The effect of acute and 14-day exogenous ketone supplementation on glycemic control in adults with type 2 diabetes: two randomized controlled trials.

Acute ingestion of the exogenous ketone monoester supplement [(R)-3-hydroxybutyl-(R)-3-hydroxybutyrate] lowers blood glucose, suggesting therapeutic potential in individuals with impaired glucose metabolism. However, it is unknown how acute or repeated ingestion of exogenous ketones affects blood glucose control in individuals with type 2 diabetes (T2D). We conducted two randomized, counterbalanced, double-blind, placebo-controlled crossover trials to determine if 1) acute exogenous ketone monoester (0.3 g/kg body mass; N = 18) or 2) 14-day thrice daily premeal exogenous ketone monoester (15 g; N = 15) supplementation could lower blood glucose in individuals living with T2D. A single dose of the ketone monoester supplement elevated blood ß-OHB to ∼2 mM. There were no differences in the primary outcomes of plasma glucose concentration (acutely) or serum fructosamine (glycemic control across 14 days) between conditions. Ketone monoester ingestion acutely increased insulin and lowered nonesterified fatty acid concentrations; plasma metabolomics confirmed a reduction in multiple free fatty acids species and select gluconeogenic amino acids. In contrast, no changes were observed in fasting metabolic outcomes following 14 days of supplementation. In the context of these randomized controlled trials, acute or repeated ketone monoester ingestion in adults with T2D did not lower blood glucose when consumed acutely in a fasted state and did not improve glycemic control following thrice daily premeal ingestion across 14 days. Future studies exploring the mechanistic basis for the (lack of) glucose-lowering effect of exogenous ketone supplementation in T2D and other populations are warranted.NEW & NOTEWORTHY Exogenous ketone supplements can acutely lower blood glucose, suggesting therapeutic potential in individuals with impaired glucose metabolism. However, the effect of exogenous ketones on glucose metabolism in adults with type 2 diabetes has not been investigated in a controlled setting. In adults with type 2 diabetes, ketone monoester ingestion did not lower blood glucose acutely in a fasted state and did not improve glycemic control across thrice daily premeal ingestion across 14 days.

Effect of the ketone beta-hydroxybutyrate on markers of inflammation and immune function in adults with type 2 diabetes.

Pre-clinical and cell culture evidence supports the role of the ketone beta-hydroxybutyrate (BHB) as an immunomodulatory molecule that may inhibit inflammatory signalling involved in several chronic diseases such as type 2 diabetes (T2D), but studies in humans are lacking. Therefore, we investigated the anti-inflammatory effect of BHB in humans across three clinical trials. To investigate if BHB suppressed pro-inflammatory cytokine secretion, we treated LPS-stimulated leukocytes from overnight-fasted adults at risk for T2D with BHB (Study 1). Next (Study 2), we investigated if exogenously raising BHB acutely in vivo by ketone monoester supplementation (KME) in adults with T2D would suppress pro-inflammatory plasma cytokines. In Study 3, we investigated the effect of BHB on inflammation via ex vivo treatment of LPS-stimulated leukocytes with BHB and in vivo thrice-daily pre-meal KME for 14 days in adults with T2D. Ex vivo treatment with BHB suppressed LPS-stimulated IL-1ß, TNF-α, and IL-6 secretion and increased IL-1RA and IL-10 (Study 1). Plasma IL-10 increased by 90 min following ingestion of a single dose of KME in T2D, which corresponded to peak blood BHB (Study 2). Finally, 14 days of thrice-daily KME ingestion did not significantly alter plasma cytokines or leukocyte subsets including monocyte and T-cell polarization (Study 3). However, direct treatment of leukocytes with BHB modulated TNF-α, IL-1ß, IFN-γ, and MCP-1 secretion in a time- and glucose-dependent manner (Study 3). Therefore, BHB appears to be anti-inflammatory in T2D, but this effect is transient and is modulated by the presence of disease, glycaemia, and exposure time.

