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PubMedDate not supplied

Glutamine supplementation fails to affect muscle protein kinetics in critically ill patients.

BACKGROUND: In vitro work suggests that glutamine availability may be an important factor in controlling the rate of muscle protein synthesis. The objective of this study was to determine if enteral administration of glutamine affects muscle protein metabolism in critically ill patients. METHODS: Six postsurgical patients requiring prolonged mechanical ventilation for pneumonia (age, 51 +/- 12 years, Acute Physiology and Chronic Health Evaluation [APACHE] 22 +/- 6, mean +/- SEM) and 6 normal healthy volunteers (age, 33 +/- 4 years) underwent evaluation of whole body and muscle protein metabolism using an 8-hour infusion of d5-phenylalanine, 5(15)N glutamine, and d3-alanine with serial blood sampling from the femoral artery and vein and biopsies from the vastus lateralis muscle. Metabolic measurements were obtained while subjects received Peptamen enterally (Basal Period) and with glutamine supplementation (24 g/3 h; Glutamine Period). RESULTS: Glutamine concentration in muscle was significantly less in the critically ill patients. Glutamine supplementation increased the arterial plasma concentration of glutamine, yet with no demonstratable effect on muscle glutamine concentration or on the rate of muscle protein synthesis in either volunteers or patients. Furthermore, muscle glutamine kinetics (incorporation into muscle, release from muscle, and rate of de novo glutamine synthesis in muscle) were not affected by glutamine supplementation in the critically ill patients. In contrast, there was a significant decrease in these kinetic parameters with glutamine supplementation within the muscle of healthy subjects. Metabolism of alanine was unaffected by administration of glutamine in either group. CONCLUSIONS: Enteral glutamine supplementation to critically ill patients fails to alter muscle glutamine metabolism or muscle protein synthesis. This suggests a possible restriction in transport of glutamine into muscle of critically ill patients.

Adult↗
PubMed1997

Role of glutamine as a glucose precursor in fasting humans.

Recently, significant incorporation of labeled carbon into plasma glucose was documented during infusion of 14C-labeled glutamine in postabsorptive humans. Such labeling of plasma glucose can occur as a result of two different processes: either 1) through incorporation of glutamine carbon into glucose via glutamine entering Krebs cycle at alpha-ketoglutarate or 2) through simple fixation of labeled CO2 resulting from oxidation of labeled glutamine. Therefore, these studies were designed to determine 1) whether glutamine contributes carbon to gluconeogenesis other than through mere CO2 fixation, and, if so, 2) whether the apparent transfer of carbon from glutamine to glucose increases with fasting. Eight healthy adults were studied on two consecutive days: once after an overnight (18-h) fast and again on the second day of fasting (42-h fast). On each study day, subjects received a simultaneous 5-h infusion of D-[6,6-2H2lglucose, L-[3,4-13C2lglutamine, and L-[1-14C]leucine. Apparent rates of incorporation of glutamine carbon into glucose were estimated from the appearance of 13C into plasma glucose; glucose and glutamine production rates (appearance rate [Ra]) were determined from plasma [2H2]glucose and [13C2]glutamine enrichments, respectively. The appearance of 14C into plasma glucose was used to correct the measured rates of carbon transfer from glutamine to glucose as a result of CO2 fixation. We observed that of the apparent contribution of labeled glutamine to gluconeogenesis, only 4% occurred as a result of fixation of labeled CO2, while 96% seemed to occur through other routes. We also observed that between 18 and 42 h of fasting, 1) the relative contribution of protein breakdown to glutamine production was enhanced, while that of de novo synthesis declined; 2) the apparent contribution of glutamine to glucose production rose from 8 +/- 1 to 16 +/- 3% of overall glucose Ra; and 3) the relative apparent contribution of glutamine to gluconeogenesis remained constant. From the current data, it cannot be ascertained to what extent the apparent carbon transfer from glutamine to glucose represents a true contribution of glutamine to gluconeogenesis or mere carbon exchange between the trichloroacetic acid cycle and the gluconeogenic pathway. These findings are nevertheless compatible with a role of glutamine as a significant precursor of glucose in fasting humans.

Adult↗
PubMed1996

[Glutamine: effects on the immune system, protein balance and intestinal functions].

