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PubMed1998

Metabolic alteration in neural tissue of rat embryos exposed to beta-hydroxybutyrate during organogenesis.

Hyperketonemia has been identified as an important factor in diabetic pregnancy affecting growth and development of the offspring. In order to assess the immediate metabolic alterations in embryos caused by excess ketone bodies, we studied rat embryonic neural tissue exposed to a high concentration of beta-hydroxybutyrate in vitro. Beta-hydroxybutyrate inhibited oxygen uptake of the neural tissue of day 9 and day 10 embryos by 12.8% and 1 1.2%, but did not affect that of day 11 and day 12 tissue. In contrast, glucose utilization of the neural tissue of day 9 and day 10 embryos was not altered. However, a 30% decrease in glucose utilization was observed in the neural tissue of day 11 and day 12 embryos exposed to beta-hydroxybutyrate. Thus, beta-hydroxybutyrate induced different metabolic alterations in the embryonic neural tissue during early and late organogenesis, which suggests different modes of teratogenic action of ketone bodies in different parts of gestation.

3-Hydroxybutyric Acid↗
PubMed1983

Effect of 3-hydroxybutyrate in obese subjects on very-low-energy diets and during therapeutic starvation.

Sodium DL-3-hydroxybutyrate was administered to obese subjects (more than 150% ideal body-weight) who were either receiving a 2 . 5 MJ (600 kcal) diet containing 34 g protein on one day with a total fast (water and vitamins only) on the next day, for 21 days, or were undergoing therapeutic starvation for 14 days. Both intravenous and oral hydroxybutyrate significantly reduced net body protein loss as measured by total urinary nitrogen and 3-methylhistidine excretion. Hydroxybutyrate administration did not significantly affect the rate of weight-loss but seemed to increase the fat/lean ratio of the tissue loss. The subjects experienced no untoward effects and none complained of hunger while receiving 3-hydroxybutyrate.

3-Hydroxybutyric Acid↗
PubMed2003

An automatic flow procedure for the determination of 3-hydroxybutyrate in animal serum and plasma.

An automatic flow procedure based on the multicommutation concept, comprising three-way solenoid valves, for the spectrophotometric determination of 3-hydroxybutyrate in animal serum and plasma is proposed. The 3-hydroxybutyrate was enzymatically converted to acetoacetate with the reduction of NAD+ to NADH monitored at 340 nm. It was possible to carry out up to 600 determinations without a significant decrease in the analytical signal, with 5 mg of 3-hydroxybutyrate dehydrogenase immobilized on porous silica beads and packed in a column. The system enabled 60 determinations/h of 3-hydroxybutyrate in the range of 10-150 mg L(-1), with a consumption of 0.9 mg of NAD+ and 200 microL of sample per determination. A detection limit of 2 mg L(-1) for both animal serum and plasma and coefficients of variation of 1.4% and 1.2% (n = 17), respectively, were determined. Animal serum and plasma samples were analyzed without previous treatment, the results of which agreed with those obtained using the conventional method (UV kit, Sigma).

3-Hydroxybutyric Acid↗
PubMed1986

Lactate utilization by the neonatal rat brain in vitro. Competition with glucose and 3-hydroxybutyrate.

The maximum rates of lactate oxidation and lipogenesis from lactate by early-neonatal brain slices were considerably greater than those for utilization of glucose and 3-hydroxybutyrate at physiological concentrations. Lactate inhibited glucose utilization, but enhanced 3-hydroxybutyrate utilization. 3-Hydroxybutyrate inhibited lactate and glucose utilization. Glucose slightly inhibited oxidation of lactate and 3-hydroxybutyrate, but scarcely enhanced lipogenesis from these substrates.

3-Hydroxybutyric Acid↗
PubMed1982

Effect of fasting on the disappearance of injected alanine and 3-hydroxybutyrate in obese subjects.

