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PubMed2006

The effect of glutamine on prevention of glucocorticoid-induced skeletal muscle atrophy is associated with myostatin suppression.

Excess glucocorticoids (GCs) cause muscle atrophy. Glucocorticoid-induced muscle atrophy is associated with increased intramuscular myostatin expression. Myostatin is a negative regulator of skeletal muscle mass. Glutamine prevents GC-induced muscle atrophy. We hypothesized that glutamine effect on reversal of GC-induced muscle atrophy is mediated in part by suppression of myostatin. We administered daily to male Sprague-Dawley rats dexamethasone, dexamethasone plus glutamine, saline or saline plus glutamine, all pair-fed. Animals were killed on day 5. Body weight and weights of gastrocnemius muscles were measured. Myostatin expression was measured by Northern and Western blots, and was compared with glyceraldehyde-3-phosphate dehydrogenase. Myoblast C2C12 cells were exposed to dexamethasone, or dexamethasone and glutamine, and their myostatin messenger RNA and protein expression compared with glyceraldehyde-3-phosphate dehydrogenase. Myostatin promoter activity was measured by luciferase activity of transfected C2C12 cells, grown in medium including dexamethasone, or dexamethasone plus glutamine. Rats that received dexamethasone showed significant body and muscle weight loss accompanied by an increase in intramuscular myostatin expression, compared with their saline-treated controls. Pair-fed rats given dexamethasone plus glutamine had significantly less reduction in body and muscle weights and lower myostatin expression when compared with those treated with dexamethasone alone. In C2C12 myoblast cells, addition of glutamine to dexamethasone prevented the hyperexpression of myostatin induced by dexamethasone. Myostatin promoter activity increased in cells exposed to dexamethasone, but this increase was partially blocked by addition of the glutamine. Administration of glutamine partially prevents GC-induced myostatin expression and muscle atrophy, providing a potential mechanism for the prevention of muscle atrophy induced by glucocorticoids.

Animals↗
PubMed2006

Glutamine supplementation in the newborn infant.

Glutamine is a non-essential amino acid that can be synthesized de novo from glutamate. This synthesis can be increased by intravenous infusion of carbon precursors (alpha-ketoglutarate or amino acids) in adults and in infants. The metabolism of glutamine is highly compartmentalized between the splanchnic tissues and the periphery, so that orally administered glutamine is completely metabolized in the splanchnic compartment. Data from studies in adults and children show that plasma levels of glutamine decline during acute stress and illness. Because of its importance in several physiological functions (the demonstrated benefits of supplemental glutamine in adult burns and trauma patients and the inhibitory effect on proteolysis in the skeletal muscle in vitro), it has been suggested that during 'acute stress' the demands of glutamine outweigh its de novo synthesis, resulting in a fall in plasma glutamine levels. As a consequence, glutamine has been considered a 'conditionally essential' amino acid. Because of its instability in solution, glutamine is not routinely added to the parenteral amino acid mixtures. A number of clinical trials of parenteral and enteral supplementation of glutamine have been performed. The outcome measures examined have varied between acute effects and long-term complex clinical events such as mortality and risk of infections. Although acute studies in LBW babies have shown some beneficial effects such as changes in protein metabolism and activation of immune system, these have not been translated into prolonged advantages such as reduction in mortality or in nosocomial infection. The reasons for these differences are discussed.

Dietary Supplements↗
PubMed2004

Short-term enteral glutamine does not enhance protein accretion in burned children: a stable isotope study.

