1Sources and Biological Significance
1.1. Sources and Synthesis
Glutamine is found in high amounts in most meat and animal products, as well as any dairy product or by-product such as whey or casein protein.[3] Levels of glutamine in various foods range from:
Beef at 4.7% protein[3] where meat in general fluctuates between 4.4% and 4.8%[3]
Skim Milk at 8.08% protein[3] whereas milk products in general tend to fluctuate between 8.7% and 9.2%[3]
White Rice at 11.1% protein[3]
Corn at 16.2% protein[3]
Tofu at 9.1% protein[3]
Eggs at 4.3% protein[3]
Average dietary intake of glutamine, according to the Nurse's Study of 70,356 women, is around 6.85+/-2.19 g glutamine daily.[3]
It should be noted that the above percentages are based on total protein content, and not total caloric content nor weight. If assessed by weight, beef protein has 1.23g of glutamine per 100g product whereas skim milk has 0.28g glutamine per 100g product.[3]
It is also noted that some of these levels of glutamine may be underreported, and subsequently levels of glutamate higher than expected; this is due to one of the historically used methods of amino acid analysis, hydrolysis, inducing conversion of glutamine to glutamate[4][5] or pyroglutamic acid.[6] The sequencing study cited above[3] demonstrates the higher range of values, and it's methods are described here.[7] Comparing results between conventional methods and gene sequencing can yield differences of up to 4% in total amino acids (influence on glutamine would be dependent on glutamine content of food).[3]
Glutamine analysis hasn't been too accurate in the past for exact numbers (due to degradation and conversion of glutamine) but the general trend of meat and dairy being the best dietary sources of glutamine exists. Interestingly, some plant sources have a higher glutamine content on a percentage basis, but they are not the best sources of dietary glutamine due to the low overall amount of protein from plant sources relative to meat and dairy sources
1.2. Structure and Properties
Glutamine is one of the conditionally essential amino acids, with the standard amino acid backbone and a 3-carbon side-chain with a ketone group on the furthest carbon from the amine group and culminating with a nitrogen on the end of the side-chain.
Glutamine is not highly soluble in an aqueous environment, and thus when used in intravenous infusion it tends to be bound to the amino acid Alanine as Alanyl-glutamine.[8]
1.3. Biological Significance
Glutamine is a semi-conditional amino acid, with it's biological need being increased in certain states such as disease or cachexia.[9][10]
It is the most abundant amino acid in human tissue (mostly muscle tissue) and plasma. It has various biological roles including acting as a nitrogen transport between tissues alongside alanine, acting as a precursor for the antioxidant glutathione, acting as a precursor for nucleotides, regulating acid/base metabolism and being involved as a substrate in gluconeogenesis.[11] It can also stimulate production of L-citrulline and L-glycine via acting as substrate.[12]
Plasma levels in healthy humans are typically 500-750 umol/L after a morning fast. Muscle concentrations are typically regulated at 20umol/kg wet weight and release 50 umol/L into plasma per hour in a fed state. This is due to muscle being a prime location for glutamine synthesis via the enzyme glutamine synthetase.[13] These plasma levels are typically reduced in periods of critical illness due to increased usage of glutamine as substrate in various metabolic processes.
