet in dogs with epilepsy and found a significant seizure reduction compared to the control group. This study was the essence for the development of the Purina Neurocare diet. However, in this authors opinion, a client may have better control of MCT / ketone levels by supplementing their own MCT oil to their dog’s diet. Another recent study proposed that there is a direct anti-seizure effect from the MCT decanoic acid (C10) by inhibition of the AMPA subunit on glutamate receptors in the brain. Glutamate is the major excitatory neurotransmitter in the brain which has a major role in the propagation of the seizure activity. The ketogenic diet can be used to supplement a patient’s medical regimen, especially if refractory. Blood ketones can be monitored with several handheld devices. A probable ideal range would be between 0.5-1 mMol/L.
While the most common therapeutic application of ketogenic diet is for seizures, many other disease states have shown benefit. The ketogenic diet may have a role in treating cancer. This line of thinking supports the ‘metabolic theory’ in that cancer is a result of broken cellular metabolism in the mitochondria. Because mitochondrial dysfunction is at the root of most neurodegenerative diseases their evidence that a ketogenic may improve neurologic function in human patients with amyotrophic lateral sclerosis (ALS), Alzheimer’s disease and Parkinson’s disease.  Because of the very low carbohydrate content in a ketogenic diet, it would make sense this dietary strategy would be successful treating patients with Type II diabetes. As emerging evidence supports the use of treating chronic disease states with ketogenic diets, we will likely see growing use in the veterinary practice.

Submitted by: David Brewer DVM, DACVIM (Neurology)







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