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PubMed1980

The stimulus-secretion coupling of amino acid-induced insulin release: metabolism and cationic effects of leucine.

When isolated rat pancreatic islets are exposed to L-leucine (20 mM), the rate of NH4 production is close to the summed rates of L-[1-14C] leucine decarboxylation and alpha-ketoisocarproate production, whereas the rates of acetoacetate production and L-[U-14C]-leucine oxidation are compatible with conversion of each mole of the amino acid to one mole of acetoacetate and three moles of CO2. ATP content, ATP/ADP ratio, and adenylate charge are maintained at normal values by L-leucine, whereas the NADH/NAD+ ratio (but not the NADPH/NADP+ ratio) is significantly increased. The release of insulin evoked by L-leucine is potentiated by 2-ketoisovalerate, unaffected by L-valine, and inhibited by menadione. L-leucine mimicks the effect of D-glucose on 86Rb+ and 45Ca2+ handling by the islets. However, relative to its rate of oxidation, the insulinotropic effect of L-leucine is less marked than that of D-glucose. This may be due, in part at least, to a decrease in the oxidation of endogenous nutrients. It is concluded that the metabolic, cationic, and secretory effects of L-leucine in isolated islets are not incompatible with the fuel hypothesis for insulin release.

Acetoacetates↗
PubMedDate not supplied

Comparison of efficacy of human and porcine insulin in treatment of diabetic ketoacidosis.

The efficacy of semisynthetic human insulin (HI) and monocomponent porcine insulin (PI) in treatment of diabetic ketoacidosis (DKA) was compared in 10 (PI) and 11 (HI) patients in a double-blind randomized study. Insulin (8 U/h i.v.), fluid replacement (0.65% NaCl and 5% glucose), and KCl supplements were administered according to a fixed protocol. Glucose, potassium, sodium, creatinine, calcium, phosphate, and free-insulin concentrations were never significantly different during the study. At the start, mean +/- SD of pH was 7.10 +/- 0.14 in the HI group and 7.10 +/- 0.12 in the PI group. The time to reach arbitrary values for pH, bicarbonate, base excess, and beta-hydroxybutyrate was shorter during HI treatment, but the differences were not statistically significant. During HI treatment, the arbitrary value of 1.0 mM of acetoacetate was reached faster than during PI treatment (5.2 +/- 2.6 and 8.4 +/- 0.9 h, respectively; P less than .05). The concentration of acetoacetate was significantly different between the two groups after 6 and 7 h of insulin treatment (6 h: HI 0.82 +/- 0.50 mM and PI 2.19 +/- 1.65 mM, P less than .05; 7 h: HI 0.51 +/- 0.40 mM and PI 1.74 +/- 1.54 mM, P = .05). We conclude that recovery from DKA during treatment with HI might be slightly faster than during treatment with PI. If this difference is real, it does not seem clinically important.

3-Hydroxybutyric Acid↗
PubMed1989

Metabolic response to short term starvation in non-pregnant and late pregnant cafeteria-obese rats.

We have determined the blood metabolite responses to a 24-h starvation period of cafeteria obese rats, in both non-pregnant and late pregnant states. In the fed condition the concentrations of glucose, lactate, pyruvate, glycerol and urea do not differ when compared in control and obese rats, but acetoacetate and 3-hydroxybutyrate levels are higher in the obese group. The overall response of the cafeteria-obese rats to starving seems characterized by decreased rates of glucose and amino-acids utilization, substituted by a more intense utilization of lipid fuels, with excess ketone bodies production and increased utilization of the mobilized glycerol. What we observed in the obese pregnant response to starvation can be summarized as the additional or superimposed effects of excess fat reserves. In the obese pregnant starved rats a less severe hypoglycaemia, lower levels of glycerol (as a consequence of increased utilization), reduced urea levels, and increased acetoacetate and 3-hydroxybutyrate levels were observed. It can be assumed that the pregnant obese rat response to starvation is related to the size of the fat deposits: the more obese, the more hyperketonaemia and less hypoglycaemia, and even diminished rates of amino-acid utilization, as indicated by a lower levels, when compared to the lean pregnant.

