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Very-low-calorie ketogenic diet (VLCKD) in the management of metabolic diseases: systematic review and consensus statement from the Italian Society of Endocrinology (SIE)

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Abstract

Background

Weight loss is a milestone in the prevention of chronic diseases associated with high morbility and mortality in industrialized countries. Very-low calorie ketogenic diets (VLCKDs) are increasingly used in clinical practice for weight loss and management of obesity-related comorbidities. Despite evidence on the clinical benefits of VLCKDs is rapidly emerging, some concern still exists about their potential risks and their use in the long-term, due to paucity of clinical studies. Notably, there is an important lack of guidelines on this topic, and the use and implementation of VLCKDs occurs vastly in the absence of clear evidence-based indications.

Purpose

We describe here the biochemistry, benefits and risks of VLCKDs, and provide recommendations on the correct use of this therapeutic approach for weight loss and management of metabolic diseases at different stages of life.

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References

  1. Ng M, Fleming T, Robinson M, Thomson B, Graetz N, Margono C et al (2014) Global, regional, and national prevalence of overweight and obesity in children and adults during 1980–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 384(9945):766–781

    Article  PubMed  PubMed Central  Google Scholar 

  2. Gregg EW, Shaw JE (2017) Global health effects of overweight and obesity. N Engl J Med 377(1):80–81

    Article  PubMed  Google Scholar 

  3. (NCD-RisC) NRFC (2016) Worldwide trends in diabetes since 1980: a pooled analysis of 751 population-based studies with 4.4 million participants. Lancet. 387(10027):1513–1530

    Article  Google Scholar 

  4. Hruby A, Hu FB (2015) The epidemiology of obesity: a big picture. Pharmacoeconomics 33(7):673–689

    Article  PubMed  PubMed Central  Google Scholar 

  5. Verhaegen AA, Van Gaal LF (2017) Drug-induced obesity and its metabolic consequences: a review with a focus on mechanisms and possible therapeutic options. J Endocrinol Invest 40(11):1165–1174

    Article  CAS  PubMed  Google Scholar 

  6. Piaggi P, Vinales KL, Basolo A, Santini F, Krakoff J (2018) Energy expenditure in the etiology of human obesity: spendthrift and thrifty metabolic phenotypes and energy-sensing mechanisms. J Endocrinol Invest 41(1):83–89

    Article  CAS  PubMed  Google Scholar 

  7. Dehghan M, Mente A, Zhang X, Swaminathan S, Li W, Mohan V et al (2017) Associations of fats and carbohydrate intake with cardiovascular disease and mortality in 18 countries from five continents (PURE): a prospective cohort study. Lancet 390(10107):2050–2062

    Article  CAS  PubMed  Google Scholar 

  8. Ramsden CE, Domenichiello AF (2017) PURE study challenges the definition of a healthy diet: but key questions remain. Lancet 390(10107):2018–2019

    Article  PubMed  Google Scholar 

  9. (NCD-RisC) NRFC (2016) 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. 387(10026):1377–1396

    Article  Google Scholar 

  10. Scherer PE, Hill JA (2016) Obesity, diabetes, and cardiovascular diseases: a compendium. Circ Res 118(11):1703–1705

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Saklayen MG (2018) The global epidemic of the metabolic syndrome. Curr Hypertens Rep 20(2):12

    Article  PubMed  PubMed Central  Google Scholar 

  12. Jensen MD, Ryan DH, Apovian CM, Ard JD, Comuzzie AG, Donato KA et al (2014) 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. J Am Coll Cardiol. 63(25 Pt B):2985–3023

    Article  PubMed  Google Scholar 

  13. Siraj ES, Williams KJ (2015) Another agent for obesity-will this time be different? N Engl J Med 373(1):82–83

    Article  CAS  PubMed  Google Scholar 

  14. Montesi L, El Ghoch M, Brodosi L, Calugi S, Marchesini G, Dalle Grave R (2016) Long-term weight loss maintenance for obesity: a multidisciplinary approach. Diabetes Metab Syndr Obes. 9:37–46

    PubMed  PubMed Central  Google Scholar 

  15. Patel DK, Stanford FC (2018) Safety and tolerability of new-generation anti-obesity medications: a narrative review. Postgrad Med 130(2):173–182

    Article  PubMed  PubMed Central  Google Scholar 

  16. Pories WJ (2008) Bariatric surgery: risks and rewards. J Clin Endocrinol Metab 93(11 Suppl 1):S89–S96

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Abbasi J (2018) Interest in the ketogenic diet grows for weight loss and type 2 diabetes. JAMA 319(3):215–217

    Article  PubMed  Google Scholar 

  18. Merra G, Miranda R, Barrucco S, Gualtieri P, Mazza M, Moriconi E et al (2016) Very-low-calorie ketogenic diet with aminoacid supplement versus very low restricted-calorie diet for preserving muscle mass during weight loss: a pilot double-blind study. Eur Rev Med Pharmacol Sci 20(12):2613–2621

    CAS  PubMed  Google Scholar 

  19. Merra G, Gratteri S, De Lorenzo A, Barrucco S, Perrone MA, Avolio E et al (2017) Effects of very-low-calorie diet on body composition, metabolic state, and genes expression: a randomized double-blind placebo-controlled trial. Eur Rev Med Pharmacol Sci 21(2):329–345

    CAS  PubMed  Google Scholar 

  20. Bueno NB, de Melo IS, de Oliveira SL, da Rocha Ataide T (2013) Very-low-carbohydrate ketogenic diet v. low-fat diet for long-term weight loss: a meta-analysis of randomised controlled trials. Br J Nutr 110(7):1178–1187

    Article  CAS  PubMed  Google Scholar 

  21. Westman EC, Yancy WS, Mavropoulos JC, Marquart M, McDuffie JR (2008) 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) 5:36

    Article  CAS  Google Scholar 

  22. Hussain TA, Mathew TC, Dashti AA, Asfar S, Al-Zaid N, Dashti HM (2012) Effect of low-calorie versus low-carbohydrate ketogenic diet in type 2 diabetes. Nutrition 28(10):1016–1021

    Article  CAS  PubMed  Google Scholar 

  23. Paoli A, Rubini A, Volek JS, Grimaldi KA (2013) Beyond weight loss: a review of the therapeutic uses of very-low-carbohydrate (ketogenic) diets. Eur J Clin Nutr 67(8):789–796

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Cicero AF, Benelli M, Brancaleoni M, Dainelli G, Merlini D, Negri R (2015) 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. 22(4):389–394

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Wilder RM (1921) The effects of ketonemia on the course of epilepsy. Mayo Clin Proc 2:307–308

    Google Scholar 

  26. Nagy R (1974) Dr. Atkins’ diet revolution: a review. Va Med Mon 101(5):383–385

    CAS  PubMed  Google Scholar 

  27. Blackburn GL, Flatt JP, Clowes GH, O’Donnell TF, Hensle TE (1973) Protein sparing therapy during periods of starvation with sepsis of trauma. Ann Surg 177(5):588–594

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Bistrian BR, Blackburn GL, Flatt JP, Sizer J, Scrimshaw NS, Sherman M (1976) Nitrogen metabolism and insulin requirements in obese diabetic adults on a protein-sparing modified fast. Diabetes 25(6):494–504

