How does the ketogenic diet work?

English: of beta-hydroxybutyric acid. Created ...

English: of beta-hydroxybutyric acid. Created using ACD/ChemSketch 10.0, and vim. (Photo credit: Wikipedia)

The ketogenic diet is a high fat, adequate protein, low carbohydrate diet, which has been used for almost a century to treat cases of epilepsy resisting to anticonvulsant medications (see my previous post for more details). However, although its efficiency is now widely accepted, the exact mechanisms by which it operates are still not completely understood.

Understanding how the ketogenic diet and its variations alleviate epileptic symptoms is an important step in understanding the correlation between health and nutrition. It also helps predict beneficial applications of the diet to other ailments.

Forcing the body to switch sources of energy

When the body receives carbohydrates, the preferred source of energy is glucose, which produces cellular energy or ATP (adenosine triphosphate) through glycolysis. Excess carbohydrates is stored in the glycogen of the muscles and liver.

In the absence of carbohydrates in the diet, the body uses up glycogen stores and switches to other sources of energy such as fats and proteins. Fat stores liberate fatty acids, which are metabolized by the cells in Acetyl-coA and ATP. However, when there is an excess fat intake, or prolonged lack of carbohydrates, the liver starts producing ketones from Acetyl-coA. Ketones are an efficient fuel, used by the heart and kidneys. One specific ketone, acetone, cannot be used and is excreted through the kidneys and lungs (where it gives a characteristic smell to the breath).

Are ketones responsible for the effect of the diet?

During the ketogenic diet, increased intake of fats and reduced intake of carbohydrates generates ketone bodies (hence the name ketogenic). Therefore, the first hypotheses concerning the mechanisms of the ketogenic diet involved an anticonvulsant role for ketones. In agreement with this hypothesis, anticonvulsant properties of ketones such as acetoacetate and acetone were found in animals.

However, the more recent use of modified versions of the ketogenic diet, including Medium-chain triglyceride (MCT), modified Atkins diet, and the low glycemic index therapy (LGIT) are putting this hypothesis in question (those variations will be detailed and discussed in a future post). In particular, the low glycemic index therapy (LGIT) results in little or no ketosis, yet produces significant reductions in rates of seizures in epileptic patients. This indicates that other mechanisms are at least partially responsible for the anticonvulsant power of the ketogenic diet.

Several possible modes of actions

Inhibition of excitatory synaptic transmission. Neurons communicate through chemicals liberated at the synaptic level. Glutamate is the main excitatory neurotransmitter in vertebrates. Ketones produced by the ketogenic diet have been shown to block the glutamatergic pathway. This inhibition results in a decrease in hyperexcitability of brain cells, beneficial in epilepsy.

Carbohydrate depletion. This mode of action is confirmed by the anticonvulsant effect of 2-deoxy-D-glucose, which partially inhibits glycolysis, mimicking the effect of carbohydrate depletion. Taking away the main source of energy of the brain actually helps reducing periods of high excitability such as seizures. This mechanism along with the previous one suggest a beneficial use of the ketogenic diet in other ailments based on the hyperexcitability of brain cells.

Changes in mitochodrial metabolism. Mitochondria are the structures that supply the cell with energy (ATP). The ketogenic diet changes mitochodrial metabolism. Those changes are different in the muscle and in the brain. Whereas prolonged ketogenic diet results in decreased numbers of mitochodria in the the muscles, it results in increased mitochodrial capacity and biogenesis in the brain. This increase results in a better ability to sustain energy levels during periods of high demands (such as seizures), and in turn supports stability of brain activity. This specific mechanism suggests an interest of the ketogenic diet in mitochodrial disorders.

Inhibition of key protein pathways. The ketogenic diet inhibits the mammalian target of rapamycin or mTOR, a protein, which is involved in the integration of many critical functions such as the regulation of cellular proliferation and survival. This mechanism suggests an interest of the ketogenic diet in cancer treatments.

It is probable that all those mechanisms contribute to the anticonvulsant effects of the ketogenic diet. Each of the modes of action suggests potential uses of the ketogenic diet for other ailments. In addition, resistance to hyperexcitability and improved mitochondrial function seem to confer neuroprotection, which suggests benficial uses of the ketogenic diet in neurodegenerative disorders, such as Alzheimer’s disease and Parkinson’s disease.

Applications of the ketogenic diet to ailments beyond epilepsy will be discussed in a future post.

References used in this article

Kim do YRho JM., The ketogenic diet and epilepsy. Curr Opin Clin Nutr Metab Care. 2008 Mar;11(2):113-20. 

Dhamija REckert SWirrell E., Ketogenic diet. Can J Neurol Sci. 2013 Mar;40(2):158-67.

Danial NNHartman ALStafstrom CEThio LL., How Does the Ketogenic Diet Work?: Four Potential Mechanisms. J Child Neurol. 2013 May 13. 

Bough, K. J., Wetherington, J., Hassel, B., Pare, J. F., Gawryluk, J. W., Greene, J. G., Shaw, R., Smith, Y., Geiger, J. D. and Dingledine, R. J. (2006), Mitochondrial biogenesis in the anticonvulsant mechanism of the ketogenic diet . Ann Neurol., 60: 223–235. 


Copyright (see copyright page): © “Food, Science and Health” ( by Barbara Cerf-Allen, 2013 All Rights Reserved

Disclaimer: I am not advocating any of the above mentioned diets, nor am I making any claim about their usefulness for your specific condition. I am not a medical doctor and I am not giving medical advice. This blog is about sharing scientific information and my personal anecdotal experience,

2 thoughts on “How does the ketogenic diet work?

  1. Hi, Am just starting this journey. Can you help with a couple of questions? I’m about 20 to 30 gms of carbs as best I can count. But the keto stick doesn’t show a change from the base color. Except when one day I drank apple cider vinegar. Did that possibly help or just give me a fake response?
    Is there anything I can do to adhere better? I am feeling a lot better but I have serious amt of weigtht to lose and it’s not coming off?

  2. Hi! Thank you for reading my blog! I am not a medical doctor, nor a ketogenic diet specialist, so I am not really qualified to answer your questions. I can only tell you what comes to mind when reading your comments, so please take my answers with a grain of salt. What type of fats do you eat? Are they mainly Long Chain Triglycerides (most of the fats we generally eat are of this type, including vegetable oils), or are they Medium Chain Triglycerides or MCT (like Coconut oil)? The fact that apple cider vinegar helped producing ketones (assuming that it was not a fake response) could be related to a facilitation of assimilation of fats through a stimulation of the gallbladder. An interesting characteristic of MCT is that they do not require gallbladder function to be digested, did you give those a try? Thank you for your interest in this blog!

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