1.4. Splanchnic Bed
Up to 13% of circulating glutamine tends to be redirected to the splanchnic bed to be used as energy substrate by the liver and intestinal enterocytes.[14]
1.5. De novo Synthesis
When oral or intravenous glutamine is administered, de novo synthesis rates of glutamine will decrease.[15][16] This may indirectly preserve amino acids that could be generated into glutamine, such as leucine which experiences a reduction in oxidation rates.[16]
2.1. Absorption and Bioavailability
The amount of glutamine devoted to intestinal and hepatic tissue (splanchic extraction) does not differ between food-bound sources and supplemental dosages.[17]
2.2. Serum
In some instances, supplementation of glutamine has been found to increase plasma glutamine concentrations. This includes in persons with chronic stable angina where 80 mg/kg glutamine increased plasma concentrations from 419 µM to 649 µM (55% increase).[18]
3.1. Cardiac Tissue
Ischemia/reperfusion (I/R) is an injury to tissue caused by a restriction of oxygen availability (ischemia) followed by an excessive feed of oxygen to the tissue which causes large amounts of oxidative damage (reperfusion). Glutamine appears to, in vitro, be protective against I/R in cardiac tissue[19] and this has been replicated in rats given glutamine injections either 18 hours before damage[20] or an infusion for the immediate four hours preceding damage.[21]
This protection is thought to be associated with enhanced cardiac glutathione concentrations (a deficiency of which exacerbates damage[22]) or the induction of heat shock proteins, particularly HSP70.[23]
Glutamine appears to reduce the damage associated with ischemia/reperfusion injury in cardiac cells, which may be associated with enhancing antioxidant and heat shock protein defenses
When given to humans around the time of surgery associated with I/R injury (cardiopulmonary bypass[24]), supplementation of 500 mg/kg glutamine (as alanyl-glutamine) for three days prior to surgery is associated with less clinical and biochemical indicators of damage in three days of followup[25] which has been previously seen with IV administration of 400 mg/kg glutamine (as Dipeptiven).[26]
In persons with chronic stable angina a single oral dose of 80 mg/kg glutamine is able to enhance physical performance as assessed by a Bruce test, suggestive of protective effects.[18]
Supplementation of glutamine to persons with cardiac impairments or around the time of cardiac surgery has been shown to be cardioprotective, and this has been confirmed with oral supplementation. It is not sure how this information applies to otherwise healthy individuals
4Interactions with Glucose Metabolism
4.1. Absorption
Glutamine has been shown to be able to 'blunt' the blood glucose spikes in response to dietary carbohydrate, attenuating rises and Cmax values of blood glucose and insulin in response to dietary carbohydrate ingestion.[27] When investigated as to whether this is due to non-significant delays in gastric emptying, it does not appear to be the case.[27]
5Inflammation and Immunology
5.1. Leukocytes
Glutamine is known to be the main energy substrate used by the immune cells called leukocytes and contributes to the proliferation of these cells,[28] the reason for glutamine being the fuel substrate for leukocytes is the need for a quicker energy source than glucose (similar to intestinal mucosa and bone marrow).[28] Leukocytes cannot synthesize glutamine on their own, and thus are reliant on glutamine provided from other tissues that possess the glutamine synthetase enzyme, or from dietary intake.
Leukocyte growth rates are highest at a concentration of approximately 600 umol/L, a concentration well within normal human physiology.[29] For this reason glutamine and it's supplemental usage tends to be practically limited to times where synthesis or intake is suppressed or redirected, such as critical illness or prolonged cardiovascular exercise.[30]
6Exercise and Skeletal Muscle
6.1. Muscle Protein Synthesis
Glutamine is an amino acid intimately linked in vitro with muscle homeostasis and muscle protein synthesis, in which a surplus causes anabolism and prevents breakdown while a deficit causes catabolism.[31][32][33] This correlation has been seen in vivo when glutamine is infused[32][34] (some counter evidence[35][36]) and appears to be specific for glutamine.[32][37]
In vitro, glutamine is known to reduce the rates of leucine oxidation and increase the deposition of leucine, which increases the effects of leucine in a skeletal muscle cell.[16]
When looking at cellular cultures and isolated cells, glutamine appears to dose-dependently increase muscle protein synthesis. When glutamine is increased in the blood via injections, this relationship is still observed
Studies using glutamine in otherwise healthy persons and investigating either muscle protein synthesis or lean mass gains have noted a failure with 900 mg/kg lean mass (placbo being 900mg/kg maltodextrin) in youth paired with resistance training.[38]
The addition of glutamine to creatine[1] or extra glutamine (300 mg/kg bodyweight) to a protein and carbohydrate shake[2] or amino acid and carbohydrate shake[2] have also failed to outperform the supplements ingested without glutamine, suggesting no role as a synergistic.
