Insulin, ketone bodies, and mitochondrial energy transduction

Sato, Ko; Kashiwaya, Yoshiaki; Keon, Claudia A.; Tsuchiya, Naotaka; King, Michael; Radda, George K.; Chance, Britton; Clarke, Kieran; Veech, Richard L.

doi:10.1096/fasebj.9.8.7768357

Cited by 396 publications

(412 citation statements)

References 2 publications

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“…Tissue pH was determined using 31 P magnetic resonance spectroscopy in heart (22,23) (24) and applying the Henderson-Hasselbalch equation (25). Heart free phosphate species were calculated (23) from free cytosolic [ Pi] determined using magnetic resonance spectroscopy and corrected for intracellular pH and free [Mg 2+ ] (22,12). Because obtaining free cytosolic Pi in liver required anesthesia with attendant changes in hepatic circulation, an alternative method for determining free cytosolic [ Pi] was used.…”

Section: Methodsmentioning

confidence: 99%

“…The G of ATP hydrolysis, G ATP , for each tissue was calculated as described previously (10,12,29) from the G o of ATP hydrolysis determined at 38 • C, ionic strength of 0.25, and specified free [Mg 2+ ] and pH (30). The G of ATP hydrolysis was then calculated for the sum species of products over reactants of the ATP hydrolysis reaction:…”

Section: Calculations Of G [Ion Z ] O/i and G Atpmentioning

confidence: 99%

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The Energetics of Ion Distribution: The Origin of the Resting Electric Potential of Cells

Veech¹,

Kashiwaya²,

Gates³

et al. 2002

IUBMB Life

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SummaryThe relation between the energies of ion movement and ATP hydrolysis is unknown in tissues with widely varying electric potentials. Consequently, we measured the concentration of the nine major inorganic ions in the extra-and intracellular phases in heart, liver, and red cells with resting electrical potentials, E N , of −86, −28, and −6 mV, respectively, under six different physiological conditions. We calculated the Nernst electric potential and the energy of ion movement between the phases. We found that the energy of ATP hydrolysis was essentially constant, between −54 and −58 kJ/mol, in all tissues and conditions. In contrast, as E N decreased, the energies of the Na + and K + gradients decreased, with slopes approximating their valence. The difference between the energies of Na + and K + gradients remained constant at 17 kJ/mol, which is approximately one third of the energy of ATP hydrolysis, demonstrating near-equilibrium of the Na + /K + ATPase in all tissues under all conditions. All cations, except K + , were pumped out of cells and all anions, except Cl − in liver and red cell, were pumped into cells. We conclude that the energy of ATP was expressed in Na + /K + ATPase and its linked inorganic ion transporters to create a Gibbs-Donnan near-equilibrium system, an inherent part of which was the electric potential.

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Section: Methodsmentioning

confidence: 99%

Section: Calculations Of G [Ion Z ] O/i and G Atpmentioning

confidence: 99%

The Energetics of Ion Distribution: The Origin of the Resting Electric Potential of Cells

Veech¹,

Kashiwaya²,

Gates³

et al. 2002

IUBMB Life

View full text Add to dashboard Cite

show abstract

“…30,31 This increase in metabolic efficiency has been studied extensively in seminal work done by Veech and colleagues. 22,32 Working in perfused rat hearts, Sato et al 32 found that treatment of cells with levels of KB found during starvation (4 mM BHB and 1 mM ACA) increased cardiac efficiency by 13% compared with control hearts. The increase in metabolic efficiency can be attributed to several key features of KB metabolism (FIG.…”

Section: Properties Of Kbmentioning

confidence: 99%

“…Briefly, when BHB is converted to ACA it generates NADH (the reduced form of nicotinamide adenine dinucleotide [NAD]), thereby reducing the mitochondrial NAD/NADH couple and increasing the oxidation of the co-enzyme Q couple. 32 In addition, KB metabolism increases the mitochondrial pool of acetylCoA and succinate. 33 The net effect of these changes is increased metabolic efficiency.…”

