Lactate Utilization Research Articles

Cadmium chloride inhibits lactate gluconeogenesis in mouse renal proximal tubules: An in vitro metabolomic approach with (13)C NMR.

Using isolated mouse renal proximal tubules incubated with lactate as substrate, we have found that the addition of 1-50 μM cadmium chloride (CdCl2) caused a concentration-dependent decrease in lactate utilization, in glucose production and in the cellular level of ATP, coenzyme A, acetyl-coenzyme A and glutathione (reduced and oxidized forms). Combining enzymatic and (13)C NMR measurements in a cellular metabolomic approach, we have shown that, in the presence of 10 μM CdCl2, fluxes through the key-enzymes of gluconeogenesis, phosphoenolpyruvate carboxykinase and glucose-6-phosphatase were greatly depressed by cadmium. This was accompanied by a reduction in fluxes through the enzymes of the tricarboxylic acid cycle. Comparing the mouse and human renal metabolic responses to cadmium, it is interesting to observe that the mouse renal proximal tubule was much more sensitive than the human renal proximal tubule to the adverse effects of CdCl2. As far as renal gluconeogenesis is concerned, the mouse seems to be an appropriate and convenient animal model to study the mechanism of cadmium nephrotoxicity. However, the data obtained in the mouse should be extrapolated to humans with caution because the inhibition of fluxes through the enzymes of the tricarboxylic acid cycle in mouse tubules were not observed in human tubules.

The primary pathway for lactate oxidation in Desulfovibrio vulgaris.

The ability to respire sulfate linked to lactate oxidation is a key metabolic signature of the Desulfovibrio genus. Lactate oxidation by these incomplete oxidizers generates reductants through lactate dehydrogenase (LDH) and pyruvate-ferredoxin oxidoreductase (PFOR), with the latter catalyzing pyruvate conversion into acetyl-CoA. Acetyl-CoA is the source of substrate-level phosphorylation through the production of ATP. Here, we show that these crucial steps are performed by enzymes encoded by a nonacistronic transcriptional unit named now as operon luo (for lactate utilization operon). Using a combination of genetic and biochemical techniques, we assigned a physiological role to the operon genes DVU3027-28 and DVU3032-33. The growth of mutant Δ26-28 was highly disrupted on D-lactate, whereas the growth of mutant Δ32-33 was slower on L-lactate, which could be related to a decrease in the activity of D-lactate or L-lactate oxidase in the corresponding mutants. The DVU3027-28 and DVU3032-33 genes thus encode functional D-LDH and L-LDH enzymes, respectively. Scanning of the genome for lactate utilization revealed several lactate permease and dehydrogenase homologs. However, transcriptional compensation was not observed in any of the mutants except for lactate permease. Although there is a high degree of redundancy for lactate oxidase, it is not functionally efficient in LDH mutants. This result could be related to the identification of several operon enzymes, including LDHs, in the PFOR activity bands, suggesting the occurrence of a lactate-oxidizing supermolecular structure that can optimize the performance of lactate utilization in Desulfovibrio species.

Molecular action of metformin in hepatocytes: an updated insight.

Although, metformin is a drug of the first choice in the treatment of type 2 diabetes mellitus, its molecular action is not fully determined. It is widely accepted that the antihyperglycemic effect of metformin is a result of a decrease in hepatic glucose production, and several cellular targets of the drug have been proposed. The reduction of gluconeogenesis evoked by metformin may be a result of an energy deficit evoked through the inhibition of mitochondrial respiratory chain complex I and/or increased cytosolic redox state and decreased mitochondrial redox state elicited by the inhibition of mitochondrial glycerophosphate dehydrogenase (mGPD). Metformin mediated reduction of hepatic gluconeogenesis was found to be AMP-activated protein kinase (AMPK) dependent and independent, including the inhibition of gluconeogenesis gene expression and allosteric regulation of key gluconeogenesis enzymes. Recently, it was reported that inhibition of mGPD by metformin decreases the level of dihydroxyacetone phosphate and reduces the conversion of lactate to pyruvate, that in consequence diminishes the utilization of glycerol and lactate for gluconeogenesis. The purpose of this paper is to discus molecular mechanisms responsible for the metabolic action of metformin.