In studies of otherwise healthy humans given glutamine supplementation, it does not appear to enhance the rates of muscle protein synthesis
6.2. Exercise Immunology
Plasma glutamine levels are either increased or unchanged in short term, high intensity activities[39][40] and tend to be unchanged with eccentric muscle damage[41] suggesting that extra glutamine supplementation will not benefit short term intensity exercise or weightlifting by any means which act through serum glutamine levels (such as immunosuppression or catabolism).
In contrast to this, endurance events exceeding 2 hours do tend to show decreases in serum glutamine levels.[42][43] Both supplementation of glutamine and increasing protein intake from food (in the dose of 20-30g animal source protein) can alleviate this decline in serum glutamine[44] and potentially can reduce damage to immune cells associated with prolonged cardiovascular exercise.[45] This decrease in serum glutamine levels may also suppress release of interleukin-6 (IL-6) from muscle tissue, and supplementation of glutamine can preserve IL-6 levels.[46]
These results are consistent with the theory that prolonged cardiovascular exercise, via reductions in glutamine, can suppress immunological function via hindering leukocyte differentiation.[42][47]
6.3. Power Output
300 mg/kg glutamine ingestion in otherwise healthy weightlifters has failed to modify power output more than placebo[48] and higher doses (900 mg/kg lean body mass) have similarly failed elsewhere in active populations.[38]
6.4. Endurance Performance
Supplementation with glutamine during longer duration cardiovascular exercise, via decreasing ammonia, has also been noted to increase performance.[49] The decrease in ammonia per se is also seen as desirable.[49]
An oral load of 2 g glutamine has been shown to increase plasma bicarbonate levels in vivo[50]. This has been shown to not affect high intensity exercise to any noticeable degree[51], whether it aids in endurance events or not is not known.
By attenuating or otherwise preventing glutamine depletion in exericse lasting for more than one hour, performance may indirectly increase relative to the glutamine depleted state. This is not so much performance 'enhancement' as it is performance 'preservation'
6.5. Skeletal Muscle Catabolism
Glutamine ingestion, at 0.5 g/kg daily, has been shown in a small study on hypercortisolemic patients (induced be prednisone at a dose to induce muscle protein breakdown) noted less of a catabolic state via reducing essential amino acid conversion into glutamine, and less of a leucine expenditure.[52]
6.6. Glycogen
There is some evidence that oral glutamine can increase glycogen replishment rates when consumed alongside carbohydrates[53] but more studies are needed to see whether this method holds benefit over food sources of glutamine or holds true with higher carbohydrate intakes.
Glutamine itself, in the absence of carbohydrates, may enhance muscle glycogen stores.[54]
7Interactions with Intestinal Health
7.1. Protein Synthesis
Glutamine supplementation has been shown to stimulate protein synthesis in the gut of healthy humans to a similar potency as mixed amino acids.[55]
7.2. Intestinal Integrity/Permeability
Glutamine is investigated to aiding a 'leaky gut' as it is a regulator of intestinal tight junction barriers.[56] Intentional depletion of intracellular glutamine and inhibition of glutamine synthesis in vitro leads to rapid increases in gut permeability.[57][58][59] In the absence of dietary glutamine, de novo synthesis via glutamine synthetase is the main source of glutamine.[56]
Glutamine has been implicated in also alleviating the increased permeability done to the gut by acetaldehyde, the metabolite of alcohol[60] as well as chemotherapy[61] and radiation therapy.[62] Glutamine can alleviate the increase in permeability associated with sepsis in vivo, but not prevent it.[63]
In an intervention study on preterm infants, it was demonstrated that glutamine supplementation at 0.3g/kg could aid in intestinal integrity and reduce the occurrence of septicemia and increase recovery;[64] and these results have been replicated with both positive[65] and negative results.[66]
A study with 15g oral glutamine on critically ill patients did not find significant decreases in intestinal permeability.[67]
At least one study has shown glutamine, in adults, to confer protection from adverse chemotherapy induced changes in intestinal permeability.[68]
7.3. Crohn's Disease
Crohn's disease is a disease characterized by increased intestinal permeability as well as an inflammatory response in the intestinal membrane.
