Dietary Ketosis in the Treatment of Overweight, Obesity and Metabolic Syndrome

Dr. Dana Myatt

Dietary ketosis, a normal metabolic state in fasted Homo sapiens, has a broad range of therapeutic applications including the treatment of overweight, obesity and metabolically-related conditions.

Ketosis is a much maligned and largely misunderstood state of normal metabolism, distinct from ketoacidosis. The difference between dietary ketosis and diabetic ketoacidosis is as significant as the difference between intentional weight loss and cachexia. Unfortunately, lack of clarity about the utility of dietary ketosis and the distinction between ketosis and ketoacidosis has caused many physicians to shy away from prescribing therapeutic ketogenic diets even in instances where it should be considered the diet of choice.

Ketosis Versus Ketoacidosis

In diabetic ketoacidosis, severe insulin deficiency causes ketone bodies to rise precipitously, often exceeding 25 mM in blood, a level of ketosis rarely seen in normal individuals even during advanced starvation(1-2). Non-diabetic ketoacidosis can also occur as a result of alcohol or drug-induced states(3-8), during exuberant lactation(9) and extreme hyperthyroidism(10).

The counter-regulatory bicarbonate system can be stressed until blood buffering ability is exhausted. The combination of pathologically high ketone levels and loss of blood buffering systems result in severe acidosis. In addition, hypovolemia from urinary water loss secondary to hyperglycemia and glycosuria, and sodium and potassium loss from severe ketonuria, converge to create a perfect storm of life-threatening potential(1,12-14).

In dietary ketosis, the conversion of stored fats to useable energy allows blood ketones to typically reach levels of 2 to 7 mM, an evolutionary adaptation necessary to prevent conversion of vital muscle mass to glucose in times of famine. Episodic fasting evolved as a normal state during the evolution of our hunter-gatherer ancestors and this mild ketosis resulting from fasting is unique to homo sapiens (except in some ruminants during exuberant lactation or twinning)(1-2). Humans are also distinguished from other animals by the large brain-to-body weight ratio and brain’s high energy requirements. At rest, 20% of total oxygen consumption supports 1.5 kg of brain which is approximately 2% of body weight.

Beneficial Effects of Ketosis on Obesity, Overweight and Metabolic Syndrome

Research has shown that ketogenic diets result in faster weight (fat) loss and a faster correction of the elements of metabolic syndrome than non-ketogenic diets of identical caloric composition(15-17). Further, animal and human studies have demonstrated that correctly applied ketogenic diets are not only safe, but in fact confer protective benefits to normal cells(18-23).

Dietary ketosis affords numerous metabolic advantages for the correction of overweight, obesity and metabolic syndrome including:

            1.)  decreased hunger(16, 24-26)

            2.)  protein sparing(27-30)

            3.)  increased insulin sensitivity and decreased glucose levels (27, 31-33)

            4.)  improved lipid profile including increased HDL (17,31,34-35), decreased TG’s (17,35), decreased total
                  cholesterol (34-35) , lower LDL (34) , a shift from small LDL to large LDL (36), and decreased VLDL(36) .

            5.)  decreased inflammation(37-41)

            6.)  decreased radical oxygen species (ROS)(1,42-45)

            7.)  lower blood pressure(34, 46-47)

            8.)  faster weight loss(16-17,27)

            9.)  improved mitochondrial function(48-52)

This presentation will serve as a review of the biochemistry of dietary-induced ketosis and will present documented clinical nutritional strategies for using a calorie-controlled ketogenic diet in the treatment of overweight, obesity and metabolic syndrome. Specific guidelines for clinical implementation will be highlighted.

References

1.) Veech RL, Chance B, Kashiwaya Y, Lardy HA, Cahill GF Jr. Ketone bodies,  potential therapeutic uses. IUBMB Life. 2001; 51 :241-7.

2.) Williamson, D.H. (2005). Ketosis. Encyclopedia of Human Nutrition, 91-98.

3.) Khaira A, Gupta A, Tandon N, Agarwal SK. Gatifloxacin-induced severe hyperglycaemia and ketoacidosis in a non-diabetic renal transplant recipient. Clin Exp Nephrol. 2009 Feb;13(1):89-91. Epub 2008 Jul 17.

4.) Varma MK, Connolly K, Fulton B. Life-threatening hyperglycemia and acidosis related to olanzapine: a case report and review of the literature. J Intensive Care Med. 2007 Jan-Feb;22(1):52-5.

5.) Duffens K, Marx JA. Alcoholic ketoacidosis–a review. J Emerg Med. 1987 Sep-Oct;5(5):399-406.

6.) Adams SL. Alcoholic ketoacidosis. Emerg Med Clin North Am. 1990 Nov;8(4):749-60.

7.) Lee P, Campbell L. Diabetic Ketoacidosis: the Usual Villain or a Scapegoat? A novel cause of severe metabolic acidosis in type 1 diabetes. Diabetes Care March 2008 vol. 31 no. 3 e13. 

