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PubMed2004

Glutamine: recent developments in research on the clinical significance of glutamine.

PURPOSE OF REVIEW: The aim of this review is to describe the clinical relevance of supplementation of glutamine from the recent literature. First, new basic research is examined and subsequently recent clinical trials and a metaanalysis are illustrated. RECENT FINDINGS: Glutamine has a major impact on the functionality of the immune system. It has recently been established that glutamine not only has a protective effect on cells of the immune system, but also on other cells of the body, for instance cardiomyocytes. Evidence is accumulating for an effect of glutamine via glutathione, heat shock proteins as well as taurine. Another area of interest is the way glutamine enhances gut barrier function. More and more research is concentrating on the positive effect of glutamine on the gut-associated lymphoid tissue. SUMMARY: Based on a recent meta-analysis and up-to-date clinical trials, we may conclude that glutamine has a beneficial effect on infectious complications and reduces hospital stay. In critically ill patients glutamine supplementation may reduce morbidity and mortality. The greatest effect was observed in patients receiving high dose parenteral glutamine. A recent study with high dose enteral glutamine demonstrated a reduced mortality in the glutamine supplemented group. In the future more trials with larger numbers of participants are needed, especially with high dose enteral glutamine in the perioperatively and the intensive care unit setting.

Animals↗
PubMed2000

Effects of glutamine supplementation, GH, and IGF-I on glutamine metabolism in critically ill patients.

During critical illness glutamine deficiency may develop. Glutamine supplementation can restore plasma concentration to normal, but the effect on glutamine metabolism is unknown. The use of growth hormone (GH) and insulin-like growth factor I (IGF-I) to prevent protein catabolism in these patients may exacerbate the glutamine deficiency. We have investigated, in critically ill patients, the effects of 72 h of treatment with standard parenteral nutrition (TPN; n = 6), TPN supplemented with glutamine (TPNGLN; 0.4 g x kg(-1) x day(-1), n = 6), or TPNGLN with combined GH (0.2 IU. kg(-1). day(-1)) and IGF-I (160 microg x kg (-1) x day(-1)) (TPNGLN+GH/IGF-I; n = 5) on glutamine metabolism using [2-(15)N]glutamine. In patients receiving TPNGLN and TPNGLN+GH/IGF-I, plasma glutamine concentration was increased (338 +/- 22 vs. 461 +/- 24 micromol/l, P < 0.001, and 307 +/- 65 vs. 524 +/- 71 micromol/l, P < 0.05, respectively) and glutamine uptake was increased (5.2 +/- 0.5 vs. 7.4 +/- 0.7 micromol x kg(-1) x min(-1), P < 0.05 and 5.2 +/- 1.1 vs. 7.6 +/- 0.8 micromol x kg(-1) x min(-1), P < 0.05). Glutamine production and metabolic clearance rates were not altered by the three treatments. These results suggest that there is an increased requirement for glutamine in critically ill patients. Combined GH/IGF-I treatment with TPNGLN did not have adverse effects on glutamine metabolism.

Adult↗
PubMedDate not supplied

Does glutamine supplementation decrease the response of muscle glutamine synthesis to fasting in muscle in adult and very old rats?

BACKGROUND: Glutamine synthetase (GS), a key enzyme in the production of glutamine, is preserved in rat skeletal muscle during aging but is increased with advanced age in vivo. The aim of this study was to determine whether glutamine supplementation affects up-regulation of GS by fasting in vivo in adult and very old female rats. METHODS: Muscle GS activities were assessed in 5-day-fasted female Wistar adult (6 months) and very old (27 months) rats refed and supplemented with glutamine or other amino acids (alanine or glycine). Fed rats were used to investigate the possible effect of glutamine supplementation in the fed state. RESULTS: After 5 days' fasting, the up-regulated GS activity was decreased whatever the type of amino acid supplementation (glutamine, alanine, and glycine) in adults, whereas it was only decreased by glutamine supplementation in very old rats). In the fed state, no effect of glutamine supplementation was observed even if GS activity remained up-regulated whatever the age and the period of supplementation. CONCLUSIONS: These results confirm that glutamine has a specific role in very old rats. The up-regulated GS activity was decreased by an exogenous supply of glutamine only if intramuscular glutamine was depleted; this was confirmed by studies in the fed state. The up-regulated GS activity in both fed and fasted rats may be associated with increased glutamine requirements in the whole body.

