Ketone Monoester Research Articles

Ketone monoester ingestion increases postexercise serum erythropoietin concentrations in healthy men.

Intravenous ketone body infusion can increase erythropoietin (EPO) concentrations, but responses to ketone monoester ingestion postexercise are currently unknown. The purpose of this study was to assess the effect of ketone monoester ingestion on postexercise erythropoietin (EPO) concentrations. Nine healthy men completed two trials in a randomized, crossover design (1-wk washout). During trials, participants performed 1 h of cycling (initially alternating between 50% and 90% of maximal aerobic capacity for 2 min each interval, and then 50% and 80%, and 50% and 70% when the higher intensity was unsustainable). Participants ingested 0.8 g·kg-1 sucrose with 0.4 g·kg-1 protein immediately after exercise, and at 1, 2, and 3 h postexercise. During the control trial (CONTROL), no further nutrition was provided, whereas on the ketone monoester trial (KETONE), participants also ingested 0.29 g·kg-1 of the ketone monoester (R)-3-hydroxybutyl (R)-3-hydroxybutyrate immediately postexercise and at 1 and 2 h postexercise. Blood was sampled immediately postexercise, every 15 min in the first hour and hourly thereafter for 4 h. Serum EPO concentrations increased to a greater extent in KETONE than in CONTROL (time × condition interaction: P = 0.046). Peak serum EPO concentrations were higher with KETONE (means ± SD: 9.0 ± 2.3 IU·L-1) compared with CONTROL (7.5 ± 1.5 IU·L-1, P < 0.01). Serum β-hydroxybutyrate concentrations were also higher, and glucose concentrations lower, with KETONE versus CONTROL (both P < 0.01). In conclusion, ketone monoester ingestion increases postexercise erythropoietin concentrations, revealing a new avenue for orally ingestible ketone monoesters to potentially alter hemoglobin mass.NEW & NOTEWORTHY To our knowledge, this study was the first to assess the effects of ketone monoester ingestion on erythropoietin concentrations after exercise. We demonstrated that ingestion of a ketone monoester postexercise increased serum erythropoietin concentrations and reduced serum glucose concentrations in healthy men. These data reveal the possibility for ketone monoesters to alter hemoglobin mass.

Energy Intake Compensation and Satiety After Acute Consumption of an Exogenous Ketone Monoester Drink in People With Type 2 Diabetes

Nutritional ketosis has been suggested to lower glucose levels and suppress appetite, posing therapeutic potential for people with type 2 diabetes (T2D). Recently developed exogenous ketone supplements present an alternative method to induce ketosis without severe dietary restrictions. The aims of this study were to determine if acute consumption of an exogenous ketone monoester drink influenced perceptions of hunger/fullness, energy intake and energy compensation. In a randomized, placebo-controlled, cross-over study, participants (N=18) with T2D consumed a ketone monoester drink (0.3 g/kg, equating to ∼134 kcal) or placebo (0 kcal).

The Effect of Different Ketone Supplements on Blood Beta-hydroxybutyrate and Glucose in Healthy Individuals

Acute increases in blood beta-hydroxybutyrate (BHB) temporarily reduce blood glucose but therapeutic application has been limited due to the need for ketone infusion or severe dietary restriction. Recently developed exogenous ketone monoester supplements allow to acutely raise blood BHB without the need for other nutritional modifications or invasive procedures. However, unpleasant taste and the potential for gastrointestinal discomfort make adherence to a supplement regimen challenging. Two novel ketone supplements have been developed that promise an improved consumer experience but differ in their chemical properties; it is currently unknown how these affect blood BHB and blood glucose compared to the original ketone monoester supplement.

Ketone Monoester Ingestion Alters Metabolism and Simulated Rugby Performance in Professional Players

Ketone ingestion can alter metabolism but effects on exercise performance are unclear, particularly with regard to the impact on intermittent-intensity exercise and team-sport performance. Nine professional male rugby union players each completed two trials in a double-blind, randomized, crossover design. Participants ingested either 90 ± 9g carbohydrate (CHO; 9% solution) or an energy matched solution containing 20 ± 2g CHO (3% solution) and 590mg/kg body mass β-hydroxybutyrate monoester (CHO + BHB-ME) before and during a simulated rugby union-specific match-play protocol, including repeated high-intensity, sprint and power-based performance tests. Mean time to complete the sustained high-intensity performance tests was reduced by 0.33 ± 0.41s (2.1%) with CHO + BHB-ME (15.53 ± 0.52s) compared with CHO (15.86 ± 0.80s) placebo (p = .04). Mean time to complete the sprint and power-based performance tests were not different between trials. CHO + BHB-ME resulted in blood BHB concentrations that remained >2mmol/L during exercise (p < .001). Serum lactate and glycerol concentrations were lower after CHO + BHB-ME than CHO (p < .05). Coingestion of a BHB-ME with CHO can alter fuel metabolism (attenuate circulating lactate and glycerol concentrations) and may improve high-intensity running performance during a simulated rugby match-play protocol, without improving shorter duration sprint and power-based efforts.

