How does glutamine work

Thus, the activity of the aforementioned enzyme appears to be controlled through the intracellular glutamine concentration by means of a post-transcriptional control mechanism, which increases the GS enzyme activity when the intracellular glutamine concentration decreases.

However, the GS enzyme is relatively unstable in the presence of glutamine; therefore, the increased intracellular glutamine concentration leads to faster GS degradation. In addition, glucocorticoids and intracellular glutamine depletion work synergistically by increasing the GS expression in the skeletal muscle [ 57 ]. In vitro studies conducted with several cell types demonstrated that glutamine can also change the gene expression of contractile proteins.

Other studies highlight the relevant role played by glutamine in mediating the activation of pathways, such as the mammalian target of rapamycin mTOR , which is considered an essential tissue size and mass regulator, either in healthy or ill patients. In fact, the use of amino acids, mainly of leucine, as anabolic inducers in muscle cells has its action compromised via mTOR when glutamine is not available [ 17 ]. Despite the essential role played by glutamine in regulating the expression of muscle content-associated genes, there are no in vivo studies supporting the hypothesis that supplementation applied alone can promote muscle mass increase.

Another significant role played by glutamine is associated with its capacity of modulating protective and resistance responses to injuries, which are also known as antioxidant and cytoprotective effects. Reactive oxygen species ROS , both the radical and the non-radical species, react to minerals, to phospholipid membranes, and to proteins, among other relevant compounds, to cellular homeostasis [ 59 ].

Glutamine can modulate the expression of heat shock proteins HSP. Results concerning skeletal and liver muscles were recorded at protein and gene expression levels. In addition, other genes were highly responsive to glutamine, such as the heat shock factor 1 HSF-1 , which is important for HSP synthesis, and enzymes linked to the antioxidant system Figure 3.

The glutamate resulting from glutamine is an essential substrate for glutathione synthesis, a fact that changes the expression of genes, such as glutathione S-reductase GSR and glutathione peroxidase 1 GPx1. The liver is highly metabolic and has many functions, including the detoxification of blood constituents arriving from the digestive tract, production of bile to aid digestion, metabolism of carbohydrates, lipids, proteins, and drugs, blood pH balance, synthesis of plasma proteins, and the storage and synthesis of glycogen and lipids.

Therefore, glutamine is crucial for energy metabolism and proliferation of hepatocytes in the liver. In addition, glutamine is an important precursor for gluconeogenesis, the process of glucose production from other non-carbohydrate constituents, which is a central metabolic pathway in the liver that allows maintenance of blood glucose levels in fasting and starvation conditions following depletion of glycogen stores.

During severe illness, the skeletal muscle is the major supplier of glutamine, while the liver is a major consumer [ 28 , 60 ].

This consumption supports many of the liver activities listed above, but as a key amino acid involved in nitrogen metabolism, the uptake of glutamine in liver hepatocytes regulates the activity of the urea cycle due to its conversion to glutamate NH 3 by GLS [ 61 ]. Consequently, the liver regulates blood pH and the detoxification of NH 3 via the urea cycle using glutamine. Under the action of ornithine transcarbamylase, ornithine reacts with CP to form citrulline.

This subsequently undergoes various biochemical reactions forming arginine, fumarate, and, ultimately, urea, which is excreted from the hepatocyte cytosol into the blood. In the final urea-forming reaction, ornithine is regenerated to allow the cyclic continuation of the urea cycle with additional NH 3.

Importantly, glutamine concentrations in the mitochondria regulate flux through CP generation. Consequently, both of these biochemical mechanisms result in a high flux toward urea formation due to the elevated levels of NH 3 in the mitochondrial sourced from digestive tract blood and glutamine degradation , the high affinity of CPS for NH 3 , and the increased activity of GLS.

However, the ultimate generation of urea appears to be regulated by the sub-cellular level of glutamine and, consequently, its uptake from the extracellular environment. The liver architecture is exquisitely designed such that periportal hepatocytes near the portal vein receiving blood and nutrients from the gut are primarily responsible for urea production using glutamine as outlined above. The intercellular or liver compartmentalized cycling of glutamine between these liver regions is also mediated by specific membrane transporters in periportal and perivenous hepatocytes.

In essence, this directional transport is also regulated by the relative pH difference between the intracellular and extracellular space, such that periportal hepatic glutamine uptake leads to extracellular acidification and intracellular alkalization, while glutamine export from perivenous hepatocytes leads to intracellular acidification and extracellular alkalization [ 61 ].