    Article  CAS  PubMed  Google Scholar 

  29. Bistrian BR (1978) Clinical use of a protein-sparing modified fast. JAMA 240(21):2299–2302

    Article  CAS  PubMed  Google Scholar 

  30. Palgi A, Read JL, Greenberg I, Hoefer MA, Bistrian BR, Blackburn GL (1985) Multidisciplinary treatment of obesity with a protein-sparing modified fast: results in 668 outpatients. Am J Public Health 75(10):1190–1194

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Walters JK, Hoogwerf BJ, Reddy SS (1997) The protein-sparing modified fast for obesity-related medical problems. Cleve Clin J Med 64(5):242–244

    Article  CAS  PubMed  Google Scholar 

  32. Pezzana A, Amerio ML, Fatati G, Caregaro Negrin L, Muratori F, Rovera GM et al (2014) La dieta chetogenica—fondazione ADI: position Paper. ADI 6:38–43

    Google Scholar 

  33. Italian Standards for Treatment of Obesity, released by the Italian Society for the Study of Obesity (SIO) and the Italian Association of Dietetics and Clinical Nutrition (ADI) (2016–2017)

  34. Paoli A (2014) Ketogenic diet for obesity: friend or foe? Int J Environ Res Public Health 11(2):2092–2107

    Article  PubMed  PubMed Central  Google Scholar 

  35. Antonio J, Ellerbroek A, Silver T, Vargas L, Tamayo A, Buehn R et al (2016) A high protein diet has no harmful effects: a one-year crossover study in resistance-trained males. J Nutr Metab 2016:9104792

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Bakhach M, Shah V, Harwood T, Lappe S, Bhesania N, Mansoor S et al (2016) The protein-sparing modified fast diet: an effective and safe approach to induce rapid weight loss in severely obese adolescents. Glob Pediatr Health. 3:2333794X15623245

    PubMed  PubMed Central  Google Scholar 

  37. Atkinson RL, Dietz WH, Foreyt JP, Goodwin NJ, Hill JO, Hirsch J et al (1993) Very low-calorie diets. National task force on the prevention and treatment of obesity. National Institutes of Health. JAMA 270(8):967–974

    Article  Google Scholar 

  38. Paoli A, Bosco G, Camporesi EM, Mangar D (2015) Ketosis, ketogenic diet and food intake control: a complex relationship. Front Psychol 6:27

    Article  PubMed  PubMed Central  Google Scholar 

  39. Swiglo BA, Murad MH, Schünemann HJ, Kunz R, Vigersky RA, Guyatt GH et al (2008) A case for clarity, consistency, and helpfulness: state-of-the-art clinical practice guidelines in endocrinology using the grading of recommendations, assessment, development, and evaluation system. J Clin Endocrinol Metab 93(3):666–673

    Article  CAS  PubMed  Google Scholar 

  40. Fukao T, Lopaschuk GD, Mitchell GA (2004) Pathways and control of ketone body metabolism: on the fringe of lipid biochemistry. Prostaglandins Leukot Essent Fatty Acids 70(3):243–251

    Article  CAS  PubMed  Google Scholar 

  41. Grabacka M, Pierzchalska M, Dean M, Reiss K (2016) Regulation of ketone body metabolism and the role of PPARα. Int J Mol Sci 17(12):2093

    Article  PubMed Central  CAS  Google Scholar 

  42. Mitchell GA, Kassovska-Bratinova S, Boukaftane Y, Robert MF, Wang SP, Ashmarina L et al (1995) Medical aspects of ketone body metabolism. Clin Invest Med 18(3):193–216

    CAS  PubMed  Google Scholar 

  43. Laffel L (1999) Ketone bodies: a review of physiology, pathophysiology and application of monitoring to diabetes. Diabetes Metab Res Rev. 15(6):412–426

    Article  CAS  PubMed  Google Scholar 

  44. McPherson PA, McEneny J (2012) The biochemistry of ketogenesis and its role in weight management, neurological disease and oxidative stress. J Physiol Biochem. 68(1):141–151

    Article  CAS  PubMed  Google Scholar 

  45. Garber AJ, Menzel PH, Boden G, Owen OE (1974) Hepatic ketogenesis and gluconeogenesis in humans. J Clin Invest 54(4):981–989

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Newman JC, Verdin E (2014) Ketone bodies as signaling metabolites. Trends Endocrinol Metab 25(1):42–52

    Article  CAS  PubMed  Google Scholar 

  47. Wolfrum C, Besser D, Luca E, Stoffel M (2003) Insulin regulates the activity of forkhead transcription factor Hnf-3beta/Foxa-2 by Akt-mediated phosphorylation and nuclear/cytosolic localization. Proc Natl Acad Sci USA 100(20):11624–11629

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. von Meyenn F, Porstmann T, Gasser E, Selevsek N, Schmidt A, Aebersold R et al (2013) Glucagon-induced acetylation of Foxa2 regulates hepatic lipid metabolism. Cell Metab 17(3):436–447

    Article  CAS  Google Scholar 

  49. Krebs HA (1966) The regulation of the release of ketone bodies by the liver. Adv Enzyme Regul 4:339–354

    Article  CAS  PubMed  Google Scholar 

  50. Veldhorst MA, Westerterp-Plantenga MS, Westerterp KR (2009) Gluconeogenesis and energy expenditure after a high-protein, carbohydrate-free diet. Am J Clin Nutr 90(3):519–526

    Article  CAS  PubMed  Google Scholar 

  51. McDonald L (1998) The basics of fuel utilization. In: The Ketogenic diet: a complete guide for the dieter and practitioner, Chapter 3, 1st edn. Morris Publishing, pp 18–27. ISBN: 0967145600

  52. Urbain P, Bertz H (2016) Monitoring for compliance with a ketogenic diet: what is the best time of day to test for urinary ketosis? Nutr Metab (Lond). 13:77

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Handelsman Y, Henry RR, Bloomgarden ZT, Dagogo-Jack S, DeFronzo RA, Einhorn D et al (2016) American association of clinical endocrinologists and American College of endocrinology position statement on the association of sglt-2 inhibitors and diabetic ketoacidosis. Endocr Pract 22(6):753–762

    Article  PubMed  Google Scholar 

  54. Dashti HM, Mathew TC, Hussein T, Asfar SK, Behbahani A, Khoursheed MA et al (2004) Long-term effects of a ketogenic diet in obese patients. Exp Clin Cardiol 9(3):200–205

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Dashti HM, Mathew TC, Khadada M, Al-Mousawi M, Talib H, Asfar SK et al (2007) Beneficial effects of ketogenic diet in obese diabetic subjects. Mol Cell Biochem 302(1–2):249–256

    Article  CAS  PubMed  Google Scholar 

  56. Ryan DH (2016) Guidelines for Obesity Management. Endocrinol Metab Clin N Am 45(3):501–510

    Article  Google Scholar 

  57. Stegenga H, Haines A, Jones K, Wilding J, Group GD (2014) Identification, assessment, and management of overweight and obesity: summary of updated NICE guidance. BMJ. 349:g6608

