Interstitial Lactate Research Articles

Intestinal monocarboxylate transporter 1 mediates lactate transport in the gut and regulates metabolic homeostasis of mouse in a sex-dimorphic pattern

Abstract The monocarboxylate transporter 1 (MCT1), encoded by gene Slc16a1, is a proton-coupled transporter for lactate and other monocarboxylates. MCT1-mediated lactate transport was recently found to regulate various biological functions. However, how MCT1 and lactate in the intestine modulate the physiology and pathophysiology of the body is unclear. In this study, we generated a mouse model with specific deletion of Slc16a1 in the intestinal epithelium (Slc16a1IKO mice) and investigated the functions of MCT1 in the gut. When fed a high-fat diet, Slc16a1IKO male mice had improvement in glucose tolerance and insulin sensitivity, while Slc16a1IKO female mice only had increased adiposity. Deficiency of intestinal MCT1 in male mice was associated with downregulation of pro-inflammatory pathways, together with decreased circulating levels of inflammatory cytokines including tumor necrosis factor alpha (TNFα) and C–C motif chemokine ligand 2 (CCL2). Lactate had a stimulatory effect on pro-inflammatory macrophages in vitro. The number of intestinal macrophages was reduced in Slc16a1IKO male mice in vivo. Intestinal deletion of Slc16a1 in male mice reduced interstitial lactate level in the intestine. In addition, treatment of male mice with estrogen lowered interstitial lactate level in the intestine and abolished the difference in glucose homeostasis between Slc16a1IKO and wild-type mice. Deficiency of intestinal MCT1 also blocked the transport of lactate and short-chain fatty acids from the intestine to the portal vein. The effect of Slc16a1 deletion on glucose homeostasis in male mice was partly mediated by alterations in gut microbiota. In conclusion, our work reveals that intestinal MCT1 regulates glucose homeostasis in a sex-dependent manner.

Interstitial Glucose Metabolism Monitoring as an Additional Method for Objective Assessment of Donor Liver, Prediction and Immediate Diagnosis of Early Graft Dysfunction.

A retrospective observational single-center study included 32 cases of liver transplantation. Along with standard methods for assessing the initial function of grafts during the first week after surgery, interstitial (in the transplanted liver) concentrations of glucose and its metabolites were monitored. In 18 cases, the interstitial glucose metabolism was also studied during static cold storage (SCS). With the development of early allograft dysfunction (EAD), compared with the uneventful post-transplant period, statistically significantly higher interstitial lactate concentrations were observed as early as 3 h after reperfusion: 12.3 [10.1; 15.6] mmol/L versus 7.2 [3.9; 9.9] mmol/L (p=0.003). A value above 8.8 mmol/L may be considered as a criterion for the immediate diagnosis of EAD (sensitivity - 89%, specificity - 65%).Interstitial lactate concentration at the end of SCS and the area under the "lactate concentration-SCS duration" curve were associated with the initial graft function. Values of these parameters greater than 15.4 mmol/L and 76.1 mmol/L·h, respectively, with a sensitivity of 100% in both cases and a specificity of 77 and 85%, may be used to assess the risk of primary EAD. Monitoring of interstitial concentrations of glucose and its metabolites, primarily, lactate, is an objective additional method for the assessment of the donor liver viability both during SCS and in the early postoperative period.

Assessment and monitoring of liver graft viability and initial function using interstitial microdialysis

