scholarly journals Regulation of glucose and ketone-body metabolism in brain of anaesthetized rats

1974 ◽  
Vol 138 (1) ◽  
pp. 1-10 ◽  
Author(s):  
Neil B. Ruderman ◽  
Peter S. Ross ◽  
Michael Berger ◽  
Michael N. Goodman
Keyword(s):  
Glucose Uptake ◽  
Ketone Body ◽  
Ketone Bodies ◽  
Acetyl Coa ◽  
Total Blood ◽  
Diabetic Ketosis ◽  
Pyruvate Oxidation ◽  
Ketone Body Metabolism ◽  
Arteriovenous Difference ◽  
The Brain

1. The effects of starvation and diabetes on brain fuel metabolism were examined by measuring arteriovenous differences for glucose, lactate, acetoacetate and 3-hydroxybutyrate across the brains of anaesthetized fed, starved and diabetic rats. 2. In fed animals glucose represented the sole oxidative fuel of the brain. 3. After 48h of starvation, ketone-body concentrations were about 2mm and ketone-body uptake accounted for 25% of the calculated O2 consumption: the arteriovenous difference for glucose was not diminished, but lactate release was increased, suggesting inhibition of pyruvate oxidation. 4. In severe diabetic ketosis, induced by either streptozotocin or phlorrhizin (total blood ketone bodies >7mm), the uptake of ketone bodies was further increased and accounted for 45% of the brain 's oxidative metabolism, and the arteriovenous difference for glucose was decreased by one-third. The arteriovenous difference for lactate was increased significantly in the phlorrhizin-treated rats. 5. Infusion of 3-hydroxybutyrate into starved rats caused marked increases in the arteriovenous differences for lactate and both ketone bodies. 6. To study the mechanisms of these changes, steady-state concentrations of intermediates and co-factors of the glycolytic pathway were determined in freeze-blown brain. 7. Starved rats had increased concentrations of acetyl-CoA. 8. Rats with diabetic ketosis had increased concentrations of fructose 6-phosphate and decreased concentrations of fructose 1,6-diphosphate, indicating an inhibition of phosphofructokinase. 9. The concentrations of acetyl-CoA, glycogen and citrate, a potent inhibitor of phosphofructokinase, were increased in the streptozotocin-treated rats. 10. The data suggest that cerebral glucose uptake is decreased in diabetic ketoacidosis owing to inhibition of phosphofructokinase as a result of the increase in brain citrate. 11. The inhibition of brain pyruvate oxidation in starvation and diabetes can be related to the accelerated rate of ketone-body metabolism; however, we found no correlation between the decrease in glucose uptake in the diabetic state and the arteriovenous difference for ketone bodies. 12. The data also suggest that the rates of acetoacetate and 3-hydroxybutyrate utilization by brain are governed by their concentrations in plasma. 13. The finding of very low concentrations of acetoacetate and 3-hydroxybutyrate in brain compared with plasma suggests that diffusion across the blood –brain barrier may be the rate-limiting step in their metabolism.

scholarly journals Why the diabetic heart is energy inefficient: A ketogenesis and ketolysis perspective

2021 ◽  
Author(s):  
Paras Kumar Mishra
Keyword(s):  
Energy Efficiency ◽  
Ketogenic Diet ◽  
Ketone Body ◽  
Ketone Bodies ◽  
Metabolic Flexibility ◽  
Metabolic Abnormalities ◽  
Acetyl Coa ◽  
Cardiac Energy ◽  
Ketone Body Metabolism ◽  
Very High

