Ketones: potential to achieve brain energy rescue and sustain cognitive health during ageing.

Alzheimer's disease (AD) is the most common major neurocognitive disorder of ageing. Although largely ignored until about a decade ago, accumulating evidence suggests that deteriorating brain energy metabolism plays a key role in the development and/or progression of AD-associated cognitive decline. Brain glucose hypometabolism is a well-established biomarker in AD but was mostly assumed to be a consequence of neuronal dysfunction and death. However, its presence in cognitively asymptomatic populations at higher risk of AD strongly suggests that it is actually a pre-symptomatic component in the development of AD. The question then arises as to whether progressive AD-related cognitive decline could be prevented or slowed down by correcting or bypassing this progressive 'brain energy gap'. In this review, we provide an overview of research on brain glucose and ketone metabolism in AD and its prodromal condition ­ mild cognitive impairment (MCI) ­ to provide a clearer basis for proposing keto-therapeutics as a strategy for brain energy rescue in AD. We also discuss studies using ketogenic interventions and their impact on plasma ketone levels, brain energetics and cognitive performance in MCI and AD. Given that exercise has several overlapping metabolic effects with ketones, we propose that in combination these two approaches might be synergistic for brain health during ageing. As cause-and-effect relationships between the different hallmarks of AD are emerging, further research efforts should focus on optimising the efficacy, acceptability and accessibility of keto-therapeutics in AD and populations at risk of AD.

A ketogenic drink improves cognition in mild cognitive impairment: Results of a 6-month RCT.

INTRODUCTION: Counteracting impaired brain glucose metabolism with ketones may improve cognition in mild cognitive impairment (MCI). METHODS: Cognition, plasma ketone response, and metabolic profile were assessed before and 6 months after supplementation with a ketogenic drink containing medium chain triglyceride (ketogenic medium chain triglyceride [kMCT]; 15 g twice/day; n = 39) or placebo (n = 44). RESULTS: Free and cued recall (Trial 1; P = .047), verbal fluency (categories; P = .024), Boston Naming Test (total correct answers; P = .033), and the Trail-Making Test (total errors; P = .017) improved significantly in the kMCT group compared to placebo (analysis of covariance; pre-intervention score, sex, age, education, and apolipoprotein E4 as covariates). Some cognitive outcomes also correlated positively with plasma ketones. Plasma metabolic profile and ketone response were unchanged. CONCLUSIONS: This kMCT drink improved cognitive outcomes in MCI, at least in part by increasing blood ketone level. These data support further assessment of MCI progression to Alzheimer's disease.

Sprint exercise snacks: a novel approach to increase aerobic fitness.

PURPOSE: Sprint interval training (SIT), involving brief intermittent bursts of vigorous exercise within a single training session, is a time-efficient way to improve cardiorespiratory fitness (CRF). It is unclear whether performing sprints spread throughout the day with much longer (≥ 1 h) recovery periods can similarly improve CRF, potentially allowing individuals to perform "sprint snacks" throughout the day to gain health benefits. METHODS: Healthy, young, inactive adults (~ 22 years, peak oxygen uptake [VO2peak] ~ 35 ml kg- 1 min- 1) were randomly assigned to one of two groups and performed 18 training sessions over 6 wks. Sprint snacks (SS) involved 3 × 20-s 'all out' cycling bouts separated by 1-4-h rest (n = 12, 7 females). Traditional SIT involved 3 × 20-s bouts interspersed with 3-min rest within a 10-min training session (n = 16, 7 females). The primary outcome was CRF determined by a VO2peak test conducted before and after training. Secondary outcomes included a 150 kJ cycling time trial and exercise enjoyment. RESULTS: Absolute VO2peak increased by ~ 6% after SIT and ~ 4% for SS (main effect of time P = 0.002) with no difference between groups (group × time interaction, P = 0.52). 150 kJ time trial performance improved by ~ 13% in SIT and ~ 9% in SS (main effect of time, P < 0.001) with no difference between groups (group × time interaction, P = 0.36). CONCLUSION: CRF was similarly increased by a protocol involving sprint snacks spread throughout the day and a traditional SIT protocol in which bouts were separated by short recovery periods within a single training session.

Prior ingestion of exogenous ketone monoester attenuates the glycaemic response to an oral glucose tolerance test in healthy young individuals.