Assessing the viability and monitoring the function of liver graft in the early postoperative period are critical clinical tasks. One possible solution is to determine the changes in concentration of blood glucose, its metabolites and glycerol in the graft using interstitial microdialysis. Objective: to study the dynamics of interstitial glucose, lactate, pyruvate and glycerol in the early post-liver transplant period – depending on the initial graft function (IGF) – and to compare with the results of standard laboratory blood tests. Materials and methods. Four selected clinical observations of deceased donor liver transplantation are presented. Two of the observations showed normal IGF, one observation – early allograft dysfunction (EAD), complicated by hepatic artery thrombosis (HAT), while one observation demonstrated primary non-function (PNF). Collection of microdialysis samples began after arterial reperfusion of the liver graft and continued continuously for 7 days or until death. Standard blood biochemistry and coagulation tests were performed at least once a day. Results. With normal IGF and a smooth postoperative period, interstitial concentrations of glucose, lactate, pyruvate and glycerol remained stable throughout the observation period, ranging from 5 to 20 mmol/L, 1.1 to 7.5 mmol/L, 90 to 380 μmol/L, and 10–100 μmol/L, respectively. EAD was associated with initially higher levels of glucose, lactate, and pyruvate. With HAT development, there was a rapid (within 2–4 hours) five-fold increase in interstitial concentration of lactate with simultaneous decrease in glucose and pyruvate levels to 0.1 mmol/L and 11 μmol/L, respectively. In the case of PNF, there was an initially high concentration of interstitial lactate – 16.4 mmol/L, which increased further to 35.5 mmol/L. Glucose concentration was close to 0. Changes in interstitial glucose, its metabolites and glycerol concentrations chronologically preceded the corresponding changes in peripheral blood composition by 3–5 hours. Conclusion. Microdialysis measurement of interstitial glucose, lactate, pyruvate and glycerol concentrations facilitates real-time monitoring of liver graft viability and function. The high sensitivity of the method could help in accelerating diagnosis of vascular complications (HAT in particular), as well as graft dysfunction with other causes. Therefore, the method is feasible in clinical practice.

Cerebral effects of resuscitation with either epinephrine or vasopressin in an animal model of hemorrhagic shock.

The use of epinephrine (EN) or vasopressin (VP) in hemorrhagic shock is well established. Due to its specific neurovascular effects, VP might be superior in concern to brain tissue integrity. The aim of this study was to evaluate cerebral effects of either EN or VP resuscitation after hemorrhagic shock. After shock induction fourteen pigs were randomly assigned to two treatment groups. After 60min of shock, resuscitation with either EN or VP was performed. Hemodynamics, arterial blood gases as well as cerebral perfusion pressure (CPP) and brain tissue oxygenation (PtiO2) were recorded. Interstitial lactate, pyruvate, glycerol and glutamate were assessed by cerebral and subcutaneous microdialysis. Treatment-related effects were compared using one-way ANOVA with post hoc Bonferroni adjustment (p < 0.05) for repeated measures. Induction of hemorrhagic shock led to a significant (p < 0.05) decrease of mean arterial pressure (MAP), cardiac output (CO) and CPP. Administration of both VP and EN sufficiently restored MAP and CPP and maintained physiological PtiO2 levels. Brain tissue metabolism was not altered significantly during shock and subsequent treatment with VP or EN. Concerning the excess of glycerol and glutamate, we found a significant EN-related release in the subcutaneous tissue, while brain tissue values remained stable during EN treatment. VP treatment resulted in a non-significant increase of cerebral glycerol and glutamate. Both vasopressors were effective in restoring hemodynamics and CPP and in maintaining brain oxygenation. With regards to the cerebral metabolism, we cannot support beneficial effects of VP in this model of hemorrhagic shock.

Neuronal nitric oxide inhibition attenuates the protective effect of HBO2 during cyanide poisoning

Purpose: Experiments have shown that hyperbaric oxygen (HBO2) therapy reduces cyanide-induced cerebral distress. The exact mechanism behind HBO2’s neuroprotective effect is unknown, but has been proposed to be mediated by an increased neuronal nitric oxide (NO) bioavailability, which may compete with cyanide for the active site of cytochrome oxidase in the mitochondrial respiratory chain. We hypothesized that the ameliorating effect of HBO2 is caused by an increased bioavailability of NO, which can be attenuated by injection of the selective neuronal NO synthase inhibitor, 7-nitroindazole, preceding the HBO2 procedure. Methods: A total of 41 anesthetized female Sprague-Dawley rats were allocated to four groups: 1) vehicle [1.2 ml isotonic NaCl via intra-arterial administration]; cyanide [5.4 mg/kg potassium CN (KCN) intra-arterial] + 7-nitroindazole [25 mg/kg 7-nitroindazole via intraperitoneal injection]; cyanide+7-nitroindazole + HBO2 [284 kPa for 90 minutes]; cyanide + 7-nitroindazole + normobaric oxygen [101.3 kPa for 90 minutes]. Cerebral interstitial lactate, glucose, glycerol and pyruvate were evaluated by means of microdialysis. Results: HBO2 during inhibition of nNOS worsened cerebral metabolism compared to both solely CN-intoxicated animals and normobaric oxygen-treated animals. This was indicated by elevated lactate (in mM; 0.85 vs. 0.63 and 0.42, P=0.006 and P&lt;0.001, respectively), glycerol (in mM; 46 vs. 17 and 14, both P&lt;0.001), glucose (in mM; 0.58 vs. 0.31 and 0.32, both P&lt;0.001). Conclusions: The results indicate that a specific nNOS inhibition offsets the ameliorating effect of HBO2 during cerebral CN intoxication. However, other factors might contribute to this neuroprotective effect as well.