8.) Delaney MF, Zisman A, Kettyle WM. Diabetic ketoacidosis and hyperglycemic hyperosmolar nonketotic syndrome. Endocrinol Metab Clin North Am. 2000 Dec;29(4):683-705, V.

9.) Heffner AC, Johnson DP. A case of lactation “bovine” ketoacidosis.J Emerg Med. 2008 Nov;35(4):385-7. Epub 2007 Sep 17.

10.) Wood ET, Kinlaw WB. Nondiabetic ketoacidosis caused by severe hyperthyroidism. Thyroid. 2004 Aug;14(8):628-30.

12.) Baena MG, Cayón M, Ortego-Rojo J, Aguilar-Diosdado M. Diabetic Ketoacidosis Associated with Severe Hypoglycemia.J Endocrinol Invest. 2010 Apr 12. [Epub ahead of print]

13.) Fasanmade OA, Odeniyi IA, Ogbera AO. Diabetic ketoacidosis: diagnosis and management. Afr J Med Med Sci. 2008 Jun;37(2):99-105.

14.) Yared Z, Chiasson JL. Ketoacidosis and the hyperosmolar hyperglycemic state in adult diabetic patients. Diagnosis and treatment. Minerva Med. 2003 Dec;94(6):409-18.

15.) Gardner CD, Kiazand A, Alhassan S, Kim S, Stafford RS, Balise RR, Kraemer HC, King AC. 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 Mar 7;297(9):969-77.

16.) 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. American Journal of Clinical Nutrition, Vol. 87, No. 1, 44-55, January 2008.

17.) Yancy WS Jr, Olsen MK, Guyton JR, Bakst RP, Westman EC. A low-carbohydrate, ketogenic diet versus a low-fat diet to treat obesity and hyperlipidemia: a randomized, controlled trial.Ann Intern Med. 2004 May 18;140(10):769-77.

18.) Al-Zaid NS, Dashti HM, Mathew TC, Juggi JS. Low carbohydrate ketogenic diet enhances cardiac tolerance to global ischaemia. Acta Cardiol. 2007 Aug;62(4):381-9.

19.) Kodde IF, van der Stok J, Smolenski RT, de Jong JW. Metabolic and genetic regulation of cardiac energy substrate preference. Comp Biochem Physiol A Mol Integr Physiol. 2007 Jan;146(1):26-39. Epub 2006 Oct 3.

20.) Smith SL, Heal DJ, Martin KF.KTX 0101: a potential metabolic approach to cytoprotection in major surgery and neurological disorders. CNS Drug Rev. 2005 Summer;11(2):113-40

21.) Cahill GF Jr, Veech RL. Ketoacids? Good medicine? Trans Am Clin Climatol Assoc. 2003;114:149-61; discussion 162-3.

22.) Suzuki M, Suzuki M, Sato K, Dohi S, Sato T, Matsuura A, Hiraide A. Effect of beta-hydroxybutyrate, a cerebral function improving agent, on cerebral hypoxia, anoxia and ischemia in mice and rats. Jpn J Pharmacol. 2001 Oct;87(2):143-50

23.) 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.

24.) Kinzig KP, Taylor RJ. Maintenance on a ketogenic diet: voluntary exercise, adiposity and neuroendocrine effects. nt J Obes (Lond). 2009 Aug;33(8):824-30. Epub 2009 Jun 9

25.) Krilanovich N. Benefits of ketogenic diets.American Journal of Clinical Nutrition, Vol. 85, No. 1, 238-239, January 2007.

26.) Wadden TA, Stunkard AJ, Brownell KD, Day SC. A comparison of two very-low-calorie diets: protein-sparing-modified fast versus protein-formula-liquid diet. Am J Clin Nutr. 1985 Mar;41(3):533-9.

27.) Sharman MJ, Gómez AL, Kraemer WJ, Volek JS. Very low-carbohydrate and low-fat diets affect fasting lipids and postprandial lipemia differently in overweight men. J Nutr. 2004 Apr;134(4):880-5.

28.) Thompson JR, Wu G. The effect of ketone bodies on nitrogen metabolism in skeletal muscle. Comp Biochem Physiol B. 1991;100(2):209-16.

29.) Vazquez JA, Adibi SA. Protein sparing during treatment of obesity: ketogenic versus nonketogenic very low calorie diet. Metabolism. 1992 Apr;41(4):406-14.

30.) Willi SM, Oexmann MJ, Wright NM, Collop NA, Key LL Jr. The effects of a high-protein, low-fat, ketogenic diet on adolescents with morbid obesity: body composition, blood chemistries, and sleep abnormalities. Pediatrics. 1998 Jan;101(1 Pt 1):61-7.

