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PubMed1975

The effects of a polychlorinated biphenyl mixture (Aroclor 1254) on liver gluconeogenic enzymes of normal and alloxan-diabetic rats.

Normal and alloxan-diabetic rats were fed ground Purina Laboratory Chow with or without 500 ppm of Aroclor 1254 (AR) ad lib for 2 weeks. In both normal and diabetic rats, AR administration decreased food consumption, weight gain and blood glucose concentration, and increased liver weight, liver:body weight ratio, total liver lipid, liver protein and malic enzyme (ME) activity. In the normal rat, AR increased the concentrations of acetoacetate and beta-hydroxybutyrate in blood, but in the diabetic rat the concentrations were markedly reduced. AR administration decreased the activity of phosphoenolpyruvate carboxykinase (PEPck) in normal liver and the activities of pyruvate carboxylase (PC), PEPck and glucose-6-phosphatase (G6Pase) in diabetic liver.

Acetoacetates↗

PubMed1979

The effect of rumen epithelial development on metabolic activities and ketogenesis by the tissue in vitro.

1. An investigation was made on oxygen consumption, glucose and lactate uptake and ketogenesis from butyrate by rumen epithelium in vitro from lambs at various stages of development. 2. Oxygen uptake was decreased by about 35% and glucose uptake by about 90% between 2 weeks and 1/2 year of age. 3. The uptake of L-lactate and the utilization of butyrate as a substrate for respiration were increased during epithelial development. 4. The production of D(-)-3-hydroxybutyrate and acetoacetate from butyrate by the epithelium was largely increased between 4 to 10 weeks of age, independently of rumen fermentation. 5. A synergistic effect of glucose on the production of D(-)-3-hydroxybutyrate and on total ketone bodies from butyrate by the epithelium was observed. It accounted to 40-80% over butyrate depending on the stage of epithelial development.

3-Hydroxybutyric Acid↗

PubMed1979

A comparative study of ketone body metabolism between the camel (Camelus dromedarius) and the sheep (Ovis aries).

1. Plasma levels of beta-hydroxybutyrate (BHB), and acetoacetate (AcAc) have been measured in camels (Camelus dromedarius) and sheep (Ovis aries). The activity of beta-hydroxybutyrate dehydrogenase (BHB-deH2) (E.C. 1.1.1.30) was studied in the rumen epithelium and the liver of these animals. 2. Concentrations of plasma BHB and AcAc in the camel were in respective order 33 and 4 times lower than that of the sheep. The ratios of BHB to AcAc were 0.61 and 4.8 for the camel and sheep, respectively. 3. The activity of BHB-deH2 in the rumen epithelium of the camel and sheep were 7.15 and 66 mumol/hr/g wet wt tissue, respectively. The activity in both species was higher in the rumen epithelium than in the liver.

Acetoacetates↗

PubMed1983

Ketone bodies in cold-acclimated rats.

Acclimation temperature (28 or 5 degrees C) modifies acetoacetate (AA) and beta-hydroxybutyrate (BOH) levels in blood and liver. In the fed state AA and BOH levels were increased in blood and liver of 5 degrees C adapted rats. In the fasting state (24 or 48 hr) an antiketotic action of cold acclimation was observed. It was found to be more pronounced with high fat diet. These effects were more marked in the blood than in the liver. The variations in ketonemia are discussed with relation to the role of liver in cold adapted rats.

3-Hydroxybutyric Acid↗

PubMed1991

The effect of ketone bodies on nitrogen metabolism in skeletal muscle.

1. The ketone bodies, D-beta-hydroxybutyrate and acetoacetate, inhibit glycolysis thereby reducing pyruvate availability which leads to a marked inhibition of branched-chain amino acid metabolism and alanine synthesis in skeletal muscles from fasted mammalian and avian species. 2. The rate of glutamine release from skeletal muscles from fasted birds is increased at the expense of alanine in the presence of elevated concentrations of ketone bodies because of an increase in the availability of glutamate for glutamine synthesis. 3. Ketone bodies inhibit both protein synthesis and protein degradation in skeletal muscles from fasted mammalian and avian species in vitro. The mechanisms involved remain unknown. 4. Inhibition of amino acid metabolism and protein turnover in skeletal muscle by ketone bodies may be an important survival mechanism during adaptation to catabolic states such as prolonged fasting.