OBJECTIVE: Glutamine is a nonessential amino acid that, in recent years, has been found to play important roles in several metabolic and immunologic processes. It has been theorized that, in a stressed state, it may become "conditionally essential" because the patient's ability to manufacture glutamine may not be adequate to meet their needs under this condition. We chose to evaluate the ability of 48 hours of enteral glutamine to enhance immediate nitrogen accretion in stressed pediatric burn patients. METHODS: Nine children with serious burns who were tolerating tube feedings were enrolled in a human studies committee-approved protocol in which they received 48 hours of enteral feedings with glutamine replacing 20% of essential and nonessential amino acids and 48 hours of isonitrogenous, isocaloric standard enteral feedings. This interval was chosen to help ensure that the study periods were comparable from a metabolic perspective. At the end of each period, protein kinetics were determined by a primed constant infusion of L-[1-(13)C] leucine tracer. The order of the studies was randomized. Seven children completed both phases of the study. Results were compared by paired t test and are presented as mean +/- standard error of the mean. RESULTS: During the glutamine feeding period, the leucine flux and leucine oxidation rate were significantly lower than those in the conventional feeding period. This reflects a reduction in total leucine intake from 80 +/- 11 to 62 +/- 10 micromol/kg per hour. However, there was no significant difference in the net balance of leucine accretion into proteins between these 2 dietary periods, which indicated that enriched glutamine feeding for 48 hours did not result in an immediate whole body protein gain in this group of pediatric patients. In addition, plasma glutamine concentration showed a moderate increase after 48 hours of supplementation but did not reach significance. CONCLUSION: Rapid protein accretion does not occur with short-term enteral glutamine supplementation. Several days of glutamine supplementation may be required to restore plasma glutamine levels and stimulate protein synthesis.

Adolescent↗
PubMed1996

Claude H. Organ, Jr. Honorary Lectureship. Glutamine, cancer, and its therapy.

OBJECTIVE: This overview on glutamine, cancer and its therapy discusses some of the in vitro and in vivo work on glutamine and tumor growth, and summarizes animal and human data on the potential benefits of glutamine in the tumor-bearing host receiving radiation or chemotherapy. BACKGROUND: Glutamine is the most abundant amino acid in the body. A tumor can act as a "glutamine trap," depleting host glutamine stores and resulting in cachexia. In vitro evidence of the dependence of tumor growth on glutamine has deterred its use in the clinic setting. METHODS: Data from a variety of investigations studying glutamine's interaction with the tumor-bearing host receiving radiation or chemotherapy were compiled and summarized. RESULTS: A large body of evidence in vivo suggests that supplemental glutamine does not make tumors grow but in fact results in decreased growth through stimulation of the immune system. When given with radiation or chemotherapy, glutamine protects the host and actually increases the selectivity of therapy for the tumor. CONCLUSION: Further prospective randomized trials are needed to demonstrate the safety and efficacy in humans undergoing radiation and chemotherapy.

Clinical Trials as Topic↗
PubMed1987

Metabolism of glutamine and glutamate in monkey lens.

In rat and bovine lenses, the primary source of intracellular glutamate has been shown to be glutamine transported from the surrounding fluids, whereas extracellular glutamate is less readily utilized. For comparison, glutamine and glutamate metabolism were studied in a primate. Fresh, intact lenses from Rhesus monkeys (Macaca mulatta) were incubated in balanced salt medium containing [15N]glutamate (Group A) or amino-labeled [15N]glutamine (Group B). In contrast to other species, the monkey lenses metabolized the glutamate more rapidly than the glutamine, although glutamine entered the lenses more rapidly than glutamate. Formation of labeled aspartate, alanine, proline, and serine was more rapid in Group A than in Group B, but labeling of the lenticular glutamate + glutamine pool was more rapid in Group B. This indicated that, in monkey lenses, deamidation of glutamine is sufficiently slow to limit the entry of glutamine into pathways requiring or preferring glutamate. The difference in rates of deamidation of glutamine in intact monkey lenses and rat lenses was confirmed by measuring the rate of ammonia release by lenses incubated with glutamine.

Amino Acids↗
PubMed2000

Glutamine metabolism stimulates intestinal cell MAPKs by a cAMP-inhibitable, Raf-independent mechanism.