    Article  PubMed  Google Scholar 

  58. Raynor HA, Champagne CM (2016) Position of the academy of nutrition and dietetics: interventions for the treatment of overweight and obesity in adults. J Acad Nutr Diet 116(1):129–147

    Article  PubMed  Google Scholar 

  59. Gibson AA, Seimon RV, Lee CM, Ayre J, Franklin J, Markovic TP et al (2015) Do ketogenic diets really suppress appetite? A systematic review and meta-analysis. Obes Rev 16(1):64–76

    Article  CAS  PubMed  Google Scholar 

  60. Pilone V, Tramontano S, Renzulli M, Romano M, Cobellis L, Berselli T et al (2018) Metabolic effects, safety, and acceptability of very low-calorie ketogenic dietetic scheme on candidates for bariatric surgery. Surg Obes Relat Dis. 14(7):1013–1019

    Article  PubMed  Google Scholar 

  61. Gershuni VM, Yan SL, Medici V (2018) Nutritional Ketosis for Weight Management and Reversal of Metabolic Syndrome. Curr Nutr Rep. 7(3):97–106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Bhanpuri NH, Hallberg SJ, Williams PT, McKenzie AL, Ballard KD, Campbell WW et al (2018) 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 17(1):56

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  64. Gomez-Arbelaez D, Bellido D, Castro AI, Ordoñez-Mayan L, Carreira J, Galban C et al (2017) Body composition changes after very-low-calorie ketogenic diet in obesity evaluated by 3 standardized methods. J Clin Endocrinol Metab 102(2):488–498

    Article  PubMed  Google Scholar 

  65. Temmerman JC, Friedman AN (2013) Very low calorie ketogenic weight reduction diet in patients with cirrhosis: a case series. Nutr Diabetes. 3:e95

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Sumithran P, Proietto J (2008) Safe year-long use of a very-low-calorie diet for the treatment of severe obesity. Med J Aust 188(6):366–368

    Article  PubMed  Google Scholar 

  67. Parretti HM, Jebb SA, Johns DJ, Lewis AL, Christian-Brown AM, Aveyard P (2016) Clinical effectiveness of very-low-energy diets in the management of weight loss: a systematic review and meta-analysis of randomized controlled trials. Obes Rev 17(3):225–234

    Article  CAS  PubMed  Google Scholar 

  68. Chang JJ, Bena J, Kannan S, Kim J, Burguera B, Kashyap SR (2017) Limited carbohydrate refeeding instruction for long-term weight maintenance following a ketogenic, very-low-calorie meal plan. Endocr Pract. 23(6):649–656

    Article  PubMed  Google Scholar 

  69. Paoli A, Bianco A, Grimaldi KA, Lodi A, Bosco G (2013) Long term successful weight loss with a combination biphasic ketogenic Mediterranean diet and Mediterranean diet maintenance protocol. Nutrients 5(12):5205–5217

    Article  PubMed  PubMed Central  Google Scholar 

  70. Parrott J, Frank L, Rabena R, Craggs-Dino L, Isom KA, Greiman L (2017) American society for metabolic and bariatric surgery integrated health nutritional guidelines for the surgical weight loss patient 2016 update: micronutrients. Surg Obes Relat Dis 13(5):727–741

    Article  PubMed  Google Scholar 

  71. Mechanick JI, Youdim A, Jones DB, Timothy Garvey W, Hurley DL, Molly McMahon M et al (2013) Clinical practice guidelines for the perioperative nutritional, metabolic, and nonsurgical support of the bariatric surgery patient—2013 update: cosponsored by American Association of Clinical Endocrinologists, the Obesity Society, and American Society for Metabolic & Bariatric Surgery. Surg Obes Relat Dis 9(2):159–191

    Article  PubMed  Google Scholar 

  72. Naseer F, Shabbir A, Livingstone B, Price R, Syn NL, Flannery O (2018) The efficacy of energy-restricted diets in achieving preoperative weight loss for bariatric patients: a systematic review. Obes Surg 28(11):3678–3690

    Article  PubMed  Google Scholar 

  73. Schiavo L, Scalera G, Sergio R, De Sena G, Pilone V, Barbarisi A (2015) Clinical impact of Mediterranean-enriched-protein diet on liver size, visceral fat, fat mass, and fat-free mass in patients undergoing sleeve gastrectomy. Surg Obes Relat Dis 11(5):1164–1170

    Article  PubMed  Google Scholar 

  74. Ross LJ, Wallin S, Osland EJ, Memon MA (2016) Commercial very low energy meal replacements for preoperative weight loss in obese patients: a systematic review. Obes Surg 26(6):1343–1351

    Article  PubMed  Google Scholar 

  75. Leonetti F, Campanile FC, Coccia F, Capoccia D, Alessandroni L, Puzziello A et al (2015) Very low-carbohydrate ketogenic diet before bariatric surgery: prospective evaluation of a sequential diet. Obes Surg 25(1):64–71

    Article  PubMed  Google Scholar 

  76. Albanese A, Prevedello L, Markovich M, Busetto L, Vettor R, Foletto M (2018) Pre-operative very low calorie ketogenic diet (VLCKD) vs. very low calorie diet (VLCD): surgical impact. Obes Surg. 29:292–296

    Article  Google Scholar 

  77. Schiavo L, Pilone V, Rossetti G, Barbarisi A, Cesaretti M, Iannelli A (2018) A 4-week preoperative ketogenic micronutrient-enriched diet is effective in reducing body weight, left hepatic lobe volume, and Micronutrient deficiencies in patients undergoing bariatric surgery: a prospective pilot study. Obes Surg 28(8):2215–2224

    Article  PubMed  Google Scholar 

  78. Colles SL, Dixon JB, Marks P, Strauss BJ, O’Brien PE (2006) Preoperative weight loss with a very-low-energy diet: quantitation of changes in liver and abdominal fat by serial imaging. Am J Clin Nutr 84(2):304–311

    Article  CAS  PubMed  Google Scholar 

  79. Bertoli S, Trentani C, Ferraris C, De Giorgis V, Veggiotti P, Tagliabue A (2014) Long-term effects of a ketogenic diet on body composition and bone mineralization in GLUT-1 deficiency syndrome: a case series. Nutrition 30(6):726–728

    Article  CAS  PubMed  Google Scholar 

  80. Klement RJ, Sweeney RA (2016) Impact of a ketogenic diet intervention during radiotherapy on body composition: I. Initial clinical experience with six prospectively studied patients. BMC Res Notes. 9:143

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. Colica C, Merra G, Gasbarrini A, De Lorenzo A, Cioccoloni G, Gualtieri P et al (2017) Efficacy and safety of very-low-calorie ketogenic diet: a double blind randomized crossover study. Eur Rev Med Pharmacol Sci. 21(9):2274–2289

    CAS  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Tinsley GM, Willoughby DS (2016) Fat-free mass changes during ketogenic diets and the potential role of resistance training. Int J Sport Nutr Exerc Metab 26(1):78–92

    Article  CAS  PubMed  Google Scholar 

  84. Vargas S, Romance R, Petro JL, Bonilla DA, Galancho I, Espinar S et al (2018) Efficacy of ketogenic diet on body composition during resistance training in trained men: a randomized controlled trial. J Int Soc Sports Nutr 15(1):31

