Beyond weight loss: a review of the therapeutic uses of very-low-carbohydrate (ketogenic) diets

A Paoli, A Rubini, J S Volek, K A Grimaldi, A Paoli, A Rubini, J S Volek, K A Grimaldi

Abstract

Very-low-carbohydrate diets or ketogenic diets have been in use since the 1920s as a therapy for epilepsy and can, in some cases, completely remove the need for medication. From the 1960s onwards they have become widely known as one of the most common methods for obesity treatment. Recent work over the last decade or so has provided evidence of the therapeutic potential of ketogenic diets in many pathological conditions, such as diabetes, polycystic ovary syndrome, acne, neurological diseases, cancer and the amelioration of respiratory and cardiovascular disease risk factors. The possibility that modifying food intake can be useful for reducing or eliminating pharmaceutical methods of treatment, which are often lifelong with significant side effects, calls for serious investigation. This review revisits the meaning of physiological ketosis in the light of this evidence and considers possible mechanisms for the therapeutic actions of the ketogenic diet on different diseases. The present review also questions whether there are still some preconceived ideas about ketogenic diets, which may be presenting unnecessary barriers to their use as therapeutic tools in the physician's hand.

Figures

Figure 1
Figure 1
Suggested mechanisms for the therapeutic action of ketogenic diets in pathologies for which there exists strong (a) and emerging (b) evidence.

References

    1. Atkins RC. Dr Atkins' Diet Revolution: The High Calorie Way to Stay Thin Forever. D. McKay Co: New York, NY, USA; 1972.
    1. WHO Medicines: Corruption and PharmaceuticalsWHO Fact Sheet, WHO; 2009
    1. Veech RL. The therapeutic implications of ketone bodies: The effects of ketone bodies in pathological conditions: ketosis, ketogenic diet, redox states, insulin resistance, and mitochondrial metabolism. Prostaglandins Leukot Essent Fatty Acids. 2004;70:309–319.
    1. Owen OE, Morgan AP, Kemp HG, Sullivan JM, Herrera MG, Cahill GF., Jr Brain metabolism during fasting. J Clin Invest. 1967;46:1589–1595.
    1. Kessler SK, Neal EG, Camfield CS, Kossoff EH. Dietary therapies for epilepsy: future research. Epilepsy Behav. 2011;22:17–22.
    1. Fukao T, Lopaschuk GD, Mitchell GA. Pathways and control of ketone body metabolism: on the fringe of lipid biochemistry. Prostaglandins Leukot Essent Fatty Acids. 2004;70:243–251.
    1. Veldhorst MA, Westerterp-Plantenga MS, Westerterp KR. Gluconeogenesis and energy expenditure after a high-protein, carbohydrate-free diet. Am J Clin Nutr. 2009;90:519–526.
    1. Krebs HA. The regulation of the release of ketone bodies by the liver. Adv Enzyme Regul. 1966;4:339–354.
    1. Paoli A, Canato M, Toniolo L, Bargossi AM, Neri M, Mediati M, et al. The ketogenic diet: an underappreciated therapeutic option. Clin Ter. 2011;162:e145–e153.
    1. Cahill GF., Jr Fuel metabolism in starvation. Annu Rev Nutr. 2006;26:1–22.
    1. Paoli A, Grimaldi K, Toniolo L, Canato M, Bianco A, Fratter A. Nutrition and acne: therapeutic potential of ketogenic diets. Skin Pharmacol Physiol. 2012;25:111–117.
    1. Westerterp-Plantenga MS, Nieuwenhuizen A, Tome D, Soenen S, Westerterp KR. Dietary protein, weight loss, and weight maintenance. Annu Rev Nutr. 2009;29:21–41.
    1. Feinman RD, Fine EJ. Nonequilibrium thermodynamics and energy efficiency in weight loss diets. Theor Biol Med Model. 2007;4:27.
