Ketogenic diet

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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[1]. The therapeutic benefits of a ketogenic diet are believed to be due to β-hydroxybutyrate which acts as a signalling molecule.[2]

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).[3]

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.[4]

Types of Ketogenic Diets[edit | edit source]

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.[5]

Evidence for a ketogenic diet[edit | edit source]

General Effects[edit | edit source]

In an animal model, a ketogenic diet was shown to increase mitochondrial biogenesis.[6] A similar result was found in a study of fasting mice.[7] Ketone bodies scavenge free radicals in vivo. [8] Ketogenic diets reduce circulating levels of insulin and insulin-like growth factors.[9] Acute nutritional ketosis is shown to reduce lactate production and improve performance potential in cycling activity. It is shown to prevent muscle wasting.[10]

Epilepsy[edit | edit source]

Neurotransmitters regulate nerve impulses is 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.[11]

The Charlie Foundation supports the use of ketogenic diets with children with severe epilepsy.[12]

Neurodegenerative Disease[edit | edit source]

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.[13]

Mice fed a ketogenic diet had increased activity of dopaminergic neurons.[14] In a rat model of Parkinson's, a ketogenic diet was protective against neurotoxicity by up-regulating glutathione.[15] 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. [16] Another study found dietary ketosis enhanced memory in patients with mild cognitive impairment.[17]

Traumatic Brain Injury (TBI)[edit | edit source]

The ketogenic diet is an effective treatment for TBI recovery in rats and shows potential in humans.[18]

Migraine[edit | edit source]

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.[19]

Multiple Sclerosis[edit | edit source]

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.[20]

Chronic Fatigue Syndrome[edit | edit source]

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[21][22] citing mitochondrial dysfunction[23], immune dysfunction, and neuroinflammation as pathways through which ketogenic diets could confer some benefit.

Risks & Side Effects[edit | edit source]

  • 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.[24] 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.[9]
  • Two children on the diet for refractory epilepsy had selenium deficiency which resulted in sudden cardiac death.[25]
  • Up to 6% of those on a ketogenic diet may experience kidney stones.[26]
  • Ketogenic diets may require additional supplemental nutrition to prevent deficiencies. Common deficiencies include calcium, zinc, selenium, and copper.[26]
  • 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). [27] It is safe for those with mitochondrial defects in complexes I, II, and IV[28] and pyruvate dehydrogenase complex deficiency.[29]

Notable studies[edit | edit source]

Medium chain triglycerides (MCT)[edit | edit source]

Supplementation with medium-chain triglycerides (MCTs) increases blood levels of ketones.[30] 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[31]. A study showed improved cognition in Alzheimer's disease patients taking MCTs.[32]

Exogenous ketones[edit | edit source]

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.[2] 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. [33]

Clinical use[edit | edit source]

Doctor Sarah Myhill has a page on her web site describing the ketogenic diet.[34] Dr. Courtney Craig has published a hypothesis on the use of ketogenic diets in ME/CFS and offers dietary consulting to patients.[35]

Learn more[edit | edit source]

See also[edit | edit source]

References[edit | edit source]

