A great study about Glutamine

[Bane]

I was browsing my university database while at the library and i did a search for Glutamine. this is what i found. I have uploaded the pdf here:
http://us.f1.yahoofs.com/bc/69659c64...Gw.NDBOF_AEP8q

Below is the full text with some bolded from me.

[Bane]

Review

Muscle glutamine depletion in the intensive care unit

Gianni Biolo, , Francesca Zorat, Raffaella Antonione and Beniamino Ciocchi

Department of Clinical, Morphological and Technological Sciences, University of Trieste, Trieste, Italy

Received 28 October 2004; revised 3 May 2005; accepted 4 May 2005. Available online 31 May 2005.




Abstract
Glutamine is primarily synthesized in skeletal muscle and enables transfer of nitrogen to splanchnic tissues, kidneys and immune system. Discrepancy between increasing rates of glutamine utilization at whole body level and relative impairment of de novo synthesis in skeletal muscle leads to systemic glutamine deficiency and characterizes critical illness. Glutamine depletion at whole body level may contribute to gut, liver and immune system disfunctions, whereas its intramuscular deficiency may directly contribute to lean body mass loss. Severe intramuscular glutamine depletion also develops because of outward transport system upregulation, which is not counteracted by increased de novo synthesis. The negative impact of systemic glutamine depletion on critically ill patients is suggested both by the association between a lower plasma glutamine concentration and poor outcome and by a clear clinical benefit after glutamine supplementation. Enteral glutamine administration preferentially increases glutamine disposal in splanchnic tissues, whereas parenteral supplementation provides glutamine to the whole organism. Nonetheless, systemic administration was ineffective in preventing muscle depletion, due to a relative inability of skeletal muscle to seize glutamine from the bloodstream. Intramuscular glutamine depletion could be potentially counteracted by promoting de novo glutamine synthesis with pharmacological or nutritional interventions.

Keywords: Glutamine; Kinetics; Skeletal muscle; Critical illness


Article Outline
1. Introduction
2. Inter-organ glutamine kinetics
2.1. Glutamine appearance
2.2. Storage in skeletal muscle
2.3. Transmembrane glutamine transport
2.4. Splanchnic metabolism of dietary glutamine
2.5. Whole body glutamine utilization
3. Regulation of muscle glutamine synthesis
4. Systemic and muscle glutamine depletion in critical illness
5. Clinical consequences of glutamine depletion
6. Glutamine supplementation
References


1. Introduction
Following tissue injury or severe infections, critically ill patients experience metabolic alterations leading to muscle proteolysis activation, enhanced liver gluconeogenesis and tissue insulin resistance (Griffiths, 2003). In addition, these patients exhibit marked reductions in plasma and tissue concentrations of glutamine, the most abundant free amino acid in body compartments (Melis, ter Wengel, Boelens, & van Leeuwen, 2004). Glutamine is primarily synthesized in skeletal muscle and enables transfer of nitrogen to splanchnic tissues, kidneys and immune system. Furthermore, glutamine plays a regulatory role in several specific cell processes. In critically ill patients, glutamine depletion is proportional to severity of illness (Oudemans-van Straaten, Bosman, Treskes, van der Spoel, & Zandstra, 2001) and is not readily reversible by nutrition or other therapeutical approaches (Tjader et al., 2004). Evidence indicates that supplementation with exogenous glutamine in order to enhance its inter-organ flux is often associated with improved outcome of patients (Novak, Heyland, Avenell, Drover, & Su, 2002). In this paper, we will review recent data on glutamine metabolism both in health and disease states, aiming at defining kinetic mechanisms that lead to glutamine depletion.