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. Carnauba RA, Baptistella AB, Paschoal V, Hübscher GH (2017) Diet-induced low-grade metabolic acidosis and clinical outcomes: a review. Nutrients 9(6):538

    Article  PubMed Central  CAS  Google Scholar 

  86. Yuan FL, Xu MH, Li X, Xinlong H, Fang W, Dong J (2016) The roles of acidosis in osteoclast biology. Front Physiol 7:222

    Article  PubMed  PubMed Central  Google Scholar 

  87. European Food Safety Authority (EFSA) (2015) Scientific Opinion on the essential composition of total diet replacements for weight control. EFSA J 13(1):3957

    Article  CAS  Google Scholar 

  88. Gissel T, Poulsen CS, Vestergaard P (2007) Adverse effects of antiepileptic drugs on bone mineral density in children. Expert Opin Drug Saf 6(3):267–278

    Article  CAS  PubMed  Google Scholar 

  89. Bergqvist AG, Schall JI, Stallings VA, Zemel BS (2008) Progressive bone mineral content loss in children with intractable epilepsy treated with the ketogenic diet. Am J Clin Nutr 88(6):1678–1684

    Article  CAS  PubMed  Google Scholar 

  90. Carter JD, Vasey FB, Valeriano J (2006) The effect of a low-carbohydrate diet on bone turnover. Osteoporos Int 17(9):1398–1403

    Article  CAS  PubMed  Google Scholar 

  91. Barengolts E (2016) Gut microbiota, prebiotics, probiotics, and synbiotics in management of obesity and prediabetes: review of randomized controlled trials. Endocr Pract 22(10):1224–1234

    Article  PubMed  Google Scholar 

  92. David LA, Maurice CF, Carmody RN, Gootenberg DB, Button JE, Wolfe BE et al (2014) Diet rapidly and reproducibly alters the human gut microbiome. Nature 505(7484):559–563

    Article  CAS  PubMed  Google Scholar 

  93. Singh RK, Chang HW, Yan D, Lee KM, Ucmak D, Wong K et al (2017) Influence of diet on the gut microbiome and implications for human health. J Transl Med 15(1):73

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  94. McAllan L, Skuse P, Cotter PD, O’Connor P, Cryan JF, Ross RP et al (2014) Protein quality and the protein to carbohydrate ratio within a high fat diet influences energy balance and the gut microbiota in C57BL/6J mice. PLoS One 9(2):e88904

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  95. Heinsen FA, Fangmann D, Müller N, Schulte DM, Rühlemann MC, Türk K et al (2016) Beneficial effects of a dietary weight loss intervention on human gut microbiome diversity and metabolism are not sustained during weight maintenance. Obes Facts 9(6):379–391

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Olson CA, Vuong HE, Yano JM, Liang QY, Nusbaum DJ, Hsiao EY (2018) The gut microbiota mediates the anti-seizure effects of the ketogenic diet. Cell 173(7):1728-41.e13

    Article  CAS  Google Scholar 

  97. Gu Y, Yu H, Li Y, Ma X, Lu J, Yu W et al (2013) Beneficial effects of an 8-week, very low carbohydrate diet intervention on obese subjects. Evid Based Complement Alternat Med 2013:760804

    PubMed  PubMed Central  Google Scholar 

  98. Svendsen PF, Jensen FK, Holst JJ, Haugaard SB, Nilas L, Madsbad S (2012) The effect of a very low calorie diet on insulin sensitivity, beta cell function, insulin clearance, incretin hormone secretion, androgen levels and body composition in obese young women. Scand J Clin Lab Invest 72(5):410–419

    Article  CAS  PubMed  Google Scholar 

  99. Demol S, Yackobovitch-Gavan M, Shalitin S, Nagelberg N, Gillon-Keren M, Phillip M (2009) Low-carbohydrate (low & high-fat) versus high-carbohydrate low-fat diets in the treatment of obesity in adolescents. Acta Paediatr 98(2):346–351

    Article  CAS  PubMed  Google Scholar 

  100. Kirk S, Brehm B, Saelens BE, Woo JG, Kissel E, D’Alessio D et al (2012) Role of carbohydrate modification in weight management among obese children: a randomized clinical trial. J Pediatr 161(2):320–327.e1

    Article  PubMed Central  CAS  Google Scholar 

  101. Krebs NF, Gao D, Gralla J, Collins JS, Johnson SL (2010) Efficacy and safety of a high protein, low carbohydrate diet for weight loss in severely obese adolescents. J Pediatr 157(2):252–258

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Partsalaki I, Karvela A, Spiliotis BE (2012) Metabolic impact of a ketogenic diet compared to a hypocaloric diet in obese children and adolescents. J Pediatr Endocrinol Metab 25(7–8):697–704

    CAS  PubMed  Google Scholar 

  103. Lim EL, Hollingsworth KG, Aribisala BS, Chen MJ, Mathers JC, Taylor R (2011) Reversal of type 2 diabetes: normalisation of beta cell function in association with decreased pancreas and liver triacylglycerol. Diabetologia 54(10):2506–2514

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Malandrucco I, Pasqualetti P, Giordani I, Manfellotto D, De Marco F, Alegiani F et al (2012) Very-low-calorie diet: a quick therapeutic tool to improve β cell function in morbidly obese patients with type 2 diabetes. Am J Clin Nutr 95(3):609–613

    Article  CAS  PubMed  Google Scholar 

  105. Viljanen AP, Lautamäki R, Järvisalo M, Parkkola R, Huupponen R, Lehtimäki T et al (2009) Effects of weight loss on visceral and abdominal subcutaneous adipose tissue blood-flow and insulin-mediated glucose uptake in healthy obese subjects. Ann Med 41(2):152–160

    Article  CAS  PubMed  Google Scholar 

  106. Steven S, Hollingsworth KG, Al-Mrabeh A, Avery L, Aribisala B, Caslake M et al (2016) Very low-calorie diet and 6 months of weight stability in type 2 diabetes: pathophysiological changes in responders and nonresponders. Diabetes Care 39(5):808–815

    Article  CAS  PubMed  Google Scholar 

  107. Jackness C, Karmally W, Febres G, Conwell IM, Ahmed L, Bessler M et al (2013) Very low-calorie diet mimics the early beneficial effect of Roux-en-Y gastric bypass on insulin sensitivity and β-cell Function in type 2 diabetic patients. Diabetes 62(9):3027–3032

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Goday A, Bellido D, Sajoux I, Crujeiras AB, Burguera B, García-Luna PP et al (2016) 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 6(9):e230

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Rothberg AE, McEwen LN, Kraftson AT, Fowler CE, Herman WH (2014) Very-low-energy diet for type 2 diabetes: an underutilized therapy? J Diabetes Complic 28(4):506–510

    Article  Google Scholar 

  110. Capstick F, Brooks BA, Burns CM, Zilkens RR, Steinbeck KS, Yue DK (1997) Very low calorie diet (VLCD): a useful alternative in the treatment of the obese NIDDM patient. Diabetes Res Clin Pract 36(2):105–111

