Release Of Pyruvate Research Articles

A Comparison of Brain Glucose Metabolism in Diabetes as Measured by Positron Emission Tomography or by Arteriovenous Techniques

[U-11-C]-glucose and positron emission tomography was used to evaluate transport and oxidative metabolism of glucose in the brain of non-diabetic and insulin dependent diabetic (IDDM) subjects. These results were compared with results obtained by the Fick principle. Blood glucose was regulated by a Biostator controlled glucose infusion during a constant insulin infusion. [U-11-C]-glucose was injected during normoglycemia as well as during moderate hypoglycemia. The tracer data were analysed using a three compartment model with a fixed correction for [11-C]-CO2 egress. During normoglycemia the influx rate constant (k1) and blood brain glucose flux of the two groups were similar. During hypoglycemia k1 increased significantly and to the same extent in both groups. During normoglycemia the tracer calculated metabolism of glucose was higher in the brain of non-diabetic than of diabetic subjects. When measured by the Fick principle the net uptake of glucose was broadly the same for the groups. During normoglycemia the molar ratio of O2 to glucose uptake was, however, lower in IDDM than in non-diabetic subjects (4.67 vs 5.50, P less than 0.05, Wilcoxon test). A significant release of lactate and pyruvate was seen in IDDM but not in non-diabetic subjects. The results imply that a larger fraction of glucose is non-oxidatively metabolized in IDDM than in non-diabetic subjects.

The lung as a target organ for thyroxine.

The isolated perfused in situ rat lung preparation was used to investigate the chronic effect of thyroxine on the intermediary metabolism in the mammalian lung. Treatment with thyroxine caused stimulation of the rate of glucose utilization (91 +/- 11 mumol/g dry weight/hr versus 54 +/- 5 mumol/g dry weight/hr). The increase in the rate of glucose uptake was not accompanied by a similar increase in lactate output. Alanine and pyruvate release were also similar in both groups. The implication is that oxidative metabolism of glucose was increased. This study provides the first unequivocal evidence that the mammalian lung is a target organ for thyroxine.

Cerebral effects of anaesthesia and hypothermia.

Cerebral blood flow, cerebral oxygen and glucose consumption, and cerebral lactate and pyruvate release were measured; spectral analysis of the EEG was recorded in 10 male patients who had coronary artery bypass surgery. The measurements were taken to evaluate the effects of fentanyl-midazolam anaesthesia during normothermia and during hypothermic nonpulsatile cardiopulmonary bypass at 26 degrees C venous blood temperature, when a temperature-corrected PaCO2-value of 5.3 kPa was maintained. Anaesthesia with fentanyl 7 micrograms/kg and midazolam 200 micrograms/kg as induction doses, followed by infusions of fentanyl 0.15 micrograms/kg/minute and midazolam 3 micrograms/kg/minute, was characterised by a decrease in fast-wave activity and an increase in high-amplitude, slow-wave activity in the EEG. There was also a decrease in cerebral blood flow (38%), oxygen consumption (22%) and glucose consumption (25%), while lactate and pyruvate production remained unchanged. Hypothermia of 26 degrees C venous blood temperature suppressed EEG almost completely and decreased oxygen and glucose consumption by a further 61% and 54%, respectively, with no changes in lactate and pyruvate production while cerebral blood flow increased by 145%. These results show that the effects of fentanyl-midazolam anaesthesia on cerebral metabolism are enhanced during hypothermic cardiopulmonary bypass while the influence of anaesthesia on cerebral blood flow is overshadowed by the practice of a temperature-corrected acid-base management.

Splanchnic and renal exchange of infused fructose in insulin-deficient type 1 diabetic patients and healthy controls.

Fructose raises blood glucose and lactate levels in normal as well as diabetic man, but the tissue origin (liver and/or kidney) of these responses and the role of insulin in determining the end products of fructose metabolism have not been fully established. Splanchnic and renal substrate exchange was therefore examined during intravenous infusion of fructose or saline in six insulin-deficient type I diabetics who fasted overnight and in five healthy controls. Fructose infusion resulted in similar arterial concentrations and regional uptake of fructose in the two groups. Splanchnic glucose output increased threefold in the diabetics but remained unchanged in controls in response to fructose infusion, and the arterial glucose concentration rose more in diabetics (+5.5 mmol/liter) than in controls (+0.5 mmol/liter). Splanchnic uptake of both lactate and pyruvate increased twofold in response to fructose infusion in the diabetics. In contrast, a consistent splanchnic release of both lactate and pyruvate was seen during fructose infusion in controls. In diabetics fructose-induced hyperglycemia was associated with no net renal glucose exchange, while there was a significant renal glucose production during fructose infusion in the controls. In both groups fructose infusion resulted in renal output of lactate and pyruvate. In the diabetics this release corresponded to the augmented uptake by splanchnic tissues. In two diabetic patients given insulin infusion, all responses to fructose infusion were normalized. Fructose infusion in diabetics did not influence either splanchnic ketone body production or its relationship to splanchnic FFA inflow. We conclude that in insulin-deficient, mildly ketotic type I diabetes, (a) both the liver, by virtue of lactate, pyruvate, and fructose-derived gluconeogenesis, and the kidneys , by virtue of fructose-derived lactate and pyruvate production, contribute to fructose-induced hyperglycemia; (b) outcome of hepatic fructose metabolism; and (c) fructose does not exert an antiketogenic effect. These data suggest that while total fructose metabolism is not altered in diabetics, intermediary hepatic fructose metabolism is dependent on the presence of insulin.

The effect of ketone bodies on alanine and glutamine metabolism in isolated skeletal muscle from the fasted chick.

The effects of ketone bodies on the metabolism of alanine and glutamine were studied in isolated extensor digitorum communis (EDC) muscles from 24 h-fasted chicks. (1) Acetoacetate and DL-beta-hydroxybutyrate (4 mM) markedly inhibit branched-chain amino acid (BCAA) transamination and alanine formation. (2) Ketone bodies (1 and 4 mM) increase the intracellular concentration and release of glutamate and glutamine, suggesting that inhibition of BCAA transamination does not limit intracellular availability of glutamate for alanine synthesis. (3) Ketone bodies (1 and 4 mM) do not affect glucose uptake by muscles, but decrease the rate of glycolysis as well as the intracellular concentration and release of pyruvate in muscles. (4) Addition of 12 mM-glucose increases the formation of alanine in muscles incubated in the absence of ketone bodies, but has no effect in muscles incubated in the presence of 4 mM ketone bodies. (5) Addition of 5 mM-pyruvate to the media prevents the inhibiting effect of ketone bodies on BCAA transamination and alanine synthesis. These results suggest that ketone bodies decrease alanine synthesis by limiting the intracellular availability of pyruvate, owing to inhibition of glycolysis, and inhibit BCAA transamination by decreasing the intracellular concentration of amino-group acceptors such as pyruvate in EDC muscles from fasted chicks.

Carbohydrate utilization by exercising muscle following pre-exercise glucose ingestion.

The effect on exercising muscle metabolism of prior ingestion of 200 g glucose was examined in six healthy subjects during 40 min leg exercise at 30% of maximal oxygen uptake. Leg glucose uptake during exercise was on average two- to three-fold higher after glucose (E + G) compared to exercise without glucose (E) and could account for 44-48% of the oxidative leg metabolism (control value: 19%, P less than 0.05-0.01). In contrast to E, which was associated with a significant release of leg lactate, pyruvate and alanine, E + G gave no leg production of lactate or alanine and an uptake of pyruvate. The respiratory exchange ratios (R) were higher during G + E and corresponded to a carbohydrate oxidation of 54-69% as against 46-49% (P less than 0.05-0.01) during E. Estimated from R-values and leg oxygen and glucose uptakes, carbohydrate oxidation during G less than E was almost completely accounted for by blood glucose. During E, on the other hand, carbohydrate oxidation exceeded leg glucose uptake, indicating a small but significant muscle glycogen breakdown (P less than 0.01). The rate of glycogen utilization during E or G + E was too small to be detected by direct measurements of muscle glycogen content. The results demonstrate that glucose ingestion prior to light exercise is followed by increased uptake and more efficient oxidation of glucose, as well as by insignificant muscle glycogen degradation by exercising muscle. Although the present findings suggest a glycogen-conserving effect of glucose ingestion under these conditions, the main fuel shift is from fat to glucose oxidation.

Increased response to insulin of glucose metabolism in the 6-day unloaded rat soleus muscle.

Hind leg muscles of female rats (85-99 g) were unloaded by tail cast suspension for 6 days. In the fresh-frozen unloaded soleus, the significantly greater concentration of glycogen correlated with a lower activity ratio of glycogen phosphorylase (p less than 0.02). The activity ratio of glycogen synthase also was lower (p less than 0.001), possibly due to the higher concentration of glycogen. In isolated unloaded soleus, insulin (0.1 milliunit/ml) increased the oxidation of D-[U-14C]glucose, release of lactate and pyruvate, incorporation of D-[U-14C]glucose into glycogen, and the concentration of glucose 6-phosphate more (p less than 0.05) than in the weight-bearing soleus. At physiological doses of insulin, the percent of maximal uptake of 2-deoxy-D-[1,2-3H]glucose/muscle also was greater in the unloaded soleus. Unloading of the soleus increased by 50% the concentration of insulin receptors, due to no decrease in total receptor number during muscle atrophy. This increase may account for the greater response of glucose metabolism to insulin in this muscle. The extensor digitorum longus, which generally shows little response to unloading, displayed no differential response of glucose metabolism to insulin.

Effects of dipyridamole on myocardial glucose uptake in the newborn lamb

Carbohydrates are an important source of energy for the immature myocardium. Since dipyridamole (DPY) has been reported to facilitate glucose uptake in the adult heart, the present study was designed to determine whether DPY could enhance glucose uptake in the nonischemic newborn. In anesthetized, open chest lambs ( n = 8), circumflex coronary blood flow (CBF), myocardial adenine nucleotide content, and aortic and coronary sinus concentrations of glucose, lactate, and pyruvate were determined before and after a single dose of DPY (0.2 mg/kg, intravenously). Adenine nucleotides were measured by HPLC. The consumption of substrates was calculated as the product of CBF and the aortic-coronary sinus difference in substrate concentration. Coronary blood flow averaged 114 ± 6 ml/min/100 g in the untreated animals, and increased by 44% following treatment with dipyridamole ( P < 0.01). This was associated with a 32% decrease in coronary vascular resistance ( P < 0.01). Glucose uptake increased from 9 to 46 μmoles/min/100 g ( P < 0.01) following dipyridamole treatment; lactate uptake decreased by 97% ( P < 0.01). There was a net release of pyruvate from the neonatal hearts; this increased from 18 to 25 μmole/min/100 g ( P < 0.05). Myocardial ATP content averaged 4.08 μmole/g wet wt in the untreated animals, and increased 11% to 4.52 following DPY ( P < 0.01). The agent had no effect on the myocardial tissue levels of AMP or ADP. These data indicate that DPY is a coronary vasodilator in the newborn lamb and augments both glucose uptake and myocardial ATP content. These metabolic effects provide a rationale for further studies during periods of hypoxia and ischemia.

Uptake of glucose and release of fatty acids and glycerol by rat brown adipose tissue in vivo

The net in vivo uptake or release of free fatty acids glycerol, glucose, lactate, and pyruvate by the interscapular brown adipose tissue (IBAT) of barbital-anesthetized, cold-acclimated rats was determined from measurements of plasma arteriovenous concentration differences across IBAT and tissue blood flow. Measurements were made without stimulation of the tissue and also during submaximal and maximal stimulation by infused noradrenaline (NA), the physiological activator of BAT thermogenesis. There was no appreciable uptake of glucose or release of fatty acids and glycerol by the nonstimulated tissue. At both levels of stimulation there was significant uptake of glucose (1.7 and 2.0 mumol/min) and release of glycerol (0.9 and 1.2 mumol/min), but only at maximal stimulation was there significant release of fatty acids (1.9 mumol/min). Release of lactate and pyruvate accounted for 33% of the glucose taken up at submaximal stimulation and 88% at maximal stimulation. By calculation, the remainder of the glucose taken up was sufficient to have fueled about 12% of the thermogenesis at submaximal stimulation, but only about 2% at maximal stimulation. As estimated from the rate of glycerol release, the rate of triglyceride hydrolysis was sufficient at submaximal stimulation to fuel IBAT thermogenesis entirely with the resulting fatty acids, but it was not sufficient to do so at maximal stimulation when some of the fatty acid was exported. It is suggested that at maximal NA-induced thermogenesis a portion of lipolysis proceeded only to the level of mono- and di-glycerides with the result that glycerol release did not fully reflect the rate of fatty acid formation.(ABSTRACT TRUNCATED AT 250 WORDS)

Alanine and glutamine release from the human forearm: effects of glucose administration.

The effect of glucose infusion alone (175 mg/kg bolus dose followed by 4 mg min-1 kg-1 for 70 min) and in combination with forearm exercise on the exchange of glucose, alanine, glutamine and other metabolites and amino acids across forearm muscle was studied in six healthy individuals after an overnight fast. Arterial and deep venous blood was sampled and a mercury strain gauge plethysmograph was used to measure forearm blood flow. Total body energy expenditure and net glucose and fat oxidation were assessed by indirect calorimetry. The infusion of glucose increased the mean arterial blood glucose concentration from 4.95 +/- 0.19 (SEM) to a plateau of 9.6-9.9 mmol/l (P less than 0.01). The arterial blood concentrations of alanine and glutamine were not significantly altered but that of lactate increased from 0.50 +/- 0.02 to 0.65 +/- 0.05 mmol/l (P less than 0.02) and that of pyruvate increased from 46 +/- 5 to 72 +/- 6 mumol/l (P less than 0.01). In the resting state glucose administration did not significantly affect the lactate/pyruvate ratio in arterial or venous blood. Arterial plasma insulin concentration increased four-fold and total ketone body concentration decreased two- to three-fold. After glucose administration, alanine release was suppressed (in all subjects) from a mean value of 153 +/- 22 to 57 +/- 16 nmol min-1 100 ml-1 of forearm (P less than 0.02) whereas that of glutamine was not significantly affected (160 +/- 30 to 143 +/- 29 nmol min-1 100 ml-1 of forearm). Lactate release, like that of alanine, decreased, whereas pyruvate was slowly released in the basal state and was taken up during glucose administration (P less than 0.01). These changes were associated with a decrease in the uptake of total ketone bodies to one-fifth to one-tenth of that in the basal state. The net amino acid balance across the forearm muscle bed was negative throughout the study but decreased from a mean value of -567 in the basal state to -300 nmol min-1 100 ml-1 of forearm after glucose administration for 60 min. This was predominantly due to decreased release of effluxing amino acids, particularly alanine.(ABSTRACT TRUNCATED AT 400 WORDS)

Toxic effects of daunorubicin on isolated and cultured heart cells from neonatal rats

Various aspects of the cardiotoxicity of the anthracycline derivative and antineoplastic drug daunorubicin were investigated using isolated and cultured cells from neonatal rat hearts as a model system. Treatment of the cells with concentrations of daunorubicin of the same order of magnitude as those used in chemotherapy was accompanied by marked toxic effects, e.g. a decreased or abolished contraction, and release of lactate dehydrogenase, pyruvate and oxidized glutathione to the medium. A decreased frequency of contraction appeared to be the most sensitive probe of daunorubicin toxicity, followed by release of pyruvate and oxidized glutathione/lactate dehydrogenase. Daunorubicin and/or its metabolites also bound to cellular protein and DNA. Exposure to daunorubicin was shown to be accompanied by a rapid induction of primarily DT-diaphorase and a slower induction of glutathione transferase. The latter observations are interpreted to indicate a protective role of quinone- and peroxide-metabolizing enzymes, respectively, and support the hypothesis that daunorubicin toxicity involves generation of free radical derivatives, which initiate lipid peroxidation. This conclusion is further substantiated by the demonstration that addition of daunorubicin leads to an increased oxygen consumption.

An HPLC method for the determination of acetyl and pyruvyl groups in polysaccharides

A method for the quantitative analysis of pyruvate and acetate groups in polysaccharides has been developed, using HPLC on a cation exchange resin in the protonated form and u.v. detection at 210 nm. Procedures for release of acetate and pyruvate from polysaccharides are described. In the case of xanthan gum, most of the pyruvate is removed if the sample is autoclaved in water during preparation, and about 25% is lost if autoclaved in 0·1 m sodium chloride solution.

Branched-chain amino acid metabolism and alanine formation in rat diaphragm muscle in vitro. Effects of dichloroacetate.

Dichloroacetate (which activates pyruvate dehydrogenase) decreases the release of alanine, pyruvate and lactate in hemidiaphragm incubations with valine. Dichloroacetate interferes with alanine formation by diverting pyruvate into oxidative pathways, which not only limits pyruvate availability for direct transamination to form alanine but also indirectly affects branched-chain amino acid transamination by limiting 2-oxoglutarate regeneration from glutamate.

Leg citrate metabolism at rest and during exercise in relation to diet and substrate utilization in man.

Previously we have demonstrated a lower rate of carbohydrate utilization in skeletal muscle after a fat than after a carbohydrate rich diet both at rest and during exercise. To test the hypothesis of citrate as a regulator of glycolysis (1) arterial-femoral venous (a-fv) differences for oxygen, citrate, pyruvate and lactate and (2) muscle citrate and glucose-6-phosphate (G-6-P) were determined at rest and after 5 and 25 min of submaximal bicycle exercise. Citrate release and muscle citrate concentration were higher after fat than after carbohydrate diet at rest and 5 min exercise, but did not differ between diets at 25 min exercise. Lactate release and muscle lactate concentration were lower after fat diet at 5 and 25 min exercise. Pyruvate release at 5 min exercise was higher after fat diet. The G-6-P concentration was higher at rest, insignificantly higher after 5 min exercise and lower at 25 min exercise after the fat diet. The findings support the notion that at rest and 5 min exercise fat diet induced inhibition of glycolysis might be mediated through increased intramuscular citrate acting on phosphofructokinase. In addition, the greater pyruvate release at 5 min exercise after fat diet in spite of a smaller lactate release, indicates a decreased pyruvate dehydrogenase activity and/or NADH to NAD ratio after fat diet. The inhibition of glycolysis at 25 min exercise after fat diet on the other hand does not seem to be citrate mediated.

Actions of glucagon on flux rates in perfused rat liver. 1. Kinetics of the inhibitory effect on glycolysis and the stimulatory effect on glycogenolysis.

Changes in the rates of glucose, lactate and pyruvate production following infusion of glucagon were studied in isolated livers from fed or fasted rats perfused with non-recirculating Krebs-Henseleit bicarbonate buffer. Evidence was presented that under these experimental conditions, the release of lactate plus pyruvate into the perfusate represents 80-90% of the total glycolytic flux; oxidation of pyruvate derived from glucose and/or glycogen accounts for the remaining 10-20%, whereas recycling of pyruvate to glucose is negligible. In the presence of glucagon, rates of lactate plus pyruvate production were diminished to less than 30% in the fed state (glycogen as substrate) and to less than 10% in the fasted state (glucose as substrate). Rates of pyruvate oxidation were unchanged. Although recycling of pyruvate to glucose was enhanced, it could account for not more than 20% of the decrease in lactate plus pyruvate production. The data indicate a strong inhibition of the substrate flux through glycolysis. The glucagon concentration for half-maximal inhibition of glycolysis was 0.2 nM, independent of the substrate (glucose or glycogen) and the nutritional state. The effective concentrations were within the physiological range of glucagon concentrations reported for portal venous blood. Transient state analyses indicated that the inhibition of glycolysis precedes the stimulation of glycogenolysis. When after a delay glycogenolysis was accelerated, it was followed by a transient stimulation of glycolysis. The stimulatory component in the glucagon effect on glycolysis was diminished in glycogen-depleted livers and when glucose was the main substrate. The coordinated control of glycolysis and glycogenolysis by glucagon and the interaction of the two processes in the transient state are discussed.

Skeletal muscle metabolism in neonatal lean and obese pigs.

Nine lean and nine obese male pigs were examined at 14 d of age. The biceps femoris muscle of the obese pigs had a greater (P less than .05) percentage dry matter, protein and triglycerides than the muscle of lean pigs. The rate of oxidation of glucose to CO2 by the biceps femoris muscle was not influenced (P greater than .05) by phenotype but the rate was greater (P less than .05) when incubations were conducted in either the presence of leucine or palmitate. Glycolytic flux was lower (P less than .05) in the muscle of the obese pigs than in the muscle of lean pigs. Glycolytic flux was enhanced (P less than .05) by addition of leucine or palmitate to the incubation media. The rate of release of lactate, pyruvate, alanine, glutamine and glutamate into the media was similar between phenotypes and was not influenced by the presence of leucine or palmitate (P greater than .05). The total amount of leucine transaminated was greater (P less than .05) in the muscle of lean pigs than in the muscle of obese pigs. This was because of greater (P less than .05) rates of decarboxylation of leucine and release of alpha-ketoisocaproic acid into the media by the muscle of lean pigs when compared with the muscle of obese pigs. However, the ratio of leucine decarboxylated to alpha-ketoisocaproic acid released was similar (P greater than .05) between the two phenotypes. The ratio of palmitate oxidized (to CO2) to palmitate esterified was greater (P less than .01) in the muscle of the lean pigs than in the muscle of obese pigs. This latter finding may partially explain the greater triglyceride content of obese pig muscle. The generally lower rates of oxidation of substrates and of glycolytic flux in the biceps femoris muscle of obese pigs, when compared with lean pigs, may be associated with differences in body composition that develop during growth of lean and obese pigs.

Relative effects of pregnancy and corticosterone administration on skeletal muscle metabolism in the rat.

The effects of pregnancy and corticosterone treatment on skeletal muscle metabolism were compared using a noncyclically perfused rat hindlimb preparation. Animal groups studied included 3-week-pregnant animals, rats injected with corticosterone (7.5 mg/100 g BW . day) for 3 days, and age-matched control rats. All were fasted 24 h before perfusion. In baseline perfusions devoid of insulin, no differences were observed among the groups with respect to muscle glucose uptake and the release of lactate, pyruvate, and glycerol. Baseline alanine and phenylalanine release were significantly increased in corticosterone-treated rats compared to values observed in control and pregnant animals. In perfusions with 100 or 500 microU/ml insulin, glucose uptake was increased 5-fold above baseline uptake in the control group. At 100 microU/ml insulin concentrations, glucose uptake in pregnant and corticosterone-treated rats achieved only 50% of the increase seen in control experiments. With 500 microU/ml insulin, glucose uptake was decreased 20% in pregnant animals and 40% in rats receiving corticosterone relative to control values. Alanine release was significantly reduced below baseline after the administration of 500 microU/ml insulin in control rats. In these rats, phenylalanine release, an index of net protein degradation, also was reduced with both 100 and 500 microU/ml insulin. Similar insulin concentrations did not suppress the efflux of either amino acid below baseline in pregnant or corticosterone-treated groups. Corticosterone administration to nonpregnant rats appears to duplicate changes in skeletal muscle metabolism that occur during late rat pregnancy. Insulin resistance in both states is manifested by a decrease in insulin-stimulated glucose uptake and an inability of insulin to suppress net muscle proteolysis. Since plasma free glucocorticoid concentrations are increased in late human as well as rat gestation, these steroids may have an important role in the development of insulin resistance at skeletal muscle sites in this state.

Changes in Availability of Glucogenic and Ketogenic Substrates and Liver Metabolism in Fed or Starved Rats

The characteristics of the digestive and hepatic metabolism of glucogenic and ketogenic substrates were studied in vivo in fed or starved rats. For this purpose, a procedure for blood flow measurements in the splanchnic area was developed, based on an indicator-dilution technique. Hepatic blood flow (HBF) was markedly reduced after 24 h starvation, mainly corresponding to the decrease of portal blood supply; however, HBF expressed per gram liver was almost unchanged. In overnight-fed rats, glucose absorption was limited and glucose was released by the liver, essentially after gluconeogenesis from C3 units: alanine was the main glucogenic substrate removed by the liver, then propionate and lactate, whereas only a slight release of pyruvate occurred. As large amounts of lactate were released by the digestive tract, there was a net production of lactate in the splanchnic area. In contrast, in starved rats, lactate became the main glucogenic substrate removed by the liver as its fractional extraction was raised from 7% (fed) to 58% (starved) whereas the contribution of alanine and propionate to gluconeogenesis was limited by their availability, their hepatic extraction being highly efficient in fed and in starved rats. The present results are consistent with the view that glucose turnover was practically halved during starvation and suggest that net glucose cycling via lactate was very low in fed rats but could correspond to about 40% of produced glucose in starved rats. Besides propionate, acetate and butyrate made a significant contribution to fuel supply for hepatic metabolism in fed rats, acetate availability for extrasplanchnic tissues remained relatively constant. FFA were extensively removed by the liver (50%) in starved rats and ketogenesis could account for 68% of removed FFA. In spite of low concentrations in the artery, acetoacetate was released by the liver at a higher rate than 3-hydroxybutyrate. This process could correspond to a higher turnover rate for acetoacetate, nevertheless not evident in portal-drained viscera where net 3-hydroxybutyrate uptake was observed only.

3 Hormonal control of ketone body metabolism in the normal and diabetic state

Background/Aims: This study aimed to characterize the exchange of fuel substrates in the splanchnic circulation in acute liver failure.Methods: Liver vein catheterization was used in 22 patients with acute liver failure after development of hepatic encephalopathy grade III-IV. Healthy controls, patients with cirrhosis and patients with acute on chronic liver disease were also studied.Results: In acute liver failure there was splanchnic removal of glucose (0.21±0.44 mmol/min), release of lactate (0.34±0.37 mmol/min), pyruvate (0.08±0.06 mmol/min) and ketone bodies (0.04±0.02 mmol/min), while extraction of amino acids and free fatty acids was insignificant. In the acute liver failure group, a normal hepatic venous oxygen saturation (0.69±0.12) and normal pyruvate/lactate ratio suggested absence of hypoxia even though the acetoacetate/β-hydroxybutyrate ratio was decreased. Only in the acute liver failure group did the measured splanchnic oxygen content difference exceed what could be accounted for even by hypothesizing complete oxidation of all extracted blood-borne fuel substrates; oxidation of endogenous substrates may be quantitatively important in this condition.Conclusion: Acute liver failure was associated with a state of accelerated glycolysis in the splanchnic region, leading to release of lactate in the absence of splanchnic hypoxia.

Pigeon liver malic enzyme.

Malic enzyme of pigeon liver is a tetrameric molecule with identical, or nearly-identical subunits. It catalyzes, in addition to oxidative decarboxylation of L-malate, the following metal activated component reactions: Oxalacetate decarboxylase; reductase with broad specificity on α-ketocarboxylic acids; a NADP+-dependent dismutation of L-malate to L-lactate; and proton exchange between pyruvate and medium water. The kinetic mechanism of oxidative decarboxylase is sequential and ordered, with NADP+ adding first to the metal enzyme, followed by L-malate, and by the release of products CO2, pyruvate, and NADPH. NADPH release, or a conformation change preceeding it, is rate-limiting in the overall reaction.