Experiments in perfused rat livers have shown that a slight alkali increase in extracellular pH 0. Mitochondrial glutamine concentration increased to about 15—50 mM, while the extracellular 0. Therefore, the regulation and flux through GLS in periportal hepatocytes are regulated by the sub-cellular concentration of glutamine, and not just the rate of glutamine entry from extracellular sources.

Importantly, glutamine importation and exportation also affect osmotic balance and therefore influences hepatocyte volume. This has additional consequences for hepatic function, including bile synthesis and release [ 72 ], but also regulates anabolic processes, such as glycogen, lipid, and protein synthesis [ 61 ]. Largely, glutamine uptake enhances hepatocyte cell swelling and hydration [ 73 ], which leads to increased glycogen and fatty acid synthesis [ 74 , 75 ], and reduced proteolysis mediated by P38 mitogen-activated protein kinases p38 MAPK signalling [ 76 ].

Other amino acids, such as glycine and alanine, along with anabolic hormones, such as insulin, promoted hepatocyte swelling, leading to increased biosynthetic processes [ 77 ], while catabolic hormones, like glucagon, reduced intracellular glutamine levels induced hepatocyte shrinkage [ 78 ]. Consequently, dehydration due to reduced intracellular glutamine levels is characterized by decreased cell volume, initiation of the catabolic process, and insulin-resistant conditions, and it was recently shown that hypertonic infusion can cause glucose dysregulation in humans [ 79 ].

The liver is an insulin-sensitive organ and like skeletal muscle, is responsible for glucose disposal via glycogen synthesis. Development of insulin resistance and subsequent glucotoxic conditions can progress to chronic disorders, such as non-alcoholic fatty liver disease NAFLD , characterized by excessive lipid accumulation, and non-alcoholic steatohepatitis NASH , characterized by increased extracellular matrix ECM deposition [ 80 , 81 ].

These chronic disorders may lead to further hepatocyte damage, manifesting as liver cirrhosis and possibly hepatocellular carcinoma. The liver can be damaged in various ways, including infection e.

This damage elicits a pro-inflammatory hepatic environment, which leads to liver tissue fibrosis, causing impaired hepatic function [ 80 ]. Untreated fibrosis ultimately progresses to cirrhosis, which is mostly irreversible [ 80 ]. A key mediator of liver fibrosis is the hepatic stellate cell HSC , which is a mesenchymal, fibrogenic cell that resides in the sub-endothelial space of Disse between the hepatocyte epithelium and the sinusoids.

While normally in a quiescent state, these cells become activated following liver insult, and they respond to cytokines and proliferate to aid injury repair. However, overactivation or a failure to resolve their activation status chronic activation from continued exposure to pro-inflammatory stimuli can lead to the increased ECM deposition in the space of Disse that has a negative consequence for hepatocyte function and normal liver architecture, such as loss of microvilli [ 80 , 82 ].

Kupffer cells, a liver macrophage, are also activated in these conditions, and together with HSCs promote a pro-inflammatory hepatic environment. Pro-inflammatory activators of these cells are beyond the scope of this manuscript, but it has been demonstrated that HSCs require glutamine metabolism to maintain proliferation. In addition, glutamine can be used as a precursor for proline synthesis, which is a key component of collagen and ECM formation [ 82 ]. At present, there is some evidence to indicate that glutamine supplements slow NAFLD [ 83 ] or NASH [ 84 ] progression, but most studies have been conducted in rodents.

There is no convincing evidence to indicate that glutamine supplements prevent NAFLD or NASH progression in humans, which may be due to the complexity of multiple factors contributing to these disorders. The liver is a remarkable organ and has the ability to regenerate, and some research has indicated that glutamine supplementation may be advantageous for liver growth and repair after resection, but are again limited to animal studies [ 85 ].

However, others have suggested that raised glutamine levels are associated with liver failure, and the severity correlated with plasma glutamine [ 86 ]. Consequently, the effects of glutamine on liver function beyond urea synthesis have not been fully explored, and the administration of exogenous glutamine to those with compromised hepatic function needs to be considered carefully [ 86 ].

Glutamine was first considered a biologically important molecule in when indirect evidence helped to characterize it as a structural component of proteins; then, in , abundant free glutamine was found in certain plants.

Interestingly, the number of studies only increased after the research conducted by Sir Hans Adolf Krebs — in the s. At that time, and for the first time in science history, Sir Krebs found that mammalian tissues can hydrolyse and synthesize glutamine [ 22 ]. In the s, Eagle, et al. Further work at that stage was hampered because glutamine was classified as a non-essential amino acid and it was difficult to measure the levels in plasma and tissues.