    1. Freedman MR, King J, Kennedy E. Popular diets: A scientific review. Obes Res. 2001;9 (Suppl 1:1S–40S.
    1. Brehm BJ, Seeley RJ, Daniels SR, D'Alessio DA. A randomized trial comparing a very low carbohydrate diet and a calorie-restricted low fat diet on body weight and cardiovascular risk factors in healthy women. J Clin Endocrinol Metab. 2003;88:1617–1623.
    1. Gardner CD, Kiazand A, Alhassan S, Kim S, Stafford RS, Balise RR, et al. Comparison of the atkins, zone, ornish, and LEARN diets for change in weight and related risk factors among overweight premenopausal women: The A TO Z weight loss study: a randomized trial. JAMA. 2007;297:969–977.
    1. Shai I, Schwarzfuchs D, Henkin Y, Shahar DR, Witkow S, Greenberg I, et al. Weight loss with a low-carbohydrate, mediterranean, or low-fat diet. N Engl J Med. 2008;359:229–241.
    1. Fine EJ, Feinman RD. Thermodynamics of weight loss diets. Nutr Metab (Lond) 2004;1:15.
    1. Halton TL, Hu FB. The effects of high protein diets on thermogenesis, satiety and weight loss: a critical review. J Am Coll Nutr. 2004;23:373–385.
    1. Paoli A, Grimaldi K, Bianco A, Lodi A, Cenci L, Parmagnani A.Medium term effects of a ketogenic diet and a mediterranean diet on resting energy expenditure and respiratory ratio BMC Proceedings 20126(Suppl 3): P37
    1. Sumithran P, Prendergast LA, Delbridge E, Purcell K, Shulkes A, Kriketos A, et al. Ketosis and appetite-mediating nutrients and hormones after weight loss Eur J Clin Nutr 2013;. e-pub ahead of print 1 May 2013; doi:10.1038/ejcn.2013.90
    1. Veldhorst M, Smeets A, Soenen S, Hochstenbach-Waelen A, Hursel R, Diepvens K, et al. Protein-induced satiety: effects and mechanisms of different proteins. Physiol Behav. 2008;94:300–307.
    1. Johnstone AM, Horgan GW, Murison SD, Bremner DM, Lobley GE. Effects of a high-protein ketogenic diet on hunger, appetite, and weight loss in obese men feeding ad libitum. Am J Clin Nutr. 2008;87:44–55.
    1. Paoli A, Cenci L, Fancelli M, Parmagnani A, Fratter A, Cucchi A, et al. Ketogenic diet and phytoextracts comparison of the efficacy of mediterranean, zone and tisanoreica diet on some health risk factors. Agro Food Ind Hi-Tech. 2010;21:24.
    1. Nordmann AJ, Nordmann A, Briel M, Keller U, Yancy WS, Jr, Brehm BJ, et al. Effects of low-carbohydrate vs low-fat diets on weight loss and cardiovascular risk factors: a meta-analysis of randomized controlled trials. Arch Intern Med. 2006;166:285–293.
    1. Blackburn GL, Phillips JC, Morreale S.Physician's guide to popular low-carbohydrate weight-loss diets Cleve Clin J Med 200168761–766.768–9, 773–4.
    1. Volek JS, Phinney SD, Forsythe CE, Quann EE, Wood RJ, Puglisi MJ, et al. Carbohydrate restriction has a more favorable impact on the metabolic syndrome than a low fat diet. Lipids. 2009;44:297–309.
    1. Sharman MJ, Kraemer WJ, Love DM, Avery NG, Gomez AL, Scheett TP, et al. A ketogenic diet favorably affects serum biomarkers for cardiovascular disease in normal-weight men. J Nutr. 2002;132:1879–1885.
    1. Volek JS, Sharman MJ, Forsythe CE. Modification of lipoproteins by very low-carbohydrate diets. J Nutr. 2005;135:1339–1342.
    1. Jornayvaz FR, Samuel VT, Shulman GI. The role of muscle insulin resistance in the pathogenesis of atherogenic dyslipidemia and nonalcoholic fatty liver disease associated with the metabolic syndrome. Annu Rev Nutr. 2010;30:273–290.
    1. Hellerstein MK. De novo lipogenesis in humans: Metabolic and regulatory aspects. Eur J Clin Nutr. 1999;53 (Suppl 1:S53–S65.