Microdialysis as a Part of Invasive Cerebral Monitoring During Porcine Septic Shock.

Metabolic changes in critically ill patients with endotoxin-induced septic shock are measured primarily by techniques that afford organ-specific metabolic monitoring based on interstitial fluid samples. The present study was designed to evaluate the role of cerebral microdialysis (MD) as a part of invasive neuromonitoring during endotoxemia in a porcine model. Continuous endotoxin infusion was administered to 7 female pigs and, in addition to hemodynamic monitoring and blood chemistry, interstitial lactate, pyruvate, glucose and glycerol concentrations in muscle, liver, and cerebral tissue were measured via in vivo MD for an observation period of 180 minutes. The cerebral concentrations of lactate and glycerol showed no significant increases, whereas the hepatic and muscular levels rose dramatically under endotoxemia. However, the lactate/pyruvate ratio and especially the lactate/glucose ratio showed a profound and significant increase in brain tissue as well. Cerebral perfusion pressure decreased from 77 to 50 mm Hg without reaching pathologic values. Although our results confirm the special protection of the brain during endotoxemia compared with other organs, early metabolic changes become evident by increasing lactate/pyruvate ratio and lactate/glucose ratio. MD appears to be a suitable additional technique in invasive neuromonitoring for obtaining early information about metabolic deterioration in the brain during septic shock.

A 3-day EGCG-supplementation reduces interstitial lactate concentration in skeletal muscle of overweight subjects

Green tea, particularly epigallocatechin-3-gallate (EGCG), may affect body weight and composition, possibly by enhancing fat oxidation. The aim of this double-blind, randomized placebo-controlled cross-over study was to investigate whether 3-day supplementation with EGCG (282mg/day) stimulates fat oxidation and lipolysis in 24 overweight subjects (age = 30 ± 2yrs, BMI = 27.7 ± 0.3 kg/m2). Energy expenditure, substrate metabolism and circulating metabolites were determined during fasting and postprandial conditions. After 6 h, a fat biopsy was collected to examine gene expression. In 12 subjects, skeletal muscle glycerol, glucose and lactate concentrations were determined using microdialysis. EGCG-supplementation did not alter energy expenditure and substrate oxidation compared to placebo. Although EGCG reduced postprandial circulating glycerol concentrations (P = 0.015), no difference in skeletal muscle lipolysis was observed. Fasting (P = 0.001) and postprandial (P = 0.003) skeletal muscle lactate concentrations were reduced after EGCG-supplementation compared to placebo, despite similar tissue blood flow. Adipose tissue leptin (P = 0.05) and FAT/CD36 expression (P = 0.08) were increased after EGCG compared to placebo. In conclusion, 3-day EGCG-supplementation decreased postprandial plasma glycerol concentrations, but had no significant effects on skeletal muscle lipolysis and whole-body fat oxidation in overweight individuals. Furthermore, EGCG decreased skeletal muscle lactate concentrations, which suggest a shift towards a more oxidative muscle phenotype.

Channel-mediated lactate release by K⁺-stimulated astrocytes.

Excitatory synaptic transmission is accompanied by a local surge in interstitial lactate that occurs despite adequate oxygen availability, a puzzling phenomenon termed aerobic glycolysis. In addition to its role as an energy substrate, recent studies have shown that lactate modulates neuronal excitability acting through various targets, including NMDA receptors and G-protein-coupled receptors specific for lactate, but little is known about the cellular and molecular mechanisms responsible for the increase in interstitial lactate. Using a panel of genetically encoded fluorescence nanosensors for energy metabolites, we show here that mouse astrocytes in culture, in cortical slices, and in vivo maintain a steady-state reservoir of lactate. The reservoir was released to the extracellular space immediately after exposure of astrocytes to a physiological rise in extracellular K(+) or cell depolarization. Cell-attached patch-clamp analysis of cultured astrocytes revealed a 37 pS lactate-permeable ion channel activated by cell depolarization. The channel was modulated by lactate itself, resulting in a positive feedback loop for lactate release. A rapid fall in intracellular lactate levels was also observed in cortical astrocytes of anesthetized mice in response to local field stimulation. The existence of an astrocytic lactate reservoir and its quick mobilization via an ion channel in response to a neuronal cue provides fresh support to lactate roles in neuronal fueling and in gliotransmission.

