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PubMed2001

Interactions among glucose, lactate and adenosine regulate energy substrate utilization in hippocampal cultures.

Glucose is the major energy source during normal adult brain activity. However, it appears that glial-derived lactate is preferred as an energy substrate by neurons following hypoxia-ischemia. We examined factors influencing this switch in energetic bias from glucose to lactate in cultured hippocampal neurons, focusing on the effects of the physiological changes in lactate, glucose and adenosine concentrations seen during hypoxia-ischemia. We show that with typical basal concentrations of lactate and glucose, lactate had no effect on glucose uptake. However, at the concentrations of these metabolites found after hypoxia-ischemia, lactate inhibited glucose uptake. Reciprocally, glucose had no effect on lactate utilization regardless of glucose and lactate concentrations. Furthermore, we find that under hypoglycemic conditions adenosine had a small, but significant, inhibitory effect on glucose uptake. Additionally, adenosine increased lactate utilization. Thus, the relative concentrations of glucose, lactate and adenosine, which are indicative of the energy status of the hippocampus, influence which energy substrates are used. These results support the idea that after hypoxia-ischemia, neurons are biased in the direction of lactate rather than glucose utilization and this is accomplished through a number of regulatory steps.

Adenosine↗
PubMed2001

Effects of lactate on glucose-sensing neurons in the solitary tract nucleus.

For nervous tissue, lactate is a valuable energy substrate that can be extracted from glucose by astrocytes and released for neuronal use. Therefore, we hypothesized that the glucose-sensing neurons that signal the glycemic changes involved in the control of body energy homeostasis may be responsive to extracellular lactate as well. To test this hypothesis, neuronal activity was recorded extracellularly in the solitary tract nucleus of anesthetized rats in order to compare the effects of microelectrophoretic applications of glucose and lactate and of moderate hyperglycemia and to assess the possible effects of lactate on the response to glucose. About 90% of the investigated neurons behaved in a similar manner after local ejections of glucose and lactate. Among them, most neurons activated by glucose were also activated by lactate and all neurons depressed by glucose were also depressed by lactate. This result suggests that the response to these two compounds is mediated by a common mechanism related to their utilization as oxidizible substrates. In half of the tested neurons, the response to glucose was eliminated or significantly reduced after repeated lactate ejections. This inhibitory effect is a likely result of a modification in glucose metabolism induced by a high extracellular lactate level. Most glycemia-sensitive neurons responded similarly to moderate hyperglycemia and to local lactate ejection, suggesting that high brain lactate levels might interfere with the brain mechanisms that mediate glucoprivic eating.

Animals↗
PubMed2005

Effects on plasma glucose and lactate.

Injection of amylin or amylin agonists, including human and rat amylin, pramlintide, salmon calcitonin, and calcitonin gene-related peptide (CGRP), increases the plasma levels of lactate and glucose in non-diabetic fasting rats and mice. This response can be useful in identifying and defining amylin agonists (amylinomimetic agents) (Cooper et al.) and has been investigated in several studies. Increases in plasma glucose and lactate are not present in all species. In humans, for example, increases in lactate are observed at high pramlintide doses but not at doses that would be used to therapeutically regulate plasma glucose. In species where it occurs, the increase in plasma lactate with amylin is comparable to that observed with exercise or adrenergic agents, and it is distinguishable from the very high levels observed during lactic acidosis (as may occur with biguanides). In contrast to lactic acidosis, the plasma lactate with amylin is derived from skeletal muscle rather than liver. Increases in plasma lactate and glucose in some species may initially appear inconsistent with a glucose-lowering effect of amylin agonists. But glycemic effects are due to actions in skeletal muscle and are present only in some species, whereas glucose-lowering actions are attributable to effects in gastrointestinal systems and are present in all species studied to date. And while glycemic effects are most pronounced in the fasted state, glucose-lowering effects are most pronounced in the postprandial state. Since they were discovered first, effects of higher doses of amylin on plasma glucose, especially in the fasted state, are described first and are related to concomitant changes in plasma lactate. These effects are prominent in rodents but are barely discernible in humans. Effects of lower doses of pramlintide to suppress plasma glucose profiles in the postprandial period are also observable in normal and diabetic rats, however, and are covered here as well. The relationship between plasma lactate and glucose concentrations can be confusing. Via some mechanisms, changes in plasma glucose can drive changes in lactate, while via different mechanisms, changes in lactate can drive changes in glucose concentration. The recursive loop created by these separate links, and for which its discoverers received the Nobel prize, is the Cori cycle (Cori, 1931). This cycle of substrate fluxes, simplified as plasma glucose --> muscle glycogen --> plasma lactate --> liver glycogen --> plasma glucose, is important in the redistribution of carbohydrate fuels in some species (Cori and Cori, 1929) and is discussed here in relation to the role of amylin.