    1. Bistrian BR, Blackburn GL, Flatt JP, Sizer J, Scrimshaw NS, Sherman M. Nitrogen metabolism and insulin requirements in obese diabetic adults on a protein-sparing modified fast. Diabetes. 1976;25:494–504.
    1. Gumbiner B, Wendel JA, McDermott MP. Effects of diet composition and ketosis on glycemia during very-low-energy-diet therapy in obese patients with non-insulin-dependent diabetes mellitus. Am J Clin Nutr. 1996;63:110–115.
    1. 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;142:403–411.
    1. Dashti HM, Al-Zaid NS, Mathew TC, Al-Mousawi M, Talib H, Asfar SK, et al. Long term effects of ketogenic diet in obese subjects with high cholesterol level. Mol Cell Biochem. 2006;286:1–9.
    1. 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;2:34.
    1. Nielsen JV, Joensson EA. Low-carbohydrate diet in type 2 diabetes: Stable improvement of bodyweight and glycemic control during 44 months follow-up. Nutr Metab (Lond) 2008;5:14.
    1. Basu S, Yoffe P, Hills N, Lustig RH. The relationship of sugar to population-level diabetes prevalence: An econometric analysis of repeated cross-sectional data. PLoS One. 2013;8:e57873.
    1. Hartman AL, Gasior M, Vining EP, Rogawski MA. The neuropharmacology of the ketogenic diet. Pediatr Neurol. 2007;36:281–292.
    1. McDaniel SS, Rensing NR, Thio LL, Yamada KA, Wong M. The ketogenic diet inhibits the mammalian target of rapamycin (mTOR) pathway. Epilepsia. 2011;52:e7–e11.
    1. Hartman AL, Lyle M, Rogawski MA, Gasior M. Efficacy of the ketogenic diet in the 6-hz seizure test. Epilepsia. 2008;49:334–339.
    1. Kossoff E. The fat is in the fire: ketogenic diet for refractory status epilepticus. Epilepsy Curr. 2011;11:88–89.
    1. Cordain L, Eaton SB, Sebastian A, Mann N, Lindeberg S, Watkins BA, et al. Origins and evolution of the western diet: health implications for the 21st century. Am J Clin Nutr. 2005;81:341–354.
    1. Smith RN, Mann NJ, Braue A, Makelainen H, Varigos GA. The effect of a high-protein, low glycemic-load diet versus a conventional, high glycemic-load diet on biochemical parameters associated with acne vulgaris: A randomized, investigator-masked, controlled trial. J Am Acad Dermatol. 2007;57:247–256.
    1. Smith R, Mann N. Acne in adolescence: a role for nutrition. Nutr Diet. 2007;64:S147–S149.
    1. Cordain L. Implications for the role of diet in acne. Semin Cutan Med Surg. 2005;24:84–91.
    1. Kristiansen SB, Endoh A, Casson PR, Buster JE, Hornsby PJ. Induction of steroidogenic enzyme genes by insulin and IGF-I in cultured adult human adrenocortical cells. Steroids. 1997;62:258–265.
    1. Goodman-Gruen D, Barrett-Connor E. Sex hormone-binding globulin and glucose tolerance in postmenopausal women. the rancho bernardo study. Diabetes Care. 1997;20:645–649.
    1. Powell DR, Suwanichkul A, Cubbage ML, DePaolis LA, Snuggs MB, Lee PD. Insulin inhibits transcription of the human gene for insulin-like growth factor-binding protein-1. J Biol Chem. 1991;266:18868–18876.
    1. Denley A, Carroll JM, Brierley GV, Cosgrove L, Wallace J, Forbes B, et al. Differential activation of insulin receptor substrates 1 and 2 by insulin-like growth factor-activated insulin receptors. Mol Cell Biol. 2007;27:3569–3577.
    1. Giovannucci E, Harlan DM, Archer MC, Bergenstal RM, Gapstur SM, Habel LA, et al. Diabetes and cancer: a consensus report. CA Cancer J Clin. 2010;60:207–221.
