Abstract
Purpose of Review
The goal of this paper is to review current literature on nutritional ketosis within the context of weight management and metabolic syndrome, namely, insulin resistance, lipid profile, cardiovascular disease risk, and development of non-alcoholic fatty liver disease. We provide background on the mechanism of ketogenesis and describe nutritional ketosis.
Recent Findings
Nutritional ketosis has been found to improve metabolic and inflammatory markers, including lipids, HbA1c, high-sensitivity CRP, fasting insulin and glucose levels, and aid in weight management. We discuss these findings and elaborate on potential mechanisms of ketones for promoting weight loss, decreasing hunger, and increasing satiety.
Summary
Humans have evolved with the capacity for metabolic flexibility and the ability to use ketones for fuel. During states of low dietary carbohydrate intake, insulin levels remain low and ketogenesis takes place. These conditions promote breakdown of excess fat stores, sparing of lean muscle, and improvement in insulin sensitivity.
Similar content being viewed by others
Notes
This is in stark contrast to, and should not be confused with, the pathophysiologic state of type 1 diabetic ketoacidosis (DKA). Despite similar sounding names, they are two distinct metabolic processes. The production of endogenous insulin is protective against the occurrence of DKA; the range of ketones present in DKA is 5-10 fold greater than the levels achieved during nutritional ketosis. Additionally, while in nutritional ketosis, the body is able to maintain normal blood glucose levels and maintain a normal pH, as opposed to extremely elevated blood sugars and acidic pH associated with DKA.
References
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major Importance
Obesity and Overweight Fact Sheet. Vol. 2018. World Health Organization; 2017.
Kaur J. A comprehensive review on metabolic syndrome. Cardiol Res Pract. 2014;2014:943162.
Wilson PW, D'Agostino RB, Parise H, Sullivan L, Meigs JB. Metabolic syndrome as a precursor of cardiovascular disease and type 2 diabetes mellitus. Circulation. 2005;112:3066–72.
Saslow LR, Kim S, Daubenmier JJ, Moskowitz JT, Phinney SD, Goldman V, et al. A randomized pilot trial of a moderate carbohydrate diet compared to a very low carbohydrate diet in overweight or obese individuals with type 2 diabetes mellitus or prediabetes. PLoS One. 2014;9:e91027.
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.
Laffel L. Ketone bodies: a review of physiology, pathophysiology and application of monitoring to diabetes. Diabetes Metab Res Rev. 1999;15:412–26.
Randle PJ, Garland PB, Hales CN, Newsholme EA. The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet. 1963;1:785–9.
Sato K, Kashiwaya Y, Keon CA, Tsuchiya N, King MT, Radda GK, et al. Insulin, ketone bodies, and mitochondrial energy transduction. FASEB J. 1995;9:651–8.
Veech RL, Chance B, Kashiwaya Y, Lardy HA, Cahill GF Jr. Ketone bodies, potential therapeutic uses. IUBMB Life. 2001;51:241–7.
Westman EC, Feinman RD, Mavropoulos JC, Vernon MC, Volek JS, Wortman JA, et al. Low-carbohydrate nutrition and metabolism. Am J Clin Nutr. 2007;86:276–84.
Volek JS, Phinney SD. The art and science of low carbohydrate living. Miami: Beyond Obesity, LLC.
Bough KJ, Wetherington J, Hassel B, Pare JF, Gawryluk JW, Greene JG, et al. Mitochondrial biogenesis in the anticonvulsant mechanism of the ketogenic diet. Ann Neurol. 2006;60:223–35.
Ahola-Erkkila S, et al. Ketogenic diet slows down mitochondrial myopathy progression in mice. Hum Mol Genet. 2010;19:1974–84.
Newman JC, Verdin E. Beta-hydroxybutyrate: much more than a metabolite. Diabetes Res Clin Pract. 2014;106:173–81.
•• 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;67:789–96. Excellent review that explains the role of physiologic ketosis and possible mechanisms for reversing chronic disease.
Volek JS, Feinman RD. Carbohydrate restriction improves the features of metabolic syndrome. Metabolic Syndrome may be defined by the response to carbohydrate restriction. Nutr Metab (Lond). 2005;2:31.
Volek JS, Fernandez ML, Feinman RD, Phinney SD. Dietary carbohydrate restriction induces a unique metabolic state positively affecting atherogenic dyslipidemia, fatty acid partitioning, and metabolic syndrome. Prog Lipid Res. 2008;47:307–18.
Sacks FM, Bray GA, Carey VJ, Smith SR, Ryan DH, Anton SD, et al. Comparison of weight-loss diets with different compositions of fat, protein, and carbohydrates. N Engl J Med. 2009;360:859–73.
