Ketogenic diets as treatment of obesity and type 2 diabetes mellitus

Abstract

During the last decades, several interventions for the management of overweight and obesity have been proposed. Among diets, the first studies focused on the effect of water only and total fasting diets with or without proteins. Unfortunately, they were found to be associated with adverse events which lead to the abandon of these strategies. Interestingly, despite the radical approach, total fasting was effective and generally well tolerated. A strict connection between protein-calorie malnutrition and increased in morbidity and mortality in hospitalized patients was found at that time. Then, the seminal works of Blackburn and his collaborators lead to the introduction of the protein-sparing modified fast. Encouraged by the early results using this intervention, diets evolved to the current very-low-calorie ketogenic diets (VLCKD). In the present review, results of studies on the VLCKDs are presented and discussed, with a particular reference to the protocolled VLCKD. Also, a recent proposal on the nomenclature on the ketogenic diets is reported. Available evidence suggests VLCKDs to be effective in achieving a rapid and significant weight loss by means of an easily reversible intervention which could be repeated, if needed. Muscle mass and strength are preserved, resting metabolic rate is not impaired, hunger, appetite and mood are not worsened. Symptoms and abnormal laboratory findings can be there, but they have generally been reported as of mild intensity and transient. Preliminary studies suggest VLCKDs to be a potential game-changer in the management of type 2 diabetes too. Therefore, VLCKDs should be considered as an excellent initial step in properly selected and motivated patients with obesity or type 2 diabetes, to be delivered as a part of a multicomponent strategy and under strict medical supervision.

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References

  1. 1.

    Flegal KM, Carroll MD, Kit BK, Ogden CL. Prevalence of obesity and trends in the distribution of body mass index among US adults, 1999–2010. JAMA. 2012;307:491–7.

    PubMed  Google Scholar 

  2. 2.

    Gutierrez-Fisac JL, Guallar-Castillon P, Leon-Muñoz LM, Graciani A, Banegas JR, Rodriguez-Artalejo F. Prevalence of general and abdominal obesity in the adult population of Spain, 2008–2010: the ENRICA study. Obes Rev. 2012;13:388–92.

    CAS  PubMed  Google Scholar 

  3. 3.

    Seidell JC. Obesity, insulin resistance and diabetes -a worldwide epidemic. Br J Nutr. 2000;83(Suppl. 1):S5–8.

    CAS  PubMed  Google Scholar 

  4. 4.

    Apovian CM. The obesity epidemic – understanding the disease and the treatment. N Engl J Med. 2016;374:177–9.

    PubMed  Google Scholar 

  5. 5.

    Global BMI Mortality Collaboration, Di Angelantonio E, ShN B, Wormser D, Gao P, Kaptoge S, et al. Body-mass index and all-cause mortality: individual-participant-data meta-analysis of 239 prospective studies in four continents. Lancet. 2016;388(10046):776–86.

    CAS  PubMed  Google Scholar 

  6. 6.

    NCD Risk Factor Collaboration (NCD-RisC). Trends in adult body-mass index in 200 countries from 1975 to 2014: a pooled analysis of 1698 population-based measurement studies with 19·2 million participants. Lancet. 2016;387(10026):1377–96.

    Google Scholar 

  7. 7.

    Bray GA, Heisel WE, Afshin A, Jensen MD, Dietz WH, Long M, Kushner RF, Daniels SR, Wadden TA, Tsai AG, Hu FB, Jakicic JM, Ryan DH, Wolfe BM, Inge TH. The science of obesity management: an Endocrine Society scientific statement. Endocr Rev. 2018;39(2):79–132.

    PubMed  PubMed Central  Google Scholar 

  8. 8.

    Bray GA, Kim KK, Wilding JPH. Obesity: a chronic relapsing progressive disease process. A position statement of the world obesity federation. Obes Rev. 2017;18:715–23.

    CAS  PubMed  Google Scholar 

  9. 9.

    Garrido-Miguel M, Cavero-Redondo I, Alvarez-Bueno C, Rodriguez-Artalejo F, Moreno LA, Ruiz JR, et al. Prevalence and trends of overweight and obesity in european children from 1999 to 2016. A systematic review and meta-analysis. JAMA Pediatr. 2019;173:e192430.