Evaluation of Acute Supplementation With the Ketone Ester (R)-3-Hydroxybutyl-(R)-3-Hydroxybutyrate (deltaG) in Healthy Volunteers by Cardiac and Skeletal Muscle 31P Magnetic Resonance Spectroscopy.

In this acute intervention study, we investigated the potential benefit of ketone supplementation in humans by studying cardiac phosphocreatine to adenosine-triphosphate ratios (PCr/ATP) and skeletal muscle PCr recovery using phosphorus magnetic resonance spectroscopy (31P-MRS) before and after ingestion of a ketone ester drink. We recruited 28 healthy individuals: 12 aged 23–70 years for cardiac 31P-MRS, and 16 aged 60–75 years for skeletal muscle 31P-MRS. Baseline and post-intervention resting cardiac and dynamic skeletal muscle 31P-MRS scans were performed in one visit, where 25 g of the ketone monoester, deltaG®, was administered after the baseline scan. Administration was timed so that post-intervention 31P-MRS would take place 30 min after deltaG® ingestion. The deltaG® ketone drink was well-tolerated by all participants. In participants who provided blood samples, post-intervention blood glucose, lactate and non-esterified fatty acid concentrations decreased significantly (−28.8%, p ≪ 0.001; −28.2%, p = 0.02; and −49.1%, p ≪ 0.001, respectively), while levels of the ketone body D-beta-hydroxybutyrate significantly increased from mean (standard deviation) 0.7 (0.3) to 4.0 (1.1) mmol/L after 30 min (p ≪ 0.001). There were no significant changes in cardiac PCr/ATP or skeletal muscle metabolic parameters between baseline and post-intervention. Acute ketone supplementation caused mild ketosis in blood, with drops in glucose, lactate, and free fatty acids; however, such changes were not associated with changes in 31P-MRS measures in the heart or in skeletal muscle. Future work may focus on the effect of longer-term ketone supplementation on tissue energetics in groups with compromised mitochondrial function.

No Effect of a Ketone Monoester on Markers of Stress and Performance in a Live-Burn Search and Rescue in Firefighters.

Waldman, HS, Bryant, AR, Shepherd, BD, Egan, B, and McAllister, MJ. No effect of a ketone monoester on markers of stress and performance in a live-burn search and rescue in firefighters. J Strength Cond Res 36(3): 763-771, 2022-Firefighters experience a range of stressors that impair performance and elevate the risk for developing cardiometabolic diseases. β-Hydroxybutyrate (βHB) has been shown to mitigate markers of oxidative stress and inflammation and serve as an alternative fuel with implications to physical performance. On 2 occasions in a double-blind, counterbalanced, and crossover design, 14 professional firefighters performed a live-burn, search and rescue (S&R) 30 minutes after ingestion of a ketone monoester (KME; 0.5 g·kg-1) or a placebo (PLA). Dependent variables collected before and after the S&R included salivary markers of stress and inflammation (cortisol, α-amylase, interleukin-1 beta, uric acid), perceptual markers (profile of mood state [POMS]), gastrointestinal distress (GI), rating of perceived exertion [RPE]), time to completion, and capillary blood measurement of βHB and glucose. KME resulted in capillary βHB concentrations of approximately 2.1-3.2 mM throughout the protocol. Capillary glucose concentrations were lower for the KME compared with PLA (∼7%) (interaction effect, p < 0.001). Salivary markers of stress, GI, and time to complete the S&R (∼10 minutes) did not differ between trials, although KME ingestion resulted in significantly higher RPE after the live-burn S&R (KME,6 ± 1; PLA, 4 ± 1). However, POMS data showed the KME also lowered subjective states of nervousness (KME, 0.0 ± 0.0; PLA, 0.6 ± 0.8) and anxiety (KME, 0.0 ± 0.0; PLA, 0.6 ± 0.7) before the S&R (all p < 0.05; large effect sizes). Compared with PLA, ingestion of a KME by firefighters did not mitigate the rise in various markers of salivary stress or impact physical performance during a live-burn S&R. However, differences in RPE and POMS variables were observed, suggesting a possible cognitive role for βHB.