Antifungal activity of clotrimazole against Candida albicans depends on carbon sources, growth phase and morphology.

Vulvovaginal candidiasis, a superficial infection caused predominantly by the pathogenic fungus Candida albicans, is frequently treated with clotrimazole. Some drug formulations contain lactate for improved solubility. Lactate may modify C. albicans physiology and drug sensitivity by serving as a carbon source for the fungus and/or affecting local pH. Here, we explored the effects of lactate, in combination with pH changes, on C. albicans proliferation, morphology and clotrimazole sensitivity. Moreover, we determined the influence of growth phase and morphology per se on drug sensitivity. We showed that utilization of lactate as a carbon source did not promote fast fungal proliferation or filamentation. Lactate had no influence on clotrimazole-mediated killing of C. albicans in standard fungal cultivation medium but had an additive effect on the fungicidal clotrimazole action under in vitro vagina-simulative conditions. Moreover, clotrimazole-mediated killing was growth-phase and morphology dependent. Post-exponential cells were resistant to the fungicidal action of clotrimazole, whilst logarithmic cells were sensitive, and hyphae showed the highest susceptibility. Finally, we showed that treatment of pre-formed C. albicans hyphae with sublethal concentrations of clotrimazole induced a reversion to yeast-phase growth. As C. albicans hyphae are considered the pathogenic morphology during mucosal infections, these data suggest that elevated fungicidal activity of clotrimazole against hyphae plus clotrimazole-induced hyphae-to-yeast reversion may help to dampen acute vaginal infections by reducing the relative proportion of hyphae and thus shifting to a non-invasive commensal-like population. In addition, lactate as an ingredient of clotrimazole formulations may potentiate clotrimazole killing of C. albicans in the vaginal microenvironment.

Metabolism of the working diaphragm.

The diaphragm receives an excellent blood supply at all levels of contractile effort, and the O2 requirements of the working diaphragm are met to a greater extent by increasing blood flow than by increasing extraction of O2 from the blood. No evidence for blood flow limitation of contractile effort has been found in the diaphragm, in contrast to the situation in limb skeletal muscle. The efficiency of the diaphragm is highest when ventilation is increased, but it decreases progressively in the presence of increased inspiratory airflow resistance. The working diaphragm appears to derive approximately one half of its energy requirements from carbohydrate metabolism, primarily in the form of lactate utilization. The remaining energy source is probably oxidation of free fatty acids. The diaphragm is quite resistant to net anaerobic metabolism, only producing lactate in significant quantities when it is severely hypoxic. The blood perfusion and metabolic behavior of the diaphragm are much more like those of th...

Comparing biomarkers of traumatic shock: the utility of anion gap, base excess, and serum lactate in the ED

BackgroundBiomarkers such as serum lactate, anion gap (AG), and base excess (BE) have been shown to be of use in determining shock in patients with seemingly normal vital signs. We seek to determine if these biomarkers can be used interchangeably in patients with trauma in the emergency setting based on their test characteristics and correlation to each other. MethodsA prospective observational cohort study was undertaken at an urban level 1 trauma center. Baseline vital signs, point-of-care BE, AG, and serum lactate were recorded in all patients who presented for trauma. Correlation was determined by linear regression model. Overall test characteristics and relative risk were calculated. ResultsOne hundred patients were enrolled. The median age was 30 years (interquartile range, 24-42 years), and 89% were male. Fifty-three percent of injuries were blunt trauma. Pearson correlation of serum lactate to BE was −0.81 (r2 = 0.66; 95% confidence interval [CI], 0.53-0.75; P < .001), that of BE to AG was −0.71 (r2 = 0.5; 95% CI, −0.80 to −0.57; P < .01), and that for serum lactate to AG was 0.71 (r2 = 0.5; 95% CI, 0.57-0.80; P < .01). ConclusionsThis study demonstrates that the biomarkers have similar test characteristics which may make them interchangeable as indicators for the presence of occult shock in patients with trauma. Lactate and BE correlate well with each other; however, AG was not as strongly correlated with either.

NAD-Independent L-Lactate Dehydrogenase Required for L-Lactate Utilization in Pseudomonas stutzeri A1501.