  1. Dedkova, Elena N.; Blatter, Lothar A. (2014). "Role of β-hydroxybutyrate, its polymer poly-β-hydroxybutyrate and inorganic polyphosphate in mammalian health and disease". Frontiers in Physiology. 5: 260. doi:10.3389/fphys.2014.00260. ISSN 1664-042X. PMC 4102118Freely accessible. PMID 25101001. 
  2. 2.02.1 Achanta, Lavanya B.; Rae, Caroline D. (Jan 2017). "β-Hydroxybutyrate in the Brain: One Molecule, Multiple Mechanisms". Neurochemical Research. 42 (1): 35–49. doi:10.1007/s11064-016-2099-2. ISSN 1573-6903. PMID 27826689. 
  3. Achanta, Lavanya B.; Rae, Caroline D. (Jan 2017). "β-Hydroxybutyrate in the Brain: One Molecule, Multiple Mechanisms". Neurochemical Research. 42 (1): 35–49. doi:10.1007/s11064-016-2099-2. ISSN 1573-6903. PMID 27826689. 
  4. Gross, Elena C.; Klement, Rainer J.; Schoenen, Jean; D’Agostino, Dominic P.; Fischer, Dirk (Apr 10, 2019). "Potential Protective Mechanisms of Ketone Bodies in Migraine Prevention". Nutrients. 11 (4). doi:10.3390/nu11040811. ISSN 2072-6643. PMC 6520671Freely accessible. PMID 30974836. 
  5. Hashim, Sami A.; VanItallie, Theodore B. (Sep 2014). "Ketone body therapy: from the ketogenic diet to the oral administration of ketone ester". Journal of Lipid Research. 55 (9): 1818–1826. doi:10.1194/jlr.R046599. ISSN 1539-7262. PMC 4617348Freely accessible. PMID 24598140. 
  6. Rho, Jong M; Rogawski, Michael A (Mar 2007), "The Ketogenic Diet: Stoking the Powerhouse of the Cell", Epilepsy Currents, 7 (2): 58–60, doi:10.1111/j.1535-7511.2007.00170.x, PMID 17505556 
  7. Cerqueira, Fernanda M; Laurindo, Francisco R M; Kowaltowski, Alicia J (Mar 31, 2011), "Mild Mitochondrial Uncoupling and Calorie Restriction Increase Fasting eNOS, Akt and Mitochondrial Biogenesis", PLOS ONE, 6 (3): –18433, doi:10.1371/journal.pone.0018433 
  8. Haces, María L.; Hernández-Fonseca, Karla; Medina-Campos, Omar N.; Montiel, Teresa; Pedraza-Chaverri, José; Massieu, Lourdes (May 2008). "Antioxidant capacity contributes to protection of ketone bodies against oxidative damage induced during hypoglycemic conditions". Experimental Neurology. 211 (1): 85–96. doi:10.1016/j.expneurol.2007.12.029. ISSN 0014-4886. PMID 18339375. 
  9. 9.09.1 Athinarayanan, Shaminie J.; Adams, Rebecca N.; Hallberg, Sarah J.; McKenzie, Amy L.; Bhanpuri, Nasir H.; Campbell, Wayne W.; Volek, Jeff S.; Phinney, Stephen D.; McCarter, James P. (2019). "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". Frontiers in Endocrinology. 10: 348. doi:10.3389/fendo.2019.00348. ISSN 1664-2392. PMC 6561315Freely accessible. PMID 31231311. 
  10. Cavaleri, Franco; Bashar, Emran (Apr 1, 2018). "Potential Synergies of β-Hydroxybutyrate and Butyrate on the Modulation of Metabolism, Inflammation, Cognition, and General Health". Journal of Nutrition and Metabolism. 2018. doi:10.1155/2018/7195760. ISSN 2090-0724. PMC 5902005Freely accessible. PMID 29805804. 
  11. Hartman, Adam L; Gasior, Maciej; Vining, Eileen P G; Rogawski, Michael A (May 2007), "The Neuropharmacology of the Ketogenic Diet", Pediatric neurology, 36 (5): 281–292, doi:10.1016/j.pediatrneurol.2007.02.008, PMID 17509459 
  12. | title = The Charlie Foundation for Ketogenic Therapies | url =
  13. Gasior, Maciej; Rogawski, Michael A; Hartman, Adam L (Sep 2006), "Neuroprotective and disease-modifying effects of the ketogenic diet", Behavioural Pharmacology, 17 (5-6): 431–439, PMID 16940764 
  14. Church, William H; Adams, Ryan E; Wyss, Livia S (Jun 13, 2014), "Ketogenic diet alters dopaminergic activity in the mouse cortex", Neuroscience Letters, 571: 1–4, doi:10.1016/j.neulet.2014.04.016, PMID 24769322 
  15. Cheng, Baohua; Yang, Xinxin; An, Liangxiang; et al. (Aug 25, 2009), "Ketogenic diet protects dopaminergic neurons against 6-OHDA neurotoxicity via up-regulating glutathione in a rat model of Parkinson's disease", Brain Research, 1286: 25–31, doi:10.1016/j.brainres.2009.06.060 
  16. Phillips, Matthew C. L.; Murtagh, Deborah K. J.; Gilbertson, Linda J.; Asztely, Fredrik J. S.; Lynch, Christopher D. P. (Aug 2018). "Low-fat versus ketogenic diet in Parkinson's disease: A pilot randomized controlled trial". Movement Disorders: Official Journal of the Movement Disorder Society. 33 (8): 1306–1314. doi:10.1002/mds.27390. ISSN 1531-8257. PMC 6175383Freely accessible. PMID 30098269. 
