Studies on the carbohydrate metabolism of sheep. VIII. Hypoglycaemia and hyperketonaemia in undernourished and fasted pregnant ewes

1959 ◽  
Vol 10 (1) ◽  
pp. 81 ◽  
Author(s):  
RL Reid ◽  
JP Hogan
Keyword(s):  
Fatty Acids ◽  
Blood Glucose ◽  
Tricarboxylic Acid Cycle ◽  
Tricarboxylic Acid ◽  
Blood Levels ◽  
Acetyl Coa ◽  
Mean Values ◽  
Acid Cycle ◽  
Wide Range ◽  
Highly Correlated

Relationships between blood levels of glucose, ketone bodies, volatile fatty acids (V.F.X.), and citrate have been studied in ewes fed on a submaintenance diet of wheaten chaff during the last 5 weeks of pregnancy. Pre-feeding levels, changes during S hr after feeding, and changes during fasting were studied. Pre-feeding hypoglycaemia was consistently more severe and the post'-prandial increase in blood glucose was less in ewes carrying twins than in ewes carrying single lambs. Blood citrate consistently increased after feeding, the magnitude of the increase depending on the extent of the increase in blood glucose. Mean citrate levels after feeding were highly correlated with mean glucose levels, which suggested that blood citrate reflected the activity of the tricarboxylic acid cycle in tissues. Pre-feeding ketone levels tended to vary inversely as blood glucose when hyperlietonaemia was moderate (less than 20 mg per cent. ketones) hut the correlation disappeared v-hen hyperketonaemia was severe (20-53 mg per cent.). When glucose increased appreciably after feeding, ketones usually declined and V.F.A. levels were normal, but when the increase in glucose was small and levels remained below 30 mg per cent. after feeding, ketone levels often did not change and V.F.A. levels were high. Mean values for ketones over a period of 8 hr after feeding were highly correlated with mean values for V.F.A. over a wide range. This can be explained on the basis of present knowledge of the metabolism of the acetyl-coenzyme A (acetyl- Co4) derived from absorbed acetate and from oxidation of higher fatty acids; it is suggested that the oxidation of acetyl-CoA is impaired as a result of depression of tricarboxylic acid cycle activity. During fasting, blood ketones varied inversely with glucose, but very high ketone levels (above 30 mg per cent.) were probably not due simply to the hypoglycaemia. The hypothesis is advanced that an excess of circulating hydrocortisone further depressed acetyl-CoA metabolism. The apparent correlations between blood glucose and ketones would then be due largely to the fact that the magnitude of the adrenal response, at any particular time in these experiments, was a function of the severity of hypoglycaemia and of the period during which it was previously maintained.

13C isotopomer model for estimation of anaplerotic substrate oxidation via acetyl-CoA

1996 ◽  
Vol 271 (4) ◽  
pp. E788-E799 ◽  
Author(s):  
F. M. Jeffrey ◽  
C. J. Storey ◽  
A. D. Sherry ◽  
C. R. Malloy
Keyword(s):  
Biochemical Analysis ◽  
Tricarboxylic Acid Cycle ◽  
Tricarboxylic Acid ◽  
Acetyl Coa ◽  
Acid Cycle ◽  
Propionate Metabolism ◽  
13C Nuclear Magnetic Resonance ◽  
Isotopomer Analysis ◽  
Tricarboxylic Acid Cycle Intermediates ◽  
Anaplerotic Pathway

