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PubMed1980

Cerebral blood flow and exchange of oxygen, glucose ketone bodies, lactate, pyruvate and amino acids in anesthetized children.

Cerebral blood flow (CBF) and cerebral av differences of oxygen, glucose, 3-hydroxybutyrate, acetoacetate, lactate, pyruvate and amino acids were measured in anaesthetized children before elective surgery in order to study possible age-dependent variations. CBF was measured in 70 children, aged 11 days to 15 years. Cerebral av differences were studied in approximately 50% of the subjects. Mean values were: CBF 0.65 ml x g-1 x min-1, cerebral exchange in nmoles x g-1 x min-1; 1348, glucose 248, acetoacetate 12,3-hydroxybutyrate 34 (uptake), lactate-48, pyruvate-8 (release). No net exchange of amino acids was found with the exception of histidine (uptake). Neither CBF nor the cerebral exchange of oxygen and circulating substrates showed any correlation to age within the group. Compared with adults anesthetized by the same technique (barbiturate induction, nitrous oxide-oxygen relaxant) the children had a slightly higher mean CBF, while the cerebral uptake of oxygen and glucose were equal to values in adults. The cerebral uptake of ketone bodies was higher in children than reported values in adults investigated in the awake state after comparable periods of fasting.

Acetoacetates↗
PubMed1967

Bacterial metabolism of mevalonic acid.

Soluble cell-free extracts of actinomycete S4 grown on media containing mevalonate catalyze acetoacetate formation from mevalonate, mevaldate, and beta-hydroxy-beta-methylglutaryl-coenzyme A (CoA). Conversion of mevalonate to acetoacetate involves formation of free beta-hydroxy-beta-methylglutaryl-CoA, but not free mevaldate. The reaction favors mevalonate oxidation, and nicotinamide adenine dinucleotide, rather than nicotinamide adenine dinucleotide phosphate, acts as oxidant.

Acetoacetates↗
PubMed1976

Degradation of homogentisate by strains of Bacillus and Moraxella.

The metabolic pathways whereby strains of Moraxella and Bacillus degrade homogentisate (2,5-dihydroxyphenylacetate) are delineated. The Moraxella (strain OA3) is shown to degrade homogentisate via the pathway previously described in liver: homogentisate is cleaved by a 1,2-dioxygenase (E.C 1.13.11.5) yielding maleylacetoacetate which is isomerized by a GSH-dependent isomerase to fumarylacetoacetate before hydrolysis to acetoacetate and fumarate. A strain of Bacillus (B11c) is shown to catabolize homogentisate via a previously undescribed version of the above sequence: homogentisate is cleaved by a 1,2-dioxygenase (E.C 1.13.11.5) yielding maleylacetoacetate which is hydrolyzed directly to acetoacetate and maleate.

Acetoacetates↗
PubMed1979

Substrate oxidation specificity in different types of mammalian muscle.

The maximal capacity of homogenates prepared from cardiac, fast-oxidative-glycogenolytic (FOG) vastus lateralis, fast-glycogenolytic (FG) vastus lateralis, and slow-oxidative (SO) soleus muscle to oxidize pyruvate, palmitate, alpha-glycerophosphate, and acetoacetate was assessed by measuring oxygen consumption under conditions of nonlimiting substrate and cofactors. Pyruvate oxidation varied eight-fold among the muscle types and was highest in cardiac, followed by FOG, SO, and FG muscle. Palmitate was oxidized at 97%, 85%, 77%, and 57% of the relative rate for pyruvate in cardiac, FOG, SO, and FG muscle, respectively. In contrast, alpha-glycerophosphate oxidation rates were highest in FG muscle, followed by cardiac, FOG, and SO muscle. Although cardiac muscle possessed the highest absolute rate for acetoacetate oxidation, it had the lowest capacity relative to pyruvate (19%), whereas SO muscle possessed the highest (61%). FOG and FG muscle had similar relative capacities for this substrate (30%). These results provide further evidence to suggest that mammalian muscle types are differentiated in terms of both mitochondrial mass and substrate oxidation specificity.

Acetoacetates↗
PubMed1990

Ketone bodies and islet function: 45Ca handling, insulin synthesis, and release.