Amyloid↗
PubMed2004

Milk L-lactate concentration is increased during mastitis.

A study was undertaken in cattle to evaluate changes in milk L-lactate in relation to mastitis. A healthy, rear quarter of the udder of each of ten cows in mid-lactation was infused with 1000 colony-forming units (cfu) of Streptococcus uberis following an afternoon milking. Foremilk samples were taken at each milking from control and treated quarters and antibiotic treatment was applied following the onset of clinical mastitis or after 72 h. One cow did not become infected. Six quarters showed clinical symptoms of mastitis within 24-40 h and this was associated with a more than 30-fold increase in milk L-lactate (to 3.3 mM) and an increase in somatic cell count (SCC) from 4.5 x 10(3) to 1 x 10(7) cells/ml. Three cows were subclinical, with cell counts ranging from 1.5 x 10(6) to 1 x 10(7) cells/ml. In these animals, milk lactate ranged from 0.7 to 1.5 mM in the infected quarters up to 40 h post-infection, compared with less than 0.1 mM in control quarters. Milk was examined from 137 cows in mid-lactation which were known to have mastitis. Foremilk samples were taken aseptically from control and infected quarters of cows on commercial farms. Mean milk L-lactate concentrations and SCC were 0.14 +/- 0.02 mM and 1.85 +/- 0.3 x 10(5) cells/ml, respectively, in control (bacteriologically negative) samples. However, L-lactate concentrations exceeded 2.5 mM in the presence of some types of infection, the level of the lactate response being closely related to the impact of the infection on SCC. L-Lactate concentrations were relatively elevated in milk samples taken post partum, declining from 0.8 to 0.14 mM oyer the first few days of lactation. In conclusion, milk L-lactate has potential as an indicator of clinical and subclinical mastitis in dairy cows.

Animals↗
PubMed2001

Point-of-care (POC) testing of lactate in the intensive care patient. Accuracy, reliability, and costs of different measurement systems.

BACKGROUND: Point-of-care (POC) monitoring may facilitate diagnostic and therapeutic interventions in the critically ill. In a prospective study reliability and costs of two POC lactate testing devices were compared to the central laboratory lactate monitoring method. METHODS: From arterial whole blood and capillary blood samples of 40 intensive care unit (ICU) patients lactate concentrations were measured using either a battery-powered hand-held lactate analyser (Accusport) or a bench-top blood gas analyser (Chiron 865 series) and compared with lactate measured by the hospital's central laboratory ('reference' method). Measurements were carried out on the day of inclusion in the study ('baseline'), 8 h later, and in the morning of the 1st, 2nd, and 3rd days thereafter. Costs for blood lactate measurements were analysed for each method. RESULTS: A total of 197 lactate measurements were done with each system. Lactate measured from arterial blood using the Accusport and the central laboratory showed excellent agreement (bias: -0.15 mmol/l; relative error: -2.74%). Lactate measured by the blood gas analyser had also excellent agreement with the reference method (bias: 0.09 mmol/l; relative error: 2.24%) and the hand-held device (bias: -0.24 mmol/l; relative error: -5.06%). Time from blood sampling to availability of data was significantly longer for the central laboratory (85+/-35 min [range: 45-168 min]) than for both POC systems (range: 1-10 min). Total cost for measuring blood lactate was lowest using the Accusport device. CONCLUSION: The trend towards miniaturizing laboratory monitoring devices will continue, resulting in greater flexibility of management of the critically ill. Blood lactate can rapidly, easily, accurately, and economically be measured at the bedside with the hand-held monitor apparatus Accusport and the bench-top blood gas analyser.

Aged↗
PubMed1997

Lactate-bicarbonate interrelationship during exercise and recovery in lean and obese Zucker rats.