1. The blood concentrations of 3-hydroxybutyrate and alanine were measured before and after they were separately injected into obese patients who were taking a 1.68 MJ (400 kcal) diet and again when they had starved for 4 days and 28 days. 2. The disappearance of the injected metabolite was exponential and its half-life and volume of distribution were calculated. 3. The disappearance of ketones (both 3-hydroxybutyrate and acetoacetate) was raised in the patients when they were taking the low-calorie diet and increased a further sevenfold during starvation. This further increase was associated with an increase in the half-life of injected 3-hydroxybutyrate. 4. The pre-injection concentration of alanine almost halved during starvation and the half-life of injected alanine increased. 5. If the changes in half-life of exogenous 3-hydroxybutyrate and alanine apply to endogenous metabolites, then these results suggest that the increase in blood ketone concentration during starvation is at least partly due to a decreased clearance of ketones and the decrease in blood alanine concentrations is associated with a marked decrease in production rate of alanine.

3-Hydroxybutyric Acid↗
PubMed1996

3-Hydroxybutyrate decreases noradrenaline affinity for rat erythrocyte ghost beta 2-adrenergic receptors.

The effects of physiological levels of 3-hydroxybutyrate on noradrenaline binding to rat erythrocyte membranes were studied. The binding of noradrenaline to membranes was determined by measuring the union of 3H-noradrenaline in the presence of varying concentrations of 3-hydroxybutyrate. Scatchard plots of the results were used to determine that 3-hydroxybutyrate provoked a loss of affinity of the beta 2-adrenergic receptors for adrenaline. Thus high (but physiological) 3-hydroxybutyrate levels can lower the binding of the catecholamine, thus diminishing the extent or intensity of adrenergic-driven responses.

3-Hydroxybutyric Acid↗
PubMed1986

Effect of DL-3-hydroxybutyrate infusions on leucine and glucose kinetics in burned rats receiving TPN.

Whole-body leucine and plasma glucose kinetics were simultaneously measured in burned rats after 2 d of total parenteral nutrition (TPN) containing sodium DL-3-hydroxybutyrate or sodium acetate to evaluate the ketone bodies as energy substrates during stress. TPN solutions consisted of dextrose and amino acids [200 kcal/(kg . d); 13 g amino acids/(kg . d)] and contained 34.3 mEq/(kg . d) either as sodium DL-3-hydroxybutyrate (n = 8) or sodium acetate (n = 7). Whole-body leucine appearance, incorporation into protein, release from protein breakdown and oxidation rates, as measured after a constant infusion of L-[1-14C]leucine did not significantly differ between the groups. In contrast, D-[6-3H]glucose appearance rates after constant infusion of this tracer were significantly higher in rats given sodium DL-3-hydroxybutyrate [209.3 +/- 3.8 mumol/(kg body weight . min)] than in those given sodium acetate [162.4 +/- 9.7 mumol/(kg body weight . min)] (P less than 0.01). Since leucine kinetics did not differ, the results suggest that sodium DL-3-hydroxybutyrate infusions increase endogenous glucose production [61.0 +/- 4.6 mumol/(100 kg body weight . min)] by enhancing glucose recycling. However, there was no unique protein-sparing effect of ketone bodies identified during injury.

3-Hydroxybutyric Acid↗
PubMed1994

Metabolic effects of a D-beta-hydroxybutyrate infusion in septic patients: inhibition of lipolysis and glucose production but not leucine oxidation.