Interstitial lactate, lactate/pyruvate and glucose in rat muscle before, during and in the recovery from global hypoxia.

BackgroundHypoxia results in an imbalance between oxygen supply and oxygen consumption. This study utilized microdialysis to monitor changes in the energy-related metabolites lactate, pyruvate and glucose in rat muscle before, during and after 30 minutes of transient global hypoxia. Hypoxia was induced in anaesthetised rats by reducing inspired oxygen to 6% O2 in nitrogen.ResultsBasal values for lactate, the lactate/pyruvate ratio and glucose were 0.72 ± 0.04 mmol/l, 10.03 ± 1.16 and 3.55 ± 0.19 mmol/l (n = 10), respectively. Significant increases in lactate and the lactate/pyruvate ratio were found in the muscle after the induction of hypoxia. Maximum values of 2.26 ± 0.37 mmol/l for lactate were reached during early reperfusion, while the lactate/pyruvate ratio reached maximum values of 35.84 ± 7.81 at the end of hypoxia. Following recovery to ventilation with air, extracellular lactate levels and the lactate/pyruvate ratio returned to control levels within 30–40 minutes. Extracellular glucose levels showed no significant difference between hypoxia and control experiments.ConclusionsIn our study, the complete post-hypoxic recovery of metabolite levels suggests that metabolic enzymes of the skeletal muscle and their related cellular components may be able to tolerate severe hypoxic periods without prolonged damage. The consumption of glucose in the muscle in relation to its delivery seems to be unaffected.

Cerebral metabolism during experimental endotoxin shock and after preconditioning with monophosphoryl lipid A

PurposePreconditioning with low doses of monophosphoryl lipid A (MPL) has been shown to induce endotoxin tolerance and to reduce the metabolic and hemodynamic consequences of endotoxin shock. However, no data are available about the effects of endotoxin preconditioning on cerebral metabolism during endotoxemia. The study was designed to determine the effects of endotoxin preconditioning with MPL on cerebral metabolism via microdialysis compared to muscle tissue metabolism during experimental endotoxemia. MethodsIn a controlled animal study, continuous endotoxin infusion (1μg/kg b.w. per h) was administrated to 7 female mixed-breed pigs after pretreatment with MPL in incremental doses of endotoxin during days 5–2 before the experiments. In the control group, 7 animals received a saline pretreatment. In addition to hemodynamic monitoring and blood gas analyses, interstitial lactate, pyruvate, glucose and glycerol concentrations in muscle and cerebral tissue were measured using in vivo microdialysis. ResultsThere were no significant differences between the two groups with respect to hemodynamic parameters, while mixed venous oxygen saturation (SvO2), arterial blood pH and mean pulmonary arterial pressure (MPAP) were significantly higher in the preconditioned group. Cerebral perfusion pressure (CPP) and brain tissue oxygen pressure (ptiO2) values stayed stable throughout the experiment with no inter-group differences. While interstitial concentrations of lactate and glycerol as well as the lactate/pyruvate (LP) and the lactate/glucose (LG) ratio in muscle tissues were significantly increased in control animals compared to those who had been pretreated with MPL; the results of cerebral microdialysis showed no significant changes in interstitial lactate or glycerol levels in both groups. However, the lactate/glucose (LG) ratio in the control group showed a significantly higher increase than in the preconditioned group. ConclusionsPreconditioning with low doses of MPL ameliorates the negative metabolic effects of endotoxin shock in muscle tissue. With regard to cerebral metabolism, the present study suggests that MLP preconditioning provides moderate advantages, at least in an experimental model of endotoxin shock.

Combined administration of hyperbaric oxygen and hydroxocobalamin improves cerebral metabolism after acute cyanide poisoning in rats