Glutamine is the most abundant free amino acid of the human body. In catabolic stress situations such as after operations, trauma and during sepsis the enhanced transport of glutamine to splanchnic organs and to blood cells results in an intracellular depletion of glutamine in skeletal muscle. Glutamine is an important metabolic substrate for cells cultivated under in vitro conditions and is a precursor for purines, pyrimidines and phospholipids. Increasing evidence suggests that glutamine is a crucial substrate for immunocompetent cells. Glutamine depletion in the cultivation medium decreases the mitogen-inducible proliferation of lymphocytes, possibly by arresting the cells in the G0-G1 phase of the cell cycle. Glutamine depletion in lymphocytes prevents the formation of signals necessary for late activation. In monocytes glutamine deprivation downregulates surface antigens responsible for antigen preservation and phagocytosis. Glutamine is a precursor for the synthesis of glutathionine and stimulates the formation of heat-shock proteins. Moreover, there are suggestions that glutamine plays a crucial role in osmotic regulation of cell volume and causes phosphorylation of proteins, both of which may stimulate intracellular protein synthesis. Experimental studies revealed that glutamine deficiency causes a necrotising enterocolitis and increases the mortality of animals subjected to bacterial stress. First clinical studies have demonstrated a decrease in the incidence of infections and a shortening of the hospital stay in patients after bone marrow transplantation by supplementation with glutamine. In critically ill patients parenteral glutamine reduced nitrogen loss and caused a reduction of the mortality rate. In surgical patients glutamine evoked an improvement of several immunological parameters. Moreover, glutamine exerted a trophic effect on the intestinal mucosa, decreased the intestinal permeability and thus may prevent the translocation of bacteria. In conclusion, glutamine is an important metabolic substrate of rapidly proliferating cells, influences the cellular hydration state and has multiple effects on the immune system, on intestinal function and on protein metabolism. In several disease states glutamine may consequently, become an indispensable nutrient, which should be provided exogenously during artificial nutrition.

Animals↗
PubMed1995

Dietary regulation of the hepatic system n glutamine transporter in tumor-bearing rats.

BACKGROUND: Hepatocytes possess a novel, plasma-membrane, sodium ion (Na+)-independent, glutamine transporter (system n), which functions to transport glutamine out of the cell into the blood. In the tumor-bearing rat, the activity of system n increases but its regulation is unknown. We hypothesized that the increase in system n that occurs in rats with cancer was related to a fall in the circulating glutamine concentration. METHODS: Ten male rats underwent flank implantation with a cube of methylcholanthrene-induced fibrosarcoma cells and 10 rats underwent a sham operation. After 9 days of standard diet, all rats were randomized to receive either a glutamine-enriched oral diet or an isonitrogenous diet without supplemental glutamine, for 1 week. Tumors and livers were harvested 16 days postimplantation. Arterial blood samples were obtained from all animals. Hepatic plasma membrane vesicles were prepared and the carrier-mediated, Na(+)-independent transport of glutamine was assayed. RESULTS: When compared to nontumor-bearing animals, tumor-bearing rats that were fed a control diet exhibited hypoglutaminemia and a 2.3-fold increase in the activity of system n. Glutamine dietary supplementation produced blood glutamine levels that were similar in both tumor-bearing and nontumor-bearing rats, apparently abrogating the increase in system n activity that was observed in tumor-bearing rats that were not fed supplemental glutamine. Tumor-bearing animals receiving supplemental glutamine had a decreased number of system n carriers (Vmax) in the hepatic plasma membrane compared to that of tumor-bearing animals receiving a control diet; this apparently abrogated the glutamine efflux rate. Glutamine feeding did not alter system n activity in nontumor-bearing controls. CONCLUSIONS: In the tumor-bearing animal model, system n is modulated by the circulating glutamine concentration. This is the first study that demonstrates the ability of specialized nutrition to "downregulate" transport activity in vivo. Provision of glutamine-enriched diets to the host with cancer may maintain hepatic glutamine levels and prevent host glutamine depletion.

Animals↗
PubMed1997

Aspects of glutamine metabolism in human tumour cells.