3-Hydroxybutyric Acid↗
PubMed2004

Evaluation and use of three cowside tests for detection of subclinical ketosis in early postpartum cows.

The objective was to evaluate the performance of 3 cowside diagnostic tests for detection of subclinical ketosis, defined as a serum beta-hydroxybutyrate (BHBA) concentration >or=1400 micromol/L. On 16 d over a 5-mo period, samples of serum, milk, and urine were collected on a large dairy facility from cows of all parities between 2 and 15 DIM. The sample proportion of subclinical ketosis was 7.6% (n = 859 samples from 545 cows). The KetoCheck powder (Great States Animal Health, St. Joseph, MO) detecting acetoacetate in milk samples was very specific (99%) but poorly sensitive (41%). Respective sensitivities and specificities of the Ketostix strip detecting acetoacetate in urine samples (Bayer Corporation, Elkhart, IN) were 78 and 96% with a cut-off point of "small", or 49 and 99% with a cut-off of "moderate." The KetoTest strip (Sanwa Kagaku Kenkyusho Co. Ltd., Nagoya, Japan) using milk samples had a sensitivity and specificity of 73 and 96% with a cut-off of 100 micromol of BHBA/L or 27 and 99% with a cut-off of 200 micromol of BHBA/L. On average, use of the Ketostix at the "small" cut-off point or the KetoTest at 100 micromol/L would result in no more than 3 or 4 false positives per 100 cows screened, with prevalence levels ranging from 5 to 30%, whereas the number of false negatives would range from one false negative at 5% prevalence to 7 or 8 false negatives at 30% prevalence. Either the Ketostix or KetoTest strips would provide acceptable results for screening individual cows on commercial dairies to detect subclinical ketosis. Over this prevalence range, the KetoCheck powder test would have limited application as a screening test. Despite only one false positive per 100 animals screened, false negatives resulting from screening with the KetoCheck test would be too frequent, ranging from 3 false negatives at 5% prevalence to 18 at 30% prevalence in a population of 100 tested cows. Finally, given their relative imprecision, use of any of these individual cowside tests to estimate herd prevalence must be done cautiously, especially when only a small number of animals are sampled.

3-Hydroxybutyric Acid↗
PubMed1986

Characterization of metabolic changes during a protocol for inducing lactation ketosis in dairy cows.

During the 5 wk immediately after parturition, five high producing cows that were overfed prepartum completed a protocol for inducement of ketosis. By 12 d postpartum, hepatic glycogen decreased by 75% and hepatic triglyceride, beta-hydroxybutyrate, and acetoacetate increased by 6, 4, and 2.5 times. The protocol, initiated at 2 wk postpartum, consisted of a 15 to 20% decrease from ad libitum feed intake plus dietary supplementation with 1,3-butanediol, a ketogenic substrate. Severity of the ketotic state increased gradually, and four cows developed clinical signs of ketosis at an average of 36 d postpartum. Glycogen was 90% depleted, and triglycerides, beta-hydroxybutyrate, and acetoacetate concentrations in liver were increased to 10, 10, and 15 times above average prepartum concentrations. In plasma, beta-hydroxybutyrate increased and glucose decreased. Plasma insulin exhibited an initial postpartal decrease (40%) but then was stable at that concentration through 36 d. After treatment for ketosis, glucose and insulin concentrations of plasma were greater than prepartal concentrations. Results indicate that a relatively simple protocol of prolonged energy deficit combined with an influx of ketone body precursors can induce experimental lactation ketosis in overfed cows. The protocol should be a valuable tool for ketosis research.

Acetoacetates↗
PubMed1991

Changes in blood glucose, nonesterified fatty acids, and ketones in response to weaning and feed intake in young calves.