[Bane]

2. Inter-organ glutamine kinetics
2.1. Glutamine appearance
Tracer kinetic studies in normal volunteers indicate that approximately 90 g of glutamine appear every day in the bloodstream, 80 g from body tissues and 10 g from nutrient intake (Biolo, Fleming, Maggi, & Wolfe, 1995) (Fig. 1). Thus, approximately one-third of all nitrogen derived from protein metabolism is transported in the form of glutamine. The bulk of glutamine entering plasma is derived from skeletal muscle (Biolo et al., 1995). All together, lung, liver and adipose tissue do not therefore account for more than 50% of whole body glutamine appearance. Lung glutamine release has been directly assessed in humans by determining the pulmonary artero-systemic arterial concentration difference with the Fick principle (Herskowitz et al., 1991). Relatively healthy subjects were studied before elective surgery to determine lung glutamine exchange (Herskowitz et al., 1991). In these conditions, lung glutamine release appeared to be lower than that observed in skeletal muscle in a different study (Biolo et al., 1995). When turnover of free glutamine was assessed in muscle (Fig. 1), the rate of appearance in cell cytoplasm was three times greater than its release into the bloodstream (Biolo et al., 1995). Glutamine de novo synthesis accounted for 85% of intramuscular appearance, whereas only 15% of the intracellular amino acid was derived from proteolysis (Biolo et al., 1995).


(15K)

Fig. 1. Body glutamine kinetics assessed by stable isotopes in physiological conditions, numerical data are calculated from Biolo et al. (1995). CNS, central nervous system; GABA, gamma-aminobutyric acid.



2.2. Storage in skeletal muscle
In skeletal muscle, after de novo synthesis, free glutamine is largely stored in the cytoplasm. In muscle, glutamine is the most abundant free amino acid: its concentration is infact 50–200 times greater than that of the all essential amino acids (Biolo et al., 1995). In physiological conditions, intramuscular free glutamine concentrations range from 10 to 20 mmol/l of tissue water. Thus, this amino acid significantly contributes to total cell osmolarity and hydration (Haussinger, Roth, Lang, & Gerok, 1993). Osmo-sensing structures located inside cells, allow transduction of information depending on the extent of cell hydration, and therefore, allow enzyme activity and gene expression modifications. Indeed, through this mechanism, changes in glutamine muscle cell concentrations may directly regulate protein synthesis and degradation (Table 1), since cell swelling and shrinking are major anabolic and catabolic signals, respectively (Haussinger, Graf, & Weiergraber, 2001). The difference between intracellular and interstitial concentrations of glutamine is determinant of muscle cell hydration. Such transmembrane concentration gradient is largely dependent on cell membrane transport system activity.

Table 1.

Organ-specific regulative potential of glutamine Immune cells
Nucleotide synthesis precursor
Fuel for proliferating immune cells
Modulation of cytokine secretion
Enhances T-lymphocyte response
Synthesis of immunoglobulins A
Modulation of heat shock proteins
Attenuation of NO formation
Supports neutrophil and macrophage functions
Gastrointestinal tract
Nucleotide synthesis precursor
Fuel for proliferating enterocytes
Maintenance of gut-associated lymphoid tissue
Maintenance of gut barrier
Modulation of heat shock proteins
Attenuation of NO formation
Liver
Substrate for ureagenesis
Gluconeogenetic precursor
Glutathione synthesis (antioxidant)
Osmotic signaling mechanism in regulation of protein synthesis and degradation
Precursor of taurine
Modulation of heat shock proteins
Attenuation of NO formation
Precursor of taurine
Kidney
Substrate for renal gluconeogenesis
Acid/base regulation
Ammoniogenesis
Skeletal muscle
Ammonia scavenger
Nitrogen transport (one third of circulating nitrogen)
Osmotic signaling in regulation of protein synthesis and degradation
Lung
Fuel for proliferating endothelial cells
Nitrogen transport
Modulation of heat shock proteins
Central nervous system
Shuttle for glutamate
GABA synthesis


NO, nitric oxide; GABA, gamma-aminobutyric acid.




2.3. Transmembrane glutamine transport
In physiological conditions, transport systems maintain a large transmembrane gradient because intracellular glutamine concentration is 25–30 times greater than extracellular values. Several glutamine transporters have been described in human skeletal muscle (Bode, 2001). Na+-dependent glutamine transporters include ASC, B0,+, y1L, A and N systems, while Na+-independent transporters include L, b0,+ and n systems. Every glutamine transporter exhibits overlapping affinity for the transport of several other amino acids. Transmembrane Na+ electrochemical gradient, maintained by the Na+/K+-ATPase, drives the uptake of amino acids against their concentration gradient through Na+-dependent transporters. This accounts for the maintenance of glutamine cytoplasmatic levels above their transmembrane equilibrium distribution (Bode, 2001).