NAD-independent L-lactate dehydrogenases (l-iLDHs) play important roles in L-lactate utilization of different organisms. All of the previously reported L-iLDHs were flavoproteins that catalyze the oxidation of L-lactate by the flavin mononucleotide (FMN)-dependent mechanism. Based on comparative genomic analysis, a gene cluster with three genes (lldA, lldB, and lldC) encoding a novel type of L-iLDH was identified in Pseudomonas stutzeri A1501. When the gene cluster was expressed in Escherichia coli, distinctive L-iLDH activity was detected. The expressed L-iLDH was purified by ammonium sulfate precipitation, ion-exchange chromatography, and affinity chromatography. SDS-PAGE and successive matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) analysis of the purified L-iLDH indicated that it is a complex of LldA, LldB, and LldC (encoded by lldA, lldB, and lldC, respectively). Purified L-iLDH (LldABC) is a dimer of three subunits (LldA, LldB, and LldC), and the ratio between LldA, LldB, and LldC is 1:1:1. Different from the FMN-containing L-iLDH, absorption spectra and elemental analysis suggested that LldABC might use the iron-sulfur cluster for the L-lactate oxidation. LldABC has narrow substrate specificity, and only L-lactate and DL-2-hydrobutyrate were rapidly oxidized. Mg(2+) could activate L-iLDH activity effectively (6.6-fold). Steady-state kinetics indicated a ping-pong mechanism of LldABC for the L-lactate oxidation. Based on the gene knockout results, LldABC was confirmed to be required for the L-lactate metabolism of P. stutzeri A1501. LldABC is the first purified and characterized L-iLDH with different subunits that uses the iron-sulfur cluster as the cofactor. Providing new insights into the diversity of microbial lactate utilization could assist in the production of valuable chemicals and understanding microbial pathogenesis. An NAD-independent L-lactate dehydrogenase (L-iLDH) encoded by the gene cluster lldABC is indispensable for the L-lactate metabolism in Pseudomonas stutzeri A1501. This novel type of enzyme was purified and characterized in this study. Different from the well-characterized FMN-containing L-iLDH in other microbes, LldABC in P. stutzeri A1501 is a dimer of three subunits (LldA, LldB, and LldC) and uses the iron-sulfur cluster as a cofactor.

Glycolysis and the significance of lactate in traumatic brain injury

In traumatic brain injury (TBI) patients, elevation of the brain extracellular lactate concentration and the lactate/pyruvate ratio are well-recognized, and are associated statistically with unfavorable clinical outcome. Brain extracellular lactate was conventionally regarded as a waste product of glucose, when glucose is metabolized via glycolysis (Embden-Meyerhof-Parnas pathway) to pyruvate, followed by conversion to lactate by the action of lactate dehydrogenase, and export of lactate into the extracellular fluid. In TBI, glycolytic lactate is ascribed to hypoxia or mitochondrial dysfunction, although the precise nature of the latter is incompletely understood. Seemingly in contrast to lactate's association with unfavorable outcome is a growing body of evidence that lactate can be beneficial. The idea that the brain can utilize lactate by feeding into the tricarboxylic acid (TCA) cycle of neurons, first published two decades ago, has become known as the astrocyte-neuron lactate shuttle hypothesis. Direct evidence of brain utilization of lactate was first obtained 5 years ago in a cerebral microdialysis study in TBI patients, where administration of 13C-labeled lactate via the microdialysis catheter and simultaneous collection of the emerging microdialysates, with 13C NMR analysis, revealed 13C labeling in glutamine consistent with lactate utilization via the TCA cycle. This suggests that where neurons are too damaged to utilize the lactate produced from glucose by astrocytes, i.e., uncoupling of neuronal and glial metabolism, high extracellular levels of lactate would accumulate, explaining the association between high lactate and poor outcome. Recently, an intravenous exogenous lactate supplementation study in TBI patients revealed evidence for a beneficial effect judged by surrogate endpoints. Here we review the current state of knowledge about glycolysis and lactate in TBI, how it can be measured in patients, and whether it can be modulated to achieve better clinical outcome.