BACKGROUND & AIMS: Infectious diarrhea caused by viruses plus enterotoxigenic bacteria is often more severe than diarrhea induced by either pathogen alone. We postulated that the increased cell adenosine 3',5'-cyclic monophosphate (cAMP) concentration observed during infection by enterotoxigenic organisms retards the intestinal repair process by blocking activation of mitogen-activated protein kinases (MAPKs) in proliferating intestinal cells. METHODS: We evaluated the effects of glutamine on MAPK activity, thymidine incorporation, and cell number in glutamine-starved and -sufficient rat intestinal crypt cells (IEC-6). RESULTS: In glutamine-starved cells, 10 mmol/L glutamine in the absence of serum stimulated [(3)H]thymidine incorporation 8-fold. This effect was inhibited by 60% with 8-(4-chlorophenylthio) (8-CPT)-cAMP (100 micromol/L) + isobutyl methylxanthine (100 micromol/L). In cells not starved of glutamine, glutamine stimulated thymidine incorporation by 3-fold, and 8-CPT-cAMP completely blocked the mitogenic effect. Inhibition of proliferation by cAMP persisted for at least 68 hours after cAMP removal. In vitro kinase assays showed that glutamine signaling requires an intact ERK (extracellular signal-related kinase) pathway in unstarved cells. In starved cells, at least one other pathway (JNK) was activated by glutamine, and the mitogenic inhibition by 8-CPT-cAMP was incomplete. Other intestinal fuels (glucose and acetate) were not mitogenic. CONCLUSIONS: Increased levels of intracellular cAMP inhibit ERKs but only partially reduce glutamine-stimulated proliferation in enterocytes adapted to low glutamine.

Cell Division↗
PubMed1996

Oral glutamine to prevent chemotherapy induced stomatitis: a pilot study.

Mucositis is a common toxicity of cancer chemotherapy. Glutamine appears to be the major energy source for intestinal epithelium, and animal studies have suggested that dietary supplementation with glutamine may protect the gut from both radiation and chemotherapy. Patients experiencing stomatitis after a course of chemotherapy were offered the opportunity to enter the current study if no clinical parameters precluded receiving the same chemotherapy doses during the next course of treatment. Patients received the same chemotherapy regimen as during the previous treatment but in addition received a suspension of L-glutamine, 4 gm swish and swallow twice a day, from day 1 of chemotherapy for 28 days or for 4 days past the resolution of any post-chemotherapy mucositis. Twelve patients receiving doxorubicin, 1 receiving etoposide, and 1 receiving ifosfamide, etoposide, and carboplatinum were entered into the study. The maximum grade (CALGB criteria) of mucositis decreased in 12 of 14 patients with glutamine supplementation (median score 2A vs 0.5, p < 0.001). Similarly, after glutamine supplementation, the total number of days of mucositis was decreased in 13 of 14 patients (2.7 +/- 0.8 (mean +/- SEM) vs 9.9 +/- 1.1, p > or = 0.001). Thirteen of the 14 patients felt that the mucositis was less severe with the addition of glutamine. No change in the nadir neutrophil count was noted with glutamine, and no toxicity of glutamine was observed. We conclude that oral supplementation with glutamine can significantly decrease the severity of chemotherapy-induced stomatitis, an important cause of morbidity in the treatment of patients with cancer. Glutamine supplementation in patients receiving therapy for cancer warrants further study.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Increased red cell glutamine availability in sickle cell anemia: demonstration of increased active transport, affinity, and increased glutamate level in intact red cells.