OBJECTIVE: To study the effect of a D-beta-hydroxybutyrate infusion on protein metabolism, lipolysis, and endogenous glucose production in septic patients. DESIGN: Prospective, randomized trial. SETTING: Intensive care unit (ICU) and metabolic unit at a university hospital. PATIENTS: Twelve ICU patients with sepsis and six healthy normal subjects. INTERVENTIONS: Septic patients were administered 4-hr infusions of either D-beta-hydroxybutyrate or a control solution, 12 hrs after parenteral nutrition was replaced with an isotonic saline infusion. MEASUREMENTS AND MAIN RESULTS: The appearance and oxidation rates of leucine (L[1-13C]leucine) and endogenous glucose production (D[6,6-2H2]glucose), plasma fatty acids, and glycerol values were measured before and at the end of infusion of D-beta-hydroxybutyrate or control solution. Unlike the control test, the D-beta-hydroxybutyrate infusion decreased glucose production, fatty acids, and glycerol concentrations, but failed to decrease the leucine oxidation rate. CONCLUSION: Exogenous ketone-bodies infusion decreased lipolysis and glucose production in septic patients but had no beneficial effect on protein metabolism, as evaluated with L[1-13C]leucine.

3-Hydroxybutyric Acid↗
PubMed1982

Effects of injected lipid emulsion on oxygen consumption, RQ, triglyceride, free-fatty-acid and beta-hydroxybutyrate levels in small-for-gestational-age (SGA) infants.

UNLABELLED: Ten SGA infants were studied from 4 hours after birth (day l) and again at 28 hours (day 2) before and for 4 hours after single injections of 0.5 g of Intralipid fat/kg b.w. (IL-group). Eight other SGA infants were given 9-10 ml/kg of breast milk (BM-group). After lipid injection the elimination of triglycerides (TG) from plasma was markedly delayed. On day 2 lipolysis had improved but was still slower than in previously studied AGA infants. The initial FFA plasma level was higher on day 1 than on day 2. Oxidation of released fatty acids was confirmed by a significant increase of VO2 and a decrease of RQ on day 1 and 2. In all infants the beta-hydroxybutyrate level in plasma increased and was still elevated 4 hours after injection of fat. A negative correlation was found between beta-hydroxybutyrate levels and RQ. In the BM-group changes in TG and beta-hydroxybutyrate levels were small and insignificant. FFA had decreased 60 min after breast milk on day 1. IN CONCLUSION: TG elimination from plasma was impaired on day 1 and had slightly improved on day 2. The fatty acids released by lipolysis were oxidized as seen by increasing VO2, falling RQ and increasing beta-hydroxybutyrate plasma levels both on day 1 and day 2.

3-Hydroxybutyric Acid↗
PubMed1997

3-hydroxybutyrate blocks the transient K+ outward current in myocardial mouse cells in a stereoselective fashion.

1. Mouse ventricular myocytes develop a large transient K+ outward current (I(TO)) which accelerates repolarization and is a crucial determinant for the regulation of the action potential duration at various heart rates. The effect of 3-hydroxybutyrate on I(TO) was investigated under voltage- and current-clamp conditions. 2. The drug blocked I(TO) in a stereoselective manner with the L-enantiomer being the effective and the D-enantiomer, the ineffective form. The blocking action of the L-enantiomer was established immediately and it could be completely washed out within several tens of seconds. 3. The dose-response characteristic for the peak I(TO) showed a strict 1:1 binding of the drug to the receptor with a concentration of half-maximum effect of 2.1 mmol l(-1). 4. The action of L-hydroxybutyrate was voltage independent, did not need channel opening and preferentially affected the slow component of both inactivation and recovery from inactivation. 5. At the high concentration of 20 mmol l(-1) the optically inactive form, the racemate, did not affect I(TO), indicating that the ineffective D-enantiomer interacts with the channels at much lower concentrations. 6. At a concentration of 10 mmol l(-1), L-hydroxybutyrate prolonged the action potential by 218 +/- 26 and 127 +/- 10% (means +/- S.E.M.) at 50 and 90% repolarization, respectively. 7. It is concluded that the non-physiological L-hydroxybutyrate is a novel type of blocker of I(TO), It interacts either with the channel itself, or with a receptor protein closely related to the channel and preferentially affects slow inactivation.

3-Hydroxybutyric Acid↗
PubMed2002

Identification of an acetoacetyl coenzyme A synthetase-dependent pathway for utilization of L-(+)-3-hydroxybutyrate in Sinorhizobium meliloti.