KEY POINTS: The recent development of exogenous ketone supplements allows direct testing of the metabolic effects of elevated blood ketones without the confounding influence of widespread changes experienced with ketogenic diets or prolonged fasting. In the present study, we determined the effect of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate ketone monoester on the glycaemic response and insulin sensitivity index during a 2 h oral glucose tolerance test (OGTT) in humans. The results obtained show that consuming a ketone monoester supplement 30 min prior to an OGTT reduced the glycaemic response and markers of insulin sensitivity without affecting insulin secretion. The findings of the present study provides evidence that ketone supplements could have therapeutic potential for future application as a glucose-lowering nutritional supplement. ABSTRACT: The main objectives of the present study were: (i) to determine whether acute ingestion of ketone monoester (Kme ); (R)-3-hydroxybutyl (R)-3-hydroxybutyrate impacts plasma glucose levels during a standardized oral glucose tolerance test (OGTT) and (ii) to compare changes in insulin concentrations and estimates of insulin sensitivity after acute Kme supplementation. Twenty healthy participants (n = 10 males/females) aged between 18 and 35 years took part in a randomized cross-over study. After an overnight fast, participants consumed a Kme supplement (ΔG®; TΔS Ltd, UK, Oxford, UK; 0.45 ml kg-1 body weight) or placebo (water) 30 min before completing a 75 g OGTT. Blood samples were collected every 15-30 min over 2.5 h. The participants and study personnel performing the laboratory analyses were blinded to the study condition. Kme acutely raised blood d-beta-hydroxybutyrate (ß-OHB) to 3.2 ± 0.6 mm within 30 min with levels remaining elevated throughout the entire OGTT. Compared to placebo, Kme significantly decreased the glucose area under the curve (AUC; -17%, P = 0.001), non-esterified fatty acid AUC (-44%, P < 0.001) and C-peptide incremental AUC (P = 0.005), at the same time as improving oral glucose insulin sensitivity index by ∼11% (P = 0.001). In conclusion, a Kme supplement that acutely increased ß-OHB levels up to ∼3 mm attenuated the glycaemic response to an OGTT in healthy humans. The reduction in glycaemic response did not appear to be driven by an increase in insulin secretion, although it was accompanied by improved markers of insulin sensitivity. These results suggest that ketone monoester supplements could have therapeutic potential in the management and prevention of metabolic diseases.

Carbohydrate restriction with postmeal walking effectively mitigates postprandial hyperglycemia and improves endothelial function in type 2 diabetes.

Postprandial hyperglycemia has deleterious effects on endothelial function. Restricting carbohydrate intake and postmeal walking have each been shown to reduce postprandial hyperglycemia, but their combination and subsequent effects on endothelial function have not been investigated. Here, we sought to examine the effect of blunting postprandial hyperglycemia by following a low-carbohydrate diet, with or without postmeal walking exercise, on markers of vascular health in type 2 diabetes (T2D). In a randomized crossover design, individuals with T2D ( n = 11) completed three 4-day controlled diet interventions consisting of 1) low-carbohydrate diet alone (LC), 2) low-carbohydrate diet with 15-min postmeal walks (LC + Ex), and 3) low-fat control diet (CON). Fasting blood samples and brachial artery flow-mediated dilation (%FMD) were measured before and after each intervention. Total circulating microparticles (MPs), endothelial MPs, platelet MPs, monocyte-platelet aggregates, and adhesion molecules were assessed as biomarkers of vascular health. There was a significant condition × time interaction for %FMD ( P = 0.01), with post hoc tests revealing improved %FMD after LC + Ex (+0.8 ± 1.0%, P = 0.02), with no change after LC or CON. Endothelial MPs were significantly reduced with the LC diet by ~45% (from 99 ± 60 to 44 ± 31 MPs/µl, P = 0.02), with no change after LC + Ex or CON (interaction: P = 0.04). Total MPs were lower (main effect time: P = 0.02), whereas monocyte-platelet aggregates were higher (main effect time: P < 0.01) after all interventions. Plasma adhesion molecules and C-reactive protein were unaltered. Attenuating postprandial hyperglycemic excursions using a low-carbohydrate diet combined with postmeal walking appears to be an effective strategy to improve endothelial function in individuals with T2D. NEW & NOTEWORTHY Carbohydrate restriction and postmeal walking lower postprandial hyperglycemia in individuals with type 2 diabetes. Here, we show that the combination significantly improved endothelial function and that carbohydrate restriction alone reduced circulating endothelial microparticles in individuals with type 2 diabetes. Listen to this article's corresponding podcast at http://ajpheart.podbean.com/e/low-carb-diet-and-exercise-improve-endothelial-health/ .

