scholarly journals Turnover rates of ketone bodies in normal, starved and alloxan-diabetic rats

1968 ◽  
Vol 110 (4) ◽  
pp. 655-661 ◽  
Author(s):  
Margaret W. Bates ◽  
H. A. Krebs ◽  
D. H. Williamson
Keyword(s):  
Ketone Body ◽  
Alloxan Diabetes ◽  
Ketone Bodies ◽  
Diabetic Rats ◽  
Turnover Rates ◽  
Blood Concentrations ◽  
Order Of Magnitude ◽  
The Mean ◽  
Body Production ◽  
Body Concentration

1. Rates of appearance and disappearance of total ketone bodies were determined in normal, starved and alloxan-diabetic rats by measuring specific radioactivities and concentrations of blood acetoacetate and 3-hydroxybutyrate at different times after injection of 3-hydroxy[14C]butyrate. 2. The mean rates of appearance were 1·7, 4·2 and 10·9μmoles/min./100g. body wt. respectively for normal, starved and alloxan-diabetic rats. The rates of disappearance were of the same order of magnitude as the rates of appearance. 3. There was a direct correlation between the rates of appearance and disappearance and the blood concentrations of the ketone bodies. 4. The results indicate that in the rat increased ketone-body production is paralleled by increased ketone-body utilization and that the raised ketone-body concentration in the blood in starvation and alloxan-diabetes is due to a slight imbalance between the rates of production and utilization. 5. The findings are discussed in relation to the concept that ketone bodies can serve as fuels of respiration when the supply of carbohydrate is limited.

scholarly journals Metabolic interactions of dichloroacetate and insulin in experimental diabetic ketoacidosis. Studies on whole animals and after functional hepatectomy

1975 ◽  
Vol 146 (2) ◽  
pp. 447-456 ◽  
Author(s):  
P J Backshear ◽  
P A H Holloway ◽  
K G M M Alberti
Keyword(s):  
Blood Glucose ◽  
Diabetic Ketoacidosis ◽  
Blood Lactate ◽  
Ketone Body ◽  
Ketone Bodies ◽  
Blood Concentrations ◽  
Metabolic Interactions ◽  
Lactate And Pyruvate ◽  
Body Production ◽  
Body Concentration

1. The infusion of sodium dichloroacetate into rats with severe diabetic ketoacidosis over 4h caused a 2mM decrease in blood glucose, and small falls in blood lactate and pyruvate concentrations. Similar findings had been reported in normal rats (Blackshear et al., 1974). In contrast there was a marked decrease in blood ketone-body concentration in the diabetic ketoacidotic rats after dichloroacetate treatment. 2. The infusion of insulin alone rapidly decreased blood glucose and ketone bodies, but caused an increase in blood lactate and pyruvate. 3. Dichloroacetate did not affect the response to insulin of blood glucose and ketone bodies, but abolished the increase of lactate and pyruvate seen after insulin infusion. 4. Neither insulin nor dichloroacetate stimulated glucose disappearance after functional hepatectomy, but both agents decreased the accumulation in blood of lactate, pyruvate and alanine. 5. Dichloroacetate inhibited 3-hydroxybutyrate uptake by the extra-splachnic tissues; insulin reversed this effect. Ketone-body production must have decreased, as hepatic ketone-body content was unchanged by dicholoracetate yet blood concentrations decreased. 6. It was concluded that: (a) dichloroacetate had qualitatively similar effects on glucose metabolism in severely ketotic rats to those observed in non-diabetic starved animals; (b) insulin and dichloroacetate both separately and together, decreased the net release of lactate, pyruvate and alanine from the extra-splachnic tissues, possibly through a similar mechanism; (c) insulin reversed the inhibition of 3-hydroxybutyrate uptake caused by dichloroacetate; (d) dichloroacetate inhibited ketone-body production in severe ketoacidosis.

