Generic placeholder image

Current Pharmaceutical Design


ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

Review Article

Potential Therapeutic Effects of Exogenous Ketone Supplementation for Type 2 Diabetes: A Review

Author(s): Jeremy J. Walsh, Étienne Myette-Côté, Helena Neudorf and Jonathan P. Little*

Volume 26, Issue 9, 2020

Page: [958 - 969] Pages: 12

DOI: 10.2174/1381612826666200203120540

Price: $65


Type 2 diabetes (T2D) is among the most prevalent non-communicable lifestyle diseases. We propose that overnutrition and low levels of physical activity can contribute to a vicious cycle of hyperglycemia, inflammation and oxidative stress, insulin resistance, and pancreatic β-cell dysfunction. The pathophysiological manifestations of T2D have a particular impact on the vasculature and individuals with T2D are at high risk of cardiovascular disease. Targeting aspects of the vicious cycle represent therapeutic approaches for improving T2D and protecting against cardiovascular complications. The recent advent of exogenous oral ketone supplements represents a novel, non-pharmacological approach to improving T2D pathophysiology and potentially protecting against cardiovascular disease risk. Herein, we review the emerging literature regarding the effects of exogenous ketone supplementation on metabolic control, inflammation, oxidative stress, and cardiovascular function in humans and highlight the potential application for breaking the vicious cycle of T2D pathophysiology.

Keywords: Ketone monoester, diabetes, inflammation, oxidative stress, ketosis, immunometabolism, cardiovascular disease, nutrition.

