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PubMed1987

Ketone bodies increase glomerular filtration rate in normal man and in patients with type 1 (insulin-dependent) diabetes mellitus.

The purpose of this study was to investigate whether the administration of acetoacetic and hydrochloric acids in a group of control and Type 1 (insulin-dependent) diabetic patients influenced renal haemodynamics. Renal plasma flow increased from 657 +/- 88 to 762 +/- 81 ml X min-1. 1.73 m-2 in diabetic patients (p less than 0.01) and from 590 +/- 71 to 691 +/- 135 in control subjects (p less than 0.01). Glomerular filtration rate increased from 135 +/- 9 to 180 +/- 8 ml X min-1. 1.73 m-2 in diabetic patients (p less than 0.001) and from 117 +/- 8 to 145 +/- 7 in control subjects (p less than 0.01). Similar effects on renal haemodynamics, even if less pronounced, were observed with low dose acetoacetic but not with hydrochloric acid infusion. Total protein, beta 2-microglobulin but not albumin excretion rates were increased by acetoacetic acid. We conclude that an acute increase in blood concentration of ketone bodies within the range found in diabetic patients with poor metabolic control increases renal plasma flow and glomerular filtration rate both in control subjects and diabetic patients and causes a tubular proteinuria.

Acetoacetates↗
PubMedDate not supplied

Substrate selection in the isolated working rat heart: effects of reperfusion, afterload, and concentration.

A study of substrate selection in the isolated heart was made using 13C NMR isotopomer analysis, a method that unequivocally identifies relative substrate utilization. This technique has several advantages over conventional approaches used to study this problem. It detects the labeling of metabolic end-products present in tissue, as opposed to more indirect methods such as measurement of respiratory quotient, arteriovenous differences, or specific activity changes in the added substrate. It also has advantages over methods such as 14CO2 release, which may involve dilution of label with unlabeled pools before CO2 release. Furthermore, it can measure the relative oxidation of up to four substrates in a single experiment, which other labeling techniques cannot conveniently achieve. Substrate selection was considered in light of its effects on myocardial efficiency and recovery from ischemia. A mixture of four substrates (acetoacetate, glucose, lactate, and a mixture of long chain fatty acids), present at physiological concentration (0.17, 5.5, 1.2, and 0.35 mM, respectively), was examined. This is the first use of such a mixture in the study of substrate selection in an isolated organ preparation. At these concentrations, it was found that fatty acids supplied the majority of the acetyl-CoA (49%), and a substantial contribution was also provided by acetoacetate (23%). This suggests that the ketone bodies are a more important substrate than generally considered. Indeed, normalizing the relative utilizations on the basis of acetyl-CoA equivalents, ketone bodies were by far the preferred substrate. The relative lactate oxidation was only 15%, and glucose oxidation could not be detected. No change in utilization was detected after 15 min of ischemia followed by 40 min of reperfusion. The change in substrate selection with afterload was examined, to mimic the stress-related changes in workload found with ischemia. Only minor changes were found. Substrate selection from the same group of substrates, but employing concentrations observed during starvation, was also assessed. This represents the state during which most clinical treatments and evaluations are performed. In this case, acetoacetate was the most used substrate (78%), with small and equal contributions from fatty acids and endogenous substrates; the oxidation of lactate was suppressed.

Acetoacetates↗
PubMed1983

Possible interrelationship between gluconeogenesis and ketogenesis in the liver.

Effects of various ketogenic substrates on gluconeogenesis from lactate were examined. D,L-3-Hydroxybutyrate (5 mM) stimulated gluconeogenesis by 41%, the effect being the same as that of 5 mM acetate (49%). No stimulating effect of acetoacetate was observed; conversely, acetoacetate (up to 40 mM) partially or completely abolished the observed stimulating effects of acetate, oleate, and 3-hydroxybutyrate. The results suggest that, in intact liver cells, pyruvate is transported into mitochondria in exchange for acetoacetate and that an interrelationship between gluconeogenesis and ketogenesis at the level of mitochondrial pyruvate carrier may exist in the liver.

3-Hydroxybutyric Acid↗
PubMed1992

Effects of diabetes and insulin on ketone bodies metabolism in heart.