Bueno NB, de Melo IS, de Oliveira SL, da Rocha Ataide T. Very-low-carbohydrate ketogenic diet v. low-fat diet for long-term weight loss: a meta-analysis of randomised controlled trials. Br J Nutr. 2013;110:1178–87.
Santos FL, Esteves SS, da Costa Pereira A, Yancy WS Jr, Nunes JP. Systematic review and meta-analysis of clinical trials of the effects of low carbohydrate diets on cardiovascular risk factors. Obes Rev. 2012;13:1048–66.
Ebbeling CB, Swain JF, Feldman HA, Wong WW, Hachey DL, Garcia-Lago E, et al. Effects of dietary composition on energy expenditure during weight-loss maintenance. JAMA. 2012;307:2627–34.
Cardillo S, Seshadri P, Iqbal N. The effects of a low-carbohydrate versus low-fat diet on adipocytokines in severely obese adults: three-year follow-up of a randomized trial. Eur Rev Med Pharmacol Sci. 2006;10:99–106.
Seshadri P, Samaha FF, Stern L, Ahima RS, Daily D, Iqbal N. Adipocytokine changes caused by low-carbohydrate compared to conventional diets in obesity. Metab Syndr Relat Disord. 2005;3:66–74.
Woods SC, Lutz TA, Geary N, Langhans W. Pancreatic signals controlling food intake; insulin, glucagon and amylin. Philos Trans R Soc Lond Ser B Biol Sci. 2006;361:1219–35.
Rodin J, Wack J, Ferrannini E, DeFronzo RA. Effect of insulin and glucose on feeding behavior. Metabolism. 1985;34:826–31.
Asrih M, Jornayvaz FR. Diets and nonalcoholic fatty liver disease: the good and the bad. Clin Nutr. 2014;33:186–90.
Cox PJ, Kirk T, Ashmore T, Willerton K, Evans R, Smith A, et al. Nutritional ketosis alters fuel preference and thereby endurance performance in athletes. Cell Metab. 2016;24:256–68.
Sackner-Bernstein J, Kanter D, Kaul S. Dietary intervention for overweight and obese adults: comparison of low-carbohydrate and low-fat diets. A meta-analysis. PLoS One. 2015;10:e0139817.
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.
Phinney SD, Bistrian BR, Wolfe RR, Blackburn GL. The human metabolic response to chronic ketosis without caloric restriction: physical and biochemical adaptation. Metabolism. 1983;32:757–68.
Bistrian BR. Recent developments in the treatment of obesity with particular reference to semistarvation ketogenic regimens. Diabetes Care. 1978;1:379–84.
Samaha FF, Iqbal N, Seshadri P, Chicano KL, Daily DA, McGrory J, et al. A low-carbohydrate as compared with a low-fat diet in severe obesity. N Engl J Med. 2003;348:2074–81.
Johnstone AM, Murison SD, Duncan JS, Rance KA, Speakman JR. Factors influencing variation in basal metabolic rate include fat-free mass, fat mass, age, and circulating thyroxine but not sex, circulating leptin, or triiodothyronine. Am J Clin Nutr. 2005;82:941–8.
Veldhorst MA, Westerterp KR, Westerterp-Plantenga MS. Gluconeogenesis and protein-induced satiety. Br J Nutr. 2012;107:595–600.
Veldhorst MA, Westerterp-Plantenga MS, Westerterp KR. Gluconeogenesis and energy expenditure after a high-protein, carbohydrate-free diet. Am J Clin Nutr. 2009;90:519–26.
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;94:300–7.
Veldhorst MA, Westerterp KR, van Vught AJ, Westerterp-Plantenga MS. Presence or absence of carbohydrates and the proportion of fat in a high-protein diet affect appetite suppression but not energy expenditure in normal-weight human subjects fed in energy balance. Br J Nutr. 2010;104:1395–405.
Wilson JM, et al. The effects of ketogenic dieting on body composition, strength, power, and hormonal profiles in resistance training males. J Strength Cond Res. 2017. https://www.ncbi.nlm.nih.gov/pubmed/28399015.
Egan B, D'Agostino DP. Fueling performance: ketones enter the mix. Cell Metab. 2016;24:373–5.
Noakes T, Volek JS, Phinney SD. Low-carbohydrate diets for athletes: what evidence? Br J Sports Med. 2014;48:1077–8.