Effects of weaning age on blood glucose, ketones, and nonesterified fatty acids were examined using 16 Holstein heifer calves. Animals entered the study at 6 +/- 3.5 d of age and were fed 1.8 kg of milk twice daily to 28 (early weaning) or 56 d (late weaning) and a commercial pelleted calf starter from 0 (early) or 28 d (late). Blood was sampled once weekly for 14 wk and analyzed for beta-hydroxybutyrate and acetoacetate. Plasma was analyzed for glucose and nonesterified fatty acids. Blood beta-hydroxybutyrate increased with increasing grain intake and was greater during wk 0 to 4 and 5 to 8 in calves weaned early than in those weaned late. Blood acetoacetate followed trends similar to beta-hydroxybutyrate and averaged 23.8 and 16.1 microM in calves weaned early and late, respectively. Plasma glucose and nonesterified fatty acids declined with age and were lower during 5 to 8 wk in calves weaned early. Data suggest that ketone concentrations resulted from alimentary ketogenesis, which increased rapidly after weaning.

3-Hydroxybutyric Acid↗
PubMed1997

Effect of volatile fatty acid infusion on development of the rumen epithelium in neonatal sheep.

The purpose of this study was to determine whether the continuous intraruminal infusion of calculated physiological concentrations of volatile fatty acids (VFA) stimulated the metabolic development of the neonatal rumen. Eight 1-wk-old lambs were assigned to one of three treatments: saline infusion (three lambs), VFA infusion (three lambs), or no infusion (two lambs). Rumen catheters were surgically implanted into lambs in the infusion groups. The amount of VFA infused, beginning at 2 wk of age, increased weekly in equal increments of 12.5% of the estimated net energy requirement until, at 6 wk of age, lambs received 50% of their estimated net energy requirement from the infused VFA. All lambs consumed milk replacer for ad libitum intake and had free access to water. The lambs that were infused with VFA tended to have longer rumen papillae. There were no differences in width or number of papillae per square centimeter across treatments. Rumen epithelial cells isolated from lambs that were infused with VFA tended to oxidize less glucose and produce more acetoacetate than did cells from lambs that were infused with saline or from uninfused lambs. beta-Hydroxybutyrate production by isolated rumen epithelial cells and concentrations of blood glucose, acetoacetate, and beta-hydroxybutyrate were not different among the three treatments. Thus, infusion of physiological concentrations of VFA appears to stimulate some aspects of rumen metabolic development.

Acetoacetates↗
PubMed1991

The effect of glucose administration on carbohydrate metabolism after head injury.

The role of intravenous infusion of glucose in limiting ketogenesis and the effect of glucose on cerebral metabolism following severe head injury were studied in 21 comatose patients. The patients were randomly assigned to alimentation with or without glucose. Systemic protein wasting, arterial concentrations of energy substrates, and cerebral metabolism of these energy substrates were monitored for 5 days postinjury. Both groups were in negative nitrogen balance, and had wasting of systemic proteins despite substantial protein intake. Blood and cerebrospinal fluid (CSF) glucose concentrations were highest on Day 1, but remained higher than normal fasting levels on all days of study, even in the patients who received no exogenous glucose. Although there were no differences in blood or CSF glucose concentrations in the two groups of patients, the glucose group had higher plasma insulin levels, with a mean +/- standard deviation of 14.8 +/- 7.3 microU/ml compared to 10.3 +/- 4.2 microU/ml in the saline group. The blood concentrations of beta-hydroxybutyrate, acetoacetate, pyruvate, glycerol, and the free fatty acids were higher in the saline group than in the glucose group. Cerebral oxygen consumption was similar in the two groups, while the cerebral metabolism of glucose and of the ketone bodies was dependent on whether glucose was administered. In the glucose group, glucose was the only energy substrate utilized by the brain. In the saline group, the ketone bodies beta-hydroxybutyrate and acetoacetate replaced glucose to the extent of 16% of the brain's total energy production. Cerebral lactate production and CSF lactate concentration were lower in the saline group. These studies suggest that administration of glucose during the early recovery period of severe head injury is a major cause of suppressed ketogenesis, and may increase production of lactic acid by the traumatized brain by limiting the availability of nonglycolytic energy substrates.