The importance of the non-essential amino acid, glutamine, to the proliferation of human tumour cells was investigated. All of the cells studied had a high activity of phosphate-dependent glutaminase and were found to utilise glutamine from the culture medium during long term culture. The rate of cell proliferation, determined by [6-3H]-thymidine incorporation, was dependent on glutamine concentration with the exception of Hs578T and MOLT 4 cells. The glutamine concentration giving half maximal growth (ED50) ranged from 0.02-0.24 mM. The glutamine analogue, acivicin [L-(alpha S,5S)-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid], markedly inhibited cell proliferation in the absence of glutamine. However, in the presence of glutamine acivicin only caused inhibition of proliferation in certain cell lines. Replacement of glutamine in the culture medium by glutamate resulted in an increase in the rate of cell proliferation when compared with rates in the absence of glutamine with no glutamate supplement. In addition, cells grown in the presence of the glutamine synthetase inhibitor, methionine sulphoximine, showed a marked decrease in proliferation. These data suggested the presence of glutamine synthetase in human tumour cells, which was confirmed by radiochemical assay of maximal glutamine synthetase activity. The breast tumour cells Hs578T, with high glutamine synthetase activity, were able to proliferate at rates similar to that in the presence of glutamine, when glutamine-deficient medium was supplemented with purine nucleosides. However, the breast tumour cells MCF7, with low glutamine synthetase activity, were unable to proliferate at comparable rates in the presence of either purine or pyrimidine nucleoside supplements.

Alanine Transaminase↗
PubMed2001

Glutamine metabolism in sepsis and infection.

Severe infection causes marked derangements in the flow of glutamine among organs, and these changes are accompanied by significant alterations in regional cell membrane transport and intracellular glutamine metabolism. Skeletal muscle, the major repository of glutamine, exhibits a twofold increase in glutamine release during infection, which is associated with a significant increase in endogenous glutamine biosynthesis. Despite an increase in glutamine synthetase activity in skeletal muscle, the intracellular glutamine pool becomes depleted, indicating that release rates exceed rates of synthesis. Simultaneously, the circulating pool of glutamine does not increase, indicating accelerated uptake by other organs. The liver appears to be the major organ of glutamine uptake in severe infection; studies in endotoxemic rodents have shown net hepatic glutamine uptake to increase by as much as 8- to 10-fold. This increase is due partially to increases in liver blood flow, but also to a three- to fourfold increase in hepatocyte System N activity in the liver. Cytokines and glucocorticoids mediate the increased uptake of glutamine by the liver in septic states as well as other compounds. Sepsis does not appear to induce an increase in System N gene expression, indicating that the increase in hepatic glutamine transport observed during severe infection is probably regulated at the protein level. The bowel displays a decrease in glutamine utilization during sepsis, a response that may be related to the decrease in circulating insulin-like growth factor-1 (IGF-1) levels that is characteristic of sepsis. Recent studies suggest that IGF-1 has a direct effect on stimulating glutamine transport across the gut lumen and thus may represent a therapeutic avenue for improving gut nutrition during severe infection. The cells of the immune system (lymphocytes, macrophages) are also major glutamine consumers during inflammatory states in which cell proliferation is increased. Under these conditions, glutamine availability can become rate limiting for key cell functions, such as phagocytosis and antibody production.

Animals↗
PubMed1993

Influence of progressive tumor growth on glutamine metabolism in skeletal muscle and kidney.

OBJECTIVE: The effects of progressive malignant growth on glutamine metabolism in skeletal muscle and in kidney were investigated. SUMMARY BACKGROUND DATA: Fast-growing tumors consume considerable quantities of glutamine and lead to a decrease in circulating glutamine concentrations. METHODS: Experiments were performed at various stages of tumor growth in rats implanted subcutaneously with the non-metastasizing methylcholanthrene-induced (MCA) fibrosarcoma and in pair-fed non tumor-bearing controls. RESULTS: Tumor growth stimulated a twofold increase in hindquarter (muscle) glutamine release, which was not due to an increase in blood flow, but rather to a doubling in the fractional release rate. Consequently, a progressive decrease in skeletal muscle glutamine concentrations was observed over time. Simultaneously, the activity of glutamine synthetase (GS), the principal enzyme of de novo glutamine biosynthesis, increased more than twofold. This increase in muscle GS activity was accompanied by an increase in GS mRNA but the augmentation in GS expression apparently could not match the increased rate of efflux since muscle depletion developed. In rats with large tumors and severe glutamine depletion, GS activity was not elevated. Glutamine feeding increased muscle glutamine concentrations and glutamine synthetase specific activity. Although tumor growth led to the development of mild systemic acidemia, the classic renal adaptations normally observed, i.e., elevated glutaminase activity and accelerated renal glutamine utilization, were not present in acidotic tumor-bearing rats. Instead, renal GS activity was increased in tumor-bearing animals and ammoniagenesis was enhanced, in spite of a reduction in net renal glutamine uptake. CONCLUSIONS: These data suggest that marked alterations in muscle and renal glutamine handling occur in the host with cancer; the enhanced muscle glutamine release in conjunction with no increase in renal consumption is consistent with increased glutamine uptake in other organs, most likely the tumor itself and the liver.