    1. Rose DP, Vona-Davis L. The cellular and molecular mechanisms by which insulin influences breast cancer risk and progression. Endocr Relat Cancer. 2012;19:R225–R241.
    1. Renehan AG, Frystyk J, Flyvbjerg A. Obesity and cancer risk: the role of the insulin-IGF axis. Trends Endocrinol Metab. 2006;17:328–336.
    1. AA.VV. Research in cancer Science 192562x+xii+xiv.
    1. Warburg O, Wind F, Negelein E. The metabolism of tumors in the body. J Gen Physiol. 1927;8:519–530.
    1. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–674.
    1. Warburg O. On respiratory impairment in cancer cells. Science. 1956;124:269–270.
    1. Pelicano H, Xu RH, Du M, Feng L, Sasaki R, Carew JS, et al. Mitochondrial respiration defects in cancer cells cause activation of akt survival pathway through a redox-mediated mechanism. J Cell Biol. 2006;175:913–923.
    1. Sandri M, Barberi L, Bijlsma AY, Blaauw B, Dyar KA, Milan G, et al. Signalling pathways regulating muscle mass in ageing skeletal muscle. the role of the IGF1-akt-mTOR-FoxO pathway Biogerontology 2013;. e-pub ahead of print 19 May 2013.
    1. Schwertfeger KL, McManaman JL, Palmer CA, Neville MC, Anderson SM. Expression of constitutively activated akt in the mammary gland leads to excess lipid synthesis during pregnancy and lactation. J Lipid Res. 2003;44:1100–1112.
    1. Klement RJ, Kammerer U. Is there a role for carbohydrate restriction in the treatment and prevention of cancer. Nutr Metab (Lond) 2011;8:75.
    1. Tisdale MJ, Brennan RA, Fearon KC. Reduction of weight loss and tumour size in a cachexia model by a high fat diet. Br J Cancer. 1987;56:39–43.
    1. Beck SA, Tisdale MJ. Effect of insulin on weight loss and tumour growth in a cachexia model. Br J Cancer. 1989;59:677–681.
    1. Ho VW, Leung K, Hsu A, Luk B, Lai J, Shen SY, et al. A low carbohydrate, high protein diet slows tumor growth and prevents cancer initiation. Cancer Res. 2011;71:4484–4493.
    1. Otto C, Kaemmerer U, Illert B, Muehling B, Pfetzer N, Wittig R, et al. Growth of human gastric cancer cells in nude mice is delayed by a ketogenic diet supplemented with omega-3 fatty acids and medium-chain triglycerides. BMC Cancer. 2008;8:122.
    1. Seyfried BT, Kiebish M, Marsh J, Mukherjee P. Targeting energy metabolism in brain cancer through calorie restriction and the ketogenic diet. J Cancer Res Ther. 2009;5 (Suppl 1:S7–S15.
    1. Zhou W, Mukherjee P, Kiebish MA, Markis WT, Mantis JG, Seyfried TN. The calorically restricted ketogenic diet, an effective alternative therapy for malignant brain cancer. Nutr Metab (Lond) 2007;4:5.
    1. Schmidt M, Pfetzer N, Schwab M, Strauss I, Kammerer U. Effects of a ketogenic diet on the quality of life in 16 patients with advanced cancer: a pilot trial. Nutr Metab (Lond) 2011;8:54.
    1. Nebeling LC, Lerner E. Implementing a ketogenic diet based on medium-chain triglyceride oil in pediatric patients with cancer. J Am Diet Assoc. 1995;95:693–697.
    1. 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;14:202–208.
    1. Fine EJ, Segal-Isaacson CJ, Feinman RD, Herszkopf S, Romano MC, Tomuta N, et al. Targeting insulin inhibition as a metabolic therapy in advanced cancer: a pilot safety and feasibility dietary trial in 10 patients. Nutrition. 2012;28:1028–1035.
