A ketone monoester drink reduces postprandial blood glucose concentrations in adults with type 2 diabetes: a randomised controlled trial.

AIMS/HYPOTHESIS: The aim of the present study was to conduct a randomised, placebo-controlled, double-blind, crossover trial to determine whether pre-meal ketone monoester ingestion reduces postprandial glucose concentrations in individuals with type 2 diabetes. METHODS: In this double-blind, placebo-controlled, crossover design study, ten participants with type 2 diabetes (age 59±1.7 years, 50% female, BMI 32±1 kg/m2, HbA1c 54±2 mmol/mol [7.1±0.2%]) were randomised using computer-generated random numbers. The study took place at the Nutritional Physiology Research Unit, University of Exeter, Exeter, UK. Using a dual-glucose tracer approach, we assessed glucose kinetics after the ingestion of a 0.5 g/kg body mass ketone monoester (KME) or a taste-matched non-caloric placebo before a mixed-meal tolerance test. The primary outcome measure was endogenous glucose production. Secondary outcome measures were total glucose appearance rate and exogenous glucose appearance rate, glucose disappearance rate, blood glucose, serum insulin, ß-OHB and NEFA levels, and energy expenditure. RESULTS: Data for all ten participants were analysed. KME ingestion increased mean ± SEM plasma beta-hydroxybutyrate from 0.3±0.03 mmol/l to a peak of 4.3±1.2 mmol/l while reducing 2 h postprandial glucose concentrations by ~18% and 4 h postprandial glucose concentrations by ~12%, predominately as a result of a 28% decrease in the 2 h rate of glucose appearance following meal ingestion (all p<0.05). The reduction in blood glucose concentrations was associated with suppressed plasma NEFA concentrations after KME ingestion, with no difference in plasma insulin concentrations between the control and KME conditions. Postprandial endogenous glucose production was unaffected by KME ingestion (mean ± SEM 0.76±0.15 and 0.88±0.10 mg kg-1 min-1 for the control and KME, respectively). No adverse effects of KME ingestion were observed. CONCLUSIONS/INTERPRETATION: KME ingestion appears to delay glucose absorption in adults with type 2 diabetes, thereby reducing postprandial glucose concentrations. Future work to explore the therapeutic potential of KME supplementation in type 2 diabetes is warranted. TRIAL REGISTRATION: ClinicalTrials.gov NCT05518448. FUNDING: This project was supported by a Canadian Institutes of Health Research (CIHR) Project Grant (PJT-169116) and a Natural Sciences and Engineering Research Council (NSERC) Discovery Grant (RGPIN-2019-05204) awarded to JPL and an Exeter-UBCO Sports Health Science Fund Project Grant awarded to FBS and JPL.

Direct assessment of leukocyte signalling and cytokine secretion reveals exercise intensity-dependent reductions in anti-inflammatory cytokine action.