D-(-)-3-Hydroxybutyrate (DHB), the immediate depolymerization product of the intracellular carbon store poly-3-hydroxybutyrate (PHB), is oxidized by the enzyme 3-hydroxybutyrate dehydrogenase to acetoacetate (AA) in the PHB degradation pathway. Externally supplied DHB can serve as a sole source of carbon and energy to support the growth of Sinorhizobium meliloti. In contrast, wild-type S. meliloti is not able to utilize the L-(+) isomer of 3-hydroxybutyrate (LHB) as a sole source of carbon and energy. In this study, we show that overexpression of the S. meliloti acsA2 gene, encoding acetoacetyl coenzyme A (acetoacetyl-CoA) synthetase, confers LHB utilization ability, and this is accompanied by novel LHB-CoA synthetase activity. Kinetics studies with the purified AcsA2 protein confirmed its ability to utilize both AA and LHB as substrates and showed that the affinity of the enzyme for LHB was clearly lower than that for AA. These results thus provide direct evidence for the LHB-CoA synthetase activity of the AcsA2 protein and demonstrate that the LHB utilization pathway in S. meliloti is AcsA2 dependent.

3-Hydroxybutyric Acid↗
PubMed1964

DEPOLYMERIZATION OF POLY-BETA-HYDROXYBUTYRATE BY INTRACELLULAR ENZYME SYSTEM.

Merrick, J. M. (State University of New York, Buffalo), and M. Doudoroff. Depolymerization of poly-beta-hydroxybutyrate by an intracellular enzyme system. J. Bacteriol. 88:60-71. 1964.-The poly-beta-hydroxybutyric acid contained in the "lipid granules" of Bacillus megaterium is hydrolyzed to d(-)-beta-hydroxybutyric acid by a complex enzyme system present in the soluble enzyme fraction of polymer-depleted cells of Rhodospirillum rubrum. This system consists of a thermostable "activator," a thermolabile "depolymerase," and an "esterase." Under certain conditions, the activator can be replaced by trypsin. Various chemical and physical treatments inactivate the "native lipid granules," and make them unsuitable as a substrate for the digestive enzymes. This inactivation of the granules is often expressed in the extent rather than the rate of their digestion, and is not correlated with the destruction of the polymer-synthesizing enzymes associated with the granules. The principal product of depolymerase action is d(-)-beta-hydroxybutyric acid, but small amounts of esterified products are also released. These are hydrolyzed by the esterase.

Bacillus megaterium↗
PubMed1990

Effects of D-glucose and beta-hydroxybutyric acid on the in vitro development of (pre)chondrocytes from embryos of normal and diabetic rats.

In order to elucidate cellular mechanisms causing skeletal malformations in offspring of diabetic rats we studied the incorporation of thymidine and sulphate into embryonic (pre)chondrocytes exposed to increased levels of D-glucose and beta-hydroxybutyric acid for six days in vitro. The (pre)chondrocytes were prepared from embryos of normal or diabetic rats of a malformation-prone strain or from embryos of normal rats of a non-malformation-prone strain. Diabetic female rats of the former strain are known to produce a high proportion of offspring with mandibular and lumbosacral malformations. Increased beta-hydroxybutyric acid caused decreased thymidine incorporation in all types of chondrocytes, and decreased sulphate incorporation in limb bud cells from embryos of normal rats from both strains. Elevated D-glucose levels yielded a slight decrease in thymidine incorporation in mandibular arch cells from embryos of normal rats of the malformation-prone strain, and a marked decrease of both sulphate and thymidine incorporation in mandibular arch cells from embryos of diabetic rats of this strain. The observations suggest that elevated levels of D-glucose or beta-hydroxybutyric acid are able to inhibit the differentiation and growth of (pre)-chondrocytes and illustrate a selective sensitivity of mandibular arch (pre)chondrocytes to a diabetic environment. The data are compatible with the view that both D-glucose and beta-hydroxybutyric acid may cause aberrations in the development of rat mandibular arch chondrocytes, suggesting a role for these compounds in diabetic teratogenesis.