One study using 21g oral glutamine daily in a small sample size noted that glutamine was not effective in reducing intestinal permeability associated with Crohn's Disease.[69] A response to this study concurred with reports of a study done on children with Crohn's having the same results[70] and hypothesized that the benefits of glutamine on the intestinal wall could be getting negated by glutamine enhancing T-cell and Nitric Oxide function,[71] of which are adverse pathology associated with Crohn's disease.[70] These results are supported by one study using intravenous glutamine at 0.3 g/kg finding no apparent benefit.[72]
In contrast to the null effects, a more recent study found improvements in intestinal permeability associated with both glutamine and the active control of whey protein, both at 0.5 g/kg bodyweight daily for 2 months,[73] and one intravenous study has noted improvements in intestinal permeability.[74] It is hypothesized that this may be due to the higher dosage of glutamine used.[73]
7.4. Water absorption
Glutamine has also been shown to aid in the uptake of water from the gut, potentially leading it to be a rehydration aid. However, the increase seen, when compared to other methods such as glucose or sodium is neglibible.[75]
8.1. Sickness and Glutamine Depletion
In the critically ill (hospitalized) glutamine has an elevated importance. Demand for glutamine is increased in the kidneys, immune cells, and the intestinal mucosa during these periods in response to cachexia, infection, and trauma.[76][77] It is common, however, for glutamine need during these states to exceed the capacity of skeletal muscle to synthesis glutamine; this results in a reduction of the free (intra-cellular) glutamine pool in the body.[76][77] With this reduction in glutamine comes a reduction in protein economy and alterations in metabolism (increase in protein catabolism, decreased levels of enzymes and hormones using glutamine as a building block).[78] Due to these reasons, one of the main interventions for glutamine is rehabilitative and in response to sickness rather than merely preventative.
8.2. Negation of Glutamine Depletion
Due to the ubiquitous nature of glutamine in the body, bodily stores of glutamine are depleted in an attempt to counter the increased metabolic activity typical of critical illness. Since skeletal muscle is largely glutamine it is at a higher risk for catabolism during periods of illness.[79] Supplementing with glutamine in the critically ill alleviates the decline in muscle mass significantly, although it does not necessarily prolong life or survivial outcomes.[80]
Glutathione, an important endogenous anti-oxidant that is created from glutamine, also is decreased in situations of critical illness and trauma. As provision of glutamine becomes the rate-limiting step, administration of 0.5 g/kg bodyweight glutamine intravenously increases glutathione levels in this population.[81][82]
The Observed Safety Limit of glutamine supplementation, of which is the highest amount one can take and be assured of no side effects, has been suggested as being 14g/d in supplemental form (above food intake).[83] Higher levels than this have been tested and well tolerated, but there is not enough evidence to suggest that higher doses are completely free from harm over a lifetime of supplementation nor enough evidence to assume harm exists. Limited evidence suggests that 50-60g for a period of a few weeks is not associated with significant adverse effects.[84][85]
Acutely, doses of around 0.75g/kg bodyweight have been implicated in increasing plasma ammonia levels above the tolerated safety limit.[86] A study in elderly persons (69+/-8.8 years) with 0.5g/kg oral glutamine has shown no effects on plasma ammonia levels, but was associated with an increase in serum urea and creatinine that was deemed not clinically relevant.[87] A transient decrease in the kidney's glomerular filtration rate was seen.[87]
