Effect of major hepatectomy on glucose and lactate metabolism.

BACKGROUND: The liver plays an important role in glucose and lactate metabolism. Major hepatectomy may therefore be suspected to cause alterations of glucose and lactate homeostasis. METHODS: Thirteen subjects were studied: six patients after major hepatectomy and seven healthy subjects who had fasted overnight. Glucose turnover was measured with 6,6(2)H glucose. Lactate metabolism was assessed using two complementary approaches: 13C-glucose synthesis and 13CO2 production from an exogenous 13C-labeled lactate load infused over 15 minutes were measured, then the plasma lactate concentrations observed over 185 minutes after lactate load were fitted using a biexponential model to calculate lactate clearance, endogenous production, and half-lives. RESULTS: Three to five liver segments were excised. Compared to healthy controls, the following results were observed in the patients: 1) normal endogenous glucose production; 2) unchanged 13C-lactate oxidation and transformation into glucose; 3) similar basal plasma lactate concentration, lactate clearance, and lactate endogenous production; 4) decreased plasma lactate half-life 1 and increased half-life 2. CONCLUSIONS: Glucose and lactate metabolism are well maintained in patients after major hepatectomy, demonstrating a large liver functional reserve. Reduction in the size of normal liver parenchyma does not lead to hyperlactatemia. The use of a pharmacokinetic model, however, allows the detection of subtle alterations of lactate metabolism.

Lactate quartile concentration and prognosis in severe sepsis and septic shock.

Introduct ion The Surviving Sepsis Campaign (SSC) indicates that a lactate (LT) concentration greater than 4ımmol/l indicates early resuscitation bundles. However, several recent studies have suggested that LT values lower than 4ımmol/l may be a prognostic marker of adverse outcome. The aim of this study was to identify clinical and analytical prognostic parameters in severe sepsis (SS) or septic shock (ShS) according to quartiles of blood LT concentration. Methods A cohort study was designed in a polyvalent ICU. We studied demographic, clinical and analytical parameters in 148 critically ill adults, within 24ıhours from SS or ShS onset according to SSC criteria. We tested for diı erences in baseline characteristics by lactate interval using a KruskalıWallis test for continuous data or a chi-square test for categorical data and reported the median and interquartile ranges; SPSS version 15.0 (SPSS Inc., Chicago, IL, USA). Results We analyzed 148 consecutive episodes of SS (16%) or ShS (84%). The median age was 64 (interquartile range, 48.7 to 71)ıyears; male: 60%. The main sources of infection were respiratory tract 38% and intra-abdomen 45%; 70.7% had medical pathology. Mortality at 28ıdays was 22.7%. Quartiles of blood LT concentration were quartile 1 (Q1): 1.87ımmol/l or less, quartile 2 (Q2): 1.88 to 2.69ımmol/l, quartile 3 (Q3): 2.7 to 4.06ımmol/l, and quartile 4 (Q4): 4.07ımmol/l or greater (Tableı1). The median LT concentrations of each quartile were 1.43 (Q1), 2.2 (Q2), 3.34 (Q3), and 5.1 (Q4) mmol/l (Pı<0.001). The diı erences between these quartiles were that the patients in Q1 had signiı cantly lower APACHE II scores (Pı=ı0.04), SOFA score (Pı=ı0.024), number of organ failures (NOF) (Pı<0.001) and ICU mortality (Pı=ı0.028), compared with patients in Q2, Q3 and Q4. Patients in Q1 had signiı cantly higher cholesterol (Pı=ı0.06) and lower procalcitonin (Pı=ı0.05) at enrolment. At the extremes, patients in Q1 had decreased 28-day mortality (Pı=ı0.023) and, patients in Q4 had increased 28-day mortality, compared with the other quartiles of patients (Pı=ı0.009). Interestingly, patients in Q2 had signiı cant increased mortality compared with patients in Q1 (Pı=ı0.043), whereas the patients in Q2 had no signiı cant diı erence in 28-day mortality compared with patients in Q3. Conclusion Adverse outcomes and several potential risk factors, including organ failure, are signiı cantly associated with higher quartiles of LT concentrations. It may be useful to revise the cutoı value of lactate according to the SSC (4 mmol/l).