Use of ethyl lactate to extract bioactive compounds from Cytisus scoparius: Comparison of pressurized liquid extraction and medium scale ambient temperature systems

An important trend in the extraction of chemical compounds is the application of new environmentally friendly, food grade solvents. Ethyl lactate (ethyl 2-hydroxypropanoate), produced by fermentation of carbohydrates, is miscible with both hydrophilic and hydrophobic compounds being a potentially good solvent for bioactive compounds. Despite its relatively wide use as a general solvent, the utilization of ethyl lactate as an extraction solvent has only recently been considered. Here, we evaluate the possible use of ethyl lactate to extract phenolic compounds from wild plants belonging to Cytisus scoparius, and we compare the characteristics of the extracts obtained by Pressurized Solvent Extraction (the total phenolics content, the antioxidant activity and the concentration of the major polyphenols) with those of other extracts obtained with methanol. In order to explore the industrial production of the ethyl lactate Cytisus extract, we also evaluate medium scale ambient temperature setups. The whole plant and the different parts (flowers, branches, and seed pods) were evaluated separately as potential sources of polyphenols. All extracts were analyzed by LC–MS/MS for accurate identification of the major polyphenols. Similar phenolic profiles were obtained when using ethyl lactate or methanol. The main bioactives found in the Cytisus extract were the non-flavonoid phenolic compounds caffeic and protocatechuic acids and 3,4-dihydroxybenzaldehyde; the flavonoids rutin, kaempferol and quercetin; the flavones chrysin, orientin and apigenin; and the alkaloid lupanine. Regarding the comparison of the extraction systems, although the performance of the PLE was much better than that of the ambient-temperature columns, the energy consumption was also much higher. Ethyl lactate has resulted an efficient extraction solvent for polyphenols from C. scoparius, yielding extracts with high levels of plant phenolics and antioxidant activity. The antimicrobial activity of these extracts was also tested, showing antibacterial activity against Gram +ve bacteria. Qualitatively similar extracts were obtained either by using PLE or medium-scale-ambient-temperature systems, these last rendering larger volumes of extract with lower energy cost. Good results have been obtained with whole plant extracts; nevertheless, extracts enriched in a particular polyphenol can be obtained from different parts of the plant.

Lactate as substrate for mitochondrial respiration in alveolar epithelial type II cells.

Because of the many energy-demanding functions they perform and their physical location in the lung, alveolar epithelial type II (ATII) cells have a rapid cellular metabolism and the potential to influence substrate availability and bioenergetics both locally in the lung and throughout the body. A thorough understanding of ATII cell metabolic function in the healthy lung is necessary for determining how metabolic changes may contribute to pulmonary disease pathogenesis; however, lung metabolism is poorly understood at the cellular level. Here, we examine lactate utilization by primary ATII cells and the ATII model cell line, MLE-15, and link lactate consumption directly to mitochondrial ATP generation. ATII cells cultured in lactate undergo mitochondrial respiration at near-maximal levels, two times the rates of those grown in glucose, and oxygen consumption under these conditions is directly linked to mitochondrial ATP generation. When both lactate and glucose are available as metabolic substrate, the presence of lactate alters glucose metabolism in ATII to favor reduced glycolytic function in a dose-dependent manner, suggesting that lactate is used in addition to glucose when both substrates are available. Lactate use by ATII mitochondria is dependent on monocarboxylate transporter (MCT)-mediated import, and ATII cells express MCT1, the isoform that mediates lactate import by cells in other lactate-consuming tissues. The balance of lactate production and consumption may play an important role in the maintenance of healthy lung homeostasis, whereas disruption of lactate consumption by factors that impair mitochondrial metabolism, such as hypoxia, may contribute to lactic acid build-up in disease.

Hyperpolarized 13C NMR observation of lactate kinetics in skeletal muscle.