Hyperbaric oxygen therapy (HBOT) or intravenous hydroxocobalamin (OHCob) both abolish cyanide (CN)-induced surges in interstitial brain lactate and glucose concentrations. HBOT has been shown to induce a delayed increase in whole blood CN concentrations, whereas OHCob may act as an intravascular CN scavenger. Additionally, HBOT may prevent respiratory distress and restore blood pressure during CN intoxication, an effect not seen with OHCob administration. In this report, we evaluated the combined effects of HBOT and OHCob on interstitial lactate, glucose, and glycerol concentrations as well as lactate-to-pyruvate ratio in rat brain by means of microdialysis during acute CN poisoning. Anesthetized rats were allocated to three groups: 1) vehicle (1.2 ml isotonic NaCl intra-arterially); 2) potassium CN (5.4 mg/kg intra-arterially); 3) potassium CN, OHCob (100 mg/kg intra-arterially) and subsequent HBOT (284 kPa in 90 min). OHCob and HBOT significantly attenuated the acute surges in interstitial cerebral lactate, glucose, and glycerol concentrations compared with the intoxicated rats given no treatment. Furthermore, the combined treatment resulted in consistent low lactate, glucose, and glycerol concentrations, as well as in low lactate-to-pyruvate ratios compared with CN intoxicated controls. In rats receiving OHCob and HBOT, respiration improved and cyanosis disappeared, with subsequent stabilization of mean arterial blood pressure. The present findings indicate that a combined administration of OHCob and HBOT has a beneficial and persistent effect on the cerebral metabolism during CN intoxication.

The Selective Phosphodiesterase-5 Inhibitor Tadalafil Induces Microvascular and Metabolic Effects in Type 2 Diabetic Postmenopausal Females

The objective of the study was to explore the acute in vivo effects of the selective phosphodiesterase-5 inhibitor tadalafil on local microcirculation and regional metabolism in skeletal muscle and adipose tissue (AT). We studied eight postmenopausal female patients with type 2 diabetes (T2D) and eight nondiabetic controls (Ctrl) in the postabsorptive state and 180 min after the administration of tadalafil 10 mg. Intramuscular and sc microdialysis were combined with measurements of forearm (FBF) and AT blood flow as well as with arterial and deep venous blood sampling. Muscle capillary recruitment, as ascertained by the permeability surface area product for glucose (PS(glu)), forearm glucose uptake (FGU), interstitial lactate, and glycerol concentrations, was measured. When compared with Ctrl, T2D patients exhibited lower (P = 0.01) PS(glu) but similar FGU and FBF. After tadalafil, PS(glu) (P = 0.01) and muscle interstitial-arterial (I-A) lactate concentration gradient (P < 0.01) increased significantly in both groups, whereas FBF, FGU, and I-A glycerol remained unchanged. In AT, tadalafil did not significantly affect local blood flow, whereas the sc interstitial (I) lactate and I-A lactate concentrations increased (P < 0.01), and the I-A glycerol decreased in both groups. Finally, in multivariate analysis the PS(glu) was a strong and independent predictor of muscle glucose disposal (β: 0.737 and 0.963, P < 0.05, in Ctrl and T2D, respectively). Tadalafil emerges as an acutely acting modulator of microvascular recruitment and glucose metabolism in skeletal muscle and adipose tissue. We suggest that selective phosphodiesterase-5 blockade may provide a path forward to new therapeutics in the setting of insulin resistance.

Acute feedback control of astrocytic glycolysis by lactate

Neuronal activity is accompanied by a rapid increase in interstitial lactate, which is hypothesized to serve as a fuel for neurons and a signal for local vasodilation. Using FRET microscopy, we report here that the rate of glycolysis in cultured mice astrocytes can be acutely modulated by physiological changes in extracellular lactate. Glycolytic inhibition by lactate was not accompanied by detectable variations in intracellular pH or intracellular ATP and was not dependent of mitochondrial function. Pyruvate was also inhibitory, suggesting that the effect of lactate is not mediated by the NADH/NAD(+) ratio. We propose that lactate serves as a fast negative feedback signal limiting its own production by astrocytes and therefore the amplitude of the lactate surge. The inhibition of glucose usage by lactate was much stronger in resting astrocytes than in K(+)-stimulated astrocytes, which suggests that lactate may also help diverting glucose from resting to active zones.