Throughout the s, s, and s, Hans Krebs, Philip Randle — , Derek Williamson — , and Eric Newsholme — all worked on metabolic regulation utilizing different research models, from isolated cells in vitro, to human and in vivo experiments. One of the authors of this review, Newsholme P et al. Pithon-Curi et al. The studies by Eric and Philip Newsholme on glutamine metabolism in lymphocytes and macrophages, respectively, prompted many other publications, which jumped from an average of two or three publications per year in the late s and early s to about 50 publications per year in the last 20 years.

However, the increased demand for glutamine by immune system cells, along with the increased use of this amino acid by other tissues, such as the liver, may lead to a glutamine deficit in the human body.

In addition, one of the most important sites of glutamine synthesis, the skeletal muscles, reduce their contribution to maintaining plasma glutamine concentration Figure 2.

In immune cells, glucose is mainly converted into lactate glycolysis , whereas glutamine is converted into glutamate, aspartate, and alanine by undergoing partial oxidation to CO 2 , in a process called glutaminolysis [ 3 ] Figure 3.

This unique conversion plays a key role in the effective functioning of immune system cells. Furthermore, through the pentose phosphate pathway, a metabolic pathway parallel to the glycolysis pathway, cells can produce ribosephosphate a five-carbon sugar , which is a precursor for the pentose sugars seen in the RNA and DNA structure, as well as glycerolphosphate for phospholipid synthesis [ 94 ].

On the other hand, the degradation of glutamine, and thus formation of NH 3 , and aspartate leads to the synthesis of purines and pyrimidines of the DNA and RNA. The expression of several genes in immune system cells is largely dependent on glutamine availability [ 3 ]. For example, the role glutamine plays in the control of proliferation of immune system cells occurs through activation of proteins, such as ERK and JNK kinases. Both proteins act on the activation of transcription factors, such as JNK and AP-1, and it leads to the transcription of cell proliferation-related genes.

Thus, glutamine acts as an energy substrate for leukocytes and plays an essential role in cell proliferation, tissue repair process activity, and intracellular pathways associated with pathogen recognition [ 97 ]. The primary substrate for neutrophil survival endocytosis and ROS generation is glucose.

However, glucose is not the only energy metabolite source by these cells. Interestingly, when compared to other leukocytes, such as macrophages and lymphocytes, neutrophils consume glutamine at the highest rates [ 98 , 99 ]. Much of the glutamine is converted to glutamate, aspartate via Krebs cycle activity , and lactate in neutrophils. Neutrophils use protein structures composed of uncondensed chromatin and of antimicrobial factors also called neutrophilic extracellular traps NETs.

The action of NETs requires ROS formation, synthesis of enzymes, such as myeloperoxidase MPO and elastase, as well as components capable of overriding virulence factors and destroying extracellular bacteria [ ]. Glutamine increases expressions of these three proteins either in the absence or in the presence of PMA. Glutamine enhances superoxide production in neutrophils, probably via the generation of ATP and regulation of the expression of components of the NADPH oxidase complex [ ].

Glutamine plays a role to prevent the changes in NADPH oxidase activity and superoxide production induced by adrenaline in neutrophils [ ]. Metabolism of glucose and glutamine is profoundly affected during the macrophage activation process [ , ]. Either thioglycollate or BCG enhances activities of hexokinase and citrate synthase, and also glucose oxidation whereas BCG markedly increases glutamine metabolism.

Lipopolysaccharide LPS administration also causes pronounced changes in macrophage metabolism and function for a review, see Nagy and Haschemi [ ]. Glucose and glutamine metabolism is also involved in polarizing signals that up-regulate the transcriptional programs required in the macrophage capacity to perform specialized functions.

For instance, extracellular glutamine may function as the specific starvation-induced nutrient signal to regulate mTORC1. Different populations of macrophages have now been identified, such as M1 and M2 [ , , ]. The M1 and M2 are in fact two extremes of a still not completely known spectrum of macrophage activation states [ , , ]. Reprogramming signalling pathways are involved in the formation of M1 or M2 phenotype macrophages. The metabolic reprogramming of macrophages include key changes in glutamine and glucose metabolism [ ].

No reports identified the requirement of fatty acids for human macrophage IL-4 induced polarization [ ]. This issue, however, remains controversial. Interestingly, macrophages reprogram their metabolism and function to polarize for pro- or anti-inflammatory cells, and this is a consequence of the environmental conditions and stimuli [ ].