Cho NH, Shaw JE, Karuranga S, et al. IDF Diabetes Atlas: Global estimates of diabetes prevalence for 2017 and projections for 2045. Diabetes Res Clin Pract 2018; 138: 271-81.
[] [PMID: 29496507]
Baena-Díez JM, Peñafiel J, Subirana I, et al. FRESCO Investigators. Risk of cause-specific death in individuals with diabetes: a competing risks analysis. Diabetes Care 2016; 39(11): 1987-95.
[] [PMID: 27493134]
McCrimmon RJ, Ryan CM, Frier BM. Diabetes and cognitive dysfunction. Lancet 2012; 379(9833): 2291-9.
[] [PMID: 22683129]
Cherbuin N, Walsh EI. Sugar in mind: Untangling a sweet and sour relationship beyond type 2 diabetes. Front Neuroendocrinol 2019; 54: 100769
[] [PMID: 31176793]
Doucet G, Beatty M. The cost of diabetes in Canada: the economic Tsunami. Can J Diabetes 2010; 34.
Hotamisligil G, Shargill N, Spiegelman B. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 1993; 259(5091): 87-91.
Hotamisligil GS, Arner P, Caro JF, Atkinson RL, Spiegelman BM. Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance. J Clin Invest 1995; 95(5): 2409-15.
[] [PMID: 7738205]
Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 2003; 112(12): 1796-808.
[] [PMID: 14679176]
Plomgaard P, Bouzakri K, Krogh-Madsen R, Mittendorfer B, Zierath JR, Pedersen BK. Tumor necrosis factor-alpha induces skeletal muscle insulin resistance in healthy human subjects via inhibition of Akt substrate 160 phosphorylation. Diabetes 2005; 54(10): 2939-45.
[] [PMID: 16186396]
Hotamisligil GS. Mechanisms of TNF-α-induced insulin resistance. Exp Clin Endocrinol Diabetes 1999; 107(2): 119-25.
[] [PMID: 10320052]
Hotamisligil GS, Murray DL, Choy LN, Spiegelman BM. Tumor necrosis factor alpha inhibits signaling from the insulin receptor. Proc Natl Acad Sci USA 1994; 91(11): 4854-8.
[] [PMID: 8197147]
Dasu MR, Jialal I. Free fatty acids in the presence of high glucose amplify monocyte inflammation via Toll-like receptors. Am J Physiol Endocrinol Metab 2011; 300(1): E145-54.
Boden G. Fatty acid-induced inflammation and insulin resistance in skeletal muscle and liver. Curr Diab Rep 2006; 6(3): 177-81.
[] [PMID: 16898568]
Tripathy D, Mohanty P, Dhindsa S, et al. Elevation of free fatty acids induces inflammation and impairs vascular reactivity in healthy subjects. Diabetes 2003; 52(12): 2882-7.
[] [PMID: 14633847]
Inoguchi T, Li P, Umeda F, et al. High glucose level and free fatty acid stimulate reactive oxygen species production through protein kinase C--dependent activation of NAD(P)H oxidase in cultured vascular cells. Diabetes 2000; 49(11): 1939-45.
[] [PMID: 11078463]
Ceriello A, Esposito K, Piconi L, et al. Oscillating glucose is more deleterious to endothelial function and oxidative stress than mean glucose in normal and type 2 diabetic patients. Diabetes 2008; 57(5): 1349-54.
[] [PMID: 18299315]
Ghanim H, Mohanty P, Deopurkar R, et al. Acute modulation of toll-like receptors by insulin. Diabetes Care 2008; 31(9): 1827-31.
Blüher M. Adipose tissue inflammation: a cause or consequence of obesity-related insulin resistance? Clin Sci (Lond) 2016; 130(18): 1603-14.
[] [PMID: 27503945]
Shimobayashi M, Albert V, Woelnerhanssen B, et al. Insulin resistance causes inflammation in adipose tissue. J Clin Invest 2018; 128(4): 1538-50.
[] [PMID: 29528335]
Altomare F, Kherani A, Lovshin J. Diabetes Canada 2018 clinical practice guidelines for the prevention and management of diabetes in Canada: retinopathy. Can J Diabetes 2018; S1-S325.
Laffel L. Ketone bodies: a review of physiology, pathophysiology and application of monitoring to diabetes. Diabetes Metab Res Rev 1999; 15(6): 412-26.
[<412::AID-DMRR72>3.0.CO;2-8] [PMID: 10634967]