Circulating interleukin (IL)-6 and IL-10 concentrations are widely used to evaluate the anti-inflammatory effects of exercise but do not capture cytokine action at the cellular level. Whether and how acute exercise impacts anti-inflammatory cytokine action in humans is unknown. To determine how exercise intensity and pattern impact IL-6 and IL-10 action in blood leukocytes, 16 active adults (eight males/eight females; age: 30 ± 3 years; body mass index: 22.8 ± 2.3 kg/m2; V ̇ O 2 peak ${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}{\mathrm{peak}}}}$ : 51 ± 6 mL/kg/min) completed a no-exercise control condition (CTL) or isocaloric bouts of cycling performed below (moderate continuous exercise; MCE) or above (heavy continuous or heavy intermittent exercise; HCE or HIE, respectively) lactate threshold. Venous blood (before, after, 30 min after and 90 min after exercise) was analysed for immune cell subpopulations, plasma cytokine concentrations, anti-inflammatory cytokine action and monocyte phenotype. Exercise induced rapid leukocytosis (P < 0.001) and increased plasma IL-6 (P < 0.001), IL-10 (P = 0.0145) and tumour necrosis factor-⍺ (TNF-⍺) (P = 0.0338) concentrations in an intensity-dependent manner (HCE and/or HIE vs. CTL). These systemic changes coincided with a diminished ability of IL-10/6 to phosphorylate STAT3 (P < 0.001) and inhibit TNF-⍺ secretion (P = 0.0238) in blood leukocytes following HCE and HIE. Monocyte polarization experiments revealed lower CD80 [MCE (P = 0.0933) and HIE (P = 0.0187) vs. CTL] and a tendency for higher CD163 expression (HCE vs. CTL, P = 0.0985), suggesting that hyporesponsiveness to anti-inflammatory cytokine action does not impede the ability of exercise to promote an anti-inflammatory monocyte phenotype. These findings provide novel insights into the immunomodulatory effects of exercise in humans and highlight the importance of directly measuring cellular cytokine action when evaluating the anti-inflammatory effects of exercise. KEY POINTS: Circulating cytokine concentrations are frequently used to evaluate the anti-inflammatory effects of exercise but may not capture changes in cytokine action occurring at the cellular level. We directly assessed anti-inflammatory cytokine action - measured using a combination of intracellular signalling and cytokine secretion ex vivo - in distinct immune cell subpopulations after acute calorie-matched exercise bouts differing in intensity and pattern. Anti-inflammatory cytokine action was blunted following higher intensity exercise despite corresponding increases in circulating cytokine concentrations and immune cell counts. Changes in cytokine action were not explained by changes in cytokine receptor expression on circulating immune cells. Our findings provide new insights into the immunomodulatory effects of exercise in humans and highlight the importance of directly measuring cellular cytokine action when evaluating the anti-inflammatory effects of exercise.

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.

Exogenous ketone supplementation: an emerging tool for physiologists with potential as a metabolic therapy.

NEW FINDINGS: What is the topic of this review? The integrative physiological response to exogenous ketone supplementation. What advances does it highlight? The physiological effects and therapeutic potential of exogenous ketones on metabolic health, cardiovascular function, cognitive processing, and modulation of inflammatory pathways and immune function. Also highlighted are current challenges and future directions of the field. ABSTRACT: Exogenous oral ketone supplements, primarily in form of ketone salts or esters, have emerged as a useful research tool for manipulating metabolism with potential therapeutic application targeting various aspects of several common chronic diseases. Recent literature has investigated the effects of exogenously induced ketosis on metabolic health, cardiovascular function, cognitive processing, and modulation of inflammatory pathways and immune function. This narrative review provides an overview of the integrative physiological effects of exogenous ketone supplementation and highlights current challenges and future research directions. Much of the existing research on therapeutic applications - particularly mechanistic studies - has involved pre-clinical rodent and/or cellular models, requiring further validation in human clinical studies. Existing human studies report that exogenous ketones can lower blood glucose and improve some aspects of cognitive function, highlighting the potential therapeutic application of exogenous ketones for type 2 diabetes and neurological diseases. There is also support for the ability of exogenous ketosis to improve cardiac metabolism in rodent models of heart failure with supporting human studies emerging; long-terms effects of exogenous ketone supplementation on the human cardiovascular system and lipid profiles are needed. An important avenue for future work is provided by research accelerating technologies that enable continuous ketone monitoring and/or the development of more palatable ketone mixtures that optimize plasma ketone kinetics to enable sustained ketosis. Lastly, research exploring the physiological interactions between exogenous ketones and varying metabolic states (e.g., exercise, fasting, metabolic disease) should yield important insights that can be used to maximize the health benefits of exogenous ketosis.

Can In-Task Affect During Interval and Continuous Exercise Predict 12-Month Physical Activity Behavior? Findings from a Randomized Trial.