Aging↗
PubMed1997

Increased whole-body protein and glutamine turnover in advanced cancer is not matched by an increased muscle protein and glutamine turnover.

In the progress of cancer major disturbances in protein and glutamine metabolism have been observed. Muscle is the major protein pool and glutamine source in the body. The aim of this study was to investigate whether changes in whole-body protein and glutamine turnover, induced by cancer, are matched by similar changes in regional muscle metabolism. A MCA sarcoma was implanted subcutaneously in female Lewis rats. Rats were studied bearing small (5-15% of body weight) or large (15-30% of body weight) tumor loads and compared with sham-implanted free-fed and pair-fed controls. Body composition was determined by the distribution of an ip bolus of 3H2O. With the rat under anesthesia a primed constant infusion of L-[2,6-3H]phenylalanine and L-[3,4-3H]glutamine was given, and at steady state, whole-body, hindquarter-muscle, and tumor protein and glutamine turnover were calculated using compartment modeling. Anorexia was not observed in tumor-bearing rats. A small decrease in host carcass weight was observed in large-tumor-bearing rats by decreased fat mass. Whole-body protein turnover increased from 115 +/- 14 (nmole x 100 g body weight-1 x min-1) in free-fed controls rats to 239 +/- 29 in the large-tumor-bearing rats. Net tumor protein synthesis accounted for 28 +/- 1 and 49 +/- 1 nmole x 100 g body weight-1 x min-1. Muscle protein breakdown increased in the small-tumor-bearing group and decreased to control values in the large-tumor-bearing rats. Whole-body glutamine turnover remained unchanged in the small-tumor-bearing animals (2481 +/- 248 and 1996 +/- 268 nmole x 100 g body weight-1 x min-1 in control and small-tumor-bearing rats, respectively) and increased by 25% in the large-tumor-bearing animals. In contrast, muscle glutamine turnover more than doubled in the small-tumor-bearing group but returned to control values in the large-tumor-bearing animals. The current study show that in the presence of a small tumor whole-body protein turnover increased and that this was in part related to protein turnover of the tumor. Muscle protein breakdown increased in these rats with a concomitant increase in glutamine production from the hindquarter. In animals bearing larger tumors whole-body glutamine turnover increased. This increase, however, was only for a small part caused by tumor metabolism. Muscle glutamine turnover even decreased. Therefore, the increase in whole-body glutamine turnover appears to be caused by increased turnover in visceral organs.

Ammonia↗
PubMed2002

Glutamine transport in isolated epithelial intestinal cells. Identification of a Na+-dependent transport mechanism, highly specific for glutamine.

L-glutamine transport was evaluated in isolated cells from the guinea-pig small intestine by measuring [(3)H]- L-glutamine uptake. Villous and crypt cells expressed Na(+)-dependent and Na(+)-independent transport mechanisms. Glutamine transport systems were identified using various amino acids and analogues as inhibitors. In both villous and crypt cells, 2-(methylamino)-isobutyrate (MeAIB), a system A inhibitor, did not inhibit Na(+)-dependent glutamine influx. 2-Aminobicyclo(2,2,1)heptane-2-carboxylate (BCH), a system B(0) and B(0,+) substrate, had no effect on Na(+)-dependent influx. Serine, cysteine and threonine, system ASC inhibitors, reduced Na(+)-dependent influx by 50%. Asparagine, but not histidine, system N inhibitors, reduced Na(+)-dependent glutamine influx by 50%, however the effect of asparagine was not additive to that of threonine. The remaining Na(+)-dependent glutamine influx (50%) was only inhibited by glutamine itself, by Na(+) substitution ( N-methyl-glucamine, K(+), Li(+)) or by external pH reduction. Phenyl-acetyl-glutamine (PAG), a synthetic amino acid analogue, also inhibited this Na(+)-dependent, threonine-insensitive glutamine influx (IC(50) 2.45 mM). The Na(+)-independent uptake was partially inhibited by BCH, a system L inhibitor, and other neutral amino acids, but was not affect by PAG. Our results suggest that glutamine is transported in both villous and crypt cells by the Na(+)-independent system L, by the Na(+)-dependent system ASC and by an as yet undescribed Na(+)-dependent transport mechanism, highly specific for glutamine.