    Article  CAS  PubMed  Google Scholar 

  111. Baker ST, Jerums G, Prendergast LA, Panagiotopoulos S, Strauss BJ, Proietto J (2012) Less fat reduction per unit weight loss in type 2 diabetic compared with nondiabetic obese individuals completing a very-low-calorie diet program. Metabolism 61(6):873–882

    Article  CAS  PubMed  Google Scholar 

  112. Jazet IM, de Craen AJ, van Schie EM, Meinders AE (2007) Sustained beneficial metabolic effects 18 months after a 30-day very low calorie diet in severely obese, insulin-treated patients with type 2 diabetes. Diabetes Res Clin Pract 77(1):70–76

    Article  PubMed  Google Scholar 

  113. Brehm BJ, Seeley RJ, Daniels SR, D’Alessio DA (2003) 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 88(4):1617–1623

    Article  CAS  PubMed  Google Scholar 

  114. Samaha FF, Iqbal N, Seshadri P, Chicano KL, Daily DA, McGrory J et al (2003) A low-carbohydrate as compared with a low-fat diet in severe obesity. N Engl J Med 348(21):2074–2081

    Article  CAS  PubMed  Google Scholar 

  115. Foster GD, Wyatt HR, Hill JO, McGuckin BG, Brill C, Mohammed BS et al (2003) A randomized trial of a low-carbohydrate diet for obesity. N Engl J Med 348(21):2082–2090

    Article  CAS  PubMed  Google Scholar 

  116. Yancy WS, Olsen MK, Guyton JR, Bakst RP, Westman EC (2004) A low-carbohydrate, ketogenic diet versus a low-fat diet to treat obesity and hyperlipidemia: a randomized, controlled trial. Ann Intern Med 140(10):769–777

    Article  PubMed  Google Scholar 

  117. Stern L, Iqbal N, Seshadri P, Chicano KL, Daily DA, McGrory J et al (2004) The effects of low-carbohydrate versus conventional weight loss diets in severely obese adults: one-year follow-up of a randomized trial. Ann Intern Med 140(10):778–785

    Article  PubMed  Google Scholar 

  118. Dashti HM, Al-Zaid NS, Mathew TC, Al-Mousawi M, Talib H, Asfar SK et al (2006) Long term effects of ketogenic diet in obese subjects with high cholesterol level. Mol Cell Biochem 286(1–2):1–9

    Article  CAS  PubMed  Google Scholar 

  119. Zelber-Sagi S, Ratziu V, Oren R (2011) Nutrition and physical activity in NAFLD: an overview of the epidemiological evidence. World J Gastroenterol 17(29):3377–3389

    Article  PubMed  PubMed Central  Google Scholar 

  120. Petersen KF, Dufour S, Befroy D, Lehrke M, Hendler RE, Shulman GI (2005) Reversal of nonalcoholic hepatic steatosis, hepatic insulin resistance, and hyperglycemia by moderate weight reduction in patients with type 2 diabetes. Diabetes 54(3):603–608

    Article  CAS  PubMed  Google Scholar 

  121. European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD), European Association for the Study of Obesity (EASO) (2016) Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol. 64(6):1388–1402

    Article  Google Scholar 

  122. Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, Torres-Gonzalez A, Gra-Oramas B, Gonzalez-Fabian L et al (2015) Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis. Gastroenterology. 149(2):367–378.e5 (quiz e14-5)

    Article  Google Scholar 

  123. Anania C, Perla FM, Olivero F, Pacifico L, Chiesa C (2018) Mediterranean diet and nonalcoholic fatty liver disease. World J Gastroenterol 24(19):2083–2094

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Chalasani N, Younossi Z, Lavine JE, Charlton M, Cusi K, Rinella M et al (2018) The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases. Hepatology 67(1):328–357

    Article  PubMed  Google Scholar 

  125. Browning JD, Baker JA, Rogers T, Davis J, Satapati S, Burgess SC (2011) Short-term weight loss and hepatic triglyceride reduction: evidence of a metabolic advantage with dietary carbohydrate restriction. Am J Clin Nutr 93(5):1048–1052

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Bian H, Hakkarainen A, Lundbom N, Yki-Järvinen H (2014) Effects of dietary interventions on liver volume in humans. Obesity (Silver Spring). 22(4):989–995

    Article  CAS  Google Scholar 

  127. Haghighatdoost F, Salehi-Abargouei A, Surkan PJ, Azadbakht L (2016) The effects of low carbohydrate diets on liver function tests in nonalcoholic fatty liver disease: a systematic review and meta-analysis of clinical trials. J Res Med Sci 21:53

    Article  PubMed  PubMed Central  Google Scholar 

  128. Bortolotti M, Kreis R, Debard C, Cariou B, Faeh D, Chetiveaux M et al (2009) High protein intake reduces intrahepatocellular lipid deposition in humans. Am J Clin Nutr 90(4):1002–1010

    Article  CAS  PubMed  Google Scholar 

  129. Bortolotti M, Maiolo E, Corazza M, Van Dijke E, Schneiter P, Boss A et al (2011) Effects of a whey protein supplementation on intrahepatocellular lipids in obese female patients. Clin Nutr 30(4):494–498

    Article  CAS  PubMed  Google Scholar 

  130. Theytaz F, Noguchi Y, Egli L, Campos V, Buehler T, Hodson L et al (2012) Effects of supplementation with essential amino acids on intrahepatic lipid concentrations during fructose overfeeding in humans. Am J Clin Nutr 96(5):1008–1016

    Article  CAS  PubMed  Google Scholar 

  131. Drummen M, Dorenbos E, Vreugdenhil AC, Raben A, Fogelholm M, Westerterp-Plantenga MS et al (2018) Long-term effects of increased protein intake after weight loss on intrahepatic lipid content and implications for insulin sensitivity—a preview study. Am J Physiol Endocrinol Metab 315:E885–E891

    Article  CAS  PubMed  Google Scholar 

  132. Drummen M, Tischmann L, Gatta-Cherifi B, Adam T, Westerterp-Plantenga M (2018) Dietary protein and energy balance in relation to obesity and co-morbidities. Front Endocrinol (Lausanne). 9:443

    Article  PubMed  PubMed Central  Google Scholar 

  133. Westerterp-Plantenga MS, Lemmens SG, Westerterp KR (2012) Dietary protein—its role in satiety, energetics, weight loss and health. Br J Nutr 108(Suppl 2):S105–S112

    Article  CAS  PubMed  Google Scholar 

  134. Torres N, Tovar AR (2007) The role of dietary protein on lipotoxicity. Nutr Rev 65(6 Pt 2):S64–S68

    Article  PubMed  Google Scholar 

  135. Hudgins LC, Hellerstein MK, Seidman CE, Neese RA, Tremaroli JD, Hirsch J (2000) Relationship between carbohydrate-induced hypertriglyceridemia and fatty acid synthesis in lean and obese subjects. J Lipid Res 41(4):595–604

    Article  CAS  PubMed  Google Scholar 

  136. Schwarz JM, Neese RA, Turner S, Dare D, Hellerstein MK (1995) Short-term alterations in carbohydrate energy intake in humans. Striking effects on hepatic glucose production, de novo lipogenesis, lipolysis, and whole-body fuel selection. J Clin Invest 96(6):2735–2743

