The Medically Indicated Ketogenic Diet: Evidence for nutritional ketosis as part of clinical practice

Kevin Waggoner, Joelle M. Mendez-Hinds, Donna L. Herber*

Introduction: The ketogenic diet, a long history of clinical use and effectiveness

The ketogenic diet is characterized by a high fat content paired with moderate protein and very low carbohydrate intake [1].  Typically, a ketogenic ratio is used to describe the macronutrient profile of the diet by comparing grams of fat to the combined grams of protein plus carbohydrates.  Thus, ratios where the fat content is greater than one indicates a “ketogenic” diet. The diet is ketogenic in that the high fat consumption required trains the body to switch from using glucose and carbohydrates as the primary metabolic fuel source to using fatty acids and ketone bodies as fuel [2].  There are ensuing metabolic regulatory effects on blood glucose and blood insulin levels, where increasing amounts of serum ketones act to decrease circulating glucose, reduce the insulin response, and maintain homeostasis [3].  

The ketogenic diet allows the body to shift from carbohydrate-based metabolism to fat-based metabolism, thus stimulating hepatic ketogenesis, and entering nutritional ketosis [4].  Nutritional ketosis is a state where the blood levels of ketone bodies are significantly above baseline, typically >0.5 mmol/L. The ketone bodies, acetoacetate and beta-hydroxybutyrate, are energy substrates used by mitochondria to produce adenosine triphosphate (ATP), and can be used as alternative fuels to glucose by the brain, heart, and skeletal muscles [3].  

The ketogenic diet has been documented in the clinical literature as a therapeutic nutritional intervention for nearly 100 years [5].  What began as a thoughtful approach for children with refractory epilepsy has grown in use in populations living with obesity and/or type 2 diabetes.  This review is intended to summarize the large body of evidence for the medical use of the ketogenic diet.

Epilepsy: The hope to become seizure free, medication free

Fasting has been recognized as a potential treatment for seizures since ancient times, and dietary intervention that mimicked fasting was introduced in the 1920s [1].  For both children and adults with refractory epilepsy, dietary interventions which raise blood ketones (therapeutic nutritional ketosis) are efficacious and safe [6-10].  Patients that have failed to respond to three or more anti-epileptic drugs (about 30% of all patients) can see improvements in as little as two weeks with dietary intervention, though a three-month trial is recommended in order to assess effectiveness [11].  

Patients can expect to see a 40-50% chance of a 50% reduction in seizures with the ketogenic diet, though there are certain conditions that see as high as a 70% response rate (glucose transporter 1 deficiency syndrome (GLUT1DS), pyruvate dehydrogenase deficiency (PDCD), epilepsy with myoclonic-atonic seizures, infantile spasms, tuberous sclerosis complex, children with gastrostomy tubes, and Dravet syndrome) [11].  The diet is recommended as first line therapy for children with GLUT1D, PDCD, West Syndrome, and Doose Syndrome [12]. There are individual reports where children are able to discontinue all medications as seizures are completely controlled by the ketogenic diet alone [13]. Additionally, many pediatric patients who have been on the diet 2-3 years can discontinue the diet at the onset of puberty with no recurrence of seizures [11].  Some patients or their caregivers may choose to try dietary intervention even when seizures are well controlled by pharmacotherapy in an effort to reduce the amount of medication used – and resultant side effects – as well as the potential to improve cognitive function [14]. 

The classical ketogenic diet that is traditionally used with drug resistant seizures has a ratio of 4:1 or 3:1 of (grams of fat): (grams of protein plus grams of carbohydrate), making it an extremely restrictive diet [1].  Many patients discontinue the diet even when it effectively controls seizures if modifications cannot be made [10]. Several variants of the diet that are effective include the Modified Atkins Diet (MAD), medium chain triglyceride (MCT) diet, and low glycemic index therapy (LGIT) [7, 15-18]. These approaches have a lower ketogenic ratio (1.5:1 or 2:1) and/or add highly ketogenic fats (such as MCT) in order to improve diet adherence and add in additional protein or carbohydrate content.  The mechanism of action of ketosis for seizure control is poorly understood and many potential mechanisms may be at play [19-24].

