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Ketone bodies are neuroprotective in neurological disorders such as epilepsy. We randomly studied nine healthy human subjects twice-with and without continuous infusion of 3-hydroxybutyrate-to define potential underlying mechanisms, assessed regionally (parietal, occipital, temporal, cortical grey, and frontal) by PET scan. During 3-hydroxybutyrate infusions concentrations increased to 5.5±0.4 mmol/l and cerebral glucose utilisation decreased 14%, oxygen consumption remained unchanged, and cerebral blood flow increased 30%. We conclude that acute 3-hydroxybutyrate infusion reduces cerebral glucose uptake and increases cerebral blood flow in all measured brain regions, without detectable effects on cerebral oxygen uptake though oxygen extraction decreased. Increased oxygen supply concomitant with unchanged oxygen utilisation may contribute to the neuroprotective effects of ketone bodies.

Acute ingestion of exogenous ketone supplements in the form of a (R)‐3‐hydroxybutyl (R)‐3‐hydroxybutyrate (R‐BD R‐βHB) ketone monoester (KME) can attenuate declines in oxygen availability during hypoxic exposure and might impact cognitive performance at rest and in response to moderate‐intensity exercise. In a single‐blind randomized crossover design, 16 males performed assessments of cognitive performance before and during hypoxic exposure with moderate exercise [2 × 20 min weighted ruck (∼22 kg) at 3.2 km/h at 10% incline] in a normobaric altitude chamber (4572 m, 11.8% O2). The R‐BD R‐βHB KME (573 mg/kg) or a calorie‐ and taste‐matched placebo (∼50 g maltodextrin) were co‐ingested with 40 g of dextrose before exposure to hypoxia. The R‐βHB concentrations were rapidly elevated and sustained (>3 mM; P < 0.001) by KME. The decline in oxygen saturation during hypoxic exposure was attenuated in KME conditions by 2.4%–4.2% (P < 0.05) compared with placebo. Outcomes of cognitive performance tasks, in the form of the Defense Automated Neurobehavioral Assessment (DANA) code substitution task, the Stroop color and word task, and a shooting simulation, did not differ between trials before and during hypoxic exposure. These data suggest that the acute exogenous ketosis induced by KME ingestion can attenuate declining blood oxygen saturation during acute hypoxic exposure both at rest and during moderate‐intensity exercise, but this did not translate into differences in cognitive performance before or after exercise in the conditions investigated. What is the central question of this study? Can exogenous ketosis act as a countermeasure to declines in blood oxygen saturation and cognitive performance during acute hypoxic exposure while performing a weighted ruck exercise? What is the main finding and its importance? Acute exogenous ketosis via ingestion of a drink containing the (R)‐3‐hydroxybutyl (R)‐3‐hydroxybutyrate ketone monoester prior to acute hypoxic exposure attenuated hypoxia‐induced declines in blood oxygen saturation but had no effect on cognitive performance during exercise.

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/m 2 , HbA 1c 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, β-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. Graphical Abstract

