Effect of bicarbonate and lactate buffer on glucose and lactate metabolism during hemodiafiltration in patients with multiple organ failure.

OBJECTIVE: To compare the effects of sodium bicarbonate and lactate for continuous veno-venous hemodiafiltration (CVVHDF) in critically ill patients. DESIGN AND SETTINGS: Prospective crossed-over controlled trial in the surgical and medical ICUs of a university hospital. PATIENTS: Eight patients with multiple organ dysfunction syndrome (MODS) requiring CVVHDF. INTERVENTION: Each patient received the two buffers in a randomized sequence over two consecutive days. MEASUREMENTS AND RESULTS: The following variables were determined: acid-base parameters, lactate production and utilization ((13)C lactate infusion), glucose turnover (6,6(2)H(2)-glucose), gas exchange (indirect calorimetry). No side effect was observed during lactate administration. Baseline arterial acid-base variables were equal with the two buffers. Arterial lactate (2.9 versus 1.5 mmol/l), glycemia (+18%) and glucose turnover (+23%) were higher in the lactate period. Bicarbonate and glucose losses in CVVHDF were substantial, but not lactate elimination. Infusing (13)C lactate increased plasma lactate levels equally with the two buffers. Lactate clearance (7.8+/-0.8 vs 7.5+/-0.8 ml/kg per min in the bicarbonate and lactate periods) and endogenous production rates (14.0+/-2.6 vs 13.6+/-2.6 mmol/kg per min) were similar. (13)C lactate was used as a metabolic substrate, as shown by (13)CO(2) excretion. Glycemia and metabolic rate increased significantly and similarly during the two periods during lactate infusion. CONCLUSION: Lactate was rapidly cleared from the blood of critically ill patients without acute liver failure requiring CVVHDF, being transformed into glucose or oxidized. Lactate did not exert undesirable effects, except moderate hyperglycemia, and achieved comparable effects on acid-base balance to bicarbonate.

Kinetics of dexamethasone-induced alterations of glucose metabolism in healthy humans.

Six healthy human subjects were studied during three 75-g oral, [13C]glucose tolerance tests to assess the kinetics of dexamethasone-induced impairment of glucose tolerance. On one occasion, they received dexamethasone (4 x 0.5 mg/day) during the previous 2 days. On another occasion, they received a single dose (0. 5 mg) of dexamethasone 150 min before ingestion of the glucose load. On the third occasion, they received a placebo. Postload plasma glucose was significantly increased after both 2 days dexamethasone and single dose dexamethasone compared with control (P < 0.05). This corresponded to a 20-23% decrease in the metabolic clearance rate of glucose, whereas total glucose turnover ([6,6-2H]glucose), total (indirect calorimetry) and exogenous glucose oxidation (13CO2 production), and suppression of endogenous glucose production were unaffected by dexamethasone. Plasma insulin concentrations were increased after 2 days of dexamethasone but not after a single dose of dexamethasone. In a second set of experiments, the effect of a single dose of dexamethasone on insulin sensitivity was assessed in six healthy humans during a 2-h euglycemic hyperinsulinemic clamp. Dexamethasone did not significantly alter insulin sensitivity. It is concluded that acute administration of dexamethasone impairs oral glucose tolerance without significantly decreasing insulin sensitivity.

Protein turnover, ureagenesis and gluconeogenesis.