Efecto del phlebodium decumanum y de la coenzima q10 sobre el rendimiento deportivo en jugadores profesionales de voleibol

INTRODUCTION: Physical training programmes are based on provoking transitory states of fatigue in order to induce super compensation by the biological systems involved in the activity, in order to improve the athlete's medium-long term performance. The administration of nutritional supplements with antioxidant and immunomodulatory properties, such as Phlebodium decumanum and coenzyme Q10, can be a very advantageous means of achieving recovery from the inflammation and tissue damage caused by the stress of prolonged, intense exercise. METHODOLOGY: An experimental, longitudinal, double- blind experiment was conducted, with three randomised groups obtained from a sample of 30 male volleyball players (aged 22-32 years) at the University of Granada, with a high level of training (17 hours a week during the 6 months preceding the study). The effects were then evaluated of a month-long physical training programme, common to all the study groups, associated with the simultaneous administration of the following nutritional supplements: Phlebodium decumanum (4 capsules of 400 mg/capsule, daily), Experimental Group 1; Phlebodium decumanum (same dose andchedule as Group 1) plus coenzyme Q10 (4 capsules of 30 mg/ capsule, daily), Experimental Group 2; a placebo substance, Control Group. The following dependent blood variables were examined to assess the effects of the intervention on the basal immune and endocrine-metabolic profile: cortisol and interleukin-6, both related to the axis of exercise-induced stress; and lactic acid and ammonium, related essentially to the anaerobic metabolism of energy. RESULTS: All the study groups presented favourable adaptive changes with respect to the endocrine-metabolic and immune profile, as reflected by a significant decrease in the post-test concentrations of cortisol, interleukin 6, lactic acid and ammonium, compared to the values recorded before the physical activity with/without nutritional supplement, per protocol. The groups that achieved the most favourable profile were those which had received nutritional supplementation, rather than the placebo, and among the former, those which had received the double- strength supplement with Phlebodium decumanum plus coenzyme Q10. CONCLUSIONS: The intake of Phlebodium decumanum plus coenzyme Q10 for 4 weeks produced protective effects on the endocrine-metabolic and immune profile, which we attribute to the immunomodulatory and antioxidant properties of these substances, which are highly beneficial not only in terms of delaying fatigue and improving athletic performance, but also in reducing the risk of injuries associated with high intensity exercise.

Immune cell impact of three differently coated lipid nanocapsules: pluronic, chitosan and polyethylene glycol.

Lipid nanocapsules (NCs) represent promising tools in clinical practice for diagnosis and therapy applications. However, the NC appropriate functionalization is essential to guarantee high biocompatibility and molecule loading ability. In any medical application, the immune system-impact of differently functionalized NCs still remains to be fully understood. A comprehensive study on the action exerted on human peripheral blood mononuclear cells (PBMCs) and major immune subpopulations by three different NC coatings: pluronic, chitosan and polyethylene glycol-polylactic acid (PEG) is reported. After a deep particle characterization, the uptake was assessed by flow-cytometry and confocal microscopy, focusing then on apoptosis, necrosis and proliferation impact in T cells and monocytes. Cell functionality by cell diameter variations, different activation marker analysis and cytokine assays were performed. We demonstrated that the NCs impact on the immune cell response is strongly correlated to their coating. Pluronic-NCs were able to induce immunomodulation of innate immunity inducing monocyte activations. Immunomodulation was observed in monocytes and T lymphocytes treated with Chitosan-NCs. Conversely, PEG-NCs were completely inert. These findings are of particular value towards a pre-selection of specific NC coatings depending on biomedical purposes for pre-clinical investigations; i.e. the immune-specific action of particular NC coating can be excellent for immunotherapy applications.

Activity-dependent regulation of energy metabolism by astrocytes: an update.

Astrocytes play a critical role in the regulation of brain metabolic responses to activity. One detailed mechanism proposed to describe the role of astrocytes in some of these responses has come to be known as the astrocyte-neuron lactate shuttle hypothesis (ANLSH). Although controversial, the original concept of a coupling mechanism between neuronal activity and glucose utilization that involves an activation of aerobic glycolysis in astrocytes and lactate consumption by neurons provides a heuristically valid framework for experimental studies. In this context, it is necessary to provide a survey of recent developments and data pertaining to this model. Thus, here, we review very recent experimental evidence as well as theoretical arguments strongly supporting the original model and in some cases extending it. Aspects revisited include the existence of glutamate-induced glycolysis in astrocytes in vitro, ex vivo, and in vivo, lactate as a preferential oxidative substrate for neurons, and the notion of net lactate transfer between astrocytes and neurons in vivo. Inclusion of a role for glycogen in the ANLSH is discussed in the light of a possible extension of the astrocyte-neuron lactate shuttle (ANLS) concept rather than as a competing hypothesis. New perspectives offered by the application of this concept include a better understanding of the basis of signals used in functional brain imaging, a role for neuron-glia metabolic interactions in glucose sensing and diabetes, as well as novel strategies to develop therapies against neurodegenerative diseases based upon improving astrocyte-neuron coupled energetics.