Section: Properties Of Kbmentioning

confidence: 99%

Ketone Bodies as a Therapeutic for Alzheimer's Disease

Henderson¹

2008

Neurotherapeutics

294

116

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Summary: An early feature of Alzheimer's disease (AD) is region-specific declines in brain glucose metabolism. Unlike other tissues in the body, the brain does not efficiently metabolize fats; hence the adult human brain relies almost exclusively on glucose as an energy substrate. Therefore, inhibition of glucose metabolism can have profound effects on brain function. The hypometabolism seen in AD has recently attracted attention as a possible target for intervention in the disease process. One promising approach is to supplement the normal glucose supply of the brain with ketone bodies (KB), which include acetoacetate, ␤-hydroxybutyrate, and acetone. KB are normally produced from fat stores when glucose supplies are limited, such as during prolonged fasting. KB have been induced both by direct infusion and by the administration of a high-fat, low-carbohydrate, low-protein, ketogenic diets. Both approaches have demonstrated efficacy in animal models of neurodegenerative disorders and in human clinical trials, including AD trials. Much of the benefit of KB can be attributed to their ability to increase mitochondrial efficiency and supplement the brain's normal reliance on glucose. Research into the therapeutic potential of KB and ketosis represents a promising new area of AD research.

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“…Sato et al [226] concluded that in working rat hearts, the addition of insulin or a physiological ratio of ketone bodies (␤-hydroxybutyrate and acetoacetate) to physiological solutions containing 10 mM glucose increased the hydraulic work efficiency from 10.5 to 13.4%, and insulin and ketones together allowed the efficiency to reach 14.3%. They did not measure basal metabolism, but explained the increase in efficiency caused by ketones as being compatible with a decrease in protein leakage across the mitochondria consequent on a fall in mitochondrial membrane potential to Ϫ120 mV with addition of ketones, from Ϫ143 mV in glucose-perfused hearts, with or without insulin.…”

Section: Modifiers Of Basal Metabolismmentioning

confidence: 99%

Cardiac Basal Metabolism.

Gibbs

Loiselle²

2001

JJP

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The cardiac basal metabolism is the rate of energy expenditure of the quiescent myocardium. It is also called the resting metabolism or the arrested heart metabolism. It has been measured in numerous ways, and in vivo there is good evidence that it accounts for about 1/5 to 1/3 of the total energy flux. The difficulty arises, however, when the heart is stopped because the magnitude of the basal metabolism depends, as blood viscosity, on how and under what physiological condition it is measured. It is possible for the in vivo basal value to fall to less than 1/5 of its original value without cellular damage or to increase to values 5 times greater than its probable in vivo magnitude (i.e., to rise to values in excess of the energy flux of the normally beating heart) by altering the composition of the perfusion medium. We have written on this subject several times [1][2][3], but believe that developments in knowledge now make it possible for us to speculate in a more informed manner. Since several million openheart operations are performed on arrested hearts worldwide each year, it would seem imperative that we understand the cellular mechanisms that can change the magnitude of basal metabolism.A. V. Hill [4] has pointed out that in examining physiological activities, it is necessary to assume a baseline from which some quantity or rate can be measured. If the energy flux produced by the beating heart were very large compared with the energy flux of the arrested heart, baseline ambiguity would be relatively unimportant. But this is not so in regard to the heart; its basal metabolism is high. Within a species, the basal metabolism of cardiac tissue is several-fold higher than the resting metabolism of skeletal muscle and is an order of magnitude greater than the resting metabolism of amphibian skeletal muscle.Species differences are clearly evident in the magnitude of cardiac basal metabolism, and we believe that the major reason for these differences relates to the leakiness of cell membranes, such as those of the sarcolemma and sarcoplasmic reticulum and those of Japanese Journal of Physiology, 51, 399-426, 2001 Key words: whole hearts, isolated preparations, biochemical contributors, modifiers, species difference, temperature, substrate, hypoxia. Abstract:We endeavor to show that the metabolism of the nonbeating heart can vary over an extreme range: from values approximating those measured in the beating heart to values of only a small fraction of normal-perhaps mimicking the situation of nonflow arrest during cardiac bypass surgery. We discuss some of the technical issues that make it difficult to establish the magnitude of basal metabolism in vivo. We consider some of the likely contributors to its magnitude and point out that the biochemical reasons for a sizable fraction of the heart's basal ATP usage remain unresolved. We consider many of the physiological factors that can alter the basal metabolic rate, stressing the importance of substrate supply. We point out that the protective effect of hypothermia ...

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Insulin, ketone bodies, and mitochondrial energy transduction

Cited by 396 publications

References 2 publications

The Energetics of Ion Distribution: The Origin of the Resting Electric Potential of Cells

The Energetics of Ion Distribution: The Origin of the Resting Electric Potential of Cells

Ketone Bodies as a Therapeutic for Alzheimer's Disease

Cardiac Basal Metabolism.

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