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 ß-hydroxybutyrate (ß-OHB) are a purported therapeutic strategy for improving brain health in at-risk populations. We tested the hypothesis that short-term ß-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; aged 56 ± 12 years; body mass index = 33.8 ± 6.9 kg m-2 ) consumed 30 mL (12 g) of ß-OHB or placebo thrice-daily for 14 days. 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 14 days 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, ß-OHB did not impact fasting serum and plasma BDNF. ß-OHB supplementation improved cognition in adults with obesity, which may be partly facilitated by improvements in cerebral blood flow. ß-OHB supplementation was well-tolerated and appears to be safe for cerebrovascular health, suggesting potential therapeutic benefits of ß-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 ß-hydroxybutyrate (ß-OHB) reduce postprandial hyperglycaemia, which may increase CBF and BDNF, thereby protecting against obesity-related cognitive dysfunction. We show for the first time that 14 days of thrice-daily ß-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 ß-OHB supplementation. This trial provides a foundation for the potential non-pharmacological therapeutic application of ß-OHB supplementation in patient groups at risk of hyperglycaemic cerebrovascular disease and cognitive dysfunction.

Changes in the Brain-Derived Neurotrophic Factor Are Associated with Improvements in Diabetes Risk Factors after Exercise Training in Adolescents with Obesity: The HEARTY Randomized Controlled Trial.

Obesity in youth increases the risk of type 2 diabetes (T2D), and both are risk factors for neurocognitive deficits. Exercise attenuates the risk of obesity and T2D while improving cognitive function. In adults, these benefits are associated with the actions of the brain-derived neurotrophic factor (BDNF), a protein critical in modulating neuroplasticity, glucose regulation, fat oxidation, and appetite regulation in adults. However, little research exists in youth. This study examined the associations between changes in diabetes risk factors and changes in BDNF levels after 6 months of exercise training in adolescents with obesity. The sample consisted of 202 postpubertal adolescents with obesity (70% females) aged 14-18 years who were randomized to 6 months of aerobic and/or resistance training or nonexercise control. All participants received a healthy eating plan designed to induce a 250/kcal deficit per day. Resting serum BDNF levels and diabetes risk factors, such as fasting glucose, insulin, homeostasis model assessment (HOMA-B-beta cell insulin secretory capacity) and (HOMA-IS-insulin sensitivity), and hemoglobin A1c (HbA1c), were measured after an overnight fast at baseline and 6 months. There were no significant intergroup differences on changes in BDNF or diabetes risk factors. In the exercise group, increases in BDNF were associated with reductions in fasting glucose (ß = -6.57, SE = 3.37, p = 0.05) and increases in HOMA-B (ß = 0.093, SE = 0.03, p = 0.004) after controlling for confounders. No associations were found between changes in diabetes risk factors and BDNF in controls. In conclusion, exercise-induced reductions in some diabetes risk factors were associated with increases in BDNF in adolescents with obesity, suggesting that exercise training may be an effective strategy to promote metabolic health and increases in BDNF, a protein favoring neuroplasticity. This trial is registered with ClinicalTrials.gov NCT00195858, September 12, 2005 (funded by the Canadian Institutes of Health Research).

Regulation of plasma agouti-related protein and its relationship with hunger in lean and obese men.

Agouti-related protein (AgRP) is an orexigenic (appetite stimulating) neuropeptide suggested to exert tonic control over long-term energy balance. While some have speculated AgRP is not involved in the episodic (i.e. meal to meal energy intake) control, acute decreases in plasma agouti-related protein (AgRP) following a meal have been observed in humans in a role consistent with episodic control for AgRP. Whether changes in plasma AgRP are associated with episodic, and/or tonic changes in appetite has yet to be directly examined. The present study examined the relationship between agouti-related protein (AgRP), leptin and the regulation of appetite following a 48-h fast and an acute meal challenge. Blood samples were obtained from young lean and obese men before and after a 48 h fast (lean n = 10; obese n = 7). Fasting resulted in an increase in AgRP and a decrease in leptin with these changes being greater in lean than obese. In addition, blood samples were obtained from lean men before and 1, 2, 3 and 4 h after a meal (n = 8). Following a meal, AgRP was reduced from 2 to 4 h, a change that was dissociated from both leptin and subjective measures of hunger and satiety. These results demonstrate that AgRP is not associated with changes in hunger or satiety, and can change without corresponding changes in leptin. This suggests that AgRP may not be involved in the episodic control of appetite and the release of AgRP may involve signals other than leptin.