Treatment of macrophages with LPS promotes a switch from glucose-dependent oxidative phosphorylation to aerobic glycolysis—the Warburg effect [ ]. Due to this mechanism, M1 macrophages exhibit a quick increase in ATP formation that is required for the host defence response [ , , ]. The TCA cycle of M2 macrophages has no metabolic flux escape whereas M1 macrophages treated with LPS have two points of substrate flux deviation, one occurring at the isocitrate dehydrogenase step reaction and another one at post succinate formation.

As a result, there is an accumulation of TCA cycle intermediates e. Itaconate has anti-inflammatory properties through activation of nuclear factor erythroid 2-related factor 2 Nrf2 via Kelch-like ECH-associated protein 1 KEAP1 alkylation [ 97 ]. The glutamine seems to be fully required for IL-4 induction of macrophage alternative activation [ , ]. Liu, et al. Macrophage metabolism feature varies with the specific-tissue microenvironment, and this is of critical importance for the tissue-resident macrophage function.

The peritoneum is rich in glutamate, a product of glutamine metabolism that is used by resident macrophage to induce specific metabolic changes under microbial sensing [ ]. Taken as a whole, glutamine metabolism does play a very important role as a synergistic supporter and modulator of macrophage activation. Lymphocyte activation is associated with specific metabolic pathways to optimize its function.

Associated bioenergetic processes are dependent on the activation of AMPK, indicating cross-talk between metabolism and signalling pathways in immune cell differentiation. Greiner, et al. Glutamine plays an important role for the function of these cells in different ways. Pyruvate is a common product of glucose and glutamine metabolism in the cells. Curi, et al. Mitochondria have been reported to be able to regulate leukocyte activation. Succinate, fumarate, and citrate, metabolites of the Krebs cycle and produced through glucose and glutamine metabolism, participate in the control of immunity and inflammation either in innate and adaptive immune cells [ 97 ].

Most glucose molecules are transported via glucose transporter 1 GLUT1 , which is not observed in non-activated lymphocytes [ ].

GLUT1 is an important metabolic marker of lymphocyte activation as it migrates rapidly to the cell surface after stimulation. Activation of intracellular signalling by Akt beyond GLUT1 protein levels further increases glucose uptake and T cell activation. In contrast, the AMPK pathway inhibits mTOR by suppressing the signalling of this protein and promotes activation of mitochondrial oxidative metabolism rather than the glycolytic pathway [ , ].

The evidence has now accumulated that glutamine metabolism plays a key role in the activation of lymphocytes. Glutamine is required for human B lymphocyte differentiation to plasma cell and to lymphoblastic transformation [ ]. The cell proliferation process requires both ATP for high-energy expenditure and precursors for the biosynthesis of complex molecules, such as lipids cholesterol and triglycerides and nucleotides for RNA and DNA synthesis.

To perform rapid proliferation activity under the certain stimulus, lymphocytes switch from oxidative phosphorylation to aerobic glycolysis plus glutaminolysis, and so markedly increase glucose and glutamine utilization. The metabolic transition in a Th0 lymphocyte is crucial for the activation of T cells, since glucose metabolism provides intermediates for the biosynthetic pathways, being a prerequisite for the growth and differentiation of T cells [ ].

Therefore, the high glycolytic activity is closely associated with the differentiation of Th0 to Th1 cells [ ]. Inhibition of the glycolytic pathway blocks this process whereas it promotes differentiation into Treg cells.

Increased glycolysis by proliferating cells is linked to increased uptake of glucose and increased expression and activity of glycolytic enzymes, whereas glucose utilization in the oxidative phosphorylation pathway OXPHOS is decreased. Inadequate nutrient delivery or specific metabolic inhibition prevents the activation and proliferation of T cells since the inability to use glucose inhibits T cell differentiation in vitro and in vivo [ , ].

Mitochondrial dynamics are closely associated with T lymphocyte metabolism and function. Activated effector T cells have punctate mitochondria and augmented the activity of anabolic pathways whereas memory T lymphocytes exhibit fused mitochondria and enhanced oxidative phosphorylation activity [ ]. This factor controls leukocyte metabolism reprogramming, through changes in gene expression, and thus immune cell functions [ ].

Glycolysis and glutaminolysis are strongly associated to ensure appropriateness for lymphocyte function. Hexosamine biosynthesis requires glucose and glutamine for the de novo synthesis of uridine diphosphate N -acetylglucosamine UDP-GlcNAc.