This work investigates the effect of alloxan-induced short-term diabetes (24 h) on D-3-hydroxybutyrate metabolism at physiological and non-physiological concentrations of the ketone body in the isolated non-working perfused rat heart. Also the effect of insulin (2 mU.ml-1) on D-3-hydroxybutyrate metabolism was investigated in hearts from normal and diabetic rats. The rates of D-3-hydroxybutyrate utilization and oxidation and of acetoacetate production were proportional to D-3-hydroxybutyrate concentration. The utilization of D-3-hydroxybutyrate showed saturation kinetics in hearts from normal and diabetic rats, in the presence and absence of insulin. Acute short-term diabetes augmented D-3-hydroxybutyrate utilization and oxidation at 1.25 and 2.5 mM DL-3-HB, with no significant effect at higher concentrations, but increased acetoacetate production at all investigated concentrations. In hearts from normal rats, insulin enhanced D-3-hydroxybutyrate utilization and oxidation at 2.5, 5, and 10 mM DL-3-HB, but no effect was observed at the lowest (1.25 mM) and highest (16 mM) DL-3-HB concentrations. Insulin had no effect on D-3-hydroxybutyrate metabolism in hearts from diabetic rats. No significant effect of insulin on the rate of acetoacetate production in normal and diabetic states was observed.

3-Hydroxybutyric Acid↗
PubMed1983

Sensitive and simplified method for the differential determination of serum levels of ketone bodies.

A highly sensitive and simplified method for the differential determination of serum ketone bodies has been developed. Serum was deproteinized with perchloric acid, and acetoacetate contained in the supernate was reacted with newly synthesized p-nitrobenzene diazonium fluoroborate at 37 degrees C for 10 min. The formed hydrazo compound was converted by alkali to the more stable azo compound which has a peak absorbance at 645 nm. For the determination of 3-hydroxybutyrate, this was enzymatically converted to acetoacetate using 3-hydroxybutyrate dehydrogenase, LDH, NAD and pyruvate. Using 0.2 ml serum, acetoacetate and 3-hydroxybutyrate could be quantitated in 30 min. The described method is five times more sensitive than the enzymatic photometric method and can detect individual ketone bodies at concentrations as low as 20 mumol/l. Differential determination of serum levels of ketone bodies is clinically useful for the diagnosis of type 1 diabetes and in monitoring diabetic control.

3-Hydroxybutyric Acid↗
PubMed1989

Augmented production of platelet-activating factor in human polymorphonuclear leukocytes by ketone bodies.

The production of platelet-activating factor (PAF) in A23187-stimulated human polymorphonuclear leukocytes was markedly increased in the presence of 5 mM acetoacetate and beta-hydroxybutyrate. Such an augmentation was observed even at 500 microM but not at 50 microM. The augmented production of PAF by acetoacetate was also observed in the presence of autologous serum and was most prominent in the case of opsonized zymosan-stimulation rather than A23187-stimulation. These observations suggest that increased levels of acetoacetate and beta-hydroxybutyrate in blood may lead to the augmented production of PAF, which would amplify the various PAF-mediated biological reactions.

3-Hydroxybutyric Acid↗
PubMed1975

Inhibition of ketogenesis by ketone bodies in fasting humans.