3-Hydroxybutyric Acid↗
PubMed1981

Effect of pH and 3-hydroxybutyrate on insulin binding and action in cultured human fibroblasts.

The influence of pH and 3-hydroxybutyrate on insulin binding and action has been studied in cultured human fibroblasts. When the pH of the incubation medium was decreased from 7.6 to 6.8, insulin stimulation of glycogen synthase and total glucose uptake was decreased. The decreased pH induced both an increase in the insulin concentration for half-maximal response, and a decrease in maximal responsiveness. When insulin binding was measured at lower pH, receptor affinity was decreased. The effect of 3-hydroxybutyrate on insulin binding and action was assessed at pH 7.4 and 6.9. In the presence of 3-hydroxybutyrate, insulin binding increased, but insulin action on glycogen synthase and total glucose uptake was unaffected. The data show that insulin action is impaired at lower pH. The decreased sensitivity is probably related to the decrease in insulin binding affinity at lower pH, but decreased maximal responsiveness implies that postreceptor components are also affected by lower pH. The results also suggest that 3-hydroxybutyrate induced a dissociation between binding and response, since an increase of insulin binding was not accompanied by changes in the regulation of glycogen synthase and total glucose uptake.

3-Hydroxybutyric Acid↗
PubMed1983

Failure of infused beta-hydroxybutyrate to decrease proteolysis in man.

Ketone bodies have been suggested to have a protein-sparing effect, since infusion of Na-beta-hydroxybutyrate in man decreases plasma alanine concentrations and urinary nitrogen (N) excretion. To test this hypothesis, six normal postabsorptive volunteers were infused with Na-beta-hydroxybutyrate for 3 h. Rates of glucose, leucine carbon, and alanine appearance and disappearance from the plasma space were traced with [3-3H]glucose, L-[6,6,6-2H3]leucine, and [2,3,3,3-2H4]alanine. Rates of leucine N appearance and disappearance and the rate of transfer of leucine N to alanine were assessed with [15N]leucine. During ketone body infusion, plasma alanine decreased (P less than 0.05), whereas plasma leucine increased (P less than 0.05). Rates of alanine appearance increased (5.3 +/- 0.3 to 7.8 +/- 0.6 mumol/kg X min), but the increase in its rate of disappearance was slightly greater, accounting for the decrease in plasma alanine concentration. Leucine N flux and the rate and percent of leucine N transferred to alanine increased, whereas leucine carbon flux was unchanged. To determine the effect of the alkalemia induced by Na-beta-hydroxybutyrate, four additional subjects were infused with NaHCO3. Alkalemia had no effect on leucine N or carbon flux or on the rate of appearance of alanine, but increased the rate of alanine disappearance, resulting in a decrease in the plasma alanine concentration. Since the rate of appearance of leucine carbon was unaltered during the infusion of Na-beta-hydroxybutyrate, it is unlikely that hyperketonemia per se decreases proteolysis in postabsorptive man.

3-Hydroxybutyric Acid↗
PubMed1993

Evidence for a role for insulin and growth hormone in overnight regulation of 3-hydroxybutyrate in normal and diabetic adolescents.

