Advanced Cardiovascular Physiology in an Individual with Type 1 Diabetes After 10-Year Ketogenic Diet.

Adults with type 1 diabetes (T1D) have an elevated risk for cardiovascular disease (CVD) compared with the general population. HbA1c is the primary modifiable risk factor for CVD in T1D. Fewer than 1% of patients achieve euglycemia (<5.7%HbA1c). Ketogenic diets (KD; ≤50g carbohydrate/day) may improve glycemia and downstream vascular dysfunction in T1D by reducing HbA1c and insulin load. However, there are concerns regarding the long-term CVD risk from a KD. Therefore, we compared data collected in a 60-day window in an adult with T1D on exogenous insulin who consumed a KD for 10 years versus normative values in those with T1D (T1D norms). The participant achieved euglycemia with an HbA1c of 5.5%, mean glucose of 98[5]mg/dL(median[IQR]), and 90[11]%time-in-range 70-180mg/dL (T1D norms: 1st percentile for all); and low insulin requirements of 0.38±0.03IU/kg/day (T1D norms: 8th percentile). Seated systolic blood pressure (SBP) was 113mmHg (T1D norms: 18th percentile) while ambulatory awake SBP was 132±15mmHg (T1D target: <130mmHg), blood triglycerides were 69mg/dL (T1D norms: 34th percentile), low-density lipoprotein was 129mg/dL (T1D norms: 60th percentile), heart rate was 56bpm (T1D norms: >1SD below the mean), carotid-femoral pulse wave velocity was 7.17m/s (T1D norms: lowest quartile of risk), flow-mediated dilation was 12.8% (T1D norms: >1SD above mean), and cardiac vagal baroreflex gain was 23.5ms/mmHg (T1D norms: >1SD above mean). Finally, there was no indication of left ventricular diastolic dysfunction from echocardiography. Overall, these data demonstrate below-average CVD risk relative to T1D norms despite concerns regarding the long-term impact of a KD on CVD risk.

Metabolic and ruck performance effects of a novel, light-weight, energy-dense ketogenic bar.

NEW FINDINGS: What is the central question of the study? Can a novel, energy-dense and lightweight ketogenic bar (1000 kcal) consumed 3 h before exercise modulate steady-state incline rucksack march ('ruck') performance compared to isocaloric carbohydrate bars in recreationally active, college-aged men? What is the main finding and its importance? Acute ingestion of either nutritional bar sustained ∼1 h of exhaustive rucking with a 30% of body weight rucksack. This proof-of-concept study is the first to demonstrate that carbohydrate bars and lipid bars are equally feasible for preserving ruck performance. Novel ketogenic nutrition bars may have military-relevant applications to lessen carry load without compromising exercise capacity. ABSTRACT: Rucksack marches ('rucks') are strenuous, military-relevant exercises that may benefit from pre-event fuelling. The purpose of this investigation was to explore whether acute ingestion of carbohydrate- or lipid-based nutritional bars before rucking can elicit unique advantages that augment exercise performance. Recreationally active and healthy males (n = 29) were randomized and counterbalanced to consume 1000 kcal derived from a novel, energy-dense (percentage energy from carbohydrate/fat/protein: 5/83/12) ketogenic bar (KB), or isocaloric high-carbohydrate bars (CB; 61/23/16) 3 h before a time-to-exhaustion (TTE) ruck. Conditions were separated by a 1-week washout. The rucksack weight was standardized to 30% of bodyweight. Steady-state treadmill pace was set at 3.2 km/h (0.89 m/s) and 14% grade. TTE was the primary outcome; respiratory exchange ratio (RER), capillary ketones (R-ß-hydroxybutyrate), glucose and lactate, plus subjective thirst/hunger were the secondary outcomes. Mean TTE was similar between conditions (KB: 55 ± 25 vs. CB: 54 ± 22 min; P = 0.687). The RER and substrate oxidation rates revealed greater fat and carbohydrate oxidation after the KB and CB, respectively (all P < 0.0001). Capillary R-ßHB increased modestly after the KB ingestion (P < 0.0001). Neither bar influenced glycaemia. Lactate increased during the ruck independent of the condition (P < 0.0001). Thirst/fullness perceptions changed independent of the nutritional bar consumed. A novel KB nutritional bar produced equivalent TTE ruck results to the isocaloric CBs. The KB's energy density relative to CB (6.6 vs. 3.8 kcal/g) may provide a lightweight (-42% weight), pre-event fuelling alternative that does not compromise ruck physical performance.