Amino Acid Transport Systems↗
PubMed2006

Glutamine, insulin and glucocorticoids regulate glutamine synthetase expression in C2C12 myotubes, Hep G2 hepatoma cells and 3T3 L1 adipocytes.

The cell-specific regulation of glutamine synthetase expression was studied in three cell lines. In C2C12 myotubes, glucocorticoids increased the abundance of both glutamine synthetase protein and mRNA. Culture in the absence of glutamine also resulted in very high glutamine synthetase protein abundance but mRNA levels were unchanged. Glucocorticoids also increased the abundance of glutamine synthetase mRNA in Hep G2 hepatoma cells but this was not reflected in changes in protein abundance. Culture of Hep G2 cells without glutamine resulted in very high levels of protein, again with no change in mRNA abundance. Insulin was without effect in both C2C12 and Hep G2 cells. In 3T3 L1 adipocytes glucocorticoids increased the abundance of both glutamine synthetase mRNA and protein, insulin added alone had no effect but in the presence of glucocorticoids resulted in lower mRNA levels than seen with glucocorticoids alone, although protein levels remained high under such conditions. In contrast to the other cell lines glutamine synthetase protein levels were relatively unchanged by culture in the absence of glutamine. The results support the hypothesis that in myocytes, and hepatomas, but not in adipocytes, glutamine acts to moderate glutamine synthetase induction by glucocorticoids.

3T3-L1 Cells↗
PubMed1974

Glutamine-binding subunit of glutamate synthase and partial reactions catalyzed by this glutamine amidotransferase.

In the course of studies on glutamine-dependent carbamyl phosphate synthetase from Aerobacter aerogenes, we purified another protein which was found to be glutamate synthase (EC 2.6.1.53). The enzyme, obtained in apparently homogeneous form (monomer molecular weight about 227,000; s(20,omega) = 17.6 S), was found to be a typical glutamine amidotransferase in that it exhibits glutaminase activity and can utilize ammonia in place of glutamine as a nitrogen donor. The enzyme also catalyzes at low rates the oxidative deamination of glutamate in the presence of TPN, and it exhibits TPNH oxidase activity. The enzyme is similar to the glutamate synthase found in Escherichia coli in that it is an iron-sulfide flavoprotein. Treatment of the enzyme with sodium dodecyl sulfate or potassium thiocyanate dissociates it into nonidentical subunits exhibiting molecular weights of about 175,000 and 51,500. The glutamine-dependent activity of the enzyme is inhibited by L-2-amino-4-oxo-5-chloropentanoic acid, but this chloroketone analog of glutamine does not affect the ammonia-dependent glutamate synthase activity. Studies with [(14)C]chloroketone show that the reagent binds to the heavy subunit only. Inhibition by the chloroketone and its binding to the heavy subunit are markedly reduced in the presence of L-glutamine. Sedimentation velocity studies carried out in potassium thiocyanate indicate that iron-sulfide and flavin sites are also located on the heavy subunit. While these studies show that glutamate synthase resembles other glutamine amidotransferases in certain of its catalytic properties, the findings indicate that the light subunit of this enzyme, in contrast to that of several other glutamine amidotransferases, does not function to bind glutamine. It is of interest that the enzyme exhibits an unusually high affinity for ammonia as compared to a number of other glutamine amidotransferases. Glutamate synthase is inhibited (competitively with respect to glutamine) by low concentrations of methionine sulfone, methionine sulfoximine, and methionine sulfoxide.

Binding Sites↗
PubMed1989

Possible sources of glutamine for parenteral nutrition: impact on glutamine metabolism.

Due to its instability, glutamine is not included in solutions for parenteral solution. This problem can be obviated by providing glutamine as acetyl-, glycyl-, or alanylglutamine. Using an organ balance technique in conscious dogs, we investigated metabolism of these three sources of glutamine. Liver, gut, kidney, and muscle participated in clearance of glycyl- and alanylglutamine from plasma, but among these organs only kidney cleared acetylglutamine. Furthermore, there was a large urinary excretion for acetylglutamine (38 +/- 6% of amount infused) but only a trace amount for either dipeptide. The infusion of glutamine-dipeptides resulted in similar increases in blood level of free glutamine. The main source of this increase appeared to be hydrolysis of dipeptides by kidney and release of free glutamine to circulation. During the infusion of both dipeptides, glutamine balance (free and dipeptide forms) was always positive (net uptake) across liver, gut, and kidney but was neutral across muscle. Liver or gut glutamine balances were not significantly different during the infusion of dipeptides, but kidney glutamine balance was twofold greater during the infusion of glycyl- than alanylglutamine. We conclude that among these three sources of glutamine, acetylglutamine is least desirable for use in parenteral nutrition. Glycylglutamine may be preferable over alanylglutamine if the objective is to target glutamine for kidney.