Puchalska P, Crawford PA. Multi-dimensional roles of ketone bodies in fuel metabolism, signaling, and therapeutics. Cell Metab 2017; 25(2): 262-84.
[] [PMID: 28178565]
Robinson AM, Williamson DH. Physiological roles of ketone bodies as substrates and signals in mammalian tissues. Physiol Rev 1980; 60(1): 143-87.
[] [PMID: 6986618]
Cox PJ, Clarke K. Acute nutritional ketosis: implications for exercise performance and metabolism. Extrem Physiol Med 2014; 3(1): 17.
[] [PMID: 25379174]
Newman JC, Verdin E. β-Hydroxybutyrate: a signaling metabolite. Annu Rev Nutr 2017; 37(1): 51-76.
[] [PMID: 28826372]
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(3): 309-19.
Pagoto SL, Appelhans BM. A call for an end to the diet debates. Jama 2013; 310(7): 687-8.
Johnston CS, Tjonn SL, Swan PD, White A, Hutchins H, Sears B. Ketogenic low-carbohydrate diets have no metabolic advantage over nonketogenic low-carbohydrate diets. Am J Clin Nutr 2006; 83(5): 1055-61.
[] [PMID: 16685046]
Veech RL. Ketone ester effects on metabolism and transcription. J Lipid Res 2014; 55(10): 2004-6.
[] [PMID: 24714648]
Stubbs BJ, Cox PJ, Evans RD, et al. On the metabolism of exogenous ketones in humans. Front Physiol 2017; 8(848): 848.
[] [PMID: 29163194]
O’Malley T, Myette-Cote E, Durrer C, Little JP. Nutritional ketone salts increase fat oxidation but impair high-intensity exercise performance in healthy adult males. Appl Physiol Nutr Metab 2017; 42(10): 1031-5.
[] [PMID: 28750585]
Desrochers S, David F, Garneau M, Jetté M, Brunengraber H. Metabolism of R- and S-1,3-butanediol in perfused livers from meal-fed and starved rats. Biochem J 1992; 285(Pt 2): 647-53.
[] [PMID: 1637355]
Webber RJ, Edmond J. Utilization of L(+)-3-hydroxybutyrate, D(-)-3-hydroxybutyrate, acetoacetate, and glucose for respiration and lipid synthesis in the 18-day-old rat. J Biol Chem 1977; 252(15): 5222-6.
[PMID: 885847]
Stubbs BJ, Cox PJ, Kirk T, Evans RD, Clarke K. Gastrointestinal effects of exogenous ketone drinks are infrequent, mild and vary according to ketone compound and dose. Int J Sport Nutr Exerc Metab 2019. In press.
[] [PMID: 31034254]
Kesl SL, Poff AM, Ward NP, et al. Effects of exogenous ketone supplementation on blood ketone, glucose, triglyceride, and lipoprotein levels in Sprague-Dawley rats. Nutr Metab (Lond) 2016; 13(1): 9.
[] [PMID: 26855664]
Clarke K, Tchabanenko K, Pawlosky R, et al. Kinetics, safety and tolerability of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate in healthy adult subjects. Regul Toxicol Pharmacol 2012; 63(401): 8.
Myette-Côté É, Neudorf H, Rafiei H, Clarke K, Little JP. Prior ingestion of exogenous ketone monoester attenuates the glycaemic response to an oral glucose tolerance test in healthy young individuals. J Physiol 2018; 596(8): 1385-95.
Cox PJ, Kirk T, Ashmore T, et al. Nutritional ketosis alters fuel preference and thereby endurance performance in athletes. Cell Metab 2016; 124(2): 256-68.
Leckey JJ, Ross ML, Quod M, Hawley JA, Burke LM. Ketone Diester ingestion impairs time-trial performance in professional cyclists. Front Physiol 2017; 8: 806.
[] [PMID: 29109686]
Carlson OD, David JD, Schrieder JM, et al. Contribution of nonesterified fatty acids to insulin resistance in the elderly with normal fasting but diabetic 2-hour postchallenge plasma glucose levels: the Baltimore Longitudinal Study of Aging. Metabolism 2007; 56(10): 1444-51.
[] [PMID: 17884459]
Boden G, Chen X. Effects of fat on glucose uptake and utilization in patients with non-insulin-dependent diabetes. J Clin Invest 1995; 96(3): 1261-8.
[] [PMID: 7657800]
Kehlenbrink S, Koppaka S, Martin M, et al. Elevated NEFA levels impair glucose effectiveness by increasing net hepatic glycogenolysis. Diabetologia 2012; 55(11): 3021-8.