A previous model using 13C nuclear magnetic resonance isotopomer analysis provided for direct measurement of the oxidation of 13C-enriched substrates in the tricarboxylic acid cycle and/or their entry via anaplerotic pathways. This model did not allow for recycling of labeled metabolites from tricarboxylic acid cycle intermediates into the acetyl-CoA pool. An extension of this model is now presented that incorporates carbon flow from oxaloacetate or malate to acetyl-CoA. This model was examined using propionate metabolism in the heart, in which previous observations indicated that all of the propionate consumed was oxidized to CO2 and water. Application of the new isotopomer model shows that 2 mM [3-13C]propionate entered the tricarboxylic acid cycle as succinyl-CoA (an anaplerotic pathway) at a rate equal to 52% of tricarboxylic acid cycle turnover and that all of this carbon entered the acetyl-CoA pool and was oxidized. This was verified using standard biochemical analysis; from the rate (mumol.min-1.g dry wt-1) of propionate uptake (4.0 +/- 0.7), the estimated oxygen consumption (24.8 +/- 5) matched that experimentally determined (24.4 +/- 3).

Effect ofEchinococcus multilocularison the origin of acetyl-CoA entering the tricarboxylic acid cycle in host liver

2002 ◽  
Vol 76 (1) ◽  
pp. 31-36 ◽  
Author(s):  
C. Kepron ◽  
M. Novak ◽  
B.J. Blackburn
Keyword(s):  
Carbohydrate Metabolism ◽  
Tricarboxylic Acid Cycle ◽  
Tricarboxylic Acid ◽  
Meriones Unguiculatus ◽  
Host Liver ◽  
Acetyl Coa ◽  
Acid Cycle ◽  
A Value ◽  
Alveolar Hydatid Disease ◽  
And Control

AbstractCarbon-13 nuclear magnetic resonance (NMR) spectroscopy was employed to investigate alterations in hepatic carbohydrate metabolism inMeriones unguiculatusinfected withEchinococcus multilocularis. Following portal vein injections of an equimolar mixture of ]#x005B;1,2-13C2]acetate and [3-13C]lactate, perchloric acid extracts of the livers were prepared and NMR spectra obtained. Isotopomer analysis using glutamate resonances in these spectra showed that the relative contributions of endogenous and exogenous substrates to the acetyl-CoA entering the tricarboxylic acid cycle differed significantly between infected and control groups. The mole fraction of acetyl-CoA that was derived from endogenous, unlabelled sources (FU) was 0.50±0.10 in controls compared to 0.34±0.04 in infected animals. However, the fraction of acetyl-CoA derived from [3-13C]lactate (FLL) was larger in livers of infected animals than those from controls with values of 0.27±0.04 and 0.18±0.04, respectively. Similarly, the fraction of acetyl-CoA derived from [1,2-13C2]acetate (FLA) was larger in livers of infected animals compared to those in controls; the fractions were 0.38±0.01 and 0.32±0.07, respectively. The ratio of FLA:FLLwas significantly smaller in the infected group with a value of 1.42±0.18 compared to 1.74±0.09 for the controls. These results indicate that alveolar hydatid disease has a pronounced effect on the partitioning of substrates within the pathways of carbohydrate metabolism in the host liver.

A general model for analysis of the tricarboxylic acid cycle with use of [13C]glutamate isotopomer measurements

1994 ◽  
Vol 266 (6) ◽  
pp. E1012-E1022 ◽  
Author(s):  
J. A. Vogt ◽  
A. J. Fischman ◽  
M. Kempf ◽  
Y. M. Yu ◽  
R. G. Tompkins ◽  
...  
Keyword(s):  
13C Nmr ◽  
Tricarboxylic Acid Cycle ◽  
Nonlinear Least Squares ◽  
Tricarboxylic Acid ◽  
Acetyl Coa ◽  
Metabolic System ◽  
Acid Cycle ◽  
Nmr Data ◽  
13C Nuclear Magnetic Resonance ◽  
Model Equations