The major processes discussed below are protein turnover (degradation and synthesis), degradation into urea, or conversion into glucose (gluconeogenesis, Figure 1). Daily protein turnover is a dynamic process characterized by a double flux of amino acids: the amino acids released by endogenous (body) protein breakdown can be reutilized and reconverted to protein synthesis, with very little loss. Daily rates of protein turnover in humans (300 to 400 g per day) are largely in excess of the level of protein intake (50 to 80 g per day). A fast growing rate, as in premature babies or in children recovering from malnutrition, leads to a high protein turnover rate and a high protein and energy requirement. Protein metabolism (synthesis and breakdown) is an energy-requiring process, dependent upon endogenous ATP supply. The contribution made by whole-body protein turnover to the resting metabolic rate is important: it represents about 20 % in adults and more in growing children. Metabolism of proteins cannot be disconnected from that of energy since energy balance influences net protein utilization, and since protein intake has an important effect on postprandial thermogenesis - more important than that of fats or carbohydrates. The metabolic need for amino acids is essentially to maintain stores of endogenous tissue proteins within an appropriate range, allowing protein homeostasis to be maintained. Thanks to a dynamic, free amino acid pool, this demand for amino acids can be continuously supplied. The size of the free amino acid pool remains limited and is regulated within narrow limits. The supply of amino acids to cover physiological needs can be derived from 3 sources: 1. Exogenous proteins that release amino acids after digestion and absorption 2. Tissue protein breakdown during protein turnover 3. De novo synthesis, including amino acids (as well as ammonia) derived from the process of urea salvage, following hydrolysis and microflora metabolism in the hind gut. When protein intake surpasses the physiological needs of amino acids, the excess amino acids are disposed of by three major processes: 1. Increased oxidation, with terminal end products such as CO₂ and ammonia 2. Enhanced ureagenesis i. e. synthesis of urea linked to protein oxidation eliminates the nitrogen radical 3. Gluconeogenesis, i. e. de novo synthesis of glucose. Most of the amino groups of the excess amino acids are converted into urea through the urea cycle, whereas their carbon skeletons are transformed into other intermediates, mostly glucose. This is one of the mechanisms, essential for life, developed by the body to maintain blood glucose within a narrow range, (i. e. glucose homeostasis). It includes the process of gluconeogenesis, i. e. de novo synthesis of glucose from non-glycogenic precursors; in particular certain specific amino acids (for example, alanine), as well as glycerol (derived from fat breakdown) and lactate (derived from muscles). The gluconeogenetic pathway progressively takes over when the supply of glucose from exogenous or endogenous sources (glycogenolysis) becomes insufficient. This process becomes vital during periods of metabolic stress, such as starvation.

Relation entre glucose cérébral et systémique chez le sujet neurolésé: une étude par microdialyse cérébrale

Introduction: Le glucose est le principal substrat énergétique cérébral. Sa concentration dans le cerveau est étroitement liée à la glycémie. Chez le patient neurolésé, du fait de l'augmentation des besoins énergétiques, les réserves cérébrales de glucose sont limitées. Une glycémie suffisamment élevée paraît nécessaire pour assurer un apport adéquat de glucose au cerveau. Objectifs : Le but de cette étude est de mieux comprendre la relation entre glucose cérébral et glycémie lors de lésion cérébrale en analysant la physiologie cérébrale chez des patients neurolésés. Plus précisément nous investiguerons: La relation entre le glucose cérébral et le glucose systémique et son association avec le pronostic vital, l'association entre la neuroglucopénie et différents paramètres cérébraux tel que l'hypertension intracrânienne (HTIC) ou la dysfonction énergétique et finalement l'effet d'une perfusion de glucose 10% sur le glucose cérébral lors d'état de neuroglucopénie. Méthodologie : Analyse d'une base de données prospective comportant des patients souffrant d'un traumatisme crânio-cérébral (TCC) ou une hémorragie sous- arachnoïdienne (HSA) sévères. Les patients comateux sont monitorés par un dispositif intra-parenchymateux avancé, comprenant un cathéter de microdialyse cérébrale et un capteur de PbO2. Résultats : 34 patients consécutifs (moyenne d'âge 42 ans, moyenne de temps jusqu'au début du monitoring : 1.5 jours ± 1 ; moyenne de la durée maximale du monitoring : 6 jours ± 3) ont été étudiés, 25 patients souffrant d'un TCC et 9 patients avec une HSA. Nous avons obtenu une corrélation individuelle entre le glucose cérébral et la glycémie chez 52.9 % des patients. Lorsque la glycémie est inférieure à 5 mmol/l, on observe plus fréquemment des épisodes de neuroglucopénie en comparaison aux valeurs intermédiaires de glycémie (5 - 9.9 mmol/l). Les épisodes d'HTIC (pression intracrânienne (PIC) > 20 mmHg) sont plus fréquemment associés à des épisodes de neuroglucopénie que lorsque la pression intracrânienne est normale 75 % vs. 35%. La dysfonction énergétique est plus souvent associés à des épisodes de neuroglucopénie que lorsque le LPR est normal: 55% contre 36%. Un coefficient de corrélation entre glucose cérébral et glycémie significativement plus élevé a été obtenu chez les survivants que chez les non-survivants (0.1 [interquartile range 0.02- 0.3] contre 0.32 [0.17-0.61]). Chez les patients neuroglucopéniques ayant une corrélation entre glucose cérébral et glycémie, la perfusion de glucose i.v. fait monter le glucose cérébral jusqu'à l'arrêt de la perfusion. Conclusion : Malgré une étroite relation entre glycémie et glucose cérébral en conditions stables, cette relation peut être altérée par des causes cérébrales chez les patients neurolésés montrant que la diminution de la disponibilité du glucose extracellulaire ne résulte pas uniquement d'une hypoglycémie relative mais également de causes cérébrales tel que l'hypoperfusion, l'HTIC ou la dysfonction énergétique.