BACKGROUND: In-task affective responses to moderate-intensity continuous exercise training (MICT) have been shown to predict future physical activity behavior. However, limited research has investigated whether this affect-behavior relationship is similar for high-intensity interval training (HIIT) and whether it holds true over the longer term. This study aims to determine (1) if in-task affect during 2 weeks of supervised MICT and HIIT predicted changes to unsupervised moderate-to-vigorous physical activity (MVPA) behavior 12 months post-intervention and (2) if this predictive relationship was moderated by exercise type (MICT vs. HIIT). METHOD: Ninety-nine adults (69.7% female; 50.9 ± 9.4 years) who were low active and overweight were randomized to 2 weeks of exercise training of MICT (n = 52) or HIIT (n = 47), followed by 12 months of accelerometry-assessed free-living MVPA. RESULTS: The pooled moderation model was not significant, F(3, 94) = 2.54, p = .07 (R2 = 0.085), with a non-significant group by affect interaction (p = .06). The conditional effect for MICT was significant (B = 17.27, t = 2.17, p = .03), suggesting that 12-month change in MVPA increased by 17.27 min/week for every one-point increase in in-task affect. The conditional effect for HIIT was not significant (p = .85), suggesting that in-task affect was not predictive of 12-month change in MVPA. CONCLUSION: The current findings raise important questions about whether the affect-behavior relationship may vary depending on exercise type. For HIIT-based exercise in particular, additional psychological constructs beyond in-task affect should be considered when attempting to predict future physical activity behavior.

Sex differences in IL-10's anti-inflammatory function: greater STAT3 activation and stronger inhibition of TNF-α production in male blood leukocytes ex vivo.

Interleukin-10 (IL-10) inhibits proinflammatory cytokine production in blood leukocytes-an effect mediated by signal transducer and activator of transcription 3 (STAT3) activation. To examine potential sex-based differences in IL-10's anti-inflammatory function, we treated whole blood from healthy males and females (n = 16 participants of each sex; age: 28 ± 6 yr; body mass index: 23.5 ± 2.3 kg/m2) with increasing concentrations of IL-10 (1-100 ng/mL) and quantified changes in phosphorylated STAT3 (pSTAT3) in CD14+ monocytes and CD4+ lymphocytes via flow cytometry. In parallel, liposaccharide (LPS)-stimulated whole blood cultures were used to assess sex-based differences in IL-10's ability to inhibit tumor necrosis factor (TNF)-α production. IL-10 concentration dependently increased pSTAT3 median fluorescent intensity (MFI) in CD14+ and CD4+ cells (main effects of concentration, P < 0.01) with males exhibiting larger changes in pSTAT3 MFI in both cell types (main effects of sex, P < 0.01). Accordingly, IL-10-mediated inhibition of TNF-α production was more pronounced in males (main effect of sex, P < 0.01) with changes in other monocyte-derived cytokines (IL-1ß, IL-1RA, and IL-15) also supporting a sexual dimorphism in IL-10 action (P < 0.05). These sex-based differences were not explained by differences in circulating plasma IL-10 concentrations, basal IL-10 receptor expression in unstimulated CD14+ and CD4+ cells, nor the basal expression of IL-10 signaling proteins (STAT3, SHIP1, and p38 MAPK) in unstimulated peripheral blood mononuclear cells. We conclude that IL-10's anti-inflammatory function differs between male and female blood leukocytes ex vivo. This sexual dimorphism should be considered in future work investigating IL-10's anti-inflammatory action in humans as it may represent a mechanism contributing to sex differences in overall immune function.

Low-volume high-intensity interval training for cardiometabolic health.

High-intensity interval training (HIIT) is characterised by short bouts of high-intensity submaximal exercise interspersed with rest periods. Low-volume HIIT, typically involving less than 15 min of high-intensity exercise per session, is being increasingly investigated in healthy and clinical populations due to its time-efficient nature and purported health benefits. The findings from recent trials suggest that low-volume HIIT can induce similar, and at times greater, improvements in cardiorespiratory fitness, glucose control, blood pressure, and cardiac function when compared to more traditional forms of aerobic exercise training including high-volume HIIT and moderate intensity continuous training, despite requiring less time commitment and lower energy expenditure. Although further studies are required to elucidate the precise mechanisms of action, metabolic improvements appear to be driven, in part, by enhanced mitochondrial function and insulin sensitivity, whereas certain cardiovascular improvements are linked to increased left ventricular function as well as greater central and peripheral arterial compliance. Beyond the purported health benefits, low-volume HIIT appears to be safe and well-tolerated in adults, with high rates of reported exercise adherence and low adverse effects.

Exercise training remodels subcutaneous adipose tissue in adults with obesity even without weight loss.