    PubMed Central  Google Scholar 

  10. 10.

    Van Gaal LF, Mertens IL, De Block CE. Mechanisms linking obesity with cardiovascular disease. Nature. 2006;444:875–80.

    PubMed  Google Scholar 

  11. 11.

    Pi-Sunyer X. The medical risks of obesity. Postgrad Med. 2009;121:21–33.

    PubMed  PubMed Central  Google Scholar 

  12. 12.

    Lauby-Secretan B, Scoccianti C, Loomis D, Grosse Y, Bianchini F, Straif K. International agency for research on cancer handbook working group. N Engl J Med. 2016;375:794–8.

    PubMed  PubMed Central  Google Scholar 

  13. 13.

    Emerging Risk Factors Collaboration, Di Angelantonio E, Kaptoge S, Wormser D, Willeit P, Butterworth AS, Bansal N, O’Keeffe LM, Gao P, Wood AM, Burgess S, Freitag DF, Pennells L, Peters SA, Hart CL, Håheim LL, Gillum RF, Nordestgaard BG, Psaty BM, Yeap BB, Knuiman MW, Nietert PJ, Kauhanen J, Salonen JT, Kuller LH, Simons LA, van der Schouw YT, Barrett-Connor E, Selmer R, Crespo CJ, Rodriguez B, Verschuren WM, Salomaa V, Svärdsudd K, van der Harst P, Björkelund C, Wilhelmsen L, Wallace RB, Brenner H, Amouyel P, Barr EL, Iso H, Onat A, Trevisan M, D’Agostino RB Sr, Cooper C, Kavousi M, Welin L, Roussel R, Hu FB, Sato S, Davidson KW, Howard BV, Leening MJ, Leening M, Rosengren A, Dörr M, Deeg DJ, Kiechl S, Stehouwer CD, Nissinen A, Giampaoli S, Donfrancesco C, Kromhout D, Price JF, Peters A, Meade TW, Casiglia E, Lawlor DA, Gallacher J, Nagel D, Franco OH, Assmann G, Dagenais GR, Jukema JW, Sundström J, Woodward M, Brunner EJ, Khaw KT, Wareham NJ, Whitsel EA, Njølstad I, Hedblad B, Wassertheil-Smoller S, Engström G, Rosamond WD, Selvin E, Sattar N, Thompson SG, Danesh J. Association of cardiometabolic multimorbidity with mortality. JAMA. 2015;314(1):52–60.

    Google Scholar 

  14. 14.

    Stewart ST, Cutler DM, Rosen AB. Forecasting the effects of obesity and smoking on U.S. life expectancy. N Engl J Med. 2009;361:2252–60.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Harrison MT, Harden RM. The long-term value of fasting in the treatment of obesity. Lancet. 1966;2:1340–2.

    CAS  PubMed  Google Scholar 

  16. 16.

    Diabetes Prevention Program Research Group. Long-term effects of lifestyle intervention or metformin on diabetes development and microvascular complications over 15-year follow-up: the diabetes prevention program outcomes study. Lancet Diabetes Endocrinol. 2015;3(11):866–75.

    PubMed Central  Google Scholar 

  17. 17.

    Ma C, Avenell A, Bolland M, Hudson J, Stewart F, Robertson C, et al. Effects of weight loss interventions for adults who are obese on mortality, cardiovascular disease, and cancer: systematic review and meta-analysis. BMJ. 2017;359:j4849.

    PubMed  PubMed Central  Google Scholar 

  18. 18.

    Dattilo AM, Kris-Etherton PM. Effects of weight reduction on blood lipids and lipoproteins: a meta-analysis. Am J Clin Nutr. 1992;56(2):320–8.

    CAS  PubMed  Google Scholar 

  19. 19.

    Apovian CM, Aronne LJ, Bessesen DH, McDonnell ME, Hassan Murad M, Pagotto U, et al. Pharmacological management of obesity: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2015;100:342–62.

    CAS  PubMed  Google Scholar 

  20. 20.

    Pories WJ. Bariatric surgery: risks and rewards. J Clin Endocrinol Metab. 2008;93(11 Suppl 1):S89–96.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Kalm LM, Semba RD. They starved so that others be better fed: remembering Ancel Keys and the Minnesota experiment. J Nutr. 2005;135:1347–52.