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Ortega FB, Lavie CJ, Blair SN (2016) Obesity and cardiovascular disease. Circ Res 118(11):1752–1770

    Article  CAS  PubMed  Google Scholar 

  138. Khan SS, Ning H, Wilkins JT, Allen N, Carnethon M, Berry JD et al (2018) Association of body mass index with lifetime risk of cardiovascular disease and compression of morbidity. JAMA Cardiol 3(4):280–287

    Article  PubMed  PubMed Central  Google Scholar 

  139. Armani A, Berry A, Cirulli F, Caprio M (2017) Molecular mechanisms underlying metabolic syndrome: the expanding role of the adipocyte. FASEB J 31(10):4240–4255

    Article  CAS  PubMed  Google Scholar 

  140. Yancy WS, Westman EC, McDuffie JR, Grambow SC, Jeffreys AS, Bolton J et al (2010) A randomized trial of a low-carbohydrate diet vs orlistat plus a low-fat diet for weight loss. Arch Intern Med 170(2):136–145

    Article  CAS  PubMed  Google Scholar 

  141. Hammer S, Snel M, Lamb HJ, Jazet IM, van der Meer RW, Pijl H et al (2008) Prolonged caloric restriction in obese patients with type 2 diabetes mellitus decreases myocardial triglyceride content and improves myocardial function. J Am Coll Cardiol 52(12):1006–1012

    Article  CAS  PubMed  Google Scholar 

  142. Jonker JT, Snel M, Hammer S, Jazet IM, van der Meer RW, Pijl H et al (2014) Sustained cardiac remodeling after a short-term very low calorie diet in type 2 diabetes mellitus patients. Int J Cardiovasc Imaging 30(1):121–127

    Article  PubMed  Google Scholar 

  143. Aubert G, Martin OJ, Horton JL, Lai L, Vega RB, Leone TC et al (2016) The failing heart relies on ketone bodies as a fuel. Circulation 133(8):698–705

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Ferrannini E, Baldi S, Frascerra S, Astiarraga B, Heise T, Bizzotto R et al (2016) Shift to fatty substrate utilization in response to sodium-glucose cotransporter 2 inhibition in subjects without diabetes and patients with type 2 diabetes. Diabetes 65(5):1190–1195

    Article  CAS  PubMed  Google Scholar 

  145. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S et al (2015) Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 373(22):2117–2128

    Article  CAS  PubMed  Google Scholar 

  146. Abdul-Ghani MA, Norton L, DeFronzo RA (2015) Renal sodium-glucose cotransporter inhibition in the management of type 2 diabetes mellitus. Am J Physiol Renal Physiol 309(11):F889–F900

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Kimura I, Inoue D, Maeda T, Hara T, Ichimura A, Miyauchi S et al (2011) Short-chain fatty acids and ketones directly regulate sympathetic nervous system via G protein-coupled receptor 41 (GPR41). Proc Natl Acad Sci USA 108(19):8030–8035

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Forsythe CE, Phinney SD, Fernandez ML, Quann EE, Wood RJ, Bibus DM et al (2008) Comparison of low fat and low carbohydrate diets on circulating fatty acid composition and markers of inflammation. Lipids 43(1):65–77

    Article  CAS  PubMed  Google Scholar 

  149. Youm YH, Nguyen KY, Grant RW, Goldberg EL, Bodogai M, Kim D et al (2015) The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Nat Med 21(3):263–269

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Prattichizzo F, De Nigris V, Micheloni S, La Sala L, Ceriello A (2018) Increases in circulating levels of ketone bodies and cardiovascular protection with SGLT2 inhibitors: is low-grade inflammation the neglected component? Diabetes Obes Metab 20(11):2515–2522

    Article  CAS  PubMed  Google Scholar 

  151. Haffner SM, Shaten J, Stern MP, Smith GD, Kuller L (1996) Low levels of sex hormone-binding globulin and testosterone predict the development of non-insulin-dependent diabetes mellitus in men. MRFIT Research Group. Multiple risk factor intervention trial. Am J Epidemiol 143(9):889–897

    Article  CAS  PubMed  Google Scholar 

  152. Haffner SM (2000) Sex hormones, obesity, fat distribution, type 2 diabetes and insulin resistance: epidemiological and clinical correlation. Int J Obes Relat Metab Disord 24(Suppl 2):S56–S58

    Article  CAS  PubMed  Google Scholar 

  153. Abate N, Haffner SM, Garg A, Peshock RM, Grundy SM (2002) Sex steroid hormones, upper body obesity, and insulin resistance. J Clin Endocrinol Metab 87(10):4522–4527

    Article  CAS  PubMed  Google Scholar 

  154. Livingstone C, Collison M (2002) Sex steroids and insulin resistance. Clin Sci (Lond). 102(2):151–166

    Article  CAS  PubMed  Google Scholar 

  155. Kaukua J, Pekkarinen T, Sane T, Mustajoki P (2003) Sex hormones and sexual function in obese men losing weight. Obes Res 11(6):689–694

    Article  CAS  PubMed  Google Scholar 

  156. Ng Tang Fui M, Prendergast LA, Dupuis P, Raval M, Strauss BJ, Zajac JD et al (2016) Effects of testosterone treatment on body fat and lean mass in obese men on a hypocaloric diet: a randomised controlled trial. BMC Med 14(1):153

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  157. Niskanen L, Laaksonen DE, Punnonen K, Mustajoki P, Kaukua J, Rissanen A (2004) Changes in sex hormone-binding globulin and testosterone during weight loss and weight maintenance in abdominally obese men with the metabolic syndrome. Diabetes Obes Metab 6(3):208–215

    Article  CAS  PubMed  Google Scholar 

  158. Khoo J, Piantadosi C, Worthley S, Wittert GA (2010) Effects of a low-energy diet on sexual function and lower urinary tract symptoms in obese men. Int J Obes (Lond). 34(9):1396–1403

    Article  CAS  Google Scholar 

  159. La Vignera S, Condorelli RA, Vicari E, Calogero AE (2012) Negative effect of increased body weight on sperm conventional and nonconventional flow cytometric sperm parameters. J Androl 33(1):53–58

    Article  PubMed  CAS  Google Scholar 

  160. Conway G, Dewailly D, Diamanti-Kandarakis E, Escobar-Morreale HF, Franks S, Gambineri A et al (2014) The polycystic ovary syndrome: a position statement from the European Society of Endocrinology. Eur J Endocrinol 171(4):P1–P29

    Article  CAS  PubMed  Google Scholar 

  161. Tosi F, Bonora E, Moghetti P (2017) Insulin resistance in a large cohort of women with polycystic ovary syndrome: a comparison between euglycaemic-hyperinsulinaemic clamp and surrogate indexes. Hum Reprod 32(12):2515–2521

    Article  CAS  PubMed  Google Scholar 

  162. Repaci A, Gambineri A, Pasquali R (2011) The role of low-grade inflammation in the polycystic ovary syndrome. Mol Cell Endocrinol 335(1):30–41