Background Cardiovascular disease (CVD) is a leading cause of death among adults with type 2 diabetes mellitus (T2D). We recently reported that glycemic control in patients with T2D can be significantly improved through a continuous care intervention (CCI) including nutritional ketosis. The purpose of this study was to examine CVD risk factors in this cohort. Methods We investigated CVD risk factors in patients with T2D who participated in a 1 year open label, non-randomized, controlled study. The CCI group (n = 262) received treatment from a health coach and medical provider. A usual care (UC) group (n = 87) was independently recruited to track customary T2D progression. Circulating biomarkers of cholesterol metabolism and inflammation, blood pressure (BP), carotid intima media thickness (cIMT), multi-factorial risk scores and medication use were examined. A significance level of P < 0.0019 ensured two-tailed significance at the 5% level when Bonferroni adjusted for multiple comparisons. Results The CCI group consisted of 262 participants (baseline mean (SD): age 54 (8) year, BMI 40.4 (8.8) kg m −2 ). Intention-to-treat analysis (% change) revealed the following at 1-year: total LDL-particles (LDL-P) (− 4.9%, P = 0.02), small LDL-P (− 20.8%, P = 1.2 × 10 −12 ), LDL-P size (+ 1.1%, P = 6.0 × 10 −10 ), ApoB (− 1.6%, P = 0.37), ApoA1 (+ 9.8%, P < 10 −16 ), ApoB/ApoA1 ratio (− 9.5%, P = 1.9 × 10 −7 ), triglyceride/HDL-C ratio (− 29.1%, P < 10 −16 ), large VLDL-P (− 38.9%, P = 4.2 × 10 −15 ), and LDL-C (+ 9.9%, P = 4.9 × 10 −5 ). Additional effects were reductions in blood pressure, high sensitivity C-reactive protein, and white blood cell count (all P < 1 × 10 −7 ) while cIMT was unchanged. The 10-year atherosclerotic cardiovascular disease (ASCVD) risk score decreased − 11.9% (P = 4.9 × 10 −5 ). Antihypertensive medication use was discontinued in 11.4% of CCI participants (P = 5.3 × 10 −5 ). The UC group of 87 participants [baseline mean (SD): age 52 (10) year, BMI 36.7 (7.2) kg m −2 ] showed no significant changes. After adjusting for baseline differences when comparing CCI and UC groups, significant improvements for the CCI group included small LDL-P, ApoA1, triglyceride/HDL-C ratio, HDL-C, hsCRP, and LP-IR score in addition to other biomarkers that were previously reported. The CCI group showed a greater rise in LDL-C. Conclusions A continuous care treatment including nutritional ketosis in patients with T2D improved most biomarkers of CVD risk after 1 year. The increase in LDL-cholesterol appeared limited to the large LDL subfraction. LDL particle size increased, total LDL-P and ApoB were unchanged, and inflammation and blood pressure decreased. Trial registration Clinicaltrials.gov: NCT02519309. Registered 10 August 2015

Background/Objective: Treatment of subjects with non-alcoholic fatty liver disease (NAFLD) with omega-3 polyunsaturated fatty acids (FAs) suggests high levels of docosahexaenoic acid (DHA) tissue enrichment decrease liver fat content. We assessed whether changes in erythrocyte DHA enrichment (as a surrogate marker of changes in tissue enrichment) were associated with alterations in hepatic de novo lipogenesis (DNL), postprandial FA partitioning and hepatic and peripheral insulin sensitivity in a sub-study of the WELCOME trial (Wessex Evaluation of fatty Liver and Cardiovascular markers in NAFLD (non-alcoholic fatty liver disease) with OMacor thErapy). Subjects/Methods: Sixteen participants were randomised to 4 g/day EPA+DHA ( n =8) or placebo ( n =8) for 15–18 months and underwent pre- and post-intervention measurements. Fasting and postprandial hepatic FA metabolism was assessed using metabolic substrates labelled with stable-isotope tracers ( 2 H 2 O and [U 13 C]palmitate). Insulin sensitivity was measured by a stepped hyperinsulinaemic-euglycaemic clamp using deuterated glucose. Participants were stratified according to change in DHA erythrocyte enrichment (< or ⩾2% post intervention). Results: Nine participants were stratified to DHA⩾2% (eight randomised to EPA+DHA and one to placebo) and seven to the DHA<2% group (all placebo). Compared with individuals with erythrocyte <2% change in DHA abundance, those with ⩾2% enrichment had significant improvements in hepatic insulin sensitivity, reduced fasting and postprandial plasma triglyceride concentrations, decreased fasting hepatic DNL, as well as greater appearance of 13 C from dietary fat into plasma 3-hydroxybutyrate (all P <0.05). Conclusions: The findings from our pilot study indicate that individuals who achieved a change in erythrocyte DHA enrichment ⩾2% show favourable changes in hepatic FA metabolism and insulin sensitivity, which may contribute to decreasing hepatic fat content.