A generalized steady-state model was developed for determining tricarboxylic acid cycle fractional fluxes from 13C nuclear magnetic resonance (NMR) data. The model relates the measured mole fractions of [13C]glutamate isotopomers to the fractional fluxes and predicted mole fractions of isotopomers of oxaloacetate (OAA) and acetyl-CoA. This model includes cycling between OAA and fumarate. Fractional fluxes are determined by fitting the model equations to NMR parameters by use of nonlinear least squares. Although only fractional fluxes can be determined from 13C-NMR data, when they are combined with mass spectroscopic measurements, absolute values can be derived. A specific metabolic system represented by published 13C-NMR data from extracts of hearts perfused with [13C]acetate, [13C]pyruvate (PYR), and [13C]acetate plus [13C]PYR was used to test the model. The intensities of predicted 13C-NMR splitting patterns were compared with observed values, and there was excellent agreement between observed and predicted signal intensities. With this model, important physiological parameters, including the OAA-derived fraction of inflow to PYR, PYR-derived fraction of inflow to acetyl-CoA, citrate-derived fraction of inflow to OAA, and PYR-derived fraction of inflow to OAA, can be determined.

scholarly journals Flux control exerted by mitochondrial outer membrane carnitine palmitoyltransferase over β-oxidation, ketogenesis and tricarboxylic acid cycle activity in hepatocytes isolated from rats in different metabolic states

1996 ◽  
Vol 317 (3) ◽  
pp. 791-795 ◽  
Author(s):  
Lesley DRYNAN ◽  
Patti A. QUANT ◽  
Victor A. ZAMMIT
Keyword(s):  
Fatty Acids ◽  
Tricarboxylic Acid Cycle ◽  
Tricarboxylic Acid ◽  
Mitochondrial Outer Membrane ◽  
Flux Control ◽  
Acid Cycle ◽  
Metabolic States ◽  
Flux Control Coefficients ◽  
Cpt I ◽  
Control Coefficients

The Flux Control Coefficients of mitochondrial outer membrane carnitine palmitoyltransferase (CPT I) with respect to the overall rates of β-oxidation, ketogenesis and tricarboxylic acid cycle activity were measured in hepatocytes isolated from rats in different metabolic states (fed, 24 h-starved, starved–refed and starved/insulin-treated). These conditions were chosen because there is controversy as to whether, when significant control ceases to be exerted by CPT I over the rate of fatty oxidation [Moir and Zammit (1994) Trends Biochem. Sci. 19, 313–317], this is transferred to one or more steps proximal to acylcarnitine synthesis (e.g. decreased delivery of fatty acids to the liver) or to the reaction catalysed by mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase [Hegardt (1995) Biochem. Soc. Trans. 23, 486–490]. Therefore isolated hepatocytes were used in the present study to exclude the involvement of changes in the rate of delivery of non-esterified fatty acids (NEFA) to the liver, such as occur in vivo, and to ascertain whether, under conditions of constant supply of NEFA, CPT I retains control over the relevant fluxes of fatty acid oxidation to ketones and carbon dioxide, or whether control is transferred to another (intrahepatocytic) site. The results clearly show that the Flux Control Coefficients of CPT I with respect to overall β-oxidation and ketogenesis are very high under all conditions investigated, indicating that control is not lost to another intrahepatic site during the metabolic transitions studied. The control of CPT I over tricarboxylic acid cycle activity was always very low. The significance of these findings for the integration of fatty acid and carbohydrate metabolism in the liver is discussed.

Sources of acetyl-CoA entering the tricarboxylic acid cycle as determined by analysis of succinate carbon-13 isotopomers

Biochemistry ◽  
1993 ◽  
Vol 32 (45) ◽  
pp. 12240-12244 ◽  
Author(s):  
John G. Jones ◽  
A. Dean Sherry ◽  
F. Mark H. Jeffrey ◽  
Charles J. Storey ◽  
Craig R. Malloy
Keyword(s):  
Tricarboxylic Acid Cycle ◽  
Tricarboxylic Acid ◽  
Acetyl Coa ◽  
Acid Cycle

Address of the President Sir Howard Florey, at the Anniversary Meeting, 30 November 1961