Effects of lactate on glucose metabolism in healthy subjects and in severely injured hyperglycemic patients.

Hepatic glucose production is autoregulated during infusion of gluconeogenic precursors. In hyperglycemic patients with multiple trauma, hepatic glucose production and gluconeogenesis are increased, suggesting that autoregulation of hepatic glucose production may be defective. To better understand the mechanisms of autoregulation and its possible alterations in metabolic stress, lactate was coinfused with glucose in healthy volunteers and in hyperglycemic patients with multiple trauma or critical illness. In healthy volunteers, infusion of glucose alone nearly abolished endogenous glucose production. Lactate increased gluconeogenesis (as indicated by a decrease in net carbohydrate oxidation with no change in total [13C]carbohydrate oxidation) but did not increase endogenous glucose production. In patients with metabolic stress, endogenous glucose production was not suppressed by exogenous glucose, but lactate did not further increase hepatic glucose production. It is concluded that 1) in healthy humans, autoregulation of hepatic glucose production during infusion of lactate is still present when glycogenolysis is suppressed by exogenous glucose and 2) autoregulation of hepatic glucose production is not abolished in hyperglycemic patients with metabolic stress.

Brain energetics (thought needs food).

PURPOSE OF REVIEW: Almost 15 years after its initial proposal, the astrocyte-neuron lactate shuttle hypothesis still occupies the center stage in research on brain energetics. Recent developments have provided further evidence for its validity and have extended its application to different areas of neuroscience. RECENT FINDINGS: Description of cell-specific metabolic characteristics have reinforced the view that a prominent conversion of glucose into lactate takes place in astrocytes, whereas neurons preferentially take up and oxidize lactate over glucose-derived pyruvate. Indeed, specific mechanisms are activated by glutamatergic activity to favor such a net lactate transfer between the two cell types. Moreover, demonstration in vivo of the existence and implication of the astrocyte-neuron lactate shuttle hypothesis for particular neurophysiological processes is beginning to appear. SUMMARY: Brain energetics has undertaken its revolution. A new concept based on metabolic compartmentalization between astrocytes and neurons is establishing itself as the leading paradigm that opens new perspectives in areas such as functional brain imaging and regulation of energy homeostasis.

Sweet sixteen for ANLS.

Since its introduction 16 years ago, the astrocyte-neuron lactate shuttle (ANLS) model has profoundly modified our understanding of neuroenergetics by bringing a cellular and molecular resolution. Praised or disputed, the concept has never ceased to attract attention, leading to critical advances and unexpected insights. Here, we summarize recent experimental evidence further supporting the main tenets of the model. Thus, evidence for distinct metabolic phenotypes between neurons (mainly oxidative) and astrocytes (mainly glycolytic) have been provided by genomics and classical metabolic approaches. Moreover, it has become clear that astrocytes act as a syncytium to distribute energy substrates such as lactate to active neurones. Glycogen, the main energy reserve located in astrocytes, is used as a lactate source to sustain glutamatergic neurotransmission and synaptic plasticity. Lactate is also emerging as a neuroprotective agent as well as a key signal to regulate blood flow. Characterization of monocarboxylate transporter regulation indicates a possible involvement in synaptic plasticity and memory. Finally, several modeling studies captured the implications of such findings for many brain functions. The ANLS model now represents a useful, experimentally based framework to better understand the coupling between neuronal activity and energetics as it relates to neuronal plasticity, neurodegeneration, and functional brain imaging.

Effects of lactate infusion on hepatic gluconeogenesis and glycogenolysis.

Endogenous glucose production rate (EGPR) remains constant when lactate is infused in healthy humans. A decrease of glycogenolysis or of gluconeogenesis from endogenous precursors or a stimulation of glycogen synthesis, may all be involved; This autoregulation does not depend on changes in glucoregulatory hormones. It may be speculated that alterations in basal sympathetic tone may be involved. To gain insights into the mechanisms responsible for autoregulation of EGPR, glycogenolysis and gluconeogenesis were measured, with a novel method (based on the prelabelling of endogenous glycogen with 13C glucose, and determination of hepatic 13C glycogen enrichment from breath 13CO2 and respiratory gas exchanges) in healthy humans infused with lactate or saline. These measurements were performed with or without beta-adrenergic receptor blockade (propranolol). Infusion of lactate increased energy expenditure, but did not increase EGPR; the relative contributions of gluconeogenesis and glycogenolysis to EGPR were also unaltered. This indicates that autoregulation is attained, at least in part, by inhibition of gluconeogenesis from endogenous precursors. beta-adrenergic receptor blockade alone (with propranolol) did not alter EGPR, glycogenolysis or gluconeogenesis. During infusion of lactate, propranolol decreased the thermic effect of lactate but EGPR remained constant. This indicates that alterations of beta-adrenergic activity is not required for autoregulation of EGPR.