Rationale Glucose is the principal energy substrate for the brain, although ketone bodies are an effective alternative. Evidence suggests that elevation of plasma ketone body levels through oral intake of medium chain triglycerides (MCTs) may improve cognitive function. Objectives We tried to examine the possible effects of a ketogenic meal serving on cognition in elderly non-demented subjects. Methods Subjects were 19 non-demented elderly adults over 60 years old (13 females; mean age: 66.1 ± 2.9 years) who underwent neurocognitive tests 90 and 180 min after oral intake of a ketogenic meal (Ketonformula®) containing 20 g of MCTs and an isocaloric placebo meal without MCTs on separate days. Results Elevation of plasma ketone concentration after intake of a single ketogenic meal containing 20 g of MCTs was confirmed (all p  < 0.001). As for cognition, improvements were observed in the digit span test, Trail-Making Test B, and the global score ( Z  = −2.4, p  = 0.017) following the ketogenic meal and the change in the executive functioning score was positively correlated with that of the plasma β-hydroxybutyrate level. The cognition-enhancing effect was observed predominantly for individuals who had a relatively low global score at baseline ( Z  = −2.8, p  = 0.005), compared to individuals with a high global score (Z = −0.7, p  = 0.51). Conclusions Plasma levels of ketone bodies were successfully increased after intake of the ketogenic meal. The ketogenic meal was suggested to have positive effects on working memory, visual attention, and task switching in non-demented elderly.

Background Recent studies indicated that sodium glucose cotransporter (SGLT)2 inhibition increases levels of ketone bodies in the blood in patients with type 1 and 2 diabetes. Other studies suggested that in patients with chronic heart failure (CHF), increased myocardial oxygen demand can be provided by ketone bodies as a fuel substrate. Experimental studies reported that ketone bodies, specifically beta-hydroxybutyrate (β-OHB) may increase blood pressure (BP) by impairing endothelium-dependant relaxation, thereby leading to increased vascular stiffness. In our study we assessed whether the SGLT 2 inhibition with empagliflozin increases ketone bodies in patients with stable CHF and whether such an increase impairs BP and vascular function. Methods In a prospective, double blind, placebo controlled, parallel-group single centre study 75 patients with CHF (left ventricular ejection fraction 39.0 ± 8.2%) were randomised (2:1) to the SGLT-2 inhibitor empagliflozin 10 mg orally once daily or to placebo, 72 patients completed the study. After a run-in phase we evaluated at baseline BP by 24 h ambulatory blood pressure (ABP) monitoring, vascular stiffness parameters by the SphygmoCor system (AtCor Medical, Sydney, NSW, Australia) and fasting metabolic parameters, including β-OHB by an enzymatic assay (Beckman Coulter DxC 700 AU). The same measurements were repeated 12 weeks after treatment. In 19 of the 72 patients serum levels of β-OHB were beneath the lower border of our assay (< 0.05 mmol/l) therefore being excluded from the subsequent analysis. Results In patients with stable CHF, treatment with empagliflozin (n = 36) was followed by an increase of β-OHB by 33.39% (p = 0.017), reduction in 24 h systolic (p = 0.038) and diastolic (p = 0.085) ABP, weight loss (p = 0.003) and decrease of central systolic BP (p = 0.008) and central pulse pressure (p = 0.008). The increase in β-OHB was related to an attenuated decrease of empagliflozin-induced 24 h systolic (r = 0.321, p = 0.069) and diastolic (r = 0.516, p = 0.002) ABP and less reduction of central systolic BP (r = 0.470, p = 0.009) and central pulse pressure (r = 0.391, p = 0.033). No significant changes were seen in any of these parameters after 12 weeks of treatment in the placebo group (n = 17). Conclusion In patients with stable CHF ketone bodies as assessed by β-OHB increased after treatment with empagliflozin. This increase led to an attenuation of the beneficial effects of empagliflozin on BP and vascular parameters. Trial registration The study was registered at http://www.clinicaltrials.gov (NCT03128528).