Orienteering combines vigorous-intensity exercise with navigation to improve human cognition and increase brain-derived neurotrophic factor.

Exercise enhances aspects of human cognition, but its intensity may matter. Recent animal research suggests that vigorous exercise, which releases greater amounts of lactate, activates more brain-derived neurotrophic factor (BDNF) in the hippocampus and, thus, may be optimal for supporting cognitive function. The cognitive benefits of exercise may be further augmented when combined with cognitive training. The sport of orienteering simultaneously combines exercise with spatial navigation and, therefore, may result in greater cognitive benefits than exercising only, especially at vigorous intensities. The present study aimed to examine the effects of an acute bout of orienteering at different intensities on cognition and BDNF compared to exercising only. We hypothesized that vigorous-intensity orienteering would increase lactate and BDNF and improve cognition more than moderate-intensity orienteering or vigorous exercise alone. Sixty-three recreationally active, healthy young adults (Mage = 21.10±2.75 years) with no orienteering experience completed a 1.3 km intervention course by navigating and exercising at a vigorous (80-85% of heart rate reserve) or moderate (40-50% of heart rate reserve) intensity or exercising vigorously without navigation. Exercise intensity was monitored using peak lactate, heart rate and rating of perceived exertion. Serum BDNF was extracted immediately before and after the intervention. Memory was assessed using the Mnemonic Similarity Task (high-interference memory) and the Groton Maze Learning Test (spatial memory). Both exercising and orienteering at a vigorous intensity elicited greater peak lactate and increases in BDNF than moderate-intensity orienteering, and individuals with higher peak lactate also had greater increases in BDNF. High-interference memory improved after both vigorous-intensity interventions but did not improve after the moderate-intensity intervention. Spatial memory only increased after vigorous-intensity orienteering, suggesting that orienteering at a vigorous intensity may particularly benefit spatial cognition. Overall, the results demonstrate the benefits of vigorous exercise on human cognition and BDNF.

Impact of an Acute Bout of Submaximal Aerobic Exercise on Circulating Leukocytes in Individuals with Spinal Cord Injury.

Individuals with spinal cord injury (SCI) may experience cardiovascular, musculoskeletal and organ function dysregulation. Sequelae include reduced catecholamine secretion and attenuated immune responses which may impact exercise-induced leukocytosis. The purpose of this study was to characterize major leukocyte subtypes following 30 minutes of acute, submaximal aerobic exercise, in line with updated international SCI exercise guidelines for adults. It was hypothesized that exercise would increase major leukocyte subtypes when compared to fasted baseline. Eight participants with SCI (incomplete n = 6; complete n = 2) completed a 30-minute bout of aerobic exercise on an arm cycle ergometer at 60% of their peak power output followed by 90 minutes of recovery, or a 2-hour seated control condition, in a randomized crossover design, separated by 7-14 days. Blood samples were taken at baseline, post exercise, and 90 minutes after exercise (with time matched control). Leukocyte subtypes were analyzed via flow cytometry and plasma catecholamines by ELISA. Several leukocytes increased from pre- to post-exercise (time X condition interaction; all P < 0.05; mean ± SD), including CD3+ Lymphocytes (19 ± 16%), CD4+ T helper (16 ± 13%), CD8+ T cytotoxic (24 ± 23%), CD3+/CD56+ natural killer T (31 ± 34%), and CD3-/CD56+ natural killer (63 ± 82%). CD16+/CD14dim monocytes decreased by 27 ± 38% following exercise to 90 minutes post-exercise. No changes were observed for catecholamines for either condition. Thirty minutes of acute submaximal aerobic exercise sufficiently increased most lymphocyte subsets with effector functions, while leading to decreased proinflammatory monocytes during the recovery phase. This exercise duration and intensity appear to be an appropriate option for modulating circulating immune cells in individuals with SCI.

Acute submaximal exercise does not impact aspects of cognition and BDNF in people with spinal cord injury: A pilot study.