D-(-)-beta-Hydroxybutyrate and acetoacetate cause a rapid, sustained, and rapidly reversible stimulation of insulin release from rat pancreatic islets incubated in the presence, but not absence, of D-glucose. This coincides with stimulation of both proinsulin biosynthesis and 45Ca net uptake. The ketone bodies also decrease 45Ca outflow from prelabeled islets perifused in the absence of Ca2+ and, in contrast, enhance effluent radioactivity in the presence of Ca2+. In the presence of D-glucose, the secretory response to D-(-)-beta-hydroxybutyrate is concentration related in the 2.5-20 mM range, abolished in the absence of Ca2+ or presence of KCN, and enhanced by theophylline and forskolin. It corresponds grossly to a shift to the left of the sigmoidal curve relating insulin output to the ambient concentration of D-glucose. The secretory, biosynthetic, and cationic response to acetoacetate is less marked than that evoked by an equimolar concentration of D-(-)-beta-hydroxybutyrate. These features are compatible with the view that the insulinotropic action of ketone bodies would be causally linked to their metabolism in islet cells.

3-Hydroxybutyric Acid↗
PubMed1997

Malonyl-CoA regulation in skeletal muscle: its link to cell citrate and the glucose-fatty acid cycle.

Malonyl-CoA is an inhibitor of carnitine palmitoyltransferase I, the enzyme that controls the oxidation of fatty acids by regulating their transfer into the mitochondria. Despite this, knowledge of how malonyl-CoA levels are regulated in skeletal muscle, the major site of fatty acid oxidation, is limited. Two- to fivefold increases in malonyl-CoA occur in rat soleus muscles incubated with glucose or glucose plus insulin for 20 min [Saha, A. K., T. G. Kurowski, and N. B. Ruderman. Am. J. Physiol. 269 (Endocrinol. Metab. 32): E283-E289, 1995]. In addition, as reported here, acetoacetate in the presence of glucose increases malonyl-CoA levels in the incubated soleus. The increases in malonyl-CoA in all of these situations correlated closely with increases in the concentration of citrate (r2 = 0.64) and to an even greater extent the sum of citrate plus malate (r2 = 0.90), an antiporter for citrate efflux from the mitochondria. Where measured, no increase in the activity of acetyl-CoA carboxylase (ACC) was found. Inhibition of ATP citrate lyase with hydroxycitrate markedly diminished the increases in malonyl-CoA in these muscles, indicating that citrate was the major substrate for the malonyl-CoA precursor, cytosolic acetyl-CoA. Studies with enzyme purified by immunoprecipitation indicated that the observed increases in citrate could have also allosterically activated ACC. The results suggest that in the presence of glucose, insulin and acetoacetate acutely increase malonyl-CoA levels in the incubated soleus by increasing the cytosolic concentration of citrate. This novel mechanism could complement the glucose-fatty acid cycle in determining how muscle chooses its fuels. It could also provide a means by which glucose acutely modulates signal transduction in muscle and other cells (e.g., the pancreatic beta-cell) in which its metabolism is determined by substrate availability.

Acetoacetates↗
PubMed1992

Hepatic dysoxia commences during O2 supply dependence.

Hepatic O2 consumption (VO2) remains relatively constant (O2 supply independent) as O2 delivery (DO2) progressively decreases, until a critical DO2 (DO2c) is reached below which hepatic VO2 also decreases (O2 supply dependence). Whether this decrease in VO2 represents an adaptive reduction in O2 demand or a manifestation of tissue dysoxia, i.e., O2 supply that is inadequate to support O2 demand, is unknown. We tested the hypothesis that the decrease in hepatic VO2 during O2 supply dependence represents dysoxia by evaluating hepatic mitochondrial NAD redox state during O2 supply independence and dependence induced by progressive hemorrhage in six pentobarbital-anesthetized dogs. Hepatic mitochondrial NAD redox state was estimated by measuring hepatic venous beta-hydroxybutyrate-to-acetoacetate ratio (beta OHB/AcAc). The value of DO2c was 5.02 +/- 1.64 (SD) ml.100 g-1.min-1. The beta-hydroxybutyrate-to-acetoacetate ratio was constant until a DO2 value (3.03 +/- 1.08 ml.100 g-1.min-1) was reached (P = 0.05 vs. DO2c) and then increased linearly. Peak liver lactate extraction ratio was 15.2 +/- 14.1%, occurring at a DO2 of 5.48 +/- 2.54 ml.100 g-1.min-1 (P = NS vs. DO2c). Our data support the hypothesis that the decrease in VO2 during O2 supply dependence represents tissue dysoxia.