A Non-Invasive Determination of Ketosis-Induced Elimination of Chronic Daytime Somnolence in a Patient with Late-Stage Dementia (Assessed with Type 3 Diabetes): A Potential Role of Neurogenesis.

Background:The study involved a female patient diagnosed with late-stage dementia, with chronic daytime somnolence (CDS) as a prominent symptom.Objective:To explore whether her dementia resulted from Type 3 diabetes, and whether it could be reversed through ketosis therapy.Methods:A ketogenic diet (KD) generating low-dose 100 μM Blood Ketone Levels (BKL) enhanced by a brief Ketone Mono Ester (KME) regimen with high-dose 2–4 mM BKLs was used.Results:Three sets of data describe relief (assessed by % days awake) from CDS: 1) incremental, slow, time-dependent KD plus KME-induced sigmoid curve responses which resulted in partial wakefulness (0–40% in 255 days) and complete wakefulness (40–85% in 50 days); 2) both levels of wakefulness were shown to be permanent; 3) initial permanent relief from CDS with low-dose ketosis from 6.7% to 40% took 87 days. Subsequent low-dose recovery from illness-induced CDS (6.9% to 40%) took 10 days. We deduce that the first restoration involved permanent repair, and the second energized the repaired circuits.Conclusion:The results suggest a role for ketosis in the elimination of CDS with the permanent functional restoration of the awake neural circuits of the Sleep-Wake cycle. We discuss whether available evidence supports ketosis-induced bioenergetics alone or whether other mechanisms of functional renewal were the basis for the elimination of CDS. Given evidence for permanent repair, two direct links between ketosis and neurogenesis in the adult mammalian brain are discussed: Ketosis-induced 1) brain-derived neurotrophic factor, resulting in neural progenitor/stem cell proliferation, and 2) mitochondrial bioenergetics-induced stem cell biogenesis.

Short-term ketone monoester supplementation improves cerebral blood flow and cognition in obesity: A randomized cross-over trial.

Adults with obesity are at increased risk of neurocognitive impairments, partly as a result of reduced cerebral blood flow and brain-derived neurotrophic factor (BDNF). Ketone supplements containing β-hydroxybutyrate (β-OHB) are a purported therapeutic strategy for improving brain health in at-risk populations. We tested the hypothesis that short-term β-OHB supplementation will elevate cerebral blood flow and BDNF, as well as improve cognition in adults with obesity. In a placebo-controlled double-blind, cross-over design, 14 adults with obesity (10 females; aged56±12years; body mass index=33.8±6.9kgm-2 ) consumed 30mL (12g) of β-OHB or placebo thrice-daily for 14days. Blood flow (Q) and cerebrovascular conductance (CVC) were measured in the common carotid (CCA), internal carotid (ICA) and vertebral (VA) arteries by duplex ultrasound. BDNF was measured by an enzyme-linked immunosorbent assay. Cognition was assessed by the digit-symbol substitution (DSST), Stroop and task-switching tests. Following 14days of ketone supplementation, we observed significant improvements in cerebrovascular outcomes including QCCA (+12%), QVA (+11%), VACVC (+12%) and VA shear rate (+10%). DSST performance significantly improved following ketone supplementation (+2.7 correct responses) and improved DSST performance was positively associated improvements in cerebrovascular outcomes including QCCA , CCACVC , QVA and VACVC . By contrast to one hypothesis, β-OHB did not impact fasting serum and plasma BDNF. β-OHB supplementation improved cognition in adults with obesity, which may be partly facilitated by improvements in cerebral blood flow. β-OHB supplementation was well-tolerated and appears to be safe for cerebrovascular health, suggesting potential therapeutic benefits of β-OHB in a population at risk of neurocognitive impairment. KEY POINTS: People with obesity are at increased risk of neurocognitive dysfunction, partly as a result of -induced reductions in cerebral blood flow (CBF) and brain-derived neurotrophic factor (BDNF). Ketone supplements containing β-hydroxybutyrate (β-OHB) reduce postprandial hyperglycaemia, which may increase CBF and BDNF, thereby protecting against obesity-related cognitive dysfunction. We show for the first time that 14days of thrice-daily β-OHB supplementation improves aspects of cognition and increases cerebrovascular flow, conductance and shear rate in the extracranial arteries of adults with obesity. Our preliminary data indicate a significant positive relationship between elevated CBF and improved cognition following β-OHB supplementation. This trial provides a foundation for the potential non-pharmacological therapeutic application of β-OHB supplementation in patient groups at risk of hyperglycaemic cerebrovascular disease and cognitive dysfunction.