Type 2 Diabetes: An intuitive, rational approach with tangible health and economic benefits

Carbohydrates are converted to the basic energy molecule glucose through normal digestion and metabolism, thus having the greatest impact on circulating blood glucose levels compared to fat and protein [25].  Prior to the development of medications for the treatment of diabetes, this disease was treated through dietary restriction of carbohydrates [26]. Even with the advent of injectable insulin, patients are counseled to calculate the amount of carbohydrates eaten and then administer the appropriate amount of insulin [27].  It is abundantly clear that the adverse physiological effects of both type 1 and type 2 diabetes revolve around the consumption of carbohydrates [28]. In particular, type 2 diabetes has been called by many a lifestyle disease, where susceptible individuals become diabetic through excess long-term consumption of carbohydrates, and resultant obesity, and also respond well to lifestyle modifications that reduce carbohydrate intake [29].

Single meal interventions in patients with type 2 diabetes demonstrate the power of macronutrient profiles to modify blood glucose levels and the resultant insulin response.  Replacing just breakfast and lunch with low carbohydrate meals led to significantly lower blood glucose and insulin compared to low fat meals [30]. Similarly, a high fat, high protein, low carbohydrate breakfast demonstrated greater reductions in fasting glucose, HbA1c and systolic blood pressure, reductions in medications, as well as less hunger, when compared to a high carbohydrate meal [31].

Very low carbohydrate dietary interventions lead to a metabolic state known as nutritional ketosis.  This is not biochemically the same as diabetic ketoacidosis (DKA) [32]. In DKA, the insulin/glucose axis is not intact, and when blood sugar levels rise without the compensatory insulin mechanisms, tissues cannot utilize glucose for fuel, leading the body to produce ketones.  During DKA, glucose is consistently over 300 mg/dL, ketones above 8 mmol/L, and blood pH below 7.3 [33]. In contrast, nutritional ketosis occurs with normal blood glucose levels, ketones between 0.5-4 mmol/L, and normal blood pH. The ketogenic diet has been demonstrated to be safe for type 2 diabetics, and may even be suitable for some type 1 diabetics with close monitoring [26, 34-37].  

In clinical protocols involving patients with type 2 diabetes, the ratio of fat:protein+carbohydrates is much less restrictive (1.5-2:1) than is the case of the classical ketogenic diet used with epilepsy (3-4:1), with a greater protein allowance.  The ketogenic diet has been shown to have greater beneficial effects on fasting blood glucose, HbA1c, circulating lipids, and cholesterol than low glycemic or low-fat approaches [26, 38-39]. One mechanism behind this may be related to a natural reduction in caloric intake (even though this is not part of the diet prescription), and the greater rate of adherence to the diet at 6 months [40].  Importantly, the lower the amount of dietary carbohydrate in the diet, the greater the benefits on health and weight [39]. Regarding type 2 diabetes and medication requirements, studies have shown that dietary carbohydrate restriction allowed for the majority of patients to lower or discontinue their diabetes medications, in addition to significantly decreasing hemoglobin A1c, body weight, and fasting triglyceride levels [35, 39]. The health benefits are routinely demonstrated when using a ketogenic diet, but economic benefits are realized as well with reductions and even elimination of reliance on medications in many patients [39].

Obesity: Improved dietary adherence, satiety, and long-term benefits

In-patient fasting protocols were common practice in the mid-20th century as a clinical solution to obesity.  Diets were soon developed in the 1960s that mimicked the state of ketosis, driving the body not towards fasting ketosis but rather towards nutritional ketosis.  Dietary intervention protocols targeting weight loss typically reduce calories below the 2000 kcal/day recommendation for healthy, normal weight individuals, but in most cases, the ketogenic diet is administered without intentionally restricting calories [39, 41].  Similar to the approach to the patient with type 2 diabetes, clinical protocols involving patients with obesity use a ketogenic ratio of fat:protein+carbohydrates at 1.5-2:1, with a greater protein allowance.  

The biochemistry underlying nutritional ketosis is complicated, but dietary intake of fat leads to the direct use of triglycerides for fuel by most tissues (except the brain) as well as hepatic ketogenesis to generate ketone bodies to fuel the brain [3].  As this fat utilization machinery starts to work harder than the enzymes and pathways relating to glycolysis (burning carbohydrates for fuel), stored body fat is also recruited as a fuel source [2]. Coupled with the typical reduction in calories seen with ketogenic diets, the body uses both dietary and stored fat for fuel in a way that is not possible when carbohydrates loads are high, as in a typical American diet.