Although there exists some indirect evidence that circulating ketone bodies might inhibit their own production rate, the direct demonstration of this homeostatic feed-back phenomenon is still lacking. The present work aims at demonstrating the operation of this control mechanism in human fasting ketosis. Six obese subjects, who fasted 2-23 days, were given a primed constant i.v. infusion of 3- 14C-acetoacetate for 4 hr. After a control period of 2 hr, unlabeled sodium acetoacetate was administered as a primed constant i.v. infusion at the rate of 0.688-1.960 mmol/min until the end of the study. During both periods, the rates of inflow of ketones were estimated from the specific activity of total ketones measured under near isotopic steady state conditions. During the control period, total ketone concentration amounted to 3.98-9.65 mumol/ml and production rates of total ketones ranged between 1.450 and 2.053 mmol/min. The levels of free fatty acids, glycerol, glucose, and insulin averaged respecitvely 1.30 mumol/ml, 0.11 mumol/ml, 74 mg/100 ml, and 5.2 muU/ml. The administration of exogenous ketones during the second phase of the study induced a 47%-92% increase in total ketone levels. During this period, the endogenous production of ketones (calculated as the difference between total inflow rate and acetoacetate infusion rate) amounted only to 67%-90% of control values. Among other factors, this inhibition of ketogenesis was probably partially related to the direct antilipolytic effect of infused ketones. Indeed, there was a concomitant fall in FFA and in glycerol levels averaging respectively 13.5% and 17.3%, without significant changes in peripheral insulin concentrations. Our results demonstrate that during fasting, circulating ketone bodies exert an inhibitory influence on the rate of ketogenesis. This mechanism might play an important role in preventing the development of uncontrolled hyperketonemia during starvation.

Acetoacetates↗
PubMed1979

Kinetics of ketone body metabolism in fasting humans.

The rates of production of total ketone bodies (acetoacetate + beta-hydroxybutyrate) were determined using an isotope tracer technique in 23 obese subjects submitted to a fast of variable duration (15 hr--23 days). Constant infusions of 14C-acetoacetate were used in most studies, but similar results were obtained with pulse injections of this tracer or with constant infusions of 14C-D(-)-beta-hydroxybutyrate. Blood concentration, production rate, and urinary elimination of total ketones rose during approximately the first 3 days of fast and plateaued thereafter at values amounting, respectively, to 7.09 +/- 0.32 mumole/ml, 1908 +/- 80 mumole/min and 167 +/- 14 mumole/min. The rates of ketogenesis are significantly higher than those usually reported in the literature. Ketonemia was an exponential function of production rate suggesting that tissue uptake becomes progressively saturated as inflow rate rises. The same type of relationship between concentration and inflow rate was observed in nine control overnight fasted obese subjects rendered hyperketonemic with infusions of variable amounts of unlabeled acetoacetate. The comparison between the fasted and the control subjects at ketone concentrations of 3--10 mumole/ml showed that on an average, starvation is associated with a 35% decrease in the metabolic clearance rate of ketones. These data suggest that fasting is associated with an impairment of mechanisms for utilizing ketones, this defect contributing to the hyperketonemia of food deprivation.

Acetoacetates↗
PubMed1989

Effects of free fatty acids and ketone bodies on in vivo non-insulin-mediated glucose utilization and production in humans.

The current study was undertaken to examine the effect of an acute elevation of serum levels of free fatty acids (FFA) and ketone bodies (KB) on non-insulin-mediated glucose uptake (NIMGU) in humans. The study group consisted of 11 healthy men, mean age (+/- SD) 30 (+/- 7) years and mean weight (+/- SD) 72 (+/- 7) kg. To examine the effects of FFA levels on NIMGU and insulin-mediated glucose uptake (IMGU), glucose uptake was measured isotopically (3H-3-glucose) in six subjects on four separate days during saline infusion or lipid + heparin infusion with concomitant infusions of somatostatin (SHIF, 0.16 micrograms/kg/min) with or without insulin infusion (40 mU/m2/min) while the serum glucose level was clamped at approximately 11 mmol/L. To examine the effect of KB on NIMGU, saline or sodium acetoacetate (20 mumol/kg/min) was infused in five subjects on separate days during SRIF-induced insulinopenia while the serum glucose level was clamped sequentially at euglycemia and at approximately 11 mmol/L. During insulinopenia basal FFA levels rose twofold during saline infusion and sixfold during infusion of lipid + heparin. Rates of NIMGU were 2.49 +/- 0.27 v 2.41 +/- 0.14 mg/kg/min during saline and lipid infusion, respectively (P = NS). Rates of IMGU were decreased by 55% during lipid + heparin infusion. During insulinopenia basal beta-hydroxybutyrate (BOB) levels rose twofold during saline and approximately 11-fold during sodium acetoacetate infusion. Rates of NIMGU were unchanged by the sodium acetoacetate infusion at euglycemia and hyperglycemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetoacetates↗
PubMed1993

A top-down control analysis in isolated rat liver mitochondria: can the 3-hydroxy-3-methylglutaryl-CoA pathway be rate-controlling for ketogenesis?