Validation of a tracer technique to determine nonsteady-state ketone body turnover rates in man

1981 ◽  
Vol 240 (3) ◽  
pp. E253-E262 ◽  
Author(s):  
U. Keller ◽  
G. E. Sonnenberg ◽  
W. Stauffacher
Keyword(s):  
Ketone Body ◽  
Specific Activity ◽  
Ketone Bodies ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
Turnover Rates ◽  
Production Rates ◽  
Nonsteady State ◽  
Body Production ◽  
Beta Hydroxybutyrate

The features of a single-compartment model of total ketone bodies were evaluated using primed constant infusions of [3-14C]acetoacetate (AcAc) and of D-[3-14C]beta-hydroxybutyrate (beta OHB) in 12 postabsorptive subjects. The volume of distribution (VD) of AcAc was 0.18 +/- 0.01 liter/kg (n = 9), and that of beta OHB was similar, 0.18 +/- 0.02 liter/kg (n = 3). The production rate of total ketone bodies was calculated using the combined specific activity of AcAc and of beta OHB. The mean basal total ketone body production rates were similar using either [14C]AcAc (6.5 mumol . kg-1 . min-1) or [14C]beta OHB (6.8 mumol . kg-1 . min-1). To determine the pool fraction that was rapidly mixed during nonsteady state of ketone body inflow, unlabeled AcAc was infused with stepwise increasing and decreasing rates between 5 and 25 mumol . kg-1 . m-1 to mimic nonsteady-state ketone body production rates. The "functional" pool fraction P was determined as the pool fraction that provided the best match between tracer-determined rates of ketone production and rates of AcAc infusion. P of total ketone bodies was almost equal to 1 using either [14C]AcAc (1.05 +/- 0.16) or [14C]beta OHB (1.00 +/- 0.06), suggesting rapid mixing of ketone bodies throughout the entire pool. The described pool model may be used to determine total ketone body kinetics during acute perturbations of the steady state.

scholarly journals Gluconeogenesis in the cow. The effects of a glucocorticoid on hepatic intermediary metabolism

1970 ◽  
Vol 116 (5) ◽  
pp. 865-874 ◽  
Author(s):  
G. D. Baird ◽  
R. J. Heitzman
Keyword(s):  
Blood Glucose ◽  
Ketone Body ◽  
Ketone Bodies ◽  
Tyrosine Aminotransferase ◽  
Aspartate Transaminase ◽  
Blood Concentrations ◽  
Lactating Cows ◽  
Glycolytic Intermediates ◽  
Blood Glucose Concentrations ◽  
Parallel Measurements

1. The hepatic concentrations of the ketone bodies and of metabolites and activities of enzymes involved in gluconeogenesis were measured in healthy lactating and non-lactating cows 48h after administration of Voren, an ester of dexamethasone, and compared with those found in control animals given saline. Parallel measurements were also made of the blood concentrations of several of the metabolites. 2. Blood glucose concentrations were raised in the Voren-treated animals, whereas blood ketone body and free fatty acid concentrations were unaltered. Similarly there was no change in the hepatic concentrations of the ketone bodies. 3. Significant increases were found in the hepatic concentrations of citrate, 2-oxo-glutarate and malate in both groups of animals given Voren. 4. The hepatic concentrations of those glycolytic intermediates that were measured either decreased or did not change after Voren treatment. 5. The enzymes aspartate transaminase and fructose 1,6-diphosphatase were unchanged in activity after Voren administration, whereas phosphopyruvate carboxylase (EC 4.1.1.32) activity was depressed in the lactating group. However, glucose 6-phosphatase, tryptophan oxygenase and tyrosine aminotransferase increased in activity. 6. In several cases those hepatic metabolites that increased in concentration after Voren administration were present in lower concentration in normal lactating cows than in normal non-lactating cows. The same applied mutatis mutandis to those metabolites that were decreased by Voren. 7. These findings are discussed in relation to the use of glucocorticoids in the treatment of bovine ketosis.

scholarly journals Evidence for hypothalamic ketone body sensing: impact on food intake and peripheral metabolic responses in mice

2016 ◽  
Vol 310 (2) ◽  
pp. E103-E115 ◽  
Author(s):  
Lionel Carneiro ◽  
Sarah Geller ◽  
Xavier Fioramonti ◽  
Audrey Hébert ◽  
Cendrine Repond ◽  
...  
Keyword(s):  
Food Intake ◽  
Ketone Body ◽  
Energy Homeostasis ◽  
Ketone Bodies ◽  
Glucose Production ◽  
Body Level ◽  
Homeostasis Regulation ◽  
The Impact ◽  
Body Concentration