The results from clinical trials studying ketogenic diets for weight loss are impressive and expansive, and can have long-term benefits [42-43].  Ketogenic diets (in comparison to low fat or Mediterranean style diets) show significantly greater initial reductions in weight, as well as better maintenance of weight loss [39, 44].  This very low carbohydrate approach (typically less than 30g per day) also reduces circulating triglyceride levels and improves high density lipoprotein levels (long term) [45]. The long-term safety of the ketogenic diet has been well documented [46-47].  National programs for promoting a healthy diet led to the characterization of fat as promoting heart disease, but the ketogenic diet has not been found to do so [48]. This may be due to a high intake of fat in the absence of a high intake of carbohydrates. 

In general, patients and clinicians report that a high fat, low carb dietary lifestyle is more satiating, with less reported hunger compared to low fat diets.  The satiety effects of ketone bodies have been well studied, as well as the role of fats and protein in promoting a sense of satiation [49]. Concurrently, when consuming a ketogenic diet, blood glucose levels, and the corresponding insulin response, do not fluctuate to the same extent as when consuming a high carbohydrate diet.  Therefore, the hunger cues and physiological effects of a “sugar crash” are not experienced. Importantly, a low-fat dietary intervention to promote weight loss purposefully reduces caloric intake by 500 kcal in order to achieve meaningful weight loss [41]. The ketogenic diet does not typically prescribe caloric restriction. However, investigators routinely report that patients will naturally reduce caloric intake when they are instructed to limit carbohydrate intake [40].  This may be due to the removal of high calorie, now restricted, foods, or due to the satiating effects of the diet. In any case, patients are not under the burden to restrict calories.

Other Disorders: Shifting whole body metabolism to improve patient nutrition

Acne, cancer, polycystic ovarian disease, neurodegenerative diseases and neuropsychiatric disorders are all the subject of numerous preclinical and clinical research programs for the utility of the ketogenic diet in boosting patient nutrition and their ability to fight disease [50].  There are currently 31 studies that are listed with clinicaltrials.gov looking at ketogenic dietary intervention for patients with cancer of a variety of types. The prototypical tumor type studied is glioma, as well as other brain tumors such as astrocytomas, given the blood brain barrier and difficulties in delivering traditional chemotherapy to the lesion site [51-53].  Ketones not only cross the blood brain barrier but also may be preferentially used by healthy cells, with tumors relying more on glucose metabolism [54-55]. The role of ketones in fueling the brain further comes into play when considering neurodegenerative diseases such as Alzheimer’s, Parkinson’s, Amyotrophic Lateral Sclerosis, migraine, autism, and head trauma [56-61]. When glucose utilization is disrupted at the level of neurons and glia, ketones can play an essential role in restoring normal cellular function.

Conclusion: Adherence, convenience, accessibility, palatability

The ketogenic diet, and resulting nutritional ketosis, is an important therapeutic tool for several medical indications including seizures, diabetes, and obesity.  While results are striking in the short and midterm, adherence beyond 6-12 months often proves difficult. Adherence to dietary interventions is directly related to the amount of social support and intervention provided by the program.  While high intervention programs lead to measurable nutritional ketosis, significant reductions in carbohydrate intake, and long-term health benefits, low intervention programs do not show the same success [39, 41]. Dietary interventions can include education, biomarker tracking, weekly calls or meetings with study coordinators, social group support meetings or online forums, recipes, food intake tracking tools, meal replacement formulations, and even study center provided whole food meals.  However, if these programs do not make the lifestyle convenient, accessible, and palatable, long term adherence will always be a challenge.

References:

1. Peterman, MG. The ketogenic diet in the treatment of epilepsy: a preliminary report.  Am J Dis Child 1924; 28:28-33

2. Balasse EO, Féry F. Ketone body production and disposal: effects of fasting, diabetes, and exercise. Diabetes Metab Rev. 1989 May;5(3):247-70. Review. PubMed PMID: 2656155

3. Hall SE, Wastney ME, Bolton TM, Braaten JT, Berman M. Ketone body kinetics in humans: the effects of insulin-dependent diabetes, obesity, and starvation. J Lipid Res. 1984 Nov;25(11):1184-94. PubMed PMID: 6440941.