Acetoacetates↗

PubMed1985

Effects of chronic ethanol treatment on glucose tolerance, insulin response and circulating metabolites in the pregnant rat.

The effects of chronic ethanol treatment on intravenous glucose tolerance and insulin response in non-pregnant and pregnant rats were studied. Basal circulating glucose, insulin, and ketone bodies levels were also determined during the treatment. Basal blood glucose concentration did not change during the ethanol treatment whereas plasma insulin levels were lower at the beginning of gestation and at the 15 and 18 days of pregnancy in ethanol-treated rats. Blood beta-OH-butyrate levels were higher and acetoacetate concentrations unchanged during the ethanol treatment, resulting in augmented beta-OH-butyrate/acetoacetate ratio. Intravenous glucose tolerance was not modified in ethanol-treated rats whilst the associated insulin response was lower in both non-pregnant and pregnant ethanol-treated rats. Data show that ethanol treatment during pregnancy alters glucose-insulin relationships despite being associated with unchanged maternal glycemia.

3-Hydroxybutyric Acid↗

PubMed1976

Some histological and metabolic properties of an isolated perfused rat brain preparation with special reference to monoamine metabolism.

A method is described for perfusing the rat head which results in perfusion of the brain, its covering and the bony skull only. Dye and latex injection studies showed that there was no perfusion of extracranial tissue and thus it was not necessary to remove the lower jaw and facial tissues as described by previous authors. Perfusion with fluorescein demonstrated that the whole brain was perfused. Light microscopy after two hours of perfusion revealed no deterioration in brain-structure. Electron microscopy showed a small increase in the extracellular space and the perivascular space with good preservation of subcellular organelles. Glucose and acetoacetate removal were very similar to those reported for the adult rat in vivo as measured by arterio-venous differences. The concentrations of 5-hydroxytryptamine, dopamine and noradrenaline are maintained at values close to those in vivo during a 2-hr perfusion with a basal medium and the preparation will maintain linear rates of 5-hydroxytryptamine synthesis for 2 h when the medium contains L-tryptophan and tranylcypromine, at rates similar to those measured in vivo. The rate of uptake of L-tryptophan into the brain is similar to that reported after L-tryptophan loading in vivo. The histological and metabolic properties of the preparation are close to those observed in vivo. The method could provide a way in which monoamine metabolism in particular could be studied using an experimental model closer in its properties to the in vivo situation than tissue preparations such as slices or homogenates.

Acetoacetates↗

PubMed1995

Alcoholic ketoacidosis as a cause of death in forensic cases.

Forensic pathologists are familiar with alcohol abusers, who are found dead and in whom the cause of death cannot be ascertained. In order to examine the possible role of ketoacidosis for the cause of death in this group of alcohol abusers, the concentrations of ketone bodies (acetone, acetoacetate, D-beta-hydroxybutyrate) were determined in post mortem blood specimens. Determination of the ketone body concentrations were made by a coupled enzymatic head-space gas chromatographic method. The material consisted of blood specimens from 131 deceased persons and was divided into three groups: Group 1: controls, 79 cases of non alcohol abusers; group 2: 35 cases of alcohol abusers with known causes of death and group 3: 17 cases of alcohol abusers without ascertainable cause of death. The geometric means for the sum of the ketone body concentrations in blood were: controls, 109 mumol/l; alcohol abusers with known causes of death, 152 mumol/l; and alcohol abusers without known cause of death, 590 mumol/l. The limit value between the controls and the group of alcoholics with unascertainable cause of death was by logistic regression found to be 531 mumol/l (343-1224 mumol/l). The term 'ketoalcoholic death' is, therefore, suggested, when the measured post mortem blood ketone body concentration in an alcoholic with otherwise unknown cause of death exceeds 531 mumol/l.

3-Hydroxybutyric Acid↗

PubMed1993

Changes in the parameters of oxygen metabolism in a clinical course recovering from potassium cyanide.