    Article  CAS  PubMed  Google Scholar 

  163. Pasquali R, Gambineri A, Cavazza C, Ibarra Gasparini D, Ciampaglia W, Cognigni GE et al (2011) Heterogeneity in the responsiveness to long-term lifestyle intervention and predictability in obese women with polycystic ovary syndrome. Eur J Endocrinol 164(1):53–60

    Article  CAS  PubMed  Google Scholar 

  164. Teede HJ, Misso ML, Costello MF, Dokras A, Laven J, Moran L et al (2018) Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome. Fertil Steril 110(3):364–379

    Article  PubMed  PubMed Central  Google Scholar 

  165. Mehrabani HH, Salehpour S, Amiri Z, Farahani SJ, Meyer BJ, Tahbaz F (2012) Beneficial effects of a high-protein, low-glycemic-load hypocaloric diet in overweight and obese women with polycystic ovary syndrome: a randomized controlled intervention study. J Am Coll Nutr 31(2):117–125

    Article  CAS  PubMed  Google Scholar 

  166. Gower BA, Goss AM (2015) A lower-carbohydrate, higher-fat diet reduces abdominal and intermuscular fat and increases insulin sensitivity in adults at risk of type 2 diabetes. J Nutr 145(1):177S–183S

    Article  CAS  PubMed  Google Scholar 

  167. Mavropoulos JC, Yancy WS, Hepburn J, Westman EC (2005) The effects of a low-carbohydrate, ketogenic diet on the polycystic ovary syndrome: a pilot study. Nutr Metab (Lond) 2:35

    Article  CAS  Google Scholar 

  168. Stuenkel CA, Davis SR, Gompel A, Lumsden MA, Murad MH, Pinkerton JV et al (2015) Treatment of symptoms of the menopause: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 100(11):3975–4011

    Article  CAS  PubMed  Google Scholar 

  169. El Khoudary SR, Thurston RC (2018) Cardiovascular implications of the menopause transition: endogenous sex hormones and vasomotor symptoms. Obstet Gynecol Clin N Am 45(4):641–661

    Article  Google Scholar 

  170. Thurston RC, Chang Y, Barinas-Mitchell E, Jennings JR, von Känel R, Landsittel DP et al (2017) Physiologically assessed hot flashes and endothelial function among midlife women. Menopause 24(8):886–893

    Article  PubMed  PubMed Central  Google Scholar 

  171. Gold EB, Crawford SL, Shelton JF, Tepper PG, Crandall CJ, Greendale GA et al (2017) Longitudinal analysis of changes in weight and waist circumference in relation to incident vasomotor symptoms: the Study of Women’s Health Across the Nation (SWAN). Menopause 24(1):9–26

    Article  PubMed  PubMed Central  Google Scholar 

  172. Thurston RC, Ewing LJ, Low CA, Christie AJ, Levine MD (2015) Behavioral weight loss for the management of menopausal hot flashes: a pilot study. Menopause 22(1):59–65

    Article  PubMed  PubMed Central  Google Scholar 

  173. Heussinger N, Della Marina A, Beyerlein A, Leiendecker B, Hermann-Alves S, Dalla Pozza R et al (2018) 10 patients, 10 years—long term follow-up of cardiovascular risk factors in Glut1 deficiency treated with ketogenic diet therapies: a prospective, multicenter case series. Clin Nutr 37(6 Pt A):2246–2251

    Article  CAS  PubMed  Google Scholar 

  174. van der Louw E, van den Hurk D, Neal E, Leiendecker B, Fitzsimmon G, Dority L et al (2016) Ketogenic diet guidelines for infants with refractory epilepsy. Eur J Paediatr Neurol 20(6):798–809

    Article  PubMed  Google Scholar 

  175. Kossoff EH, Zupec-Kania BA, Auvin S, Ballaban-Gil KR, Christina Bergqvist AG, Blackford R et al (2018) Optimal clinical management of children receiving dietary therapies for epilepsy: updated recommendations of the International Ketogenic Diet Study Group. Epilepsia Open 3(2):175–192

    Article  PubMed  PubMed Central  Google Scholar 

  176. Styne DM, Arslanian SA, Connor EL, Farooqi IS, Murad MH, Silverstein JH et al (2017) Pediatric obesity-assessment, treatment, and prevention: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 102(3):709–757

    Article  PubMed  PubMed Central  Google Scholar 

  177. Gibson LJ, Peto J, Warren JM, dos Santos Silva I (2006) Lack of evidence on diets for obesity for children: a systematic review. Int J Epidemiol 35(6):1544–1552

    Article  PubMed  Google Scholar 

  178. Gow ML, Garnett SP, Baur LA, Lister NB (2016) The effectiveness of different diet strategies to reduce type 2 diabetes risk in youth. Nutrients 8(8):486

    Article  PubMed Central  CAS  Google Scholar 

  179. Figueroa-Colon R, von Almen TK, Franklin FA, Schuftan C, Suskind RM (1993) Comparison of two hypocaloric diets in obese children. Am J Dis Child 147(2):160–166

    CAS  PubMed  Google Scholar 

  180. Berkowitz RI, Wadden TA, Gehrman CA, Bishop-Gilyard CT, Moore RH, Womble LG et al (2011) Meal replacements in the treatment of adolescent obesity: a randomized controlled trial. Obesity (Silver Spring) 19(6):1193–1199

    Article  Google Scholar 

  181. Peña L, Peña M, Gonzalez J, Claro A (1979) A comparative study of two diets in the treatment of primary exogenous obesity in children. Acta Paediatr Acad Sci Hung 20(1):99–103

    PubMed  Google Scholar 

  182. Sondike SB, Copperman N, Jacobson MS (2003) Effects of a low-carbohydrate diet on weight loss and cardiovascular risk factor in overweight adolescents. J Pediatr 142(3):253–258

    Article  CAS  PubMed  Google Scholar 

  183. Willi SM, Martin K, Datko FM, Brant BP (2004) Treatment of type 2 diabetes in childhood using a very-low-calorie diet. Diabetes Care 27(2):348–353

    Article  PubMed  Google Scholar 

  184. de Lau LM, Bornebroek M, Witteman JC, Hofman A, Koudstaal PJ, Breteler MM (2005) Dietary fatty acids and the risk of Parkinson disease: the Rotterdam study. Neurology 64(12):2040–2045

    Article  PubMed  CAS  Google Scholar 

  185. Cunnane SC, Courchesne-Loyer A, St-Pierre V, Vandenberghe C, Pierotti T, Fortier M et al (2016) Can ketones compensate for deteriorating brain glucose uptake during aging? Implications for the risk and treatment of Alzheimer’s disease. Ann N Y Acad Sci 1367(1):12–20

    Article  CAS  PubMed  Google Scholar 

  186. Castellano CA, Nugent S, Paquet N, Tremblay S, Bocti C, Lacombe G et al (2015) Lower brain 18F-fluorodeoxyglucose uptake but normal 11C-acetoacetate metabolism in mild Alzheimer’s disease dementia. J Alzheimers Dis 43(4):1343–1353