Monocarboxylates have been implicated in the control of energy homeostasis. Among them, the putative role of ketone bodies produced notably during high-fat diet (HFD) has not been thoroughly explored. In this study, we aimed to determine the impact of a specific rise in cerebral ketone bodies on food intake and energy homeostasis regulation. A carotid infusion of ketone bodies was performed on mice to stimulate sensitive brain areas for 6 or 12 h. At each time point, food intake and different markers of energy homeostasis were analyzed to reveal the consequences of cerebral increase in ketone body level detection. First, an increase in food intake appeared over a 12-h period of brain ketone body perfusion. This stimulated food intake was associated with an increased expression of the hypothalamic neuropeptides NPY and AgRP as well as phosphorylated AMPK and is due to ketone bodies sensed by the brain, as blood ketone body levels did not change at that time. In parallel, gluconeogenesis and insulin sensitivity were transiently altered. Indeed, a dysregulation of glucose production and insulin secretion was observed after 6 h of ketone body perfusion, which reversed to normal at 12 h of perfusion. Altogether, these results suggest that an increase in brain ketone body concentration leads to hyperphagia and a transient perturbation of peripheral metabolic homeostasis.

Model of the kinetics of ketone bodies in humans

1982 ◽  
Vol 243 (1) ◽  
pp. R7-R17 ◽  
Author(s):  
C. Cobelli ◽  
R. Nosadini ◽  
G. Toffolo ◽  
A. McCulloch ◽  
A. Avogaro ◽  
...  
Keyword(s):  
Ketone Body ◽  
Specific Activity ◽  
Ketone Bodies ◽  
Mathematical Representation ◽  
Parameter Estimates ◽  
Extrahepatic Tissues ◽  
Body Compartments ◽  
Body Production ◽  
Kinetics Of

The kinetics of ketone bodies was studied in normal humans by giving a combined bolus intravenous injection of labeled acetoacetate ([14C]AcAc) and D(--)-beta-hydroxybutyrate (beta-[14C]-OHB) to seven subjects after an overnight fast, on two different occasions, and by collecting frequent blood samples for 100 min. Kinetic data were analyzed with both noncompartmental and compartmental modeling techniques. A four-compartment model, representing AcAc and beta-OHB in blood and two equilibrating ketone body compartments, inside the liver and extrahepatic tissues, was chosen as the most reliable mathematical representation; it is physiologically plausible and was able to accurately fit the data. The model permitted evaluation of the in vivo rate of ketone body production in the liver, the individual plasma clearance rates of AcAc and beta-OHB, their initial volumes of distribution, and the transfer rate parameters among the four ketone body compartments. Moreover, the model provided estimates of the components of the rates of appearance of AcAc and beta-OHB in plasma due to newly synthesized ketone body from acetyl-CoA in the liver, and to interconversion and recycling in the liver and extrahepatic tissues. The model also was used to evaluate other methodologies currently employed in the analysis of ketone body turnover data: the conventional approach based on use of the combined specific activity of AcAc and beta-OHB required assumptions not satisfied in vivo, leading to substantial errors in key parameter estimates.

Acetoacetate turnover and oxidation rates in ovine pregnancy ketosis

1964 ◽  
Vol 206 (2) ◽  
pp. 449-452 ◽  
Author(s):  
E. N. Bergman ◽  
K. Kon
Keyword(s):  
Turnover Rate ◽  
Ketone Bodies ◽  
Plasma Concentrations ◽  
Turnover Rates ◽  
Acetoacetic Acid ◽  
Oxidation Rates ◽  
Tracer Dose ◽  
Pregnant Sheep ◽  
The Mean ◽  
Normal Twin

Labeled acetoacetic acid (AcAc) was administered as a tracer dose and as a continuous infusion to 24 twin-pregnant ewes with varying degrees of spontaneous or fasting hypoglycemic ketosis. The mean AcAc turnover rate of five normal twin-pregnant sheep (plasma AcAc < 1 mg/100 ml) was only 0.04 g/hr kg3/4 or 1.0 g/sheep hr. During ketosis the turnover rate of AcAc was directly proportional to the plasma AcAc concentration until a maximal concentration of about 10 mg/100 ml was attained (total ketone bodies, expressed as acetone, would be about 20 mg/100 ml). At higher plasma concentrations, the AcAc turnover rates remained constant at nearly 0.4 g/hr kg3/4 (9 g/sheep hr). About one-half of this AcAc was oxidized to CO2 regardless of the actual amount utilized. The mean percentage of the total exhaled CO2 derived from AcAc metabolism increased from 2% in normal ewes to a maximum of about 20% during pregnancy ketosis. Comparisons of these data to values obtained in previous experiments on artificially ketotic nonpregnant sheep indicate that an overproduction of ketone bodies, rather than an underutilization, is the major cause of ruminant ketosis.