Excessive adipose tissue mass underlies much of the metabolic health complications in obesity. Although exercise training is known to improve metabolic health in individuals with obesity, the effects of exercise training without weight loss on adipose tissue structure and metabolic function remain unclear. Thirty-six adults with obesity (body mass index = 33 ± 3 kg · m-2 ) were assigned to 12 weeks (4 days week-1 ) of either moderate-intensity continuous training (MICT; 70% maximal heart rate, 45 min; n = 17) or high-intensity interval training (HIIT; 90% maximal heart rate, 10 × 1 min; n = 19), maintaining their body weight throughout. Abdominal subcutaneous adipose tissue (aSAT) biopsy samples were collected once before and twice after training (1 day after last exercise and again 4 days later). Exercise training modified aSAT morphology (i.e. reduced fat cell size, increased collagen type 5a3, both P ≤ 0.05, increased capillary density, P = 0.05) and altered protein abundance of factors that regulate aSAT remodelling (i.e. reduced matrix metallopeptidase 9; P = 0.02; increased angiopoietin-2; P < 0.01). Exercise training also increased protein abundance of factors that regulate lipid metabolism (e.g. hormone sensitive lipase and fatty acid translocase; P ≤ 0.03) and key proteins involved in the mitogen-activated protein kinase pathway when measured the day after the last exercise session. However, most of these exercise-mediated changes were no longer significant 4 days after exercise. Importantly, MICT and HIIT induced remarkably similar adaptations in aSAT. Collectively, even in the absence of weight loss, 12 weeks of exercise training induced changes in aSAT structure, as well as factors that regulate metabolism and the inflammatory signal pathway in adults with obesity. KEY POINTS: Exercise training is well-known to improve metabolic health in obesity, although how exercise modifies the structure and metabolic function of adipose tissue, in the absence of weight loss, remains unclear. We report that both 12 weeks of moderate-intensity continuous training (MICT) and 12 weeks of high-intensity interval training (HIIT) induced modifications in adipose tissue structure and factors that regulate adipose tissue remodelling, metabolism and the inflammatory signal pathway in adults with obesity, even without weight loss (with no meaningful differences between MICT and HIIT). The modest modifications in adipose tissue structure in response to 12 weeks of MICT or HIIT did not lead to changes in the rate of fatty acid release from adipose tissue. These results expand our understanding about the effects of two commonly used exercise training prescriptions (MICT and HIIT) on adipose tissue remodelling that may lead to advanced strategies for improving metabolic health outcomes in adults with obesity.

Oligofructose-Enriched Inulin Intake, Gut Microbiome Characteristics, and the V̇O2 Peak Response to High-Intensity Interval Training in Healthy Inactive Adults.

BACKGROUND: The gut microbiome has been associated with cardiorespiratory fitness. OBJECTIVES: To assess the effects of oligofructose (FOS)-enriched inulin supplementation on the gut microbiome and the peak oxygen uptake (V̇O2peak) response to high-intensity interval training (HIIT). METHODS: The study was a randomized controlled trial. Forty sedentary and apparently healthy adults [n = 31 women; aged 31.8 ± 9.8 y, BMI (in kg⋅m-2) 25.9 ± 4.3] were randomly allocated to 1) 6 wk of supervised HIIT (4 × 4-min bouts at 85-95% peak heart rate, interspersed with 3 min of active recovery, 3·wk-1) + 12 g·d-1 of FOS-enriched inulin (HIIT-I) or 2) 6 wk of supervised HIIT (3·wk-1, 4 × 4-min bouts) + 12 g·d-1 of maltodextrin/placebo (HIIT-P). Each participant completed an incremental treadmill test to assess V̇O2peak and ventilatory thresholds (VTs), provided a stool and blood sample, and completed a 24-h diet recall questionnaire and FFQ before and after the intervention. Gut microbiome analyses were performed using metagenomic sequencing. Fecal short-chain fatty acids were measured by mass spectrometry. RESULTS: There were no differences in the mean change in V̇O2peak response between groups (P = 0.58). HIIT-I had a greater improvement in VTs than HIIT-P [VT1 (lactate accumulation): mean difference + 4.3% and VT2 (lactate threshold): +4.2%, P < 0.05]. HIIT-I had a greater increase in the abundance of Bifidobacterium taxa [false discovery rate (FDR) < 0.05] and several metabolic processes related to exercise capacity (FDR < 0.05). Exploratory analysis of merged data found participants with a greater response to HIIT (V̇O2peak ≥3.5 mL⋅kg-1⋅min-1) had a 2.2-fold greater mean abundance of gellan degradation pathways (FDR < 0.05) and a greater, but not significant, abundance of Bifidobacterium uniformis species (P < 0.00023, FDR = 0.08). CONCLUSIONS: FOS-enriched inulin supplementation did not potentiate HIIT-induced improvements in V̇O2peak but led to gut microbiome changes possibly associated with greater ventilatory threshold improvements in healthy inactive adults. Gellan degradation pathways and B. uniformis spp. were associated with greater V̇O2peak responses to HIIT.