[] [PMID: 22847060]
W LAM, L JIANG, GM BUTRICO, et al. Elevated nonesterified fatty acids (NEFA) are associated with blunted hyperglycemiainduced increments in brain glucose levels. Diabetes 2018; 67(Suppl. 1)
Neptune EM. Changes in blood glucose during metabolism of ß hydroxybutyrate. Am J Physiol 1956; 187(3): 451-3.
Balasse E, Ooms HA. Changes in the concentrations of glucose, free fatty acids, insulin and ketone bodies in the blood during sodium beta-hydroxybutyrate infusions in man. Diabetologia 1968; 4(3): 133-5.
[] [PMID: 5738351]
Mikkelsen KH, Seifert T, Secher NH, Grøndal T, van Hall G. Systemic, cerebral and skeletal muscle ketone body and energy metabolism during acute hyper-D-β-hydroxybutyratemia in post-absorptive healthy males. J Clin Endocrinol Metab 2015; 100(2): 636-43.
[] [PMID: 25415176]
Miles JM, Haymond MW, Gerich JE. Suppression of glucose production and stimulation of insulin secretion by physiological concentrations of ketone bodies in man. J Clin Endocrinol Metab 1981; 52(1): 34-7.
[] [PMID: 7005257]
Taggart A, Kero J, Gan X, et al. (D)-β-Hydroxybutyrate inhibits adipocyte lipolysis via the nicotinic acid receptor. PUMA-G 2005; 280(29): 26649-52.
Egan B. The glucose-lowering effects of exogenous ketones: is there therapeutic potential? J Physiol 2018; 596(8): 1317-8.
[] [PMID: 29473164]
Stubbs BJ, Cox PJ, Evans RD, Cyranka M, Clarke K, de Wet H. A ketone ester drink lowers human ghrelin and appetite. Obesity (Silver Spring) 2018; 26(2): 269-73.
[] [PMID: 29105987]
Vossen M, Tödter K, Altenburg C, Beisiegel U, Scheja L. Plasma triglycerides after oral glucose load specifically associate with metabolic risk markers in healthy type 2 diabetes offspring. Atherosclerosis 2011; 217(1): 214-9.
[] [PMID: 21474138]
Evans M, Egan B. Intermittent running and cognitive performance after ketone ester ingestion. Med Sci Sports Exerc 2018; 50(11): 2330-8.
[] [PMID: 29944604]
Dearlove DJ, Faull OK, Rolls E, Clarke K, Cox PJ. Nutritional ketoacidosis during incremental exercise in healthy athletes. Front Physiol 2019; 10: 290.
[] [PMID: 30984015]
Evans M, Patchett E, Nally R, Kearns R, Larney M, Egan B. Effect of acute ingestion of β-hydroxybutyrate salts on the response to graded exercise in trained cyclists. Eur J Sport Sci 2018; 18(3): 376-86.
[] [PMID: 29338584]
Holdsworth DA, Cox PJ, Kirk T, Stradling H, Impey SG, Clarke K. A ketone ester drink increases postexercise muscle glycogen synthesis in humans. Med Sci Sports Exerc 2017; 49(9): 1789-95.
[] [PMID: 28398950]
Vandoorne T, De Smet S, Ramaekers M, et al. Intake of a ketone ester drink during recovery from exercise promotes mTORC1 signaling but not glycogen resynthesis in human muscle. Front Physiol 2017; 8: 310.
[] [PMID: 28588499]
Sherwin RS, Hendler RG, Felig P. Effect of ketone infusions on amino acid and nitrogen metabolism in man. J Clin Invest 1975; 55(6): 1382-90.
[] [PMID: 1133179]
Thomsen HH, Rittig N, Johannsen M, et al. Effects of 3-hydroxybutyrate and free fatty acids on muscle protein kinetics and signaling during LPS-induced inflammation in humans: anticatabolic impact of ketone bodies. Am J Clin Nutr 2018; 108(4): 857-67.
[] [PMID: 30239561]
Ferrannini E, Barrett EJ, Bevilacqua S, DeFronzo RA. Effect of fatty acids on glucose production and utilization in man. J Clin Invest 1983; 72(5): 1737-47.
[] [PMID: 6138367]
Owen OE, Morgan AP, Kemp HG, Sullivan JM, Herrera MG, Cahill GF Jr. Brain metabolism during fasting. J Clin Invest 1967; 46(10): 1589-95.
[] [PMID: 6061736]
Clarke K, Pawlosky R, Carter E, et al. Oral 28-day and developmental toxicity studies of (R)-3-hydroxybutyrate. Regl Toxicol Pharmacol 2012; 63(2): 196-208.