Targeting the Warburg effect for cancer treatment: Ketogenic diets for management of glioma.

Gliomas are a highly heterogeneous tumor, refractory to treatment and the most frequently diagnosed primary brain tumor. Although the current WHO grading system (2016) demonstrates promise towards identifying novel treatment modalities and better prediction of prognosis over time, to date, existing targeted and mono therapy approaches have failed to elicit a robust impact on disease progression and patient survival. It is possible that tumor heterogeneity as well as specifically targeted agents fail because redundant molecular pathways in the tumor make it refractory to such approaches. Additionally, the underlying metabolic pathology, which is significantly altered during neoplastic transformation and tumor progression, is unaccounted for. With several molecular and metabolic pathways implicated in the carcinogenesis of CNS tumors, including glioma, we postulate that a systemic, broad spectrum approach to produce robust targeting of relevant and multiple molecular and metabolic regulation of growth and survival pathways, critical to the modulation of hallmarks of carcinogenesis, without clinically limiting toxicity, may provide a more sustained impact on clinical outcomes compared to the modalities of treatment evaluated to date. The objective of this review is to examine the emerging hallmark of reprogramming energy metabolism of the tumor cells and the tumor microenvironment during carcinogenesis, and to provide a rationale for exploiting this hallmark and its biological capabilities as a target for secondary chemoprevention and treatment of glioma. This review will primarily focus on interventions to induce ketosis to target the glycolytic phenotype of many cancers, with specific application to secondary chemoprevention of low grade glioma- to halt the progression of lower grade tumors to more aggressive subtypes, as evidenced by reduction in validated intermediate endpoints of disease progression including clinical symptoms.

Nutritional Ketosis with Ketogenic Diets or Exogenous Ketones: Features, Convergence, and Divergence.

Athletes, clinicians, and practitioners are increasingly interested in the proposed performance and therapeutic benefits of nutritional ketosis (NK). NK is best operationally defined as a nutritionally induced metabolic state resulting in blood ß-hydroxybutyrate concentrations of ≥0.5 mM. Most tissues readily metabolize ketone bodies (KBs), and KBs in turn regulate metabolism and signaling in both a systemic and tissue-specific manner. During fasting, starvation, or ketogenic diets, endogenous synthesis of KBs is amplified resulting in a state of NK. Orally administered exogenous ketone supplements rapidly elevate circulating KBs and produce a similar, but far from identical, metabolic state. NK results in a number of convergent features regardless of endogenous or exogenous induction; however, important differences also are observed. The implications of NK across health, disease, and performance is rapidly becoming more evident, thus acknowledging the convergent and divergent features of NK is critical for fully understanding the potential utility of this metabolic state.

Pathogenesis of depression- and anxiety-like behavior in an animal model of hypertrophic cardiomyopathy.