Sickle red blood cells (RBCs) have been shown to have an increase in total nicotinamide adenine dinucleotide (NAD) content by an as-yet-unknown mechanism. Because glutamine is an essential precursor in NAD biosynthesis, we have examined the rates of active RBC glutamine transport and glutamine transport kinetics with Michaelis-Menten constant (K[m]) and maximum velocity (V[max]) in RBCs from patients with sickle cell disease, patients with high reticulocyte counts, and normal volunteers. In addition, plasma and RBC levels of glutamine and glutamate in the three groups were analyzed. The rate of active glutamate transport in sickle RBCs increased threefold over that in high-reticulocyte RBCs and increased 15-fold over that in normal RBCs. Glutamine transport K(m) in sickle RBCs was decreased fivefold in comparison with that in the high-reticulocyte group and that in normal control subjects. Glutamine transport V(max) for sickle RBCs was twofold and eightfold higher in comparison with those in the high-reticulocyte RBCs and normal control RBCs, respectively. Finally, the level of RBC glutamate (a byproduct of glutamine in NAD synthesis) in the sickle group was significantly increased in comparison with that in the high-reticulocyte group, whereas the RBC glutamine level was not. The higher glutamate level in sickle cells may suggest a higher glutamine turnover in these cells. These data suggest that sickle RBCs have an increased glutamine availability and affinity that may facilitate the increase in total NAD in sickle RBCs.

Anemia, Sickle Cell↗
PubMed1998

Effects of glucagon on renal and hepatic glutamine gluconeogenesis in normal postabsorptive humans.

Glutamine is an important gluconeogenic amino acid in postabsorptive humans. To assess the effect of glucagon on renal and hepatic glutamine gluconeogenesis, we infused six normal healthy postabsorptive subjects with glucagon at a rate chosen to produce circulating glucagon concentrations found during hypoglycemia and, using a combination of isotopic and net balance techniques, determined the systemic, renal, and hepatic glucose release and renal and hepatic production of glucose from glutamine. Infusion of glucagon increased systemic and hepatic glucose release (both P < .02), but had no effect on renal glucose release (P = .26). Systemic and hepatic glutamine gluconeogenesis increased from 0.45 +/- 0.3 and 0.11 +/- 0.02 micromol x kg(-1) x min(-1), respectively, to 0.61 +/- 0.04 (P = .002) and 0.31 +/- 0.03 micromol x kg(-1) x min(-1) (P = .001), respectively, whereas renal glutamine gluconeogenesis was unchanged (from 0.33 +/- 0.03 to 0.30 +/- 0.04 micromol x kg(-1) x min(-1), P = .20). The hepatic contribution to systemic glutamine gluconeogenesis increased from 25.2% +/- 6.2% to 51.6% +/- 5.5% (P = .002), while that of the kidney decreased from 74.8% +/- 6.2% to 48.4% +/- 5.5% (P = .003). Glucagon had no effect on the renal net balance, fractional extraction, or uptake and release of either glucose or glutamine. We thus conclude that glucagon stimulates glutamine gluconeogenesis in normal postabsorptive humans, predominantly due to an increase in hepatic glutamine conversion to glucose. Thus, under certain conditions such as counterregulation of hypoglycemia, the liver may be an important site of glutamine gluconeogenesis.

Adult↗
PubMed1997

Regulation of protein turnover by glutamine in heat-shocked skeletal myotubes.

Skeletal muscle accounts for approximately one-half of the protein pool in the whole body. Regulation of protein turnover in skeletal muscle is critical to protein homeostasis in the whole body. Glutamine has been suggested to exert an anabolic effect on protein turnover in skeletal muscle. In the present work, we characterized the effect of glutamine on the rates of protein synthesis and degradation in cultured rat skeletal myotubes under both normal and heat-stress conditions. We found that glutamine has a stimulatory effect on the rate of protein synthesis in stressed myotubes (21%, P < 0.05) but not in normal-cultured myotubes. Glutamine shows a differential effect on the rate of degradation of short-lived and long-lived proteins. In both normal-cultured and stressed myotubes, the half-life of short-lived proteins was not altered while the half-life of long-lived proteins increased with increasing concentrations of glutamine in a concentration-dependent manner. In normal-cultured myotubes, when glutamine concentration increased from 0 to 15 mM, the half-life of long-lived proteins increased 35% (P < 0.001) while in stressed myotubes, it increased 27% (P < 0.001). We also found that glutamine can significantly (P < 0.001) increase the levels of heat-shock protein 70 (HSP70) in stressed myotubes, indicating that HSP 70 may participate in the mechanism underlying the effect of glutamine on protein turnover. We conclude that in cultured skeletal myotubes the stimulatory effect of glutamine on the rate of protein synthesis is condition-dependent, and that the inhibitory effect of glutamine on the rate of protein degradation occurs only on long-lived proteins.