Lack of glucose uptake compromises metabolic flexibility and reduces energy efficiency in the diabetes mellitus (DM) heart. Although increased utilization of fatty acid to compensate glucose substrate has been studied, less is known about ketone body metabolism in the DM heart. Ketogenic diet reduces obesity, a risk factor for T2DM. How ketogenic diet affects ketone metabolism in the DM heart remains unclear. At the metabolic level, the DM heart differs from the non-DM heart due to altered metabolic substrate and the T1DM heart differs from the T2DM heart due to insulin levels. How these changes affect ketone body metabolism in the DM heart are poorly understood. Ketogenesis produces ketone bodies by utilizing acetyl CoA whereas ketolysis consumes ketone bodies to produce acetyl CoA, showing their opposite roles in the ketone body metabolism. Cardiac-specific transgenic upregulation of ketogenesis enzyme or knockout of ketolysis enzyme causes metabolic abnormalities leading to cardiac dysfunction. Empirical evidence demonstrates upregulated transcription of ketogenesis enzymes, no change in the levels of ketone body transporters, very high levels of ketone bodies, and reduced expression and activity of ketolysis enzymes in the T1DM heart. Based on these observations, I hypothesize that increased transcription and activity of cardiac ketogenesis enzyme suppresses ketolysis enzymes in the DM heart, which decreases cardiac energy efficiency. The T1DM heart exhibits highly upregulated ketogenesis compared to T2DM due to lack of insulin that inhibits ketogenesis enzyme.

scholarly journals Hepatic ketone-body metabolism in developing sheep and pregnant ewes

1978 ◽  
Vol 40 (2) ◽  
pp. 359-367 ◽  
Author(s):  
G. Carole E. Varnam ◽  
Marjorie K. Jeacock ◽  
D. A. L. Shepherd
Keyword(s):  
Ketone Body ◽  
Ketone Bodies ◽  
Marked Change ◽  
Acetyl Coa ◽  
Adult Rats ◽  
Adult Sheep ◽  
Pregnant Sheep ◽  
Foetal Life ◽  
Ketone Body Metabolism

1. In order to establish whether or not there is a relationship between the blood ketone-body concentrations and the potential ability of the liver to synthesize ketone bodies in sheep on varying nutritional regimens, a study has been made of the concentrations of acetoacetate and 3-hydroxybutyrate in blood and the activities of enzymes concerned with ketogenesis in liver of developing sheep from mid-way through gestation to maturity, in pregnant ewes from mid-way through pregnancy and in starved pregnant and non-pregnant ewes.2. During development the most marked change in blood 3-hydroxybutyrate concentration occurred when the lambs were weaned. Blood acetoacetate concentrations did not change during development. When mature ewes were starved both 3-hydroxybutyrate and acetoacetate concentrations in blood were increased.3. Changes found in the activity of 3-hydroxybutyrate dehydrogenase (EC 1.1.1.30) in the liver were correlated with the changes in blood 3-hydroxybutyrate concentrations during development but no such relationship existed in pregnant or fasted ewes. No correlation was found between the ability of the liver to synthesize acetoacetate and blood ketone body concentrations in either developing or pregnant adult sheep. The rate of acetoacetate production expressed per g liver increased during foetal life but values observed in lambs 1 d after birth were similar to those found in suckling and mature sheep. During the last month of pregnancy and when non-pregnant sheep were starved the hepatic potential for ketogenesis was increased. During development the activity of acetyl-CoA acetyltransferase (EC 2.3.1.9) was correlated with the rate of hepatic acetoacetate production.4. These changes have been contrasted with those that occur in developing and starved adult rats.5. It is concluded that hepatic production of ketone bodies cannot be the only factor in the regulation of blood ketone body concentrations in developing and pregnant sheep.

scholarly journals Ketone-body metabolism in tumour-bearing rats

1986 ◽  
Vol 233 (2) ◽  
pp. 485-491 ◽  
Author(s):  
A M Rofe ◽  
R Bais ◽  
R A Conyers
Keyword(s):  
Blood Glucose ◽  
Ketone Body ◽  
Ketone Bodies ◽  
Hepatic Glycogen ◽  
Turnover Rates ◽  
Total Blood ◽  
Normal Tissues ◽  
Tumour Bearing ◽  
And Control