Role of Na+-K+-ATPase in insulin-induced lactate release by skeletal muscle.

Hyperinsulinemia increases lactate release by various organs and tissues. Whereas it has been shown that aerobic glycolysis is linked to Na+-K+-ATPase activity, we hypothesized that stimulation by insulin of skeletal muscle Na+-K+-ATPase is responsible for increased muscle lactate production. To test this hypothesis, we assessed muscle lactate release in healthy volunteers from the [13C]lactate concentration in the effluent dialysates of microdialysis probes inserted into the tibialis anterior muscles on both sides and infused with solutions containing 5 mmol/l [U-13C]glucose. On one side, the microdialysis probe was intermittently infused with the same solution additioned with 2.10(-5) M ouabain. In the basal state, [13C]lactate concentration in the dialysate was not affected by ouabain. During a euglycemic-hyperinsulinemic clamp, [13C]lactate concentration increased by 135% in the dialysate without ouabain, and this stimulation was nearly entirely reversed by ouabain (56% inhibition compared with values in the dialysate collected from the contralateral probe). These data indicate that insulin stimulates muscle lactate release by activating Na+-K+-ATPase in healthy humans.

Level of accumulation of epoxy fatty acid in Arabidopsis thaliana expressing a linoleic acid delta12-epoxygenase is influenced by the availability of the substrate linoleic acid.

Arabidopsis thaliana (L.) Heynh. expressing the Crepis palaestina (L.) linoleic acid delta12-epoxygenase in its developing seeds typically accumulates low levels of vernolic acid (12,13-epoxy-octadec-cis-9-enoic acid) in comparison to levels found in seeds of the native C. palaestina. In order to determine some of the factors limiting the accumulation of this unusual fatty acid, we have examined the effects of increasing the availability of linoleic acid (9cis, 12cis-octadecadienoic acid), the substrate of the delta12-epoxygenase, on the quantity of epoxy fatty acids accumulating in transgenic A. thaliana. The addition of linoleic acid to liquid cultures of transgenic plants expressing the delta12-epoxygenase under the control of the cauliflower mosaic virus 35S promoter increased the amount of vernolic acid in vegetative tissues by 2.8-fold. In contrast, the addition to these cultures of linoelaidic acid (9trans, 12trans-octadecadienoic acid), which is not a substrate of the delta12-epoxygenase, resulted in a slight decrease in vernolic acid accumulation. Expression of the delta12-epoxygenase under the control of the napin promoter in the A. thaliana triple mutant fad3/fad7-1/fad9, which is deficient in the synthesis of tri-unsaturated fatty acids and has a 60% higher level of linoleic acid than the wild type, was found to increase the average vernolic acid content of the seeds by 55% compared to the expression of the delta12-epoxygenase in a wild-type background. Together, these results reveal that the availability of linoleic acid is an important factor affecting the synthesis of epoxy fatty acid in transgenic plants.

Alteration of amino acid metabolism in neuronal aggregate cultures exposed to hypoglycaemic conditions.

The neuronal effects of glucose deficiency on amino acid metabolism was studied on three-dimensional cultures of rat telencephalon neurones. Transient (6 h) exposure of differentiated cultures to low glucose (0.25 mm instead of 25 mm) caused irreversible damage, as judged by the marked decrease in the activities of two neurone-specific enzymes and lactate dehydrogenase, 1 week after the hypoglycemic insult. Quantification of amino acids and ammonia in the culture media supernatants indicated increased amino acid utilization and ammonia production during glucose-deficiency. Measurement of intracellular amino acids showed decreased levels of alanine, glutamine, glutamate and GABA, while aspartate was increased. Added lactate (11 mm) during glucose deficiency largely prevented the changes in amino acid metabolism and ammonia production, and attenuated irreversible damage. Higher media levels of glutamine (4 mm instead of 0.25 mm) during glucose deprivation prevented the decrease of intracellular glutamate and GABA, while it further increased intracellular aspartate, ammonia production and neuronal damage. Both lactate and glutamine were readily oxidized in these neuronal cultures. The present results suggest that in neurones, glucose deficiency enhances amino acid deamination at the expense of transamination reactions. This results in increased ammonia production and neuronal damage.

Running from Paris to Beijing: biomechanical and physiological consequences.