Short‐term ketone monoester supplementation improves cerebral blood flow and cognitive function in adults with obesity: A randomized‐crossover trial

Background/Objectives Adults with obesity are at increased risk of neurocognitive impairments, due in part to reductions in cerebral blood flow (CBF) and brain-derived neurotrophic factor (BDNF). Ketone supplements containing β-hydroxybutyrate (β-OHB) are a purported therapeutic strategy for improving brain health in at-risk populations. We tested the hypothesis that short-term β-OHB supplementation will elevate CBF and BDNF, and in turn improve cognitive function in individuals with obesity. Subjects/Methods In a placebo-controlled double-blind crossover design 14 adults with obesity (10F; age=56±12 yrs; BMI=33.8±6.9 kg/m2) consumed 30 mL of either placebo or ketone supplement (12 g β-OHB) thrice-daily for 14 days. Participants were provided with all meals and snacks, which were matched between each 14-day period. CBF, cerebrovascular conductance (CVC), and shear rate were measured in the common carotid (CCA), internal carotid (ICA), and vertebral (VA) arteries by duplex ultrasound. Plasma and serum BDNF were measured by ELISA. Cognitive function was assessed by the digit-symbol substitution task (DSST), Stroop test, and task-switching test. All measures were taken in the fasting, non-supplemented state. Results CCA blood flow (25 mL×min-1 [12, 38], P=0.001), ICA shear rate (42 s-1 [15, 69], P=0.004), VA blood flow (18 mL×min-1 [10, 26], P<0.001), VACVC (0.08 mL×min-1×mmHg-1 [0.01, 0.15], P=0.027), and VA shear rate (34 s-1 [10, 59], P=0.008) significantly increased following 14-days of ketone supplementation. DSST performance (correct responses; CR) increased following ketone supplementation (+2.7 CR [1.3, 4.1], P<0.001) and this was positively associated with CCA blood flow (0.001 mL×min-1×CR-1 [0.001, 0.02], P=0.033) and CCACVC (1.24 ml×min-1×mmHg-1 CR-1 [0.24, 2.24], P=0.024), VA blood flow (0.034 mL×min-1×CR-1 [0.002, 0.066], P=0.039) and VACVC (3.32 1.24 ml×min-1×mmHg-1 CR-1 [0.20, 6.43], P=0.04). There were no differences in serum (301.8 pg/mL [-1033.4, 1637.2], P=0.65) and plasma BDNF (-380.4 pg/mL [-1023.9, 263.2], P=0.24) following ketone supplementation. Conclusions Short-duration ketone supplementation improved aspects of cognitive function, which may have been facilitated by enhanced CBF in adults with obesity. Ketone supplementation was well-tolerated and appears safe for cerebrovascular health, suggesting potential therapeutic benefits of β-OHB for brain health in adults with obesity.

Acute Nutritional Ketosis and Its Implications for Plasma Glucose and Glucoregulatory Peptides in Adults with Prediabetes: A Crossover Placebo-Controlled Randomized Trial

The potential of a ketone monoester (β-hydroxybutyrate; KEβHB) supplement to rapidly mimic a state of nutritional ketosis offers a new therapeutic possibility for diabetes prevention and management. While KEβHB supplementation has a glucose-lowering effect in adults with obesity, its impact on glucose control in other insulin-resistant states is unknown. The primary objective was to investigate the effect of KEβHB-supplemented drink on plasma glucose in adults with prediabetes. The secondary objective was to determine its impact on plasma glucoregulatory peptides. This randomized controlled trial [called CETUS (Cross-over randomizEd Trial of β-hydroxybUtyrate in prediabeteS)] included 18 adults [67% men, mean age=55 y, mean BMI (kg/m2)=28.4] with prediabetes (glycated hemoglobin between 5.7% and 6.4% and/or fasting plasma glucose between 100 and 125mg/dL). Participants were randomly assigned to receive KEβHB-supplemented and placebo drinks in a crossover sequence (washout period of 7-10 d between the drinks). Blood samples were collected from 0 to 150 min, at intervals of 30 min. Paired-samples t tests were used to investigate the change in the outcome variables [β-hydroxybutyrate (βHB), glucose, and glucoregulatory peptides] after both drinks. Repeated measures analyses were conducted to determine the change in concentrations of the prespecified outcomes over time. Blood βHB concentrations increased to 3.5mmol/L within 30 minutes after KEβHB supplementation. Plasma glucose AUC was significantly lower after KEβHB supplementation than after the placebo [mean difference (95% CI): -59(-85.3, -32.3) mmol/L × min]. Compared with the placebo, KEβHB supplementation led to significantly greater AUCs for plasma insulin [0.237 (0.044, 0.429) nmol/L × min], C-peptide [0.259 (0.114, 0.403) nmol/L × min], and glucose-dependent insulinotropic peptide [0.243 (0.085, 0.401) nmol/L × min], with no significant differences in the AUCs for amylin, glucagon, and glucagon-like peptide 1. Ingestion of the KEβHB-supplemented drink acutely increased the blood βHB concentrations and lowered the plasma glucose concentrations in adults with prediabetes. Further research is needed to investigate the dynamics of repeated ingestions of a KEβHB supplement by individuals with prediabetes, with a view to preventing new-onset diabetes. This trial was registered at www.clinicaltrials.gov as NCT03889210.