1961 ◽  
Vol 265 (1320) ◽  
pp. 1-14 ◽  
Keyword(s):  
Carbon Dioxide ◽  
Fatty Acids ◽  
Tricarboxylic Acid Cycle ◽  
Tricarboxylic Acid ◽  
Biological Degradation ◽  
Tissue Slices ◽  
Carbamyl Phosphate ◽  
Acid Cycle ◽  
Main Route ◽  
Carbon Fragment

Award of Medals 1961 The Copley Medal is awarded to Sir Hans Krebs, F.R.S. Sir Hans Krebs has made outstanding contributions to knowledge of the chemical pathways of metabolism. In 1932, with Henseleit, he used tissue slices to demonstrate the synthesis of urea and found that additions of ornithine stimulated the process. Ornithine was regarded as uniting with carbon dioxide and ammonia to give arginine, with citrulline as an intermediate. The enzyme arginase liberated urea and a molecule of ornithine, so that the process could begin again. Subsequent research has shown that the postulated cycle is essentially valid, although more detail has been introduced; carbamyl phosphate, argininosuccinate and adenosine triphosphate have been brought in and aspartic acid has replaced ammonia in the reaction with citrulline. The more complicated version owes much to the fundamental work initiated by Krebs in 1937 on the tricarboxylic acid cycle. This process is now seen as the main route for oxidizing the two-carbon fragment produced in the biological degradation of carbohydrates, fatty acids and arninoacids.

VARIATIONS IN LIPID INTAKE AND THEIR INFLUENCE ON RESPIRATION AND TRICARBOXYLIC ACID CYCLE ACTIVITY

1965 ◽  
Vol 43 (9) ◽  
pp. 1575-1587 ◽  
Author(s):  
Hector F. DeLuca
Keyword(s):  
Fatty Acids ◽  
Vitamin D ◽  
Vitamin A ◽  
Tricarboxylic Acid Cycle ◽  
Essential Fatty Acids ◽  
Respiratory Control ◽  
Liver Mitochondria ◽  
Tricarboxylic Acid ◽  
Membrane Systems ◽  
Acid Cycle

The possible role of dietary lipids and lipid-soluble constituents in the tricarboxylic acid cycle, respiratory systems, and mitochondrial structure is discussed, with special emphasis on vitamin D, vitamin A, and essential fatty acids. Deficiency of any of these substances produces structural alterations in isolated kidney or liver mitochondria. In the case of vitamin D deficiency the structural alteration in kidney mitochondria is accompanied by an increased rate of citrate and isocitrate oxidation and a decreased transfer of calcium ions from inside to outside the mitochondria. Vitamin D added in vitro or given to the intact rat specifically decreases citrate oxidation and increases the translocation of calcium. Vitamin A deficiency increases the respiration of liver homogenates and mitochondria in the absence of phosphate acceptor, an effect which could readily be reversed within 48 hours after vitamin A administration. Increased ATPase and decreased respiratory control were also noted in liver mitochondria from vitamin A deficient rats. The structural change as well as the biochemical lesions could also be reversed within 48 hours after vitamin A administration. Similar experiments with essential fatty acid deficient mitochondria also revealed a high ATPase, low respiratory control, and marked structural damage. These changes could be reversed by the feeding of essential fatty acids to the deficient animals for 1–3 weeks. Despite many attempts, it was not possible to demonstrate structural changes in mitochondria in situ as a result of any of the deficiencies described. It is suggested that the respiratory and tricarboxylic acid cycle changes that have been attributed to the lipid constituents of the diet are secondary to alterations in subcellular membrane systems. The use of these membrane systems as tools or models in a study of the mechanism of action of the dietary lipid and lipid-soluble materials is discussed.

scholarly journals Metabolism of glucose, glutamine, long-chain fatty acids and ketone bodies by murine macrophages

1986 ◽  
Vol 239 (1) ◽  
pp. 121-125 ◽  
Author(s):  
P Newsholme ◽  
R Curi ◽  
S Gordon ◽  
E A Newsholme
Keyword(s):  
Fatty Acids ◽  
Citrate Synthase ◽  
Ketone Bodies ◽  
Tricarboxylic Acid Cycle ◽  
Tricarboxylic Acid ◽  
The Body ◽  
Acid Cycle ◽  
Coa Transferase ◽  
Very High