We incubated isolated liver mitochondria with palmitoyl-CoA, 2,4-dinitrophenol and malonate. Under these conditions all the flux of carbon from palmitoyl-CoA was directed towards acetoacetate synthesis. We measured the rate of acetyl-CoA formation from palmitoyl-CoA (by measuring the rate of oxygen consumption) and the rate of acetoacetate production from acetyl-CoA at three different acetyl-CoA/CoA ratios. Using the top-down approach of metabolic control analysis we calculated the control over ketogenesis exerted by (a) the conversion of extramitochondrial palmitoyl-CoA to intramitochondrial acetyl-CoA and by (b) the conversion of acetyl-CoA to acetoacetate (the 'HMG-CoA pathway'). The overall flux control coefficients of the groups of enzymes involved in (a) and (b) over ketogenesis were 0.28 and 0.72, respectively. Our results show that it is possible for significant control to be exerted over ketogenesis by the enzymes of the HMG-CoA pathway.

Acetoacetates↗
PubMed2006

Involvement of the AtoS-AtoC signal transduction system in poly-(R)-3-hydroxybutyrate biosynthesis in Escherichia coli.

The AtoS-AtoC signal transduction system in E. coli, which induces the atoDAEB operon for the growth of E. coli in short-chain fatty acids, can positively modulate the levels of poly-(R)-3-hydroxybutyrate (cPHB) biosynthesis, a biopolymer with many physiological roles in E. coli. Increased amounts of cPHB were synthesized in E. coli upon exposure of the cells to acetoacetate, the inducer of the AtoS-AtoC two-component system. While E. coli that overproduce both components of the signal transduction system synthesize higher quantities of cPHB (1.5-4.5 fold), those that overproduce either AtoS or AtoC alone do not display such a phenotype. Lack of enhanced cPHB production was also observed in cells overexpressing AtoS and phosphorylation-impaired AtoC mutants. The results were not affected by the nature of the carbon source used, i.e., glucose, acetate or acetoacetate. An E. coli strain with a deletion in the atoS-atoC locus (delta atoSC) synthesized lower amounts of cPHB compared to wild-type cells. When the delta atoSC strain was transformed with a plasmid carrying a 6.4-kb fragment encoding the AtoS-AtoC system, cPHB biosynthesis was restored to the level of the atoSC+ cells. Introduction of a multicopy plasmid carrying a functional atoDAEB operon, but not one with a promoterless operon, resulted in increased cPHB synthesis only in atoSC+ cells in the presence of acetoacetate. These results indicate that the presence of both a functional AtoS-AtoC two-component signal transduction system and a functional atoDAEB operon is critical for the enhanced cPHB biosynthesis in E. coli.

Acetoacetates↗
PubMed1982

Ketone interference in estimation of urinary creatinine; effect on creatinine clearance in diabetic ketoacidosis.

Acetoacetate is known to spuriously raise serum creatinine concentration in patients with diabetic ketoacidosis. Its effect on urinary creatinine has not been studied. Since the renal threshold for ketoacids is low, large amounts of acetoacetate may be present in the urine of uncontrolled diabetics. We investigated this interference using three different automated analysers. We found that +3 or +4 reactions with Ketostix, equivalent to greater than 10 - 15 mmol/L of acetoacetate caused significant interference with the Abbott VP and Beckman Astra instruments. This could cause errors in the calculation of creatinine clearance especially when serum creatinine is close to a normal level. We recommend that measurement of creatinine clearance be delayed until better diabetic control is achieved or the creatinine be measured by a method which is free from ketone interference, e.g., by the Dupont aca.

Acetoacetates↗
PubMed2000

The redox state of endogenous pyridine nucleotides can determine both the degree of mitochondrial oxidative stress and the solute selectivity of the permeability transition pore.