3-Hydroxybutyric Acid↗
PubMed1987

Hyperketotic states due to inherited defects of ketolysis.

From the description of 2 unrelated patients with succinyl-CoA transferase (3-OAT) deficiency and 1 patient with acetoacetyl-CoA thiolase (AAT) deficiency, we have attempted to draw the clinical and metabolic consequences of such defects. The association of recurrent attacks of severe ketoacidosis with blood glucose levels generally high or normal, low lactacidemia and low ammonemia is the most common presentation of these disorders. In 3-OAT deficiency, a potentially fatal disorder, there is a permanent ketosis with the only excretion of 3-hydroxybutyrate, acetoacetate and 3-hydroxyisovalerate. AAT patients usually excrete, in addition to the usual ketone bodies, 2-methyl-3-hydroxybutyrate and tiglylglycine; 2-methyl-acetoacetate may also be present. Both conditions can be identified by enzymatic analysis in cultured fibroblast. These disorders can mimic diabetic ketoacidosis or salicylism and can easily be missed. The knowledge of these ketolytic defects must severely question the complacent diagnosis of 'fasting ketoacidosis' or 'idiopathic ketotic hypoglycemia', mainly when severe metabolic acidosis is present.

Acetoacetates↗
PubMed1969

Liver and kidney metabolism during prolonged starvation.

This study quantifies the concentrations of circulating insulin, growth hormone, glucose, free fatty acids, glycerol, beta-hydroxybutyrate, acetoacetate, and alpha amino nitrogen in 11 obese subjects during prolonged starvation. The sites and estimated rates of gluconeogenesis and ketogenesis after 5-6 wk of fasting were investigated in five of the subjects. Blood glucose and insulin concentrations fell acutely during the 1st 3 days of fasting, and alpha amino nitrogen after 17 days. The concentration of free fatty acids, beta-hydroxybutyrate, and acetoacetate did not reach a plateau until after 17 days. Estimated glucose production at 5-6 wk of starvation is reduced to approximately 86 g/24 hr. Of this amount the liver contributes about one-half and the kidney the remainder. Approximately all of the lactate, pyruvate, glycerol, and amino acid carbons which are removed by liver and kidney are converted into glucose, as evidenced by substrate balances across these organs.

Acetoacetates↗
PubMed1970

Effect of insulin and acute diabetes on plasma FFA and ketone bodies in the fasting rat.

The metabolism of FFA and ketone bodies was studied in fasted rats by infusing at a constant rate tracer amounts of FFA-(3)H, beta-hydroxybutyrate-(14)C or acetoacetate-(14)C for periods up to 2 hr. Blood that was removed for analyses was replaced by continuous transfusion. The rates of turnover of FFA, beta-hydroxybutyrate, and acetoacetate in rats fasted for 2 days were, respectively, 3.2, 5.6, and 2.5 mumoles/100 g body weight per min. Infusion of mannoheptulose with anti-insulin serum increased plasma glucose, FFA, and ketone body concentrations and decreased the specific activity of plasma FFA. Injection of insulin (20 mU i.v.) decreased almost simultaneously plasma glucose, FFA, and ketone body concentrations and increased the specific activity of FFA, but it did not affect the plasma concentration of FFA-(3)H. The findings indicate that insulin deprivation increased and insulin injection decreased the release of FFA from body tissues in fasting rats. The plasma FFA concentration in fasting rats was increased by infusing chylomicrons and heparin, but this had very little effect on either plasma ketone body or glucose concentrations. Insulin injection (20 mU i.v.) lowered the plasma ketone body concentration in these animals. Studies using beta-hydroxybutyrate-(14)C showed that insulin (50 mU i.v.) decreased ketogenesis in the presence of a sustained high plasma FFA concentration and had no effect on uptake of circulating ketone bodies. The results indicate that plasma FFA concentration is not the sole determinant of plasma ketone body concentration and that insulin can suppress ketone body production through some means other than lowering plasma FFA concentration.