Objective: To investigate the effect of acute submaximal exercise, based on the spinal cord injury (SCI) Exercise Guidelines, on cognition and brain-derived neurotrophic factor (BDNF) in people with SCI. Design: Eight adults (7 males) with traumatic SCI volunteered in this pre-registered pilot study. In randomized order, participants completed submaximal intensity arm cycling (60% of measured peak-power output at 55-60 rpm) for 30 min or time-matched quiet rest (control condition) on separate days. Blood-borne BDNF was measured in serum and plasma at pre-intervention, 0 min and 90 min post-intervention. Cognition was assessed using the Stroop Test and Task-Switching Test on an electronic tablet pre- and 10 min post-intervention. Results: Submaximal exercise had no effect on plasma [F(2,12) = 1.09; P = 0.365; η² = 0.069] or serum BDNF [F(2,12) = 0.507; P = 0.614; η² = 0.024] at either 0 min or 90 min post-intervention. Similarly, there was no impact of exercise on either Stroop [F(1,7) = 2.05; P = 0.195; η² = 0.065] or Task-Switching performance [F(1,7) = 0.016; P = 0.903; η² < 0.001] compared to the control condition. Interestingly, there was a positive correlation between years since injury and resting levels of both plasma (r = 0.831; P = 0.011) and serum BDNF (r = 0.799; P = 0.023). However, there was not relationship between years since injury and the BDNF response to exercise. Conclusions: Acute guideline-based exercise did not increase BDNF or improve aspects of cognition in persons with SCI. This work establishes a foundation for continued investigations of exercise as a therapeutic approach to promoting brain health among persons with SCI.

Interindividual Differences in Trainability and Moderators of Cardiorespiratory Fitness, Waist Circumference, and Body Mass Responses: A Large-Scale Individual Participant Data Meta-analysis.

Although many studies have assumed variability reflects variance caused by exercise training, few studies have examined whether interindividual differences in trainability are present following exercise training. The present individual participant data (IPD) meta-analysis sought to: (1) investigate the presence of interindividual differences in trainability for cardiorespiratory fitness (CRF), waist circumference, and body mass; and (2) examine the influence of exercise training and potential moderators on the probability that an individual will experience clinically important differences. The IPD meta-analysis combined data from 1879 participants from eight previously published randomized controlled trials. We implemented a Bayesian framework to: (1) test the hypothesis of interindividual differences in trainability by comparing variability in change scores between exercise and control using Bayes factors; and (2) compare posterior predictions of control and exercise across a range of moderators (baseline body mass index (BMI) and exercise duration, intensity, amount, mode, and adherence) to estimate the proportions of participants expected to exceed minimum clinically important differences (MCIDs) for all three outcomes. Bayes factors demonstrated a lack of evidence supporting a high degree of variance attributable to interindividual differences in trainability across all three outcomes. These findings indicate that interindividual variability in observed changes are likely due to measurement error and external behavioural factors, not interindividual differences in trainability. Additionally, we found that a larger proportion of exercise participants were expected to exceed MCIDs compared with controls for all three outcomes. Moderator analyses identified that larger proportions were associated with a range of factors consistent with standard exercise theory and were driven by mean changes. Practitioners should prescribe exercise interventions known to elicit large mean changes to increase the probability that individuals will experience beneficial changes in CRF, waist circumference and body mass.

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

CONTEXT: Postprandial hyperglycemia increases systemic inflammation and is a risk factor for cardiovascular disease. A ketone monoester (KME) drink containing ß-hydroxybutyrate (ß-OHB) rapidly lowers plasma glucose, which may be a strategy protecting against postprandial hyperglycemia. OBJECTIVE: We hypothesized that KME would attenuate 2-hour postprandial glucose, lower systemic inflammation, and improve vascular function in adults with obesity. METHODS: In a randomized crossover design, 14 participants with obesity (age = 56 ±â€…12 years; body mass index = 32.8 ±â€…7.7 kg/m2) consumed KME (12 g ß-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. RESULTS: 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  ±â€… 1.5% to 8.9 ±â€…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. CONCLUSIONS: 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.

Perceived mental strain dissociates from perceived physical strain during relative intensity submaximal exercise on ascent from low to high altitude.