During starvation for 72 h, tumour-bearing rats showed accelerated ketonaemia and marked ketonuria. Total blood [ketone bodies] were 8.53 mM and 3.34 mM in tumour-bearing and control (non-tumour-bearing) rats respectively (P less than 0.001). The [3-hydroxybutyrate]/[acetoacetate] ratio was 1.3 in the tumour-bearing rats, compared with 3.2 in the controls at 72 h (P less than 0.001). Blood [glucose] and hepatic [glycogen] were lower at the start of starvation in tumour-bearing rats, whereas plasma [non-esterified fatty acids] were not increased above those in the control rats during starvation. After functional hepatectomy, blood [acetoacetate], but not [3-hydroxybutyrate], decreased rapidly in tumour-bearing rats, whereas both ketone bodies decreased, and at a slower rate, in the control rats. Blood [glucose] decreased more rapidly in the hepatectomized control rats. Hepatocytes prepared from 72 h-starved tumour-bearing and control rats showed similar rates of ketogenesis from palmitate, and the distribution of [1-14C] palmitate between oxidation (ketone bodies and CO2) and esterification was also unaffected by tumour-bearing, as was the rate of gluconeogenesis from lactate. The carcinoma itself showed rapid rates of glycolysis and a poor ability to metabolize ketone bodies in vitro. The results are consistent with the peripheral, normal, tissues in tumour-bearing rats having increased ketone-body and decreased glucose metabolic turnover rates.

scholarly journals Ketone body metabolism and cardiovascular disease

2013 ◽  
Vol 304 (8) ◽  
pp. H1060-H1076 ◽  
Author(s):  
David G. Cotter ◽  
Rebecca C. Schugar ◽  
Peter A. Crawford
Keyword(s):  
Cardiovascular Disease ◽  
Ketone Body ◽  
De Novo ◽  
Ketone Bodies ◽  
Tricarboxylic Acid Cycle ◽  
De Novo Lipogenesis ◽  
Short Supply ◽  
Nutritional Interventions ◽  
Diagnostic Strategies ◽  
Ketone Body Metabolism

Ketone bodies are metabolized through evolutionarily conserved pathways that support bioenergetic homeostasis, particularly in brain, heart, and skeletal muscle when carbohydrates are in short supply. The metabolism of ketone bodies interfaces with the tricarboxylic acid cycle, β-oxidation of fatty acids, de novo lipogenesis, sterol biosynthesis, glucose metabolism, the mitochondrial electron transport chain, hormonal signaling, intracellular signal transduction pathways, and the microbiome. Here we review the mechanisms through which ketone bodies are metabolized and how their signals are transmitted. We focus on the roles this metabolic pathway may play in cardiovascular disease states, the bioenergetic benefits of myocardial ketone body oxidation, and prospective interactions among ketone body metabolism, obesity, metabolic syndrome, and atherosclerosis. Ketone body metabolism is noninvasively quantifiable in humans and is responsive to nutritional interventions. Therefore, further investigation of this pathway in disease models and in humans may ultimately yield tailored diagnostic strategies and therapies for specific pathological states.

scholarly journals Ketone Body Metabolism in the Ischemic Heart

2021 ◽  
Vol 8 ◽  
Author(s):  
Stephen C. Kolwicz
Keyword(s):  
Ketone Body ◽  
Ketone Bodies ◽  
Ischemia Reperfusion ◽  
Ischemic Heart ◽  
Myocardial Infarctions ◽  
Ketogenic Diets ◽  
Health And Disease ◽  
Ketone Body Metabolism ◽  
Artery Disease ◽  
Fuel Source