Cardiovascular dysfunction is highly comorbid with mood disorders, such as anxiety and depression. However, the mechanisms linking cardiovascular dysfunction with the core behavioral features of mood disorder remain poorly understood. In this study, we used mice bearing a knock-in sarcomeric mutation, which is exhibited in human hypertrophic cardiomyopathy (HCM), to investigate the influence of HCM over the development of anxiety and depression. We employed behavioral, MRI, and biochemical techniques in young (3-4 mo) and aged adult (7-8 mo) female mice to examine the effects of HCM on the development of anxiety- and depression-like behaviors. We focused on females because in both humans and rodents, they experience a 2-fold increase in mood disorder prevalence vs. males. Our results showed that young and aged HCM mice displayed echocardiographic characteristics of the heart disease condition, yet only aged HCM females displayed anxiety- and depression-like behaviors. Electrocardiographic parameters of sympathetic nervous system activation were increased in aged HCM females vs. controls and correlated with mood disorder-related symptoms. In addition, when compared with controls, aged HCM females exhibited adrenal gland hypertrophy, reduced volume in mood-related brain regions, and reduced hippocampal signaling proteins, such as brain-derived neurotrophic factor and its downstream targets vs. controls. In conclusion, prolonged systemic HCM stress can lead to development of mood disorders, possibly through inducing structural and functional brain changes, and thus, mood disorders in patients with heart disease should not be considered solely a psychologic or situational condition.-Dossat, A. M., Sanchez-Gonzalez, M. A., Koutnik, A. P., Leitner, S., Ruiz, E. L., Griffin, B., Rosenberg, J. T., Grant, S. C., Fincham, F. D., Pinto, J. R. Kabbaj, M. Pathogenesis of depression- and anxiety-like behavior in an animal model of hypertrophic cardiomyopathy.

Nutritional ketosis delays the onset of isoflurane induced anesthesia.

BACKGROUND: Ketogenic diet (KD) and exogenous ketone supplements can evoke sustained ketosis, which may modulate sleep and sleep-like effects. However, no studies have been published examining the effect of ketosis on the onset of general isoflurane induced anesthesia. Therefore, we investigated the effect of the KD and different exogenous ketogenic supplements on the onset of akinesia induced by inhalation of isoflurane. METHODS: We used a high fat, medium protein and low carbohydrate diet (KD) chronically (10 weeks) in the glucose transporter 1 (GLUT1) deficiency (G1D) syndrome mice model and sub-chronically (7 days) in Sprague-Dawley (SPD) rats. To investigate the effect of exogenous ketone supplements on anesthetic induction we also provided either 1) a standard rodent chow diet (SD) mixed with 20% ketone salt supplement (KS), or 2) SD mixed with 20% ketone ester supplement (KE; 1,3 butanediol-acetoacetate diester) to G1D mice for 10 weeks. Additionally, SPD rats and Wistar Albino Glaxo Rijswijk (WAG/Rij) rats were fed the SD, which was supplemented by oral gavage of KS or KE for 7 days (SPD rats: 5 g/kg body weight/day; WAG/Rij rats: 2.5 g/kg body weight/day). After these treatments (10 weeks for the mice, and 7 days for the rats) isoflurane (3%) was administered in an anesthesia chamber, and the time until anesthetic induction (time to immobility) was measured. Blood ketone levels were measured after anesthetic induction and correlation was calculated for blood beta-hydroxybutyrate (ßHB) and anesthesia latency. RESULTS: Both KD and exogenous ketone supplementation increased blood ketone levels and delayed the onset of isoflurane-induced immobility in all investigated rodent models, showing positive correlation between the two measurements. These results demonstrate that elevated blood ketone levels by either KD or exogenous ketones delayed the onset of isoflurane-induced anesthesia in these animal models. CONCLUSIONS: These findings suggest that ketone levels might affect surgical anesthetic needs, or could potentially decrease or delay effects of other narcotic gases.

Long term ablation of protein kinase A (PKA)-mediated cardiac troponin I phosphorylation leads to excitation-contraction uncoupling and diastolic dysfunction in a knock-in mouse model of hypertrophic cardiomyopathy.