Phinney SD, Horton ES, Sims EAH, Hanson JS, Danforth E Jr, Lagrange BM. Capacity for moderate exercise in obese subjects after adaptation to a hypocaloric, ketogenic diet. J Clin Invest. 1980;66:1152–61.
Roberts MD, et al. A putative low-carbohydrate ketogenic diet elicits mild nutritional ketosis but does not impair the acute or chronic hypertrophic responses to resistance exercise in rodents. J Appl Physiol (1985). 2016;120:1173–85.
Phinney SD. Ketogenic diets and physical performance. Nutr Metab (Lond). 2004;1:2.
Volek JS, Freidenreich DJ, Saenz C, Kunces LJ, Creighton BC, Bartley JM, et al. Metabolic characteristics of keto-adapted ultra-endurance runners. Metabolism. 2016;65:100–10.
Larosa JC, Fry AG, Muesing R, Rosing DR. Effects of high-protein, low-carbohydrate dieting on plasma lipoproteins and body weight. J Am Diet Assoc. 1980;77:264–70.
Volek JS, Sharman MJ, Forsythe CE. Modification of lipoproteins by very low-carbohydrate diets. J Nutr. 2005;135:1339–42.
Forsythe CE, Phinney SD, Feinman RD, Volk BM, Freidenreich D, Quann E, et al. Limited effect of dietary saturated fat on plasma saturated fat in the context of a low carbohydrate diet. Lipids. 2010;45:947–62.
Graham TE, Yang Q, Blüher M, Hammarstedt A, Ciaraldi TP, Henry RR, et al. Retinol-binding protein 4 and insulin resistance in lean, obese, and diabetic subjects. N Engl J Med. 2006;354:2552–63.
Foster GD, Wyatt HR, Hill JO, Makris AP, Rosenbaum DL, Brill C, et al. Weight and metabolic outcomes after 2 years on a low-carbohydrate versus low-fat diet: a randomized trial. Ann Intern Med. 2010;153:147–57.
Steckhan N, Hohmann CD, Kessler C, Dobos G, Michalsen A, Cramer H. Effects of different dietary approaches on inflammatory markers in patients with metabolic syndrome: a systematic review and meta-analysis. Nutrition. 2016;32:338–48.
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.
Dashti HM, Mathew TC, Khadada M, al-Mousawi M, Talib H, Asfar SK, et al. Beneficial effects of ketogenic diet in obese diabetic subjects. Mol Cell Biochem. 2007;302:249–56.
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;142:403–11.
Ajala O, English P, Pinkney J. Systematic review and meta-analysis of different dietary approaches to the management of type 2 diabetes. Am J Clin Nutr. 2013;97:505–16.
Gerber PA, Berneis K. Regulation of low-density lipoprotein subfractions by carbohydrates. Curr Opin Clin Nutr Metab Care. 2012;15:381–5.
Chalasani N, et al. The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology. 2012;55:2005–23.
Yki-Jarvinen H. Nutritional modulation of non-alcoholic fatty liver disease and insulin resistance. Nutrients. 2015;7:9127–38.
Feinman RD, et al. Dietary carbohydrate restriction as the first approach in diabetes management: critical review and evidence base. Nutrition. 2015;31:1–13.
Ramsden CE, et al. Re-evaluation of the traditional diet-heart hypothesis: analysis of recovered data from Minnesota Coronary Experiment (1968–73). BMJ. 2016;353:i1246.
de Souza RJ, et al. Intake of saturated and trans unsaturated fatty acids and risk of all cause mortality, cardiovascular disease, and type 2 diabetes: systematic review and meta-analysis of observational studies. BMJ. 2015;351:h3978.
Gershuni VM. Curr Nutr Rep (2018). https://doi.org/10.1007/s13668-018-0238-x
Kosinski C, Jornayvaz FR. Effects of ketogenic diets on cardiovascular risk factors: evidence from animal and human studies. Nutrients. 2017;9. https://www.ncbi.nlm.nih.gov/pubmed/28534852.
Tiniakos DG, Vos MB, Brunt EM. Nonalcoholic fatty liver disease: pathology and pathogenesis. Annu Rev Pathol. 2010;5:145–71.
Hokanson JE, Austin MA. Plasma triglyceride level is a risk factor for cardiovascular disease independent of high-density lipoprotein cholesterol level: a meta-analysis of population-based prospective studies. J Cardiovasc Risk. 1996;3:213–9.
Phinney SD, Bistrian BR, Evans WJ, Gervino E, Blackburn GL. The human metabolic response to chronic ketosis without caloric restriction: preservation of submaximal exercise capability with reduced carbohydrate oxidation. Metabolism. 1983;32:769–76.