Animals↗
PubMed1998

Glutamine-supplemented total parenteral nutrition reduces blood mononuclear cell interleukin-8 release in severe acute pancreatitis.

Glutamine, a conditionally essential amino acid, is important for immune function. It is now being formulated for incorporation into total parenteral nutrition (TPN). The aims of this study were to examine the effect of glutamine administration on lymphocyte proliferation and proinflammatory cytokine release in patients with severe acute pancreatitis. Fourteen patients were randomized (in a double-blind fashion) to receive either conventional or isocaloric, isonitrogenous glutamine-supplemented (0.22 g glutamine x kg(-1) x d(-1) as glycyl-glutamine) TPN for 7 d. DNA synthesis (index of lymphocyte proliferation) and the 24-h release of tumor necrosis factor (TNF), interleukin (IL)-6, and IL-8 from peripheral blood mononuclear cells were measured in vitro on days 0, 4, and 7. Thirteen patients completed the study protocol (6 glutamine TPN, 7 conventional TPN). Glutamine supplementation increased median DNA synthesis by 3099 cpm over the study period against 219 cpm in the conventional group (increase not significantly different between the two groups) . Glutamine supplementation did not significantly influence TNF or IL-6 release, but, in contrast, median IL-8 release was reduced by day 7 in the glutamine group while it was increased in the conventional group (-17.7 ng/mL (median change over study period) versus +43.3 ng/mL, respectively; P=0.045). Small patient numbers and substantial interindividual variation limit the conclusions, but there is a trend for the glutamine group to have improved lymphocyte proliferation, and in the case of IL-8, reduced proinflammatory cytokine release.

Adult↗
PubMedDate not supplied

Effect of glutamine on immune function in the surgical patient.

The beneficial effects of glutamine on immune function in vitro have been well described. Severely ill surgical patients undergo glutamine depletion and this has been implicated as a cause of immune dysfunction in vivo. With the introduction of the stable dipeptides of glutamine into total parenteral nutrition (TPN) regimens, the clinical effects of glutamine on the immune system have taken on an increased relevance and importance. In a randomized clinical trial, we have shown that glutamine-supplemented TPN increased the T cell mitogenic response in patients undergoing colorectal resection. This was not associated with an altered production of the pro-inflammatory cytokines interleukin-6 (IL-6) or tumor necrosis factor (TNF). In a subsequent clinical trial comparing glutamine-supplemented TPN with control TPN in patients with severe acute pancreatitis there was a similar modest enhancement of the T cell response in the glutamine-supplemented group. Although Il-6 and TNF production were again unchanged, there was a significant reduction in IL-8 production in the glutamine-supplemented group. Glutamine may exert its immunological effects by a direct action on the cells of the immune system. Possible indirect mechanisms by which glutamine may influence the immune system include the maintenance of gut barrier function, or the preservation of action of the antioxidant glutathione.

Glutamine↗
PubMed1998

The role of glutamine, serum and energy factors in growth of enterocyte-like cell lines.

BACKGROUND: Glutamine is routinely added to most cell cultures. Glutamine has been found to be the preferential nutrient to the rapidly replicating intestinal mucosa, but whether this is a metabolic effect or due to other properties of this amino acid is not determined. To study the importance of glutamine on the growth of two enterocyte-like cell lines, the effects of depriving the media or supplementing it with glutamine were assessed in media with different serum and energy supplements. METHODS: CaCo-2 and HT-29 cells were grown in serum-free medium, with fetal bovine or synthetic serum, and with or without glucose or galactose. The glutamine content was varied between 0 and 4 mM. All growth assays were performed in triplicate by counting in a hemocytometer. RESULTS: Both cell lines were dependent of serum factors for growth, but displayed distinct requirements on glutamine supplementation. Glutamine was an obligate supplement with dose-dependent correlation to growth (r = 0.87, p < 0.01) for CaCo-2 cells cultured in synthetic, but not in fetal bovine serum. In HT-29 cells, the correlation between glutamine and growth was significant (r = 0.68, p < 0.05) only in fetal bovine serum in the absence of galactose. CONCLUSION: This study shows that glutamine has different growth stimulating effects on two enterocyte-like cell lines studied. This could reflect different modes of action of glutamine on proliferation and differentiation in an enterocyte cell population.