Abdominal fat distribution modulates the metabolic effects of exogenous ketones in individuals with new-onset prediabetes after acute pancreatitis: Results from a randomized placebo-controlled trial.

Exogenous ketone supplementation is emerging as a nutritional intervention that beneficially affects blood glucose control. We hypothesized that varying abdominal fat phenotypes play a role in the effect of exogenously induced ketosis. The aim was to investigate whether intra-abdominal fat distribution modulates the effect of exogenous ketones on glucoregulatory peptides in new-onset prediabetes. Eighteen individuals with new-onset prediabetes after acute pancreatitis were randomized to receive a ketone monoester supplement or placebo in a crossover fashion. All participants underwent magnetic resonance imaging on a 3T scanner to determine their abdominal fat phenotypes. They were non-exclusively categorized as low adiposity or high adiposity phenotypes based on their abdominal and ectopic fat distribution (regardless of body mass index and waist circumference). Blood samples were analyzed for glucoregulatory peptides. Total area under the curve (AUC) over 150min was calculated for each analyte. The total AUCs for insulin and C-peptide were significantly higher after ketone supplementation in individuals with high intra-pancreatic fat deposition, skeletal muscle fat deposition, and subcutaneous fat volume; and low visceral fat volume and intra-hepatic fat deposition. The total AUC for glucose-dependent insulinotropic peptide was significantly higher after ketone supplementation in individuals with high intra-pancreatic fat deposition, skeletal muscle fat deposition, subcutaneous fat volume, and visceral fat volume. The total AUC for glucagon-like peptide-1 was not associated with any adiposity phenotype. Individuals with high depositions of intra-pancreatic fat, skeletal muscle fat, subcutaneous fat may not achieve favorable outcomes of blood glucose control following ketone supplementation. Abdominal fat distribution is an important factor in the pathogenesis of new-onset prediabetes and it may influence the effectiveness of nutritional strategies designed for these individuals. REGISTERED UNDER CLINICALTRIALS. NCT03889210.

Increased cardiorespiratory stress during submaximal cycling after ketone monoester ingestion in endurance-trained adults.

There is growing interest in the effect of exogenous ketone body supplementation on exercise responses and performance. The limited studies to date have yielded equivocal data, likely due in part to differences in dosing strategy, increase in blood ketones, and participant training status. Using a randomized, double-blind, counterbalanced design, we examined the effect of ingesting a ketone monoester (KE) supplement (600 mg/kg body mass) or flavour-matched placebo in endurance-trained adults (n = 10 males, n = 9 females; V̇O2peak = 57 ± 8 mL/kg/min). Participants performed a 30-min cycling bout at ventilatory threshold intensity (71 ± 3% V̇O2peak), followed 15 min later by a 3 kJ/kg body mass time-trial. KE versus placebo ingestion increased plasma β-hydroxybutyrate concentration before exercise (3.9 ± 1.0 vs 0.2 ± 0.3 mM, p < 0.0001, dz = 3.4), ventilation (77 ± 17 vs 71 ± 15 L/min, p < 0.0001, dz = 1.3) and heart rate (155 ± 11 vs 150 ± 11 beats/min, p < 0.001, dz = 1.2) during exercise, and rating of perceived exertion at the end of exercise (15.4 ± 1.6 vs 14.5 ± 1.2, p < 0.01, dz = 0.85). Plasma β-hydroxybutyrate concentration remained higher after KE vs placebo ingestion before the time-trial (3.5 ± 1.0 vs 0.3 ± 0.2 mM, p < 0.0001, dz = 3.1), but performance was not different (KE: 16:25 ± 2:50 vs placebo: 16:06 ± 2:40 min:s, p = 0.20; dz = 0.31). We conclude that acute ingestion of a relatively large KE bolus dose increased markers of cardiorespiratory stress during submaximal exercise in endurance-trained participants. Novelty: Limited studies have yielded equivocal data regarding exercise responses after acute ketone body supplementation. Using a randomized, double-blind, placebo-controlled, counterbalanced design, we found that ingestion of a large bolus dose of a commercial ketone monoester supplement increased markers of cardiorespiratory stress during cycling at ventilatory threshold intensity in endurance-trained adults.