Portal glucose infusion in the mouse induces hypoglycemia: evidence that the hepatoportal glucose sensor stimulates glucose utilization.

To analyze the role of the murine hepatoportal glucose sensor in the control of whole-body glucose metabolism, we infused glucose at a rate corresponding to the endogenous glucose production rate through the portal vein of conscious mice (Po-mice) that were fasted for 6 h. Mice infused with glucose at the same rate through the femoral vein (Fe-mice) and mice infused with a saline solution (Sal-mice) were used as controls. In Po-mice, hypoglycemia progressively developed until glucose levels dropped to a nadir of 2.3 +/- 0.1 mmol/l, whereas in Fe-mice, glycemia rapidly and transiently developed, and glucose levels increased to 7.7 +/- 0.6 mmol/l before progressively returning to fasting glycemic levels. Plasma insulin levels were similar in both Po- and Fe-mice during and at the end of the infusion periods (21.2 +/- 2.2 vs. 25.7 +/- 0.9 microU/ml, respectively, at 180 min of infusion). The whole-body glucose turnover rate was significantly higher in Po-mice than in Fe-mice (45.9 +/- 3.8 vs. 37.7 +/- 2.0 mg x kg(-1) x min)-1), respectively) and in Sal-mice (24.4 +/- 1.8 mg x kg(-1) x min(-1)). Somatostatin co-infusion with glucose in Po-mice prevented hypoglycemia without modifying the plasma insulin profile. Finally, tissue glucose clearance, which was determined after injecting 14C-2-deoxyglucose, increased to a higher level in Po-mice versus Fe-mice in the heart, brown adipose tissue, and the soleus muscle. Our data show that stimulation of the hepatoportal glucose sensor induced hypoglycemia and increased glucose utilization by a combination of insulin-dependent and insulin-independent or -sensitizing mechanisms. Furthermore, activation of the glucose sensor and/or transmission of its signal to target tissues can be blocked by somatostatin.

Loss of glucose-induced insulin secretion and GLUT2 expression in transplanted beta-cells.

Either 200 or 400 syngeneic islets were transplanted under the kidney capsule of normal or streptozocin-induced diabetic B6/AF1 mice. The diabetic mice with 400 islets became normoglycemic, but those with 200 islets, an insufficient number, were still diabetic after the transplantation (Tx). Two weeks after Tx, GLUT2 expression in the islet grafts was evaluated by immunofluorescence and Western blots, and graft function was examined by perfusion of the graft-bearing kidney. Immunofluorescence for GLUT2 was dramatically reduced in the beta-cells of grafts with 200 islets exposed to hyperglycemia. However, it was plentiful in grafts with 400 islets in a normoglycemic environment. Densitometric analysis of Western blots on graft homogenates demonstrated that GLUT2 protein levels in the islets, when exposed to chronic hyperglycemia for 2 weeks, were decreased to 16% of those of normal recipients. Moreover, these grafts had defective glucose-induced insulin secretion, while the effects of arginine were preserved. We conclude that GLUT2 expression in normal beta-cells is promptly down-regulated during exposure to hyperglycemia and may contribute to the loss of glucose-induced secretion of diabetes.

Food for thought: the importance of glucose and other energy substrates for sustaining brain function under varying levels of activity.