This sugar-nucleotide inhibits receptor endocytosis and signalling through promoting N-acetylglucosamine branching of Asn N -linked glycans. Araujo, et al. As a consequence, growth and pro-inflammatory T H 17 features prevail over anti-inflammatory-induced T regulatory iTreg differentiation. The authors then postulated that a primary function of concomitant high aerobic glycolysis and glutaminolysis activities is to limit precursors to N-glycan biosynthesis.

This metabolic feature of T lymphocytes has marked implications in autoimmunity and cancer. Glutamine also serves as a precursor for the synthesis of putrescine and the polyamines, spermidine and spermine. High levels of polyamines are reported in tumour cells and in autoreactive B- and T-cells in autoimmune diseases. Polyamines have been described to play a role in the control of normal immune cell function and have been associated with autoimmunity and anti-tumour immune cell properties [ ].

Plasma glutamine concentration may be decreased during intense immune cell activity in patients with critical disease conditions; as occurs in sepsis, burn, and injury. Skeletal muscle is the main source of glutamine in mammals.

This tissue synthesizes, stores, and releases this amino acid to be used by several organs and cells, such as lymphoid organs and leukocytes [ 89 ], as mentioned above. The decrease in plasma glutamine availability has been reported to contribute to the impaired immune function in several clinical conditions.

In fact, glutamine depletion reduces lymphocyte proliferation, impairs expression of surface activation proteins on and production of cytokines, and induces apoptosis in these cells [ 9 ]. Addition of glutamine to the diet increases experimental animal survival to a bacterial challenge. Glutamine given through the parenteral route has been reported to be beneficial for patients after surgery, radiation treatment, bone marrow transplantation, or injury [ 5 , ].

Administration of glutamine before the onset of infection prevents it in animals and humans, possibly by preventing deficiency of this amino acid [ ]. Concerning the mechanism of action, glutamine regulates the expression of several genes of cell metabolism, signal transduction proteins, cell defence, and repair regulators, and to activate intracellular signalling pathways [ 2 ].

Thus, the function of glutamine goes beyond that of a metabolic fuel or protein synthesis precursor. The redox state of the cells is consequently related to GSH concentrations, which are also influenced by the availability of amino acids. Glutamine via glutamate , cysteine, and glycine are the precursor amino acids for the synthesis of GSH.

However, among these three amino acids, glutamate represents the first and probably the most important step in the synthesis of GSH intermediate compounds. Glutamate synthesis, in turn, is dependent on the glutamine intracellular availability. This cycle provides GSH to be consumed locally by the liver, or under hormonal regulation e.

The intracellular and extracellular GSH concentrations are determined by the balance between its synthesis and degradation, as well as by the ability of the cell to transport GSH between the cytosol and the different organelles or the extracellular space [ ]. Free radicals and ROS production are essential for cell signalling and immune-mediated oxidative bursts found in phagocytes, such as neutrophils and macrophages.

For instance, in acute inflammatory situations, such as sepsis or viral infection, there is a rise in the intracellular redox state, and all cell compartments are vulnerable to oxidative stress characterized by increased levels of ROS, and low removal by the antioxidant system [ 10 , 39 ]. Indeed, many experimental [ 4 , 39 , , ] and observational [ 10 , 26 ] studies have already identified that during high catabolism, the low plasma concentration of glutamine is an independent risk factor for mortality [ ].

The ability of all living organisms to respond with rapid and appropriate modifications against physiological challenges is an essential feature for survival. At the most basic cellular level, living organisms respond to unfavourable conditions, such as heat shock, toxins, oxidants, infection, inflammation, and several other stressful situations, by changing the expression of stress-related genes, also known as heat shock genes.

This function assists protein transport, prevents protein aggregation during folding, and protects newly synthesized polypeptide chains against misfolding and protein denaturation [ ]. Although several HSP families have been studied in the last couple of years e.

Glutamine found at concentrations similar to those recorded for human plasma leads to a significant HSP72 gene expression increase in peripheral blood mononuclear cells subjected to LPS treatment. On the other hand, reduced glutamine concentration results in reduced HSP72 expression in monocytes; this effect depends on mRNA stability. The preoperative administration of glutamine can modulate HSP70 expression by reducing the activation levels of the cyclic AMP response element binding protein CREB , which is often associated with exacerbated inflammatory responses.

OGT [ 94 ]. Both Sp1 and eIF2 are key transcription factors for the induction of the main thermal shock eukaryotic factor, HSF-1 [ ]. In vitro [ 21 , ] and in vivo [ 4 , 39 , , , ] studies demonstrate that glutamine availability maintains cell homeostasis and promotes cell survival against environmental and physiological stress challenges through an enhanced protection mediated by intracellular HSP iHSP levels [ 94 ].

