Ketosis, the metabolic response to energy crisis, is a mechanism to sustain life by altering oxidative fuel selection. Often overlooked for its metabolic potential, ketosis is poorly understood outside of starvation or diabetic crisis. Thus, we studied the biochemical advantages of ketosis in humans using a ketone ester-based form of nutrition without the unwanted milieu of endogenous ketone body production by caloric or carbohydrate restriction. In five separate studies of 39 high-performance athletes, we show how this unique metabolic state improves physical endurance by altering fuel competition for oxidative respiration. Ketosis decreased muscle glycolysis and plasma lactate concentrations, while providing an alternative substrate for oxidative phosphorylation. Ketosis increased intramuscular triacylglycerol oxidation during exercise, even in the presence of normal muscle glycogen, co-ingested carbohydrate and elevated insulin. These findings may hold clues to greater human potential and a better understanding of fuel metabolism in health and disease.

IntroductionPhysical endurance can be limited by muscle glycogen stores, in that glycogen depletion markedly reduces external work. During carbohydrate restriction, the liver synthesizes the ketone bodies, d-β-hydroxybutyrate, and acetoacetate from fatty acids. In animals and in the presence of glucose, d-β-hydroxybutyrate promotes insulin secretion and increases glycogen synthesis. Here we determined whether a dietary ketone ester, combined with plentiful glucose, can increase postexercise glycogen synthesis in human skeletal muscle.MethodsAfter an interval-based glycogen depletion exercise protocol, 12 well-trained male athletes completed a randomized, three-arm, blinded crossover recovery study that consisted of consumption of either a taste-matched, zero-calorie control or a ketone monoester drink, followed by a 10-mM glucose clamp or saline infusion for 2 h. The three postexercise conditions were control drink then saline infusion, control drink then hyperglycemic clamp, or ketone ester drink then hyperglycemic clamp. Skeletal muscle glycogen content was determined in muscle biopsies of vastus lateralis taken before and after the 2-h clamps.ResultsThe ketone ester drink increased blood d-β-hydroxybutyrate concentrations to a maximum of 5.3 versus 0.7 mM for the control drink (P < 0.0001). During the 2-h glucose clamps, insulin levels were twofold higher (31 vs 16 mU·L−1, P < 0.01) and glucose uptake 32% faster (1.66 vs 1.26 g·kg−1, P < 0.001). The ketone drink increased by 61 g, the total glucose infused for 2 h, from 197 to 258 g, and muscle glycogen was 50% higher (246 vs 164 mmol glycosyl units per kilogram dry weight, P < 0.05) than after the control drink.ConclusionIn the presence of constant high glucose concentrations, a ketone ester drink increased endogenous insulin levels, glucose uptake, and muscle glycogen synthesis.

Exogenous ketone drinks may improve athletic performance and recovery, but information on their gastrointestinal tolerability is limited. Studies to date have used a simplistic reporting methodology that inadequately represents symptom type, frequency, and severity. Herein, gastrointestinal symptoms were recorded during three studies of exogenous ketone monoester (KME) and salt (KS) drinks. Study 1 compared low- and high-dose KME and KS drinks consumed at rest. Study 2 compared KME with isocaloric carbohydrate (CHO) consumed at rest either when fasted or after a standard meal. Study 3 compared KME+CHO with isocaloric CHO consumed before and during 3.25 hr of bicycle exercise. Participants reported symptom type and rated severity between 0 and 8 using a Likert scale at regular intervals. The number of visits with no symptoms reported after ketone drinks was n = 32/60 in Study 1, n = 9/32 in Study 2, and n = 20/42 in Study 3. Following KME and KS drinks, symptoms were acute but mild and were fully resolved by the end of the study. High-dose KS drinks caused greater total-visit symptom load than low-dose KS drinks (13.8 ± 4.3 vs. 2.0 ± 1.0; p < .05) and significantly greater time-point symptom load than KME drinks 1–2 hr postdrink. At rest, KME drinks caused greater total-visit symptom load than CHO drinks (5.0 ± 1.6 vs. 0.6 ± 0.4; p < .05). However, during exercise, there was no significant difference in total-visit symptom load between KME+CHO (4.2 ± 1.0) and CHO (7.2 ± 1.9) drinks. In summary, exogenous ketone drinks cause mild gastrointestinal symptoms that depend on time, the type and amount of compound consumed, and exercise.