Kovács Z, D’Agostino DP, Diamond D, Kindy MS, Rogers C, Ari C. therapeutic potential of exogenous ketone supplement induced ketosis in the treatment of psychiatric disorders: review of current literature. Front Psychiatry 2019; 10: 363.
[] [PMID: 31178772]
Neudorf H, Durrer C, Myette-Cote E, Makins C, O’Malley T, Little JP. Oral ketone supplementation acutely increases markers of NLRP3 inflammasome activation in human monocytes. Mol Nutr Food Res 2019; 63(11): e1801171
[] [PMID: 30912285]
Stubbs BJ, Koutnik AP, Poff AM, Ford KM, D’Agostino DP. Commentary: ketone diester ingestion impairs time-trial performance in professional cyclists. Front Physiol 2018; 9(9): 279.
[] [PMID: 29637933]
Myette-Côté É, Neudorf H, Rafiei H, Clarke K, Little JP. Prior ingestion of exogenous ketone monoester attenuates the glycaemic response to an oral glucose tolerance test in healthy young individuals. J Physiol 2018; 596(8): 1385-95.
[] [PMID: 29446830]
Hotamisligil GS. Inflammation, metaflammation and immunometabolic disorders. Nature 2017; 542(7640): 177-85.
[] [PMID: 28179656]
Febbraio MA. Role of interleukins in obesity: implications for metabolic disease. Trends Endocrinol Metab 2014; 25(6): 312-9.
[] [PMID: 24698032]
Shulman GI. Ectopic fat in insulin resistance, dyslipidemia, and cardiometabolic disease. N Engl J Med 2014; 371(12): 1131-41.
[] [PMID: 25229917]
Wright E Jr, Scism-Bacon JL, Glass LC. Oxidative stress in type 2 diabetes: the role of fasting and postprandial glycaemia. Int J Clin Pract 2006; 60(3): 308-14.
[] [PMID: 16494646]
Zhou W, Chen C, Chen Z, et al. NLRP3: A novel mediator in cardiovascular disease. J Immunol Res 2018; 2018: 5702103
Youm YH, Nguyen KY, Grant RW, et al. The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Nat Med 2015; 21(3): 263-9.
[] [PMID: 25686106]
Goldberg EL, Asher JL, Molony RD, et al. β-Hydroxybutyrate deactivates neutrophil NLRP3 inflammasome to relieve gout flares. Cell Rep 2017; 18(9): 2077-87.
[] [PMID: 28249154]
Shimazu T, Hirschey MD, Newman J, et al. Suppression of oxidative stress by beta-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Science 2012; 12339(6116): 211-4.
Kim DH, Park MH, Ha S, et al. Anti-inflammatory action of β-hydroxybutyrate via modulation of PGC-1α and FoxO1, mimicking calorie restriction. Aging (Albany NY) 2019; 11(4): 1283-304.
[] [PMID: 30811347]
Wei T, Tian W, Liu F, Xie G. Protective effects of exogenous β-hydroxybutyrate on paraquat toxicity in rat kidney. Biochem Biophys Res Commun 2014; 447(4): 666-71.
[] [PMID: 24755084]
Cnop M, Foufelle F, Velloso LA. Endoplasmic reticulum stress, obesity and diabetes. Trends Mol Med 2012; 18(1): 59-68.
[] [PMID: 21889406]
Tagawa R, Kawano Y, Minami A, et al. β-hydroxybutyrate protects hepatocytes against endoplasmic reticulum stress in a sirtuin 1-independent manner. Arch Biochem Biophys 2019; 663: 220-7.
Sumithran P, Proietto J. The defence of body weight: a physiological basis for weight regain after weight loss. Clin Sci (Lond) 2013; 124(4): 231-41.
[] [PMID: 23126426]
Paoli A, Bosco G, Camporesi EM, Mangar D. Ketosis, ketogenic diet and food intake control: a complex relationship. Front Psychol 2015; 6(27): 27.
[] [PMID: 25698989]
Bueno NB, de Melo ISV, de Oliveira SL, da Rocha Ataide T. Very-low-carbohydrate ketogenic diet v. low-fat diet for long-term weight loss: a meta-analysis of randomised controlled trials. Br J Nutr 2013; 110(7): 1178-87.
[] [PMID: 23651522]
Higgins SC, Gueorguiev M, Korbonits M. Ghrelin, the peripheral hunger hormone. Ann Med 2007; 39(2): 116-36.
[] [PMID: 17453675]