Acetoacetates↗
PubMed1970

Splanchnic metabolism of free fatty acids and production of triglycerides of very low density lipoproteins in normotriglyceridemic and hypertriglyceridemic humans.

Transport of free fatty acids from the blood into the splanchnic region and their conversion to triglycerides of very low density lipoproteins, together with estimates of splanchnic oxidation of free fatty acids to ketones and to carbon dioxide and water, have been made in the postabsorptive state in seven normolipemic subjects, six with primary endogenous hyperlipemia and one each with primary dysbetalipoproteinemia and mixed hyperlipemia. Net systemic transport of free fatty acids into the blood was the same in normolipemic and hyperlipemic groups, but a greater fraction was taken up in the splanchnic region in the latter. Transport into the blood in very low density lipoproteins of triglyceride fatty acids derived from free fatty acids was proportional and bore the same relationship to splanchnic uptake of free fatty acids in the two groups. In normolipemic subjects, near equilibration of specific activities after 4 hr infusion of palmitate-1-(14)C showed that almost all triglyceride fatty acids of very low density lipoproteins and acetoacetate were derived from free fatty acids taken up in the splanchnic region. In the hyperlipemic subjects, equilibration of free fatty acidcarbon with acetoacetate was almost complete, but not with triglyceride fatty acids, owing at least in part to increased pool size. Comparison of the rate of equilibration of triglyceride fatty acids-(14)C with rate of inflow transport from the splanchnic region, together with other data, indicated that most of the circulating triglyceride fatty acids of very low density lipoproteins in hyperlipemic subjects were also derived from free fatty acids. Although mean inflow transport of triglyceride fatty acids was greater in the hyperlipemic subjects, it correlated poorly with their concentration and it appeared that efficiency of mechanisms for extrahepatic removal must be a major determinant of the concentration of triglycerides in blood plasma of the normolipemic as well as the hyperlipemic subjects. Estimates of splanchnic respiratory quotient supported the concept that oxidation of free fatty acids accounts for almost all of splanchnic oxygen consumption in the postabsorptive state. Splanchnic oxygen consumption was greater in the hyperlipemics, but fractional oxidation of free fatty acids to ketones was higher in normolipemic subjects. Calculations of splanchnic balance indicate that a larger fraction of free fatty acids was stored in lipids of splanchnic tissues in the hyperlipemics. No differences were found between the two groups in net splanchnic transport of glucose, lactate, or glycerol.

Acetoacetates↗
PubMed1986

Inhibition of lactate removal by ketone bodies in rat liver. Evidence for a quantitatively important role of the plasma membrane lactate transporter in lactate metabolism.

We studied the effect of DL-3-hydroxybutyrate and acetoacetate on lactate transport into isolated hepatocytes and on lactate removal in the isolated perfused rat liver. Ketone bodies inhibited lactate transport into isolated hepatocytes (maximum, 35% at concentrations of 10-20 mM). Lactate removal and glucose production by perfused livers were examined before and after the introduction of a constant infusion of hydroxybutyrate, acetoacetate, or appropriate control into the portal venous limb. Lactate removal was significantly inhibited within 10 s of the appearance of increasing concentrations of ketone bodies in the effluent. Corresponding decreases in glucose production were observed. The dependence of inhibition on D-3-hydroxybutyrate concentration was documented in isolated perfused livers (maximum inhibition of lactate removal, 58% at 14 mM). This phenomenon could be a factor in the development of lactic acidosis accompanying ketoacidosis, and indicates that plasma membrane lactate transport may determine the rate of hepatic lactate removal.

3-Hydroxybutyric Acid↗
PubMed1986

Medium-chain triglycerides in infant formulas and their relation to plasma ketone body concentrations.