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Purpose: In this study, we determined ketone oxidation rates in athletes under metabolic conditions of high and low carbohydrate (CHO) and fat availability.Methods: Six healthy male athletes completed 1 h of bicycle ergometer exercise at 75% maximal power (WMax) on three occasions. Prior to exercise, participants consumed 573 mg·kg bw−1 of a ketone ester (KE) containing a 13C label. To manipulate CHO availability, athletes undertook glycogen depleting exercise followed by isocaloric high-CHO or very-low-CHO diets. To manipulate fat availability, participants were given a continuous infusion of lipid during two visits. Using stable isotope methodology, β-hydroxybutyrate (βHB) oxidation rates were therefore investigated under the following metabolic conditions: (i) high CHO + normal fat (KE+CHO); (ii) high CHO + high fat KE+CHO+FAT); and (iii) low CHO + high fat (KE+FAT).Results: Pre-exercise intramuscular glycogen (IMGLY) was approximately halved in the KE+FAT vs. KE+CHO and KE+CHO+FAT conditions (both p &lt; 0.05). Blood free fatty acids (FFA) and intramuscular long-chain acylcarnitines were significantly greater in the KE+FAT vs. other conditions and in the KE+CHO+FAT vs. KE+CHO conditions before exercise. Following ingestion of the 13C labeled KE, blood βHB levels increased to ≈4.5 mM before exercise in all conditions. βHB oxidation was modestly greater in the KE+CHO vs. KE+FAT conditions (mean diff. = 0.09 g·min−1, p = 0.03; d = 0.3), tended to be greater in the KE+CHO+FAT vs. KE+FAT conditions (mean diff. = 0.07 g·min−1; p = 0.1; d = 0.3) and were the same in the KE+CHO vs. KE+CHO+FAT conditions (p &lt; 0.05; d &lt; 0.1). A moderate positive correlation between pre-exercise IMGLY and βHB oxidation rates during exercise was present (p = 0.04; r = 0.5). Post-exercise intramuscular βHB abundance was markedly elevated in the KE+FAT vs. KE+CHO and KE+CHO+FAT conditions (both, p &lt; 0.001; d = 2.3).Conclusion: βHB oxidation rates during exercise are modestly impaired by low CHO availability, independent of circulating βHB levels.

14505 Background: Over 50,000 men developed hormone refractory prostate cancer (HRPC) in 2005 (CancerMetrics 2005). The objective of this study is to compare attitudes of patients, caregivers and physicians on the effects of advancing disease on patients. Methods: Respondents indicated attitudes towards 18 PC symptoms. Responses were analyzed by a division of Yankelovich. Grant funding from Abbott.Us TOO International conducted an online survey of HRPC patients, caregivers, and physicians in 2005. Patients and caregivers were recruited from NexCura’s database of users of the Treatment Profiler Options Tool for PC and links from PC websites (UsTOO, PCRI, PCF and PAACT). Board certified physicians who treat HRPC were recruited by J. Reckner & Associates. Respondents indicated their attitudes towards 18 symptoms of advancing PC. Responses were analyzed by TSC, a division of Yankelovich. Results: 409 HRPC patients (P), 236 caregivers (C), and 204 physicians (MD) (100 urologists/104 oncologists) participated in the study. Mean patient age was 65.7 and age at diagnosis was 60.2. Patients were identified as non-metastatic (M0) or metastatic (M+). 46% of patients were M+; 60% of caregivers are caring for M+ patients. 51% of M+ patients and 74% of M+ caregivers’ patients experienced bone pain. The most common symptom concerns were bone pain, other pain and mental changes. Conclusions: Over half of the M+ patients experienced bone pain related to PC in this survey. Once HRPC becomes M+, bone pain significantly affects the quality of life of patients and caregivers. It is the highest rated concern of patients, caregivers and physicians. Bone pain significantly alters the lives of those with advancing HRPC. New options are needed for patients with advancing PC. [Table: see text] [Table: see text]

Rowing is an endurance sport with an important skill component. This study evaluated the effects of carbohydrate (CHO) solution ingestion on rowing technique before and after 60 min of ergometer rowing. On two occasions, eight male rowers (age 22±2 years, height 182±4 cm, weight 72.9±2.1 kg, VO2max 4.9±0.2 litre/min) rowed as a group in an indoor rowing tank for 6 min at 18 strokes per minute before and after 60 min of ergometer rowing at 60% of VO2max. Participants ingested either a 6% CHO solution or a flavoured placebo (PLA) in a randomised, counterbalanced fashion. Physiological and technical measures were analysed using a repeated measures analysis of variance. Oar handle curves were analysed using Geometric Morphometrics (principal component analysis). There were no differences in heart rate or rating of perceived exertion between the treatments, indicating similar physiological strain. There were no changes in stroke length over the 60-min period with either treatment. Oar handle velocity decreased from 49.7±3.6 to 47.4±2.8°/s (p<0.05) over the 60-min period in PLA but did not change in CHO (48.9±2.2-48.2±1.9°/s). Oar handle curves did not differ between CHO and PLA (procrustes distance=0.645). Maximum blade depth declined similarly by 20±16% in both CHO and PLA (p<0.01). This change is likely to decrease the resistance of the water upon the oar blade during the drive phase of the rowing stroke. In conclusion, selected measures of rowing tank technique deteriorated in response to 60 min of ergometer rowing in both PLA and CHO. Ingestion of CHO may help to maintain velocity of movement as rowers fatigue. Future research should investigate technique during on-water rowing to evaluate the effects of fatigue and CHO ingestion on rowing technique in the natural competitive environment.