    CAS  PubMed  Google Scholar 

  22. 22.

    Benedict FG, Gooddall HW, Ash JE, Langfeld HS, Kendall AI, Higgins HL. A study of prolonged fasting. Washington, DC: Carnegie Institution of Washington; 1915.

    Google Scholar 

  23. 23.

    Keys A, Brozek J, Mickelsen O, Taylor HL. The biology of human starvation. Minneapolis: University of Minnesota Press; 1950.

    Google Scholar 

  24. 24.

    Bloom WL. Fasting as an introduction to the treatment of obesity. Metabolism. 1959;8:214–20.

    CAS  PubMed  Google Scholar 

  25. 25.

    Drenick EJ, Swendseid ME, Blahd WH, Tuttle SG. Prolonged starvation as treatment for severe obesity. JAMA. 1964;187:100–5.

    CAS  PubMed  Google Scholar 

  26. 26.

    Leiter LA, Marliss EB. Survival during fasting may depend on fat as well as protein stores. JAMA. 1982;248:2306–7.

    CAS  PubMed  Google Scholar 

  27. 27.

    Stewart WK, Fleming LW. Features of a successful therapeutic fast of 382 days’ duration. Postgrad Med J. 1973;49:203–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Thomson TJ, Runcie J, Miller J. Treatment of obesity by total fasting for up to 249 days. Lancet. 1966;2:992–6.

    CAS  PubMed  Google Scholar 

  29. 29.

    Duncan CG, Jenson WK, Fraser RI, Cristofori FG. Correction and control of intractable obesity: practicable application of intermittent periods of total fasting. JAMA. 1962;181:309–12.

    CAS  PubMed  Google Scholar 

  30. 30.

    Gilliland IC. Total fasting in the treatment of obesity. Postgrad Med J. 1968;44:58–61.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Johnsonn D, Drenick EJ. Therapeutic fasting in morbid obesity: long-term follow-up. Arch Intern Med. 1977;137:1381–2.

    Google Scholar 

  32. 32.

    Isner JM, Sours HE, Paris AL, Ferrans VJ, Roberts WG. Sudden, unexpected death in avid dieters using the liquid-protein-modified-fast diet. Observations in 17 patients and the role of the prolonged QT interval. Circulation. 1979;60:1401–12.

    CAS  PubMed  Google Scholar 

  33. 33.

    Hunscher MA. A posthospitalization study of patients treated of obesity by a total fast regimen. Metabolism. 1966;15:383–93.

    CAS  PubMed  Google Scholar 

  34. 34.

    Wadden TA, Stunkard AJ, Brownell KD, Van Itallie TB. The Cambridge diet. More mayhem? JAMA. 1983;250:2833–4.

    CAS  PubMed  Google Scholar 

  35. 35.

    Cahill GF Jr, Veech RL. Ketoacids? Good medicine? Trans Am Clin Climatol Assoc. 2003;114:149–61.

    PubMed  PubMed Central  Google Scholar 

  36. 36.

    Cahill GF Jr. Fuel metabolism in starvation. Annu Rev Nutr. 2006;26:1–22.

    CAS  PubMed  Google Scholar 

  37. 37.

    Longo VD, Mattson MP. Fasting: molecular mechanisms and clinical applications. Cell Metab. 2014;19:181–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Bistrian BR, Cochran D, Naylor J. Prevalence of malnutrition in general medical patients. JAMA. 1976;235:1567–70.

    CAS  PubMed  Google Scholar 

  39. 39.

    Bistrian BR, Sherman M, Blackburn GL, Marshall R, Shaw G. Cellular immunity in adult marasmus. Arch Intern Med. 1977;137:1408–11.

    CAS  PubMed  Google Scholar 

  40. 40.

    Bistrian BR, George DT, Blackburn GL, Wannemacher RW. The metabolic response to yellow fever immunization: protein-sparing modified fast. Am J Clin Nutr. 1981;34:229–37.

    CAS  PubMed  Google Scholar 

  41. 41.

    Thomas DD, Istfan NW, Bistrian BR, Apovian CM. Protein sparing therapies in acute illness and obesity: a review of George Blackburn’s contributions to nutrition science. Metabolism. 2018;79:83–96.