Poisoning with potassium cyanide is usually fatal because of the inhibition of cytochrome oxidase. The parameters of oxygen metabolism in a patient with cyanide poisoning who was admitted in a coma with seizures was monitored. The administration of amyl nitrite and sodium thiosulfate led to a rapid improvement: the parameters reflecting oxygen metabolism improved and the plasma level of cyanide decreased. The patient revived 1 1/2 hours after treatment. The arterial ketone body ratio (AKBR), which is the ratio of acetoacetate to beta-hydroxybutyrate in arterial blood and which reflects the redox state in liver mitochondria, improved dramatically following treatment. Because the AKBR changes in relation to electron transport in liver mitochondria, it seems to be a logical parameter for evaluating the effect of potassium cyanide poisoning on electron transport. The AKBR also reflects the efficacy of treatment for cyanide poisoning.

3-Hydroxybutyric Acid↗

PubMed1991

Effects of methylmalonate and propionate on uptake of glucose and ketone bodies in vitro by brain of developing rats.

Methylmalonate (MMA) and propionate effects on glucose and ketone body uptake in vitro by brain of fed and 30-hour-fasted 15-day-old rats were studied. In some experiments cerebrum prisms were incubated in the presence of glucose and either MMA or propionate in Krebs-Ringer bicarbonate buffer, pH 7.0. In others, the incubation medium contained beta-hydroxybutyrate (HBA) or acetoacetate (AcAc) instead of glucose. We verified that MMA increased glucose uptake by brain of fasting animals, whereas propionate had no effect. In addition, MMA diminished HBA but not AcAc incorporation into brain prisms, whereas propionate provoked a diminished utilization of both ketone bodies by brain. The in vitro effect of MMA and propionate on brain and liver beta-hydroxybutyrate dehydrogenase activity was also investigated. It was shown that MMA but not propionate significantly inhibited this activity. Rats were also injected subcutaneously three times with a MMA buffered solution, and the in vivo effects of MMA on the above-mentioned parameters assessed. Results from these experiments confirmed the previously found in vitro MMA effects. Methylmalonic acidemic patients accumulate primarily methylmalonate and secondarily propionate and other metabolites in their tissues at levels comparable to those we used in our assays. Most patients who survive early stages of the disease show a variable degree of neuromotor delay. Since glucose and sometimes ketones are the vital substrates for brain metabolism, it is possible that our findings may contribute to a certain extent to an understanding of the biochemical basis of mental retardation in these patients.

3-Hydroxybutyric Acid↗

PubMed1993

Delayed oxidation of intramitochondrial pyridine nucleotide oxidoreduction state as compared with tissue oxygenation in human liver transplantation.

Intra- and post-operative oxygenation of graft liver and subsequent oxidation of the intramitochondrial oxido-reduction state of pyridine nucleotide were studied in partial liver transplantation from living related donors with the ratio of acetoacetate to beta-hydroxybutyrate in arterial blood (AKBR), the ratio of oxidized flavoprotein to reduced pyridine nucleotide (FP/PN ratio) and oxygen saturation of hemoglobin in liver tissue (hepatic SO2). Decreased hepatic SO2 and its heterogenous distribution after reflow of portal vein and hepatic artery were normalized by the end of operation, while the intramitochondrial oxido-reduction state was still reduced at the end of operation and was normalized only at 24 h after the operation. The observed delay in oxidation of the intramitochondrial oxido-reduction state as compared with tissue oxygenation indicates the transition of the intramitochondrial oxido-reduction state associated with the initiation of metabolic activity from the cold preserved state, and suggests an important role for microcirculation in the normalization of the oxido-reduction state.

3-Hydroxybutyric Acid↗

PubMed2006

A ketogenic diet and diallyl sulfide do not elevate afterdischarge thresholds in adult kindled rats.