The production of glycolytic end products, such as lactate, usually evokes a cellular shift from aerobic to anaerobic ATP generation and O2 insufficiency. In the classical view, muscle lactate must be exported to the liver for clearance. However, lactate also forms under well-oxygenated conditions, and this has led investigators to postulate lactate shuttling from non-oxidative to oxidative muscle fiber, where it can serve as a precursor. Indeed, the intracellular lactate shuttle and the glycogen shunt hypotheses expand the vision to include a dynamic mobilization and utilization of lactate during a muscle contraction cycle. Testing the tenability of these provocative ideas during a rapid contraction cycle has posed a technical challenge. The present study reports the use of hyperpolarized [1-(13)C]lactate and [2-(13)C]pyruvate in dynamic nuclear polarization (DNP) NMR experiments to measure the rapid pyruvate and lactate kinetics in rat muscle. With a 3s temporal resolution, (13)C DNP NMR detects both [1-(13)C]lactate and [2-(13)C]pyruvate kinetics in muscle. Infusion of dichloroacetate stimulates pyruvate dehydrogenase activity and shifts the kinetics toward oxidative metabolism. Bicarbonate formation from [1-(13)C]lactate increases sharply and acetyl-l-carnitine, acetoacetate and glutamate levels also rise. Such a quick mobilization of pyruvate and lactate toward oxidative metabolism supports the postulated role of lactate in the glycogen shunt and the intracellular lactate shuttle models. The study thus introduces an innovative DNP approach to measure metabolite transients, which will help delineate the cellular and physiological role of lactate and glycolytic end products.

Carbohydrate and lactate utilisation during exercise with and without Yerba Maté ingestion

Nutritional ergogenic and thermogenic aids are commonly used to optimise carbohydrate utilisation and potentially enhance glycogen-sparing ability. However, less is known about the potential effects during exercise, particularly on the responses of carbohydrate oxidation (CHO) and blood lactate concentration (BLC), which are known indicators of exercise intensity and determine exercise performance. This study investigated whether the potential thermogenic effects of Yerba Mate (YM), the plant of (Illex Paraguariensis), affect carbohydrate oxidation rate (CHO) and BLC levels during low and moderate intensity exercise. Male and female participants (n= 11) ingested either 1 g of YM or placebo capsules (PLA) in a randomised crossover experimental design. Within laboratory conditions, participants rested for 1 hr before performing two incremental exercise ergometry tests in separate visits with the power output being initiated and increased by 0·5 W.kg−1 of body mass every 3 min stage until exhaustion. Cardiorespiratory measurements and indirect calorimetry technique were applied to analyse CHO and energy expenditure derived from carbohydrate (EEcho), and capillary blood samples were collected and analysed for BLC at rest and for each exercise intensity domain. Data were analysed using a repeated measures ANOVA design. CHO was reduced significantly (e.g. 0·37 ± 0·24 vs. 0·59 ± 0·19, 0·75 ± 0·24 vs. 1·00 ± 0·33 and 1·36 ± 0·48 vs. 1·64 ± 0·47 g.min−1 at 40, 50, 60 and 70% of VO2 peak respectively, P< 0·001, ANOVA main effects) in the YM compared with PLA at all sub-maximal exercise intensities up to the level of 70% of maximal oxygen uptake (VO2peak), which corresponded to reaching carbohydrate saturation level (respiratory exchange ratio = 1), (p< 0·001, ANOVA main effects). EECHO was also reduced in the YM compared with PLA (Table1). These effects were combined by a trend, though not significant towards a decrease in BLC (P= 0·07) at the same given exercise intensities in YM compared with PLA (Table 1).

Diversity in the utilization of glucose and lactate in synthetic mammalian myotubes generated by engineered configurations of MyoD and E12 in otherwise non-differentiation growth conditions

We previously used the expression of various combinations and configurations of MyoD and E12, two basic helix-loop-helix transcription factors (TF), to produce populations of myotubes assuming distinct morphology, myofibrillar development and Ca2+ dynamics, from mammalian C2C12 myoblasts in non-differentiation growth conditions. Here, we assessed the synthetically generated myotubes in terms of energetics, otherwise necessary to sustain their mechanical output as bio-actuators. We found that the myotubes exhibit changed expression of key regulators for the uptake and utilization of two major cellular fuels, glucose and lactate. Furthermore, while lactate transport was uniformly slowed in all the populations of myotubes, glucose uptake and utilization were modified by particular TF configuration. Our approach allows the production of a class of biomaterials with predetermined energetics that could be applied in biorobotics, where fuel of choice could be used, and also in reparative medicine where, for example, particular population of myotubes could be additionally employed as glucose sinks to mitigate effects of secondary metabolic syndrome.