    CAS  PubMed  Google Scholar 

  42. 42.

    Blackburn GL. Medicalizing obesity: individual, economic, and medical consequences. Virtual Mentor. 2011;13:890–5.

    PubMed  Google Scholar 

  43. 43.

    Benoit FL, Martin RL, Watten RH. Changes in body composition during weight reduction in obesity: balance studies comparing effects of fasting and a ketogenic diet. Ann Intern Med. 1965;63:604–12.

    CAS  PubMed  Google Scholar 

  44. 44.

    Van Gaal LF, Snyders D, De Leeuw IH, Bekaert JL. Anthropometric and calorimetric evidence for the protein sparing effects of a new protein supplemented low calorie preparation. Am J Clin Nutr. 1985;41:540–4.

    PubMed  Google Scholar 

  45. 45.

    Apfelbaum M. The effects of very restrictive high protein diets. Clin Endocrinol Metab. 1976;5:417–30.

    CAS  PubMed  Google Scholar 

  46. 46.

    Bistrian BR. Clinical use of a protein-sparing modified fast. JAMA. 1978;240:2299–302.

    CAS  PubMed  Google Scholar 

  47. 47.

    Hu FB. Calorie restriction in an obesogenic environment: reality or fiction? Lancet Diabetes Endocrinol. 2019;7:658–9.

    PubMed  Google Scholar 

  48. 48.

    Pellegrini M, Cioffi I, Evangelista A, Ponzo V, Goitre I, Ciccone G, et al. Effects of time-restricted feeding on body weight and metabolism. A systematic review and meta-analysis. Rev Endocr Metab Disord. 2020; https://doi.org/10.1007/s11154-019-09524-w.

  49. 49.

    Gomez-Arbelaez D, Crujeiras AB, Castro AI, Martinez-Olmos MA, Canton A, Ordoñez-Mayan L, et al. Resting metabolic rate of obese patients under very low calorie ketogenic diet. Nutr Metab (Lond). 2018;15:18.

    PubMed  PubMed Central  Google Scholar 

  50. 50.

    Gibson AA, Seimon RV, Lee CM, Ayre J, Franklin J, Markovic TP, et al. Do ketogenic diets really suppress appetite? A systematic review and meta-analysis. Obes Rev. 2015;16:64–76.

    CAS  PubMed  Google Scholar 

  51. 51.

    Nackers LM, Ross KM, Perri MG. The association between rate of initial weight loss and long-term success in obesity treatment: does slow and steady win the race? Int J Behav Med. 2010;17:161–7.

    PubMed  PubMed Central  Google Scholar 

  52. 52.

    Caprio M, Infante M, Moriconi E, Armani A, Fabbri A, Mantovani G, et al. Very-low-calorie ketogenic diet (VLCKD) in the management of metabolic diseases: systematic review and consensus statement from the Italian Society of Endocrinology (SIE). J Endocrinol Investig. 2019;42:1365–86.

    CAS  Google Scholar 

  53. 53.

    Li Z, Hong K, Wong E, Maxwell M, Heber D. Weight cycling in a very low-calorie diet programme has no effect on weight loss velocity, blood pressure and serum lipid profile. Diabetes Obes Metab. 2007;9:379–85.

    CAS  PubMed  Google Scholar 

  54. 54.

    Prentice AM, Jebb SA, Goldberg GR, Coward WA, Murgatroyd PR, Poppitt SD, Cole TJ. Effects of weight cycling on body composition. Am J Clin Nutr. 1992;56:209S–16S.

    CAS  PubMed  Google Scholar 

  55. 55.

    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;54:681–90.

    CAS  PubMed  Google Scholar 

  56. 56.

    Castellana M, Conte E, Cignarelli A, Perrini S, Giustina A, Giovanella L, Giorgino F, Trimboli P. Efficacy and safety of very low calorie ketogenic diet (VLCKD) in patients with overweight and obesity: a systematic review and meta-analysis. Rev Endocr Metab Disord. 2019;21:5–16. https://doi.org/10.1007/s11154-019-09514-y.

    CAS  Article  Google Scholar 

  57. 57.

    Dulloo AG, Jacquet J, Miles-Chan JL, Schutz Y. Passive and active roles of fat-free mass in the control of energy intake and body composition regulation. Eur J Clin Nutr. 2017;71:353–7.