  17. Krikorian, Robert; Shidler, Marcelle D; Dangelo, Krista; Couch, Sarah C; Benoit, Stephen C; Clegg, Deborah J (Feb 2012), "Dietary ketosis enhances memory in mild cognitive impairment", Neurobiology of Aging, 33 (2): 425–19–27, doi:10.1016/j.neurobiolaging.2010.10.006, PMID 21130529 
  18. McDougall, Alexandre; Bayley, Mark; Munce, Sarah Ep (2018). "The ketogenic diet as a treatment for traumatic brain injury: a scoping review". Brain Injury. 32 (4): 416–422. doi:10.1080/02699052.2018.1429025. ISSN 1362-301X. PMID 29359959. 
  19. Di Lorenzo, C.; Coppola, G.; Sirianni, G.; Di Lorenzo, G.; Bracaglia, M.; Di Lenola, D.; Siracusano, A.; Rossi, P.; Pierelli, F. (Jan 2015). "Migraine improvement during short lasting ketogenesis: a proof-of-concept study". European Journal of Neurology. 22 (1): 170–177. doi:10.1111/ene.12550. ISSN 1468-1331. PMID 25156013. 
  20. Bock, Markus; Karber, Mirjam; Kuhn, Hartmut (Oct 3, 2018). "Ketogenic diets attenuate cyclooxygenase and lipoxygenase gene expression in multiple sclerosis". EBioMedicine. 36: 293–303. doi:10.1016/j.ebiom.2018.08.057. ISSN 2352-3964. PMC 6197715Freely accessible. PMID 30292675. 
  21. Segura, Gabriela (Aug 9, 2013), Ketogenic diet - a connection between mitochondria and diet 
  22. Craig, Courtney (Mar 30, 2015), A Ketogenic Diet for ME/CFS & Fibro 
  23. Myhill, S; Booth, NE; McLaren-Howard, J (Jan 15, 2009), "Chronic fatigue syndrome and mitochondrial dysfunction", Int J Clin Exp Med, 2 (1): 1–16, PMID 19436827 
  24. Zhang, Xiaoyu; Qin, Juliang; Zhao, Yihan; Shi, Jueping; Lan, Rong; Gan, Yunqiu; Ren, Hua; Zhu, Bing; Qian, Min; Du, Bing (Apr 1, 2016), "Long-term ketogenic diet contributes to glycemic control but promotes lipid accumulation and hepatic steatosis in type 2 diabetic mice", Nutrition Research, 36 (4): 349–358, doi:10.1016/j.nutres.2015.12.002 
  25. Sudden Cardiac Death in Association With the Ketogenic Diet - Pediatric Neurology - December 2008
  26. 26.026.1 Hartman, Adam L.; Vining, Eileen P. G. (Jan 2007). "Clinical aspects of the ketogenic diet". Epilepsia. 48 (1): 31–42. doi:10.1111/j.1528-1167.2007.00914.x. ISSN 0013-9580. PMID 17241206. 
  27. Stafstrom, Carl E.; Rho, Jong M. (Apr 9, 2012). "The Ketogenic Diet as a Treatment Paradigm for Diverse Neurological Disorders". Frontiers in Pharmacology. 3. doi:10.3389/fphar.2012.00059. ISSN 1663-9812. PMC 3321471Freely accessible. PMID 22509165. 
  28. Kang, Hoon-Chul; Lee, Young-Mock; Kim, Heung Dong; Lee, Joon Soo; Slama, Abdelhamid (Jan 2007). "Safe and effective use of the ketogenic diet in children with epilepsy and mitochondrial respiratory chain complex defects". Epilepsia. 48 (1): 82–88. doi:10.1111/j.1528-1167.2006.00906.x. ISSN 0013-9580. PMID 17241212. 
  29. Sofou, Kalliopi; Dahlin, Maria; Hallböök, Tove; Lindefeldt, Marie; Viggedal, Gerd; Darin, Niklas (2017). "Ketogenic diet in pyruvate dehydrogenase complex deficiency: short- and long-term outcomes". Journal of Inherited Metabolic Disease. 40 (2): 237–245. doi:10.1007/s10545-016-0011-5. ISSN 0141-8955. PMC 5306430Freely accessible. PMID 28101805. 
  30. Wikipedia - Ketogenic diet, MCT oil 
  31. Achanta, Lavanya B.; Rae, Caroline D. (Jan 2017). "β-Hydroxybutyrate in the Brain: One Molecule, Multiple Mechanisms". Neurochemical Research. 42 (1): 35–49. doi:10.1007/s11064-016-2099-2. ISSN 1573-6903. PMID 27826689. 
  32. Reger, Mark A; Henderson, Samuel T; Hale, Cathy; et al. (Mar 2004), "Effects of beta-hydroxybutyrate on cognition in memory-impaired adults", Neurobiology of Aging, 25 (3): 311–314, doi:10.1016/S0197-4580(03)00087-3, PMID 15123336 
  33. Hashim, Sami A.; VanItallie, Theodore B. (Sep 2014). "Ketone body therapy: from the ketogenic diet to the oral administration of ketone ester". Journal of Lipid Research. 55 (9): 1818–1826. doi:10.1194/jlr.R046599. ISSN 1539-7262. PMC 4617348Freely accessible. PMID 24598140. 
  34. Myhill, Sarah, Ketogenic diet - the practical details 
  35. Craig, Courtney (November 2015), "Mitoprotective dietary approaches for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Caloric restriction, fasting, and ketogenic diets", Medical Hypotheses, 85 (5): 690-693, doi:10.1016/j.mehy.2015.08.013, PMID 26315446 