The purpose of this study was to examine the physiological and biomechanical changes occurring in a subject after running 8,500 km in 161 days (i.e. 52.8 km daily). Three weeks before, 3 weeks after (POST) and 5 months after (POST+5) running from Paris to Beijing, energy cost of running (Cr), knee flexor and extensor isokinetic strength and biomechanical parameters (using a treadmill dynamometer) at different velocities were assessed in an experienced ultra-runner. At POST, there was a tendency toward a 'smoother' running pattern, as shown by (a) a higher stride frequency and duty factor, and a reduced aerial time without a change in contact time, (b) a lower maximal vertical force and loading rate at impact and (c) a decrease in both potential and kinetic energy changes at each step. This was associated with a detrimental effect on Cr (+6.2%) and a loss of strength at all angular velocities for both knee flexors and extensors. At POST+5, the subject returned to his original running patterns at low but not at high speeds and maximal strength remained reduced at low angular velocities (i.e. at high levels of force). It is suggested that the running pattern changes observed in the present study were a strategy adopted by the subject to reduce the deleterious effects of long distance running. However, the running pattern changes could partly be linked to the decrease in maximal strength.

Fructose and glucose co-ingestion during prolonged exercise increases lactate and glucose fluxes and oxidation compared with an equimolar intake of glucose

BACKGROUND: When fructose is ingested together with glucose (GLUFRU) during exercise, plasma lactate and exogenous carbohydrate oxidation rates are higher than with glucose alone. OBJECTIVE: The objective was to investigate to what extent GLUFRU increased lactate kinetics and oxidation rate and gluconeogenesis from lactate (GNG(L)) and from fructose (GNG(F)). DESIGN: Seven endurance-trained men performed 120 min of exercise at approximately 60% VOmax (maximal oxygen consumption) while ingesting 1.2 g glucose/min + 0.8 g of either glucose or fructose/min (GLUFRU). In 2 trials, the effects of glucose and GLUFRU on lactate and glucose kinetics were investigated with glucose and lactate tracers. In a third trial, labeled fructose was added to GLUFRU to assess fructose disposal. RESULTS: In GLUFRU, lactate appearance (120 +/- 6 mumol . kg(1) . min(1)), lactate disappearance (121 +/- 7 mumol . kg(1) . min(1)), and oxidation (127 +/- 12 mumol . kg(1) . min(1)) rates increased significantly (P < 0.001) in comparison with glucose alone (94 +/- 16, 95 +/- 16, and 97 +/- 16 mumol . kg(1) . min(1), respectively). GNG(L) was negligible in both conditions. In GLUFRU, GNG(F) and exogenous fructose oxidation increased with time and leveled off at 18.8 +/- 3.7 and 38 +/- 4 mumol . kg(1) . min(1), respectively, at 100 min. Plasma glucose appearance rate was significantly higher (P < 0.01) in GLUFRU (91 +/- 6 mumol . kg(1) . min(1)) than in glucose alone (82 +/- 9 mumol . kg(1) . min(1)). Carbohydrate oxidation rate was higher (P < 0.05) in GLUFRU. CONCLUSIONS: Fructose increased total carbohydrate oxidation, lactate production and oxidation, and GNG(F). Fructose oxidation was explained equally by fructose-derived lactate and glucose oxidation, most likely in skeletal and cardiac muscle. This trial was registered at clinicaltrials.gov as NCT01128647.

Rise in plasma lactate concentrations with psychosocial stress: a possible sign of cerebral energy demand.

OBJECTIVE: It is known that exogenous lactate given as an i.v. energy infusion is able to counteract a neuroglycopenic state that developed during psychosocial stress. It is unknown, however, whether the brain under stressful conditions can induce a rise in plasma lactate to satisfy its increased needs during stress. Since lactate is i) an alternative cerebral energy substrate to glucose and ii) its plasmatic concentration is influenced by the sympathetic nervous system, the present study aimed at investigating whether plasma lactate concentrations increase with psychosocial stress in humans. METHODS: 30 healthy young men participated in two sessions (stress induced by the Trier Social Stress Test and a non-stress control session). Blood samples were frequently taken to assess plasma lactate concentrations and stress hormone profiles. RESULTS: Plasma lactate increased 47% during psychosocial stress (from 0.9 ± 0.05 to 1.4 ± 0.1 mmol/l; interaction time × stress intervention: F = 19.7, p < 0.001). This increase in lactate concentrations during stress was associated with an increase in epinephrine (R(2) = 0.221, p = 0.02) and ACTH concentrations (R(2) = 0.460, p < 0.001). CONCLUSION: Plasma lactate concentrations increase during acute psychosocial stress in humans. This finding suggests the existence of a demand mechanism that functions to allocate an additional source of energy from the body towards the brain, which we refer to as 'cerebral lactate demand'.