Exogenous Ketones Lower Post-exercise Acyl-Ghrelin and GLP-1 but Do Not Impact Ad libitum Energy Intake.

Ketosis and exercise are both associated with alterations in perceived appetite and modification of appetite-regulating hormones. This study utilized a ketone ester (R)-3-hydroxybutyl (R)-3-hydroxybutyrate (KE) to examine the impact of elevated ketone body D-β-hydroxybutyrate (βHB) during and after a bout of exercise on appetite-related hormones, appetite perception, and ad libitum energy intake over a 2 h post-exercise period. In a randomized crossover trial, 13 healthy males and females (age: 23.6 ± 2.4 years; body mass index: 25.7 ± 3.2 kg·m−2) completed an exercise session @ 70% VO2peak for 60 min on a cycling ergometer and consumed either: (1) Ketone monoester (KET) (0.5 g·kg−1 pre-exercise + 0.25 g·kg−1 post-exercise); or (2) isocaloric dextrose control (DEX). Transient ketonaemia was achieved with βHB concentrations reaching 5.0 mM (range 4.1–6.1 mM) during the post-exercise period. Relative to the dextrose condition, acyl-ghrelin (P = 0.002) and glucagon-like peptide-1 (P = 0.038) were both reduced by acute ketosis immediately following exercise. AUC for acyl-ghrelin was lower in KET compared to DEX (P = 0.001), however there were no differences in AUC for GLP-1 (P = 0.221) or PYY (P = 0.654). Perceived appetite (hunger, P = 0.388; satisfaction, P = 0.082; prospective food consumption, P = 0.254; fullness, P = 0.282) and 2 h post-exercise ad libitum energy intake (P = 0.488) were not altered by exogenous ketosis. Although KE modifies homeostatic regulators of appetite, it does not appear that KE acutely alters energy intake during the post-exercise period in healthy adults.

Effects of ketogenic diet and ketone monoester supplement on acute alcohol withdrawal symptoms in male mice.

After alcohol ingestion, the brain partly switches from consumption of glucose to consumption of the alcohol metabolite acetate. In heavy drinkers, the switch persists after abrupt abstinence, leading to the hypothesis that the resting brain may be "starved" when acetate levels suddenly drop during abstinence, despite normal blood glucose, contributing to withdrawal symptoms. We hypothesized that ketone bodies, like acetate, could act as alternative fuels in the brain and alleviate withdrawal symptoms. We previously reported that a ketogenic diet during alcohol exposure reduced acute withdrawal symptoms in rats. Here, our goals were to test whether (1) we could reproduce our findings, in mice and with longer alcohol exposure; (2) ketone bodies alone are sufficient to reduce withdrawal symptoms (clarifying mechanism); (3) introduction of ketogenic diets at abstinence (a clinically more practical implementation) would also be effective. Male C57BL/6NTac mice had intermittent alcohol exposure for 3 weeks using liquid diet. Somatic alcohol withdrawal symptoms were measured as handling-induced convulsions; anxiety-like behavior was measured using the light-dark transition test. We tested a ketogenic diet, and a ketone monoester supplement with a regular carbohydrate-containing diet. The regular diet with ketone monoester was sufficient to reduce handling-induced convulsions and anxiety-like behaviors in early withdrawal. Only the ketone monoester reduced handling-induced convulsions when given during abstinence, consistent with faster elevation of blood ketones, relative to ketogenic diet. These findings support the potential utility of therapeutic ketosis as an adjunctive treatment in early detoxification in alcohol-dependent patients seeking to become abstinent. clinicaltrials.gov NCT03878225, NCT03255031.

Effect of β-hydroxybutyrate monoester on markers of iron metabolism in new-onset prediabetes: findings from a randomised placebo-controlled trial.