Animals↗
PubMedDate not supplied

Accelerated glutamine synthesis in critically ill patients cannot maintain normal intramuscular free glutamine concentration.

BACKGROUND: Muscle glutamine is severely depleted in critically ill patients (by approximately 50% to 80% of normal). Because muscle protein breakdown, and thus the release of glutamine from muscle protein, is enhanced in response to metabolic stress, the depletion of intramuscular glutamine could be due to its impaired synthesis or accelerated outward transport or both. METHODS: To distinguish these possibilities, we measured skeletal muscle glutamine metabolism in five critically ill patients by means of primed, continuous infusions of 5-15N-glutamine and ring-2H5-phenylalanine and compared them to values we previously reported for healthy volunteers. RESULTS: The intramuscular free glutamine concentration in patients was approximately 70% of that in healthy volunteers (5.8 +/- 0.6 mmol/L intracellular free water vs 21.5 +/- 2.8 mmol/L). Whole-body glutamine rate of appearance was 5.8 +/- 1.0 micromol x kg (-1) body wt x min (-1), and whole-body clearance was 19.3 +/- 3.3 mL x kg(-1) x min (-1). Despite the low intramuscular glutamine concentration in the patients, the rate of unidirectional outward transport from skeletal muscle into venous blood (1.1. +/- 0.2 micromol x 100 mL x leg(-1) x min(-1)) was similar to that observed in healthy volunteers (1.6 +/- 0.2 mol x 100 mL x leg(-1) x min(-1)); intramuscular synthesis was 2.7 +/- 0.9 micromol x 100 mL x leg(-1) x min(-1) compared with a normal value of 0.6 +/- 0.06 micromol x 100 mL x leg(-1) x min(-1). Net balance across the leg was normal. CONCLUSIONS: The depletion of intramuscular glutamine in critically ill patients is not due to an impairment of the rate of synthesis. In fact, accelerated glutamine production cannot maintain normal intramuscular glutamine levels because of accelerated outward transport.

Adolescent↗
PubMed2004

[High efficiency of L-glutamine production by coupling genetic engineered bacterial glutamine synthetase with yeast alcoholic fermentation system].

Glutamine is an important conditionally necessary amino acid in human body. The effort is to establish a new and high efficient L-glutamine production system instead of traditional fermentaion. In this paper, high efficiency of L-glutamine production is obtained by coupling genetic engineered bacterial glutamine synthetase (GS) with yeast alcoholic fermentation system. Glutamine Synthetase gene (glnA) was amplified from Bacillus subtilis genomic DNA with primers designed according to sequences reported in EMBL data bank, then it was inserted into expression vector PET28b, the sequence of glnA was proved to be the same as that reported in the data bank by DNA sequencing. After transformation of this recombinant plasmid PET28b-glnA into BL-21 (DE3) strain, Lactose and IPTG were used to induce GS expression at 37 degrees C separately. Both of them can induce GS expression efficiently. The induced protein is proved to be soluble and occupies about 80% of the total proteins by SDS-PAGE analysis. The soluble GS was purified by Ni2+ chelating sepharose colum. After purification, the purified enzyme was proved active. Results reveal that the optmum temperature of this enzyme is 60 degrees C and optmum pH is 6.5 in biosynthetic reaction by using glutamate, ammonium choloride and ATP as substrates. After induction, the enzyme activity in crude extract of BL-21/PET28b-glnA is 83 times higher than that of original BL-21 extract. Mn2+ can obviously increase the activity and stability of this enzyme. Experiments show that the transformation efficiency of glutamate to glutamine is more than 95%. Because of the high cost from ATP, a system coupling GS with yeast for ATP regenaration was established. In this system, GS utilizes ATP released by yeast fermentation to synthesize L-glutamine. Yeast was treated by 2% toluence to increase its permeability and a yeast named YC001 with high yield of glutamine by coupling with recombinant GS was obtained. The good efficiency was achieved with the presence of 250 mmol/L glucose and 200 mmol/L phosphate, the transformation efficiency of glutamate to glutamine in this system is more than 80%, the average yield of glutamine is about 22g/L. This provides the basis for future large scale production of L-glutamine.