3-Hydroxybutyric Acid↗
PubMed1999

The metabolic effects of estriol in female rat liver.

The effects of estriol on oxygen uptake, glucose release, lactate and pyruvate production, beta-hydroxybutyrate and acetoacetate production in perfused rat liver as well as, carbon uptake in rat liver and intracellular calcium in isolated Kupffer cells were investigated. Basal oxygen consumption of perfused liver increased significantly in estriol or ethanol-treated rats. But these increased effects were blocked by gadolinium chloride pretreatment. In a metabolic study, pretreatment with estriol resulted in a decrease in glucose production and in glycolysis while an increase in ketogenesis. A more oxidized redox state of the mitochondria was indicated by increased ratios of perfusate [lactate]/[pyruvate] and decreased ratios of perfusate [beta-hydroxybutyrate]/[acetoacetate]. Carbon uptake of Kupffer-cell increased significantly in estriol-treated rats. But these increased uptake were not shown in rats pre-treated by gadolinium chloride blocking phagocytosis. In isolated Kupffer cells from estriol-treated rats, intracellular calcium was more significantly increased after addition of lipopolysaccharide (LPS) than in controls. These findings suggest that the metabolic effects of estriol (two mg per 100 mg body wt) can be summarized to be highly toxic in rat liver, and these findings suggest that oral administration of estrogens may induce hepatic dysfunctions and play a role in the development of liver disease.

3-Hydroxybutyric Acid↗
PubMed1976

Effects of 1,3-butanediol and 1,2-propanediol on growth, blood metabolites, and liver glycogen broiler chickens.

Control diets, and diets containing 4% 1,3-butanediol (BD), 8% BD, 4% 1,2-propanediol (PD) and 8% PD were offered ad libitum to broilers from 1 to 28 days of age. Body weight gain and feed intake were recorded, and plasma metabolites and liver glycogen were measured. When compared to the control diet, the synthetic compounds depressed (p less than 0.01) growth at the 4% level, but the effect was more pronounced (p less than 0.01) at the 8% level. The test compounds had no effect (p less than 0.05) on the efficiency of feed utilization. Four percent BD elevated (p less than 0.01) plasma beta-hydroxybutyrate and acetoacetate concentrations, and the ratio of beta-hydroxybutyrate to acetoacetate. The influence was more pronounced at the 8% level; PD did not affect (p greater than or equal to 0.05) ketone body concentrations. Neither BD, nor PD caused changes (p greater than or equal to) in plasma glucose, free fatty acids, cholesterol, or liver glycogen. Results are discussed with reference to feeding these compounds to monogastric and ruminant animals.

Acetoacetates↗
PubMed1976

Effects of glucagon and insulin on lipolysis and ketogenesis in sheep.

The hepatic and portal productions of acetoacetate and beta-hydroxybutyrate and lipolysis were studied in normal and insulin-controlled alloxan-diabetic sheep. Since hyperinsulinemia is associated with glucagon administration, the latter group of sheep were used to maintain constant plasma insulin levels. After control values were obtained glucagon was infused intraportally at 90 mug/hr for two hours. The ketone body production by portal drained viscera was not significantly affected by glucagon. In alloxanized sheep, glucagon significantly (P less than 0.01) increased net hepatic production of acetoacetate (from -0.54 +/- 0.08 to 0.46 +/- 0.07 g/hr). Lipolysis also increased. However, in the normal sheep, hyperinsulinemia prevented any stimulatory effect of glucagon on hepatic ketogenesis and lipolysis. Therefore, while glucagon appears capable of stimulating ketogenesis andlipolysis, these effects are readily suppressed by insulin.