The effect of a short-term low-carbohydrate, high-fat diet with or without postmeal walks on glycemic control and inflammation in type 2 diabetes: a randomized trial.

Lowering carbohydrate consumption effectively lowers glucose, but impacts on inflammation are unclear. The objectives of this study were to: 1) determine whether reducing hyperglycemia by following a low-carbohydrate, high-fat (LC) diet could lower markers of innate immune cell activation in type 2 diabetes (T2D) and 2) examine if the combination of an LC diet with strategically timed postmeal walking was superior to an LC diet alone. Participants with T2D ( n = 11) completed a randomized crossover study involving three 4-day diet interventions: 1) low-fat low-glycemic index (GL), 2) and 3) LC with 15-min postmeal walks (LC+Ex). Four-day mean glucose was significantly lower in the LC+Ex group as compared with LC (-5%, P < 0.05), whereas both LC+Ex (-16%, P < 0.001) and LC (-12%, P < 0.001) conditions were lower than GL. A significant main effect of time was observed for peripheral blood mononuclear cells phosphorylated c-Jun N-terminal kinase ( P < 0.001), with decreases in all three conditions (GL: -32%, LC: -45%, and LC+Ex: -44%). A significant condition by time interaction was observed for monocyte microparticles ( P = 0.040) with a significant decrease in GL (-76%, P = 0.035) and a tendency for a reduction in LC (-70%, P = 0.064), whereas there was no significant change in LC+Ex (0.5%, P = 0.990). Both LC (-27%, P = 0.001) and LC+Ex (-35%, P = 0.005) also led to significant reductions in circulating proinsulin. An LC diet improved 4-day glycemic control and fasting proinsulin levels when compared with GL, with added glucose-lowering benefits when LC was combined with postmeal walking.

Creatine Monohydrate Supplementation Does Not Augment Fitness, Performance, or Body Composition Adaptations in Response to Four Weeks of High-Intensity Interval Training in Young Females.

High-intensity interval training (HIIT) has been shown to improve cardiorespiratory fitness, performance, body composition, and insulin sensitivity. Creatine (Cr) supplementation may augment responses to HIIT, leading to even greater physiological adaptations. The purpose of this study was to determine the effects of 4 weeks of HIIT (three sessions/week) combined with Cr supplementation in recreationally active females. Seventeen females (age = 23 ± 4 yrs; BMI = 23.4 ± 2.4) were randomly assigned to either Cr (Cr; 0.3 g・kg-1・d-1 for 5 d followed by 0.1 g・kg-1・d-1 for 23 days; n = 9) or placebo (PLA; n = 8). Before and after the intervention, VO2peak, ventilatory threshold (VT), time-trial performance, lean body mass and fat mass, and insulin sensitivity were assessed. HIIT improved VO2peak (Cr = +10.2%; PLA = +8.8%), VT (Cr = +12.7%; PLA = +9.9%), and time-trial performance (Cr = -11.5%; PLA = -11.6%) with no differences between groups (time main effects, all p < .001). There were no changes over time for fat mass (Cr = -0.3%; PLA = +4.3%), whole-body lean mass (Cr = +0.5%; PLA = -0.9%), or insulin resistance (Cr = +3.9%; PLA = +18.7%). In conclusion, HIIT is an effective way to improve cardiorespiratory fitness, VT, and time-trial performance. The addition of Cr to HIIT did not augment improvements in cardiorespiratory fitness, performance or body composition in recreationally active females.

A Randomized Crossover Pilot Study Evaluating Glucose Control During Exercise Initiated 1 or 2 h After a Meal in Adults with Type 1 Diabetes Treated with an Automated Insulin Delivery System.