    1. Fauser BC, Tarlatzis BC, Rebar RW, Legro RS, Balen AH, Lobo R, et al. Consensus on women's health aspects of polycystic ovary syndrome (PCOS): the amsterdam ESHRE/ASRM-sponsored 3rd PCOS consensus workshop group Fertil Steril 20129728–38.. e25.
    1. DeUgarte CM, Bartolucci AA, Azziz R. Prevalence of insulin resistance in the polycystic ovary syndrome using the homeostasis model assessment. Fertil Steril. 2005;83:1454–1460.
    1. Tosi F, Negri C, Perrone F, Dorizzi R, Castello R, Bonora E, et al. Hyperinsulinemia amplifies GnRH agonist stimulated ovarian steroid secretion in women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2012;97:1712–1719.
    1. Blank SK, McCartney CR, Chhabra S, Helm KD, Eagleson CA, Chang RJ, et al. Modulation of gonadotropin-releasing hormone pulse generator sensitivity to progesterone inhibition in hyperandrogenic adolescent girls--implications for regulation of pubertal maturation. J Clin Endocrinol Metab. 2009;94:2360–2366.
    1. Moghetti P, Castello R, Negri C, Tosi F, Spiazzi GG, Brun E, et al. Insulin infusion amplifies 17 alpha-hydroxycorticosteroid intermediates response to adrenocorticotropin in hyperandrogenic women: apparent relative impairment of 17,20-lyase activity. J Clin Endocrinol Metab. 1996;81:881–886.
    1. Mavropoulos JC, Yancy WS, Hepburn J, Westman EC. The effects of a low-carbohydrate, ketogenic diet on the polycystic ovary syndrome: a pilot study. Nutr Metab (Lond) 2005;2:35.
    1. Baranano KW, Hartman AL. The ketogenic diet: uses in epilepsy and other neurologic illnesses. Curr Treat Options Neurol. 2008;10:410–419.
    1. Stafstrom CE, Rho JM. The ketogenic diet as a treatment paradigm for diverse neurological disorders. Front Pharmacol. 2012;3:59.
    1. Bough KJ, Rho JM. Anticonvulsant mechanisms of the ketogenic diet. Epilepsia. 2007;48:43–58.
    1. Huffman J, Kossoff EH. State of the ketogenic diet(s) in epilepsy. Curr Neurol Neurosci Rep. 2006;6:332–340.
    1. Garriga-Canut M, Schoenike B, Qazi R, Bergendahl K, Daley TJ, Pfender RM, et al. 2-deoxy-D-glucose reduces epilepsy progression by NRSF-CtBP-dependent metabolic regulation of chromatin structure. Nat Neurosci. 2006;9:1382–1387.
    1. Maalouf M, Rho JM, Mattson MP. The neuroprotective properties of calorie restriction, the ketogenic diet, and ketone bodies. Brain Res Rev. 2009;59:293–315.
    1. Palop JJ, Mucke L. Epilepsy and cognitive impairments in alzheimer disease. Arch Neurol. 2009;66:435–440.
    1. Roberson ED, Halabisky B, Yoo JW, Yao J, Chin J, Yan F, et al. Amyloid-beta/fyn-induced synaptic, network, and cognitive impairments depend on tau levels in multiple mouse models of alzheimer's disease. J Neurosci. 2011;31:700–711.
    1. Noebels J. A perfect storm: converging paths of epilepsy and alzheimer's dementia intersect in the hippocampal formation. Epilepsia. 2011;52 (Suppl 1:39–46.
    1. Kapogiannis D, Mattson MP. Disrupted energy metabolism and neuronal circuit dysfunction in cognitive impairment and alzheimer's disease. Lancet Neurol. 2011;10:187–198.
    1. Henderson ST, Vogel JL, Barr LJ, Garvin F, Jones JJ, Costantini LC. Study of the ketogenic agent AC-1202 in mild to moderate alzheimer's disease: A randomized, double-blind, placebo-controlled, multicenter trial. Nutr Metab (Lond) 2009;6:31.
    1. 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 USA. 2000;97:5440–5444.
    1. Van der Auwera I, Wera S, Van Leuven F, Henderson ST. A ketogenic diet reduces amyloid beta 40 and 42 in a mouse model of alzheimer's disease. Nutr Metab (Lond) 2005;2:28.