Maximum activities of some key enzymes of metabolism were studied in elicited (inflammatory) macrophages of the mouse and lymph-node lymphocytes of the rat. The activity of hexokinase in the macrophage is very high, as high as that in any other major tissue of the body, and higher than that of phosphorylase or 6-phosphofructokinase, suggesting that glucose is a more important fuel than glycogen and that the pentose phosphate pathway is also important in these cells. The latter suggestion is supported by the high activities of both glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase. However, the rate of glucose utilization by ‘resting’ macrophages incubated in vitro is less than the 10% of the activity of 6-phosphofructokinase: this suggests that the rate of glycolysis is increased dramatically during phagocytosis or increased secretory activity. The macrophages possess higher activities of citrate synthase and oxoglutarate dehydrogenase than do lymphocytes, suggesting that the tricarboxylic acid cycle may be important in energy generation in these cells. The activity of 3-oxoacid CoA-transferase is higher in the macrophage, but that of 3-hydroxybutyrate dehydrogenase is very much lower than those in the lymphocytes. The activity of carnitine palmitoyltransferase is higher in macrophages, suggesting that fatty acids as well as acetoacetate could provide acetyl-CoA as substrate for the tricarboxylic acid cycle. No detectable rate of acetoacetate or 3-hydroxybutyrate utilization was observed during incubation of resting macrophages, but that of oleate was 1.0 nmol/h per mg of protein or about 2.2% of the activity of palmitoyltransferase. The activity of glutaminase is about 4-fold higher in macrophages than in lymphocytes, which suggests that the rate of glutamine utilization could be very high. The rate of utilization of glutamine by resting incubated macrophages was similar to that reported for rat lymphocytes, but was considerably lower than the activity of glutaminase.

scholarly journals The activities of 2-oxoglutarate dehydrogenase and pyruvate dehydrogenase in hearts and mammary glands from ruminants and non-ruminants

1977 ◽  
Vol 164 (2) ◽  
pp. 349-355 ◽  
Author(s):  
G Read ◽  
B Crabtree ◽  
G H Smith
Keyword(s):  
Pyruvate Dehydrogenase ◽  
Tricarboxylic Acid Cycle ◽  
Mammary Glands ◽  
Tricarboxylic Acid ◽  
Acetyl Coa ◽  
Simple Method ◽  
Acid Cycle ◽  
Maximum Flux ◽  
Oxoglutarate Dehydrogenase

1. The activities of 2-oxoglutarate dehydrogenase (EC 1.2.4.2) were measured in hearts and mammary glands of rats, mice, rabbits, guinea pigs, cows, sheep, goats and in the flight muscles of several Hymenoptera. 2. The activity of 2-oxoglutarate dehydrogenase was similar to the maximum flux through the tricarboxylic acid cycle in vivo. Therefore measuring the activity of this enzyme may provide a simple method for estimating the maximum flux through the cycle for comparative investigations. 3. The activities of pyruvate dehydrogenase (EC 1.2.4.1) in mammalian hearts were similar to those of 2-oxoglutarate dehydrogenase, suggesting that in these tissues the tricarboxylic acid cycle can be supplied (under some conditions) by acetyl-CoA derived from pyruvate alone. 4. In the lactating mammary glands of the rat and mouse, the activities of pyruvate dehydrogenase exceeded those of 2-oxoglutarate dehydrogenase, reflecting a flux of pyruvate to acetyl-CoA for fatty acid synthesis in addition to that of oxidation via the tricarboxylic acid cycle. In ruminant mammary glands the activities of pyruvate dehydrogenase were similar to those of 2-oxoglutarate dehydrogenase, reflecting the absence of a significant flux of pyruvate to fatty acids in these tissues.

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