Brain energy metabolism measured by (13)C magnetic resonance spectroscopy in vivo upon infusion of [3-(13)C]lactate.

The brain uses lactate produced by glycolysis as an energy source. How lactate originated from the blood stream is used to fuel brain metabolism is not clear. The current study measures brain metabolic fluxes and estimates the amount of pyruvate that becomes labeled in glial and neuronal compartments upon infusion of [3-(13)C]lactate. For that, labeling incorporation into carbons of glutamate and glutamine was measured by (13)C magnetic resonance spectroscopy at 14.1 T and analyzed with a two-compartment model of brain metabolism to estimate rates of mitochondrial oxidation, glial pyruvate carboxylation, and the glutamate-glutamine cycle as well as pyruvate fractional enrichments. Extracerebral lactate at supraphysiological levels contributes at least two-fold more to replenish the neuronal than the glial pyruvate pools. The rates of mitochondrial oxidation in neurons and glia, pyruvate carboxylase, and glutamate-glutamine cycles were similar to those estimated by administration of (13)C-enriched glucose, the main fuel of brain energy metabolism. These results are in agreement with primary utilization of exogenous lactate in neurons rather than astrocytes.

Reconstruction of lactate utilization system in Pseudomonas putida KT2440: a novel biocatalyst for l-2-hydroxy-carboxylate production.

As an important method for building blocks synthesis, whole cell biocatalysis is hindered by some shortcomings such as unpredictability of reactions, utilization of opportunistic pathogen, and side reactions. Due to its biological and extensively studied genetic background, Pseudomonas putida KT2440 is viewed as a promising host for construction of efficient biocatalysts. After analysis and reconstruction of the lactate utilization system in the P. putida strain, a novel biocatalyst that only exhibited NAD-independent d-lactate dehydrogenase activity was prepared and used in l-2-hydroxy-carboxylates production. Since the side reaction catalyzed by the NAD-independent l-lactate dehydrogenase was eliminated in whole cells of recombinant P. putida KT2440, two important l-2-hydroxy-carboxylates (l-lactate and l-2-hydroxybutyrate) were produced in high yield and high optical purity by kinetic resolution of racemic 2-hydroxy carboxylic acids. The results highlight the promise in biocatalysis by the biotechnologically important organism P. putida KT2440 through genomic analysis and recombination.

Efficacy of dehydroepiandrosterone to overcome the effect of ovarian ageing (DITTO): a proof of principle randomised controlled trial protocol

IntroductionDehydroepiandrosterone (DHEA) has been proposed to improve pregnancy rates in women with diminished ovarian reserve undergoing in vitro fertilisation (IVF) treatment. However, evidence regarding its efficacy is supported by a...

Utility of admission serum lactate in pediatric trauma

Background/PurposeSerum lactate measurement has a predictive value in adult trauma. To date, there has been no prospective analysis of the predictive value of admission serum lactate in pediatric trauma. MethodsAdmission serum lactate was prospectively measured over a two year period on all children under age 15years who met trauma alert criteria at an urban Level 1 trauma center. Elevated serum lactate (>2.0mmol/L) was correlated with Injury Severity Scores (ISS), injury types, and hospital outcomes. ResultsA total of 277 injured children with admission lactate measurements were evaluated. Patients with elevated lactate had higher mean ISS than those with normal lactate (12.8 vs. 5.1, p<0.01), and increased need for intubation, major procedures and ICU admission. Elevated lactate was associated with low specificity (54.4%), moderate sensitivity (86.7%) and high negative predictive value (94.5%) for detecting injury (ISS>15). Lactate measurements over 4.7mmol/L were highly specific (95.8%) for injury. ConclusionsElevated admission venous lactate level is associated with injury and outcomes, but lacks adequate sensitivity and specificity. Lactate over 4.7mmol/L is strongly suggestive of severe injury, while lactate below 2.0mmol/L is reassuring for not having injury. Lactates between 2.0 and 4.7mmol/L remain indeterminate in predictive potential for injury or outcomes.