OBJECTIVE: To determine the relative effects of growth hormone and insulin on ketogenesis during puberty. RESEARCH DESIGN AND METHODS: We studied overnight changes in plasma ketones--3-hydroxybutyrate and acetoacetate--in 35 normal and 26 IDDM adolescents at different stages of puberty. The diabetic adolescents either were on their normal insulin regimen or were studied during an overnight euglycemic clamp with or without suppression of endogenous growth hormone release. RESULTS: Total ketone body and 3-hydroxybutyrate concentrations in the normal adolescents rose significantly from 2000 (29 +/- 5 microM), reaching a peak at 0200 (103 +/- 16 microM, P < 0.001 vs. 2000). After a brief fall, a further rise occurred before breakfast. Fasting 3-hydroxybutyrate concentrations showed a negative correlation with fasting insulin levels (r = -0.46, P = 0.005) and decreased with advancing puberty, while insulin concentrations increased. In the diabetic patients on their usual insulin regimen, free insulin levels waned overnight, and an exaggerated rise in ketones was observed before breakfast. During the euglycemic clamp studies, ketone levels were higher than normal throughout the night. Mean overnight growth hormone and free insulin levels also were higher than in the normal control subjects. The addition of the anticholinergic drug pirenzepine reduced growth hormone secretion and obliterated the early-night peak of 3-hydroxybutyrate. CONCLUSIONS: We conclude that the early-night peak of ketone concentrations is related to growth hormone release, whereas the fasting levels are largely determined by insulin concentration. Inadequate insulin delivery in the presence of the high growth hormone concentrations characteristic of diabetic adolescents could lead to rapid decompensation and ketoacidosis.

3-Hydroxybutyric Acid↗
PubMed1997

Treatment of diabetic ketoacidosis using normalization of blood 3-hydroxybutyrate concentration as the endpoint of emergency management. A randomized controlled study.

OBJECTIVE: To compare the efficacy of an extended insulin regimen using correction of hyperketonemia as endpoint with a more conventional regimen in the treatment of diabetic ketoacidosis. RESEARCH DESIGN AND METHODS: A total of 22 patients admitted to a Belfast teaching hospital with clinical and biochemical features of diabetic ketoacidosis (pH < 7.25 and/or bicarbonate < 16 mmol/l) were randomized to either conventional or extended insulin regimens. In the conventional regimen, insulin was administered at 5 U/h until near-normoglycemia (blood glucose < or = 10 mmol/l) and then administered at a reduced rate until clinical recovery. In the extended regimen, administration of insulin at 5 U/h was continued beyond attainment of normoglycemia, until resolution of hyperketonemia (3-hydroxybutyrate < 0.5 mmol/l). Main outcome measures were 3-hydroxybutyrate and bicarbonate levels during the 24 h after attainment of near-normoglycemia. RESULTS: After near-normoglycemia, correction of hyperketonemia was achieved earlier with the extended treatment (5.9 +/- 0.8 vs. 21.8 +/- 3.4 h, P = 0.0004 [mean +/- SD]). The area under the curve of 3-hydroxybutyrate against time for 24 h after near-normoglycemia was reduced with the extended treatment (24.9 +/- 3.8 vs. 55.9 +/- 6.7 mmol.l-1.h-1, P = 0.001). These differences remained statistically significant after adjustment for higher baseline levels of 3-hydroxybutyrate at near-normoglycemia in the extended treatment group. Bicarbonate levels at 6 and 12 h after near-normoglycemia were not significantly different between groups. CONCLUSIONS: The extended insulin regimen, which was easy to implement at ward level, produced a more rapid resolution of ketosis than the conventional regimen.

3-Hydroxybutyric Acid↗
PubMed1990

In vivo lipid and amino acid synthesis from 3-hydroxybutyrate in 15-day-old chick.

The in vivo utilization of 3-hydroxybutyrate for lipid and amino acid synthesis in liver, kidney and duodenal mucosa of overnight-starved 15-day-old chicks has been investigated. Lipid synthesis was higher in liver and duodenal mucosa than in kidney. Triglycerides were the main lipids synthesized from 3-hydroxybutyrate in liver and kidney, while in duodenal mucosa a higher amount of phospholipids was observed. This tissue utilized a high percentage of 3-hydroxybutyrate for the synthesis of free cholesterol, in agreement with the major role of intestine in body cholesterogenesis. All of the assayed tissues synthesized amino acids from 3-hydroxybutyrate at a similar rate, glutamate being always the main amino acid formed.

3-Hydroxybutyric Acid↗