Perceived fatigability, which has perception of physical strain and of mental strain as its components, can impact exercise tolerance. Upon ascent to high altitude, low landers experience reduced exercise capacity and reduced tolerance for a given absolute submaximal work rate. It is established that perceived physical strain tracks with relative exercise intensity. However, it is not known how altitude ascent affects perceived mental strain relative to perceived physical strain. We tested the hypothesis that when exercising at the same relative exercise intensity perceived physical strain will remain unchanged whereas perceived mental strain will decrease on ascent from low to high altitude in the Everest region in Nepal. Twelve hours after arriving at each of three elevations; 1400 m, 3440 m, and 4240 m, 12 untrained participants used the task effort awareness (TEA) and physical-rating of perceived exertion (P-RPE) scales to report perceived mental and physical strain during a 20 min walking test at a self-monitored heart rate reserve (HRR) range of 40-60% (Polar HR Monitor). TEA and P-RPE were recorded twice during exercise (5-7 min and 14-16 min). Neither P-RPE (1400 m: 11.1 ± 1.8, 3440 m: 10.7 ± 1.2, 4240 m: 11.5 ± 1.5) nor %HRR (1400 m: 55.25 ± 7.34, 3440 m: 51.70 ± 6.70, 4240 m: 50.17 ± 4.02) changed as altitude increased. TEA decreased at 4240 m (2.05 ± 0.71) compared to 1400 m (3.44 ± 0.84)--this change was not correlated with any change in %HRR nor was it due to a change in core affect. These findings support our hypothesis and demonstrate the independence of perceived physical and perceived mental strain components of perceived fatigability. Implications for exercise tolerance remain to be determined.

Serum and plasma brain-derived neurotrophic factor concentration are elevated by systemic but not local passive heating.

Brain-derived neurotrophic factor (BDNF) plays a key role in neuronal adaptations. While previous studies suggest that whole-body heating can elevate circulating BDNF concentration, this is not known for local heating protocols. This study investigated the acute effects of whole-body versus local passive heating on serum and plasma BDNF concentration. Using a water-perfused suit, ten recreationally active males underwent three 90 min experimental protocols: heating of the legs with upper-body cooling (LBH), whole-body heating (WBH) and a control condition (CON). Blood samples were collected before, immediately after and 1 h post-heating for the determination of serum and plasma BDNF concentration, platelet count as well as the BDNF release per platelet. Rectal temperature, cardiac output and femoral artery shear rate were assessed at regular intervals. Serum and plasma BDNF concentration were elevated after WBH (serum: 19.1±5.0 to 25.9±11.3 ng/ml, plasma: 2.74±0.9 to 4.58±2.0; p<0.044), but not LBH (serum: 19.1±4.7 to 22.3±4.8 ng/ml, plasma: 3.25±1.13 to 3.39±0.90 ng/ml; p>0.126), when compared with CON (serum: 18.6±6.4 to 16.8±3.4 ng/ml, plasma: 2.49±0.69 to 2.82±0.89 ng/ml); accompanied by an increase in platelet count (p<0.001). However, there was no change in BDNF content per platelet after either condition (p = 0.392). All physiological measures were elevated to a larger extent after WBH compared with LBH (p<0.001), while shear rate and rectal temperature were higher during LBH than CON (p<0.038). In conclusion, WBH but not LBH acutely elevates circulating BDNF concentration. While these findings further support the use of passive heating to elevate BDNF concentration, a larger increase in shear rate, sympathetic activity and/or rectal temperature than found after LBH appears needed to induce an acute BDNF response by passive heating.

The Impact of Sub-maximal Exercise on Neuropathic Pain, Inflammation, and Affect Among Adults With Spinal Cord Injury: A Pilot Study.

Introduction: Persons with spinal cord injury (SCI) often report high levels of neuropathic pain (NP) and poor well-being, which may result from increased inflammation. This study examined the impact of sub-maximal aerobic exercise on NP, inflammation and psychological affect among adults with SCI. Methods: Eight active adults with tetraplegia (n-4, AIS A-C) and paraplegia (n = 4, AIS A-C) performed 30-min of arm-crank aerobic exercise and reported their ratings of perceived exertion (RPE) each minute. Measures of NP, affect, and inflammatory cytokines (IL-6, IL-10, IL-1ra, TNF-α) were taken pre-(T0), immediately post-(T1), and 90-min post-exercise (T2). Results: NP decreased between T0 and T1 for tetraplegics (-60%, d = 0.47; CI = -0.32, 2.02) and paraplegics (-16%, d = 0.15; CI = -0.30, 0.90). Correlations between change in cytokines and change in NP were medium-to large for tetraplegics (rs ranged from -0.820 to 0.965) and paraplegics (rs ranged from -0.598 to 0.833). However, the pattern of correlations between change in cytokines and affect was inconsistent between groups. Lower baseline levels of IL-1ra predicted greater decreases in NP immediately post-exercise (r = 0.83, p = 0.01). Conclusion: Sub-maximal exercise can positively impact NP for some persons with SCI. Further experimental research should identify the optimal exercise intensity to reduce NP for persons with SCI, in addition to understanding biomarkers which may predict changes in NP. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT03955523.