Aims: To assess the safety and efficacy of two exercise sessions performed 60- and 120-min postmeal with a combination of meal bolus reduction and increased glucose target to the automated insulin delivery (AID) system. Methods: A randomized crossover trial in 13 adult participants (6 females) living with type 1 diabetes using AID (A1c = 7.9% ± 0.6%, age = 53.5 ± 15.5 years, T1D duration = 29.0 ± 16.0 years) was conducted. Just before breakfast, at the time of meal bolus, the AID glucose target was increased from 6 to 9 mmol/L, and a meal bolus reduction of 33% was applied. Two 60-min exercise sessions (60% of VO2 peak) were undertaken either 60 min (60EX) or 120 min (120EX) after a standardized breakfast, followed by a 90-min recovery period. Results: The mean reduction in plasma glucose (PG) levels from prebreakfast to postexercise (-0.8 ± 2.4 mmol/L vs. +0.3 ± 2.3 mmol/L, P = 0.082) were similar between 60EX and 120EX. From prebreakfast to postexercise, PG times in range (3.9-10.0 mmol/L; 63.4% ± 43.1% 60EX vs. 51.9% ± 29.7% 120EX, P = 0.219) and time above range (>10.0 mmol/L; 36.3% ± 43.3% 60EX vs. 48.1% ± 29.7% 120EX, P = 0.211) did not differ between interventions. The 60EX attenuated the glucose rise between premeal to pre-exercise (+1.8 ± 2.1 mmol/L 60EX vs. +3.9 ± 2.1 mmol/L 120EX, P = 0.001). No hypoglycemic events (<3.9 mmol/L) occurred during the study. Conclusion: Premeal announcement combining meal bolus reduction and increased glucose target was effective and safe during 60 min of moderate-intensity aerobic exercise, whether exercise onset was 60 or 120 min following a meal. Clinical Trial Registration No.: NCT04031599.

Validity and reliability of the Horiba C-122 compact sodium analyzer in sweat samples of athletes.

Accurate sodium replacement during prolonged exercise is possible when sweat rate and sweat sodium content are directly measured. Few athletes have access to sweat sodium content measurement, as the equipment needed to perform such analyzes is costly, laboratory-based or requires technical skills. Using 70 sweat samples collected in 24 athletes from 3 anatomical sites, this study determined the reliability [single-trial and inter-day (7 samples over 3 days)] and validity (instrument error) of a pocket-sized, easy-to-use and low cost sodium analyzer (Horiba C-122, Kyoto, Japan) against reference values of an ion chromatograph, the 883 Basic IC plus (Metrohm AG, Herisau, Switzerland). The Horiba C-122 showed high single-trial reliability with an intraclass correlation coefficient (ICC) of 0.997, a typical error of measurement (EM) of 1.77 mmol/L and a coefficient of variation (CV) of 3.73%. As expected, the reliability of the 883 Basic IC plus was superior to that of the Horiba C-122 (ICC: 0.999; typical EM: 0.70 mmol/L; CV: 1.52%). The Horiba's C-122 inter-day reliability was high (ICC: 1.00; typical EM: 0.35 mmol/L). An ICC of 0.975 indicates there was a strong relationship between results provided by both analyzers. Compared with reference values, the Horiba C-122 demonstrated a mean bias of 1.71 mmol/L, a pure EM of 7.52 mmol/L and 68% limits of agreement ranging from -5.81 to 9.23 mmol/L. We propose that the Horiba C-122 is sufficiently reliable to be used under field conditions where some degree of imprecision is acceptable, but not for research purposes where high accuracy is required.

Prevalence of nocturnal hypoglycemia in free-living conditions in adults with type 1 diabetes: What is the impact of daily physical activity?

