Cardiac Carbohydrate Metabolism Research Articles

Metabolic Effects of Doxorubicin on the Rat Liver Assessed With Hyperpolarized MRI and Metabolomics.

Doxorubicin (DOX) is a successful chemotherapeutic widely used for the treatment of a range of cancers. However, DOX can have serious side-effects, with cardiotoxicity and hepatotoxicity being the most common events. Oxidative stress and changes in metabolism and bioenergetics are thought to be at the core of these toxicities. We have previously shown in a clinically-relevant rat model that a low DOX dose of 2 mg kg–1 week–1 for 6 weeks does not lead to cardiac functional decline or changes in cardiac carbohydrate metabolism, assessed with hyperpolarized [1-13C]pyruvate magnetic resonance spectroscopy (MRS). We now set out to assess whether there are any signs of liver damage or altered liver metabolism using this subclinical model. We found no increase in plasma alanine aminotransferase (ALT) activity, a measure of liver damage, following DOX treatment in rats at any time point. We also saw no changes in liver carbohydrate metabolism, using hyperpolarized [1-13C]pyruvate MRS. However, using metabolomic analysis of liver metabolite extracts at the final time point, we found an increase in most acyl-carnitine species as well as increases in high energy phosphates, citrate and markers of oxidative stress. This may indicate early signs of steatohepatitis, with increased and decompensated fatty acid uptake and oxidation, leading to oxidative stress.

High-Dose Insulin Therapy for Calcium-Channel Blocker Overdose

To evaluate the evidence for using high-dose insulin therapy with supplemental dextrose and potassium in calcium-channel blocker (CCB) overdose. Evidence of efficacy for high-dose insulin therapy with supplemental dextrose and potassium was sought by performing a search of MEDLINE and Toxline between 1966 and July 2004 using combinations of the terms calcium-channel blocker, overdose, poisoning, antidote, and insulin. Abstracts from the North American Congress of Clinical Toxicology for the years 1996-2003 were also reviewed. Identified articles, including animal studies, case reports, and case series, were evaluated for this review. No clinical trials were available. Animal models of CCB overdose demonstrate that high-dose insulin with supplemental dextrose and potassium was a more effective therapy than calcium, glucagon, or catecholamines. High-dose insulin appears to enhance cardiac carbohydrate metabolism and has direct inotropic effects. Published clinical experience is limited to 13 case reports where insulin was used after other therapies were failing; 12 of these patients survived. High-dose insulin therapy was beneficial for CCB-induced hypotension, hyperglycemia, and metabolic acidosis. Bradycardia and heart block resolved in some patients, but persisted in others. Based on animal data and limited human experience, as well as the inadequacies of available alternatives for patients with significant poisoning, high-dose insulin therapy warrants further study and judicious use in patients with life-threatening CCB poisoning.

Differential modulation of glucose, lactate, and pyruvate oxidation by insulin and dichloroacetate in the rat heart.

Despite the fact that lactate and pyruvate are potential substrates for energy production in vivo, our understanding of the control and regulation of carbohydrate metabolism is based principally on studies where glucose is the only available carbohydrate. Therefore, the purpose of this study was to determine the contributions of lactate, pyruvate, and glucose to energy production in the isolated, perfused rat heart over a range of insulin concentrations and after activation of pyruvate dehydrogenase with dichloroacetate (DCA). Hearts were perfused with physiological concentrations of [1-13C]glucose, [U-13C]lactate, [2-13C]pyruvate, and unlabeled palmitate for 45 min. Hearts were freeze clamped, and 13C NMR glutamate isotopomer analysis was performed on tissue extracts. Glucose, lactate, and pyruvate all contributed significantly to myocardial energy production; however, in the absence of insulin, glucose contributed only 25-30% of total pyruvate oxidation. Even under conditions where carbohydrates represented >95% of substrate entering the tricarboxylic acid (TCA) cycle, we found that glucose contributed at most 50-60% of total carbohydrate oxidation. Despite being present at only 0.1 mM, pyruvate contributed between approximately 10% and 30% of total acetyl-CoA entry into the TCA cycle. We also found that insulin and DCA not only increased glucose oxidation but also exogenous pyruvate oxidation; however, lactate oxidation was not increased. The differential effects of insulin and DCA on pyruvate and lactate oxidation provide further evidence for compartmentation of cardiac carbohydrate metabolism. These results may have important implications for understanding the mechanisms underlying the beneficial effects of increasing cardiac carbohydrate metabolism.