INTRODUCTION: Acetone has been shown to have broad-spectrum anticonvulsant actions in animal seizure models and has been hypothesized to play a role in the anticonvulsant mechanism of the ketogenic diet (KD). The present study examined the ability of a KD to elevate amygdaloid afterdischarge thresholds (ADT) in fully kindled rats. The effects of the KD were studied in the presence and absence of diallyl sulfide (DAS), an inhibitor of acetone metabolism. METHODS: Twenty-four adult male rats were kindled to 30 stage 5 seizures. Afterdischarge thresholds (ADT) were determined. Subjects were then administered one of the following diets: (1) KD+V (vehicle; KD+V); (2) KD+DAS; (3) control diet+V (CD+V); (4) CD+DAS. They were stimulated every second day. Blood sampling was performed every second day--on non-stimulating days--to determine levels of glucose, beta-hydroxybutyrate, acetoacetate, and acetone. After 20 days, ADTs were re-determined. RESULTS: Blood acetone concentrations were significantly higher in the KD+DAS group as compared to the other groups, although they did not reach "therapeutic levels". None of the treatments, however, elevated ADTs. CONCLUSIONS: The KD was unable to elevate amygdaloid ADTs in fully kindled rats. Although subjects in the KD+DAS group achieved significant elevations of blood acetone, these concentrations (e.g. 0.2 mM) were much lower than those (>2.0 mM) previously shown to confer anticonvulsant activity. There appears to be large difference between humans and rats in their ability to produce elevated blood acetone levels on the KD. These data suggest that adult rats are not ideal subjects for modeling the anticonvulsant actions of the KD.

3-Hydroxybutyric Acid↗

PubMed2005

Canine spongiform leukoencephalomyelopathy is associated with a missense mutation in cytochrome b.

Two families of dogs (Australian cattle dogs and Shetland sheepdogs) with an inherited "spongiform leukoencephalomyelopathy" were identified, with widespread vacuolation of white matter of the brain and spinal cord. Affected dogs of both breeds developed tremors at 2-9 weeks of age followed by progressive neurological worsening with ataxia, paresis, paralysis, spasticity, and cranial nerve dysfunction. The modes of inheritance of both families were most likely maternal. The cerebrospinal fluid (CSF) analysis showed elevated ratio of 3-OH butyrate to acetoacetic acid. Mitochondrial DNA sequencing showed a G to A transition at 14,474 nt (G14474A, GenBank accession no. NC002008 ) that results in an amino acid change of valine-98 to methionine (V98M) of mitochondrial encoded cytochrome b. Western blot analysis showed increased levels of core I and core II but decreased level of cytochrome c1 of the complex III and cytochrome c oxidase of the complex IV of the respiratory chain.

3-Hydroxybutyric Acid↗

PubMed1984

Thermodynamics of reverse electron transfer across site 1: ATP/2e- is greater than one.

ATP-driven, rotenone-sensitive, reverse electron transfer from succinate to acetoacetate was measured in rat liver mitochondria in the presence of cyanide. In the approach to equilibrium, the absolute ratio of the free energy change of electron transfer to that of ATP hydrolysis exceeded 1, tending towards about 1 1/4. The data support an H+/2e- stoichiometry of 5 for Site 1 as predicted by a thirteen-proton model of chemiosmotic coupling.

Acetoacetates↗

PubMed2003

Expression of acetoacetyl-CoA synthetase, a novel cytosolic ketone body-utilizing enzyme, in human brain.

Acetoacetyl-CoA synthetase (AACS, acetoacetate-CoA ligase, EC 6.2.1.16) is a ketone body-utilizing enzyme, the physiological role of which remains unclear yet in mammals, particularly has never been studied in human. In order to investigate the tissue distribution of AACS in human, cDNA encoding AACS was isolated from HepG2 cells. Amino acid sequence of human AACS deduced from the open reading frame showed high homology (89.3%) with that of rat AACS and much less homology (43.7%) with that of bacterial AACS. The expression level of the AACS mRNA was high in kidney, heart and brain, but low in liver, and the expression profile of AACS in the human brain was quite similar to that of 3-hydroxy-3-methylglutaryl-CoA reductase.

Acetoacetates↗

PubMed2000

Heterocyclic derivatives of sugars: the formation of 1-glycosyl-3-methylpyrazol-5-ones from hydrazones.

Conditions to effect the conversion of monosaccharide and disaccharide hydrazones to 1-glycosyl-3-methylpyrazol-5-ones were examined. The sugar pyrazolone derivatives were sensitive to oxidation, but high yields were achieved with 2,2,2-trifluoroethyl acetoacetate in mildly acidic solution. Azo coupling of the pyrazolones produced highly coloured azopyrazolone derivatives that prevented further degradation, and these may prove useful labels for chromatographic analysis of carbohydrates.