Bacillus subtilis↗
PubMed1987

Stress-induced intracellular glutamine depletion. The potential use of glutamine-containing peptides in parenteral nutrition.

Of the total pool of muscle free intracellular amino acids glutamine represents about 60%. A uniform reduction of approximately 50% of the intracellular free glutamine pool is the most typical feature in various catabolic conditions. Since nutritional or therapeutical efforts to beneficially influence cellular glutamine pool failed and because free glutamine cannot be infused owing to its instability, the question arose as to whether maintenance of this pool is feasible by intravenous provision of glutamine-containing peptides. Our basic research plan attempted to combine the synthesis and characterization of, among other peptides, L-alanyl-L-glutamine (Ala-Gln) with investigations aimed at examining in vivo uptake and subsequent utilization of this solute. The synthesis of Ala-Gln was performed by applying the N-carboxy anhydride method in the aqueous phase. The purity in the final product approached 100% and the structure could be fully confirmed by field-desorption mass spectrometry and proton magnetic resonance spectrometry. The synthetic peptide Ala-Gln is highly soluble (568 g/l H2O; 20 degrees C) and stable during heat sterilization at various pH. Thus, Ala-Gln complies with each criterion to be included in future parenteral solutions. Isotope studies with Ala[U14C]Gln in experimental rat and dog strongly indicate that the peptide is easily available and the constituent amino acids are rapidly used for protein synthesis, preferentially in muscle tissue. In catabolic rats, continuous TPN without inclusion of Ala-Gln resulted in a profound decrease in tissue free glutamine levels compared with normal rats. Inclusion of Ala-Gln to TPN was followed by an increase in tissue free glutamine pool, considerably in liver and markedly in muscle. These findings indicate a preferential capacity of muscle tissue to take up Ala-Gln and suggest subsequent utilization of the liberated free glutamine in this tissue. For the first time, in vivo utilization of Ala-Gln was evaluated in healthy humans and substantiated with kinetic studies and under conditions of continuous infusion of peptide-supplemented amino acid solution. The peptide elimination t1/2 was 3.1 +/- 0.16 min and that for the liberated free amino acids glutamine and alanine 8.2 +/- 0.82 and 6.8 +/- 0.34 min, respectively. During infusion of an amino acid solution supplemented with Ala-Gln and Gly-Tyr, the increments of plasma glutamine and tyrosine were 33% +/- 2.2 and 67% +/- 5.7 over the initial values. No peptide could be detected in the urine.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2006

Low intestinal glutamine level and low glutaminase activity in Crohn's disease: a rational for glutamine supplementation?

Intestinal glutamine utilization is integral to mucosal regeneration. We analyzed the systemic and intestinal glutamine status in Crohn's disease (CD) and evaluated the therapeutic effect of glutamine supplementation in an animal model of ileitis. In CD, glutamine concentrations were decreased systemically and in noninflamed and inflamed ileal/colonic mucosa. Mucosal glutaminase activities were depressed in the ileum independent of inflammation but were not different from controls in the colon. In experimental ileitis, oral glutamine feeding prevented macroscopic inflammation, enhanced ileal and colonic glutaminase activities above controls, and normalized the intestinal glutathione redox status. However, glutamine supplementation enhanced myeloperoxidase activity along the gastrointestinal tract and potentiated lipid peroxidation in the colon. In conclusion, glutamine metabolism is impaired in CD. In experimental ileitis, glutamine supplementation prevents inflammatory tissue damage. In the colon, however, which does not use glutamine as its principal energy source, immune enhancement of inflammatory cells by glutamine increases oxidative tissue injury.

Adult↗
PubMed1995

Glutamine and alpha-ketoglutarate prevent the decrease in muscle free glutamine concentration and influence protein synthesis after total hip replacement.