Ammonia↗
PubMed1990

Interactions between glutamine metabolism and cell-volume regulation in perfused rat liver.

1. In the presence of near-physiological glutamine concentrations, exposure of perfused rat liver to hypotonic perfusion media switched glutamine balance across the liver from net release to net uptake. This was due to both stimulation of flux through glutaminase and inhibition of flux through glutamine synthetase. Conversely, during exposure to hypertonic media, net glutamine release from the liver increased due to inhibition of glutaminase flux and slight stimulation of flux through glutamine synthetase. The effect of perfusate osmolarity on glutaminase flux was observed at an NH4Cl concentration (0.5 mM) sufficient for near-maximal ammonia stimulation of glutaminase. This indicates the involvement of different mechanisms of glutaminase flux control by extracellular osmolarity changes and ammonia. The effects of anisotonicity on flux through glutamine-metabolizing enzymes were fully reversible. Glutamine (0.6 mM) stimulated urea synthesis from NH4Cl (0.5 mM) during hypotonic and normotonic conditions. 2. Exposure to hypotonic and hypertonic media led, after initial liver-cell swelling and shrinkage, respectively to volume-regulatory K+ fluxes which largely restored the initial liver-cell volume despite the continuing osmotic challenge. Even after completion of cell-volume regulatory K+ fluxes, the effects of perfusate osmolarity on hepatic glutamine metabolism persisted. This indicates that in anisotonicity the liver cell is left in an altered metabolic state, even after completion of volume-regulatory responses. 3. During perfusion with isotonic media, addition of glutamine (3 mM) led to an increase of liver mass by about 4% within 2 min, which was accompanied by a net K+ uptake by the liver. Thereafter, the new steady state of increased liver mass was maintained throughout glutamine infusion. When the liver mass had reached this new steady state, a net release of K+ from the liver of about 3 mumol/g liver was observed during the following 10 min. Withdrawal of glutamine was followed by a slow reuptake of K+ and the liver mass returned to its initial value. Following exposure to glutamine (3 mM), the intracellular glutamine concentration (as calculated from glutamine tissue levels, taking into account the extracellular space determined with the [3H]inulin technique) rose from about 1 mM to 30-35 mM within about 12 min, indicating a 10-12-fold concentrative uptake of glutamine into the liver cells and an osmotic challenge for the hepatocyte. When intracellular glutamine had reached its steady-state concentration, net K+ efflux from the liver was also terminated.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1987

Plasma glutamine and renal ammoniagenesis in dogs with chronic metabolic acidosis.

The purpose of this investigation was to determine whether the rate of glutamine metabolism in the kidneys of normal dogs and dogs with chronic metabolic acidosis was influenced by the plasma glutamine concentration. Because glutamine is a major renal energy fuel, results were examined at a constant rate of energy or ATP turnover [i.e., per 100 ml glomerular filtration rate (GFR)]. Glutamine extraction per 100 ml GFR was directly proportional to the filtered load of glutamine in normal and acidotic dogs. The slope depicting this relationship was parallel to the filtered load of glutamine; however, in normal dogs it was lower and in acidotic dogs it exceeded the filtered load by approximately 22 mumol/100 ml GFR. With respect to the fate of the nitrogens of the glutamine extracted, alanine and ammonium were produced in normal dogs at a rate nearly equivalent to that of glutamine extracted, whereas ammonium production was almost twofold greater than the rate of glutamine extraction during acidosis. There was a relatively small but constant alanine release over the entire range of plasma glutamine concentrations in these dogs. Furthermore, infusion of glutamine to raise the plasma glutamine concentration twofold during acidosis resulted in an increased rate of glutamine extraction and ammonium production equal to that predicted from the increase in filtered load of glutamine. Therefore, variations of circulating glutamine concentration within the physiological range seem to have an important influence on the steady-state rate of renal glutamine metabolism in normal dogs and in dogs with chronic metabolic acidosis.

Acid-Base Equilibrium↗
PubMed1989

Glutamine transport in submitochondrial particles.