Cardiac carbohydrate metabolism in Zucker diabetic fatty rats.

The aim of this study was to test the hypothesis that, shortly after the development of Type-2 diabetes, alterations in cardiac carbohydrate metabolism precede the onset of abnormalities in systolic function. Hearts from 11-week-old Zucker diabetic fatty (ZDF) rats and age matched controls were perfused in the isovolumic Langendorff mode with 13C-labeled glucose, lactate and pyruvate and unlabeled fatty acids. 13C-Nuclear magnetic resonance glutamate isotopomer analysis was carried out to determine the contributions of substrates to energy production. The ZDF group was hyperglycemic and the relative flux through pyruvate dehydrogenase (PDH) was significantly depressed compared to lean controls. In the lean group, lactate, pyruvate and glucose contributed 64+/-3, 24+/-3 and 11+/-1%, respectively, to total pyruvate oxidation. In the ZDF group, the contribution of glucose both to total pyruvate oxidation and to tissue lactate and alanine formation was significantly depressed. Cardiac function assessed by the rate-pressure product was similar in both groups. The fraction of active PDH was decreased in the ZDF group compared to controls (p<0.025). These results highlight significant changes in cardiac carbohydrate metabolism shortly after the development of hyperglycemia in a model of Type 2 diabetes in the absence of overt changes in systolic function.

Cardiac carbohydrate metabolism in hearts from normal and type-2 diabetic rats

Cardiac carbohydrate metabolism in hearts from normal and type-2 diabetic rats

Glucose metabolism and left ventricular dysfunction are normalized by insulin and islet transplantation in mild diabetes in the rat

The aim of the present experimental study in the rat heart was to assess cardiac performance and metabolism in mild diabetes of 2 months' duration (postprandial blood sugar levels of 307 +/- 101 mg/dl and nearly normal fasting blood glucose of 102 +/- 40 mg/dl) using the working rat heart model at physiological workload with a perfusion time of 60 min. We also compared the effect of two forms of therapy for diabetes, islet transplantation and insulin therapy (s.c.), after 2 months. A 36% reduction in glucose utilization is metabolically characteristic for the diabetic heart, mainly caused by a 55% reduced glucose uptake (P < 0.001), but also by a nearly twofold increased lactate and pyruvate production (P < 0.001). This reduced carbohydrate metabolism is accompanied by a 37% reduction of oxygen uptake (P < 0.001) as well as a significant reduction in myocardial ATP and CP levels (P < 0.001), resulting in a significantly reduced cardiac output (P < 0.001). Moreover, the balance of energy reveals that the diabetic heart obtains 46% of its energy requirements for 1 h from endogenous glycogen, whereas the control heart obtains 91% of its energy needs (i.e. preferentially) from exogenous glucose (only 9% from endogenous glycogen). Both investigated therapeutic interventions led to a complete reversibility of the hemodynamic and metabolic alterations, indicating that the cause of diabetic cardiomyopathy in this model of mild and short-term diabetes is due to a defect in cardiac carbohydrate metabolism, which is correctable by insulin administration.

271 THE EFFECT OF ACUTE EXTRACELLULAR VOLUME EXPANSION ON MTOCARDIAL GLYCOGEN IN THE NEWBORN RAT

Glucose and its metabolites are the principal cardiac energy substrates in the fetus and neonate. Anoxia and adrenergic stimulation have been shown to deplete myocardial glycogen stores, but the effect of extracellular volume expansion on carbohydrate metabolism has not been previously studied. The effect of acute saline loading on myocardial glycogen concentration was studied in 8 littermate pairs of newborn rats, matched for age. One member of each pair, assigned to the experimental group, received an intraperitoneal bolus injection of isotonic saline, 80 ml/kg body weight. The remaining member (control) received a multielectrolyte maintenance solution, 8.4 ml/kg, in the same manner. At 2 hours, the animals were sacrificed and the hearts excised and weighed. Myocardial glycogen was assayed using a modification of the glucose oxidase method. No significant difference in cardiac weight was noted between groups (exp=.064±.003 SEM gm, cont=.057±.011gm). The glucose concentration in mg/dl/gm wet weight tissue was 176.4±17.9 in exp group and 257.7±94.4 in the cont group (p<.05). The finding of lower myocardial glucose content in the saline loaded rats in the absence of a significant increase in water content, suggests that acute extracellular volume expansion exerts a significant effect on cardiac carbohydrate metabolism in newborns.