Effects of monocarboxylate transporter 1 (MCT1) inhibition on cardiac function under ischaemic conditions: A comparison between rat and guinea-pig Langendorff hearts

The capacity of the brain to metabolize non-glucose substrates under hypoglycemic state maintains its energy requirements. We hypothesized that exercise-induced increase in capacity for brain utilization of lactate by up regulation of the monocarboxylate transporters (MCTs) may contribute metabolic substrates during hypoglycemia in diabetic rats induced by streptozotocin. The induced diabetes increased MCT1 and MCT2 expression in the cortex and the hippocampus in the sedentary diabetic animals. There were exercise-induced increases in MCT1 in the cortex and the hippocampus and MCT2 expression in the cortex in trained diabetic animals; whereas, no changes were found in the healthy trained animals. Both diabetic and healthy trained animals showed higher values for brain lactate uptake during insulin-induced hypoglycemia when animals were intraperitoneally injected by L(+)-lactic acid. However, the response of counterregulatory hormones during hypoglycemia were blunted in the diabetic trained animals which indicates to carefully monitoring of glycemic targets both during and following prolonged exercise.

Brain functioning under acute hypothermic stress supported by dynamic monocarboxylate utilization and transport in ectothermic fish

BackgroundThe vertebrate brain is a highly energy consuming organ that requires continuous energy provision. Energy metabolism of ectothermic organisms is directly affected by environmental temperature changes and has been demonstrated to affect brain energy balance in fish. Fish were hypothesized to metabolize lactate as an additional energy substrate during acute exposure to energy demanding environmental abiotic fluctuations to support brain functionality. However, to date the pathways of lactate mobilization and transport in the fish brain are not well understood, and may represent a critical physiological feature in ectotherms during acclimation to low temperature.ResultsWe found depressed routine metabolic rates in zebrafish during acute exposure to hypothermic (18°C) conditions accompanied by decreased lactate concentrations in brain tissues. No changes in brain glucose content were observed. Acute cold stress increased protein concentrations of lactate dehydrogenase 1 (LDH1) and citrate synthase (CS) in brain by 1.8- and- 2.5-fold, paralleled by an increased pyruvate to acetyl-CoA transformation. To test the involvement of monocarboxylate transporters (MCTs) under acute cold stress in zebrafish, we cloned and sequenced seven MCT1-4 homologues in zebrafish. All drMCT1-4 are expressed in brain tissues and in response to cold stress drmct2a and drmct4a transcripts were up-regulated 5- and 3-fold, respectively. On the contrary, mRNA levels of drmct1a, -1b and -4b in zebrafish brain responded with a down regulation in response to cold stress. By expressing drMCTs in Xenopus oocytes we could provide functional evidence that hypothermic stress leads to a 2-fold increase in lactate transport in drMCT4b expressing oocytes. Lactate transport of other paralogues expressed in oocytes was unaffected, or even decreased during cold stress.ConclusionThe present work provides evidence that lactate utilization and transport pathways represent an important energy homeostatic feature to maintain vital functions of brain cells during acute cold stress in ectotherms.

Optimizing Oxygen Delivery in the Critically Ill: The Utility of Lactate and Central Venous Oxygen Saturation (ScvO2) as a Roadmap of Resuscitation in Shock

BackgroundResuscitation of any critically ill patient is aimed at restoration of oxygen delivery to maintain aerobic metabolism. Thus, “endpoints” of resuscitation have been sought after as a measure of evaluating the adequacy of resuscitation. This review article describes the most commonly used endpoints, central venous oxygen saturation (ScvO2) and lactate, and provides a clinically useful paradigm for utilizing these endpoints during resuscitation of critically ill patients in the emergency department (ED). ObjectiveThis review article will summarize the pathophysiology of cellular shock, describe the available research regarding lactate and ScvO2, and provide an approach to utilizing these endpoints during resuscitation in the ED. DiscussionScvO2 and lactate each have been shown to be useful for the assessment of shock, yet each has inherent limitations. When used together, ScvO2 and lactate provide the emergency physician with a glimpse of the underlying pathophysiologic state, allowing targeted therapy to restore oxygen delivery. ConclusionScvO2 and lactate are useful endpoints of resuscitation, and when used together, provide a metabolic framework for guiding targeted therapy for critically ill patients in the ED with shock.