Objective: Studies investigating strategies to limit the risk of nocturnal hypoglycemia associated with physical activity (PA) are scarce and have been conducted in standardized, controlled conditions in people with type 1 diabetes (T1D). This study sought to investigate the effect of daily PA level on nocturnal glucose management in free-living conditions while taking into consideration reported mitigation strategies to limit the risk of nocturnal hyoglycemia in people with T1D. Methods: Data from 25 adults (10 males, 15 females, HbA1c: 7.6 ± 0.8%), 20-60 years old, living with T1D, were collected. One week of continuous glucose monitoring and PA (assessed using an accelerometer) were collected in free-living conditions. Nocturnal glucose values (midnight-6:00 am) following an active day "ACT" and a less active day "L-ACT" were analyzed to assess the time spent within the different glycemic target zones (<3.9 mmol/L; 3.9 - 10.0 mmol/L and >10.0 mmol/L) between conditions. Self-reported data about mitigation strategies applied to reduce the risk of nocturnal hypoglycemia was also analyzed. Results: Only 44% of participants reported applying a carbohydrate- or insulin-based strategy to limit the risk of nocturnal hypoglycemia on ACT day. Nocturnal hypoglycemia occurrences were comparable on ACT night versus on L-ACT night. Additional post-meal carbohydrate intake was higher on evenings following ACT (27.7 ± 15.6 g, ACT vs. 19.5 ± 11.0 g, L-ACT; P=0.045), but was frequently associated with an insulin bolus (70% of participants). Nocturnal hypoglycemia the night following ACT occurred mostly in people who administrated an additional insulin bolus before midnight (3 out of 5 participants with nocturnal hypoglycemia). Conclusions: Although people with T1D seem to be aware of the increased risk of nocturnal hypoglycemia associated with PA, the risk associated with additional insulin boluses may not be as clear. Most participants did not report using compensation strategies to reduce the risk of PA related late-onset hypoglycemia which may be because they did not consider habitual PA as something requiring treatment adjustments.

Metabolic Effect of Breaking Up Prolonged Sitting with Stair Climbing Exercise Snacks.

PURPOSE: Prolonged sitting is associated with cardiometabolic complications. The study purpose was to investigate whether breaking up prolonged sitting with brief stair climbing exercise "snacks" could lower postprandial insulin, glucose, and free fatty acids responses. METHODS: In two separate randomized crossover studies, 12 young healthy-weight men (study 1) and 11 adults with overweight/obesity (OW; study 2) completed two experimental conditions: i) sedentary (SED; 9-h sitting) and ii) stair climbing snacks (SS; 8 × 15-30 s once per hour). The same high-glycemic index meals were consumed at 0, 3, and 6 h at each condition. The primary outcome was total insulin area under the curve (AUC) across 9 h. RESULTS: In healthy-weight men, there were no significant differences between SS and SED for total (9-h) insulin AUC (P = 0.24, d = 0.4), total glucose AUC (P = 0.17, d = 0.48), total nonesterified fatty acid (NEFA) AUC (P = 0.22, d = 0.4), or total triglyceride AUC (P = 0.72). In adults with OW, total insulin AUC (-16.5%, P = 0.036, d = 0.94) and total NEFA AUC (-21%, P = 0.016, d = 1.2) were significantly lower in SS versus SED. No differences were found for total glucose and triglyceride AUC (all, P > 0.31) in participants with OW. CONCLUSIONS: Breaking up 9 h of prolonged sitting with hourly brief stair climbing exercise snacks lowered postprandial insulin and NEFA levels in adults with overweight/obesity.

Minimizing the Risk of Exercise-Induced Glucose Fluctuations in People Living With Type 1 Diabetes Using Continuous Subcutaneous Insulin Infusion: An Overview of Strategies.

Physical activity (PA) is important for individuals living with type 1 diabetes (T1D) due to its various health benefits. Nonetheless, maintaining adequate glycemic control around PA remains a challenge for many individuals living with T1D because of the difficulty in properly managing circulating insulin levels around PA. Although the most common problem is increased incidence of hypoglycemia during and after most types of PA, hyperglycemia can also occur. Accordingly, a large proportion of people living with T1D are sedentary partly due to the fear of PA-associated hypoglycemia. Continuous subcutaneous insulin infusion (CSII) offers a higher precision and flexibility to adjust insulin basal rates and boluses according to the individual's specific needs around PA practice. Indeed, for physically active patients with T1D, CSII can be a preferred option to facilitate glucose regulation. To our knowledge, there are no guidelines to manage exercise-induced hypoglycemia during PA, specifically for individuals living with T1D and using CSII. In this review, we highlight the current state of knowledge on exercise-related glucose variations, especially hypoglycemic risk and its underlying physiology. We also detail the current recommendations for insulin modulations according to the different PA modalities (type, intensity, duration, frequency) in individuals living with T1D using CSII.

The effect of a 6-month ketogenic medium-chain triglyceride supplement on plasma cardiometabolic and inflammatory markers in mild cognitive impairment.

