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 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 Differential Response of Hippocampal and Cerebrocortical Autophagy and Ketone Body Metabolism to the Ketogenic Diet

2021 ◽  
Vol 15 ◽  
Author(s):  
Daniela Liśkiewicz ◽  
Arkadiusz Liśkiewicz ◽  
Marta M. Nowacka-Chmielewska ◽  
Mateusz Grabowski ◽  
Natalia Pondel ◽  
...  
Keyword(s):  
Frontal Cortex ◽  
Ketogenic Diet ◽  
Ketone Body ◽  
Brain Aging ◽  
Ketone Bodies ◽  
Monocarboxylate Transporter ◽  
Proper Function ◽  
Monocarboxylate Transporter 1 ◽  
Coa Transferase ◽  
Ketone Body Metabolism

Experimental and clinical data support the neuroprotective properties of the ketogenic diet and ketone bodies, but there is still a lot to discover to comprehensively understand the underlying mechanisms. Autophagy is a key mechanism for maintaining cell homeostasis, and therefore its proper function is necessary for preventing accelerated brain aging and neurodegeneration. Due to many potential interconnections, it is possible that the stimulation of autophagy may be one of the mediators of the neuroprotection afforded by the ketogenic diet. Recent studies point to possible interconnections between ketone body metabolism and autophagy. It has been shown that autophagy is essential for hepatic and renal ketogenesis in starvation. On the other hand, exogenous ketone bodies modulate autophagy both in vitro and in vivo. Many regional differences occur between brain structures which concern i.e., metabolic responses and autophagy dynamics. The aim of the present study was to evaluate the influence of the ketogenic diet on autophagic markers and the ketone body utilizing and transporting proteins in the hippocampus and frontal cortex. C57BL/6N male mice were fed with two ketogenic chows composed of fat of either animal or plant origins for 4 weeks. Markers of autophagosome formation as well as proteins associated with ketolysis (BDH1—3-hydroxybutyrate dehydrogenase 1, SCOT/OXCT1—succinyl CoA:3-oxoacid CoA transferase), ketone transport (MCT1—monocarboxylate transporter 1) and ketogenesis (HMGCL, HMGCS2) were measured. The hippocampus showed a robust response to nutritional ketosis in both changes in the markers of autophagy as well as the levels of ketone body utilizing and transporting proteins, which was also accompanied by increased concentrations of ketone bodies in this brain structure, while subtle changes were observed in the frontal cortex. The magnitude of the effects was dependent on the type of ketogenic diet used, suggesting that plant fats may exert a more profound effect on the orchestrated upregulation of autophagy and ketone body metabolism markers. The study provides a foundation for a deeper understanding of the possible interconnections between autophagy and the neuroprotective efficacy of nutritional ketosis.

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 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.

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.

scholarly journals Metabolism of ketone bodies in pregnant sheep

1982 ◽  
Vol 48 (3) ◽  
pp. 549-563 ◽  
Author(s):  
D. W. Pethick ◽  
D. B. Lindsay
Keyword(s):  
Skeletal Muscle ◽  
Hind Limb ◽  
Ketone Body ◽  
Ketone Bodies ◽  
Maximum Velocity ◽  
Compartment Model ◽  
Entry Rate ◽  
Arterial Concentration ◽  
Pregnant Sheep ◽  
Ketone Body Metabolism

1. A combination of isotope-dilution and arteriovenous-difference techniques was used to determine the significance of ketones to energy homoeostasis in fasted pregnant ewes.2. There was incomplete interconversion of D(−) 3-hydroxybutyrate (3HB) and acetoacetate (AcAc) and therefore neither entry rate nor oxidation of total ketone bodies could be estimated by assuming circulating ketone bodies represent a single metabolic compartment. Total ketone body metabolism was satisfactorily summarized using a three-compartment model. In fasted pregnant ewes the mean entry rate of total ketones was 1 mmol/h per kg body-weight and of the ketones entering the circulation 87% were promptly oxidized to carbon dioxide accounting for 30% of the total COa production.3. Ketone bodies are readily utilized by hind-limb skeletal muscle such that if completely oxidized, 18±4 and 48±3% of the oxygen utilized could be accounted for in fed and fasted pregnant ewes respectively. For both 3HB and AcAc there was a hyperbolic relationship between utilization and arterial concentration. The apparent Michaelis constant (Km) values were 0·55 and 1–42 mM respectively and the maximum velocity (Vmax) 2·9 and 5·6 mmol/h per kg muscle. The arterial concentration of AcAc is always below the Km value and this limits the utilization rate. The D(−) 3HB concentration, however, may surpass that required for maximum utilization and ketoacidosis may be a consequence of this.4. A two-compartment model was used to analyse ketone body metabolism by hind-limb skeletal muscle. The results suggested substantial intercon version and production of AcAc and 3HB.5. The pregnant uterus utilized 3HB which if completely oxidized accounted for 12±2 (fed) and 25±4 (fasted) % of its O2 consumption. At least 64% of the net 3HB utilized was oxidized. AcAc was not utilized in significant quantities.