Currently, a novel and overall index of immunoinflammatory status, the extracellular to intracellular HSP70 ratio index H-index , measured in peripheral blood mononuclear cells PBMCs [ 94 ], has been established. Glutamine is found in relatively high concentrations in vegetable and animal protein-based foods Table 1.

Using a validated food frequency questionnaire FFQ of more than 70 thousand participants, Lenders, et al. Therefore, a balanced diet provides glutamine, and other essential and non-essential amino acids for homeostasis, growth, and health maintenance. During hypercatabolism, some non-essential amino acids, including glutamine, become conditionally essential. However, the efficacy of glutamine supplementation is frequently questioned due to confusing and controversial results [ , , ].

Glutamine is usually administrated by utilizing its free form also known as an isolated amino acid , or bond with another amino acid, also known as the dipeptide form Figure 4.

Several glutamine dipeptides with potential recovery health benefits have been described, such as l -glycyl- l -glutamine Gly-Gln and l -arginyl- l -glutamine Arg-Gln ; however, the most well-known is possibly l -alanyl- l -glutamine Ala-Gln [ ]. Given parenterally, many clinical and experimental studies and appropriate systematic reviews [ ] have concluded that glutamine dipeptides can reduce the rate of infectious complications [ , , , ], length of hospital stay [ 9 , ], and mortality of critically ill patients [ 10 , , ].

Moreover, free glutamine is usually commercially available as a crystalline amino acid powder and can be diluted into commercially available TPN solutions, however, this procedure requires daily preparations at a controlled temperature i. Mechanisms of enteral and parenteral glutamine GLN supply. Glutamine is an important substrate for rapidly dividing cells, such as enterocytes.

Free glutamine supplementation is mainly metabolized in the gut and poorly contribute to glutaminemia and tissue stores. On the other hand, glutamine dipeptides e. This effect is mainly attributed to the oligopeptide transporter 1 Pept-1 located in the luminal membrane of the enterocytes. However, it should be noted that although parenteral routes can secure nutrient delivery to target tissues, it is always an invasive route and may increase the risk of infections per se.

For individuals with regular enteral feeds at home or hospitals, and also elite athletes where glutamine supplementation is eventually recommended, oral or enteral routes are always more physiological. Furthermore, enteral solutions stimulate the intestinal cells to produce other intermediary amino acid derivatives important for immunological functions, and also compromised in hypercatabolic patients, such as arginine and its downstream metabolites e. However, the peak concentration and the area under the curve promoted by Ala-Gln tend to be superior when compared to free glutamine supply.

Interestingly, the effects promoted by Ala-Gln are also mediated by the presence of the amino acid, alanine, in the peptide formulation. Oral free glutamine along with free alanine promoted similar metabolic, antioxidant, and immunological effects when compared to Ala-Gln supplementation in in vivo animal models submitted to infection [ 4 , 39 ], and exhaustive aerobic [ 30 , 45 , 53 ] and resistance physical exercise [ 29 , ].

Importantly, in all of these experiments, the supplemented groups received isonitrogenous and isocaloric solutions, i. Although the precise mechanisms are still unknown, it is clear that both amino acids work in parallel, especially in absorptive cells Figure 4. For instance, alanine is rapidly metabolized via alanine aminotransferase to pyruvate, with concomitant production of glutamate from 2-oxoglutarate, which contribute to antioxidant defence mediated by GSH.

Although other free amino acid combinations need to be tested, these important discoveries may lead to the design of new formulations for specific hypercatabolic patients. However, as any other amino acid offered in excessive doses, it can promote hyperaminoacidemia and result in poor clinical outcomes. It is considered not to be the best practice to provide glutamine supplementation to patients without a proper evaluation that is supported by a nutritional assessment and biochemical laboratory tests.

Glutamine metabolism and supplementation in cancer has also raised many concerns among the scientific community, and deserve some comments.

Cancer cells take advantage of aerobic glycolysis also known as the Warburg effect , and therefore glucose to maintain the supraphysiological survival and growth [ , ].

On the other hand, there is an increasing evidence of the role of oncogenes and tumour suppressors in the regulation of nutrient metabolism [ ]. For instance, glucose, glutamine, lipids, and acetate can be utilized as carbon and energy sources [ 25 ]. For example, lung cancer cell lines are highly dependent of glutamine supply in vitro, however, in vivo experiments demonstrate that glucose is the preferred source of carbons supplied to the Krebs cycle, through the action of pyruvate carboxylase [ ], with little changes in glutamine consumption [ ].