Glutamine transport was studied in submitochondrial particles (SMP) to avoid interference from glutamine metabolism. Phosphate-dependent glutaminase activity in SMP was only 0.04% of that in intact mitochondria. The uptake of glutamine in SMP represented both the transport into vesicles and membrane binding (about one-third of total uptake). Sulfhydryl reagents inhibited glutamine uptake in SMP. The uptake of L-[3H]glutamine increased more than twofold in SMP preloaded with 1 mM L-glutamine, an effect that was not seen with 1 mM D-glutamine. The uptake of L-[3H]glutamine was inhibited in the presence of either L-glutamine or L-alanine in the incubation medium. Other amino acids did not inhibit glutamine uptake. Alanine was also shown to trans-stimulate glutamine transport in SMP and cis-inhibit glutamine transport in both SMP and intact mitochondria. Glutamine transport showed a positive cooperativity effect with a Hill coefficient of 1.45. Metabolic acidosis increased the affinity of the transporter for glutamine without any change in other kinetic parameters. These data indicated that mitochondrial glutamine transport occurs via a specific carrier with multiple binding sites and that the transport of glutamine into mitochondria has an important role in increased ammoniagenesis during metabolic acidosis.

Acidosis↗
PubMed1974

Renal hemodynamics and ammoniagenesis. Characteristics of the antiluminal site for glutamine extraction.

Renal production of ammonia by the left kidney was studied in 31 acidotic dogs (NH(4)Cl) after acute constriction of the renal artery. Renal ammoniagenesis fell in direct proportion with the reduction in glomerular filtration rate and renal plasma flow. The renal extraction of glutamine by the experimental kidney fell in direct proportion with the reduction in renal hemodynamics. Extracted glutamine remained greater than filtered glutamine indicating that both the luminal and antiluminal transport sites were operative. The relationship between renal extraction of glutamine and ammoniagenesis observed during control was maintained after renal artery constriction (1.7 mumol NH(3) produced for each mumol of glutamine extracted). Systemic venous or renal intra-arterial infusion of glutamine during arterial constriction increased renal production of ammonia to or above control values. These observations indicate that the mechanisms responsible for glutamine extraction and ammonia production were operating normally despite reduced hemodynamics. When measured immediately after arterial clamping, the renal venous pNH(3) was found to rise significantly decreasing progressively thereafter towards control values. The extracted fraction of total glutamine delivered to the kidney (31%) did not change after acute reduction of the glutamine load. Thus, the antiluminal extraction site was incapable of lowering renal venous plasma glutamine concentration below 0.33 muM/ml. In a second series of experiments, the properties of the antiluminal site of transport for glutamine were studied after complete occlusion of the left ureter in acidotic and nonacidotic animals. Under these circumstances, it was demonstrated that the antiluminal site is capable of extracting sufficient glutamine to maintain total ammonia production at 60% or more of control. In acidotic animals, changes in cellular pNH(3) appeared to play a key role on the antiluminal extraction of glutamine since the significant rise in renal blood flow often observed after ureteral occlusion prevented the rise in pNH(3) noted when blood flow remained constant. Thus, when renal blood flow rose glutamine extraction and ammonia production were maintained at control values. In these acidotic animals, glutamine infusion failed to influence ammonia production until luminal transport was restored by release of ureteral clamp and resumption of glomerular filtration. The latter observation establishes that reabsorbed glutamine is utilized at least in part for ammonia production.

Acidosis, Renal Tubular↗
PubMedDate not supplied

Tumor regulation of hepatic glutamine metabolism.

Fast-growing tumors are major glutamine consumers and may alter host glutamine metabolism to benefit the tumor. Previous studies from our laboratory have demonstrated that the liver switches from an organ of glutamine balance to one of glutamine release with progressive malignant growth. However, the regulation of this change is unclear. This study examined tumor modulation of hepatic glutamine metabolism by determining the activities of glutaminase, the principle enzyme of glutamine degradation, and glutamine synthetase, the principal enzyme of glutamine synthesis. Hepatic glutamine content was also determined. Rats with a fast-growing subcutaneous fibrosarcoma (TBR) and pair-fed controls were studied at 2 and 3 weeks after tumor or sham implantation, when the tumors comprised approximately 5% and 20% of total body weight. Arterial glutamine fell with progressive tumor growth (608 +/- 26 mumol/L in controls vs 494 +/- 15 in TBR, p less than 0.005) and was not attributable to a diminished food intake. Hepatic glutamine content was increased 45% (p less than 0.01) in tumor rats at 2 weeks due in part to a 35% fall in liver glutaminase activity. At 3 weeks, glutamine synthetase activity increased by 43% (0.58 +/- 0.07 mumol/mg of protein/hr in controls vs 0.83 +/- 0.04 in TBR, p less than 0.01) whereas glutaminase remained depressed (2.68 +/- 0.12 mumol/mg of protein/hr in controls vs 2.22 +/- 0.15 in TBR, p less than 0.05) and glutamine content fell compared to 2 week tumor-bearing rats, consistent with accelerated hepatic glutamine release. Tumors may alter liver glutamine metabolism by modulating hepatic enzyme activity in order to provide circulating glutamine for the growing malignancy.