scholarly journals Successful adaptation to ketosis by mice with tissue-specific deficiency of ketone body oxidation

2013 ◽  
Vol 304 (4) ◽  
pp. E363-E374 ◽  
Author(s):  
David G. Cotter ◽  
Rebecca C. Schugar ◽  
Anna E. Wentz ◽  
D. André d'Avignon ◽  
Peter A. Crawford
Keyword(s):  
Ketone Body ◽  
Neonatal Period ◽  
Ketone Bodies ◽  
Fatty Acyl ◽  
Carbohydrate Intake ◽  
Tissue Specific ◽  
Neonatal Mice ◽  
Coa Transferase ◽  
Low Carbohydrate ◽  
Ketone Body Metabolism

During states of low carbohydrate intake, mammalian ketone body metabolism transfers energy substrates originally derived from fatty acyl chains within the liver to extrahepatic organs. We previously demonstrated that the mitochondrial enzyme coenzyme A (CoA) transferase [succinyl-CoA:3-oxoacid CoA transferase (SCOT), encoded by nuclear Oxct1] is required for oxidation of ketone bodies and that germline SCOT-knockout (KO) mice die within 48 h of birth because of hyperketonemic hypoglycemia. Here, we use novel transgenic and tissue-specific SCOT-KO mice to demonstrate that ketone bodies do not serve an obligate energetic role within highly ketolytic tissues during the ketogenic neonatal period or during starvation in the adult. Although transgene-mediated restoration of myocardial CoA transferase in germline SCOT-KO mice is insufficient to prevent lethal hyperketonemic hypoglycemia in the neonatal period, mice lacking CoA transferase selectively within neurons, cardiomyocytes, or skeletal myocytes are all viable as neonates. Like germline SCOT-KO neonatal mice, neonatal mice with neuronal CoA transferase deficiency exhibit increased cerebral glycolysis and glucose oxidation, and, while these neonatal mice exhibit modest hyperketonemia, they do not develop hypoglycemia. As adults, tissue-specific SCOT-KO mice tolerate starvation, exhibiting only modestly increased hyperketonemia. Finally, metabolic analysis of adult germline Oxct1+/− mice demonstrates that global diminution of ketone body oxidation yields hyperketonemia, but hypoglycemia emerges only during a protracted state of low carbohydrate intake. Together, these data suggest that, at the tissue level, ketone bodies are not a required energy substrate in the newborn period or during starvation, but rather that integrated ketone body metabolism mediates adaptation to ketogenic nutrient states.

Acetoacetate and β-hydroxybutyrate in combination with other metabolites release insulin from INS-1 cells and provide clues about pathways in insulin secretion

2008 ◽  
Vol 294 (2) ◽  
pp. C442-C450 ◽  
Author(s):  
Michael J. MacDonald ◽  
Melissa J. Longacre ◽  
Scott W. Stoker ◽  
Laura J. Brown ◽  
Noaman M. Hasan ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Pancreatic Islets ◽  
Insulin Release ◽  
Ketone Body ◽  
Ketone Bodies ◽  
Short Chain ◽  
Acetyl Coa ◽  
Malonyl Coa ◽  
Chain Acyl ◽  
Stimulate Insulin Release

Mitochondrial anaplerosis is important for insulin secretion, but only some of the products of anaplerosis are known. We discovered novel effects of mitochondrial metabolites on insulin release in INS-1 832/13 cells that suggested pathways to some of these products. Acetoacetate, β-hydroxybutyrate, α-ketoisocaproate (KIC), and monomethyl succinate (MMS) alone did not stimulate insulin release. Lactate released very little insulin. When acetoacetate, β-hydroxybutyrate, or KIC were combined with MMS, or either ketone body was combined with lactate, insulin release was stimulated 10-fold to 20-fold the controls (almost as much as with glucose). Pyruvate was a potent stimulus of insulin release. In rat pancreatic islets, β-hydroxybutyrate potentiated MMS- and glucose-induced insulin release. The pathways of their metabolism suggest that, in addition to producing ATP, the ketone bodies and KIC supply the acetate component and MMS supplies the oxaloacetate component of citrate. In line with this, citrate was increased by β-hydroxybutyrate plus MMS in INS-1 cells and by β-hydroxybutyrate plus succinate in mitochondria. The two ketone bodies and KIC can also be metabolized to acetoacetyl-CoA and acetyl-CoA, which are precursors of other short-chain acyl-CoAs (SC-CoAs). Measurements of SC-CoAs by LC-MS/MS in INS-1 cells confirmed that KIC, β-hydroxybutyrate, glucose, and pyruvate increased the levels of acetyl-CoA, acetoacetyl-CoA, succinyl-CoA, hydroxymethylglutaryl-CoA, and malonyl-CoA. MMS increased incorporation of 14C from β-hydroxybutyrate into citrate, acid-precipitable material, and lipids, suggesting that the two molecules complement one another to increase anaplerosis. The results suggest that, besides citrate, some of the products of anaplerosis are SC-CoAs, which may be precursors of molecules involved in insulin secretion.

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