A mild ketosis is known to prevail in the mother, fetus, and newborn infant during the 3rd trimester and in the early neonatal period. It has been shown that during an equivalent period in the rat ketone bodies are readily oxidized and serve as key substrates for lipogenesis in brain. Since medium-chain triglycerides are known to be ketogenic, preterm infants may benefit from dietary medium-chain triglycerides beyond the point of enhanced fat absorption. Our objective was to determine the ketogenic response in preterm infants (gestational age: 33 +/- 0.8 wk) fed three different isocaloric formulas by measuring the concentrations of 3-hydroxybutyrate and acetoacetate in the plasma of these infants. At the time of entrance to the study the infants were receiving 110 kcal/kg/24 h. Study I (11 infants): the infants were fed sequentially in the order; PM 60/40 (PM), Special Care Formula (SCF), and Similac 20 (SIM). In SCF greater than 50% of the fat consists of medium-chain length fatty acids while PM and SIM contain about 25%. The concentration of 3-hydroxybutyrate in plasma was significantly higher when infants were fed SCF than PM and SIM [0.14 +/- 0.03, 0.06 +/- 0.01, and 0.05 +/- 0.01 mM, respectively (p less than 0.01)]. Study II (12 infants); the infants were fed SCF, then SIM, or the reverse. The concentration of acetoacetate in plasma was 0.05 +/- 0.01 and 0.03 +/- 0.01 mM when infants were fed SCF and SIM, respectively (0.1 greater than p greater than 0.05). The concentrations of 3-hydroxybutyrate in plasma were similar to those measured in study I for the respective formulas.(ABSTRACT TRUNCATED AT 250 WORDS)

3-Hydroxybutyric Acid↗
PubMed1995

Suppression of mitogenic response of bovine peripheral blood lymphocytes by ketone bodies.

Mitogenic response of peripheral blood lymphocytes from ketotic cows and effect of ketone bodies on lymphocyte blastogenesis were investigated. Glucose consumption index (GCI) values for phytohaemagglutinin (PHA), concanavalin A (Con A) and pokeweed mitogen (PWM) in the ketotic cows were significantly lower than those in the healthy dry cows. A significant negative correlation was observed between the GCI values and serum concentrations of total ketone and beta-hydroxybutyric acid. When lymphocytes from healthy dry cows were preincubated in the medium with acetoacetic acid or beta-hydroxybutyric acid, the GCI values for PHA and PWM were significantly lower than those in the lymphocytes without ketone bodies. These findings indicate that increased serum concentrations of acetoacetic acid and beta-hydroxybutyric acid in ketotic cows suppress lymphocyte blastogenesis.

3-Hydroxybutyric Acid↗
PubMed1994

Hemodynamic, respiratory, and metabolic effects of medium-chain triglyceride-enriched lipid emulsions following valvular heart surgery.

STUDY: A lipid emulsion containing 10 percent medium-chain triglycerides (MCT) and 10 percent long-chain triglycerides (LCT) was infused at a rate of 1 ml/kg/h (3.3 mg/kg/min) for 2 h, in 12 patients (2 males, 10 females; mean age, 54 +/- 3 (SEM) years; range, 34 to 67 years) 24 h after open-heart surgery (mitral valve replacement). METHODS: Hemodynamic factors (pulmonary and radial artery indwelling catheters), oxygen and carbon dioxide partial pressures, oxygen saturation, oxygen delivery and consumption, and intrapulmonary shunt fraction were obtained before, during, and after lipid infusion (for 2 h), at 30-s intervals, along with some metabolic indexes (triglycerides, free fatty acids, glucose, insulin, lactate, acetoacetate). RESULTS: No statistically significant changes in heart rate, cardiac index, systemic and pulmonary pressures and resistances, central venous and pulmonary capillary pressures, or arterial oxygen partial pressure were observed during infusion. Arterial carbon dioxide partial pressure values were constantly reduced throughout and after the end of lipid infusion, as compared with baseline values, while oxygen consumption was increased significantly without any change in oxygen delivery. No adverse effects on intrapulmonary shunt fraction were observed. Statistically significant increases of triglycerides, free fatty acids, acetoacetate and insulin (peak values at end of the lipid infusion) were found in comparison with baseline values. Plasma glucose increased significantly during lipid infusion and remained higher than baseline values until the end of the study. Lactate levels were unchanged except for a slight decrease at the end of the study, without any derangement of acid-base equilibrium. Neither arrhythmias nor adverse clinical reactions were observed as a consequence of lipid infusion. CONCLUSIONS: Fat emulsions containing both MCT and LCT, when given at 3.3 mg/kg/min for 120 min following valvular heart surgery, do not exert negative cardiopulmonary effects, and could represent a source of rapidly metabolized substrates.