31.) Sharman MJ, Kraemer WJ, Love DM, Avery NG, Gómez AL, Scheett TP, Volek JS.A ketogenic diet favorably affects serum biomarkers for cardiovascular disease in normal-weight men. J Nutr. 2002 Jul;132(7):1879-85

32.) Badman MK, Kennedy AR, Adams AC, Pissios P, Maratos-Flier E. A Very Low Carbohydrate Ketogenic Diet Improves Glucose Tolerance in ob/ob Mice Independent of Weight Loss. Am J Physiol Endocrinol Metab. 2009 Sep 8.

33.) Leite JO, DeOgburn R, Ratliff JC, Su R, Volek JS, McGrane MM, Dardik A, Fernandez ML. Low-carbohydrate diet disrupts the association between insulin resistance and weight gain. Metabolism. 2009 Aug;58(8):1116-22. Epub 2009 Jun 18.

34.) Jenkins DJ, Wong JM, Kendall CW, Esfahani A, Ng VW, Leong TC, Faulkner DA, Vidgen E, Greaves KA, Paul G, Singer W. The effect of a plant-based low-carbohydrate (“Eco-Atkins”) diet on body weight and blood lipid concentrations in hyperlipidemic subjects. Arch Intern Med. 2009 Jun 8;169(11):1046-54.

35.) Adam-Perrot A, Clifton P, Brouns F. Low-carbohydrate diets: nutritional and physiological aspects.Obes Rev. 2006 Feb;7(1):49-58.

36.) Westman EC, Yancy WS Jr, Olsen MK, Dudley T, Guyton JR. Effect of a low-carbohydrate, ketogenic diet program compared to a low-fat diet on fasting lipoprotein subclasses. Int J Cardiol. 2006 Jun 16;110(2):212-6. Epub 2005 Nov 16.

37.) Seyfried TN, Sanderson TM, El-Abbadi MM, McGowan R, Mukherjee P.: Role of glucose and ketone bodies in the metabolic control of experimental brain cancer. Br J Cancer. 2003 Oct 6;89(7):1375-82. 

38.) Gasior M, Rogawski MA, Hartman AL. Neuroprotective and disease-modifying effects of the ketogenic diet.Behav Pharmacol. 2006 Sep;17(5-6):431-9.

39.) Maalouf M, Rho JM, Mattson MP. The neuroprotective properties of  calorie restriction, the ketogenic diet, and ketone bodies. Brain Res Rev. 2009  Mar;59(2):293-315. Epub 2008 Sep 25.

40.) Garai J, Lóránd T, Molnár V. Ketone bodies affect the enzymatic activity of macrophage migration inhibitory factor. Life Sci. 2005 Aug 5;77(12):1375-80.

41.) Seyfried TN, Kiebish M, Mukherjee P, Marsh J. Targeting energy metabolism in  brain cancer with calorically restricted ketogenic diets. Epilepsia. 2008 Nov;49  Suppl 8:114-6.

42.) 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.

43.) Veech RL: Metabolic control analysis of ketone and insulin action: Implications for phenotyping of disease and design of therapy. Lecture: The Dynamic and Energetic Basis of Health and Aging Monday, Nov 11 – Wednesday, Nov 13, 2002, The Cloister’s, NIH, Bethesda MD.

44.) Masuda R, Monahan JW, Kashiwaya Y: D-beta-hydroxybutyrate is neuroprotective against hypoxia in serum-free hippocampal primary cultures. J Neurosci Res 2005, 80:501-509.

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

46.) Yancy WS Jr, Westman EC, McDuffie JR, Grambow SC, Jeffreys AS, Bolton J, Chalecki A, Oddone EZ. A randomized trial of a low-carbohydrate diet vs orlistat plus a low-fat diet for weight loss.Arch Intern Med. 2010 Jan 25;170(2):136-45.

47.) Pérez-Guisado J, Muñoz-Serrano A, Alonso-Moraga A. Spanish Ketogenic Mediterranean Diet: a healthy cardiovascular diet for weight loss. Nutr J. 2008 Oct 26;7:30.

48.) Maalouf M, Rho JM, Mattson MP. The neuroprotective properties of calorie restriction, the ketogenic diet, and ketone bodies. Brain Res Rev. 2009 Mar;59(2):293-315. Epub 2008 Sep 25.

49.) Studzinski CM, MacKay WA, Beckett TL, Henderson ST, Murphy MP, Sullivan PG, Burnham WM. Induction of ketosis may improve mitochondrial function and decrease steady-state amyloid-beta precursor protein (APP) levels in the aged dog.Brain Res. 2008 Aug 21;1226:209-17. Epub 2008 Jun 11.
50.) Henderson ST. Ketone bodies as a therapeutic for Alzheimer’s disease. Neurotherapeutics. 2008 Jul;5(3):470-80.

51.) Davis LM, Pauly JR, Readnower RD, Rho JM, Sullivan PG. Fasting is neuroprotective following traumatic brain injury.J Neurosci Res. 2008 Jun;86(8):1812-22.

52.) Jarrett SG, Milder JB, Liang LP, Patel M. The ketogenic diet increases mitochondrial glutathione levels. J Neurochem. 2008 Aug;106(3):1044-51. Epub 2008 May 5.