    CAS  PubMed  Google Scholar 

  58. 58.

    Linge J, Heymsfiel SB, Dahlqvist Leinhard O. On the definition of sarcopenia in the presence of aging and obesity-initial results from UK biobank. J Gerontol A Biol Sci Med Sci. 2019.

  59. 59.

    Lopez-Jaramillo P, Cohen DD, Gomez-Arbelaez D, Bosch J, Dyal L, Yusuf S, et al. Association of handgrip strength to cardiovascular mortality in prediabetic and diabetic patients: a subanalysis of the ORIGIN trial. Int J Cardiol. 2014;174:458–61.

    PubMed  Google Scholar 

  60. 60.

    Crujeiras AB, Cabia B, Carreira MC, Amil M, Cueva J, Andrade S, et al. Secreted factors derived from obese visceral adipose tissue regulate the expression of breast malignant transformation genes. Int J Obes (Lond). 2016;40:514–23.

    CAS  Google Scholar 

  61. 61.

    Lee MJ, Wu Y, Fried SK. Adipose tissue heterogeneity: implication of depot differences in adipose tissue for obesity complications. Mol Asp Med. 2013;34:1–11.

    CAS  Google Scholar 

  62. 62.

    Gomez-Arbelaez D, Bellido D, Castro AI, Ordoñez-Mayan L, Carreira J, Galban C, Martinez-Olmos MA, Crujeiras AB, Sajoux I, Casanueva FF. Body composition changes after very-low-calorie ketogenic diet in obesity evaluated by 3 standardized methos. J Clin Endocrinol Metab. 2017;102:488–98.

    PubMed  Google Scholar 

  63. 63.

    Kaul S, Rotheney MP, Peters DM, Wacker WK, Davis CE, Shapiro MD, et al. Dual-energy X-ray absorptiometry for quantification of visceral fat. Obesity. 2012;20:1313–8.

    PubMed  Google Scholar 

  64. 64.

    Micklesfield LK, Goedecke JH, Punyaritya M, Wilson KE, Kelly TL. Dual-energy X-ray performs as well as clinical computed tomography for the measurement of visceral fat. Obesity. 2012;20:1109–14.

    PubMed  Google Scholar 

  65. 65.

    Fields DA, Goran MI, McCrory MA. Body-composition assessment via air-displacement plethysmography in adults and children: a review. Am J Clin Nutr. 2002;75:453–67.

    CAS  PubMed  Google Scholar 

  66. 66.

    Le Carvennec M, Fagour C, Adenis-Lamarre E, Perlemoine C, Gin H, Rigalleau V. Body composition of obese subjects by air displacement plethysmography: the influence of hydration. Obesity. 2007;15:78–84.

    PubMed  Google Scholar 

  67. 67.

    Buchholz AC, Bartok C, Schoeller DA. The validity of bioelectrical impedance models in clinical populations. Nutr Clin Pract. 2004;19:433–46.

    PubMed  Google Scholar 

  68. 68.

    Ward LC. Bioelectrical impedance validation studies: alternative approaches to their interpretation. Eur J Clin Nutr. 2013;67(Suppl.1):S10–3.

    PubMed  Google Scholar 

  69. 69.

    Ogawa H, Fujitani K, Tsujinaka T, Imanishi K, Shirakata H, Kantani A, et al. In body 720 as a new method of evaluating visceral obesity. Hepatogastroenterology. 2011;58:42–4.

    PubMed  Google Scholar 

  70. 70.

    Siri WE. Body composition from fluid spaces and density: analysis of methods. Nutrition. 1961;9:480–91.

    Google Scholar 

  71. 71.

    Cava E, Yeat NC, Mittendorfer B. Preserving healthy muscle during weight loss. Adv Nutr. 2017;8:511–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72.

    Kyle UG, Bosaeus I, De Lorenzo AD, Deurenberg P, Elia M, Gómez JM, Heitmann BL, Kent-smith L, Melchior JC, Pirlich M, Scharfetter H, Schols AM, Pichard C. Composition of the ESPEN working group. Bioelectrical impedance analysis – part I: review of principles and methods. Clin Nutr. 2004;23:1226–43.