The cardiac troponin I (cTnI) R21C (cTnI-R21C) mutation has been linked to hypertrophic cardiomyopathy and renders cTnI incapable of phosphorylation by PKA in vivo. Echocardiographic imaging of homozygous knock-in mice expressing the cTnI-R21C mutation shows that they develop hypertrophy after 12 months of age and have abnormal diastolic function that is characterized by longer filling times and impaired relaxation. Electrocardiographic analyses show that older R21C mice have elevated heart rates and reduced cardiovagal tone. Cardiac myocytes isolated from older R21C mice demonstrate that in the presence of isoproterenol, significant delays in Ca(2+) decay and sarcomere relaxation occur that are not present at 6 months of age. Although isoproterenol and stepwise increases in stimulation frequency accelerate Ca(2+)-transient and sarcomere shortening kinetics in R21C myocytes from older mice, they are unable to attain the corresponding WT values. When R21C myocytes from older mice are treated with isoproterenol, evidence of excitation-contraction uncoupling is indicated by an elevation in diastolic calcium that is frequency-dissociated and not coupled to shorter diastolic sarcomere lengths. Myocytes from older mice have smaller Ca(2+) transient amplitudes (2.3-fold) that are associated with reductions (2.9-fold) in sarcoplasmic reticulum Ca(2+) content. This abnormal Ca(2+) handling within the cell may be attributed to a reduction (2.4-fold) in calsequestrin expression in conjunction with an up-regulation (1.5-fold) of Na(+)-Ca(2+) exchanger. Incubation of permeabilized cardiac fibers from R21C mice with PKA confirmed that the mutation prevents facilitation of mechanical relaxation. Altogether, these results indicate that the inability to enhance myofilament relaxation through cTnI phosphorylation predisposes the heart to abnormal diastolic function, reduced accessibility of cardiac reserves, dysautonomia, and hypertrophy.

School burnout and cardiovascular functioning in young adult males: a hemodynamic perspective.

This study investigated aortic and brachial hemodynamic functioning that may link school burnout to cardiovascular risk factors. Methodological improvements from previous research were implemented including (1) statistical control of depressive and anxiety symptoms (2) resting, stress-induced and cardiac recovery condition comparisons and (3) use of pulse wave analysis. Forty undergraduate young adult males completed self-report measures of school burnout, trait anxiety and depressive symptoms. Participants then completed a protocol consisting of a 10-min seated rest, 5-min baseline (BASE), 3-min cold pressor test (CPT) and a 3-min recovery period (REC). Indices of brachial and aortic hemodynamics were obtained by means of pulse wave analysis via applanation tonometry. Controlling for anxiety and depressive symptoms, planned contrasts identified no differences in cardiovascular parameters at BASE between participants in burnout and non-burnout groups. However, negative changes in hemodynamic indices occurred in burnout participants at CPT and REC as evidenced by increased aortic and brachial systolic and diastolic blood pressures, increased left ventricular work and increased myocardial oxygen consumption. Findings suggest that school burnout symptoms are associated with cardiac hyperactivity during conditions of cardiac stress and recovery and therefore may be associated with the early manifestations of cardiovascular disease. Future studies are suggested to reveal underlying autonomic mechanisms explaining hemodynamics functioning in individuals with school burnout symptomatology.

Acute passive vibration reduces arterial stiffness and aortic wave reflection in stroke survivors.

PURPOSE: Impaired leg arterial stiffness (pulse wave velocity, PWV) and vasodilatory function are found after stroke. Acute passive vibration (PV) decreases leg PWV (legPWV) and pressure wave reflection (aortic augmentation index, aAIx) in healthy men. Our objective was to evaluate the effects of acute PV on aAIx and PWV in the paretic and non-paretic sides in stroke survivors. METHODS: Eleven stroke survivors (4 females) were randomized to either no-PV (control) or PV (25 Hz and 2 mm amplitude) trials on two separated visits. Following 20 min of supine rest with legs on a vibration platform, blood pressure, PWV, and aAIx were gathered before 10 continuous minutes of control or PV. Measurements were repeated at post-5, post-15, and post-30 min after control or PV. RESULTS: LegPWV and brachial-ankle PWV (baPWV, systemic stiffness) in paretic and non-paretic sides along with aAIx were significantly (P < 0.05) decreased from baseline at post-5 min after PV compared with control. At post-15 min, paretic and non-paretic legPWV remained significantly lower than baseline, but only non-paretic legPWV was different from control. We noted correlations between changes in paretic legPWV and changes in paretic baPWV (r = 0.47, P = 0.028) and aAIx (r = 0.51, P = 0.017) at post-5 min. CONCLUSIONS: Acute PV applied to the legs of stroke survivors reduces systemic arterial stiffness and aortic wave reflection due to a reduction in leg arterial stiffness, which last longer in the non-paretic than in the paretic leg.