4. Nosadini R, Avogaro A, Doria A, Fioretto P, Trevisan R, Morocutti A. Ketone body metabolism: a physiological and clinical overview. Diabetes Metab Rev. 1989 May;5(3):299-319. Review. PubMed PMID: 2656158.

5. Wheless JW. History of the ketogenic diet. Epilepsia. 2008 Nov;49 Suppl 8:3-5. 

6. Barborka CJ. Ketogenic diet treatment of epilepsy in adults. JAMA. 1928;91(2):73–78.

7. Kossoff EH, McGrogan JR, Bluml RM, Pillas DJ, Rubenstein JE, Vining EP. A modified Atkins diet is effective for the treatment of intractable pediatric epilepsy. Epilepsia. 2006 Feb;47(2):421-4. 

8. Neal EG, Chaffe H, Schwartz RH, Lawson MS, Edwards N, Fitzsimmons G, Whitney A, Cross JH. A randomized trial of classical and medium-chain triglyceride ketogenic diets in the treatment of childhood epilepsy. Epilepsia. 2009 May;50(5):1109-17. 

9. Kverneland M, Molteberg E, Iversen PO, Veierød MB, Taubøll E, Selmer KK, Nakken KO. Effect of modified Atkins diet in adults with drug-resistant focal epilepsy: A randomized clinical trial. Epilepsia. 2018 Aug;59(8):1567-1576. 

10. Liu YM, Wang HS. Medium-chain triglyceride ketogenic diet, an effective treatment for drug-resistant epilepsy and a comparison with other ketogenic diets. Biomed J. 2013 Jan-Feb;36(1):9-15

11. The Ketogenic and Modified Atkins Diets; Treatments for epilepsy and other disorders, Sixth Edition.  Kossoff EH, Turner Z, Doerrer S, Cervenka MC, Henry BJ. 2006. Springer Publishing Company, New York, NY.

12. Kossoff EH, Zupec-Kania BA, Auvin S, Ballaban-Gil KR, Christina Bergqvist AG, Blackford R, Buchhalter JR, Caraballo RH, Cross JH, Dahlin MG, Donner EJ, Guzel O, Jehle RS, Klepper J, Kang HC, Lambrechts DA, Liu YMC, Nathan JK, Nordli DR Jr, Pfeifer HH, Rho JM, Scheffer IE, Sharma S, Stafstrom CE, Thiele EA, Turner Z, Vaccarezza MM, van der Louw EJTM, Veggiotti P, Wheless JW, Wirrell EC; Charlie Foundation; Matthew’s Friends; Practice Committee of the Child Neurology Society. Optimal clinical management of children receiving dietary therapies for epilepsy: Updated recommendations of the International Ketogenic Diet Study Group. Epilepsia Open. 2018 May 21;3(2):175-192. 

13. Shah L, Turner Z, Bessone S, Winesett P, Stanfield A, Kossoff EHW. How often is drug-free ketogenic diet therapy achieved and in whom? American Epilepsy Society 2018 Abstract No. 1.456.

14. Hallböök T, Ji S, Maudsley S, Martin B. The effects of the ketogenic diet on behavior and cognition. Epilepsy Res. 2012 Jul;100(3):304-9. 

15. Tonekaboni SH, Mostaghimi P, Mirmiran P, Abbaskhanian A, Abdollah Gorji F, Ghofrani M, Azizi F. Efficacy of the Atkins diet as therapy for intractable epilepsy in children. Arch Iran Med. 2010 Nov;13(6):492-7. 

16. Coppola G, D’Aniello A, Messana T, Di Pasquale F, della Corte R, Pascotto A, Verrotti A. Low glycemic index diet in children and young adults with refractory epilepsy: first Italian experience. Seizure. 2011 Sep;20(7):526-8.

17. Miranda MJ, Turner Z, Magrath G. Alternative diets to the classical ketogenic diet–can we be more liberal? Epilepsy Res. 2012 Jul;100(3):278-85. 

18. El-Rashidy OF, Nassar MF, Abdel-Hamid IA, Shatla RH, Abdel-Hamid MH, Gabr SS, Mohamed SG, El-Sayed WS, Shaaban SY. Modified Atkins diet vs classic ketogenic formula in intractable epilepsy. Acta Neurol Scand. 2013 Dec;128(6):402-8. 