Acetoacetates↗
PubMedDate not supplied

[Ontogenic properties of ketone body metabolism in pig tissues].

When incubating the liver slices of pig fetuses in the Krebs-Ringer phosphate buffer without substrates and with addition of butyrate and acetate a considerably lesser amount of ketone bodies is formed than with incubation of the liver slices of adult pigs. Therefore, a higher level of the ketone bodies in blood and tissues of the fetuses as compared to adult pigs is not due to ketogenesis in their liver, but is a result of their entering from the mother or formation in the placenta. When incubated in the above-mentioned medium the fetus skeletal muscle slices utilize exogenous acetoacetate in a significantly more quantity than the muscle slices of the adult animals. The liver and skeletal muscle slices of the fetuses reduce endogenous and exogenous acetoacetate into beta-hydroxybutyrate more intensively as compared to slices of the same tissues of the adult animals.

Acetates↗
PubMed1975

Influence of 1,3-butanediol on blood glucose concentration and pancreatic insulin content of streptozotocin-diabetic rats.

Male rats were made diabetic by intravenous administration of 75 mg/kg of streptozotocin and were fed, via a pair-feeding regimen, high-fat diets +/- 1,3-butanediol (BD) at 13.5 and 27% of the dietary calories for 30 days and 31 days, respectively. 1,3-Butanediol was added to the diets primarily as a replacement for fat. Food consumption and rat weight were recorded daily. Whole blood glucose concentrations were determined weekly. At sacrifice, liver, pancreas and epididymal fat pads were excised and blood samples were collected. Liver was analyzed for protein and lipid; pancreas was weighed and analyzed for insulin; fat pads were weighed and discarded; and blood was analyzed for glucose and lipid. The 13.5% BD diet increased the beta-hydroxybutyrate, acetoacetate and cholesterol concentrations, decreased the glucose concentration in blood, and increased the insulin content of the pancreas. The BD diets did not affect the concentrations of phospholipid, triglyceride, cholesterol and fatty acid in the liver; fatty acid concentrations in the blood; or the epididymal fat pad weight. The results suggest that BD produced a slight amelioration of the diabetic condition, which may have resulted from an increased capacity of the pancreas to synthesize insulin. In addition, the data provide further evidence suggesting that in the rat BD is oxidized to the ketone bodies, beta-hydroxybutyrate and acetoacetate.

Acetoacetates↗
PubMed1991

Regulatory sequences controlling short chain fatty acid metabolism in Escherichia coli.

Acetoacetate in Escherichia coli is metabolized via the combined enzymatic action of a CoA-transferase and a thiolase. Growth of E. coli on short chain fatty acids such as butyrate and valerate is also predicated upon the expression of these enzymes. The genes for these enzymes (atoDAB) are arranged in an operon and are coordinately transcribed in response to the inducer acetoacetate. A positive regulatory element, the product of the atoC gene, regulates expression of the operon. The atoC gene lies adjacent to the atoDAB operon and all the ato genes have been cloned as a single 6.2 kbp restriction fragment (kindly provided by Dr. Lauren Sallus Jenkins). We have isolated a series of mutant E. coli strains with altered regulatory properties that are either inducible by an alternate substrate, or that show constitutive expression of the atoDAB genes. The -10 and -35 regions upstream of the atoDAB operon poorly match consensus sequences. In addition, the transcriptional start is preceded by a catabolite activator protein binding site (CAP site), as well as a putative binding site for the atoC gene product as represented by a region of dyad symmetry.

Acetoacetates↗
PubMed1990

Glycolytic changes after local hyperthermia in mouse liver and adenocarcinoma.