Acetoacetate, an NADH oxidant, stimulated the ruthenium red-insensitive rat liver mitochondrial Ca(2+) efflux without significant release of state-4 respiration, disruption of membrane potential (Deltapsi) or mitochondrial swelling. This process is compatible with the opening of the currently designated low conductance state of the permeability transition pore (PTP) and, under our experimental conditions, was associated with a partial oxidation of the mitochondrial pyridine nucleotides. In contrast, diamide, a thiol oxidant, induced a fast mitochondrial Ca(2+) efflux associated with a release of state-4 respiration, a disruption of Deltapsi and a large amplitude mitochondrial swelling. This is compatible with the opening of the high conductance state of the PTP and was associated with extensive oxidation of pyridine nucleotides. Interestingly, the addition of carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone to the acetoacetate experiment promoted a fast shift from the low to the high conductance state of the PTP. Both acetoacetate and diamide-induced mitochondrial permeabilization were inhibited by exogenous catalase. We propose that the shift from a low to a high conductance state of the PTP can be promoted by the oxidation of NADPH. This impairs the antioxidant function of the glutathione reductase/peroxidase system, strongly strengthening the state of mitochondrial oxidative stress.

Acetoacetates↗
PubMed1996

Effects of glutamate and aspartate on myocardial substrate oxidation during potassium arrest.

OBJECTIVES: A recent report (J Clin Invest 1993;92:831-9) found no effect of glutamate plus aspartate on metabolic pathways in the heart, but the experimental conditions did not model clinical cardioplegia. The purpose of this study was to determine the effects of glutamate and aspartate on metabolic pathways feeding the citric acid cycle during cardioplegic arrest in the presence of physiologic substrates. METHODS: Isolated rat hearts were supplied with fatty acids, lactate, pyruvate, glucose, and acetoacetate in physiologic concentrations. These substrates were enriched with 13C, which allowed a complete analysis of substrate oxidation by 13C-nuclear magnetic resonance spectroscopy in one experiment. Three groups of hearts were studied: arrest with potassium cardioplegic solution, arrest with cardioplegic solution supplemented with glutamate and aspartate (both in concentrations of 13 mmol/L), and a control group without cardioplegic arrest. RESULTS: In potassium-arrested hearts, the contributions of fatty acids and lactate to acetyl coenzyme A were reduced, and acetoacetate was the preferred substrate for oxidation in the citric acid cycle. The addition of aspartate and glutamate in the presence of cardioplegic arrest did not further alter patterns of substrate utilization substantially, although acetoacetate use was somewhat lower than with simple cardioplegic arrest. When [U-13C]glutamate (13 mmol/L) and [U-13C]aspartate (13 mmol/L) were supplied as the only compounds labeled with 13C, little enrichment in citric acid cycle intermediates could be detected. CONCLUSIONS: Glutamate and aspartate when added to potassium cardioplegic solutions have relatively minor effects on citric acid cycle metabolism.

Acetoacetates↗
PubMed1981

Inhibition of D(--)-beta-hydroxybutyrate dehydrogenase by modifiers of disulfides, thiols, and vicinal dithiols.

D(--)-beta-hydroxybutyrate dehydrogenase of beef heart mitochondria catalyzes the reversible oxidation of D-(--)-beta-hydroxybutyrate to acetoacetate in the presence of NAD. Both the membrane-bound and the soluble forms of the enzyme are inhibited by modifiers of thiols [N-ethylmaleimide (NEM) and p-(chloromercuri)phenylsulfonate (pCMS)], vicinal dithiols [phenylarsine oxide and diazenedicarboxylic acid bis(dimethylamide) (diamide)], and disulfides (sulfite, sulfide, and cyanide). NAD and NADH, but not beta-hydroxybutyrate and acetoacetate, protect the enzyme against inhibition by NEM, pCMS, phenylarsine oxide, and diamide. As tested with NEM and diamide, the inhibitions caused by mono- and dithiol modifiers were pseudo first order, and the reaction order with respect to the concentration of either inhibitor was unity, thus indicating the modification of a single essential thiol and/or dithiol. Sulfite and sulfide inhibitions appeared to be competitive with respect to beta-hydroxybutyrate, with Ki values of 10-15 and about 240 microM, respectively. Sulfite inhibition was uncompetitive with respect to NAD, NADH, and acetoacetate. The above results have suggested the presence in D(--)-beta-hydroxybutyrate dehydrogenase of an essential thiol and/or a vicinal dithiol associated with the binding site(s) of NAD and NADH. The inhibition by sulfite, sulfide, and cyanide might be indicative of the presence of an essential disulfide or due to a ternary complex formation involving the enzyme, NAD, and the above nucleophiles.