19. Bough KJ, Rho JM. Anticonvulsant mechanisms of the ketogenic diet. Epilepsia. 2007 Jan;48(1):43-58. Review. PubMed PMID: 17241207.

20. Lutas A, Yellen G. The ketogenic diet: metabolic influences on brain excitability and epilepsy. Trends Neurosci. 2013 Jan;36(1):32-40. 

21. Rho JM. How does the ketogenic diet induce anti-seizure effects? Neurosci Lett. 2017 Jan 10;637:4-10. 

22. Youngson NA, Morris MJ, Ballard JWO. The mechanisms mediating the antiepileptic effects of the ketogenic diet, and potential opportunities for improvement with metabolism-altering drugs. Seizure. 2017 Nov;52:15-19.

23. Cantello R, Varrasi C, Tarletti R, Cecchin M, D’Andrea F, Veggiotti P, Bellomo G, Monaco F. Ketogenic diet: electrophysiological effects on the normal human cortex. Epilepsia. 2007 Sep;48(9):1756-1763.

24. Rogawski MA, Löscher W, Rho JM. Mechanisms of Action of Antiseizure Drugs and the Ketogenic Diet. Cold Spring Harb Perspect Med. 2016 May 2;6(5).

25. Carlsson, A.s., et al., Insulin and Glucagon Secretion in Patients with Slowly Progressing Autoimmune Diabetes (LADA) 1. The Journal of Clinical Endocrinology & Metabolism, 2000. 85(1): p. 76-80.

26. Feinman RD, Pogozelski WK, Astrup A, Bernstein RK, Fine EJ, Westman EC, Accurso A, Frassetto L, Gower BA, McFarlane SI, Nielsen JV, Krarup T, Saslow L, Roth KS, Vernon MC, Volek JS, Wilshire GB, Dahlqvist A, Sundberg R, Childers A, Morrison K, Manninen AH, Dashti HM, Wood RJ, Wortman J, Worm N. Dietary carbohydrate restriction as the first approach in diabetes management: critical review and evidence base. Nutrition. 2015 Jan;31(1):1-13. 

27. Bliss, M., The Discovery of Insulin. University of Chicago press. Chicago, USA, 2007.

28. Daly, M.E., et al., Dietary carbohydrates and insulin sensitivity: a review of the evidence and clinical implications. The American Journal of Clinical Nutrition, 1997. 66(5): p. 1072-85.

29. Gross, L.S., et al., Increased consumption of refined carbohydrates and the epidemic of type 2 diabetes in the United States: an ecologic assessment. The American journal of clinical nutrition, 2004. 79(5): p. 774-779.

30. Fernemark H, Jaredsson C, Bunjaku B, Rosenqvist U, Nystrom FH, Guldbrand H. A  randomized cross-over trial of the postprandial effects of three different diets in patients with type 2 diabetes. PLoS One. 2013 Nov 27;8(11):e79324. 

31. Rabinovitz HR, Boaz M, Ganz T, Jakubowicz D, Matas Z, Madar Z, Wainstein J. Big breakfast rich in protein and fat improves glycemic control in type 2 diabetics. Obesity (Silver Spring). 2014 May;22(5):E46-54. 

32. Fedorovich SV, Voronina PP, Waseem TV. Ketogenic diet versus ketoacidosis: what determines the influence of ketone bodies on neurons? Neural Regen Res. 2018 Dec;13(12):2060-2063. 

33. Kitabchi AE, Umpierrez GE, Miles JM, Fisher JN. Hyperglycemic crises in adult patients with diabetes. Diabetes Care. 2009 Jul;32(7):1335-43. doi:10.2337/dc09-9032. Review. 

34. Boden G, Sargrad K, Homko C, Mozzoli M, Stein TP. Effect of a low-carbohydrate diet on appetite, blood glucose levels, and insulin resistance in obese patients  with type 2 diabetes. Ann Intern Med. 2005 Mar 15;142(6):403-11. 

35. Yancy WS Jr, Foy M, Chalecki AM, Vernon MC, Westman EC. A low-carbohydrate, ketogenic diet to treat type 2 diabetes. Nutr Metab (Lond). 2005 Dec 1;2:34.

