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      Exogenous Ketone Supplementation and Keto-Adaptation for Endurance Performance: Disentangling the Effects of Two Distinct Metabolic States

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          Insulin, ketone bodies, and mitochondrial energy transduction.

          Addition of insulin or a physiological ratio of ketone bodies to buffer with 10 mM glucose increased efficiency (hydraulic work/energy from O2 consumed) of working rat heart by 25%, and the two in combination increased efficiency by 36%. These additions increased the content of acetyl CoA by 9- to 18-fold, increased the contents of metabolites of the first third of the tricarboxylic acid (TCA) cycle 2- to 5-fold, and decreased succinate, oxaloacetate, and aspartate 2- to 3-fold. Succinyl CoA, fumarate, and malate were essentially unchanged. The changes in content of TCA metabolites resulted from a reduction of the free mitochondrial NAD couple by 2- to 10-fold and oxidation of the mitochondrial coenzyme Q couple by 2- to 4-fold. Cytosolic pH, measured using 31P-NMR spectra, was invariant at about 7.0. The total intracellular bicarbonate indicated an increase in mitochondrial pH from 7.1 with glucose to 7.2, 7.5 and 7.4 with insulin, ketones, and the combination, respectively. The decrease in Eh7 of the mitochondrial NAD couple, Eh7NAD+/NADH, from -280 to -300 mV and the increase in Eh7 of the coenzyme Q couple, Eh7Q/QH2, from -4 to +12 mV was equivalent to an increase from -53 kJ to -60 kJ/2 mol e in the reaction catalyzed by the mitochondrial NADH dehydrogenase multienzyme complex (EC 1.6.5.3). The increase in the redox energy of the mitochondrial cofactor couples paralleled the increase in the free energy of cytosolic ATP hydrolysis, delta GATP. The potential of the mitochondrial relative to the cytosolic phases, Emito/cyto, calculated from delta GATP and delta pH on the assumption of a 4 H+ transfer for each ATP synthesized, was -143 mV during perfusion with glucose or glucose plus insulin, and decreased to -120 mV on addition of ketones. Viewed in this light, the moderate ketosis characteristic of prolonged fasting or type II diabetes appears to be an elegant compensation for the defects in mitochondrial energy transduction associated with acute insulin deficiency or mitochondrial senescence.
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            Kinetics, safety and tolerability of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate in healthy adult subjects.

            Induction of mild states of hyperketonemia may improve physical and cognitive performance. In this study, we determined the kinetic parameters, safety and tolerability of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate, a ketone monoester administered in the form of a meal replacement drink to healthy human volunteers. Plasma levels of β-hydroxybutyrate and acetoacetate were elevated following administration of a single dose of the ketone monoester, whether at 140, 357, or 714 mg/kg body weight, while the intact ester was not detected. Maximum plasma levels of ketones were attained within 1-2h, reaching 3.30 mM and 1.19 mM for β-hydroxybutyrate and acetoacetate, respectively, at the highest dose tested. The elimination half-life ranged from 0.8-3.1h for β-hydroxybutyrate and 8-14 h for acetoacetate. The ketone monoester was also administered at 140, 357, and 714 mg/kg body weight, three times daily, over 5 days (equivalent to 0.42, 1.07, and 2.14 g/kg/d). The ketone ester was generally well-tolerated, although some gastrointestinal effects were reported, when large volumes of milk-based drink were consumed, at the highest ketone monoester dose. Together, these results suggest ingestion of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate is a safe and simple method to elevate blood ketone levels, compared with the inconvenience of preparing and consuming a ketogenic diet. Copyright © 2012 Elsevier Inc. All rights reserved.
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              New Insights into the Interaction of Carbohydrate and Fat Metabolism During Exercise

              Fat and carbohydrate are important fuels for aerobic exercise and there can be reciprocal shifts in the proportions of carbohydrate and fat that are oxidized. The interaction between carbohydrate and fatty acid oxidation is dependent on the intracellular and extracellular metabolic environments. The availability of substrate, both from inside and outside of the muscle, and exercise intensity and duration will affect these environments. The ability of increasing fat provision to downregulate carbohydrate metabolism in the heart, diaphragm and peripheral skeletal muscle has been well studied. However, the regulation of fat metabolism in human skeletal muscle during exercise in the face of increasing carbohydrate availability and exercise intensity has not been well studied until recently. Research in the past 10 years has demonstrated that the regulation of fat metabolism is complex and involves many sites of control, including the transport of fat into the muscle cell, the binding and transport of fat in the cytoplasm, the regulation of intramuscular triacylglycerol synthesis and breakdown, and the transport of fat into the mitochondria. The discovery of proteins that assist in transporting fat across the plasma and mitochondrial membranes, the ability of these proteins to translocate to the membranes during exercise, and the new roles of adipose triglyceride lipase and hormone-sensitive lipase in regulating skeletal muscle lipolysis are examples of recent discoveries. This information has led to the proposal of mechanisms to explain the downregulation of fat metabolism that occurs in the face of increasing carbohydrate availability and when moving from moderate to intense aerobic exercise.
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                Author and article information

                Journal
                Sports Medicine
                Sports Med
                Springer Science and Business Media LLC
                0112-1642
                1179-2035
                April 2020
                December 9 2019
                April 2020
                : 50
                : 4
                : 641-656
                Article
                10.1007/s40279-019-01246-y
                31820376
                facfc221-a31f-49dd-bc53-ed7154dd1783
                © 2020

                http://www.springer.com/tdm

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