Wren AM, Seal LJ, Cohen MA, et al. Obesity is a modern epidemic which still has no effective medical treatment. J Clin Endocrinol Metab 2001; 86(12): 5992-2.
[] [PMID: 11739476]
Morton GJ, Cummings DE, Baskin DG, Barsh GS, Schwartz MW. Central nervous system control of food intake and body weight. Nature 2006; 443(7109): 289-95.
[] [PMID: 16988703]
Batterham RL, Cowley MA, Small CJ, et al. Gut hormone PYY(3-36) physiologically inhibits food intake. Nature 2002; 418(6898): 650-4.
[] [PMID: 12167864]
Parker HE, Gribble FM, Reimann F. The role of gut endocrine cells in control of metabolism and appetite. Exp Physiol 2014; 99(9): 1116-20.
[] [PMID: 25210110]
Poff AM, Ari C, Arnold P, Seyfried TN, D’Agostino DP. Ketone supplementation decreases tumor cell viability and prolongs survival of mice with metastatic cancer. Int J Cancer 2014; 135(7): 1711-20.
[] [PMID: 24615175]
Deemer SE, Davis RAH, Gower BA, et al. Concentration-dependent effects of a dietary ketone ester on components of energy balance in mice. Front Nutr 2019; 6: 56.
[] [PMID: 31119133]
Davis RAH, Deemer SE, Bergeron JM, et al. Dietary R, S-1,3-butanediol diacetoacetate reduces body weight and adiposity in obese mice fed a high-fat diet. FASEB J 2019; 33(2): 2409-21.
[] [PMID: 30303740]
Sowers JR, Epstein M, Frohlich ED. Diabetes, hypertension, and cardiovascular disease: an update. Hypertension 2001; 37(4): 1053-9.
[] [PMID: 11304502]
Masuo K, Cardiovascular WG. Cardiovascular and renal complications in obesity and obesity-related medical conditions: role of sympathetic nervous activity and insulin resistance. Insul Resist 2012; 6(2): 58-67.
Smorschok MP, Sobierajski FM, Purdy GM, et al. Peripheral chemoreceptor deactivation attenuates the sympathetic response to glucose ingestion. Appl Physiol Nutr Metab 2019; 44(4): 389-96.
[] [PMID: 30226994]
Huggett RJ, Scott EM, Gilbey SG, Stoker JB, Mackintosh AF, Mary DASG. Impact of type 2 diabetes mellitus on sympathetic neural mechanisms in hypertension. Circulation 2003; 108(25): 3097-101.
[] [PMID: 14676139]
Bruno RM, Ghiadoni L, Seravalle G, Dell’oro R, Taddei S, Grassi G. Sympathetic regulation of vascular function in health and disease. Front Physiol 2012; 3: 284.
[] [PMID: 22934037]
Kimura I, Inoue D, Maeda T, et al. Short-chain fatty acids and ketones directly regulate sympathetic nervous system via G protein-coupled receptor 41 (GPR41). Proc Natl Acad Sci USA 2011; 108(19): 8030-5.
[] [PMID: 21518883]
Won Y-J, Lu VB, Puhl HL III, Ikeda SR. β-Hydroxybutyrate modulates N-type calcium channels in rat sympathetic neurons by acting as an agonist for the G-protein-coupled receptor FFA3. J Neurosci 2013; 33(49): 19314-25.
[] [PMID: 24305827]
Pluznick JL. Renal and cardiovascular sensory receptors and blood pressure regulation. Am J Physiol Renal Physiol 2013; 305(4): F439-44.
[] [PMID: 23761671]
Natarajan N, Hori D, Flavahan S, et al. Microbial short chain fatty acid metabolites lower blood pressure via endothelial G protein-coupled receptor 41. Physiol Genomics 2016; 48(11): 826-34.
[] [PMID: 27664183]
Fioretto P, Trevisan R, Velussi M, et al. Glomerular filtration rate is increased in man by the infusion of both D,L-3-hydroxybutyric acid and sodium D,L-3-hydroxybutyrate. J Clin Endocrinol Metab 1987; 65(2): 331-8.
[] [PMID: 3298305]
Nielsen R, Møller N, Gormsen LC, et al. Cardiovascular effects of treatment with the ketone body 3-hydroxybutyrate in chronic heart failure patients. Circulation 2019; 118: 036459.
O’Connor A. Acute oral intake of beta-hydroxybutyrate in a pilot study transiently increased its capillary levels in healthy volunteers. J Nutr Heal Food Eng 2019; 8(4): 324-8.