    PubMed  Google Scholar 

  73. 73.

    Arab A, Mehrabani S, Moradi S, Amani R. The association between diet and mood: a systematic review of current literature. Psychiatry Res. 2019;271:428–37.

    PubMed  Google Scholar 

  74. 74.

    Teixeira PJ, Carraca EV, Marques MM, Rutter H, Oppert JM, De Bourdeaudhuij I, et al. Successful behavior change in obesity interventions in adults: a systematic review of self-regulation mediators. BMC Med. 2015;13:84.

    PubMed  PubMed Central  Google Scholar 

  75. 75.

    Castro AI, Gomez-Arbelaez D, Crujeiras AB, Granero R, Aguera Z, Jimenez-Murcia S, et al. Effect of a very low-calorie ketogenic diet on food and alcohol cravings, physical and sexual activity, sleep disturbances, and quality of life in obese patients. Nutrients. 2018;10:1–19.

    Google Scholar 

  76. 76.

    Deemer SE, Plaisance EP, Martins C. Impact of ketosis on appetite regulation – a review. Nutr Res. 2020; In press.

  77. 77.

    Rosenbaum M, Hirsch J, Gallagher DA, Leibel RL. Long-term persistence of adaptive thermogenesis in subjects who have maintained a reduced body weight. Am J Clin Nutr. 2008;88:906–12.

    CAS  PubMed  Google Scholar 

  78. 78.

    Rosenbaum M, Leibel RL. Adaptive thermogenesis in humans. In J Obes. 2010;34(Suppl 1):S47–55.

    Google Scholar 

  79. 79.

    Galgani JE, Santos JL. Insights about weight loss-induced metabolic adaptation. Obesity. 2016;24:277–8.

    PubMed  Google Scholar 

  80. 80.

    Muller MJ, Bosy-Westphal A. Adaptive thermogenesis with weight loss in humans. Obesity. 2013;21:218–28.

    CAS  PubMed  Google Scholar 

  81. 81.

    Muscogiuri G, Barrea L, Laudisio D, Pugliese G, Salzano C, Savastano S, Colao A. The management of very low-calorie ketogenic diet in obesity outpatient clinic: a practical guide. J Transl Med. 2019;17(1):356.

    PubMed  PubMed Central  Google Scholar 

  82. 82.

    Directorate-General Health and Consumer Protection. Reports on tasks for scientific cooperation report of experts participating in Task 7.3. 2002. http://www.foodedsoc.org/scoop.pdf. Accessed: 01 July 2020.

  83. 83.

    Golbidi S, Daiber A, Korac B, Li H, Essop MF, Laher I. Health benefits of fasting and caloric restriction. Curr Diab Rep. 2017;17:1–11.

    CAS  Google Scholar 

  84. 84.

    Persynaki A, Karras S, Pichard C. Unraveling the metabolic health benefits of fasting related to religious beliefs: a narrative review. Nutrition. 2017;35:14–20.

    PubMed  Google Scholar 

  85. 85.

    Gomez-Arbelaez D, Crujeiras AB, Castro AI, Goday A, Mas-Lorenzo A, Bellon A, Tejera C, Bellido D, Galban C, Sajoux I, Lopez-Jaramillo P, Casanueva FF. Acid-base safety during the course of a very-low-calorie-Ketogenic diet. Endocrine. 2017;58:81–90.

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86.

    Yancy WS, Olsen MK, Dudley T, Westman EC. Acid-base analysis of individuals following two weight loss diets. Eur J Clin Nutr. 2007;61:1416–22.

    CAS  PubMed  Google Scholar 

  87. 87.

    Wing RR. Use of very-low-calorie diet in obese patients with non-insulin dependent diabetes mellitus. J Am Diet Assoc. 1995;95:569–72.

    CAS  PubMed  Google Scholar 

  88. 88.

    Genuth SM, Castro JH, Vertes V. Weight reduction in obesity by outpatient semistarvation. JAMA. 1974;230:987–91.

    CAS  PubMed  Google Scholar 

  89. 89.

    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.

    CAS  PubMed  Google Scholar 

  90. 90.

    Wing RR, Marcus MD, Salata R. Effects of a very-low-calorie diet on long-term glycemic control in obese type 2 diabetic subjects. Ann Intern Med. 1991;115:76.