INTRODUCTION: Mild cognitive impairment (MCI) is often accompanied by metabolic abnormalities and inflammation that might play a role in the development of cognitive impairment. The use of ketogenic medium-chain triglycerides (kMCT) to improve cognition in this population has shown promising results but remains controversial because of the potentially detrimental effect of elevated intake of saturated fatty acids on cardiovascular (CV) health and perhaps inflammatory processes. The primary aim of this secondary data analysis report is to describe changes in cardiometabolic markers and peripheral inflammation during a 6-month kMCT intervention in MCI. METHODS: Thirty-nine participants with MCI completed the intervention of 30 g/day of either a kMCT drink or calorie-matched placebo (high-oleic acid) for 6 months. Plasma concentrations of cardiometabolic and inflammatory markers were collected before (fasting state) and after the intervention (2 h following the last drink). RESULTS: A mixed model ANOVA analysis revealed a time by group interaction for ketones (P < 0.001), plasma 8:0 and 10:0 acids (both P < 0.001) and IL-8 (P = 0.002) with follow up comparison revealing a significant increase in the kMCT group (+48%, P = 0.005), (+3,800 and +4,900%, both P < 0.001) and (+147%, P < 0.001) respectively. A main effect of time was observed for insulin (P = 0.004), triglycerides (P = 0.011) and non-esterified fatty acids (P = 0.036). CONCLUSION: Under these study conditions, 30 g/d of kMCT taken for six months and up to 2-hour before post-intervention testing had minimal effect on an extensive profile of circulating cardiometabolic and inflammatory markers as compared to a placebo calorie-matched drink. Our results support the safety kMCT supplementation in individuals with MCI. The clinical significance of the observed increase in circulating IL-8 levels is presently unknown and awaits future studies.

The Impact of Acute Ingestion of a Ketone Monoester Drink on LPS-Stimulated NLRP3 Activation in Humans with Obesity.

Activation of the NOD-like receptor pyrin-domain containing 3 (NLRP3) inflammasome is associated with chronic low-grade inflammation in metabolic diseases such as obesity. Mechanistic studies have shown that ß-hydroxybutyrate (OHB) attenuates activation of NLRP3, but human data are limited. In a randomized, double-blind, placebo-controlled crossover trial (n = 11) we tested the hypothesis that acutely raising ß-OHB by ingestion of exogenous ketones would attenuate NLRP3 activation in humans with obesity. Blood was sampled before and 30 min post-ingestion of a ketone monoester drink ((R)-3-hydroxybutyl (R)-3-hydroxybutyrate, 482 mg/kg body mass) or placebo. A 75 g oral glucose load was then ingested, and a third blood sample was obtained 60 min following glucose ingestion. NLRP3 activation was quantified by assessing monocyte caspase-1 activation and interleukin (IL)-1ß secretion in ex vivo lipopolysaccharide (LPS)-stimulated whole-blood cultures. LPS-stimulated caspase-1 activation increased following glucose ingestion (main effect of time; p = 0.032), with no differences between conditions. IL-1ß secretion did not differ between conditions but was lower 60 min post-glucose ingestion compared to the fasting baseline (main effect of time, p = 0.014). Plasma IL-1ß was detectable in ~80% of samples and showed a decrease from fasting baseline to 60 min in the ketone condition only (condition × time interaction, p = 0.01). In individuals with obesity, an excursion into hyperglycemia following ingestion of a glucose load augments LPS-induced activation of caspase-1 in monocytes with no apparent impact of raising circulating ß-OHB concentration via ingestion of exogenous ketones. Exogenous ketone supplementation may impact plasma IL-1ß, but these findings require confirmation in studies with larger sample sizes.

The Effect of Exogenous Ketone Monoester Ingestion on Plasma BDNF During an Oral Glucose Tolerance Test.