The brain requires a constant and substantial energy supply to maintain its main functions. For decades, it was assumed that glucose was the major if not the only significant source of energy for neurons. This view was supported by the expression of specific facilitative glucose transporters on cerebral blood vessels, as well as neurons. Despite the fact that glucose remains a key energetic substrate for the brain, growing evidence suggests a different scenario. Thus astrocytes, a major type of glial cells that express their own glucose transporter, play a critical role in coupling synaptic activity with glucose utilization. It was shown that glutamatergic activity triggers an enhancement of aerobic glycolysis in this cell type. As a result, lactate is provided to neurons as an additional energy substrate. Indeed, lactate has proven to be a preferential energy substrate for neurons under various conditions. A family of proton-linked carriers known as monocarboxylate transporters has been described and specific members have been found to be expressed by endothelial cells, astrocytes and neurons. Moreover, these transporters are subject to fine regulation of their expression levels and localization, notably in neurons, which suggests that lactate supply could be adjusted as a function of their level of activity. Considering the importance of energetics in the aetiology of several neurodegenerative diseases, a better understanding of its cellular and molecular underpinnings might have important implications for the future development of neuroprotective strategies.

Training in hypoxia fails to further enhance endurance performance and lactate clearance in well-trained men and impairs glucose metabolism during prolonged exercise.

The aim of this study was to investigate the synergistic effects of endurance training and hypoxia on endurance performance in normoxic and hypoxic conditions (approximately 3000 m above sea level) as well as on lactate and glucose metabolism during prolonged exercise. For this purpose, 14 well-trained cyclists performed 12 training sessions in conditions of normobaric hypoxia (HYP group, n = 7) or normoxia (NOR group, n = 7) over 4 weeks. Before and after training, lactate and glucose turnover rates were measured by infusion of exogenous lactate and stable isotope tracers. Endurance performance was assessed during incremental tests performed in normoxia and hypoxia and a 40 km time trial performed in normoxia. After training, performance was similarly and significantly improved in the NOR and HYP groups (training, P < 0.001) in normoxic conditions. No further effect of hypoxic training was found on markers of endurance performance in hypoxia (training x hypoxia interaction, n.s.). In addition, training and hypoxia had no significant effect on lactate turnover rate. In contrast, there was a significant interaction of training and hypoxia (P < 0.05) on glucose metabolism, as follows: plasma insulin and glucose concentrations were significantly increased; glucose metabolic clearance rate was decreased; and the insulin to glucagon ratio was increased after training in the HYP group. In conclusion, our results show that, compared with training in normoxia, training in hypoxia has no further effect on endurance performance in both normoxic and hypoxic conditions or on lactate metabolic clearance rate. Additionally, these findings suggest that training in hypoxia impairs blood glucose regulation in endurance-trained subjects during exercise.

Stimulation of thermogenesis in men after combined glucose-long-chain triglyceride infusion.

The effect of combined long-chain triglyceride infusion (Intralipid 20%) with graded doses of insulin/glucose on energy expenditure was examined in 17 healthy young male volunteers by using the euglycemic insulin clamp technique in combination with indirect calorimetry. Intralipid was infused for 90 min at a constant rate of 0.23 g/min; plasma free fatty acids increased from base-line values of 380 +/- 8 mumol/l to steady state levels of 650 +/- 12 mumol/l. After 90 min the Intralipid was continued and insulin was infused at three rates (0.5, 2, and 4 mU/kg . min) to achieve steady state hyperinsulinemic plateaus of 63 +/- 4, 167 +/- 10, and 410 +/- 15 microU/ml. Plasma glucose concentration was maintained constant at basal euglycemic levels (insulin clamp technique) by infusing glucose at 0.24, 0.48, and 0.59 g/min, respectively. Glucose storage during the insulin clamp (ie, glucose uptake minus glucose oxidation) was 0.13, 0.33, and 0.40 g/min for each group and exogenous lipid storage was 0.17, 0.18, and 0.19 g/min, respectively. The net increment in energy expenditure was 0.15, 0.24, and 0.26 kcal/min, respectively, which represents 8.5% of the energy content of the total amount of glucose and lipid stored. The experimentally determined value (approximately 9%) for the cost of storing both glucose and lipid was found to be significantly greater than predicted by stoichiometric calculations. However, the experimental value for the combined infusion was less than that observed for glucose storage alone (12%). This finding provides support for the use of combined glucose/fat infusions in parenteral nutrition as it is used more economically than when glucose is infused alone.