Post‐conditioning with cyclosporine A fails to reduce the infarct size in an in vivo porcine model

Cyclosporine A has generated intense interest in the field of cardioprotection due to its ability to protect the mitochondria at reperfusion by blocking the opening of the mitochondrial permeability transition pore. The aim of our study was to examine the cardioprotective effect of Sandimmun, a clinically available formulation of cyclosporine A, in an in vivo large mammal model. Forty-eight pigs were randomly allocated to one of three groups: (i) Control group (Con, n=19), (ii) Cyclosporine group, (Cyclo, n=19) Sandimmun 10 mg/kg i.v. bolus 5 min before reperfusion and (iii) Pre-conditioning group (Precon, n=10) two cycles of 10 min ischemia interspersed with 30-min reperfusion. The study was further sub-divided into a metabolic protocol, evaluating myocardial metabolism by measuring changes in the interstitial lactate concentration, and a coronary flow protocol. All animals were subjected to 40 min of left anterior descending coronary artery occlusion, followed by 180 min of reperfusion before histochemical staining and assessment of infarct size by planimetry. Infarct sizes were measured as: Con 51.4 +/- 16.5%, Cyclo 47.3 +/- 15.7% and Precon 2.4 +/- 3.6%, with no significant difference between the Con and Cyclo groups but a highly significant difference between the Precon and Cyclo and Con groups (P<0.0001 for both comparisons). In the Cyclo group, the interstitial lactate concentration was significantly increased compared with the Con group at 6-min reperfusion, although significantly lower at 14 min presumably due to accelerated washout. In this large animal model, a 10 mg/kg bolus administration of Sandimmun 5 min before reperfusion did not reduce the infarct size.

Towards single-cell real-time imaging of energy metabolism in the brain

Towards single-cell real-time imaging of energy metabolism in the brain

Myocardial metabolism assessed by microdialysis: A prospective randomized study in on- and off-pump coronary bypass surgery

Objective The aim of the study was to compare energetic metabolism in the myocardium during coronary surgery with and without cardiopulmonary bypass by means of microdialysis. Methods Twenty-six low-risk patients were prospectively randomized to off-pump versus on-pump surgery. Microdialysis was used to sample myocardial interstitial fluid during and for 23 hours after surgery. Results Preoperative characteristics and clinical outcome were similar in both groups. Blood glucose and lactate did not differ between groups throughout the observation time. During surgery, intramyocardial levels of glucose, pyruvate and urea were unaffected in off-pump patients, while the same substances significantly decreased ( p < 0.05) in on-pump patients during cardioplegic arrest, and increased during reperfusion. Interstitial lactate levels were higher during off-pump surgery ( p < 0.05). From 3 to 15 hours after surgery, intramyocardial concentrations of glucose, urea and lactate were higher in off-pump patients ( p < 0.001), while pyruvate was higher in on-pump patients ( p < 0.01). Intramyocardial lactate/pyruvate ratio never differed between groups. Postoperatively, cumulative blood release of troponin-T was significantly higher in the on-pump group ( p < 0.005). Conclusions Microdialysis could demonstrate significant differences in energetic metabolism between the two groups. Our data confirm and might help in explaining the lower release of myocardial ischemic markers after off-pump surgery.

An In-Vivo Metabolic Test for Detecting Malignant Hyperthermia Susceptibility in Humans: A Pilot Study

In vitro contracture testing to diagnose malignant hyperthermia (MH) susceptibility requires a muscle biopsy, which may be associated with severe side effects for the patient. After investigation of several different protocols, we present a less invasive metabolic test that involves IM injection of caffeine and halothane, and subsequent measurement of interstitial lactate to differentiate between MH susceptible (MHS) and MH non-susceptible (MHN) individuals. Two microdialysis probes with attached microtubing for trigger injection were inserted into the lateral vastus muscle of eight previously diagnosed MHS patients (representing three genetic variants Gly2434Arg, Thr2206Met, and Arg614Cys), seven MHN patients, and seven control individuals. After equilibration and lactate baseline recording, a single bolus of 200 muL caffeine 80 mM and a suspension of 200 muL halothane 4%V/V in soy bean oil (triggers) were injected locally. Lactate was measured spectrophotometrically. Data are presented as medians and interquartile ranges. Although baseline lactate values were similar in the investigated groups before trigger injection, caffeine increased local lactate in MHS patients significantly more (2.0 [1.8-2.6] mM) than in MHN (0.8 [0.6-1.1] mM) or in control individuals (0.8 [0.6-0.8 mM]). Similarly, halothane lead to a significant lactate increase in MHS compared to MHN and control individuals (8.6 [3.7-8.9] mM vs 0.9 [0.5-1.1] mM and 1.7 [0.9-2.3] mM, respectively). However, a relevant increase of lactate was observed in one MHN and in two control individuals. Systemic hemodynamic and metabolic variables did not differ between the investigated groups. Metabolic monitoring of IM lactate after local caffeine and halothane injection may allow less invasive testing to detect MH susceptibility, without systemic side effects.