Animals↗
PubMed2004

Enhanced effect of glycyl-L-glutamine on mouse preimplantation embryos in vitro.

A comparison of the effects of replacing L -glutamine with either glycyl-L-glutamine or alanyl-L-glutamine in a KSOM-type medium on the development of mouse preimplantation embryos in vitro has been made. Alanyl-L-glutamine has no significant effect on the rates of blastocyst formation, onset or completion of hatching, and on the numbers of inner cell mass and trophectoderm cells that develop. Glycyl-L-glutamine has no effect on the rate of blastocyst formation; it stimulates slightly the onset of hatching, but significantly increases the numbers of inner cell mass and trophectoderm cells that develop. Embryo transfer experiments comparing media containing either glutamine or glycyl-L-glutamine have not produced any gross abnormal fetal development. Recently, alanyl-L-glutamine has been used to replace glutamine in media for the culture of human preimplantation embryos. The results in this paper suggest that glycyl-L-glutamine may be a better choice of dipeptide.

Amino Acids↗
PubMed1982

Effects of acute metabolic acidosis on renal, gut, liver, and muscle metabolism of glutamine and ammonia in the dog.

Previous studies have shown a rise in arterial glutamine in acute acidosis in the dog. In these experiments glutamine and ammonia metabolism was studied in anesthetized dogs during normal acid-base status and following acute hydrochloric acidosis to determine the mechanism for the rise in arterial glutamine in acidosis. Splanchnic, liver, renal, and hind-half extraction/production were measured by arteriovenous (A-V) sampling and simultaneous blood flow measurements using electromagnetic flow probes. In the normal dog, muscle produced glutamine, and the kidneys, gut, hepatosplanchnic bed, and liver extracted it. Whole blood arterial glutamine rose in acidosis. Renal and muscle glutamine and ammonia extraction/production were unchanged. Gut ammonia release and hepatic ammonia uptake increased by similar amounts in acidosis, but no change in gut glutamine uptake occurred. Hepatic and total hepatosplanchnic glutamine uptake was markedly reduced thereby contributing to the raised arterial glutamine. These results demonstrate that acute metabolic acidosis in the dog-influences marked changes in glutamine extraction and ammonia metabolism across the hepatosplanchnic bed without significant changes in kidney or muscle metabolism.

Acidosis↗
PubMed1977

The transport and metabolism of glutamine by kidney-cortex mitochondria from normal and acidotic rats.

1. The oxidation of glutamine by kidney-cortex mitochondria from normal and acidotic rats was not inhibited by avenaciolide, which did inhibit glutamate uptake and oxidation. The oxidation of glutamine by these mitochondria was always greater than that of glutamate. Direct measurements of the metabolism of [1-14C]glutamine in the presence of glutamate, and of [1-14C]glutamate in the presence of glutamine, demonstrated that the uptake and metabolism of external glutamate is insufficient to account for the observed rate of glutamine uptake and metabolism. Thus the postulated glutamine/glutamate antiport does not play a quantitatively important role in the metabolism of glutamine by renal mitochondria. 2. Rapid swelling of these mitochondria was observed in iso-osmotic solutions of L-glutamine and L-glutamyl-gamma-monohydroxamate but not in D-glutamine or L-isoglutamine (1-amido-2-aminoglutaric acid). Thus a relatively specific glutamine uniport exists in these mitochondria. 3. The utilization of glutamine was increased about 3-fold in mitochondria from chronically acidotic rats. Thus mitochondrial adaptations play an important part in the renal response to metabolic acidosis.