Acetoacetates↗

PubMed1998

Ketosis resistance in the male offspring of protein-malnourished rat dams.

Plasma beta-hydroxybutyrate concentrations were measured in the offspring of rats that were fed either a control (20% protein) diet or low-protein (8% protein) diet during pregnancy and lactation. Low-protein offspring had significantly lower plasma beta-hydroxybutyrate compared with controls in the fed state (P < .04) and after fasting for 24 hours (P < .001) and 48 hours (P < .04). There were no differences in blood glucose, acetoacetate, plasma glucagon, cholesterol, or glycerol between control and low-protein offspring. However, plasma nonesterified fatty acids (NEFAs) were significantly higher in low-protein offspring in the fed state (P < .05). In contrast, plasma triglycerides and insulin were significantly lower in low-protein offspring compared with controls when fed (P < .001) and after a 24-hour fast (P < .001). These results suggest that poor maternal and early postnatal nutrition can have long-term effects on ketone body metabolism in the offspring during adulthood. This apparent ketosis resistance is similar to that observed in some forms of human diabetes.

3-Hydroxybutyric Acid↗

PubMed1998

Effects of low-dose recombinant human insulin-like growth factor-I on insulin sensitivity, growth hormone and glucagon levels in young adults with insulin-dependent diabetes mellitus.

Despite recent interest in the therapeutic potential of recombinant human insulin-like growth factor-I (rhIGF-I) in the treatment of diabetes mellitus, its mechanism of action is still not defined. We have studied the effects of low-dose bolus subcutaneous rhIGF-I (40 microg/kg and 20 microg/kg) on insulin sensitivity, growth hormone (GH) and glucagon levels in seven young adults with insulin-dependent diabetes mellitus (IDDM) using a randomized double-blind placebo-controlled crossover study design. Each was subjected to a euglycemic clamp (5 mmol/L) protocol consisting of a variable-rate insulin infusion clamp (6:00 PM to 8:00 AM) followed by a two-dose hyperinsulinemic clamp (insulin infusion of 0.75 mU x kg(-1) x min(-1) from 8 to 10 AM and 1.5 mU x kg(-1) x min(-1) from 10 AM to 12 noon) incorporating [6,6 2H2]glucose tracer for determination of glucose production/utilization rates. Following rhIGF-I administration, the serum IGF-I level (mean +/- SEM) increased (40 microg/kg, 655 +/- 90 ng/mL, P < .001; 20 microg/kg, 472 +/- 67 ng/mL, P < .001; placebo, 258 +/- 51 ng/mL). Dose-related reductions in insulin were observed during the period of steady-state euglycemia (1 AM to 8 AM) (40 microg/kg, 48 +/- 5 pmol/L, P = .01; 20 microg/kg, 58 +/- 8 pmol/L, P = .03; placebo, 72 +/- 8 pmol/L). The mean overnight GH level (40 microg/kg, 9.1 +/- 1.4 mU/L, P = .04; 20 microg/kg, 9.6 +/- 2.0 mU/L, P = .12; placebo, 11.3 +/- 1.7 mU/L) and GH pulse amplitude (40 microg/kg, 18.8 +/- 2.9 mU/L, P = .04; 20 microg/kg, 17.0 +/- 3.4 mU/L, P > .05; placebo, 23.0 +/- 3.7 mU/L) were also reduced. No differences in glucagon, IGF binding protein-1 (IGFBP-1), acetoacetate, or beta-hydroxybutyrate levels were found. During the hyperinsulinemic clamp conditions, no differences in glucose utilization were noted, whereas hepatic glucose production was reduced by rhIGF-I 40 microg/kg (P = .05). Our data demonstrate that in subjects with IDDM, low-dose subcutaneous rhIGF-I leads to a dose-dependent reduction in the insulin level for euglycemia overnight that parallels the decrease in overnight GH levels, but glucagon and IGFBP-1 levels remain unchanged. The decreases in hepatic glucose production during the hyperinsulinemic clamp study observed the following day are likely related to GH suppression, although a direct effect by rhIGF-I cannot be entirely discounted.

3-Hydroxybutyric Acid↗