Decreases in myocardial glucose and increases in pyruvate but not ischaemia are observed during porcine endotoxaemia

Myocardial dysfunction occurs commonly in septic shock. It is not known whether this is due to local ischaemia and metabolic disturbances. Our hypothesis was that endotoxaemic myocardial dysfunction may be associated with interstitial ischaemic and metabolic changes, measured using interstitial microdialysis (MD). Eighteen pigs were randomized to control (n=6) or endotoxin infusion (n=12). MD catheters were inserted into the myocardium for measurement of interstitial glucose, pyruvate and lactate concentrations. Plasma glucose and lactate concentrations and systemic haemodynamic parameters were measured simultaneously. Compared with the control group, the endotoxaemic animals had significantly decreased left ventricular stroke work and venous oxygen saturation (SvO2), and increased mean pulmonary artery pressure and plasma lactate. In the endotoxaemic group, decreases in interstitial glucose were observed, occurring simultaneously with increases in interstitial pruvate. Interstitial lactate: pyruvate ratios decreased with time in all animals. Despite severe systemic and pulmonary haemodynamic changes, interstitial MD measurements revealed no evidence of anaerobic metabolism in the myocardium of endotoxaemic pigs. There were, however, changes in glucose and pyruvate concentrations, suggesting local energy metabolic disturbances.

Effect of fluorocitrate on cerebral oxidation of lactate and glucose in freely moving rats

Glucose is the primary carbon source to enter the adult brain for catabolic and anabolic reactions. Some studies suggest that astrocytes may metabolize glucose to lactate; the latter serving as a preferential substrate for neurons, especially during neuronal activation. The current study utilizes the aconitase inhibitor fluorocitrate to differentially inhibit oxidative metabolism in glial cells in vivo. Oxidative metabolism of 14C-lactate and 14C-glucose was monitored in vivo using microdialysis and quantitating 14CO2 in the microdialysis eluate following pulse labeling of the interstitial glucose or lactate pool. After establishing a baseline oxidation rate, fluorocitrate was added to the perfusate. Neither lactate nor glucose oxidation was affected by 5 micromol/L fluorocitrate. However, 20 and 100 micromol/L fluorocitrate reduced lactate oxidation by 55 +/- 20% and 68 +/- 12%, respectively (p < 0.05 for both). Twenty and 100 micromol/L fluorocitrate reduced 14C-glucose oxidation by 50 +/- 14% (p < 0.05) and 24 +/- 19% (ns), respectively. Addition of non-radioactive lactate to (14)C-glucose plus fluorocitrate decreased 14C-glucose oxidation by an additional 29% and 38%, respectively. These results indicate that astrocytes oxidize about 50% of the interstitial lactate and about 35% of the glucose. By subtraction, neurons metabolize a maximum of 50% of the interstitial lactate and 65% of the interstitial glucose.

Lactate release from adipose tissue and skeletal muscle in vivo: defective insulin regulation in insulin-resistant obese women

To study the local tissue lactate production in the normal state and its possible disturbances in insulin resistance, rates of lactate release from adipose tissue (AT) and skeletal muscle (SM) were compared postabsorptively and during a hyperinsulinemic euglycemic clamp in 11 healthy nonobese and 11 insulin-resistant obese women. A combination of microdialysis, to measure interstitial lactate, and the 133Xe clearance technique, to determine local blood flow, were used. In the controls, local blood flow increased by 40% in SM (P<0.05) and remained unchanged in AT, whereas the interstitial-plasma difference in lactate doubled in AT (P<0.005) and was unaffected in SM during hyperinsulinemia. In the obese, blood flow and interstitial-plasma difference in lactate remained unchanged in both tissues during hyperinsulinemia. The lactate release (micromol100 g-1min-1) was 1.17+/-0.22 in SM and 0.43+/-0.11 in AT among the controls (P<0.01) and 0.86+/-0.23 in SM and 0.83+/-0.25 in AT among the obese women in the postabsorptive state. During insulin infusion, lactate release in the controls increased to 1.92+/-0.26 in SM (P<0.005) and to 1.14+/-0.22 in AT (P<0.005) but remained unchanged in the obese women. It is concluded that AT and SM are both significant sources of lactate release postabsorptively, and AT is at least as responsive to insulin as SM. The ability to increase lactate release in response to insulin is impaired in AT and SM in insulin-resistant obese women, involving defective insulin regulation of both tissue lactate metabolism and local blood flow.