The effects of a high-fat/high-carbohydrate meal on leukocyte populations in adults with chronic spinal cord injury.

STUDY DESIGN: Secondary analysis of aggregated case series data. OBJECTIVES: To examine the effects of a high-fat/high-carbohydrate meal on leukocyte populations in adults with a chronic SCI. SETTING: University-based laboratories in British Columbia, Canada. METHODS: Ten individuals (M = 9) with a traumatic SCI (>1-year post-injury; M = 15.5 years; n = 2 sensory complete, n = 7 motor complete) participated in this study. Participants arrived fasted (≥12 h) prior to both the control (quiet sitting, no food/drink) and experimental meal conditions (high-fat/high-carb meal: 880 kcal, 52 g fat, 73 g carbohydrates, 29 g protein). Blood samples were taken in the fasted state and at 120-min post-meal/baseline in both conditions. Immune cell counts were assessed using multi-color flow cytometry. RESULTS: A significant time × condition interaction effect was seen in CD3+, CD4+, and CD8+ T cells as well as CD56+ and CD3+/CD56+ natural killer (NK) cells (p < 0.05). CD14+/CD16+ monocytes and CD19+ B cells approached a significant time × condition interaction (p < 0.07). A main effect of time was observed in CD19+ B cells (p < 0.05). Cell counts for T-lymphocytes and NK cells followed the general trend of an increase in the control condition from baseline to 120-min with no change observed following the experimental meal condition. CONCLUSIONS: Following the HFHC meal, immune cells did not show the same general increase observed following the control condition. Future research is needed to determine if there are any potential consequences of these immune cell responses in immunosuppressed populations and if other factors (e.g., diurnal variation) might influence immune cell response.

24-Hour Movement Behaviors and Internalizing and Externalizing Behaviors Among Youth.

PURPOSE: The Canadian 24-Hour Movement Guidelines for Children and Youth (≥60 minutes of moderate-to-vigorous physical activity per day, ≤2 hours of recreational screen time per day, and 9-11 hours of sleep per night for 5-13 years old) are associated with better physical health, but less is known about how these behaviors are related to mental health. This study examined the association of meeting these guideline recommendations with internalizing and externalizing behaviors among youth. METHODS: A large and broadly representative cross-sectional sample of 9- to 11-year-old U.S. youth (N = 11,875) from the Adolescent Brain and Cognitive Development study was analyzed. Internalizing and externalizing behaviors were measured using the Child Behaviour Checklist. Associations were examined using negative binomial regression adjusted for several confounders. RESULTS: Compared to meeting none of the recommendations, meeting recommendations for screen time and sleep but not physical activity was associated with a lower prevalence ratio of total, internalizing, and externalizing behaviors. Meeting two or all three recommendations was more strongly associated with these outcomes than meeting one recommendation or none. The prevalence ratio of the group meeting all three recommendations was .77 (95% confidence interval [CI]: .68-.86) for total problem scores, .78 (95% CI: .68-.89) for internalizing problem scores, and .79 (95% CI: .68-.91) for externalizing problem scores. CONCLUSIONS: Meeting the 24-hour movement guidelines was associated with a lower risk of internalizing and externalizing behaviors in youth. These associations were mainly explained by meeting the screen time and sleep duration recommendations.

Exploring Differences in Cardiorespiratory Fitness Response Rates Across Varying Doses of Exercise Training: A Retrospective Analysis of Eight Randomized Controlled Trials.