OBJECTIVE: To determine the relationship between muscle-derived lactate at fatigue and earlier onset of fatigue in the obese rat subjected to intense exercise. DESIGN: Rats were subjected to a short, intense exercise protocol on a treadmill. Blood was drawn from hind leg vein and artery during exercise and up to 1 h afterwards. Assuming an exercise respiratory quotient of 1.0, the extra carbon dioxide released was computed and assumed to be displaced by equimolar amounts of lactic acid produced by the rat during exercise. SUBJECTS: Conscious female adult Zucker lean and Zucker obese rats. MEASUREMENTS: Oxygen consumption and carbon dioxide release. Lactate and bicarbonate levels in hind leg venous and arterial blood; balances were estimated by measuring blood flow with fluorescent microspheres. Lactate levels in periovaric white adipose tissue were also measured. RESULTS: Muscle released, during exercise and post exercise roughly 2.3 mmol lactate in lean rats and 2.6 mmol in obese ones. Of these amounts, hind leg lactate release accounted for 0.40 mmol in lean rats and only 0.11 in the obese ones, which showed a release of acid (mainly lactate) elsewhere in the rats totalling about 19.9 mmol CO2 in lean rats and 4.4% in the obese ones; that is both hind quarters accounted for only 17.2% of all lactate produced in the lean rats and 4.4% in the obese ones. The amount of lactate produced by the rats was roughly similar. White adipose tissue lactate levels (in the basal state and after exercise) were much higher than could be expected from blood sources alone, indicating an active production of lactate. CONCLUSION: Fatigue appears earlier in the obese rats than in lean ones because of loss of buffering ability caused by massive extra-muscular glycolysis (probably in adipose tissue) and lactate production triggered by exercise-induced adrenergic stimulation.

Animals↗
PubMed2005

Lactate metabolism in acute uremia.

Lactate is a key metabolite that is produced by every cell and oxidized by most of them, provided that they do contain mitochondria. Its metabolism is connected to energetic homeostasis and the cellular redox state. It is well recognized as an indicator of severe outcome in severely ill patients, however, it is not a detrimental factor per se. Conversely, some recent data tend even to indicate a beneficial effect in several metabolic disorders. Although the liver has long been recognized as a key organ in lactate homeostasis, the kidney also plays a major role as a gluconeogenic organ significantly involved in the glucose-lactate cycle. In acute renal failure, sodium lactate is widely used as a buffer in replacement fluids because the anion (lactate - ) is metabolized and the cation (Na + ) remains, leading to decreased water dissociation and proton concentration. The metabolic disorders related to acute renal failure or associated with it, such as liver failure, may affect lactate metabolism, and therefore they are often regarded as limiting factors for the use of lactate-containing fluids in such patients. By investigating endogenous lactate production in severe septic patients with acute renal failure, we found that an acute exogenous load of lactate did not affect the basal endogenous lactate production and metabolism. This indicates that exogenous lactate is well metabolized even in patients suffering from acute renal failure and severe sepsis with a compromised hemodynamic status.

Acute Kidney Injury↗
PubMed2003

Dichloroacetate effects on glucose and lactate oxidation by neurons and astroglia in vitro and on glucose utilization by brain in vivo.

Neuronal cultures in vitro readily oxidized both D-[(14)C]glucose and l-[(14)C]lactate to (14)CO(2), whereas astroglial cultures oxidized both substrates sparingly and metabolized glucose predominantly to lactate and released it into the medium. [(14)C]Glucose oxidation to (14)CO(2) varied inversely with unlabeled lactate concentration in the medium, particularly in neurons, and increased progressively with decreasing lactate concentration. Adding unlabeled glucose to the medium inhibited [(14)C]lactate oxidation to (14)CO(2) only in astroglia but not in neurons, indicating a kinetic preference in neurons for oxidation of extracellular lactate over intracellular pyruvatelactate produced by glycolysis. Protein kinase-catalyzed phosphorylation inactivates pyruvate dehydrogenase (PDH), which regulates pyruvate entry into the tricarboxylic acid cycle. Dichloroacetate inhibits this kinase, thus enhancing PDH activity. In vitro dichloroacetate stimulated glucose and lactate oxidation to CO(2) and reduced lactate release mainly in astroglia, indicating that limitations in glucose and lactate oxidation by astroglia may be due to a greater balance of PDH toward the inactive form. To assess the significance of astroglial export of lactate to neurons in vivo, we attempted to diminish this traffic in rats by administering dichloroacetate (50 mgkg) intravenously to stimulate astroglial lactate oxidation and then examined the effects on baseline and functionally activated local cerebral glucose utilization (lCMR(glc)). Dichloroacetate raised baseline lCMR(glc) throughout the brain and decreased the percent increases in lCMR(glc) evoked by functional activation. These studies provide evidence in support of the compartmentalization of glucose metabolism between astroglia and neurons but indicate that the compartmentalization may be neither complete nor entirely obligatory.