By utilizing a new technique based on amino acid isotopic tracers in combination with the leg artero-venous technique and muscle biopsies, we were able to determine the bi-directional kinetics of membrane amino acid transport in humans (Biolo et al., 1995). We found that the relative inward transmembrane transport contribution to the intracellular turnover rate of each individual free amino acid was extremely variable. Transport from blood accounted for only 25% of the intramuscular glutamine pool turnover. In contrast, the intracellular pools of most essential amino acids, such as phenylalanine or leucine, derived largely from the extracellular space. Thus, exogenous administration of amino acids that are readily taken up by membrane transport systems will rapidly lead to increases in their intracellular concentration, while free glutamine intracellular concentration will only change slowly after exogenous supplementation (Hammarqvist, Wernerman, Ali, von der Decken, & Vinnars, 1989; Petersson, Waller, Vinnars, & Wernerman, 1994; Tjader et al., 2004).

Transmembrane amino acid transport systems have been mostly investigated focusing on their inward direction activity. Nonetheless, evidence indicates that skeletal muscle is, in all circumstances, a net exporter of glutamine (Ahmed, Peter, Taylor, Harper, & Rennie, 1995). We may predict, therefore, that outward transport systems may play an important role in the inter-organ glutamine exchange regulation. In the last years, attention was focused on the role of system N in the regulation of glutamine efflux from skeletal muscle to the bloodstream (Bode, 2001). In a previous study, we investigated the outward transport kinetics of different amino acids (Biolo et al., 1995). Outward transport rates were normalized per unit of intracellular concentration of free amino acids in order to express the ability of outward transporters to release amino acids at any given concentration. Glutamine outward transport activity of was 30–40 times lower than leucine and phenylalanine and almost eight times lower than lysine. Such relative inability of skeletal muscle to release free glutamine explains its large transmembrane gradient.

It is now evident that several factors may regulate system N activity. Cytokines, cortisol and other hormones activate this transport system in vitro (Watkins, Dudrick, Copeland, & Souba, 1994). In addition, system N-mediated glutamine transport is highly dependent on membrane electrical potential: its progressive depolarization within physiologic ranges results in a switch from glutamine uptake to glutamine release (Fei et al., 2000). Experimental evidence indicates that there is an early transmembrane potential decrease in skeletal muscle during sepsis and after trauma, possibly due to the action of a high molecular weight circulating plasma protein complex (Button et al., 2001). Critically ill patients are characterized by reduced ability to generate action potentials in muscle fibers, and this often leads to a well defined clinical myopathy (Rich & Pinter, 2003). Thus, upregulation of outward transport systems by humoral factors or electrical transmembrane potential changes may play a key role in the rapid mobilization of muscle free glutamine large reservoirs, leading to the release of the amino acid into the bloodstream when its requirements increase in tissues other than skeletal muscle.

2.4. Splanchnic metabolism of dietary glutamine
Glutamine accounts for about 8–12% of total amino acid content of dietary proteins. The total oral intake and absorption of the free amino acid is, therefore, about 10 g per day, but this represents only 12% of the whole body glutamine appearance (Fig. 1). In addition, systemic availability of enteral glutamine is further reduced by first pass splanchnic metabolism. Studies involving oral ingestion of stable isotope-labelled glutamine indicate that 50–70% of enterally administered glutamine is taken up during first pass by splanchnic organs (gut and liver) (Matthews, Marano, & Campbell, 1993) where it is largely oxidized (Haisch, Fukagawa, & Matthews, 2000). Thus, kinetic data indicate that whole body glutamine availability largely depends on the rate of endogenous synthesis in skeletal muscle.