The effect of Oxfenicine on cardiac carbohydrate metabolism in intact dogs.

Measurement of cardiac glucose oxidation (as a percentage of CO2 production) was made using the technique of infusion of 14C-D-glucose, together with measurement of 14CO2 and total CO2 produced by the myocardium. The measurements were made in 16 dogs under chloralose anaesthesia, before and after an i.v. injection of S-4-hydroxyphenylglycine (16.7 mg X kg-1, Oxfenicine: Pfizer). In one group of dogs circulating free-fatty-acid (FFA) levels were raised by infusion of intralipid heparin; in the other, circulating lactate was increased by infusion of 5 MNa-lactate (pH 7.0). In the last group of dogs the action of the drug was studied in cardiac denervated dogs. In the dogs with normal circulating substrate levels, Oxfenicine increased the glucose oxidation from 17.3 to 39.9% of total substrate oxidized. This was also the case in those dogs with high circulating FFA (9.0 to 32.3%). However, in dogs with high circulating lactate (over 5.0 mmol X l-1) the oxidation of glucose was relatively unaffected (2.0 to 7.1%). In cardiac denervated dogs, with a known inhibition of glycolysis, Oxfenicine increased glucose oxidation from 4.8 to 23.5%. These results show that Oxfenicine is able to switch the heart from the oxidation of fat to glucose or lactate as fuel.

Effect of uremia upon carbohydrate metabolism in isolated perfused rat heart

To study cardiac carbohydrate metabolism in acute or chronic uremic conditions, hearts from animals were studied at 24 h after bilateral nephrectomy (acute uremia) or 2 weeks after 5 6 nephrectomy (chronic uremia). Studies performed in isolated perfused hearts, using glucose-U- 14C and 5 m m glucose as a substrate, showed that glucose uptake and glycogen turnover were depressed in hearts from acute uremic animals. The residual glycogen content remained higher in uremic than sham hearts. These abnormalities were correctable with insulin. Although chronic uremic animals had less cardiac glycogen content than chronic sham-operated animals, there were no differences in glucose or glycogen metabolism or in response to insulin in these isolated perfused hearts. Glycolysis and oxidative metabolism appeared to be normal in acute and chronic uremic hearts. Normal hearts perfused in the presence of urea 2.5, 10, or 20 m m, guanidinosuccinic acid 0.31 m m, creatinine 0.88 m m and methylguanidine 0.46 m m alone or in combination showed normal carbohydrate metabolism in the absence and presence of insulin. Thus, abnormal carbohydrate metabolism can only be demonstrated in acute uremic rat hearts, and this resulted from the impairment of glucose transport, a diminution of the hexokinase activity, and abnormal glycogen metabolism.

Effect of ketones on metabolism of FFA by dog myocardium and skeletal muscle in vivo.