Ammonia↗
PubMedDate not supplied

Inhibition of pulmonary microvascular endothelial glutamine transport by glucocorticoids and endotoxin.

BACKGROUND: During septic states, the lungs produce increased amounts of glutamine, an event that is mediated by both endotoxin and glucocorticoid hormones and is presumed to be due to accelerated intracellular glutamine biosynthesis. Because enhanced net glutamine release in vivo could also be due to a decrease in cellular uptake, we assayed glutamine transport in cultured rat microvascular pulmonary endothelial cells. METHODS: The effect of Escherichia coli endotoxin (LPS, 1 microgram/mL), various cytokines, and dexamethasone (DEX, 0.1 mumol/L) on glutamine transport activity was studied in rat lung microvascular endothelial cells grown in varying glutamine concentrations (0, 0.1, 0.5, and 2 mmol/L). Experiments were also performed in cells treated with cycloheximide, actinomycin D, or chelerythrine chloride. RESULTS: More than 90% of glutamine transport was mediated by the Na+ -dependent transport system ASC. DEX and LPS inhibited endothelial glutamine uptake in a time- and dose-dependent manner, a response that was only observed with incubation medium contained the lower concentrations of glutamine. Neither DEX nor LPS altered transport activity in cells cultured in medium containing 2 mmol glutamine/L. There was no synergistic or additive effect when both compounds were added together. The cytokines tumor necrosis factor alpha, interleukin (IL) 1, IL-2, and IL-6 did not alter glutamine transport. both DEX and LPS inhibited glutamine transport by decreasing transporter maximal transport velocity (Vmax) without affecting transporter affinity (Km). Cycloheximide and actinomycin D abrogated the inhibition of transport activity that was observed in DEX- or LPS-treated cells, whereas the protein kinase C inhibitor chelerythrine chloride had no effect on either control or stimulated glutamine transport. CONCLUSIONS: These data suggest that DEX and LPS "down-regulate" glutamine uptake by lung microvascular endothelial cells by inducing the synthesis of an inhibitory protein that modulates the activity of the system ASC protein. This response in vitro appears to be influenced by the extracellular glutamine concentration. This decrease in microvascular endothelial glutamine transport may be one mechanism by which net lung glutamine release is enhanced during critical illness.

Animals↗
PubMed1989

Glutamine-containing dipeptides as infusion substrates in the septic state.

Recently a relationship has been postulated between lowered intracellular glutamine concentrations in the skeletal muscle and the rate of protein synthesis. We investigated the effect of 48 hours of parenteral nutrition supplemented with a solution containing glutamine in free or dipeptide form (alanylglutamine or glycylglutamine) on the intracellular glutamine pool in skeletal muscle and on the hind limb exchange of glutamine in dogs with sepsis after surgery. Before surgery, dogs were fasted for 48 hours. We used glutamine dipeptides as sources because they remain stable in an aqueous solution. Nutrition solutions were isocaloric (17.8 kcal/kg body weight/day on day 1 and 35.6 kcal/kg on day 2) and isonitrogenous (0.33 gm nitrogen/kg body weight/day), providing 2.6 mmol/kg body weight/day as glutamine source. During starvation, muscular free glutamine levels decreased by 41% to 10.4 mmol/L (p less than 0.001). On the second postoperative day the dogs had lowered plasma protein levels, a sharp drop in platelet count, an increase in the leukocyte count, and positive blood cultures. None of the solutions investigated in this study was effective in repleting the glutamine pool during 2 days of postoperative nutrition (11 +/- 2.0 mmol/L without glutamine, 10.3 +/- 2.2 mmol/L with glutamine plus alanine, 9.9 +/- 1.6 mmol/L with alanylglutamine, 7.5 +/- 1.1 mmol/L with glutamine plus glycine, and 7.2 +/- 1.2 mmol/L with glycylglutamine, respectively). The release of glutamine from the hindquarter was 631 +/- 38 nmol/kg body weight/min in the control group and decreased significantly in dogs receiving alanylglutamine (13.5 +/- 45 nmol/kg body weight/min; p less than 0.001) or the constituent amino acids (265 +/- 66 nmol/kg body weight/min; p less than 0.01) but was unchanged in dogs receiving glycylglutamine or glutamine plus glycine. We conclude that the duration and dosage of glutamine administration (equivalent to 26 gm glutamine per day in a patient weighing 70 kg) used in this study are not sufficient to restore glutamine deficiency of the skeletal muscle in the depleted state.