Background/Objectives: Ketone salt (KS) containing a racemic beta-hydroxybutyrate mixture is commonly used as an alternative fuel source as it may lead to improved health and/or performance. We postulate that KS will raise acetoacetate levels and represent the effectiveness of exogenous KS as an energy source. We conducted a pilot study to quantify changes in the circulating acetoacetate following KS and to determine if any changes in acetoacetate were associated with the changes in circulating beta-hydroxybutyrate. Methods: Thirteen adults (21.6 ± 4.3 years old; seven males/six females) completed this randomized, triple-blinded, placebo-controlled, cross-over design study. Participants consumed either KS or flavor-matched placebo with a one-week washout period between supplements. Blood samples were taken before and 30 min after consuming each supplement, and plasma acetoacetate and beta-hydroxybutyrate levels were measured by gas chromatography/mass spectrometry. Results: The consumption of KS resulted in a significant increase in acetoacetate from baseline. The increase in acetoacetate after the KS supplement was significantly greater than that following the consumption of a placebo (↑ 0.57 ± 0.44 mM vs. ↑ 0.07 ± 0.23 mM, p = 0.009, d = 0.86), and significantly and strongly related to the change in blood beta-hydroxybutyrate (r = 0.757, p < 0.001). Conclusions: Our findings indicate that KS markedly increases plasma ketone body interconversion, presumably to supply peripheral tissues for ATP generation.

Our previous studies have shown that mangiferin decreased serum triglycerides and free fatty acids (FFAs) by increasing FFAs oxidation in both animal and cell experiments. This study sought to evaluate the effects of mangiferin on serum lipid profiles in overweight patients with hyperlipidemia. Overweight patients with hyperlipidemia (serum triglyceride ≥ 1.70 mmol/L and total cholesterol ≥ 5.2 mmol/L) were included in this double-blind randomized controlled trial. Participants were randomly allocated to groups, either receiving mangiferin (150 mg/day) or identical placebo for 12 weeks. The lipid profile and serum levels of mangiferin, glucose, L-carnitine, β-hydroxybutyrate and acetoacetate were determined at baseline and 12 weeks. A total of 97 participants completed the trial. Compared with the placebo control, mangiferin supplementation significantly decreased the serum levels of triglycerides and FFAs and insulin resistance index. Mangiferin supplementation also significantly increased the serum levels of mangiferin, high-density lipoprotein cholesterol, L-carnitine, β-hydroxybutyrate and acetoacetate and increased lipoprotein lipase activity. However, there were no differences in the serum levels of total cholesterol, low-density lipoprotein cholesterol, serum glucose and insulin between groups. Mangiferin supplementation could improve serum lipid profiles by reducing serum triglycerides and FFAs in overweight patients with hyperlipidemia, partly due to the promotion of FFAs oxidation.

A common belief is that high intensity exercise (>60%VO ) is best sustained by high rates of carbohydrate oxidation. The belief is based, in part, on an idea developed by Krogh and Lindhard in 1920. In the 100 years since, few studies have tested its validity. We tested the null hypothesis that performance in competitive recreational athletes exercising at >80% VO , during simulated 5-km running time trials (5KTT) would be impaired during a 6-week period of adaption to a low-carbohydrate, high-fat (LCHF) diet, compared to their performances when they ate a diet higher in carbohydrate and lower in fat (HCLF). Seven male athletes (age 35.6 ± 8.4 years, height 178.7 ± 4.1 cm, weight 68.6 ± 1.6 kg) completed two maximal exercise (VO ) tests (Day 1 and 39) and four 5KTT (Day 4, 14, 28, and 42) in a fasted state during two 6-week periods when they ate either a HCLF or a LCHF diet, in a randomized counterbalanced, crossover design. Exercise performance during the VO tests was unchanged on either diet (p = 0.251). Performance in the initial 5KTT was significantly slower on the LCHF diet (p = 0.011). There were no diet-related performance differences in the remaining three 5KTT (p > 0.22). Subjects exercised at ~82%VO . Carbohydrate oxidation provided 94% of energy on the HCLF diet, but only 65% on the LCHF diet. 5KTT performance at ~82%VO was independent of the runners' habitual diet. The HCLF diet offered no advantage over a diet with a high-fat content. Since these athletes run faster than 88% of recreational distance runners in the United States (U.S.), this finding may have wide general application.