• Saslow LR, et al. Twelve-month outcomes of a randomized trial of a moderate-carbohydrate versus very low-carbohydrate diet in overweight adults with type 2 diabetes mellitus or prediabetes. Nutr Diabetes. 2017;7:304. Long-term, randomized human-subject dietary intervention comparing very low-carb ketogenic diet to moderate-carb low-fat diet. Demonstrating greater improvements in blood sugar (Hba1c) and weight loss, despite reducing need for hypoglycemic medications in the very low-carbohydrate ketogenic diet group.
Hussain TA, Mathew TC, Dashti AA, Asfar S, al-Zaid N, Dashti HM. Effect of low-calorie versus low-carbohydrate ketogenic diet in type 2 diabetes. Nutrition. 2012;28:1016–21.
Accurso A, Bernstein RK, Dahlqvist A, Draznin B, Feinman RD, Fine EJ, et al. Dietary carbohydrate restriction in type 2 diabetes mellitus and metabolic syndrome: time for a critical appraisal. Nutr Metab (Lond). 2008;5:9.
McKenzie AL, Hallberg SJ, Creighton BC, Volk BM, Link TM, Abner MK, et al. A novel intervention including individualized nutritional recommendations reduces hemoglobin A1c level, medication use, and weight in type 2 diabetes. JMIR Diabetes. 2017;2:e5.
• Bhanpuri NH, et al. Cardiovascular disease risk factor responses to a type 2 diabetes care model including nutritional ketosis induced by sustained carbohydrate restriction at 1 year: an open label, non-randomized, controlled study. Cardiovasc Diabetol. 2018;17:56. Examination of coronary vascular disease risk factors in a cohort of patients who participated in a long-term human-subject dietary intervention evaluating the use of a ketogenic diet vs. standard care in a continous care model for type 2 diabetes. Nutritional ketosis was associated with improvement in most biomarkers of CVD risk after 1 year. An increase in LDL-C was limited to the large LDL subfraction with incresed particle size. Inflammation and blood pressure decreased.
Hallberg SJ, et al. 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;9:583–612.
Leow ZZX, Guelfi KJ, Davis EA, Jones TW, Fournier PA. The glycaemic benefits of a very-low-carbohydrate ketogenic diet in adults with type 1 diabetes mellitus may be opposed by increased hypoglycaemia risk and dyslipidaemia. Diabet Med (2018). https://www.ncbi.nlm.nih.gov/pubmed/29737587.
Snorgaard O, Poulsen GM, Andersen HK, Astrup A. Systematic review and meta-analysis of dietary carbohydrate restriction in patients with type 2 diabetes. BMJ Open Diabetes Res Care. 2017;5:e000354.
Turton JL, Raab R, Rooney KB. Low-carbohydrate diets for type 1 diabetes mellitus: a systematic review. PLoS One. 2018;13:e0194987.
Shukla SK, Liu W, Sikder K, Addya S, Sarkar A, Wei Y, et al. HMGCS2 is a key ketogenic enzyme potentially involved in type 1 diabetes with high cardiovascular risk. Sci Rep. 2017;7:4590.
Schugar RC, Crawford PA. Low-carbohydrate ketogenic diets, glucose homeostasis, and nonalcoholic fatty liver disease. Curr Opin Clin Nutr Metab Care. 2012;15:374–80.
Browning JD, Baker JA, Rogers T, Davis J, Satapati S, Burgess SC. Short-term weight loss and hepatic triglyceride reduction: evidence of a metabolic advantage with dietary carbohydrate restriction. Am J Clin Nutr. 2011;93:1048–52.
Andersen T, Gluud C, Franzmann MB, Christoffersen P. Hepatic effects of dietary weight loss in morbidly obese subjects. J Hepatol. 1991;12:224–9.
Weiner RA. Surgical treatment of non-alcoholic steatohepatitis and non-alcoholic fatty liver disease. Dig Dis. 2010;28:274–9.
Acknowledgements
The authors would like to thank Robin Noel for her technical assistance in the creation of the graphics for the figure.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of Interest
Victoria M. Gershuni, Stephanie L. Yan, and Valentina Medici declare they have no conflict of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Additional information
This article is part of the Topical Collection on Gastroenterology, Critical Care, and Lifestyle Medicine
Rights and permissions
About this article
Cite this article
Gershuni, V.M., Yan, S.L. & Medici, V. Nutritional Ketosis for Weight Management and Reversal of Metabolic Syndrome. Curr Nutr Rep 7, 97–106 (2018). https://doi.org/10.1007/s13668-018-0235-0
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13668-018-0235-0