Alanine↗
PubMed1987

Hepatic glutamine metabolism.

The outstanding role of glutamine in hepatic nitrogen metabolism in general has been the subject of extensive research within the past few years. Hepatic glutaminase shows an extraordinary pH sensitivity, is not inhibited by glutamate and is activated by its product ammonium, thereby contrasting the kidney enzyme. In the absence of ammonium virtually no activity can be detected. Control of hepatic glutamine degradation is exerted at the level of glutaminase activity and glutamine transport across the plasma and mitochondrial membranes. These transport systems establish glutamine concentration gradients across the respective membranes: with a physiological extracellular glutamine concentration of 0.6 mM, the cytosolic and mitochondrial concentrations are 7 and 20 mM, respectively, both in vivo and in vitro. Therefore mitochondrial glutaminase is operating in vivo near its Km of 22-28 mM. In the intact liver acinus, glutaminase and the enzymes of the urea cycle are localized in the periportal hepatocytes, whereas glutamine synthetase is restricted to small hepatocyte population in the perivenous area; i.e., at the outflow of the sinusoid. Therefore, following the sinusoidal bloodstream, urea and glutamine synthesis are anatomically switched around. With respect to hepatic ammonium detoxication, this organization represents functionally the sequence of a periportal low-affinity system (urea synthesis) and a perivenous high-affinity system (glutamine synthesis) for ammonium removal. The role of glutamine synthetase is that of a scavenger for ammonium which has escaped periportal urea synthesis before the sinusoidal blood reaches the systemic circulation. The role of glutaminase is seen in a pH-modulated ammonium amplifier inside the mitochondria of the periportal compartment, thereby determining flux through the urea cycle. Periportal glutaminase and perivenous glutamine synthetase are simultaneously active, resulting in the so-called intercellular glutamine cycle. The role of this cycle is to improve the efficiency of hepatic urea synthesis at the physiologically low portal ammonium concentrations, thereby compensating the comparatively low ammonium affinity of carbamoylphosphate synthetase, the rate-controlling enzyme of the urea cycle. Normally, periportal glutamine breakdown is matched by a compensatory perivenous glutamine resynthesis; thus no net glutamine turnover is observed. In addition, intercellular glutamine cycling is an effective means of adjusting flux of portal ammonium into either urea or glutamine according to the needs of systemic pH regulation.(ABSTRACT TRUNCATED AT 400 WORDS)

Ammonia↗
PubMedDate not supplied

[Administration of glutamine and its dipeptides in parenteral nutrition. Which patients are candidates?].

Despite the fact that glutamine is not considered to be an essential amino acid, it is the amino acid found in the greatest concentration both in plasma (26%) as in skeletal muscle (75%). These levels may decrease in post-operative, trauma, or critical patients. Glutamine performs many functions in which its demand may be increased, such as: it is a precursor of the synthesis of nucleotides; it is an activator of the protein synthesis and at the same time it inhibits the degradation; it is an activator of glycogen synthesis; it is a metabolic substrate for rapidly replicating cells; it is an energy source for the enterocyte which is so important for maintaining the integrity and the function of the intestinal barrier, and the consumption thereof may be increased under conditions of stress. The administration of glutamine intravenously leads to two physical-chemical problems; the first is its low solubility in water; at 20 degrees C this is only 36 g/l, and the second problem is its low chemical stability in an aqueous solution at 22-24 degrees C, this being 11 days. This problem has led the industry to research two dipeptides of glutamine; L-alanyl-glutamine, and L-glycyl L-glutamine, both of which are much more soluble and much more stable. At present there is still a controversy regarding the dosage of glutamine and its dipeptides, with the dose being 0.19-0.29 g/kg/day of L-glutamine or its dipeptide forms, in surgical post-operative periods or to prevent bacterial translocation, and in patients who are candidates for bone marrow transplants, the administered dose has been 0.37-0.57 g/kg/day. The purpose of this study is to review the existing bibliography regarding the efficacy of L-glutamine or its dipeptides in four possible indications for its application in the daily clinical practice, such as: a) In post-operative surgical patients of major or medium surgery, glutamine or its dipeptides reduces the losses of muscular glutamine and its catabolism, showing a less negative nitrogen balance. b) Whether it avoids bacterial translocation. c) Whether it favors the response of the immunological system. d) Whether in patients who are candidates for bone marrow transplants this decreases the side effects due to chemotherapy and radiotherapy such as mucositis, or whether it decreases the number of days of neutrophil recovery. At present, on the European market there are two commercially available brands of glutamine dipeptides: Dipeptiven, by Fresenius Laboratories, Germany. A 100 ml vial which corresponds to 20 g of L-alanyl L-glutamine (8.2 g of alanine + 13.46 g of L-glutamine). This is added to the standard amino acid solution. Glamin, Pharmacia and Upjohn Laboratory, Sweden. This is an amino acid solution with 13.4% essential and non-essential amino acids which are equivalent to 22.4 g of nitrogen/l, and which contain 30.27 g L-glycyl-L-glutamine (10.27 g of glycine + 20 g of L-glutamine).