[Bane]

2.5. Whole body glutamine utilization
In physiological conditions, approximately 90 g of glutamine appear daily in the bloodstream. Eighty grams are derived from endogenous sources, mainly skeletal muscle and lung, whereas 10 g are deriving from oral intake. Thereafter, circulating glutamine is preferentially taken up by liver, kidneys, gut mucosa, central nervous system and immune cells (Fig. 1). Evidence indicates that these tissues utilize glutamine at high rates and that glutamine utilization is essential for their function (Table 1) (Newsholme, Procopio, Lima, Pithon-Curi, & Curi, 2003). Glutamine tracer kinetic studies (Perriello et al., 1997) indicate that 40–60% of plasma glutamine disappearance is due to oxidation, 10–20% to gluconeogenesis and most of the remainder to protein synthesis and incorporation into macromolecules. The immediate product of glutamine metabolism is glutamate, generated by the glutaminase enzyme (Fig. 2). Glutamine and glutamate are precursors of many compounds, including hepatic and renal glucose, urinary ammonia, intracellular glutathione, nitric oxide and nucleic acids (Fig. 2; Table 1). Furthermore, glutamine is a major fuel for rapidly dividing cells of intestinal mucosa and immune system (Table 1) (Newsholme et al., 2003). We may predict, therefore, that in pathological conditions characterized by activation of immune system, gut dysfunction, increased oxidative stress or metabolic acidosis, glutamine requirements and disposal may be increased (Newsholme, 2001). Kinetic studies in critically ill patients have shown that whole body glutamine disposal is increased both in absolute terms (Gore & Jahoor, 1994) and as metabolic amino acid clearance rate (i.e., rate of disposal divided by the prevailing glutamine concentration in plasma) (Jackson et al., 1999).


(14K)

Fig. 2. Overview of glutamine and glutamate metabolism. Glutamate is produced from glutamine through glutaminase activity. Glutamate can be converted into glutamine through glutamine synthetase activity. TCA, tricarboxylic acid; GABA, gamma-aminobutyric acid.



3. Regulation of muscle glutamine synthesis
The described kinetic studies indicate that skeletal muscle is the main site of glutamine production and release because of its large free glutamine pool and its capacity for de novo synthesis. Immediate precursors of glutamine synthesis are glutamate and free ammonia (Fig. 2); the process is catalyzed by glutamine synthetase. Glutamate is synthesized by transamination of the branched chain amino acids leucine, isoleucine and valine, which are extensively decarboxylated in skeletal muscle. In this reaction, the branched chain amino acids react with α-ketoglutarate to produce α-ketoacids and glutamate in presence of the branched chain amino acid aminotransaminase enzyme. We may, therefore, predict that muscle glutamine synthesis does not only require intramuscular availability of branched chain amino acids for transamination but also an adequate flux of energy substrates through the pyruvate dehydrogenase and the tricarboxylic acid cycle as well as an adequate source of carbon skeletons. Several lines of evidence support the key role of these regulatory mechanisms for glutamine synthesis in vivo. First, studies using infusion of leucine, labelled with nitrogen stable isotopes, demonstrated direct tracer incorporation into glutamine (Darmaun & Dechelotte, 1991). Second, in contrast to most amino acids, glutamine release from skeletal muscle is not decreased in the postprandial state: enteral and parenteral nutrient administration infact lead to significant stimulation of glutamine de novo synthesis (Darmaun et al., 1994). Third, when dicholoracetate, a potent activator of the pyruvate dehydrogenase complex through inhibition of the pyruvate dehydrogenase kinase, was infused in burnt patients, muscle glutamine concentrations increased significantly (Ferrando et al., 1998). Fourth, hyperinsulinemia, in combination with glucose infusion to maintain euglycemia, increased muscle glucose uptake with subsequent conversion to glutamine and accelerated release of the amino acid (Meyer, Woerle, & Gerich, 2004). Finally, supplementation with α-ketoglutarate was able to increase muscle free glutamine (Hammarqvist, Wernerman, von der Decken, & Vinnars, 1991). Glutamine synthesis is also regulated by glutamine synthetase activity. Hormones and substrates may directly modulate enzyme activity through transcriptional and post-transcriptional mechanisms. Glucocorticoids can up-regulate glutamine synthetase mRNA levels in muscle cells through a glucocorticoid receptor-dependent process (Max et al., 1987). In vivo, glutamine synthetase mRNA levels can increase roughly 10-fold in response to glucocorticoid administration (Max et al., 1988). In healthy humans, physiological elevations of plasma cortisol levels lead to significant stimulation of glutamine production, primarily because of an increase in glutamine de novo synthesis (Darmaun, Matthews, & Bier, 1988). Growth hormone may also potentially increase the glutamine synthetase gene expression (Nolan, Masters, & Dunn, 1990). Nonetheless, we recently found that the rate of glutamine release from leg muscle decreased after administration of growth hormone to trauma patients despite the increased enzyme gene expression (Biolo, Iscra et al., 2000). Also catecholamines are indeed important regulators of glutamine production. Effects on glutamine metabolism were studied in isolated skeletal muscle. Physiological levels of epinephrine reduced glutamine formation and release from skeletal muscle, via a beta-adrenergic receptor pathway and the adenylate cyclase system (Nie, Wallberg-Henriksson, Johansson, & Henriksson, 1989). In addition to these hormone-dependent effects, glutamine synthetase expression is directly induced in rat skeletal muscle cells by treatment with inflammatory cytokines, such as tumor necrosis factor alpha and interleukin-1 beta (Huang & O’Banion, 1998). Glutamine synthetase activity is also directly regulated by glutamine concentrations through a post-transcriptional mechanism that increases enzyme activity when tissue glutamine levels are low (Feng, Shiber, & Max, 1990).