Impact of acute whole-body cold exposure with concurrent isometric handgrip exercise on aortic pressure waveform characteristics.

PURPOSE: Adverse cardiovascular events are more prevalent during winter and in people that exercise/work in cold temperatures. Since pulse wave analysis indices, aortic systolic blood pressure (ASBP), augmentation index (AIx), and wasted left ventricular pressure energy (ΔE w), are stronger predictors of cardiovascular events and myocardial performance than brachial blood pressure (BP), we sought to evaluate the aortic hemodynamic responses during cold exposure with concurrent isometric handgrip exercise (IHG). METHODS: In a crossover randomized fashion, 20 healthy normotensive men (22.1 ± 2 years) were evaluated, by means of radial applanation tonometry, inside an environmental chamber in the supine position at cold (4 °C) and temperate (24 °C) conditions. Following a 30-min equilibration period, measurements were performed during pre-exercise baseline (REST), in the last 90 s of a 3-min IHG at 30% maximal voluntary contraction, and 3 min immediately after the finalization of IHG bout (recovery, REC). RESULTS: At REST, brachial systolic BP (BSBP) (12 ± 2 mmHg; P < 0.01), ASBP (14 ± 3 mmHg; P < 0.01), AIx (11 ± 3%; P < 0.05), and ΔE w (737 ± 128 dynes s/cm(2); P < 0.01) were higher in 4 °C compared to 24 °C trial. Compared to REST, IHG significantly increased (P < 0.01) BSBP, ASBP, AIx, and ΔEw, while BSBP and ASBP remained elevated during REC (P < 0.01). Compared to REST and temperate, AIx (11 ± 3%) and ΔE w (793 ± 145 dynes s/cm(2); P < 0.01) were higher during IHG and cold, while BSBP and ASBP were elevated during REC and cold. AIx and ΔE w returned to REST values in both trials, but AIx (11 ± 4%; P < 0.05) and ΔE w (656 ± 132 dynes s/cm(2); P < 0.05) were higher in the cold. CONCLUSIONS: Cold exposure with concurrent IHG induces a significant increase in aortic hemodynamic markers, which may evoke adverse cardiovascular events.

A Ketone Monoester with Carbohydrate Improves Cognitive Measures Postexercise, but Not Performance in Trained Females.

PURPOSE: The acute ingestion of a ketone monoester with the coingestion of a carbohydrate (KME + CHO) compared with carbohydrate (CHO) was investigated on cycling performance and cognitive performance in trained females. METHODS: Using a two condition, placebo-controlled, double-blinded and crossover design, 12 trained females (mean ± SD: age, 23 ± 3 yr; height, 1.64 ± 0.08 m; mass, 65.2 ± 12.7 kg) completed a baseline assessment of cognitive performance (psychomotor vigilance testing (PVT), task switching, and incongruent flanker), followed by 6 × 5-min intervals at 40%, 45%, 50%, 55%, 60%, and 65% of their maximal power output (W max ) and then a 10-km time trial, concluding with the same assessments of cognitive performance. Participants consumed either 375 mg·kg -1 body mass of KME with a 6% CHO solution (1 g·min -1 of exercise) or CHO alone, across three boluses (50:25:25). RESULTS: Blood ß-hydroxybutyrate concentrations averaged 1.80 ± 0.07 and 0.13 ± 0.01 mM during exercise in KME + CHO and CHO, respectively. Blood glucose decreased after drink 1 of KME + CHO (~15%; P = 0.01) but not CHO, and lactate concentrations were lower in KME + CHO at 50%, 55%, 60%, and 65% W max (all P < 0.05) compared with CHO. Despite these changes, no differences were found between conditions for time trial finishing times (KME + CHO, 29.7 ± 5.7 min; CHO, 29.6 ± 5.7 min; P = 0.92). However, only KME + CHO resulted in increases in psychomotor vigilance testing speed (~4%; P = 0.01) and faster reaction times (~14%; P < 0.01), speed (~15%; P < 0.01), and correct responses (~13%; P = 0.03) in the incongruent flanker during posttesting compared with CHO. CONCLUSIONS: The acute ingestion of a KME + CHO elevated blood ß-hydroxybutyrate and lowered glucose and lactate across multiple time points during exercise compared with CHO. Although these changes did not affect physical performance, several markers of cognitive performance were improved by the addition of a KME in trained females.