Ketone bodies have been identified as an important, alternative fuel source in heart failure. In addition, the use of ketone bodies as a fuel source has been suggested to be a potential ergogenic aid for endurance exercise performance. These findings have certainly renewed interest in the use of ketogenic diets and exogenous supplementation in an effort to improve overall health and disease. However, given the prevalence of ischemic heart disease and myocardial infarctions, these strategies may not be ideal for individuals with coronary artery disease. Although research studies have clearly defined changes in fatty acid and glucose metabolism during ischemia and reperfusion, the role of ketone body metabolism in the ischemic and reperfused myocardium is less clear. This review will provide an overview of ketone body metabolism, including the induction of ketosis via physiological or nutritional strategies. In addition, the contribution of ketone body metabolism in healthy and diseased states, with a particular emphasis on ischemia-reperfusion (I-R) injury will be discussed.

Effect of acute hyperketonemia on the cerebral uptake of ketone bodies in nondiabetic subjects and IDDM patients

2002 ◽  
Vol 283 (1) ◽  
pp. E20-E28 ◽  
Author(s):  
G. Blomqvist ◽  
M. Alvarsson ◽  
V. Grill ◽  
G. Von Heijne ◽  
M. Ingvar ◽  
...  
Keyword(s):  
Time Course ◽  
Ketone Body ◽  
Ketone Bodies ◽  
Tissue Concentration ◽  
Insulin Dependent Diabetes Mellitus ◽  
Dependent Diabetes Mellitus ◽  
Utilization Rate ◽  
Resonance Spectroscopy ◽  
Significant Difference ◽  
The Brain

Using R-β-[1-11C]hydroxybutyrate and positron emission tomography, we studied the effect of acute hyperketonemia (range 0.7–1.7 μmol/ml) on cerebral ketone body utilization in six nondiabetic subjects and six insulin-dependent diabetes mellitus (IDDM) patients with average metabolic control (HbA1c = 8.1 ± 1.7%). An infusion of unlabeled R-β-hydroxybutyrate was started 1 h before the bolus injection of R-β-[1-11C]hydroxybutyrate. The time course of the radioactivity in the brain was measured during 10 min. For both groups, the utilization rate of ketone bodies was found to increase nearly proportionally with the plasma concentration of ketone bodies (1.0 ± 0.3 μmol/ml for nondiabetic subjects and 1.3 ± 0.3 μmol/ml for IDDM patients). No transport of ketone bodies from the brain could be detected. This result, together with a recent study of the tissue concentration of R-β-hydroxybutyrate in the brain by magnetic resonance spectroscopy, indicate that, also at acute hyperketonemia, the rate-limiting step for ketone body utilization is the transport into the brain. No significant difference in transport and utilization of ketone bodies could be detected between the nondiabetic subjects and the IDDM patients.

Response of ketone body metabolism to exercise during transition from postabsorptive to fasted state

1986 ◽  
Vol 250 (5) ◽  
pp. E495-E501 ◽  
Author(s):  
F. Fery ◽  
E. O. Balasse
Keyword(s):  
Clearance Rate ◽  
Ketone Body ◽  
Turnover Rate ◽  
Ketone Bodies ◽  
Normal Subjects ◽  
Moderate Intensity ◽  
Metabolic Clearance ◽  
Metabolic Clearance Rate ◽  
Fasted State ◽  
The Brain

This study examines the effects of a 2-h exercise of moderate intensity (50% of VO2 max) on the tracer-determined turnover rate of ketone bodies (KB) in 21 normal subjects fasted for 16 h, 5 days, whose basal ketonemia ranged between 0.09 and 6.16 mM. The KB response observed at the end of exercise is a function of the initial degree of ketosis. When basal ketonemia is below 0.6 mM, exercise enhances ketogenesis (Ra), the amplitude of this process being positively correlated with KB level. There is a concomitant acceleration of the metabolic clearance rate (MCR) of KB attaining 40-50%. When ketonemia exceeds 2.5 mM, the stimulatory effects of exercise on Ra and on MCR become less marked as basal ketonemia rises and are completely abolished or even reversed when initial KB level is higher than 3-4 mM. The pattern of changes in the concentration and in the overall disposal rate of KB were similar to that of Ra. It is suggested that the parallel inhibition of the stimulatory effect of work on hepatic ketogenesis and on muscular extraction of ketones associated with increasing degrees of fasting hyperketonemia has two physiological implications: it maintains the preferential utilization of KB by nonmuscular tissues (presumably the brain) and prevents the development of uncontrolled hyperketonemia, despite the intense catabolic situation created by the combination of exercise and starvation.

