Ketogenic diet

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

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 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.[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.[31] 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[32]. A study showed improved cognition in Alzheimer's disease patients taking MCTs.[33]

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. [34]

Clinical use[edit | edit source]

Doctor Sarah Myhill has a page on her web site describing the ketogenic diet.[35] Dr. Courtney Craig has published a hypothesis on the use of ketogenic diets in ME/CFS and offers dietary consulting to patients.[36]

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 4102118. PMID 25101001.
  2. 2.0 2.1 Achanta, Lavanya B.; Rae, Caroline D. (January 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. (January 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 (April 10, 2019). "Potential Protective Mechanisms of Ketone Bodies in Migraine Prevention". Nutrients. 11 (4). doi:10.3390/nu11040811. ISSN 2072-6643. PMC 6520671. PMID 30974836.
  5. Hashim, Sami A.; VanItallie, Theodore B. (September 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 4617348. PMID 24598140.
  6. Rho, Jong M; Rogawski, Michael A (March 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 (March 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. 9.0 9.1 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 6561315. PMID 31231311.
  10. Cavaleri, Franco; Bashar, Emran (April 1, 2018). "Potential Synergies of β-Hydroxybutyrate and Butyrate on the Modulation of Metabolism, Inflammation, Cognition, and General Health". Journal of Nutrition and Metabolism. doi:10.1155/2018/7195760. ISSN 2090-0724. PMC 5902005. 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 (September 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 (June 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; Gao, Bo; Liu, Xia; Liu, Shuwei (August 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. (August 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 6175383. PMID 30098269.
  17. Krikorian, Robert; Shidler, Marcelle D; Dangelo, Krista; Couch, Sarah C; Benoit, Stephen C; Clegg, Deborah J (February 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. (January 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 (October 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 6197715. PMID 30292675.
  21. Segura, Gabriela (August 9, 2013), Ketogenic diet - a connection between mitochondria and diet
  22. Craig, Courtney (March 30, 2015), A Ketogenic Diet for ME/CFS & Fibro
  23. Myhill, S; Booth, NE; McLaren-Howard, J (January 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 (April 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. 26.0 26.1 Hartman, Adam L.; Vining, Eileen P.G. (January 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. (April 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 3321471. PMID 22509165.
  28. Kang, Hoon-Chul; Lee, Young-Mock; Kim, Heung Dong; Lee, Joon Soo; Slama, Abdelhamid (January 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 5306430. PMID 28101805.
  30. Cossington, Jo; Coe, Shelly; Liu, Yaomeng; Dawes, Helen (November 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" (PDF). Sport Science Research. 3 (2): 33–39. Retrieved March 24, 2020.
  31. Wikipedia - Ketogenic diet, MCT oil
  32. Achanta, Lavanya B.; Rae, Caroline D. (January 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.
  33. Reger, Mark A; Henderson, Samuel T; Hale, Cathy; Cholerton, Brenna; Baker, Laura D; Watson, G S; Hyde, Karen; Chapman, Darla; Craft, Suzanne (March 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
  34. Hashim, Sami A.; VanItallie, Theodore B. (September 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 4617348. PMID 24598140.
  35. Myhill, Sarah, Ketogenic diet - the practical details
  36. 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