Stimulatory effect of norepinephrine on ketogenesis in normal and insulin-deficient humans

1984 ◽  
Vol 247 (6) ◽  
pp. E732-E739 ◽  
Author(s):  
U. Keller ◽  
P. P. Gerber ◽  
W. Stauffacher
Keyword(s):  
Ketone Body ◽  
Ketone Bodies ◽  
Plasma Free Fatty Acid ◽  
Normal Subjects ◽  
Plasma Norepinephrine ◽  
Metabolic Clearance ◽  
Insulin Deficiency ◽  
Norepinephrine Infusion ◽  
Normal Humans ◽  
Body Production

Elevation of plasma norepinephrine concentrations to stress levels (1,800 pg/ml) resulted in normal subjects in a significant increase in ketone body production by 155% (determined by use of [14C]acetoacetate infusions), in a decrease of the metabolic clearance rate by 38%, hyperketonemia, and in increased plasma free fatty acid (FFA) levels by 57% after 75 min. Norepinephrine infusion during somatostatin-induced insulin deficiency resulted in an augmented and sustained increase in ketone body concentrations due to increased production and decreased peripheral clearance of ketone bodies. Norepinephrine's stimulatory effect on lipolysis waned with time, and its effect on ketogenesis in normal subjects was greater than its influence on plasma FFA levels, and thus presumably on hepatic FFA uptake, suggesting a direct stimulatory effect on hepatic ketogenesis. The data demonstrate that in normal humans the hyperketonemic effect of elevated plasma norepinephrine concentrations results from a combination of three factors: increased ketone body production from augmented FFA supply to the liver; accelerated hepatic ketogenesis; and modestly decreased metabolic clearance of ketone bodies. Acute insulin deficiency augments all these effects and results in progressive ketosis.

scholarly journals Ketone-body metabolism in tumour-bearing rats

1986 ◽  
Vol 233 (2) ◽  
pp. 485-491 ◽  
Author(s):  
A M Rofe ◽  
R Bais ◽  
R A Conyers
Keyword(s):  
Blood Glucose ◽  
Ketone Body ◽  
Ketone Bodies ◽  
Hepatic Glycogen ◽  
Turnover Rates ◽  
Total Blood ◽  
Normal Tissues ◽  
Tumour Bearing ◽  
And Control

During starvation for 72 h, tumour-bearing rats showed accelerated ketonaemia and marked ketonuria. Total blood [ketone bodies] were 8.53 mM and 3.34 mM in tumour-bearing and control (non-tumour-bearing) rats respectively (P less than 0.001). The [3-hydroxybutyrate]/[acetoacetate] ratio was 1.3 in the tumour-bearing rats, compared with 3.2 in the controls at 72 h (P less than 0.001). Blood [glucose] and hepatic [glycogen] were lower at the start of starvation in tumour-bearing rats, whereas plasma [non-esterified fatty acids] were not increased above those in the control rats during starvation. After functional hepatectomy, blood [acetoacetate], but not [3-hydroxybutyrate], decreased rapidly in tumour-bearing rats, whereas both ketone bodies decreased, and at a slower rate, in the control rats. Blood [glucose] decreased more rapidly in the hepatectomized control rats. Hepatocytes prepared from 72 h-starved tumour-bearing and control rats showed similar rates of ketogenesis from palmitate, and the distribution of [1-14C] palmitate between oxidation (ketone bodies and CO2) and esterification was also unaffected by tumour-bearing, as was the rate of gluconeogenesis from lactate. The carcinoma itself showed rapid rates of glycolysis and a poor ability to metabolize ketone bodies in vitro. The results are consistent with the peripheral, normal, tissues in tumour-bearing rats having increased ketone-body and decreased glucose metabolic turnover rates.