Levels of physical activity may also directly regulate muscle glutamine production. During exercise, substrate flux through the TCA and branched chain amino acid oxidation greatly increases (Gibala, MacLean, Graham, & Saltin, 1998). Glutamine synthesis and release are, therefore, significantly stimulated (Van Hall, Saltin, & Wagenmakers, 1999) leading to increased plasma glutamine concentrations, as observed following short-term moderate exercise or during endurance training (Hood & Terjung, 1994). Glutamine concentrations increase despite the fact that exercise in rats decreases the activity of glutamine synthetase and prevents glucocorticoid-mediated enzyme induction (Falduto, Young, & Hickson, 1992). These results suggest that after exercise, as after growth hormone administration, glutamine synthesis regulation by precursor availability may overcome the effects of changes in glutamine synthetase expression or activity. Glutamine concentration is decreased after prolonged, exhaustive training, in contrast to moderate exercise, possibly due to increased glutamine demand as a consequence of immune system activation (Rowbottom, Keast, & Morton, 1996). Athletes with overtraining syndrome also have low plasma glutamine. Glutamine levels remain low even after several weeks of rest (Hiscock & Mackinnon, 1998). It has been hypothesized that there could be a link between exercise-mediated changes in glutamine metabolism and the epidemiological data showing that athletes are at increased risk for upper respiratory tract infections during periods of heavy training and following race events (Nieman, 1997). In contrast to physical exercise, the effects of immobility on glutamine metabolism have been poorly investigated. In animal models of muscle unloading or denervation, glutamine synthesis rates and intracellular levels are decreased, despite a greater activity of glutamine synthetase (Feng, Konagaya et al., 1990; Jaspers, Jacob, & Tischler, 1986). In addition, rats exposed to 7 days of weightlessness during the Spacelab-3 shuttle flight exhibited decreased muscle levels of free glutamine (Steffen & Musacchia, 1986). In agreement with these animal studies, in a recent short-term bed rest study in normal volunteers (Biolo et al., 2004), we observed that de novo glutamine synthesis rate at the whole body level significantly decreased by about 10% following 15 days of muscle unloading (Biolo et al., unpublished). Previous evidence indicates that during muscle unloading, activities of the tricarboxylic acid cycle enzymes are reduced in both animals and humans (Berg, Dudley, Hather, & Tesch, 1993). This alteration may lead to decreased glutamate and glutamine synthesis.

[Phosphate bond]

Originally Posted by Bane

Review

Muscle glutamine depletion in the intensive care unit

Gianni Biolo, , Francesca Zorat, Raffaella Antonione and Beniamino Ciocchi

Department of Clinical, Morphological and Technological Sciences, University of Trieste, Trieste, Italy

Received 28 October 2004; revised 3 May 2005; accepted 4 May 2005. Available online 31 May 2005.