36. Accurso A, Bernstein RK, Dahlqvist A, Draznin B, Feinman RD, Fine EJ, Gleed A, Jacobs DB, Larson G, Lustig RH, Manninen AH, McFarlane SI, Morrison K, Nielsen JV, Ravnskov U, Roth KS, Silvestre R, Sowers JR, Sundberg R, Volek JS, Westman EC, Wood RJ, Wortman J, Vernon MC. Dietary carbohydrate restriction in type 2 diabetes mellitus and metabolic syndrome: time for a critical appraisal. Nutr Metab (Lond). 2008 Apr 8;5:9. 

37. Lennerz BS, Barton A, Bernstein RK, Dikeman RD, Diulus C, Hallberg S, Rhodes ET, Ebbeling CB, Westman EC, Yancy WS Jr, Ludwig DS. Management of Type 1 Diabetes With a Very Low-Carbohydrate Diet. Pediatrics. 2018 Jun;141(6). 

38. Hallberg SJ, McKenzie AL, Williams PT, Bhanpuri NH, Peters AL, Campbell WW, Hazbun TL, Volk BM, McCarter JP, Phinney SD, Volek JS. Effectiveness and Safety of a Novel Care Model for the Management of Type 2 Diabetes at 1 Year: An Open-Label, Non-Randomized, Controlled Study.  Diabetes Ther. 2018 Apr;9(2):583-612. 

39. Westman EC, Yancy WS Jr, Mavropoulos JC, Marquart M, McDuffie JR. The effect of a low-carbohydrate, ketogenic diet versus a low-glycemic index diet on glycemic control in type 2 diabetes mellitus. Nutr Metab (Lond). 2008 Dec 19;5:36.

40. Nordmann AJ, Suter-Zimmermann K, Bucher HC, Shai I, Tuttle KR, Estruch R, Briel M. Meta-analysis comparing Mediterranean to low-fat diets for modification of cardiovascular risk factors. Am J Med. 2011 Sep;124(9):841-51.e2. 

41. Iqbal N, Vetter ML, Moore RH, Chittams JL, Dalton-Bakes CV, Dowd M, Williams-Smith C, Cardillo S, Wadden TA. Effects of a low-intensity intervention  that prescribed a low-carbohydrate vs. a low-fat diet in obese, diabetic participants. Obesity (Silver Spring). 2010 Sep;18(9):1733-8.

42. Dashti HM, Mathew TC, Hussein T, Asfar SK, Behbahani A, Khoursheed MA, Al-Sayer HM, Bo-Abbas YY, Al-Zaid NS. Long-term effects of a ketogenic diet in obese patients. Exp Clin Cardiol. 2004 Fall;9(3):200-5. 

43. Paoli A. Ketogenic diet for obesity: friend or foe? Int J Environ Res Public  Health. 2014 Feb 19;11(2):2092-107. doi: 10.3390/ijerph110202092. Review.  

44. Shai I, Schwarzfuchs D, Henkin Y, Shahar DR, Witkow S, Greenberg I, Golan R,  Fraser D, Bolotin A, Vardi H, Tangi-Rozental O, Zuk-Ramot R, Sarusi B, Brickner D, Schwartz Z, Sheiner E, Marko R, Katorza E, Thiery J, Fiedler GM, Blüher M, Stumvoll M, Stampfer MJ; Dietary Intervention Randomized Controlled Trial (DIRECT) Group. Weight loss with a low-carbohydrate, Mediterranean, or low-fat diet. N Engl J Med. 2008 Jul 17;359(3):229-41.  

45. Cicero AF, Benelli M, Brancaleoni M, Dainelli G, Merlini D, Negri R. Middle and Long-Term Impact of a Very Low-Carbohydrate Ketogenic Diet on Cardiometabolic Factors: A Multi-Center, Cross-Sectional, Clinical Study. High Blood Press Cardiovasc Prev. 2015 Dec;22(4):389-94.

46. Bravata DM, Sanders L, Huang J, Krumholz HM, Olkin I, Gardner CD, Bravata DM.  Efficacy and safety of low-carbohydrate diets: a systematic review. JAMA. 2003 Apr 9;289(14):1837-50. Review. 

47. Moreno B, Crujeiras AB, Bellido D, Sajoux I, Casanueva FF. Obesity treatment  by very low-calorie-ketogenic diet at two years: reduction in visceral fat and on the burden of disease. Endocrine. 2016 Dec;54(3):681-690. 