OBJECTIVE: This study tested the hypothesis that greater mean changes in cardiorespiratory fitness (CRF), in either the absence or presence of reduced interindividual variability, explain larger CRF response rates following higher doses of exercise training. METHODS: We retrospectively analyzed CRF data from eight randomized controlled trials (RCT; n = 1590 participants) that compared at least two doses of exercise training. CRF response rates were calculated as the proportion of participants with individual confidence intervals (CIs) placed around their observed response that lay above 0.5 metabolic equivalents (MET). CIs were calculated using no-exercise control group-derived typical errors and were placed around each individual's observed CRF response (post minus pre-training CRF). CRF response rates, mean changes, and interindividual variability were compared across exercise groups within each RCT. RESULTS: Compared with lower doses, higher doses of exercise training yielded larger CRF response rates in eight comparisons. For most of these comparisons (7/8), the higher dose of exercise training had a larger mean change in CRF but similar interindividual variability. Exercise groups with similar CRF response rates also had similar mean changes. CONCLUSION: Our findings demonstrate that larger CRF response rates following higher doses of exercise training are attributable to larger mean changes rather than reduced interindividual variability. Following a given dose of exercise training, the proportion of individuals expected to improve their CRF beyond 0.5 METs is unrelated to the heterogeneity of individual responses.

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.

Acute aerobic exercise impairs aspects of cognitive function at high altitude.

Hypoxia-mediated cognitive dysfunction can be transiently mitigated by exercise in a laboratory-based setting. Whether this effect holds true in the context of high altitude hypoxia has not been determined. We investigated the effect of acute aerobic exercise on cognitive function (CF) at low (1400m) and high altitude (4240m). Fifteen volunteers (24.1±3.5yrs; 9 females) exercised for 20-min at 40-60% of their heart rate reserve at low and high altitude. CF was assessed before and 10-min after exercise using a tablet-based battery of executive function tests. A sea-level control group (n=13; 24.2±2.4 years; 9 females) performed time-matched CF tests to assess the contribution of a learning effects due to repeated testing. Measures of resting CF were unaffected by ascent to high altitude. Following high altitude exercise, performance significantly worsened on the digit symbol substitution task - a test of processing speed, working memory, and visuospatial attention (z=0.01 vs. -0.59, p=0.02, η2=0.35). No effect was found on other measures of CF following exercise. There was no association between changes in peripheral oxygen saturation and changes in CF following high altitude exercise (r=0.22, p=0.44), but higher hemoglobin concentration at high altitude was associated with a decline in CF following exercise at high altitude (r=-0.65, p=0.02). Acute aerobic exercise performed at high altitude impairs some aspects of CF, whereas other CF tests remain unchanged. The strong ecological validity of this study warrants attention and follow-up investigations are needed to better characterize selective impairment of CF with high altitude exercise.

Interindividual variability and individual responses to exercise training in adolescents with obesity.

This study investigated the impact of exercise training on interindividual variability and response rates in body composition and cardiometabolic outcomes in adolescents with obesity. Postpubertal males and females (n = 143) were randomly assigned to 6 months of a diet-only control or aerobic, resistance, or combined exercise training. Body composition indices were percentages of body fat mass and lean body mass and waist circumference. Biomarkers of cardiometabolic health were systolic blood pressure and plasma fasting glucose, triglycerides, and high-density lipoprotein cholesterol. Interindividual variability was examined by comparing the standard deviation of individual responses (SDIR) to a smallest robust change (SRC). The typical error of measurement was used to classify responses. SDIR exceeded the SRC for percent body fat mass in all exercise groups (SRC = 1.04%; aerobic SDIR = 1.50%; resistance SDIR = 1.22%; combined SDIR = 2.29%), percent lean body mass (SRC = 1.38%; SDIR = 3.2%,), systolic blood pressure (SRC = 2.06 mm Hg; SDIR = 4.92 mm Hg) in the resistance group, and waist circumference (SRC = 2.33 cm; SDIR = 4.09 cm), and fasting glucose (SRC = 0.08 mmol/L; SDIR = 0.28 mmol/L) in the combined group. However, half of the reported variables (11/21) did not have a positive SDIR. Importantly, adverse response rates were significantly lower in all 3 exercise groups compared with control for body composition. Although exercise had a small influence on interindividual variability for indices of body composition, the rate of adverse responses did not increase for any outcome. Novelty Interindividual variability and individual responses to exercise training have not been investigated in adolescents with obesity. Six months of exercise training does not increase interindividual variability in adolescents with obesity. Exercise created a positive, uniform shift in responses.