    Google Scholar 

  91. 91.

    Wing RR, Blair E, Marcus M, Epstein L, Harvey J. Year-long weight loss treatment for obese patients with type 2 diabetes: does including and intermittent very-low calorie diet improve outcome? Am J Med. 1994;97:354–62.

    CAS  PubMed  Google Scholar 

  92. 92.

    Hughes TA, Gwynne JT, Switzer BR, Herbst C, White G. Effects of caloric restriction and weight loss on glycemic control, insulin release and resistance, and atherosclerotic risk in obese patients with type 2 diabetes mellitus. Am J Med. 1984;77:7–17.

    CAS  PubMed  Google Scholar 

  93. 93.

    Goday A, Bellido D, Sajoux I, Crujeiras AB, Burguera B, García-Luna PP, Oleaga A, Moreno B, Casanueva FF. Short-term safety, tolerability and efficacy of a very low-calorie-ketogenic diet interventional weight loss program versus hypocaloric diet in patients with type 2 diabetes mellitus. Nutr Diabetes. 2016;6:e230.

    CAS  PubMed  PubMed Central  Google Scholar 

  94. 94.

    Romano L, Marchetti M, Gualtieri P, Di Renzo L, Belcastro M, De Santis GL, Perrone MA, De Lorenzo A. Effects of a personalized VLCKD on body composition and resting energy expenditure in the reversal of diabetes to prevent complications. Nutrients. 2019;11(7):1526.

    CAS  PubMed Central  Google Scholar 

  95. 95.

    Lim EL, Hollingsworth KG, Aribisala BS, Chen MJ, Mathers JC, Taylor R. Reversal of type 2 diabetes: normalisation of beta cell function in association with decreased pancreas and liver triacylglycerol. Diabetologia. 2011;54:2506–14.

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 96.

    Steven S, Hollingsworth KG, Al-Mrabeh A, Avery L, Aribisala B, Caslake M, Taylor R. Very low-calorie diet and 6 months of weight stability in type 2 diabetes: pathophysiological changes in responders and nonresponders. Diabetes Care. 2016;39(5):808–15.

    CAS  PubMed  Google Scholar 

  97. 97.

    Pilone V, Tramontano S, Renzulli M, Romano M, Cobellis L, Berselli T, Schiavo L. Metabolic effects, safety, and acceptability of very low-calorie ketogenic dietetic scheme on candidates for bariatric surgery. Surg Obes Relat Dis. 2018;14:1013–9.

    PubMed  Google Scholar 

  98. 98.

    Baker ST, Jerums G, Prendergast LA, Panagiotopoulos S, Strauss BJ, Proietto J. Less fat reduction per unit weight loss in type 2 diabetic compared with nondiabetic obese individuals completing a very-low-calorie diet program. Metabolism. 2012;61(6):873–82.

    CAS  PubMed  Google Scholar 

  99. 99.

    American Diabetes Association. Facilitating behavior change and well-being to improve health outcomes: standards of medical care in diabetes-2020. Diabetes Care. 2020;43:S48–65.

    Google Scholar 

  100. 100.

    Società Italiana di Obesità e Associazione Italiana di Dietetica e Nutrizione Clinica. Standard italiani per la cura dell’obesità SIO-ADI 2016–2017. 2016. http://www.sio-obesita.org/wp-content/uploads/2017/09/STANDARD-OBESITA-SIO-ADI.pdf. Accessed 28 February 2020.

  101. 101.

    Garvey WT, Mechanick JI, Brett EM, Garber AJ, Hurley DL, Jastreboff AM, Nadolsky K, Pessah-Pollack R, Plodkowski R, Reviewers of the AACE/ACE Obesity Clinical Practice Guidelines. Reviewers of the AACE/ACE obesity clinical practice guidelines. American Association of Clinical Endocrinologists and American College of endocrinology comprehensive clinical practice guidelines for medical care of patients with obesity. Endocr Pract. 2016;22:1–203.

    PubMed  Google Scholar 

  102. 102.

    Durrer Schutz D, Busetto L, Dicker D, Farpour-Lambert N, Pryke R, Toplak H, Widmer D, Yumuk V, Schutz Y. European practical and patient-centred guidelines for adult obesity management in primary care. Obes Facts. 2019;12:40–66.