Animals↗
PubMed1999

Effect of endurance training on blood lactate clearance after maximal exercise.

The aim of this study was to measure serial changes in the rate of blood lactate clearance (gamma2) in response to sequential periods of training and detraining in four male triathletes aged 22-44 years. There were two major phases of training and taper, each lasting 4-5 weeks (training 1 = 5 weeks, taper 1 = 2 weeks, training 2 = 4 weeks and taper 2 = 2 weeks), in preparation for a triathlon competition. The training stimulus absorbed by each subject was carefully quantified from the duration and intensity of the training exercise. A serial weekly measure of each trainee's physical response to training was evaluated as the peak power, termed a 'criterion performance', developed by a subject during a 30 W x min(-1) ramp cycle ergometer test to exhaustion each week. During 30 min of recovery after this test, 13 samples of venous blood were drawn sequentially from a subject to measure the blood lactate recovery curve. The rate constant of blood lactate clearance was estimated by a non-linear least-squares regression technique. In addition, the concurrent time to peak lactate concentration and the peak lactate concentration were also estimated to help define changing lactate kinetics. The criterion performance generally declined throughout each period of incremental training and improved during each taper period, rising iteratively in this way to be clearly above baseline by the end of the second taper. The blood lactate clearance rate increased transiently in early training before declining from the middle of the first training period to the middle of the first taper; thereafter, gamma2 increased above baseline in each trainee throughout the remaining first taper and the major portion of the second training period, decreasing only in the final criterion performance test. The time to peak lactate declined from baseline throughout all phases of training and taper. Peak blood lactate increased in all subjects to the end of the first taper before declining by the end of the second training period, rising again to baseline levels during the second taper. The change in gamma2 was examined relative to the work rate achieved in cycle ergometry above an initial baseline score (deltaCP) and against concurrent peak blood lactate. There was a clear upward shift in gamma2 above baseline throughout the first and second training and taper in two subjects; this was less clear in the remaining two subjects, each of whom had a lower deltaCP. We conclude that this indicates improved lactate clearance, manifest by the change in gamma2 induced by endurance training.

Adult↗
PubMed1999

Pulmonary lactate release in patients with acute lung injury is not attributable to lung tissue hypoxia.

OBJECTIVE: To determine whether pulmonary lactate production in patients with acute lung injury is attributable to lung tissue hypoxia. DESIGN: Prospective, controlled, clinical study. SETTING: A multidisciplinary university intensive care unit in a general hospital. PATIENTS: Seventy consecutive critically ill patients requiring mechanical ventilation and invasive hemodynamic monitoring. Of these patients, 18 had no acute lung injury (no ALI); 33 had acute lung injury (ALI) (Lung Injury Score [LIS] < or =2.5); and 19 had acute respiratory distress syndrome (ARDS) (LIS >2.5). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: After hemodynamic measurements, lactate and pyruvate concentrations were assessed in simultaneously drawn arterial (a) and mixed venous (v) blood samples. Pulmonary lactate release was calculated as the product of transpulmonary a-v lactate difference (L[a-v]) times the cardiac index. Two indices of anaerobic metabolism of the lung, i.e., the transpulmonary a-v difference of lactate pyruvate ratio (L/P[a-v]) and excess lactate formation across the lungs (XL), were calculated. L(a-v) and pulmonary lactate release were higher in patients with ARDS than in the other groups (p<.001), and they were also higher in patients with ALI compared with patients with no ALI (p<.001). In patients with ALI and ARDS (n = 52), pulmonary lactate release correlated significantly with LIS (r2 = .14, p<.01) and venous admixture (r2 = .13, p<.01). When all patients were lumped together (n = 70), pulmonary lactate release directly correlated with LIS (r2 = .30, p<.001), venous admixture (r2 = .26, p<.001), and P(A-a)O2 (r2 = .14, p<.01). Neither L/P(a-v) nor XL was significantly different among the three groups. CONCLUSION: The lungs of patients with ALI produce lactate that is proportional to the severity of lung injury. This lactate production does not seem to be attributable to lung tissue hypoxia.