Acetoacetates↗
PubMed2003

Antioxidant properties of myocardial fuels.

Oxidative metabolism of blood-borne fuels provides myocardium the energy required to sustain its contractile performance. Recent research has revealed that, in addition to supplying energy, certain fuels are able to detoxify harmful oxidants and bolster the myocardium's endogenous antioxidant defenses. These antioxidant capabilities could potentially protect the myocardium from the ravages of reactive oxygen and nitrogen intermediates generated upon reperfusion of ischemic myocardium. This article reviews experimental evidence that two fuels, pyruvate and acetoacetate, provide such antioxidant protection. Pyruvate's antioxidant properties stem in part from its alpha-keto carboxylate structure, which enables it to directly, non-enzymatically neutralize peroxides and peroxynitrite. Also, citrate, which accumulates in pyruvate-perfused myocardium following anaplerotic pyruvate carboxylation, supports NADPH production to maintain glutathione:glutathione disulfide (GSH/GSSG) redox potential, the central component of the myocardial antioxidant system. Like pyruvate, acetoacetate restores GSH/GSSG and increases contractile function of post-ischemic stunned myocardium, although some of its antioxidant mechanisms may differ from pyruvate's. Both compounds restore beta-adrenergic signaling and inotropism, which are compromised in stunned myocardium. N-acetylcysteine, a pharmacological antioxidant that does not provide energy, duplicated the salutary effects of pyruvate and acetoacetate on post-ischemic gamma-adrenergic signaling and GSH/GSSG. These findings reveal novel, energy-independent mechanisms for enhancement of post-ischemic cardiac performance by metabolic fuels.

Acetoacetates↗
PubMed1966

The fate of isotopic carbon in kidney cortex synthesizing glucose from lactate.

1. When slices of kidney cortex are incubated with lactate and acetoacetate, lactate is almost quantitatively converted into glucose whereas acetoacetate provides a major part of the fuel of respiration. 2. In apparent contrast with these findings a large fraction of (14)C-labelled acetoacetate appears in glucose and a large fraction of (14)C-labelled lactate appears in the carbon dioxide. 3. The findings can be explained by: (a) the participation of oxaloacetate as an intermediate of both gluconeogenesis and respiration; (b) the fact that the carbon dioxide formed in the course of one turn of the tricarboxylic acid cycle is exclusively derived from oxaloacetate. 4. As a result there is a ;crossing over' of the carbon of the substrate of respiration to the pathway of gluconeogenesis and of the carbon of the glucogenic precursors to the pathway of respiration. 5. In the given situation the fate of the label does not allow predictions to be made about the net fate of the labelled metabolites. 6. The implications of the findings on the interpretation of isotopic data are discussed.

Acetoacetates↗
PubMed1967

Determination of 14C-labelled ketone bodies by liquid-scintillation counting.

1. A method of assaying (14)C in ketone bodies present in blood by using liquid-scintillation counting is described. 2. d(-)-beta-Hydroxy[(14)C]butyrate is converted quantitatively into [(14)C]acetoacetate by means of a coupled oxidoreduction reaction involving NAD(+), d(-)-beta-hydroxybutyrate dehydrogenase and malic dehydrogenase in the presence of a high concentration of oxaloacetate. 3. [(14)C]Acetoacetate is decarboxylated to acetone and carbon dioxide which are trapped separately in a double-well flask and counted subsequently. 4. The method permits the determination of (14)C activity in the individual ketone bodies and allows the activity in the carboxyl carbon atoms of acetoacetate or of d(-)-beta-hydroxybutyrate to be assayed separately from the activity in the remainder of the molecule. 5. Recoveries of (14)C-labelled ketone bodies added to blood approach 100% with good reproducibility in replicate analyses.

Acetoacetates↗