Background: People with prediabetes often have altered iron metabolism and may benefit from mild exogenous ketosis, which can now be successfully achieved thanks to recent developments in chemistry of food components. Objective: The objective was to investigate the effect of acute exogenous ketone monoester (β-hydroxybutyrate) on plasma levels of markers of iron metabolism in people with prediabetes. Methods: Eighteen participants with new-onset prediabetes after acute pancreatitis aged 18 years or above took part in randomised controlled cross-over trial in Auckland, New Zealand. After an overnight fast, participants consumed the exogenous ketone supplement or placebo. Blood samples were collected in the fasted state (0 minutes) and then serially every 30 minutes for 150 minutes. Both participants and study personnel were blinded to the intervention/placebo allocation. Repeated measures analysis of variance was performed using total area under the curve to determine the change in hepcidin and ferritin over time after consumption of the exogenous ketone supplement and placebo. Results: Consumption of the exogenous ketone supplement significantly elevated blood levels of β-hydroxybutyrate from 0.20 mmol L-1 at baseline to 3.50 mmol L-1 at 30 minutes (p < 0.05) and remained significantly elevated for the duration of the trial. The total area under the curve of hepcidin was 340.5 ± 121.1 ng mL-1 after the exogenous ketone supplementation as compared with 343.2 ± 119.6 ng mL-1 min-1 after the use of placebo (p = 0.91). The total area under the curve of ferritin was 786.7 ± 129.1 ng mL-1 min-1 after the exogenous ketone supplementation as compared with 776.9 ± 131.4 ng mL-1 min-1 after the use of placebo (p = 0.10). Conclusion: Acute supplementation of β-hydroxybutyrate did not significantly affect the circulating levels of hepcidin or ferritin in people with prediabetes. Long-term effects of β-hydroxybutyrate warrant investigations in the future.

14-Day Ketone Supplementation Lowers Glucose and Improves Vascular Function in Obesity: A Randomized Crossover Trial.

Postprandial hyperglycemia increases systemic inflammation and is a risk factor for cardiovascular disease. A ketone monoester (KME) drink containing β-hydroxybutyrate (β-OHB) rapidly lowers plasma glucose, which may be a strategy protecting against postprandial hyperglycemia. We hypothesized that KME would attenuate 2-hour postprandial glucose, lower systemic inflammation, and improve vascular function in adults with obesity. In a randomized crossover design, 14 participants with obesity (age = 56 ± 12 years; body mass index = 32.8 ± 7.7 kg/m2) consumed KME (12 g β-OHB) or placebo 15 minutes prior to each meal for 14 days with all meals provided and matched between conditions. Postprandial glycemia was assessed by continuous glucose monitoring. Vascular function and inflammation were assessed before and after treatment periods. Postprandial glucose was 8.0% lower in KME versus placebo (g = 0.735; P = 0.011) and 24-hour average glucose reduced by 7.8% (g = 0.686; P = 0.0001). Brachial artery flow-mediated dilation increased from 6.2 ± 1.5% to 8.9 ± 3.3% in KME (g = 1.05; P = 0.0004) with no changes in placebo (condition × time interaction, P = 0.004). There were no changes in plasma cytokines; however, lipopolysaccharide-stimulated monocyte caspase-1 activation was lower following KME supplementation versus placebo (stimulation × condition × time interaction; P = 0.004). The KME supplement was well tolerated by participants and adherence to the supplementation regimen was very high. In adults with obesity, 14 days of premeal KME supplementation improves glucose control, enhances vascular function, and may reduce cellular inflammation. KME supplementation may be a viable, nonpharmacological approach to improving and protecting vascular health in people with heightened cardiometabolic risk.

The ketone ester, 3-hydroxybutyl-3-hydroxybutyrate, attenuates neurobehavioral deficits and improves neuropathology following controlled cortical impact in male rats

ABSTRACT Traumatic brain injury (TBI) is a leading cause of human death and disability with no effective therapy to fully prevent long-term neurological deficits in surviving patients. Ketone ester supplementation is protective in animal models of neurodegeneration, but its efficacy against TBI pathophysiology is unknown. Here, we assessed the neuroprotective effect of the ketone monoester, 3-hydroxybutyl-3-hydroxybutyrate, (KE) in male Sprague Dawley rats (n=32). TBI was induced using the controlled cortical impact (CCI) with Sham animals not receiving the brain impact. KE was administered daily by oral gavage (0.5 ml/kg/day) and provided ad libitum at 0.3% (v/v) in the drinking water. KE supplementation started immediately after TBI and lasted for the duration of the study. Motor and sensory deficits were assessed using the Neurobehavioral Severity Scale-Revised (NSS-R) at four weeks post-injury. The NSS-R total score in CCI + KE (1.2 ± 0.4) was significantly lower than in CCI + water (4.4 ± 0.5). Similarly, the NSS-R motor scores in CCI + KE (0.6 ± 0.7) were significantly lower than CCI + water (2.9 ± 1.5). Although the NSS-R sensory score in the CCI + KE group (0.5 ± 0.2) was significantly lower compared to CCI + water (1.8 ± 0.4), no difference was observed between CCI + water and Sham + water (1.0 ± 0.2) groups. The lesion volume was smaller in the CCI + KE (10 ± 3 mm3) compared to CCI + water (47 ± 11 mm3; p < 0.001). KE significantly decreased Iba1+ stained areas in the cortex and hippocampus, and GFAP+ stained areas in all brain regions analyzed – prefrontal cortex, hippocampus, cortex, amygdala (p < 0.01). In summary, our results indicate that KE can protect against TBI-induced morphological and functional deficits when administered immediately after an insult.