The Metabolic and Endocrine Effects of a 12-Week Allulose-Rich Diet.

The global rise in type 2 diabetes (T2D) and obesity necessitates innovative dietary interventions. This study investigates the effects of allulose, a rare sugar shown to reduce blood glucose, in a rat model of diet-induced obesity and T2D. Over 12 weeks, we hypothesized that allulose supplementation would improve body weight, insulin sensitivity, and glycemic control. Our results showed that allulose mitigated the adverse effects of high-fat, high-sugar diets, including reduced body weight gain and improved insulin resistance. The allulose group exhibited lower food consumption and increased levels of glucagon-like peptide-1 (GLP-1), enhancing glucose regulation and appetite control. Additionally, allulose prevented liver triglyceride accumulation and promoted mitochondrial uncoupling in adipose tissue. These findings suggest that allulose supplementation can improve metabolic health markers, making it a promising dietary component for managing obesity and T2D. Further research is needed to explore the long-term benefits and mechanisms of allulose in metabolic disease prevention and management. This study supports the potential of allulose as a safe and effective intervention for improving metabolic health in the context of dietary excess.

Expert consensus on nutrition and lower-carbohydrate diets: An evidence- and equity-based approach to dietary guidance.

There is a substantial body of clinical evidence supporting the beneficial effects of lower-carbohydrate dietary patterns on multiple established risk factors associated with insulin resistance and cardiovascular diseases in adult populations. Nutrition and health researchers, clinical practitioners, and stakeholders gathered for, "The Scientific Forum on Nutrition, Wellness, and Lower-Carbohydrate Diets: An Evidence- and Equity-Based Approach to Dietary Guidance" to discuss the evidence base around lower-carbohydrate diets, health outcomes, and dietary guidance. Consensus statements were agreed upon to identify current areas of scientific agreement and spotlight gaps in research, education, and practice to help define and prioritize future pathways. Given the evidence base and considering that most American adults are living with at least one nutrition-related chronic disease, there was consensus that including a lower-carbohydrate dietary pattern as one part of the Dietary Guidelines for Americans could help promote health equity among the general population.

A comprehensive SARS-CoV-2 and COVID-19 review, Part 2: host extracellular to systemic effects of SARS-CoV-2 infection.

COVID-19, the disease caused by SARS-CoV-2, has caused significant morbidity and mortality worldwide. The betacoronavirus continues to evolve with global health implications as we race to learn more to curb its transmission, evolution, and sequelae. The focus of this review, the second of a three-part series, is on the biological effects of the SARS-CoV-2 virus on post-acute disease in the context of tissue and organ adaptations and damage. We highlight the current knowledge and describe how virological, animal, and clinical studies have shed light on the mechanisms driving the varied clinical diagnoses and observations of COVID-19 patients. Moreover, we describe how investigations into SARS-CoV-2 effects have informed the understanding of viral pathogenesis and provide innovative pathways for future research on the mechanisms of viral diseases.

A Glutamate Scavenging Protocol Combined with Deanna Protocol in SOD1-G93A Mouse Model of ALS.