Proteomics analysis reveals diabetic kidney as a ketogenic organ in type 2 diabetes

2011 ◽  
Vol 300 (2) ◽  
pp. E287-E295 ◽  
Author(s):  
Dongjuan Zhang ◽  
Hang Yang ◽  
Xiaomu Kong ◽  
Kang Wang ◽  
Xuan Mao ◽  
...  
Keyword(s):  
Ketone Body ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Ketone Bodies ◽  
Proximal Tubule Cell ◽  
Diabetic Kidney ◽  
Mesenchymal Transition ◽  
Proteomic Approach ◽  
Body Production

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease. To date, the molecular mechanisms of DN remain largely unclear. The present study aimed to identify and characterize novel proteins involved in the development of DN by a proteomic approach. Proteomic analysis revealed that 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase 2 (HMGCS2), the key enzyme in ketogenesis, was increased fourfold in the kidneys of type 2 diabetic db/db mice. Consistently, the activity of HMGCS2 in kidneys and 24-h urinary excretion of the ketone body β-hydroxybutyrate (β-HB) were significantly increased in db/db mice. Immunohistochemistry, immunofluorescence, and real-time PCR studies further demonstrated that HMGCS2 was highly expressed in renal glomeruli of db/db mice, with weak expression in the kidneys of control mice. Because filtered ketone bodies are mainly reabsorbed in the proximal tubules, we used RPTC cells, a rat proximal tubule cell line, to examine the effect of the increased level of ketone bodies. Treating cultured RPTC cells with 1 mM β-HB significantly induced transforming growth factor-β1 expression, with a marked increase in collagen I expression. β-HB treatment also resulted in a marked increase in vimentin protein expression and a significant reduction in E-cadherin protein levels, suggesting an enhanced epithelial-to-mesenchymal transition in RPTCs. Collectively, these findings demonstrate that diabetic kidneys exhibit excess ketogenic activity resulting from increased HMGCS2 expression. Enhanced ketone body production in the diabetic kidney may represent a novel mechanism involved in the pathogenesis of DN.

scholarly journals Fatty acid metabolism in the perfused rat liver

1970 ◽  
Vol 119 (3) ◽  
pp. 525-533 ◽  
Author(s):  
H. A. Krebs ◽  
R. Hems
Keyword(s):  
Fatty Acids ◽  
Rat Liver ◽  
Ketone Body ◽  
Unsaturated Fatty Acids ◽  
Ketone Bodies ◽  
Saturated Fatty Acids ◽  
Perfused Rat Liver ◽  
Body Formation ◽  
Body Production ◽  
Chain Fatty Acids

1. The formation of acetoacetate, β-hydroxybutyrate and glucose was measured in the isolated perfused rat liver after addition of fatty acids. 2. The rates of ketone-body formation from ten fatty acids were approximately equal and independent of chain length (90–132μmol/h per g), with the exception of pentanoate, which reacted at one-third of this rate. The [β-hydroxybutyrate]/[acetoacetate] ratio in the perfusion medium was increased by long-chain fatty acids. 3. Glucose was formed from all odd-numbered fatty acids tested. 4. The rate of ketone-body formation in the livers of rats kept on a high-fat diet was up to 50% higher than in the livers of rats starved for 48h. In the livers of fat-fed rats almost all the O2 consumed was accounted for by the formation of ketone bodies. 5. The ketone-body concentration in the blood of fat-fed rats rose to 4–5mm and the [β-hydroxybutyrate]/[acetoacetate] ratio rose to 11.5. 6. When the activity of the microsomal mixed-function oxidase system, which can bring about ω-oxidation of fatty acids, was induced by treatment of the rat with phenobarbitone, there was no change in the ketone-body production from fatty acids, nor was there a production of glucose from even-numbered fatty acids. The latter would be expected if ω-oxidation occurred. Thus ω-oxidation did not play a significant role in the metabolism of fatty acids. 7. Arachidonate was almost quantitatively converted into ketone bodies and yielded no glucose, demonstrating that gluconeogenesis from poly-unsaturated fatty acids with an even number of carbon atoms does not occur. 8. The rates of ketogenesis from unsaturated fatty acids (sorbate, undecylenate, crotonate, vinylacetate) were similar to those from the corresponding saturated fatty acids. 9. Addition of oleate together with shorter-chain fatty acids gave only a slightly higher rate of ketone-body formation than oleate alone. 10. Glucose, lactate, fructose, glycerol and other known antiketogenic substances strongly inhibited endogenous ketogenesis but had no effects on the rate of ketone-body formation in the presence of 2mm-oleate. Thus the concentrations of free fatty acids and of other oxidizable substances in the liver are key factors determining the rate of ketogenesis.

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