Ketone Monoester Supplementation Does Not Expedite the Recovery of Indices of Muscle Damage After Eccentric Exercise

Purpose: The purpose of this study was to evaluate the effects of a ketone monoester supplement on indices of muscle damage during recovery after eccentric exercise.Methods: In a randomized, double-blind, independent group design, 20 moderately active healthy young adults consumed 360 mg per kg−1 bodyweight of a ketone monoester (KET) or energy-matched carbohydrate (CON) supplement twice daily following eccentric exercise (drop jumps). Maximal isometric voluntary contraction (MIVC) torque, counter-movement jump (CMJ) height, and muscle soreness were measured before (PRE), and immediately (POST), 24 h and 48 h post-exercise. Blood samples were collected for analysis of β-hydroxybutyrate (β-OHB), creatine kinase (CK), and select pro- and anti-inflammatory cytokines.Results: Peak blood β-OHB concentration after supplement intake was greater (P < 0.001) in KET (4.4 ± 0.8 mM) vs. CON (0.4 ± 0.3 mM). Exercise increased CK concentration at 24 h and 48 h vs. PRE (time: P < 0.001) with no difference between KET and CON. Exercise reduced MIVC (KET: −19.9 ± 14.6; CON: −22.6 ± 11.1%) and CMJ (KET: −11.0 ± 7.5; CON: −13.0 ± 8.7%) at POST relative PRE; however, there was no difference between KET and CON on the recovery of MIVC at 24 h (KET: −15.4 ± 20.4; CON: −18.7 ± 20.1%) or 48 h (KET: −7.2 ± 21.2; CON: −11.8 ± 20.2%), or CMJ at 24 h (KET: −9.2 ± 11.5; CON: −13.4 ± 10.8) or 48 h (KET: −12.5 ± 12.4; CON: −9.1 ± 11.7). Muscle soreness was increased during post-exercise recovery (time: P < 0.001) with no differences between KET and CON. Monocyte chemoattractant protein-1 was greater (group: P = 0.007) in CON (236 ± 11 pg/mL) vs. KET (187 ± 11 pg/mL).Conclusion: In conclusion, twice daily ingestion of a ketone monoester supplement that acutely elevates blood β-OHB concentration does not enhance the recovery of muscle performance or reduce muscle soreness following eccentric exercise in moderately active, healthy young adults.

Ketone bodies as an energy source: regular-grade, premium, or super-fuel to power the mitochondrial engine?

Ketone bodies as an energy source: regular-grade, premium, or super-fuel to power the mitochondrial engine?

Ingestion of an exogenous ketone monoester improves the glycemic response during oral glucose tolerance test in individuals with impaired glucose tolerance: A cross-over randomized trial.

Aims/IntroductionAs a low‐carbohydrate diet and the use of sodium–glucose transporter‐2 inhibitors are both known to increase D‐beta‐hydroxybutyrate levels, the effect of these levels on glucose metabolism has attracted attention. We investigated the acute effects of ketone monoester (KM) ingestion on blood glucose levels during the 75‐g oral glucose tolerance test (OGTT) in participants with impaired glucose tolerance.Materials and MethodsNine Japanese adults aged 48–62 years (4 men, 5 women) with impaired glucose tolerance participated in this study. After participants fasted overnight, we carried out OGTT for 180 min with and without KM ingestion on two separate days in a randomized cross‐over design. We compared the area under the curve (AUC) of D‐beta‐hydroxybutyrate, glucose, insulin, C‐peptide, glucagon and free fatty acids during OGTT.ResultsThe AUC of D‐beta‐hydroxybutyrate during OGTT was significantly higher with KM than without KM (KM 5995.3 ± 1257.1 mmol/L·h; without KM 116.1 ± 33.9 mmol/L·h, P < 0.0001), and the AUC of glucose with KM was significantly lower than that without KM (KM 406.6 ± 70.6 mg/dL·h; without KM 483.2 ± 74.3 mg/dL·h, P < 0.0001). This improved glucose excursion was associated with enhanced AUC of insulin during the first half (0–90 min) of OGTT, even though the AUC of C‐peptide during this period was unchanged. In contrast, the AUC of insulin, C‐peptide, glucagon and free fatty acids during 180 min of OGTT were similar in both conditions.ConclusionThe ingestion of KM decreased the AUC of glucose during 75‐g OGTT in Japanese individuals with impaired glucose tolerance, and the mechanism might involve elevated levels of circulating early phase insulin.