Acidosis↗
PubMed2003

Aspartate-107 and leucine-109 facilitate efficient coupling of glutamine hydrolysis to CTP synthesis by Escherichia coli CTP synthase.

CTP synthase catalyses the ATP-dependent formation of CTP from UTP using either NH(3) or L-glutamine as the nitrogen source. GTP is required as an allosteric effector to promote glutamine hydrolysis. In an attempt to identify nucleotide-binding sites, scanning alanine mutagenesis was conducted on a highly conserved region of amino acid sequence (residues 102-118) within the synthase domain of Escherichia coli CTP synthase. Mutant K102A CTP synthase exhibited wild-type activity with respect to NH(3) and glutamine; however, the R105A, D107A, L109A and G110A enzymes exhibited wild-type NH(3)-dependent activity and affinity for glutamine, but impaired glutamine-dependent CTP formation. The E103A, R104A and H118A enzymes exhibited no glutamine-dependent activity and were only partially active with NH(3). Although these observations were compatible with impaired activation by GTP, the apparent affinity of the D107A, L109A and G110A enzymes for GTP was reduced only 2-4-fold, suggesting that these residues do not play a significant role in GTP binding. In the presence of GTP, the k (cat) values for glutamine hydrolysis by the D107A and L109A enzymes were identical with that of wild-type CTP synthase. Overall, the kinetic properties of L109A CTP synthase were consistent with an uncoupling of glutamine hydrolysis from CTP formation that occurs because an NH(3) tunnel has its normal structure altered or fails to form. L109F CTP synthase was prepared to block totally the putative NH(3) tunnel; however, this enzyme's rate of glutamine-dependent CTP formation and glutaminase activity were both impaired. In addition, we observed that mutation of amino acids located between residues 102 and 118 in the synthase domain can affect the enzyme's glutaminase activity, suggesting that these residues interact with residues in the glutamine amide transfer domain because they are in close proximity or via a conformationally dependent signalling mechanism.

Alanine↗
PubMed2004

Conversion into GABA (gamma-aminobutyric acid) may reduce the capacity of L-glutamine as an insulin secretagogue.

We have carried out a detailed examination of L-glutamine metabolism in rat islets in order to elucidate the paradoxical failure of L-glutamine to stimulate insulin secretion. L-Glutamine was converted by isolated islets into GABA (gamma-aminobutyric acid), L-aspartate and L-glutamate. Saturation of the intracellular concentrations of all of these amino acids occurred at approx. 10 mmol/l L-glutamine, and their half-maximal values were attained at progressively increasing concentrations of L-glutamine (0.3 mmol/l for GABA; 0.5 and 1.0 mmol/l for Asp and Glu respectively). GABA accumulation accounted for most of the 14CO2 produced at various L-[U-14C]glutamine concentrations. Potentiation by L-glutamine of L-leucine-induced insulin secretion in perifused islets was suppressed by malonic acid dimethyl ester, was accompanied by a significant decrease in islet GABA accumulation, and was not modified in the presence of GABA receptor antagonists [50 micromol/l saclofen or 10 micromol/l (+)-bicuculline]. L-Leucine activated islet glutamate dehydrogenase activity, but had no effect on either glutamate decarboxylase or GABA transaminase activity, in islet homogenates. We conclude that (i) L-glutamine is metabolized preferentially to GABA and L-aspartate, which accumulate in islets, thus preventing its complete oxidation in the Krebs cycle, which accounts for its failure to stimulate insulin secretion; (ii) potentiation by L-glutamine of L-leucine-induced insulin secretion involves increased metabolism of L-glutamate and GABA via the Krebs cycle (glutamate dehydrogenase activation) and the GABA shunt (2-oxoglutarate availability for GABA transaminase) respectively, and (iii) islet release of GABA does not seem to play an important role in the modulation of the islet secretory response to the combination of L-leucine and L-glutamine.

4-Aminobutyrate Transaminase↗