Acetoacetates↗
PubMed1977

Evidence for a participation of the kallikrein-kinin system in the regulation of muscle metabolism during hypoxia.

The effect of hypoxia on muscle metabolism was studied in the human forearm by the registration of arterial-deep venous concentration differences of oxygen, glucose, lactate, pyruvate, acetoacetate, and muscular blood flow after short, transient arrest of the forearm circulation. These studies were performed during the intravenous infusion of physiological saline (n=4), of a kallikrein-trypsin inhibitor (n=4), and of kallikrein-trypsin inhibitor plus the intrabrachial-arterial infusion of bradykinin (n=4). Infusion of the kallikrein-trypsin inhibitor significantly reduced the well known hypoxia-induced acceleration of nuscular glucose uptake due to a reduction of blood flow and of muscular glucose extraction. These changes of muscular glucose metabolism were accompanied by more or less striking effects on the balances of oxygen, lactate and acetoacetate. Physiological doses of bradykinin into the brachial artery during the infusion of a kallikrein-trypsin inhibitor restored almost completely the metabolic response during hypoxia. From these data there is further evidence for a participation of the kallikrein-kinin system in the physiological regulation of muscular substrate metabolism.

Acetoacetates↗
PubMed1986

Carnitine metabolism in isolated rat kidney cortex tubules.

Renal carnitine metabolism was studied in isolated kidney cortex tubules from fed rats. The tubular distribution of free carnitine (C), acid-soluble short chain acylcarnitine (AcC), and total acid-soluble carnitine was measured. The content of the last-mentioned in rat cortical tubule suspensions was 2.85 +/- 0.15 nmol/mg protein, 46% representing AcC. In the absence of metabolic substrates the AcC/C ratio declined from 0.84 to 0.48 during incubation. The administration of 2mM acetoacetate or 2mM 3-hydroxybutyrate caused an increase in AcC by 45% and 51%, respectively. The rise in AcC was paralleled by a decrease in C, resulting in an increase of the tubular AcC/C ratio to 1.69 and 1.85, respectively. In the presence of 1 mM exogenous L-carnitine 35 +/- 6 nmol AcC/(mg protein X h) was formed. The addition of acetoacetate and 3-hydroxybutyrate led to a 3.5 to 3.8-fold rise in AcC formation. Other substrates which are likewise metabolized by proximal tubules were less effective. More than 90% of the formed AcC was recovered in the extracellular fluid. The results suggest that proximal renal tubule cells are the intrarenal site of carnitine acylation and may be involved in the regulation of blood and/or urinary carnitine acylation state.

3-Hydroxybutyric Acid↗
PubMed1976

Metabolism of forearm tissues in man. Studies with glucagon.

The role of glucagon in regulating peripheral tissue metabolism in man was assessed in the present studies. To do this, glucagon was infused for two hours into the brachial artery to produce a high but physiologic increment in the glucagon content of arterial blood supplying ipsilateral tissues. Metabolic effects on muscle and on subcutaneous adipose tissue plus skin were sought in seven overnight-fasting subjects and seven subjects starved briefly (60 hours). In the overnight-fasted group the infusion increased bassl glucagon concentration by 1,216 pg./ml. but was without effect on forearm tissue metabolism of glucose, lactate,glycerol, or amino acids. Starvation significantly reduced basal insulin (11.0 to 7.4 muU./ml.) and increased endogenous glucagon (116 to 134 pg./ml.). Basally, there was substantial ketone utilization and a decrease in glucose consumption by both muscle and subcutaneous adipose tissue plus skin. The glucagon infusion increased basal glucagon by 784 pg./ml. Muscle balances of glucose, lactate, acetoacetate, amino acids, and glycerol were unaffected. The metabolism of glucose, lactate, acetoacetate, glycerol, and free fatty acids by subcutaneous adipose tissue plus skin was also unchanged. It is concluded that physiologic increments of glucagon lasting two hours are without effect on forearm tissues in overnight-fasted and briefly starved man.

Acetoacetates↗