Biomarkers↗
PubMed1997

Small intestinal mucosal pH and lactate production during experimental ischemia-reperfusion and fecal peritonitis in pigs.

The aim of this study was to investigate mucosal pH and lactate production in a porcine model of ischemia/reperfusion and sepsis using both tonometry and a technique for segmental intestinal perfusion. Eighteen pigs (17-23 kg) were anesthetized and mechanically ventilated. They were divided into three groups and followed for 4 h. Group C (n = 6) served as controls. In the ischemia/reperfusion group (I/R; n = 6), the superior mesenteric artery was totally occluded for 60 min. In group P (n = 6), sepsis was induced by fecal peritonitis. Cardiac index (CI) was determined by thermodilution and blood flow in the superior mesenteric artery (QSMA), using a Transonic flow probe. Intramucosal pH (pHi) was calculated using tonometry. A special balloon tube for segmental perfusion was introduced in the midileum for lactate measurement. Lactate and oxygen saturation were measured in arterial blood and in the superior mesenteric vein. CI, QSMA, pHi, and lactate in blood and perfusate remained unchanged in controls. Occlusion of intestinal blood flow induced a fall in pHi from 7.28 +/- .02 to 6.76 +/- .04, a marked rise in lactate in the perfusate, and an increased arteriovenous lactate difference. During reperfusion, pHi tended to return to baseline values. Lactate in the perfusate and the arteriovenous lactate difference decreased. In sepsis there was a continuous reduction in CI and QSMA to 45 +/- 13% and 40 +/- 20% of baseline, respectively. pHi decreased moderately from 7.22 +/- .09 to 6.98 +/- .25. Lactate remained unchanged in blood and perfusate. Microscopic mucosal injury was observed in all animals subjected to ischemia/reperfusion and in three of six pigs in group P. A good association between pHi and lactate production was seen in ischemia/reperfusion. However, in sepsis, lactate in superior mesenteric venous blood or in intestinal perfusate did not increase, despite the fall in pHi. The mechanism causing ischemic mucosal injury has different characteristics in sepsis and in ischemia caused by arterial occlusion.

Animals↗
PubMedDate not supplied

Lactate stimulates endothelial cell migration.

The significance of the high lactate levels that characterize healing wounds is not fully understood. Lactate has been shown to enhance collagen synthesis by fibroblasts and vascular endothelial growth factor (VEGF) production by macrophages and endothelial cells. VEGF has been shown to induce endothelial cell migration. However, it has not been shown whether accumulated lactate correlates with the biological activity of VEGF. Therefore, we investigated the effect of lactate on migration of endothelial cells. Human umbilical vein endothelial cells and human microvascular endothelial cells were cultured to subconfluent monolayers in standard six-well tissue culture plates. Following a 24-hour serum starvation, cells were treated with the indicated concentrations of l-lactate. Cell migration was assessed using a modified Boyden chamber. VEGF protein in the cell culture supernatant was measured by enzyme-linked immunoassay. Lactate-enhanced VEGF protein synthesis in a time- and dose-dependent manner. Lactate added into the bottom well did not stimulate cellular migration from the upper well. However, lactate when added together with endothelial cells to the bottom well of the Boyden chamber increased cellular migration in a dose-dependent manner. This effect was blocked by anti-VEGF and by cycloheximide. Lactate enhances VEGF production in endothelial cells, although lactate, itself, is not a chemoattractant. We conclude that the lactate-mediated increase in cellular migration is regulated by VEGF.

Cell Movement↗
PubMed1990

Effect of Dicarboxylic Acids and Aspergillus oryzae Fermentation Extract on Lactate Uptake by the Ruminal Bacterium Selenomonas ruminantium.