Amyotrophic lateral sclerosis (ALS) is a progressive disease of neuronal degeneration in the motor cortex, brainstem, and spinal cord, resulting in impaired motor function and premature demise as a result of insufficient respiratory drive. ALS is associated with dysfunctions in neurons, neuroglia, muscle cells, energy metabolism, and glutamate balance. Currently, there is not a widely accepted, effective treatment for this condition. Prior work from our lab has demonstrated the efficacy of supplemental nutrition with the Deanna Protocol (DP). In the present study, we tested the effects of three different treatments in a mouse model of ALS. These treatments were the DP alone, a glutamate scavenging protocol (GSP) alone, and a combination of the two treatments. Outcome measures included body weight, food intake, behavioral assessments, neurological score, and lifespan. Compared to the control group, DP had a significantly slower decline in neurological score, strength, endurance, and coordination, with a trend toward increased lifespan despite a greater loss of weight. GSP had a significantly slower decline in neurological score, strength, endurance, and coordination, with a trend toward increased lifespan. DP+GSP had a significantly slower decline in neurological score with a trend toward increased lifespan, despite a greater loss of weight. While each of the treatment groups fared better than the control group, the combination of the DP+GSP was not better than either of the individual treatments. We conclude that the beneficial effects of the DP and the GSP in this ALS mouse model are distinct, and appear to offer no additional benefit when combined.

Low and high carbohydrate isocaloric diets on performance, fat oxidation, glucose and cardiometabolic health in middle age males.

High carbohydrate, low fat (HCLF) diets have been the predominant nutrition strategy for athletic performance, but recent evidence following multi-week habituation has challenged the superiority of HCLF over low carbohydrate, high fat (LCHF) diets, along with growing interest in the potential health and disease implications of dietary choice. Highly trained competitive middle-aged athletes underwent two 31-day isocaloric diets (HCLF or LCHF) in a randomized, counterbalanced, and crossover design while controlling calories and training load. Performance, body composition, substrate oxidation, cardiometabolic, and 31-day minute-by-minute glucose (CGM) biomarkers were assessed. We demonstrated: (i) equivalent high-intensity performance (@∼85%VO2max), fasting insulin, hsCRP, and HbA1c without significant body composition changes across groups; (ii) record high peak fat oxidation rates (LCHF:1.58 ± 0.33g/min @ 86.40 ± 6.24%VO2max; 30% subjects > 1.85 g/min); (iii) higher total, LDL, and HDL cholesterol on LCHF; (iv) reduced glucose mean/median and variability on LCHF. We also found that the 31-day mean glucose on HCLF predicted 31-day glucose reductions on LCHF, and the 31-day glucose reduction on LCHF predicted LCHF peak fat oxidation rates. Interestingly, 30% of athletes had 31-day mean, median and fasting glucose > 100 mg/dL on HCLF (range: 111.68-115.19 mg/dL; consistent with pre-diabetes), also had the largest glycemic and fat oxidation response to carbohydrate restriction. These results: (i) challenge whether higher carbohydrate intake is superior for athletic performance, even during shorter-duration, higher-intensity exercise; (ii) demonstrate that lower carbohydrate intake may be a therapeutic strategy to independently improve glycemic control, particularly in those at risk for diabetes; (iii) demonstrate a unique relationship between continuous glycemic parameters and systemic metabolism.

Exogenous Ketone Supplements in Athletic Contexts: Past, Present, and Future.

The ketone bodies acetoacetate (AcAc) and ß-hydroxybutyrate (ßHB) have pleiotropic effects in multiple organs including brain, heart, and skeletal muscle by serving as an alternative substrate for energy provision, and by modulating inflammation, oxidative stress, catabolic processes, and gene expression. Of particular relevance to athletes are the metabolic actions of ketone bodies to alter substrate utilisation through attenuating glucose utilisation in peripheral tissues, anti-lipolytic effects on adipose tissue, and attenuation of proteolysis in skeletal muscle. There has been long-standing interest in the development of ingestible forms of ketone bodies that has recently resulted in the commercial availability of exogenous ketone supplements (EKS). These supplements in the form of ketone salts and ketone esters, in addition to ketogenic compounds such as 1,3-butanediol and medium chain triglycerides, facilitate an acute transient increase in circulating AcAc and ßHB concentrations, which has been termed 'acute nutritional ketosis' or 'intermittent exogenous ketosis'. Some studies have suggested beneficial effects of EKS to endurance performance, recovery, and overreaching, although many studies have failed to observe benefits of acute nutritional ketosis on performance or recovery. The present review explores the rationale and historical development of EKS, the mechanistic basis for their proposed effects, both positive and negative, and evidence to date for their effects on exercise performance and recovery outcomes before concluding with a discussion of methodological considerations and future directions in this field.