Oral ketone monoester supplementation does not accelerate recovery of muscle force or modulate circulating cytokine concentrations after muscle-damaging eccentric exercise in healthy males and females.

NEW FINDINGS: What is the central question of this study? Does acute ketone monoester supplementation enhance the recovery of muscle force and modulate circulating cytokine concentrations after muscle-damaging eccentric exercise? What is the main finding and its importance? Ketone monoester supplementation increased plasma ß-hydroxybutyrate concentrations but did not attenuate the reduction in muscle force or the increase in plasma inflammatory cytokine concentrations that occurred after eccentric exercise. Notably we report novel data demonstrating a reduction in plasma TRAIL concentrations after eccentric exercise, highlighting TRAIL signalling as a possibly novel regulator of muscle recovery. ABSTRACT: Muscle-damaging eccentric exercise is associated with inflammation and impaired muscle force. ß-Hydroxybutyrate (ß-OHB) reduces muscle protein breakdown during inflammation but whether oral ketone monoester supplementation accelerates recovery of muscle force after eccentric exercise is unknown. Sixteen healthy males and females consumed thrice daily ketone monoester (27 g per dose; n = 8; six females; KES) or isocaloric maltodextrin placebo (n = 8; four females; PLA) drinks (randomized, double-blind, parallel group design) for 3 days beginning immediately after 300 unilateral eccentric quadriceps contractions during complete eucaloric dietary control (1.2 ± 0.1 g/kg BM/day standardized protein). Bilateral muscle force measurements and venous blood sampling were performed before and 3, 6, 24, 48 and 72 h after eccentric exercise. Plasma ß-OHB concentrations were greater in KES compared with PLA at 3 h (0.56 ± 0.13 vs. 0.22 ± 0.04 mM, respectively; P = 0.080) and 6 h (0.65 ± 0.41 vs. 0.23 ± 0.02 mM, respectively; P = 0.031) post-eccentric exercise. Relative to the control leg, isokinetic work (by 20 ± 21% in PLA and 21 ± 19% in KES; P = 0.008) and isometric torque (by 23 ± 13% in PLA and 20 ± 18% in KES; P < 0.001) decreased from baseline at 3 h in the eccentrically exercised leg, and remained below baseline at 48 and 72 h, with no significant group differences. Of eight measured plasma cytokines, interleukin-6 (P = 0.008) and monocyte chemoattractant protein-1 (P = 0.024) concentrations increased after 6 h, whereas tumour necrosis factor-related apoptosis-inducing ligand concentrations decreased after 3 h (P = 0.022) and 6 h (P = 0.011) post-exercise with no significant group differences. Oral ketone monoester supplementation elevates plasma ß-OHB concentrations but does not prevent the decline in muscle force or alter plasma inflammatory cytokine profiles induced by eccentric exercise.

Exercise Snacks: A Novel Strategy to Improve Cardiometabolic Health.

We define exercise snacks as isolated ≤1-min bouts of vigorous exercise performed periodically throughout the day. We hypothesize that exercise snacks are a feasible, well-tolerated, and time-efficient approach to improve cardiorespiratory fitness and reduce the negative impact of sedentary behavior on cardiometabolic health. Efficacy has been demonstrated in small proof-of-concept studies. Additional research should investigate this novel physical activity strategy.

Sex-specific longitudinal association between baseline physical activity level and cognitive decline in Chinese over 45 years old: Evidence from the China health and retirement longitudinal study.