The objective of this study was to determine the effects of l-aspartate, fumarate, l-malate, and an Aspergillus oryzae fermentation extract (Amaferm) on growth on lactate as well as lactate uptake by Selenomonas ruminantium HD4. Growth of S. ruminantium in medium that contained 2 g of dl-lactate per liter was stimulated approximately twofold by 10 mM l-aspartate, fumarate, or l-malate after 24 h. Both l-aspartate and fumarate increased lactate uptake over 4-fold, while l-malate stimulated uptake over 10-fold. Amaferm enhanced lactate uptake at all concentrations tested (0.5 to 50 g/liter), and the 10-g/liter level increased uptake over 12-fold. A filter-sterilized Amaferm filtrate increased lactate uptake over sevenfold, and growth on lactate was stimulated over twofold by either 2 or 5% (vol/vol) Amaferm filtrate. The Amaferm filtrate also increased the production of acetate, propionate, total volatile fatty acids, and Y(lactate) from lactate-grown cells. Since the increase in propionate production was greater relative to acetate, a decrease in the acetate:propionate ratio was observed. The concentration of l-malate in the Amaferm filtrate was 1.45 mM, and it appeared that the l-malate content of Amaferm played a role in the stimulation of growth on lactate as well as lactate uptake by S. ruminantium treated with Amaferm.

Journal Article↗
PubMed2005

Characterization of a Corynebacterium glutamicum lactate utilization operon induced during temperature-triggered glutamate production.

Gene expression changes of glutamate-producing Corynebacterium glutamicum were identified in transcriptome comparisons by DNA microarray analysis. During glutamate production induced by a temperature shift, C. glutamicum strain 2262 showed significantly higher mRNA levels of the NCgl2816 and NCgl2817 genes than its non-glutamate-producing derivative 2262NP. Reverse transcription-PCR analysis showed that the two genes together constitute an operon. NCgl2816 putatively codes for a lactate permease, while NCgl2817 was demonstrated to encode quinone-dependent l-lactate dehydrogenase, which was named LldD. C. glutamicum LldD displayed Michaelis-Menten kinetics for the substrate l-lactate with a K(m) of about 0.51 mM. The specific activity of LldD was about 10-fold higher during growth on l-lactate or on an l-lactate-glucose mixture than during growth on glucose, d-lactate, or pyruvate, while the specific activity of quinone-dependent d-lactate dehydrogenase differed little with the carbon source. RNA levels of NCgl2816 and lldD were about 18-fold higher during growth on l-lactate than on pyruvate. Disruption of the NCgl2816-lldD operon resulted in loss of the ability to utilize l-lactate as the sole carbon source. Expression of lldD restored l-lactate utilization, indicating that the function of the permease gene NCgl2816 is dispensable, while LldD is essential, for growth of C. glutamicum on l-lactate.

Bacterial Proteins↗
PubMed2004

Kinetics, molecular basis, and differentiation of L-lactate transport in spermatogenic cells.

Round spermatid energy metabolism is closely dependent on the presence of L-lactate in the external medium. This L-lactate has been proposed to be supplied by Sertoli cells in the seminiferous tubules. L-Lactate, in conjunction with glucose, modulates intracellular Ca(2+) concentration in round spermatids and pachytene spermatocytes. In spite of this central role of L-lactate in spermatogenic cell physiology, the mechanism of L-lactate transport, as well as possible differentiation during spermatogenesis, has not been studied in these cells. By measuring radioactive L-lactate transport and intracellular pH (pH(i)) changes with pH(i) fluorescent probes, we show that these cells transport L-lactate using monocarboxylate-H(+) transport (MCT) systems. RT-PCR, in situ mRNA hybridization, and immunocyto- and immunohistochemistry data show that pachytene spermatocytes express mainly the MCT1 and MCT4 isoforms of the transporter (intermediate- and low-affinity transporters, respectively), while round spermatids, besides MCT1 and MCT4, also show expression of the MCT2 isoform (high-affinity transporter). These molecular data are consistent with the kinetic data of L-lactate transport in these cells demonstrating at least two transport components for L-lactate. These separate transport components reflect the ability of these cells to switch between the generation of glycolytic L-lactate in the presence of external glucose and the use of L-lactate when this substrate is available in the external environment. The supply of these substrates is regulated by the hormonal control of Sertoli cell glycolytic activity.

Animals↗
PubMed2003

Pyruvate shuttle in muscle cells: high-affinity pyruvate transport sites insensitive to trans-lactate efflux.