Human and mouse gliomas exhibit high rates of glucose catabolism, and use glucose to synthesize glutamine through glutamate-ammonia ligase GLUL , which in turn promotes nucleotide biosynthesis via the pentose phosphate pathway independently of circulating glutamine [ , ]. Conversely, prostate cancer cell lines exhibit aberrant intracellular lipid metabolism [ ], and an increased gene expression of glutaminolitic enzymes and glutamine transporters, thereby stimulating cell growth via glutamine uptake [ ].

However, studies have also targeted whether a glutamine exogenous supply may attenuate the side effects promoted by chemotherapy and radiation in cancer patients [ ]. In a systematic review, Sayles, et al. Glutamine treatment reduced the side-effects induced by chemotherapy, such as intestinal absorption and permeability, diarrhea, and gut mucositis [ ].

As a whole, it is important to highlight that glutamine supplementation for cancer patients may also fuel certain types of cancer cells, and have a negative impact on health. As mentioned previously, a proper and possibly individualized patient evaluation is required to determine the suitability of glutamine supplementation.

Low plasma glutamine level hypoglutaminemia is usually used as a parameter to indicate the need for a glutamine exogenous supply. However, the correlation between the concentration of glutamine in plasma and tissue vary significantly between hypercatabolic patients, and therefore among studies [ ]. For instance, muscle glutamine was dramatically reduced in abdominal surgery patients, but no changes were detected in plasma [ ].

In critically ill patients, however, there is a profound drop in muscle glutamine, but a variable reduction in plasma [ ]. Other important glutamine sites, such as the gut and the liver, may show a concomitant plasma and tissue glutamine reduction, or even an inverse relationship during major illness [ 86 , , ].

These findings are also in agreement with data obtained in rats [ 29 , 45 , ] and mice [ 4 , ] submitted to infection and exhaustive exercise. The variations between plasma and tissue glutamine concentration are due to the fact that only a small fraction of the total body free glutamine is in plasma.

To add to the confusion, it is known that cells of the immune system, such as lymphocytes maintained in a low glutamine availability similar to low plasma glutamine concentration, e.

More in-depth studies are required to explore the specific relationship between dramatic changes in plasma glutamine and outcomes in critically ill patients. Currently, the decision of glutamine supplementation should be based in a set of immune-inflammatory parameters allied with appropriate nutritional assessment, and eventually, risk predictors.

In addition, glutamine supplementation studies cannot be judged on trials where only the very sickest patients i. Immune cells largely depend on glutamine availability to survive, proliferate, and function, and ultimately defend our body against pathogens.

It is important to consider that like glycaemia, plasma glutamine and the inter-tissue metabolic flux is maintained at constant levels even during high catabolism by key organs, such as the gut, liver, and skeletal muscles.

Not surprisingly, hypoglutaminemia conditions and severity vary significantly between human and animal studies, and by itself do not provide a rational argument for glutamine exogenous supply. In this regard, the immune properties of glutamine supplementation have been extensively studied and new questions and perspectives are formulated.

For instance, studies should determine the frequency of nutritional intervention, optimal doses associated with the disease or stress situation, and the concomitant administration with other amino acids or dipeptide combinations. In addition, the evolving metabolomics era has the potential to improve our understanding of the complex regulation of glutamine metabolism, identifying new metabolites e. Figures and Table 1 were designed by V.

All authors contributed significantly in the manuscript revision and agreed with the final submitted version. We thank the Department of Health Science, Torrens University, and the Curtin School of Pharmacy and Biomedical Sciences for financial research support and excellent research facilities, respectively. National Center for Biotechnology Information , U. Journal List Nutrients v. Published online Oct Author information Article notes Copyright and License information Disclaimer.

Received Sep 23; Accepted Oct This article has been cited by other articles in PMC. Abstract Glutamine is the most abundant and versatile amino acid in the body. Keywords: nutrition, amino acids, leukocytes, skeletal muscle, gut, liver. Introduction At the most basic level, amino acids are the building blocks of proteins in our cells and tissues, and after water are the second most abundant compound in mammals.

Open in a separate window. Figure 1. In fact, one study found that glutamine or glutamine plus carbohydrates can help reduce a blood marker of fatigue during two hours of running It has also been used to try to boost the immune function of athletes, but results vary 34 , 35 , Other research has found that it did not improve the recovery of carbohydrate stores glycogen in muscle when added to carbohydrates and certain amino acids In the end, there is no evidence that these supplements provide benefits for muscle gain or strength.