Bone Marrow Transplantation↗
PubMed2001

Specificity determining residues in ammonia- and glutamine-dependent carbamoyl phosphate synthetases.

Carbamoyl phosphate synthetases (CPSs) utilize either glutamine or ammonia for the ATP-dependent generation of carbamoyl phosphate. In glutamine-utilizing CPSs (e.g. the single Escherichia coli CPS and mammalian CPS II), the hydrolysis of glutamine to yield ammonia is catalyzed at a triad-type glutamine amidotransferase domain. Non-glutamine-utilizing CPSs (e.g. rat and human CPS I), lacking the catalytic cysteine residue, can generate carbamoyl phosphate only in the presence of free ammonia. Frog CPS I (fCPS I), unlike mammalian CPS Is, retains most of the glutamine amidotransferase residues conserved in glutamine-utilizing CPSs, including an intact catalytic triad, and could therefore be expected to use glutamine. Our work with native fCPS I provides the first demonstration of the inability of this enzyme to bind/utilize glutamine. To determine why fCPS I is unable to utilize glutamine, we compared sequences of glutamine-using and non-glutamine-using CPSs to identify residues that are present or conservatively substituted in all glutamine-utilizing CPSs but absent in fCPS I. We constructed the site-directed mutants Q273E, L270K, Q273E/N240S, and Q273E/L270K in E. coli CPS and have determined that simultaneous occurrence of the two substitutions, Gln-->Glu and Leu-->Lys, found in the frog CPS I glutamine amidotransferase domain are sufficient to eliminate glutamine utilization by the E. coli enzyme.

Adenosine Triphosphate↗
PubMed1994

Glutamine kinetics in burn patients. Comparison with hormonally induced stress in volunteers.

OBJECTIVE: To assess the acute and protracted adaptive response of peripheral glutamine kinetics to a severe injury. DESIGN: Comparison study. SETTING: Clinical research center at a university-affiliated hospital. PATIENTS: Six severely burned men and five young healthy men. INTERVENTIONS: The catabolic hormones epinephrine, cortisol, and glucagon were infused simultaneously into the femoral artery of five healthy volunteers, thus acutely simulating the hormonal milieu associated with a severe injury. MAIN OUTCOME MEASURES: Whole-body glutamine flux and peripheral glutamine kinetics were determined using glutamine labeled with nitrogen 15 and net balance measurements in patients 2 weeks following a severe burn injury. Identical measurements were made in the healthy volunteers before and following 4 hours of catabolic hormone infusion. RESULTS: Whole-body glutamine flux increased to a similar extent in both the burn patients and in volunteers following catabolic hormone infusion. In comparison with their basal kinetics, the hormonally simulated acute stress in the volunteers induced a significant efflux of glutamine from the leg by greatly increasing the rate of glutamine appearance. In contrast, burn patients had a significant decrease in their rate of glutamine appearance and achieved a similar net loss of glutamine from the leg only by a compensatory decrease in peripheral glutamine consumption. CONCLUSIONS: These findings suggest that in the acute stress response, skeletal muscle preferentially releases glutamine from its free intracellular pool. As this reserve becomes depleted, net glutamine efflux is maintained by decreasing its rate of muscle glutamine utilization. These results suggest a failure of muscle to augment de novo glutamine synthesis and support the conclusion that glutamine is a conditionally essential amino acid during critical illness.

Acute Disease↗