OBJECTIVES: To examine whether sex-specific associations between baseline PA level and follow up cognitive performance in Chinese subjects exist from the China Health and Retirement Longitudinal study (CHARLS). METHOD: A total of 3395 adults aged 45 or old from the CHARLS were used for analysis. The combined scores of measurements of mental status and verbal episodic memory were utilized for assessing cognitive function at baseline in 2011 and the follow-up survey in 2015. Baseline PA level was quantified as the total PA score. Multiple linear regression and logistic regression models were used to examine the association between baseline PA status and global cognitive function and cognitive domains. RESULTS: In the female subjects (n = 1748), compared with individuals of PA level in the lower tertile, those grouped into the upper tertile had the lowest risk of global cognitive decline [odds ratio (OR) =0.273, 95% confidence interval (CI) =0.077-0.960; p = 0.043] and verbal episodic memory decline [OR)=0.257, 95% CI =0.066-1.003; p = 0.051] from 2011 to 2015. However, no significant associations were observed in the male subjects (n = 1647). CONCLUSION: In the female subjects, higher PA level was associated with reduced risk of cognitive decline within 4 years, this might be associated with reduced decline of verbal episodic memory. Our findings confirmed that female sex would positively affect the association between PA levels and cognitive decline.

Interpreting 'anti-inflammatory' cytokine responses to exercise: focus on interleukin-10.

Circulating concentrations of canonically pro- and anti-inflammatory cytokines are commonly measured when evaluating the anti-inflammatory effects of exercise. An important caveat to interpreting systemic cytokine concentrations as evidence for the anti-inflammatory effects of exercise is the observed dissociation between circulating cytokine concentrations and cytokine function at the tissue/cellular level. The dichotomization of cytokines as pro- or anti-inflammatory also overlooks the context dependence of cytokine function, which can vary depending on the physiological state being studied, the cytokine's cellular source/target, and magnitude of cytokine responses. We re-evaluate our current understanding of anti-inflammatory cytokine responses to exercise by highlighting nuances surrounding the interpretation of altered systemic cytokine concentrations as evidence for changes in inflammatory processes occurring at the tissue/cellular level. We highlight the lesser known pro-inflammatory and immunostimulatory actions of the prototypical anti-inflammatory cytokine, interleukin (IL)-10, including the potentiation of interferon gamma production during endotoxaemia, CD8+ T cell activation in tumour bearing rodents and cancer patients in vivo, and CD8+ T lymphocyte and natural killer cell activation in vitro. IL-10's more well-established anti-inflammatory actions can also be blunted following exercise training and under chronic inflammatory states such as type 2 diabetes (T2D) independently of circulating IL-10 concentrations. The resistance to IL-10's anti-inflammatory action in T2D coincides with blunted STAT3 phosphorylation and can be restored with small-molecule activators of IL-10 signalling, highlighting potential therapeutic avenues for restoring IL-10 action. We posit that inferences based on altered circulating cytokine concentrations alone can miss important functional changes in cytokine action occurring at the tissue/cellular level.

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.

Genome wide association study of response to interval and continuous exercise training: the Predict-HIIT study.