    PubMed  PubMed Central  Google Scholar 

  103. 103.

    Stegenga H, Haines A, Jones K, Wilding J. Guideline Development Group. Identification, assessment, and management of overweight and obesity: summary of updated NICE guidance. BMJ. 2014;349:g6608.

    PubMed  Google Scholar 

  104. 104.

    Gonzalez-Campoy JM, St Jeor ST, Castorino K, Ebrahim A, Hurley D, Jovanovic L, et al. Clinical practice guidelines for healthy eating for the prevention and treatment of metabolic and endocrine diseases in adults: cosponsored by the American Association of Clinical Endocrinologists/the American College of Endocrinology and the Obesity Society. Endocr Pract. 2013;19:1–82.

    PubMed  Google Scholar 

  105. 105.

    Yumuk V, Tsigos C, Fried M, Schindler K, Busetto L, Micic D, Toplak H, Obesity Management Task Force of the European Association for the Study of Obesity. European guidelines for obesity management in adults. Obes Facts. 2015;8:402–24.

    PubMed  PubMed Central  Google Scholar 

  106. 106.

    Albanese A, Prevedello L, Markovich M, Busetto L, Vettor R, Foletto M. Pre-operative very low calorie ketogenic diet (VLCKD) vs. very low calorie diet (VLCD): surgical impact. Obes Surg. 2019;29:292–6.

    PubMed  Google Scholar 

  107. 107.

    Leonetti F, Campanile FC, Coccia F, Capoccia D, Alessandroni L, Puzziello A, Coluzzi I, Silecchia G. Very low-carbohydrate ketogenic diet before bariatric surgery: prospective evaluation of a sequential diet. Obes Surg. 2015;25:64–71.

    PubMed  Google Scholar 

  108. 108.

    The International Federation for the Surgery of Obesity and Metabolic Disorders. Fourth IFSO Global Registry Report 2018. 2018. https://www.ifso.com/pdf/4th-ifso-global-registry-report-last-2018.pdf. Accessed 28 February 2020.

  109. 109.

    World Health Organization. Obesity and overweight. 2018. https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight. Accessed 28 February 2020.

  110. 110.

    Bruci A, Tuccinardi D, Tozzi R, Balena A, Santucci S, Frontani R, Mariani S, Basciani S, Spera G, Gnessi L, Lubrano C, Watanabe M. Very low-calorie Ketogenic diet: a safe and effective tool for weight loss in patients with obesity and mild kidney failure. Nutrients. 2020;12:E333.

    PubMed  Google Scholar 

  111. 111.

    Joshi S, Ostfeld RJ, McMacken M. The ketogenic diet for obesity and diabetes-enthusiasm outpaces evidence. JAMA Intern Med. 2019;179:1163. https://doi.org/10.1001/jamainternmed.2019.2633.

    Article  Google Scholar 

  112. 112.

    Stubbs BJ, Newman JC. Ketogenic diet and adipose tissue inflammation – a simple story? Fat chance! Nat Metab. 2020;2:3–4.

    PubMed  Google Scholar 

  113. 113.

    Trimboli P, Castellana M, Bellido D, Casanueva FF. Confusion in the nomenclature of ketogenic diets blurs evidence. Rev Endocr Metab Disord. 2020;21:1–3. https://doi.org/10.1007/s11154-020-09546-9.

    Article  PubMed  Google Scholar 

  114. 114.

    Cahill GF Jr. Tans Am Clin Climatol Assoc. 2003;45:1751–69.

    Google Scholar 

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Correspondence to Felipe F. Casanueva.

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FFC, DB, AIC and ABC received research grants and conference fees from Pronokal Spain. IS is currently Medical Director of Pronokal Spain. PT, MC, GRC, DGA and MAMO declare no conflict of interest.

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Casanueva, F.F., Castellana, M., Bellido, D. et al. Ketogenic diets as treatment of obesity and type 2 diabetes mellitus. Rev Endocr Metab Disord 21, 381–397 (2020). https://doi.org/10.1007/s11154-020-09580-7

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Keywords

  • Ketogenic diet
  • Very-low-calorie ketogenic diet
  • VLCKD
  • Obesity
  • Type 2 diabetes