    1. Vanitallie TB, Nonas C, Di Rocco A, Boyar K, Hyams K, Heymsfield SB. Treatment of parkinson disease with diet-induced hyperketonemia: a feasibility study. Neurology. 2005;64:728–730.
    1. Prins ML, Fujima LS, Hovda DA. Age-dependent reduction of cortical contusion volume by ketones after traumatic brain injury. J Neurosci Res. 2005;82:413–420.
    1. Appelberg KS, Hovda DA, Prins ML. The effects of a ketogenic diet on behavioral outcome after controlled cortical impact injury in the juvenile and adult rat. J Neurotrauma. 2009;26:497–506.
    1. Schwartzkroin PA, Wenzel HJ, Lyeth BG, Poon CC, Delance A, Van KC, et al. Does ketogenic diet alter seizure sensitivity and cell loss following fluid percussion injury. Epilepsy Res. 2010;92:74–84.
    1. Siva N. Can ketogenic diet slow progression of ALS. Lancet Neurol. 2006;5:476.
    1. Zhao Z, Lange DJ, Voustianiouk A, MacGrogan D, Ho L, Suh J, et al. A ketogenic diet as a potential novel therapeutic intervention in amyotrophic lateral sclerosis. BMC Neurosci. 2006;7:29.
    1. Tagliabue A, Bertoli S, Trentani C, Borrelli P, Veggiotti P. Effects of the ketogenic diet on nutritional status, resting energy expenditure, and substrate oxidation in patients with medically refractory epilepsy: A 6-month prospective observational study. Clin Nutr. 2012;31:246–249.
    1. Sabapathy S, Morris NR, Schneider DA. Ventilatory and gas-exchange responses to incremental exercise performed with reduced muscle glycogen content. J Sci Med Sport. 2006;9:267–273.
    1. Jia Y, Hwang SY, House JD, Ogborn MR, Weiler HA, O K, et al. Long-term high intake of whole proteins results in renal damage in pigs. J Nutr. 2010;140:1646–1652.
    1. Wakefield AP, House JD, Ogborn MR, Weiler HA, Aukema HM. A diet with 35% of energy from protein leads to kidney damage in female sprague-dawley rats. Br J Nutr. 2011. pp. 1–8.
    1. Skov AR, Haulrik N, Toubro S, Molgaard C, Astrup A. Effect of protein intake on bone mineralization during weight loss: A 6-month trial. Obes Res. 2002;10:432–438.
    1. Martin WF, Armstrong LE, Rodriguez NR. Dietary protein intake and renal function. Nutr Metab (Lond) 2005;2:25.
    1. Welle S, Nair KS. Relationship of resting metabolic rate to body composition and protein turnover. Am J Physiol. 1990;258:E990–E998.
    1. Praga M. Synergy of low nephron number and obesity: A new focus on hyperfiltration nephropathy. Nephrol Dial Transplant. 2005;20:2594–2597.
    1. Eisenstein J, Roberts SB, Dallal G, Saltzman E. High-protein weight-loss diets: are they safe and do they work? A review of the experimental and epidemiologic data. Nutr Rev. 2002;60:189–200.
    1. Westerterp-Plantenga MS. How are normal, high- or low-protein diets defined. Br J Nutr. 2007;97:217–218.
    1. Pijls LT, de Vries H, Donker AJ, van Eijk JT. The effect of protein restriction on albuminuria in patients with type 2 diabetes mellitus: A randomized trial. Nephrol Dial Transplant. 1999;14:1445–1453.
    1. Pijls LT, de Vries H, van Eijk JT, Donker AJ. Protein restriction, glomerular filtration rate and albuminuria in patients with type 2 diabetes mellitus: a randomized trial. Eur J Clin Nutr. 2002;56:1200–1207.
    1. Poplawski MM, Mastaitis JW, Isoda F, Grosjean F, Zheng F, Mobbs CV. Reversal of diabetic nephropathy by a ketogenic diet. PLoS One. 2011;6:e18604.

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