The specificity of the transport mechanisms for pyruvate and lactate and their sensitivity to inhibitors were studied in L6 skeletal muscle cells. Trans- and cis-lactate effects on pyruvate transport kinetic parameters were examined. Pyruvate and lactate were transported by a multisite carrier system, i.e., by two families of sites, one with low affinity and high capacity (type I sites) and the other with high affinity and low capacity (type II). The multisite character of transport kinetics was not modified by either hydroxycinnamic acid (CIN) or p-chloromercuribenzylsulfonic acid (PCMBS), which exert different types of inhibition. The transport efficiency (TE) ratios of maximal velocity to the trans-activation dissociation constant (Kt) showed that lactate and pyruvate were preferentially transported by types I and II sites, respectively. The cis-lactate effect was observed with high Ki values for both sites. The trans-lactate effect on pyruvate transport occurred only on type I sites and exhibited an asymmetric interaction pattern (Kt of inward lactate > Kt of outward lactate). The inability of lactate to trans-stimulate type II sites suggests that intracellular lactate cannot recruit these sites. The high-affinity type II sites act as a specific pyruvate shuttle and constitute an essential relay for the intracellular lactate shuttle.

4-Chloromercuribenzenesulfonate↗
PubMed2005

Impact of flow rate on lactate uptake and gluconeogenesis in glucagon-stimulated perfused livers.

The impact of reduced hepatic flow on lactate uptake and gluconeogenesis was examined in isolated glucagon-stimulated perfused livers from 24-h-fasted rats. After surgical isolation, livers were perfused (single pass) for 30 min with Krebs-Henseleit (KH) bicarbonate buffer, fresh bovine erythrocytes (hematocrit approximately 20%), and no added substrate. After this "washout" period, steady-state perfusions were initiated with a second reservoir containing the KH buffer, bovine erythrocytes, [U-(14)C]lactate (10,000 dpm/ml), lactate (2.5 mM), and glucagon (250 microg/ml). Perfusion flow rate was adjusted to one of five rates (i.e., 1.8, 2.7, 3.9, 7.4, and 11.0 ml.min(-1).100 g body wt(-1)). After the perfusion, the liver was dissected out and weighed so as to establish the actual flow rate per gram of liver. The resulting flow rates ranged from 0.52 to 4.03 ml.min(-1).g liver(-1). As a function of flow rate, lactate uptake rose in a hyperbolic fashion to an apparent plateau of 2.34 micromol.min(-1).g liver(-1). Fractional extraction (FX) of lactate from the perfusate demonstrated an exponential decline with increased flow rates (r=0.97). At flow rates above 1.0 ml.min(-1).g liver(-1), adjustments in FX compensated for changes in lactate delivery, resulting in steady rates of lactate uptake and gluconeogenesis. Below 1.0.min(-1).g liver(-1) the increased FX was unable to compensate for the decline in lactate delivery and lactate uptake declined rapidly. Gluconeogenesis demonstrated similar kinetics to lactate uptake, reflecting its dominant role among pathways for lactate removal under the current conditions.

Animals↗
PubMed2002

Lactate induces insulin resistance in skeletal muscle by suppressing glycolysis and impairing insulin signaling.

Elevation of plasma lactate levels induces peripheral insulin resistance, but the underlying mechanisms are unclear. We examined whether lactate infusion in rats suppresses glycolysis preceding insulin resistance and whether lactate-induced insulin resistance is accompanied by altered insulin signaling and/or insulin-stimulated glucose transport in skeletal muscle. Hyperinsulinemic euglycemic clamps were conducted for 6 h in conscious, overnight-fasted rats with or without lactate infusion (120 micromol x kg(-1) x min(-1)) during the final 3.5 h. Lactate infusion increased plasma lactate levels about fourfold. The elevation of plasma lactate had rapid effects to suppress insulin-stimulated glycolysis, which clearly preceded its effect to decrease insulin-stimulated glucose uptake. Both submaximal and maximal insulin-stimulated glucose transport decreased 25-30% (P < 0.05) in soleus but not in epitrochlearis muscles of lactate-infused rats. Lactate infusion did not alter insulin's ability to phosphorylate the insulin receptor, the insulin receptor substrate (IRS)-1, or IRS-2 but decreased insulin's ability to stimulate IRS-1- and IRS-2-associated phosphatidylinositol 3-kinase activities and Akt/protein kinase B activity by 47, 75, and 55%, respectively (P < 0.05 for all). In conclusion, elevation of plasma lactate suppressed glycolysis before its effect on insulin-stimulated glucose uptake, consistent with the hypothesis that suppression of glucose metabolism could precede and cause insulin resistance. In addition, lactate-induced insulin resistance was associated with impaired insulin signaling and decreased insulin-stimulated glucose transport in skeletal muscle.

Animals↗