KETONE BODY METABOLISM IN NUTRITIONAL MYOPATHY

1964 ◽  
Vol 42 (8) ◽  
pp. 1153-1160 ◽  
Author(s):  
K. J. Jenkins
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Ketone Body ◽  
Ketone Bodies ◽  
Pectoral Muscle ◽  
Acid Oxidation ◽  
Dystrophic Muscle ◽  
Liver Homogenates ◽  
Ketone Body Metabolism

A study was conducted on the metabolism of ketone bodies in tissue preparations from normal and dystrophic chicks. The data indicated that the production of ketone bodies in liver homogenates, as a result of fatty acid oxidation, was not markedly altered by development of the dystrophic condition. Whereas acetoacetate was oxidized by normal and degenerative pectoral muscle to approximately the same extent, utilization of β-hydroxybutyrate in dystrophic muscle was markedly poorer. In view of present concepts of the reactions involved in the metabolism of ketone bodies the results suggest that in the chick myopathy the conversion of β-hydroxybutyrate to acetoacetate may be impaired.

scholarly journals A high-MUFA diet alone does not affect ketone body metabolism, but reduces glycated hemoglobin when combined with exercise training in diabetic rats

2017 ◽  
Vol 9 (1) ◽  
pp. 31-40
Author(s):  
Juraiporn Somboonwong ◽  
Khunkhong Huchaiyaphum ◽  
Onanong Kulaputana ◽  
Phisit Prapunwattana
Keyword(s):  
Exercise Training ◽  
Ketone Body ◽  
Glycated Hemoglobin ◽  
Ketone Bodies ◽  
Transferase Activity ◽  
Nonesterified Fatty Acids ◽  
Regular Diet ◽  
Coa Transferase ◽  
Ketone Body Metabolism ◽  
Mufa Diet

Abstract Background Monounsaturated fat (MUFA) also has glucose-lowering action, but its effect on ketone bodies is unknown. Objectives To examine the effects of high-MUFA diet alone or in combination with exercise training, which can improve glucose and ketone body metabolism, in a rat model of diabetes. Methods Wistar rats were administered streptozotocin to induce diabetes and then randomly divided into five groups: sedentary rats fed a regular diet (1), a high-saturated-fat diet (2), a high-MUFA diet (3); and exercisetrained rats fed a regular diet (4), and a high-MUFA diet (5). Training was by a treadmill twice daily, 5 days/week. At 12 weeks, glucose, glycated hemoglobin (HbA1c), insulin, nonesterified fatty acids (NEFA), and β-hydroxybutyrate levels were measured in cardiac blood. Activity of the overall ketone synthesis pathway was determined in liver and 3-ketoacyl-CoA transferase activity determined in gastrocnemius muscle. Results A high-MUFA diet tended to lower plasma glucose without affecting other biochemical variables. Training did not change glucose metabolism, but significantly reduced serum NEFA. Only the high-MUFA diet plus training significantly decreased HbA1c levels. Hepatic ketone synthesis was decreased and 3-ketoacyl-CoA transferase activity was increased by training alone or in combination with a high-MUFA diet. Changes in NEFA, β-hydroxybutyrate, and the enzymatic activities in response to training plus a high-MUFA diet were comparable to those caused by training alone. Conclusion A high-MUFA diet alone does not alter ketone body metabolism. Combination of a MUFA-rich diet and exercise training is more effective than either MUFA or exercise alone for lowering HbA1c.

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