Glycolytic changes in an adenocarcinoma and in liver of C57B1 mice were determined for up to twelve hours after local hyperthermia at 43 degrees C for 30 min. The metabolites studied included glucose, glucose-6-phosphate, pyruvate, lactate, acetoacetate and beta-hydroxybutyrate. Both the glucose and glucose-6-phosphate levels decreased significantly in liver and tumour and remained low for up to twelve hours. The lactate levels increased slightly immediately after heating but were decreased at later times. However, the hepatic pyruvate levels decreased for up to two hours after heating but increased later reaching control levels. In both liver and tumour the levels of beta-hydroxybutyrate were significantly enhanced immediately after hyperthermia, whereas those of acetoacetate were lowered.

3-Hydroxybutyric Acid↗
PubMed1978

Effects of total fasting in obese women. II. Acid-base balance.

Acetoacetate, beta-hydroxybutyrate, pyruvate and lactate in whole blood, the acid-base balance according to Astrup, SGOT and SGPT, and the serum and urinary sodium and potassium were estimated in 10 fasting obese women. Fasting led metabolic acidosis due to a tenfold increase of acetoacetate and beta-hydroxybutyrate, while pyruvate and lactate had a tendency to decrease. Serum and urinary sodium and potassium decreased; A tendency to increased SGOT and SGPT was observed. Sodium bicarbonate administered in general since the 8th or 9th day of fasting led in 4 to 5 days to an earlier correction of blood pH, while pCO2, actual HCO3, standard HCO3, base excess, buffer base, pO2, Hb saturation and total CO2 reached the prefasting values only several days after blood pH normalisation. The administration of NaHCO3 corrected the serum level of sodium while its excretion remained low. Bicarbonate had no influence on the decreasing trend of serum potassium, but the urinary output of potassium was stabilized. It is suggested that in fasting subjects 1. the correction of the metabolic acidosis by NaHCO3 does not reduce the rate of lipid catabolism and does not lead to fluid retention and 2. liver damage in fasting may be prevented by blood pH normalisation.

Acetoacetates↗
PubMed1989

Diurnal and individual variations in bile acids in the plasma of normal dairy cows.

Blood samples were collected every 2 h during a 24 h period from 6 cows of one herd and 10 cows of another herd. In a third herd 9 cows were sampled every 2 h from 6 a.m. to 8 p.m. Concentrations of total bile acids, acetoacetate, glucose and free fatty acids were determined in blood plasma. A marked difference in individual bile acid concentrations and patterns of diurnal variation was found. For most cows the highest bile acid values were observed between 2 and 6 a.m. (overall mean (+/- SD) at 6 a.m.: 104 +/- 84 mumol/l, range: 20-307 mumol/l). Fourteen cows with a bile acid value greater than 90 mumol/l at 6 a.m. ("high BA") were characterized as a group by showing a pronounced decrease in the mean bile acid concentration after morning feeding. In the group of 11 cows with a 6 a.m. bile acid value less than 90 mumol/l ("low BA") the time of day did not contribute significantly to the bile acid variation. For the "high BA" group a nearly synchronous variation between the mean values of the 3 feeding dependent parameters (acetoacetate, glucose and free fatty acids) and the mean values of bile acids was found. The within animal coefficients of correlation between bile acids and the feeding dependent parameters were significantly higher in the "high BA" group than in the "low BA" group. No direct connection was found between bile acid levels and the quantity of concentrates fed or the individual milk yield.

Acetoacetates↗
PubMed1987

In vivo nutrient uptake by head and neck cancers.

The arteriovenous uptake differences for glucose, lactate, pyruvate, beta-hydroxybutyrate, and acetoacetate were measured in vessels across squamous cell carcinomas in ten selected patients with tumors of the head and neck. All tumors measured took up glucose, pyruvate, beta-hydroxybutyrate, and acetoacetate. They could either produce, take up, or maintain a constant level of lactate. These tumors demonstrate a heterogeneous affinity for various metabolites, including ketone bodies which are elevated in the nutritionally depleted, tumor-burdened patient.

3-Hydroxybutyric Acid↗