ARTICLESEffect of ketones on metabolism of FFA by dog myocardium and skeletal muscle in vivo Little JR, M Goto, and JJ Spitzer Little JR, M Goto, and JJ SpitzerPublished Online:01 Nov 1970https://doi.org/10.1152/ajplegacy.1970.219.5.1458MoreSectionsPDF (2 MB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat Previous Back to Top Next Download PDF FiguresReferencesRelatedInformationCited ByExogenous Ketone Supplements in Athletic Contexts: Past, Present, and Future10 October 2022 | Sports Medicine, Vol. 52, No. S1Disorders of Ketogenesis and Ketolysis25 June 2022Nutritional ketosis improves exercise metabolism in patients with very long‐chain acyl‐CoA dehydrogenase deficiency5 February 2020 | Journal of Inherited Metabolic Disease, Vol. 43, No. 4Failing Homeostasis of Quadriceps Muscle Energy- and pH Balance During Bicycling in a Young Patient With a Fontan Circulation21 August 2019 | Frontiers in Cardiovascular Medicine, Vol. 6The effect of 1,3-butanediol and carbohydrate supplementation on running performanceJournal of Science and Medicine in Sport, Vol. 22, No. 6Myocardial Metabolism13 March 2019Metabolic Mechanisms of Exercise-Induced Cardiac Remodeling11 September 2018 | Frontiers in Cardiovascular Medicine, Vol. 5Metabolic Coordination of Physiological and Pathological Cardiac RemodelingCirculation Research, Vol. 123, No. 1Ketone Bodies and Exercise Performance: The Next Magic Bullet or Merely Hype?18 July 2016 | Sports Medicine, Vol. 47, No. 3Substrate oxidation and cardiac performance during exercise in disorders of long chain fatty acid oxidationMolecular Genetics and Metabolism, Vol. 105, No. 1Metabolism, hypoxia and the diabetic heartJournal of Molecular and Cellular Cardiology, Vol. 50, No. 4Myocardial Fatty Acid Metabolism in Health and DiseaseGary D. 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Lopaschuk1 October 2003 | American Journal of Physiology-Heart and Circulatory Physiology, Vol. 285, No. 4What is the role of medium-chain triglycerides in the management of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency?1 June 2003 | Journal of Inherited Metabolic Disease, Vol. 26, No. 4dl-3-Hydroxybutyrate administration prevents myocardial damage after coronary occlusion in rat heartsZhitian Zou, Shiro Sasaguri, Katare Gopalrao Rajesh, and Ryoko Suzuki1 November 2002 | American Journal of Physiology-Heart and Circulatory Physiology, Vol. 283, No. 5The erythrocyte-perfused “working heart” modelJournal of Pharmacological and Toxicological Methods, Vol. 41, No. 1Fatty acid oxidation defects in muscleCurrent Opinion in Neurology, Vol. 11, No. 5Lipids and KetonesSubstrate selection early after reperfusion of ischemic regions in the working rabbit heartMagnetic Resonance in Medicine, Vol. 35, No. 6Ketone Body Metabolism in the Diabetic HeartSubstrate selection in the isolated working rat heart: effects of reperfusion, afterload, and concentrationBasic Research in Cardiology, Vol. 90, No. 5Developmental cardiac metabolism in health and diseasePediatric Cardiology, Vol. 10, No. 3Myocardial Substrate Utilization in Acute and Chronic, and in Latent and Severe DiabetesEffects of dietary intake on myocardial glycogen in ratsJournal of Surgical Research, Vol. 41, No. 2Effect of LPS on Carbohydrate and Lipid MetabolismThe effect of Oxfenicine on cardiac carbohydrate metabolism in intact dogsBasic Research in Cardiology, Vol. 78, No. 1Regulation of Acetoacetyl-CoA in Isolated Perfused Rat HeartsEuropean Journal of Biochemistry, Vol. 119, No. 2LACTATE-FATTY ACID COMPETITION IN THE HEART DURING SHOCKCerebral Blood Flow and Metabolism During Hypoglycemia in Newborn DogsJournal of Neurochemistry, Vol. 35, No. 3Activities of 3-Hydroxybutyrate Dehydrogenase, 3-Oxoacid CoA-Transferase and Acetoacetyl-CoA Thiolase in Relation to Ketone-Body Utilisation in Muscles from Vertebrates and InvertebratesEuropean Journal of Biochemistry, Vol. 104, No. 1Evaluation of myocardial metabolism and perfusion with positron-emitting radionuclidesProgress in Cardiovascular Diseases, Vol. 20, No. 3A direct radioimmunoassay for human renin substrate and identification of multiple substrate types in plasma.Circulation Research, Vol. 41, No. 4Constraints on the uptake of labeled palmitate by the heart. The barriers at the capillary and sarcolemmal surfaces and the control of intracellular sequestration.Circulation Research, Vol. 41, No. 4Influence of Acetate on the Metabolism of β-Hydroxybutyrate in the Perfused Hind-Quarter of the RatActa Physiologica Scandinavica, Vol. 99, No. 1Non-Esterified Fatty Acid (FFA) Metabolism Following Severe Hemorrhage in the Conscious DogMyocardial Metabolism during Endotoxic ShockMyocardial Lipid and Carbohydrate Metabolism in Healthy, Fasting Men at Rest: Studies During Continuous Infusion of 3 H-PalmitateEuropean Journal of Clinical Investigation, Vol. 2, No. 5CoA transferase in the brain and other mammalian tissuesArchives of Biochemistry and Biophysics, Vol. 148, No. 2 More from this issue > Volume 219Issue 5November 1970Pages 1458-1463 Copyright & PermissionsCopyright © 1970 by American Physiological Societyhttps://doi.org/10.1152/ajplegacy.1970.219.5.1458PubMed5473135History Published online 1 November 1970 Published in print 1 November 1970 Metrics