Brain-derived neurotrophic factor (BDNF) is important for brain and metabolic function. Ingestion of a ketone monoester (KME) drink containing beta-hydroxybutyrate (ß-OHB) attenuates hyperglycemia in humans and increases neuronal BDNF in rodents. Whether KME affects BDNF in humans is currently unknown. This study examined the effect of KME ingestion before an oral glucose tolerance test (OGTT) on plasma BDNF in normal-weight adults (NW) and adults with obesity (OB). Methods: Exploratory, secondary analyses of two studies were performed. Study 1 included NW (n = 18; age = 25.3 ± 4.3 years; BMI = 22.2 ± 2.3 kg/m2) and Study 2 included OB (n = 12; age = 48.8 ± 9.5 years; BMI = 33.7 ± 5.0 kg/m2). Participants ingested 0.45 ml/kg-1 body weight KME or Placebo 30-min prior to completing a 75 g OGTT. ß-OHB and BDNF were measured via blood samples at fasting baseline (pre-OGTT) and 120 min post-OGTT. Results: Study 1: KME significantly increased ß-OHB by 800 ± 454% (p < 0.001). BDNF significantly decreased post-OGTT compared to pre-OGTT in Placebo (718.6 ± 830.8 pg/ml vs. 389.3 ± 595.8 pg/ml; p = 0.018), whereas BDNF was unchanged in KME (560.2 ± 689.6 pg/ml vs. 469.2 ± 791.8 pg/ml; p = 0.28). Study 2: KME significantly increased ß-OHB by 1,586 ± 602% (p < 0.001). BDNF was significantly higher post-OGTT in the KME condition in OB (time × condition interaction; p = 0.037). There was a moderate relationship between ß-OHB and ∆ %BDNF (r = 0.616; p < 0.001). Fasting plasma BDNF was significantly lower in OB compared to NW (132.8 ± 142.8 pg/ml vs. 639.4 ± 756.8 pg/ml; g = 0.845; p = 0.002). Conclusions: Plasma BDNF appears differentially impacted by KME ingestion with OGTT in OB compared to NW. Raising ß-OHB via KME may be a strategy for increasing/protecting BDNF during hyperglycemia.

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

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 ß-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.

A ketone monoester drink reduces the glycemic response to an oral glucose challenge in individuals with obesity: a randomized trial.

BACKGROUND: Exogenous ketones make it possible to reach a state of ketosis that may improve metabolic control in humans. OBJECTIVES: The main objective of this study was to determine whether the ingestion of a ketone monoester (KE) drink before a 2-h oral-glucose-tolerance test (OGTT) would lower blood glucose concentrations. Secondary objectives were to determine the impact of KE on nonesterified fatty acid (NEFA) concentration and glucoregulatory hormones. METHODS: We conducted a randomized controlled crossover experiment in 15 individuals with obesity (mean ± SD age: 47 ± 10 y; BMI: 34 ± 5 kg/m2). After an overnight fast, participants consumed a KE drink [(R)-3-hydroxybutyl (R)-3-hydroxybutyrate; 0.45 mL/kg body weight] or taste-matched control drink 30 min before completing a 75-g OGTT. Participants and study personnel performing laboratory analyses were blinded to each condition. RESULTS: The KE increased d-ß-hydroxybutyrate to a maximum of ∼3.4 mM (P < 0.001) during the OGTT. Compared with the control drink, KE reduced glucose (-11%, P = 0.002), NEFA (-21%, P = 0.009), and glucagon-like peptide 1 (-31%, P = 0.001) areas under the curve (AUCs), whereas glucagon AUC increased (+11%, P = 0.030). No differences in triglyceride, C-peptide, and insulin AUCs were observed after the KE drink. Mean arterial blood pressure decreased and heart rate increased after the KE drink (both P < 0.01). CONCLUSIONS: A KE drink consumed before an OGTT lowered glucose and NEFA AUCs with no increase in circulating insulin. Our results suggest that a single drink of KE may acutely improve metabolic control in individuals with obesity. Future research is warranted to examine whether KE could be used safely to have longer-term effects on metabolic control. This trial was registered at clinicaltrials.gov as NCT03461068.

Overnight fasting compromises exercise intensity and volume during sprint interval training but improves high-intensity aerobic endurance.