There is some limited support for other effects, but more research is needed. It has been estimated that a typical diet may contain 3 to 6 grams per day, although this amount could vary based on the types and quantities of foods consumed Studies on glutamine supplements have used a wide variety of doses, ranging from around 5 grams per day up to high doses of approximately 45 grams per day for six weeks Although no negative side effects were reported with this high dosage, blood safety markers were not specifically examined.

Other studies have reported minimal safety concerns regarding short-term supplementation of up to 14 grams per day Overall, it is believed that the short-term use of supplements is likely safe. However, some scientists have raised concerns about their sustained use Adding glutamine to a regular diet may cause a variety of changes in the way the body absorbs and processes amino acids. Yet, the long-term effects of these changes are unknown Therefore, more information is needed concerning long-term supplementation, particularly when high doses are used.

It is possible that glutamine supplements may not have the same effects if you eat an animal-based, high-protein diet, compared to a plant-based, lower-protein diet. If you follow a plant-based diet with low glutamine content, you may be able to consume supplements while still receiving a normal daily amount of it overall. If you decide to take a glutamine supplement, it is probably best to start with a conservative dose of around 5 grams per day.

L-glutamine is the important form, which is produced naturally in the body and found in many foods. It is estimated that a typical diet contains 3 to 6 grams per day. It provides fuel for immune and intestinal cells and helps keep the connections in the intestines strong. During times when your body cannot produce optimal amounts, such as during injury or severe illness, supplementing with it may be beneficial for your immune health and recovery.

Glutamine is also frequently used a sports supplement, but most research does not support its effectiveness. Supplementing appears to be safe in the short-term, but more research is needed on its long-term effects.

Before taking a glutamine supplement, consider whether the reason for taking it is supported by current evidence. There are several dietary supplements that can help increase muscle mass and strength. Here are the 6 best supplements to gain more muscle. Testosterone is crucial for many body processes, including fat loss and muscle growth.

Here are 8 of the best testosterone boosting supplements. There are many protein powders to choose from, so we've compiled some of the best options to help you pick the right one for you.

Creatine is a very popular sports supplement. It is used to increase muscle mass, boost strength and enhance exercise performance.

Glucosamine supplements are popular but controversial. This article takes a look at whether or not they are effective at treating arthritis. Protein is incredibly important for your health, weight loss, and body composition. This article explains exactly how much protein you should eat.

When it comes to sports, injuries are an unfortunate part of the game. Here are 14 foods and supplements to help you recover from an injury more…. Though weight loss is a goal for many people, others hope to gain weight, often to look and feel more muscular or to improve athletic performance….

Health Conditions Discover Plan Connect. Glutamine is an important amino acid with many functions in the body. Supplementing with Glutamine is an effective way to raise glutamine levels to ensure adequate stores after training.

It will also support muscle growth and recovery. Additionally, glutamine works to enhance the immune system and promote gut health. Taking glutamine supplements will help you improve exercise performance and gain muscles. The supplement also hydrates your body cells which are critical for repair and growth. When one is stressed, ill, or injured, the L-glutamine levels will go down, and to counter this, your body will look for the amino acid in your muscles to fill up the gap.

In the event your amino acids in the body are low, your immune system could be compromised. Glutamine supplements are recommended for illnesses or injuries such as bone marrow transplants, burns, radiation, sickle cell anemia, and chemotherapy.

Glutamine is essential for the immune system. It is a significant energy source for your white blood cells, other immune cells, and intestinal cells. For optimum and efficient functioning, your body cells need enough proteins. Glutamine has sufficient proteins to supplement amino acids produced by your body. Glutamine for muscle growth will boost your health, decrease recovery time and reduce infections.

The immune-boosting properties of this supplement will also allow it to improve your intestinal health. Your intestines make up a crucial portion of the immune system. Most of the intestinal cells bear immune functions.

Glutamine being an energy source for the intestinal cells, prevents leaky gut problems. It keeps a barrier between the inner part of your gut and the other parts of the body. The barrier prevents harmful bacteria from accessing your intestines and leaving the intestines to other body parts. Glutamine benefits bodybuilding significantly: bodybuilders and those involved in rigorous activities such as athletes, gym rats, and fitness enthusiasts can reap its rewards.

The supplement can quickly repair muscles and tissues after these activities and help you regain strength more efficiently. What is L-Glutamine?