Myette-Côté É, Caldwell HG, Ainslie PN, Clarke K, Little JP. A ketone monoester drink reduces the glycemic response to an oral glucose challenge in individuals with obesity: a randomized trial. Am J Clin Nutr 2019; 110(6): 1491-501.
[] [PMID: 31599919]
Holland AM, Qazi AS, Beasley KN, Bennett HR. Blood and cardiovascular health parameters after supplementing with ketone salts for six weeks. J Insul Resist 2019; 4(1): 1-8.
Poffé C, Ramaekers M, Van Thienen R, Hespel P. Ketone ester supplementation blunts overreaching symptoms during endurance training overload. J Physiol 2019; 597(12): 3009-27.
[] [PMID: 31039280]
Sims-Robinson C, Kim B, Feldman EL. Diabetes and cognitive dysfunction. in: neurobiology of brain disorders. Elsevier 2015; 6736: p. (12)189-201.
Prins ML, Matsumoto JH. The collective therapeutic potential of cerebral ketone metabolism in traumatic brain injury. J Lipid Res 2014; 55(12): 2450-7.
[] [PMID: 24721741]
de la Monte SM, Wands JR. Alzheimer’s disease is type 3 diabetes-evidence reviewed. J Diabetes Sci Technol 2008; 2(6): 1101-13.
[] [PMID: 19885299]
Cherbuin N, Sachdev P, Anstey KJ. Higher normal fasting plasma glucose is associated with hippocampal atrophy: The PATH Study. Neurology 2012; 79(10): 1019-26.
[] [PMID: 22946113]
Svart M, Gormsen LC, Hansen J, et al. Regional cerebral effects of ketone body infusion with 3-hydroxybutyrate in humans: Reduced glucose uptake, unchanged oxygen consumption and increased blood flow by positron emission tomography. A randomized, controlled trial. PLoS One 2018; 13(2): e0190556
[] [PMID: 29489818]
Croteau E, Castellano CAA, Fortier M, et al. A cross-sectional comparison of brain glucose and ketone metabolism in cognitively healthy older adults, mild cognitive impairment and early Alzheimer’s disease. Exp Gerontol 2018; 107: 18-26.
Xin L, Ipek Ö, Beaumont M, et al. Nutritional Ketosis Increases NAD+/NADH ratio in healthy human brain: an in vivo study by 31P-MRS. Front Nutr 2018; 5: 62.
[] [PMID: 30050907]
Vlassenko AG, Rundle MM, Raichle ME, Mintun MA. Regulation of blood flow in activated human brain by cytosolic NADH/NAD+ ratio. Proc Natl Acad Sci USA 2006; 103(6): 1964-9.
[] [PMID: 16446430]
Hasselbalch SG, Madsen PL, Hageman LP, et al. Changes in cerebral blood flow and carbohydrate metabolism during acute hyperketonemia. Am J Physiol 1996; 27(5 Pt. 1): E746-51.
Marosi K, Kim SW, Moehl K, et al. 3-Hydroxybutyrate regulates energy metabolism and induces BDNF expression in cerebral cortical neurons. J Neurochem 2016; 139(5): 769-81.
[] [PMID: 27739595]
Hu E, Du H, Zhu X, et al. Beta-hydroxybutyrate promotes the expression of BDNF in hippocampal neurons under adequate glucose supply. Neuroscience 2018; 386: 315-25.
[] [PMID: 29966721]
Marosi K, Mattson MP. BDNF mediates adaptive brain and body responses to energetic challenges. Trends Endocrinol Metab 2014; 25(2): 89-98.
[] [PMID: 24361004]
Erickson KI, Prakash RS, Voss MW, et al. Brain-derived neurotrophic factor is associated with age-related decline in hippocampal volume. J Neurosci 2010; 30(15): 5368-75.
[] [PMID: 20392958]
Krabbe KS, Nielsen AR, Krogh-Madsen R, et al. Brain-derived neurotrophic factor (BDNF) and type 2 diabetes. Diabetologia 2007; 50(2): 431-8.
[] [PMID: 17151862]
Geijselaers SLC, Sep SJS, Stehouwer CDA, Biessels GJ. Glucose regulation, cognition, and brain MRI in type 2 diabetes: a systematic review. Lancet Diabetes Endocrinol 2015; 3(1): 75-89.
[] [PMID: 25163604]
Sleiman SF, Henry J, Al-Haddad R, et al. Exercise promotes the expression of brain derived neurotrophic factor (BDNF) through the action of the ketone body β-hydroxybutyrate. Elife 2016; 5: 1-21.

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy