The effects of mefenamic acid on postprandial intestinal carbohydrate metabolism

The effects of mefenamic acid on the food-induced changes in intestinal carbohydrate metabolism were determined in an attempt to elucidate the mechanism(s) by which inhibition of prostaglandin synthesis enhances the postprandial increases in intestinal blood flow and oxygen consumption. The data show that when the luminal perfusate was was changed from saline to a nutrient/bile solution, there was an increase in carbohydrate utilization, which was offset by absorption of glucose from the lumen. Intravenous administration of mefenamic acid significantly increased both carbohydrate absorption and metabolism when food was placed in the lumen. Changes in carbohydrate absorption and metabolism have been shown to play an important role in determining the magnitude of glucose induced changes in intestinal blood flow and oxygen consumption. Therefore, it is possible that the ability of mefenamic acid to enhance significantly the food-induced increases in blood flow and oxygen consumption may be due in part to its effects on intestinal carbohydrate absorption and utilization.     

Intestinal blood flow and oxygen consumption

In this study, we examined the effects of both pharmacologically and mechanically induced increases in intestinal blood flow on intestinal oxygen consumption. Intraarterial infusions of prostacyclin (1-20 ng X kg-1 X min-1) significantly increased both blood flow and oxygen consumption under free flow conditions. However, the increase in oxygen consumption appears to be due to the corresponding increase in blood flow rather than a direct effect of prostacyclin on intestinal metabolism. This conclusion is supported by the finding that a mechanically induced increase in intestinal blood flow (60%) can also produce an increase in intestinal oxygen consumption (24%). These findings support the hypothesis that intestinal oxygen consumption is flow-dependent over a wide range of blood flows.     

Endotoxemia in Yucatan miniature pigs: metabolic derangements and experimental therapies

Endotoxemia is a frequent complication of many health disorders. It is characterized by systemic release of a variety of endogenous inflammatory mediators which effect cardiovascular depression, reductions in organ blood flow, tissue ischemia and derangements in cellular metabolism leading to death. During a continuous intravenous infusion of Escherichia coli lipopolysaccharide, the chronology of alterations in hepatosplanchnic blood flow, hepatic carbohydrate metabolism and pancreatic insulin secretion has been studied in awake Yucatan miniature pigs (Sus scrofa). Endotoxic shock in this model is characterized by reductions in portal venous and hepatic arterial blood flow, early transient increases in pancreatic insulin secretion, increases in the 3H-glucose-derived rates of glucose appearance and disappearance, profound hypoglycemia, hyperlactatemia and metabolic acidosis. Reductions in hepatic oxygen delivery are compensated for by enhanced oxygen extraction efficiency, but hepatic gluconeogenesis continues at an inadequate rate to compensate for increased glucose utilization. Experimental therapies including lidocaine, naloxone, captopril, dichloroacetate and glucagon each effect specific improvements in cardiovascular or metabolic function, but none significantly alter the composite derangements responsible for lethality in this model.     

Increased expression of SERCA in the hearts of transgenic mice results in increased oxidation of glucose

While several transgenic mouse models exhibit improved contractile characteristics in the heart, less is known about how these changes influence energy metabolism, specifically the balance between carbohydrate and fatty acid oxidation. In the present study we examine glucose and fatty acid oxidation in transgenic mice, generated to overexpress sarco(endo)plasmic reticulum calcium-ATPase (SERCA), which have an enhanced contractile phenotype. Energy substrate metabolism was measured in isolated working hearts using radiolabeled glucose and palmitate. We also examined oxygen consumption to see whether SERCA overexpression is associated with increased oxygen utilization. Since SERCA is important in calcium handling within the cardiac myocyte, we examined cytosolic calcium transients in isolated myocytes using indo-1, and mitochondrial calcium levels using pericam, an adenovirally expressed, mitochondrially targeted ratiometric calcium indicator. Oxygen consumption did not differ between wild-type and SERCA groups; however, we were able to show an increased utilization of glucose for oxidative metabolism and a corresponding decreased utilization of fatty acids in the SERCA group. Cytosolic calcium transients were increased in myocytes isolated from SERCA mice, and they show a faster rate of decay of the calcium transient. With these observations we noted increased levels of mitochondrial calcium in the SERCA group, which was associated with an increase in the active form of the pyruvate dehydrogenase complex. Since an increase in mitochondrial calcium levels leads to activation of the pyruvate dehydrogenase complex (the rate-limiting step for carbohydrate oxidation), the increased glucose utilization observed in isolated perfused hearts in the SERCA group may reflect a higher level of mitochondrial calcium.     

Glucagon-like peptide-2 (GLP-2) increases net amino acid utilization by the portal-drained viscera of ruminating calves

Glucagon-like peptide-2 (GLP-2) increases small intestinal mass and blood flow in ruminant calves, but its impact on nutrient metabolism across the portal-drained viscera (PDV) and liver is unknown. Eight Holstein calves with catheters in the carotid artery, mesenteric vein, portal vein and hepatic vein were paired by age and randomly assigned to control (0.5% bovine serum albumin in saline; n = 4) or GLP-2 (100 μg/kg BW per day bovine GLP-2 in bovine serum albumin; n = 4). Treatments were administered subcutaneously every 12 h for 10 days. Blood flow was measured on days 0 and 10 and included 3 periods: baseline (saline infusion), treatment (infusion of bovine serum albumin or 3.76 μg/kg BW per h GLP-2) and recovery (saline infusion). Arterial concentrations and net PDV, hepatic and total splanchnic fluxes of glucose, lactate, glutamate, glutamine, β-hydroxybutyrate and urea-N were measured on days 0 and 10. Arterial concentrations and net fluxes of all amino acids and glucose metabolism using continuous intravenous infusion of [U¹³-C]glucose were measured on day 10 only. A 1-h infusion of GLP-2 increased blood flow in the portal and hepatic veins when administered to calves not previously exposed to exogenous GLP-2, but after a 10-day administration of GLP-2 the blood flow response to the 1-h GLP-2 infusion was substantially attenuated. The 1-h GLP-2 infusion also did not appreciably alter nutrient fluxes on either day 0 or 10. In contrast, long-term GLP-2 administration reduced arterial concentrations and net PDV flux of many essential and non-essential amino acids. Despite the significant alterations in amino acid metabolism, glucose irreversible loss and utilization by PDV and non-PDV tissues were not affected by GLP-2. Fluxes of amino acids across the PDV were generally reduced by GLP-2, potentially by increased small intestinal epithelial growth and thus energy and amino acid requirements of this tissue. Increased PDV extraction of glutamine and alterations in PDV metabolism of arginine, ornithine and citrulline support the concept that GLP-2 influences intestine-specific amino acid metabolism. Alterations in amino acid metabolism but unchanged glucose metabolism suggests that the growth effects induced by GLP-2 in ruminants increase reliance on amino acids preferentially over glucose. Thus, GLP-2 increases PDV utilization of amino acids, but not glucose, concurrent with stimulated growth of the small intestinal epithelium in post-absorptive ruminant calves.     

Effects of dietary fibre on the intestinal absorption of dextrin, blood sugar level and growth of tilapia, Oreochromis niloticm × O. aureus

The roles of five different dietary fibres (cellulose, agar, guar gum, carrageenan and carboxy-methylcellulose) each as 10% wt/wt added into the diet, affecting the intestinal sugar absorption, blood sugar level and utilization of dextrin were studied in hybrid tilapia, Oreochromis niloticus × O. aureus ; dextrin and glucose were also included in the study as controls for comparison. There were seven dietary groups: each diet was fed to three aquaria each containing 15 fish. The experiment was carried out in a closed circulation, filtered, rearing system for 2 months. The results indicated that the weight gain percentage and food conversion ratio were significantly (P<0.05) lower in tilapia fed fibre-containing diets than those of tilapia fed dextrin or glucose diet. The intestinal absorption of carbohydrate and the blood sugar content of tilapia were low when diets contained fibre, regardless of the source.     

Oxygen regulates amino acid turnover and carbohydrate uptake during the preimplantation period of mouse embryo development

Oxygen is a powerful regulator of preimplantation embryo development, affecting gene expression, the proteome, and energy metabolism. Even a transient exposure to atmospheric oxygen can have a negative impact on embryo development, which is greatest prior to compaction, and subsequent postcompaction culture at low oxygen cannot alleviate this damage. In spite of this evidence, the majority of human in vitro fertilization is still performed at atmospheric oxygen. One of the physiological parameters shown to be affected by the relative oxygen concentration, carbohydrate metabolism, is linked to the ability of the mammalian embryo to develop in culture and remain viable after transfer. The aim of this study was, therefore, to determine the effect of oxygen concentration on the ability of mouse embryos to utilize both amino acids and carbohydrates both before and after compaction. Metabolomic and fluorometric analysis of embryo culture media revealed that when embryos were exposed to atmospheric oxygen during the cleavage stages, they exhibited significantly greater amino acid utilization and pyruvate uptake than when cultured under 5% oxygen. In contrast, postcompaction embryos cultured in atmospheric oxygen showed significantly lower mean amino acid utilization and glucose uptake. These metabolic changes correlated with developmental compromise because embryos grown in atmospheric oxygen at all stages showed significantly lower blastocyst formation and proliferation. These findings confirm the need to consider both embryo development and metabolism in establishing optimal human embryo growth conditions and prognostic markers of viability, and further highlight the impact of oxygen on such vital parameters.     

The effect of a decrease in blood pressure, associated with extracorporeal blood pumping on myocardial metabolism in the isolated dog heart preparation

A fall in systolic blood pressure was associated with the use of a blood pump for extracorporeal circulation in dogs. The change in systolic blood pressure was negatively correlated to an increase in arterial lactate and glucose levels and positively with a decrease in free fatty acid levels. The changes in arterial levels of these major metabolic sybstrates resulted in a shift in myocardial metabolism whereby myocardial utilization of carbohydrate (glucose and lactate) was enhanced while free fatty acid utilization was markedly diminished.     

Consumption of carbohydrates, amino acids and oxygen across the intestinal circulation in the fetal sheep

Since large volumes of nutrient rich amniotic fluid are swallowed by the fetus, it has been suggested that intestinal digestion and absorption contribute significantly to fetal nutrition. To see if nutrients are being gained across the intestine, we measured blood flow and intestinal arteriovenous concentration differences of glucose, alpha-amino nitrogen, lactate, fructose and oxygen in eleven third trimester fetal sheep with chronically implanted vascular catheters. We found that in fetal blood circulating through the intestine nutrient concentration decreased significantly with arterio-venous concentration differences for glucose of 0.78 +/- 0.21 (SEM) mg/dl (P < 0.002), for alpha-amino nitrogen of 0.52 +/- 0.15 mg/dl (P < 0.005), for lactate of 0.68 +/- 0.24 mg/dl (P < 0.05) and for oxygen of 1.50 +/- 0.08 ml/dl (P < 0.001). Fructose concentration did not change. Blood flow to the fetal intestine averaged 89.92 +/- 7.16 ml/min and the intestine consumed 0.74 +/- 0.24 mg of glucose, 0.43 +/- 0.17 mg of alpha-amino nitrogen, 0.83 +/- 0.28 mg of lactate and 1.37 +/- 0.14 ml of oxygen per minute. Compared to previously published values for the umbilical uptake of nutrients the fetal intestine metabolizes about 4% of the glucose, 6% of the alpha-amino nitrogen, 13% of the lactate and 6% of the oxygen obtained across the umbilical circulation. Intestinal absorption does not appear to serve as a source of simple nutrients for the rest of the fetus, in fact intestinal metabolism extracts significant amounts of nutrients from fetal blood.     

Effects of substance P on intestinal circulation and oxygen consumption

The effects of intra-arterial administration of substance P upon intestinal blood flow, oxygen consumption, intestinal motor activity, and distribution of blood flow to the compartments of the gut wall were measured in anesthetized dogs. Blood flow to the segment of distal ileum was measured with an electromagnetic blood flow meter and A-VO2 was measured spectrophotometrically. Oxygen uptake was calculated as the product of A-VO2 and total blood flow. The clearance of 86Rb was measured to estimate the density of the perfused intestinal capillaries. Changes in blood flow distribution were estimated from the distribution of radiolabeled microspheres. Motor activity was monitored from changes in intraluminal pressure. Substance P induced a dose-related increase in intestinal blood flow, oxygen consumption, and intestinal motor activity. A significant increase in 86Rb clearance and increase in blood flow to the muscles was also observed. The results of these studies indicate that substance P relaxes intestinal arterioles and precapillary sphincters thereby inducing intestinal hyperemia and increased oxygen consumption. These changes, at least in part, might be due to the increased intestinal motility with enhanced metabolic demands of the muscularis for oxygen.     

Absorption and metabolism of fructose by rat jejunum.

The absorption and metabolism of fructose was investigated in the vascularly perfused jejunum of fructose-fed rats. With 10 mM-glutamate and 10 mM-fructose in the lumen, the viability of the tissue is maintained and fructose is absorbed and utilized at high rates. With 28 mM-fructose in the lumen, glucose appears in the vascular bed. With 10 mM- or 28 mM-fructose in the presence of 10 mM- or mM-glucose in the lumen, the fructose absorption is decreased. From 10 mM- or 28 mM-sucrose in the lumen, fructose uptake is also less than from the equivalent concentration of free fructose. The rate of appearance of fructose in the vascular bed is independent of the source of fructose from which it is derived. In the presence of glucose, either free or as sucrose, there is a marked decrease in the utilization of fructose, defined as the difference between that absorbed by the jejunum and that transported unchanged into the vascular bed. In all cases about half of the carbohydrate absorbed from the lumen is converted into lactate, most of which is secreted into the blood. The absorption of glucose and the rate of vascular appearance of glucose from glucose in the lumen are about 1.5 times greater than those of fructose from fructose in the lumen. It is concluded: firstly, that fructose uptake from the lumen of rat jejunum is determined by its concentration and by the demand for it as a fuel for the intestine, a demand that is severely decreased in the presence of glucose; secondly, that in the vascularly perfused jejunum there is no evident kinetic advantage for uptake of fructose or glucose from sucrose rather than from free monosaccharide in the lumen; thirdly, that some fructose can be converted into glucose.     

OXIDATIVE METABOLISM OF THE CEREBRAL CORTEX OF THE RAT IN SEVERE INSULIN-INDUCED HYPOGLYCAEMIA

—Measurements were made of organic phosphates, carbohydrate substrates, amino acids and ammonia in the cerebral cortex, as well as of cerebral blood flow and of cerebral metabolic rate for oxygen and glucose in rats that developed an isoelectric EEG pattern (‘coma’) during insulin-induced hypoglycaemia. The results were compared to those obtained in control animals, as well as in hypoglycaemic animals with an EEG pattern of slow waves and polyspikes. In animals with slow waves and polyspikes, there was a decrease in all citric acid cycle intermediates except succinate and oxaloacetate, and a decrease in the pool size of intermediates. In animals that had an isoelectric EEG for 5–15 min, there were further decreases in citrate, isocitrate, α-ketoglutarate, malate and fumarate, but since the concentration of succinate (and oxaloacetate) increased, the pool size remained the same. In isoelectric animals, the results revealed extensive utilization of amino acids by both transamination and deamination reactions. However, since glycogen had disappeared and the amino acid pattern was constant after the first 5 min of isoelectric EEG, further oxidation must have occurred at the expense of non-carbohydrate, non-amino acid substrates. There were two- to three-fold increases in cerebral blood flow in animals with slow waves and polyspikes and in animals with isoelectric EEG, and no decrease in the cerebral metabolic rate for oxygen. Since less than half of the oxygen consumption could be accounted for in terms of glucose extraction, the data indicate that severe hypoglycaemia is associated with extensive oxidation of endogenous substrates other than carbohydrates and free acids.     

Continuous measurement of glucose utilization in heart myoblasts

Understanding quantitative aspects of cell energy metabolism and how it is influenced by environment is central to biology, medicine, and biotechnology. Most methods used for measuring metabolic fluxes associated with energy metabolism require considerable personnel effort or high maintenance instrumentation. The microphysiometer is a commercially available instrument that measures acid extrusion rates, which are commonly used for drug screening. With the addition of oxygen sensors, the instrument can also be used to measure cell oxygen consumption rates and thereby calculate glycolytic fluxes. In the work described here, oxygen consumption and acid extrusion rates were used to measure glucose utilization by the H9c2 rat heart myoblast cell line and these results are compared with fluxes measured with a radiometric assay. Both assays were used to investigate changes in H9c2 energy metabolism due to cell stimulation with carbachol and insulin. The results demonstrate the utility of the microphysiometer method for measuring both transient and sustained changes in partitioning of glucose utilization between glycolysis and oxidation in live cells.     

Effects of somatostatin on intestinal circulation and oxygen consumption

The effects of intraarterial administration of somatostatin upon intestinal blood flow, intestinal capillary surface area, oxygen consumption and intestinal motor activity were measured in anesthetized dogs. Blood flow to the segment of distal ileum was measured with an electromagnetic blood flow meter, and arteriovenous oxygen difference (AVO2) was determined spectrophotometrically. Intestinal oxygen consumption was calculated as the product of AVO2 and total blood flow. The clearance of 86Rb was measured to estimate the density of the perfused intestinal capillaries. Changes in blood flow distribution were estimated from the distribution of radiolabelled microspheres. Intestinal motor activity was monitored from changes in intraluminal pressure. Somatostatin induced a dose-related decrease in intestinal blood flow, capillary surface area and intestinal oxygen consumption. A significant increase in intestinal motor activity was also observed. The data of this study indicate that somatostatin acts on smooth muscle of both arterioles and precapillary sphincters and results in a potent vasoconstriction in the intestinal microcirculation.     

The effect of elevation of maternal plasma catecholamines on the fetus and placenta of the pregnant sheep

To study the effects of reduced uterine blood flow on fetal and placental metabolism, adrenaline has been infused at physiological doses (0.5 microgram/min per kg) into the circulation of the pregnant sheep. This gives a reduction of about one third of uterine blood flow at days 120-143 of pregnancy, but causes no significant change in umbilical blood flow. In contrast to the effects of constricting the uterine artery to reduce blood flow to a similar degree, placental oxygen consumption was reduced and that, together with a large increase in lactate production, indicated the placenta became hypoxic. The fetal blood gas status and hence oxygen consumption was not affected significantly. A consistent arterio-venous difference for glucose across the umbilical or uterine circulations was not detected unless the uterine blood flow was comparatively high. Glucose balance across the uterus showed a close linear relationship with uterine blood flow and more particularly with the supply of glucose to the uterus. There was clear evidence for glucose uptake by the placenta and fetus and also glucose output by both. The latter was more common when uterine blood flow was comparatively low or reduced by adrenaline infusion. The results are consistent with the concept that glucose supply has to be maintained to the placenta even at the expense of fetal stores, although lactate can substitute if there is enhanced output because of fetal hypoxia. They indicate that placental mobilisation of glycogen can lead to a net output of glucose to the mother. The manner of communicating to the fetus changes in placental state that occur during maternal adrenaline infusion is not clear. However towards the end of the 60 min infusion, elevation of fetal plasma adrenaline, probably resulting from a breakdown of the placental permeability barrier, may be an important signal.     

Cerebral blood flow regulation in REM sleep: a model for flow-metabolism coupling.

The pattern of metabolic and circulatory changes occurring during REM sleep in the whole brain is also observed at a regional level in different instances of functional activation. This pattern is characterized by an increase in metabolic rate, blood flow, glucose and oxygen uptake, the increase in glucose uptake generally exceeding oxygen uptake. A model of interpretation is presented, based on the assumption that substantial limitation to oxygen diffusion exists in the brain. According to the model, microregions lying at mid-distance between capillaries may become hypoxic, depending on metabolic rate and blood-cell PO2 difference. At increasing metabolic rates, O2 consumption in pericapillary microregions increases and the PO2 drop becomes steeper. As a consequence, in microregions far from capillaries a decrease in O2 availability occurs, in concomitance with the increase in metabolic rate, so that non-oxidative glucose metabolism develops locally. A similar spatial PO2 pattern forms in the case of arterial hypoxia, when capillary PO2, and then blood-cell PO2 difference, is reduced. The hypoxic microregions are the source of vasodilatatory messages, the consequent vasodilatation increasing average capillary PO2 and then favoring O2 diffusion to the tissue. Oxygen thus appears to be a better candidate than glucose as a mediator of blood flow-metabolism coupling. This is supported by its higher extraction fraction and by the fact that, in physiologic conditions, arterial hypoxia (and not hypoglycemia) acts on cerebral blood flow. Moreover, the diffusion capacity of glucose in the brain is higher than that of oxygen, so that diffusion limitation is more likely to occur for oxygen. The present model allows consistent organization of the stereotyped changes in cerebral blood flow and glucose and oxygen uptake occurring both in REM sleep and in other instances of brain activation.     

Blood flows and nutrient uptakes in growth-restricted pregnancies induced by overnourishing adolescent sheep

To establish physiological mechanisms for fetal growth restriction in pregnant adolescent ewes we studied uterine, fetal, and uteroplacental metabolism in ewes offered a high (n = 12) or moderate (n = 10) dietary intake. High intakes decreased placental (226 vs. 414 g, P < 0.001) and fetal weight (3,323 vs. 4,626 g, P < 0.01). Uterine blood flow was reduced absolutely (-36%) but proportional to conceptus weight; umbilical blood flow was reduced absolutely (-37%) and per fetal weight (-15%). Uterine oxygen uptake was decreased per conceptus weight (-14%); there was no change in fetal weight oxygen consumption. Uteroplacental oxygen consumption and clearance were reduced proportional to weight. Similar changes were measured for glucose fluxes and fetal glucose concentration; fetal insulin concentration was reduced. In this model of fetal growth restriction, therefore, maintenance of fetal weight-specific glucose and oxygen consumption rates are producing relative hypoglycemia and hypoxemia. This indicates that increased fetal glucose clearance and/or insulin sensitivity may be operating as compensatory mechanisms to preserve normal fetal metabolism while fetal growth is sacrificed.     

Effects of exercise on mammary metabolism in the lactating ewe

Mammary metabolism in multiparous lactating ewes fed either lucerne chaff:barley grain (L:B; 70:30) or lucerne chaff:lupin grain (L:Lu; 70:30) diets was measured while at rest, during exercise on a treadmill at 0.7 m s⁻¹ on a 10 ° slope for 60 min, and during 30 min recovery from exercise. The effects of these treatments on plasma glucose, lactate, alpha-amino nitrogen (-amino N), non-esterified fatty acids (NEFA) and acetate were measured. Net mammary uptake of oxygen and metabolites was calculated from mammary blood flow and arteriovenous concentration (A − V) differences.

Mammary blood flow was reduced by 25% during exercise. Arterial concentrations of oxygen, glucose, lactate, -amino N and NEFA increased during exercise, whereas acetate concentration either remained unchanged or declined. Mammary A − V differences were significantly higher for oxygen, glucose, lactate and NEFA, and tended to be higher for -amino N and lower for acetate during exercise. The mammary uptakes of oxygen, glucose, lactate and -amino N were unaffected by exercise, whereas the uptake of NEFA was significantly increased and that of acetate was significantly reduced. The changes in arterial concentrations and mammary uptakes in response to exercise were not significantly affected by the diet. The responses in acetate and NEFA fluxes across the mammary gland might bring a change in the utilization of other metabolites as well as in the fatty acid composition of milk fat.     

Carbohydrate metabolism during prolonged exercise and recovery: interactions between pyruvate dehydrogenase, fatty acids, and amino acids.

During prolonged exercise, carbohydrate oxidation may result from decreased pyruvate production and increased fatty acid supply and ultimately lead to reduced pyruvate dehydrogenase (PDH) activity. Pyruvate also interacts with the amino acids alanine, glutamine, and glutamate, whereby the decline in pyruvate production could affect tricarboxycylic acid cycle flux as well as gluconeogenesis. To enhance our understanding of these interactions, we studied the time course of changes in substrate utilization in six men who cycled at 44+/-1% peak oxygen consumption (mean+/-SE) until exhaustion (exhaustion at 3 h 23 min+/-11 min). Femoral arterial and venous blood, blood flow measurements, and muscle samples were obtained hourly during exercise and recovery (3 h). Carbohydrate oxidation peaked at 30 min of exercise and subsequently decreased for the remainder of the exercise bout (P<0.05). PDH activity peaked at 2 h of exercise, whereas pyruvate production peaked at 1 h of exercise and was reduced (approximately 30%) thereafter, suggesting that pyruvate availability primarily accounted for reduced carbohydrate oxidation. Increased free fatty acid uptake (P<0.05) was also associated with decreasing PDH activity (P<0.05) and increased PDH kinase 4 mRNA (P<0.05) during exercise and recovery. At 1 h of exercise, pyruvate production was greatest and was closely linked to glutamate, which was the predominant amino acid taken up during exercise and recovery. Alanine and glutamine were also associated with pyruvate metabolism, and they comprised approximately 68% of total amino-acid release during exercise and recovery. Thus reduced pyruvate production was primarily associated with reduced carbohydrate oxidation, whereas the greatest production of pyruvate was related to glutamate, glutamine, and alanine metabolism in early exercise.