After surgical trauma, protein synthesis, as well as the concentration of free glutamine in muscle, decreases. Total parenteral nutrition (TPN) alone does not prevent the decrease of glutamine in muscle, but TPN supplemented with glutamine or its precursor, alpha-ketoglutarate, maintains amino acid concentration in muscle and preserves protein synthesis. The aim of this study was to characterize a human trauma model using patients undergoing total hip replacement, and furthermore to investigate whether glutamine or alpha-ketoglutarate alone without TPN can prevent the postoperative decrease in muscle free glutamine. Metabolically healthy patients undergoing total hip replacement were randomized into three groups. The control group (n = 13) received glucose 2 g/kg body weight (BW) during surgery and the first 24 postoperative hours. The glutamine group (n = 10) received glucose 2 g/kg BW and glutamine 0.28 g/kg BW, and the alpha-ketoglutarate group (n = 10) received glucose 2 g/kg BW and alpha-ketoglutarate 0.28 g/kg BW. Muscle biopsies were performed before surgery and 24 hours postoperatively. Free glutamine concentration in muscle decreased from 11.62 +/- 0.67 to 9.80 +/- 0.36 mmol/kg wet weight in the control group (P < .01), whereas it remained unchanged in both the glutamine group and alpha-ketoglutarate group. Protein synthesis, as reflected by the concentration of total ribosomes, decreased significantly in the control group, but not in glutamine and alpha-ketoglutarate groups. Polyribosome concentration decreased significantly in both the control and alpha-ketoglutarate groups. Total hip replacement can be used as a reproducible trauma model, with characteristic changes in the muscle amino acid pattern and protein synthesis 24 hours postoperatively.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acids↗
PubMed1999

Is alpha-ketoisocaproyl-glutamine a suitable glutamine precursor to sustain fibroblast growth?

BACKGROUND: Glutamine is considered an essential nutrient for cellular growth. AIM: To test the suitability of alpha-ketoisocaproyl-Gln (Kic-Gln) as a new glutamine (Gln) precursor to sustain human fibroblast growth. METHODS: [3H] thymidine uptake into cellular DNA of human fibroblasts. Extracellular and intracellular amino acid patterns were determined with peptides and acylated compounds. RESULTS: L-alanyl-L-glutamine (used here as a recognized Gln precursor) promoted DNA synthesis, while N-acetyl-L-glutamine (used here as a negative control since it is known to be a poor Gln precursor) and alpha-ketoisocaproyl-glutamine had no effect. Alanyl-glutamine progressively gave rise to free glutamine in the growth medium. In contrast, glutamine supplied in acylated form was poorly available and did not appear in free form in the medium. In addition, only alanyl-glutamine increased intracellular glutamine and glutamate levels. In contrast, Kic-Gln was able to sustain net protein synthesis as judged by total protein content and reduced intracellular levels of most essential amino acids. CONCLUSION: Kic-Gln appears to be a poor extra-cellular precursor of Gln to sustain cell growth.

Biological Availability↗
PubMed2000

Glutamine metabolism in endothelial cells: ornithine synthesis from glutamine via pyrroline-5-carboxylate synthase.

L-Glutamine (the most abundant free amino acid in plasma and the body) is a potent inhibitor of endothelial NO synthesis. However, little is known about glutamine metabolism in endothelial cells (EC). As an initial step toward understanding the role of glutamine in endothelial physiology, the present study was conducted to quantify glutamine catabolism in microvascular, aortic and venous EC. For metabolic studies, EC were incubated for 1 h in Krebs bicarbonate buffer containing 5 mM glucose and 0.5-4 mM L-[U-(14)C]-glutamine. For enzymological studies, cell extracts and mitochondrial fractions were prepared to determine the activities of glutamine-degrading enzymes. Our results reveal extensive hydrolysis of glutamine to glutamate and ammonia in a concentration-dependent manner via phosphate-dependent glutaminase in all EC studied. In addition, both metabolic and enzymological evidence indicate a novel pathway for endothelial synthesis of ornithine from glutamine via pyrroline-5-carboxylate synthase. This new knowledge of glutamine metabolism may pave a new path for understanding the physiological role of glutamine in vascular function.

Alanine↗
PubMed1997

In vivo 13C NMR measurements of cerebral glutamine synthesis as evidence for glutamate-glutamine cycling.