BACKGROUND: The combined effects of sprint interval training (SIT) and exercising in the fasted state are unknown. We compared the effects of SIT with exogenous carbohydrate supplementation (SIT-CHO) and SIT following overnight fast (SIT-Fast) on aerobic capacity (peak oxygen consumption: V̇O2peak) and high-intensity aerobic endurance (time-to-exhaustion at 85% V̇O2peak [T85%]). METHODS: Twenty male cyclists were randomized to SIT-CHO and SIT-Fast. Both groups performed 30-second all-out cycling followed by 4-minute active recovery 3 times per week for 4 weeks, with the number of sprint bouts progressing from 4 to 7. Peak power output (PPO) and total mechanical work were measured for each sprint interval bout. The SIT-CHO group performed exercise sessions following breakfast and consumed carbohydrate drink during exercise, whereas the SIT-Fast group performed exercise sessions following overnight fast and consumed water during exercise. Before and after training, V̇O2peak and T85% were assessed. Blood glucose, non-esterified fatty acids, insulin and glucagon concentrations were measured during T85%. RESULTS: Overall PPO and mechanical work were lower in SIT-Fast than SIT-CHO (3664.9 vs. 3871.7 J/kg; P=0.021 and 10.6 vs. 9.9 W/kg; P=0.010, respectively). Post-training V̇O2peak did not differ between groups. Baseline-adjusted post-training T85% was longer in SIT-Fast compared to SIT-CHO (19.7±3.0 vs. 16.6±3.0 minutes, ANCOVA P=0.038) despite no changes in circulating energy substrates or hormones. CONCLUSIONS: Our results suggest that SIT-Fast compromises exercise intensity and volume but still can have a greater impact on the ability to sustain high-intensity aerobic endurance exercise compared to SIT-CHO.

Oral Ketone Supplementation Acutely Increases Markers of NLRP3 Inflammasome Activation in Human Monocytes.

SCOPE: Cell culture studies indicate that the ketone ß-hydroxybutyrate (ß-OHB) directly inhibits the NLRP3 inflammasome, a key regulator of inflammation. However, direct evidence demonstrating this effect in humans is lacking. METHODS AND RESULTS: To determine the effects of acutely raising blood ß-OHB in healthy humans, two separate randomized double-blind placebo-controlled experiments are conducted using similar methods but each employed different exogenous ketone supplements. Participants' blood ß-OHB is directly elevated by ketone salts (0.3 g ß-OHB per kg; Study 1, N = 10 males) or ketone monoester (0.482 g ß-OHB per kg; Study 2, N = 18, equal males/females). Markers of NLRP3 inflammasome activation include caspase-1, IL-1ß secretion, and IL1B and NLRP3 mRNA in LPS-stimulated whole blood collected at the baseline and 30 minutes following supplementation. Caspase-1 activation increases after ketone salt (Study 1: condition × time interaction, p = 0.012) and monoester supplementation (Study 2: condition × time interaction, p = 0.016) compared to placebo. IL-1ß secretion increases (main effect of condition, p = 0.024; Study 2) while IL1B and NLRP3 mRNA remain unchanged. CONCLUSION: Measures of NLRP3 activation increases when blood ß-OHB is elevated using ketone supplements, suggesting that increasing ß-OHB exogenously may have unintended effects that augment inflammatory activation.

Nutritional ketone salts increase fat oxidation but impair high-intensity exercise performance in healthy adult males.

This study investigated the impact of raising plasma beta-hydroxybutyrate (ß-OHB) through ingestion of ketone salts on substrate oxidation and performance during cycling exercise. Ten healthy adult males (age, 23 ± 3 years; body mass index, 25 ± 3 kg/m2, peak oxygen uptake, 45 ± 10 mL/(kg·min)-1) were recruited to complete 2 experimental trials. Before enrollment in the experimental conditions, baseline anthropometrics and cardiorespiratory fitness (peak oxygen uptake) were assessed and familiarization to the study protocol was provided. On experimental days, participants reported to the laboratory in the fasted state and consumed either 0.3 g/kg ß-OHB ketone salts or a flavour-matched placebo at 30 min prior to engaging in cycling exercise. Subjects completed steady-state exercise at 30%, 60%, and 90% ventilatory threshold (VT) followed by a 150-kJ cycling time-trial. Respiratory exchange ratio (RER) and total substrate oxidation were derived from indirect calorimetry. Plasma glucose, lactate, and ketones were measured at baseline, 30 min post-supplement, post-steady-state exercise, and immediately following the time-trial. Plasma ß-OHB was elevated from baseline and throughout the entire protocol in the ketone condition (p < 0.05). RER was lower at 30% and 60% VT in the ketone compared with control condition. Total fat oxidation was greater in the ketone versus control (p = 0.05). Average time-trial power output was ∼7% lower (-16 W, p = 0.029) in the ketone condition. Ingestion of ketone salts prior to exercise increases fat oxidation during steady-state exercise but impairs high-intensity exercise performance.