Glucose release from GLUT2-null hepatocytes: characterization of a major and a minor pathway.

We previously reported that glucose can be released from GLUT2-null hepatocytes through a membrane traffic-based pathway issued from the endoplasmic reticulum. Here, we further characterized this glucose release mechanism using biosynthetic labeling protocols. In continuous pulse-labeling experiments, we determined that glucose secretion proceeded linearly and with the same kinetics in control and GLUT2-null hepatocytes. In GLUT2-deficient hepatocytes, however, a fraction of newly synthesized glucose accumulated intracellularly. The linear accumulation of glucose in the medium was inhibited in mutant, but not in control, hepatocytes by progesterone and low temperature, as previously reported, but, importantly, also by microtubule disruption. The intracellular pool of glucose was shown to be present in the cytosol, and, in pulse-chase experiments, it was shown to be released at a relatively slow rate. Release was not inhibited by S-4048 (an inhibitor of glucose-6-phosphate translocase), cytochalasin B, or progesterone. It was inhibited by phloretin, carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone, and low temperature. We conclude that the major release pathway segregates glucose away from the cytosol by use of a membrane traffic-based, microtubule-dependent mechanism and that the release of the cytosolic pool of newly synthesized glucose, through an as yet unidentified plasma membrane transport system, cannot account for the bulk of glucose release.

Differences in glucose transporter gene expression between rat pancreatic alpha- and beta-cells are correlated to differences in glucose transport but not in glucose utilization.

Glucose exerts inverse effects upon the secretory function of islet alpha- and beta-cells, suppressing glucagon release and increasing insulin release. This diverse action may result from differences in glucose transport and metabolism between the two cell types. The present study compares glucose transport in rat alpha- and beta-cells. beta-Cells transcribed GLUT2 and, to a lesser extent, GLUT 1; alpha-cells contained GLUT1 but no GLUT2 mRNA. No other GLUT-like sequences were found among cDNAs from alpha- or beta-cells. Both cell types expressed 43-kDa GLUT1 protein which was enhanced by culture. The 62-kDa beta-cell GLUT2 protein was converted to a 58-kDa protein after trypsin treatment of the cells without detectable consequences upon glucose transport kinetics. In beta-cells, the rates of glucose transport were 10-fold higher than in alpha-cells. In both cell types, glucose uptake exceeded the rates of glucose utilization by a factor of 10 or more. Glycolytic flux, measured as D-[5(3)H]glucose utilization, was comparable in alpha- and beta-cells between 1 and 10 mmol/liter substrate. In conclusion, differences in glucose transporter gene expression between alpha- and beta-cells can be correlated with differences in glucose transport kinetics but not with different glucose utilization rates.

Effects of infused amino acids and lipids on glucose metabolism in healthy lean humans.

The effects of infusion of a triglyceride emulsion (which induces peripheral insulin resistance) and amino acids (which stimulate gluconeogenesis) on glucose metabolism were investigated in healthy lean humans during exogenous infusion of glucose. One group of subjects (n = 5) was infused for 7.5 h with 11.1 mumol/kg/min glucose; during the last 4 h, amino acids were also infused at a rate of 3.33 mg/kg/min. A second group of subjects (n = 5) was infused with glucose+lipids (Lipovenös, 10% 10 ml/min) for 7.5 h and amino acids were added during the last 4 h. Infusion of lipids suppressed the increase in glucose oxidation observed during infusion of glucose alone (delta glucose oxidation: -2.1 +/- 1.1 vs. + 4.5 +/- 1.4 mumol/kg/min; P < 0.05) and during infusion of glucose+amino acids (delta glucose oxidation: + 1.6 +/- 1.4 vs. + 10.6 +/- 1.2 mumol/kg/min; P < 0.05). Gluconeogenesis (determined from 13C glucose synthesis during infusion of 13C bicarbonate) increased from 1.1 +/- 0.2 mumol/kg/min during infusion of glucose and 1.6 +/- 0.3 during infusion of glucose+lipids to 3.2 +/- 0.4 and 3.1 +/- 0.4, respectively, when amino acid infusion was superimposed (P < 0.05 in both instances). Plasma glucose concentrations were identical during infusion of glucose alone or glucose+amino acids, with or without lipids. Insulin concentrations were significantly increased by lipids both during infusion of glucose alone and of glucose+amino acids.(ABSTRACT TRUNCATED AT 250 WORDS)

Brain energy consumption induced by electrical stimulation promotes systemic glucose uptake.