The cerebral tricarboxylic acid (TCA) cycle rate and the rate of glutamine synthesis were measured in rats in vivo under normal physiological and hyperammonemic conditions using 13C NMR spectroscopy. In the hyperammonemic animals, blood ammonia levels were raised from control values of approximately 0.05 mM to approximately 0.35 mM by an intravenous ammonium acetate infusion. Once a steady-state of cerebral metabolites was established, a [1-13C]glucose infusion was initiated, and 13C NMR spectra acquired continuously on a 7-tesla spectrometer to monitor 13C labeling of cerebral metabolites. The time courses of glutamate and glutamine C-4 labeling were fitted to a mathematical model to yield TCA cycle rate (V(TCA)) and the flux from glutamate to glutamine through the glutamine synthetase pathway (V(gln)). Under hyperammonemia the value of V(TCA) was 0.57 +/- 0.16 micromol/min per g (mean +/- SD, n = 6) and was not significantly different (unpaired t test; P > 0.10) from that measured in the control animals (0.46 +/- 0.12 micromol/min per g, n = 5). Therefore, the TCA cycle rate was not significantly altered by hyperammonemia. The measured rate of glutamine synthesis under hyperammonemia was 0.43 +/- 0.14 micromol/min per g (mean +/- SD, n = 6), which was significantly higher (unpaired t test; P < 0.01) than that measured in the control group (0.21 +/- 0.04 micromol/ min per g, n = 5). We propose that the majority of the glutamine synthetase flux under normal physiological conditions results from neurotransmitter substrate cycling between neurons and glia. Under hyperammonemia the observed increase in glutamine synthesis is comparable to the expected increase in ammonia transport into the brain and reported measurements of glutamine efflux under such conditions. Thus, under conditions of elevated plasma ammonia an increase in the rate of glutamine synthesis occurs as a means of ammonia detoxification, and this is superimposed on the constant rate of neurotransmitter cycling through glutamine synthetase.

Ammonia↗
PubMed2004

Diarrhea and reduced levels of antiretroviral drugs: improvement with glutamine or alanyl-glutamine in a randomized controlled trial in northeast Brazil.

The effects of therapy with glutamine and alanyl-glutamine on diarrhea and antiretroviral drug levels in patients with acquired immune deficiency syndrome (AIDS) were examined in a randomized, double-blinded, placebo-controlled study in northeast Brazil. Patients with AIDS and with diarrhea and/or wasting were randomized into 4 groups to determine the efficacy of glutamine or high- or low-dose alanyl-glutamine given for 7 days, compared with isonitrogenous glycine given to control subjects. All patients in whom baseline antiretroviral drug levels were determined had low levels 2 h after dosing. Gastrointestinal symptom scores improved with receipt of high-dose alanyl-glutamine (P<.05) or glutamine (P<.01). Antiretroviral drug levels increased in patients given alanyl-glutamine (P=.02) or glutamine (P=.03) by 113% (P=.02) and 14% (P=.01), respectively. Antiretroviral drug resistance mutations were common in all groups. The dose-related efficacy of alanyl-glutamine and glutamine in treating diarrhea and in increasing antiretroviral drug levels shows that these supplements may help to improve therapy for patients with AIDS who have diarrhea and/or wasting in developing, tropical areas.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Enteral glutamine modulates renal glutamine utilization.

Enteral glutamine feeding effect on renal glutamine utilization was assessed from the perspective of gamma glutamyltransferase activity-dependent cellular glutamate modulation of phosphate-dependent glutaminase. After 4d, rats fed an elemental diet supplemented with glutamine exhibited a 2 1 % higher kidney glutamate content and 27% reduction in ammonium excretion, both P < 0.05. Glutamine removal from plasma was depressed 62% in the glutamine-fed group (324 +/- 155 vs. 780 +/- 154 nmol x min(-1) x 100 g body weight (-1), P < 0.05) despite an elevated arterial plasma glutamine load delivered to the kidney. Administration of acivicin, 36 mg/kg body weight, to glutamine-fed rats inhibited gamma glutamyltransferase > 90% and decreased kidney glutamate content 42%. This reduction in kidney glutamate was associated with a 3.3-fold enhancement in both glutamine extraction (474 +/- 184 to 1548 +/- 255 nmol x min(-1) x 100 g body weight (-1)) and ammonium excretion (295 +/- 30 to 978 +/- 96 nmol x min(-1) x 100 g body weight(-1)), both P < 0.01. These findings are consistent with enteral glutamine regulation of renal glutamine utilization through an elevation of the cellular glutamate level.

Animals↗