mitochondria - Important parts of the biological cell, with each mitochondrion encased within a mitochondrial membrane. Mitochondria are best known for their role in energy production, earning them the nickname "the powerhouse of the cell". Mitochondria also participate in the detection of threats and the response to these threats. One of the responses to threats orchestrated by mitochondria is apoptosis, a cell suicide program used by cells when the threat can not be eliminated.

enzyme - a substance produced by a living organism which acts as a catalyst to bring about a specific biochemical reaction.

chronic fatigue syndrome (CFS) - A controversial term, invented by the U.S. Centers for Disease Control, that generally refers to a collection of symptoms as “fatigue”. There have been multiple attempts to come up with a set of diagnostic criteria to define this term, but few of those diagnostic criteria are currently in use. Previous attempts to define this term include the Fukuda criteria and the Oxford criteria. Some view the term as a useful diagnostic category for people with long-term fatigue of unexplained origin. Others view the term as a derogatory term borne out of animus towards patients. Some view the term as a synonym of myalgic encephalomyelitis, while others view myalgic encephalomyelitis as a distinct disease.

adverse reaction - Any unintended or unwanted response to the treatment under investigation in a clinical trial.

cognition - Thought processes, including attention, reasoning, and memory.

myalgic encephalomyelitis (ME) - A disease often marked by neurological symptoms, but fatigue is sometimes a symptom as well. Some diagnostic criteria distinguish it from chronic fatigue syndrome, while other diagnostic criteria consider it to be a synonym for chronic fatigue syndrome. A defining characteristic of ME is post-exertional malaise (PEM), or post-exertional neuroimmune exhaustion (PENE), which is a notable exacerbation of symptoms brought on by small exertions. PEM can last for days or weeks. Symptoms can include cognitive impairments, muscle pain (myalgia), trouble remaining upright (orthostatic intolerance), sleep abnormalities, and gastro-intestinal impairments, among others. An estimated 25% of those suffering from ME are housebound or bedbound. The World Health Organization (WHO) classifies ME as a neurological disease.

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From MEpedia, a crowd-sourced encyclopedia of ME and CFS science and history.