Resting-state heart rate variability after stressful events as a measure of stress tolerance among elite performers.

Introduction: A common trait of elite performers is their ability to perform well when stressed by strong emotions such as fear. Developing objective measures of stress response that reliably predict performance under stress could have far-reaching implications in selection and training of elite individuals and teams. Prior data suggests that (i) Heart rate and heart rate variability (HR/HRV) are associated with stress reaction, (ii) Higher basal sympathetic tone prior to stressful events is associated with higher performance, and (iii) Elite performers tend to exhibit greater increase in parasympathetic tone after a stressful event. Methods: The current study assesses the predictive utility of post-stressful event HR/HRV measures, an under-studied time point in HR/HRV research, in the context of military personnel selection. Specifically, we examined the relationship between a comprehensive set of HR/HRV measures and established questionnaires related to stress tolerance, experimental evaluation of executive function during stress induction, and ecologically valid selection assessment data from a week-long Special Operations Forces selection course (N = 30). Results: We found that post-stressful event HR/HRV measures generally had strong correlations with the neuroticism facet of the NEO personality inventory as well as the general and distress facets of the defensive reactivity questionnaire. HR/HRV measures correlated reliably with a change in executive function measured as a decrease in verbal fluency with exposure to a well-validated stressor. Finally, we observed a divergent pattern of correlation among elite and non-elite SOF candidates. Specifically, among elite candidates, parasympathetic nervous system (PNS) measures correlated positively and sympathetic nervous system (SNS) measures correlated negatively with evaluation of stress tolerance by experts and peers. This pattern was not present in non-elite candidates. Discussion: Our findings demonstrate that post-stressful event HR/HRV data provide an objective non-invasive method to measure the recovery and arousal state in direct reaction to the stressful event and can be used as metrics of stress tolerance that could enhance selection of elite individuals and teams.

Carbohydrate restriction for diabetes: rediscovering centuries-old wisdom.

Carbohydrate restriction, used since the 1700s to prolong survival in people with diabetes, fell out of favor after the discovery of insulin. Despite costly pharmacological and technological developments in the last few decades, current therapies do not achieve optimal outcomes, and most people with diabetes remain at high risk for micro- and macrovascular complications. Recently, low-carbohydrate diets have regained popularity, with preliminary evidence of benefit for body weight, postprandial hyperglycemia, hyperinsulinemia, and other cardiometabolic risk factors in type 2 diabetes and, with more limited data, in type 1 diabetes. High-quality, long-term trials are needed to assess safety concerns and determine whether this old dietary approach might help people with diabetes attain clinical targets more effectively, and at a lower cost, than conventional treatment.

From bedside to battlefield: intersection of ketone body mechanisms in geroscience with military resilience.

Ketone bodies are endogenous metabolites that are linked to multiple mechanisms of aging and resilience. They are produced by the body when glucose availability is low, including during fasting and dietary carbohydrate restriction, but also can be consumed as exogenous ketone compounds. Along with supplying energy to peripheral tissues such as brain, heart, and skeletal muscle, they increasingly are understood to have drug-like protein binding activities that regulate inflammation, epigenetics, and other cellular processes. While these energy and signaling mechanisms of ketone bodies are currently being studied in a variety of aging-related diseases such as Alzheimer's disease and type 2 diabetes mellitus, they may also be relevant to military service members undergoing stressors that mimic or accelerate aging pathways, particularly traumatic brain injury and muscle rehabilitation and recovery. Here we summarize the biology of ketone bodies relevant to resilience and rehabilitation, strategies for translational use of ketone bodies, and current clinical investigations in this area.