BACKGROUND: Low cardiorespiratory fitness (V̇O2peak) is highly associated with chronic disease and mortality from all causes. Whilst exercise training is recommended in health guidelines to improve V̇O2peak, there is considerable inter-individual variability in the V̇O2peak response to the same dose of exercise. Understanding how genetic factors contribute to V̇O2peak training response may improve personalisation of exercise programs. The aim of this study was to identify genetic variants that are associated with the magnitude of V̇O2peak response following exercise training. METHODS: Participant change in objectively measured V̇O2peak from 18 different interventions was obtained from a multi-centre study (Predict-HIIT). A genome-wide association study was completed (n = 507), and a polygenic predictor score (PPS) was developed using alleles from single nucleotide polymorphisms (SNPs) significantly associated (P < 1 × 10-5) with the magnitude of V̇O2peak response. Findings were tested in an independent validation study (n = 39) and compared to previous research. RESULTS: No variants at the genome-wide significance level were found after adjusting for key covariates (baseline V̇O2peak, individual study, principal components which were significantly associated with the trait). A Quantile-Quantile plot indicates there was minor inflation in the study. Twelve novel loci showed a trend of association with V̇O2peak response that reached suggestive significance (P < 1 × 10-5). The strongest association was found near the membrane associated guanylate kinase, WW and PDZ domain containing 2 (MAGI2) gene (rs6959961, P = 2.61 × 10-7). A PPS created from the 12 lead SNPs was unable to predict V̇O2peak response in a tenfold cross validation, or in an independent (n = 39) validation study (P > 0.1). Significant correlations were found for beta coefficients of variants in the Predict-HIIT (P < 1 × 10-4) and the validation study (P < × 10-6), indicating that general effects of the loci exist, and that with a higher statistical power, more significant genetic associations may become apparent. CONCLUSIONS: Ongoing research and validation of current and previous findings is needed to determine if genetics does play a large role in V̇O2peak response variance, and whether genomic predictors for V̇O2peak response trainability can inform evidence-based clinical practice. Trial registration Australian New Zealand Clinical Trials Registry (ANZCTR), Trial Id: ACTRN12618000501246, Date Registered: 06/04/2018, http://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=374601&isReview=true .

Physiological basis of brief vigorous exercise to improve health.

This review considers the physiological basis of brief vigorous exercise to improve health, with a focus on cardiorespiratory fitness (CRF) and glycaemic control, and the potential underlying mechanisms involved. We defined 'brief' as a protocol lasting ≤15 min including warm-up, cool-down and recovery, and involving a total of ≤5 min of 'vigorous' exercise, which was classified as meeting or exceeding the lower end of the range for this relative intensity as per the criteria from the American College of Sports Medicine. The physiological mechanisms responsible for the increase in CRF, as measured by maximal oxygen update ( V̇O2max ), after brief vigorous exercise are unclear and likely depend on various factors including the specific nature of the intervention as well as the time course of the response. Limited available evidence suggests the potential for an increased oxygen extraction by active muscle (i.e. greater arterio-venous oxygen difference), since an increase in V̇O2max has been reported after several weeks of brief vigorous exercise despite no measurable change in cardiac output. Emerging evidence indicates that brief vigorous exercise can improve glycaemic control, suggesting that this type of exercise could potentially play a role in the prevention and management of type 2 diabetes. The acute response is not well characterized but several studies have shown that several weeks of vigorous exercise improves estimates of insulin sensitivity as determined by various methods including by hyperinsulinaemic-euglycaemic clamp. The physiological mechanisms underlying improved CRF and glycaemic control after brief vigorous exercise, and the broader impact on health, remain fruitful areas of investigation.

Forty high-intensity interval training sessions blunt exercise-induced changes in the nuclear protein content of PGC-1α and p53 in human skeletal muscle.

Exercise-induced increases in peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) and p53 protein content in the nucleus mediate the initial phase of exercise-induced mitochondrial biogenesis. Here, we investigated whether exercise-induced increases in these and other markers of mitochondrial biogenesis were altered after 40 sessions of twice-daily high-volume, high-intensity interval training (HVT) in human skeletal muscle. Vastus lateralis muscle biopsies were collected from 10 healthy recreationally active participants before, immediately postexercise, and 3 h after a session of high-intensity interval exercise (HIIE) performed at the same absolute exercise intensity before and after HVT (pre-HVT and post-HVT, respectively). The protein content of common markers of exercise-induced mitochondrial biogenesis was assessed in nuclear- and cytosolic-enriched fractions by immunoblotting; mRNA contents of key transcription factors and mitochondrial genes were assessed by qPCR. Despite exercise-induced increases in PGC-1α, p53, and plant homeodomain finger-containing protein 20 (PHF20) protein content, the phosphorylation of p53 and acetyl-CoA carboxylase (p-p53 Ser15 and p-ACC Ser79, respectively), and PGC-1α mRNA Pre-HVT, no significant changes were observed post-HVT. Forty sessions of twice-daily high-intensity interval training blunted all of the measured exercise-induced molecular events associated with mitochondrial biogenesis that were observed pre-HVT. Future studies should determine whether this loss relates to the decrease in relative exercise intensity, habituation to the same exercise stimulus, or a combination of both.

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.