48. Bazzano LA, Hu T, Reynolds K, Yao L, Bunol C, Liu Y, Chen CS, Klag MJ, Whelton PK, He J. Effects of low-carbohydrate and low-fat diets: a randomized trial. Ann  Intern Med. 2014 Sep 2;161(5):309-18. 

49. Pawan GL, Semple SJ. Effect of 3-hydroxybutyrate in obese subjects on very-low-energy diets and during therapeutic starvation. Lancet. 1983 Jan 1;1(8314-5):15-7. 

50. Paoli A, Rubini A, Volek JS, Grimaldi KA. Beyond weight loss: a review of the therapeutic uses of very-low-carbohydrate (ketogenic) diets. Eur J Clin Nutr. 2013 Aug;67(8):789-96. 

51. Schwartz K, Chang HT, Nikolai M, Pernicone J, Rhee S, Olson K, Kurniali PC, Hord NG, Noel M. Treatment of glioma patients with ketogenic diets: report of two cases treated with an IRB-approved energy-restricted ketogenic diet protocol and  review of the literature. Cancer Metab. 2015 Mar 25;3:3. 

52. Klement RJ. The emerging role of ketogenic diets in cancer treatment. Curr Opin Clin Nutr Metab Care. 2019 Mar;22(2):129-134.  

53. Nebeling LC, Miraldi F, Shurin SB, Lerner E. Effects of a ketogenic diet on tumor metabolism and nutritional status in pediatric oncology patients: two case  reports. J Am Coll Nutr. 1995 Apr;14(2):202-8.

54. Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect:  the metabolic requirements of cell proliferation. Science. 2009 May 22;324(5930):1029-33. doi: 10.1126/science.1160809. Review.  

55. Seyfried TN, Flores RE, Poff AM, D’Agostino DP. Cancer as a metabolic disease: implications for novel therapeutics. Carcinogenesis. 2014 Mar;35(3):515-27. 

56. Orhan N, Ugur Yilmaz C, Ekizoglu O, Ahishali B, Kucuk M, Arican N, Elmas I, Gürses C, Kaya M. Effects of beta-hydroxybutyrate on brain vascular permeability in rats with traumatic brain injury. Brain Res. 2016 Jan 15;1631:113-26. 

57. Di Lorenzo C, Coppola G, Bracaglia M, Di Lenola D, Evangelista M, Sirianni G,  Rossi P, Di Lorenzo G, Serrao M, Parisi V, Pierelli F. Cortical functional correlates of responsiveness to short-lasting preventive intervention with ketogenic diet in migraine: a multimodal evoked potentials study. J Headache Pain. 2016;17:58. doi: 10.1186/s10194-016-0650-9. Epub 2016 May 31. 

58. Kashiwaya Y, Takeshima T, Mori N, Nakashima K, Clarke K, Veech RL. D-beta-hydroxybutyrate protects neurons in models of Alzheimer’s and Parkinson’s  disease. Proc Natl Acad Sci U S A. 2000 May 9;97(10):5440-4. 

59. Cheng N, Rho JM, Masino SA. Metabolic Dysfunction Underlying Autism Spectrum Disorder and Potential Treatment Approaches. Front Mol Neurosci. 2017 Feb 21;10:34. doi: 10.3389/fnmol.2017.00034. eCollection 2017. Review. 

60. Evangeliou A, Vlachonikolis I, Mihailidou H, Spilioti M, Skarpalezou A, Makaronas N, Prokopiou A, Christodoulou P, Liapi-Adamidou G, Helidonis E, Sbyrakis S, Smeitink J. Application of a ketogenic diet in children with autistic behavior: pilot study. J Child Neurol. 2003 Feb;18(2):113-8.

61. Gross E, Putananickal N, Orsini AL, Schmidt S, Vogt DR, Cichon S, Sandor P, Fischer D. Efficacy and safety of exogenous ketone bodies for preventive treatment of migraine: A study protocol for a single-centred, randomised, placebo-controlled, double-blind crossover trial. Trials. 2019 Jan 17;20(1):61. 

Like this article?

Share on facebook
Share on Facebook
Share on twitter
Share on Twitter
Share on linkedin
Share on Linkdin
Share on pinterest
Share on Pinterest
0