BACKGROUND: Controlled transcranial stimulation of the brain is part of clinical treatment strategies in neuropsychiatric diseases such as depression, stroke, or Parkinson's disease. Manipulating brain activity by transcranial stimulation, however, inevitably influences other control centers of various neuronal and neurohormonal feedback loops and therefore may concomitantly affect systemic metabolic regulation. Because hypothalamic adenosine triphosphate-sensitive potassium channels, which function as local energy sensors, are centrally involved in the regulation of glucose homeostasis, we tested whether transcranial direct current stimulation (tDCS) causes an excitation-induced transient neuronal energy depletion and thus influences systemic glucose homeostasis and related neuroendocrine mediators.METHODS: In a crossover design testing 15 healthy male volunteers, we increased neuronal excitation by anodal tDCS versus sham and examined cerebral energy consumption with (31)phosphorus magnetic resonance spectroscopy. Systemic glucose uptake was determined by euglycemic-hyperinsulinemic glucose clamp, and neurohormonal measurements comprised the parameters of the stress systems.RESULTS: We found that anodic tDCS-induced neuronal excitation causes an energetic depletion, as quantified by (31)phosphorus magnetic resonance spectroscopy. Moreover, tDCS-induced cerebral energy consumption promotes systemic glucose tolerance in a standardized euglycemic-hyperinsulinemic glucose clamp procedure and reduces neurohormonal stress axes activity.CONCLUSIONS: Our data demonstrate that transcranial brain stimulation not only evokes alterations in local neuronal processes but also clearly influences downstream metabolic systems regulated by the brain. The beneficial effects of tDCS on metabolic features may thus qualify brain stimulation as a promising nonpharmacologic therapy option for drug-induced or comorbid metabolic disturbances in various neuropsychiatric diseases.

Does fructose consumption contribute to non-alcoholic fatty liver disease?

Fructose is mainly consumed with added sugars (sucrose and high fructose corn syrup), and represents up to 10% of total energy intake in the US and in several European countries. This hexose is essentially metabolized in splanchnic tissues, where it is converted into glucose, glycogen, lactate, and, to a minor extent, fatty acids. In animal models, high fructose diets cause the development of obesity, insulin resistance, diabetes mellitus, and dyslipidemia. Ectopic lipid deposition in the liver is an early occurrence upon fructose exposure, and is tightly linked to hepatic insulin resistance. In humans, there is strong evidence, based on several intervention trials, that fructose overfeeding increases fasting and postprandial plasma triglyceride concentrations, which are related to stimulation of hepatic de novo lipogenesis and VLDL-TG secretion, together with decreased VLDL-TG clearance. However, in contrast to animal models, fructose intakes as high as 200 g/day in humans only modestly decreases hepatic insulin sensitivity, and has no effect on no whole body (muscle) insulin sensitivity. A possible explanation may be that insulin resistance and dysglycemia develop mostly in presence of sustained fructose exposures associated with changes in body composition. Such effects are observed with high daily fructose intakes, and there is no solid evidence that fructose, when consumed in moderate amounts, has deleterious effects. There is only limited information regarding the effects of fructose on intrahepatic lipid concentrations. In animal models, high fructose diets clearly stimulate hepatic de novo lipogenesis and cause hepatic steatosis. In addition, some observations suggest that fructose may trigger hepatic inflammation and stimulate the development of hepatic fibrosis. This raises the possibility that fructose may promote the progression of non-alcoholic fatty liver disease to its more severe forms, i.e. non-alcoholic steatohepatitis and cirrhosis. In humans, a short-term fructose overfeeding stimulates de novo lipogenesis and significantly increases intrahepatic fat concentration, without however reaching the proportion encountered in non-alcoholic fatty liver diseases. Whether consumption of lower amounts of fructose over prolonged periods may contribute to the pathogenesis of NAFLD has not been convincingly documented in epidemiological studies and remains to be further assessed.