    Article  CAS  PubMed  Google Scholar 

  187. Verdile G, Keane KN, Cruzat VF, Medic S, Sabale M, Rowles J et al (2015) Inflammation and oxidative stress: the molecular connectivity between insulin resistance, obesity, and alzheimer’s disease. Mediators Inflamm 2015:105828

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  188. Pinto A, Bonucci A, Maggi E, Corsi M, Businaro R (2018) Anti-oxidant and anti-inflammatory activity of ketogenic diet: new perspectives for neuroprotection in Alzheimer’s disease. Antioxidants (Basel) 7(5):63

    Article  CAS  Google Scholar 

  189. Taylor MK, Sullivan DK, Mahnken JD, Burns JM, Swerdlow RH (2018) Feasibility and efficacy data from a ketogenic diet intervention in Alzheimer’s disease. Alzheimers Dement (N Y) 4:28–36

    Article  Google Scholar 

  190. Roberts MN, Wallace MA, Tomilov AA, Zhou Z, Marcotte GR, Tran D et al (2017) A Ketogenic diet extends longevity and healthspan in adult mice. Cell Metab 26(3):539–546.e5

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  191. Newman JC, Covarrubias AJ, Zhao M, Yu X, Gut P, Ng CP et al (2017) Ketogenic diet reduces midlife mortality and improves memory in aging mice. Cell Metab 26(3):547–557.e8

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  192. Astrup A, Hjorth MF (2017) Ageing: improvement in age-related cognitive functions and life expectancy by ketogenic diets. Nat Rev Endocrinol 13(12):695–696

    Article  PubMed  Google Scholar 

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Acknowledgements

We would like to thank all the members of the Cardiovascular Endocrinology Club of the Italian Society of Endocrinology, for the scientific support during the writing of the manuscript. The Cardiovascular Endocrinology Club of the Italian Society of Endocrinology: Massimiliano Caprio (coordinator), Fausto Bogazzi (coordinator), Guglielmo Beccuti, Bernadette Biondi, Salvatore Cannavò, Iacopo Chiodini, Giuseppe De Feudis, Simona Di Francesco, Aldo Di Gregorio, Francesco Fallo, Carlo Foresta, Gilberta Giacchetti, Riccarda Granata, Andrea M. Isidori, Paolo Magni, Pasquale Maiellaro, Mirko Parasiliti Caprino, Rosario Pivonello, Riccardo Pofi, Alfredo Pontecorvi, Chiara Simeoli and all authors of the manuscript.

Funding

The study was not funded.

Author information

Authors and Affiliations

  1. Laboratory of Cardiovascular Endocrinology, IRCCS San Raffaele Pisana, Via di Val Cannuta 247, 00166, Rome, Italy

    M. Caprio, E. Moriconi & A. Armani

  2. Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Roma Open University, Rome, Italy

    M. Caprio

  3. Unit of Endocrinology and Metabolic Diseases, Department of Systems Medicine, CTO A. Alesini Hospital, ASL Roma 2, University of Rome Tor Vergata, Rome, Italy

    M. Infante & A. Fabbri

  4. Section of Medical Pathophysiology, Food Science and Endocrinology, Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy

    E. Moriconi, S. Mariani, C. Lubrano, E. Poggiogalle, L. M. Donini, S. Basciani, L. Gnessi & A. Lenzi

  5. Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Endocrinology and Diabetology Unit, Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy

    G. Mantovani

  6. Section of Health Sciences, Department of Movement, Human and Health Sciences, “Foro Italico” University of Rome, Rome, Italy

    S. Migliaccio

  7. Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy

    A. Cignarelli, E. Conte & F. Giorgino

  8. Endocrinology Unit, Obesity and Lipodystrophy Center, University Hospital of Pisa, Pisa, Italy

    G. Ceccarini & F. Santini

  9. Endocrinology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy

    F. Bogazzi & P. Vitti

  10. Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy

    L. Cimino, R. A. Condorelli, S. La Vignera & A. E. Calogero

  11. Endocrinology Unit and Center for Applied Biomedical Research, Department of Medical and Surgical Sciences, University of Bologna, S. Orsola-Malpighi Hospital, Bologna, Italy

    A. Gambineri & U. Pagotto

  12. Andrology, Women’s Endocrinology and Gender Incongruence Unit, Department of Biomedical, Experimental and Clinical Sciences, University of Florence, AOU Careggi, Florence, Italy

    L. Vignozzi

  13. Endocrinology, Department of Translational Medicine and Department of Health Sciences, University of Piemonte Orientale, Novara, Italy

    F. Prodam & G. Aimaretti

  14. Geriatrics Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy

    G. Linsalata, S. Buralli & F. Monzani

  15. Department of Experimental and Clinical Medicine, Magna Graecia University of Catanzaro, Catanzaro, Italy

    A. Aversa

  16. Department of Medicine, Internal Medicine 3, University Hospital of Padova, Padua, Italy

    R. Vettor

  17. Section of Endocrinology, Department of Clinical Medicine and Surgery, University “Federico II” of Naples, Naples, Italy

    A. Colao

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  1. M. Caprio
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  2. M. Infante
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  3. E. Moriconi
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  4. A. Armani
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  6. G. Mantovani
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  7. S. Mariani
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  8. C. Lubrano
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  9. E. Poggiogalle
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  15. G. Ceccarini
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  17. L. Cimino
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Consortia

the Cardiovascular Endocrinology Club of the Italian Society of Endocrinology

  • Massimiliano Caprio
  • , Fausto Bogazzi
  • , Guglielmo Beccuti
  • , Bernadette Biondi
  • , Salvatore Cannavò
  • , Iacopo Chiodini
  • , Giuseppe De Feudis
  • , Simona Di Francesco
  • , Aldo Di Gregorio
  • , Francesco Fallo
  • , Carlo Foresta
  • , Gilberta Giacchetti
  • , Riccarda Granata
  • , Andrea M. Isidori
  • , Paolo Magni
  • , Pasquale Maiellaro
  • , Mirko Parasiliti Caprino
  • , Rosario Pivonello
  • , Riccardo Pofi
  • , Alfredo Pontecorvi
  •  & Chiara Simeoli

Corresponding author

Correspondence to M. Caprio.

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Conflict of interest

MC. gave talks in symposia sponsored by Therascience, Eli Lilly, Novo Nordisk and New Penta, participated to advisory board for Therascience and Sanofi, and received research grants from Bayer AG; G.M. participated to advisory boards for Novartis and Shire and received honoraria for courses sponsored by Pfizer; S.B. gave talks in symposia sponsored by New Penta; L.C. and R.V. gave talks in symposia sponsored by Therascience; F.P. received grants by Difass International, Nutricia Research Foundation, and Probiotical; G.A. received honoraria from Astra Zeneca and Sanofi. All the other authors have nothing to disclose, related to this publication.

Research involving human or animals participants

This consensus statement does not contain any study with human participants or animals performed by any of the authors.

Informed consent

Not applicable.

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The members of the Cardiovascular Endocrinology Club of the Italian Society of Endocrinology are listed in acknowledgements.

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Caprio, M., Infante, M., Moriconi, E. 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 Invest 42, 1365–1386 (2019). https://doi.org/10.1007/s40618-019-01061-2

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  • DOI: https://doi.org/10.1007/s40618-019-01061-2

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