Abstract
Glutamine is primarily synthesized in skeletal muscle and enables transfer of nitrogen to splanchnic tissues, kidneys and immune system. Discrepancy between increasing rates of glutamine utilization at whole body level and relative impairment of de novo synthesis in skeletal muscle leads to systemic glutamine deficiency and characterizes critical illness. Glutamine depletion at whole body level may contribute to gut, liver and immune system disfunctions, whereas its intramuscular deficiency may directly contribute to lean body mass loss. Severe intramuscular glutamine depletion also develops because of outward transport system upregulation, which is not counteracted by increased de novo synthesis. The negative impact of systemic glutamine depletion on critically ill patients is suggested both by the association between a lower plasma glutamine concentration and poor outcome and by a clear clinical benefit after glutamine supplementation. Enteral glutamine administration preferentially increases glutamine disposal in splanchnic tissues, whereas parenteral supplementation provides glutamine to the whole organism. Nonetheless, systemic administration was ineffective in preventing muscle depletion, due to a relative inability of skeletal muscle to seize glutamine from the bloodstream. Intramuscular glutamine depletion could be potentially counteracted by promoting de novo glutamine synthesis with pharmacological or nutritional interventions.

Keywords: Glutamine; Kinetics; Skeletal muscle; Critical illness


Article Outline
1. Introduction
2. Inter-organ glutamine kinetics
2.1. Glutamine appearance
2.2. Storage in skeletal muscle
2.3. Transmembrane glutamine transport
2.4. Splanchnic metabolism of dietary glutamine
2.5. Whole body glutamine utilization
3. Regulation of muscle glutamine synthesis
4. Systemic and muscle glutamine depletion in critical illness
5. Clinical consequences of glutamine depletion
6. Glutamine supplementation
References


1. Introduction
Following tissue injury or severe infections, critically ill patients experience metabolic alterations leading to muscle proteolysis activation, enhanced liver gluconeogenesis and tissue insulin resistance (Griffiths, 2003). In addition, these patients exhibit marked reductions in plasma and tissue concentrations of glutamine, the most abundant free amino acid in body compartments (Melis, ter Wengel, Boelens, & van Leeuwen, 2004). Glutamine is primarily synthesized in skeletal muscle and enables transfer of nitrogen to splanchnic tissues, kidneys and immune system. Furthermore, glutamine plays a regulatory role in several specific cell processes. In critically ill patients, glutamine depletion is proportional to severity of illness (Oudemans-van Straaten, Bosman, Treskes, van der Spoel, & Zandstra, 2001) and is not readily reversible by nutrition or other therapeutical approaches (Tjader et al., 2004). Evidence indicates that supplementation with exogenous glutamine in order to enhance its inter-organ flux is often associated with improved outcome of patients (Novak, Heyland, Avenell, Drover, & Su, 2002). In this paper, we will review recent data on glutamine metabolism both in health and disease states, aiming at defining kinetic mechanisms that lead to glutamine depletion.

I posted this one a few times in the many "glutamine" threads we have. It's interesting that they note that muscle uptake was not enhanced by systemic IV administration.

As far as their other findings, a meta-analysis is only as good as the author's interpretation skills. That burn victim study was a good example because nobody paid attention much to what glutamine was being compared to (glycine, rather than essential amino acids or complete protein)

[Bane]

4. Systemic and muscle glutamine depletion in critical illness
Critical illness is characterized by increased production of cytokines and stress hormones, such as glucocorticoids and catecholamines. These mediators interact with bed rest and, possibly, with hyponutrition to produce a cluster of metabolic abnormalities such as muscle wasting, insulin resistance and glutamine kinetic alterations. Systemic glutamine depletion results from discrepancies between rates of skeletal muscle release and uptake in other tissues. In addition, severe intramuscular glutamine depletion develops because transport systems upregulation, accelerating outflux from muscle, is not adequately matched by an increase in de novo synthesis. Muscle and plasma glutamine concentrations decrease proportionally to severity of diseases. In addition, the ratio between muscle cells and plasma glutamine concentrations decreases progressively from physiological values of 20–30 to values of 10–15 in more severe conditions (Biolo, Fleming et al., 2000; Flaring, Rooyackers, Wernerman, & Hammarqvist, 2003; Wernerman, 2003), clearly showing an upregulation of outward transport systems. Regarding muscle glutamine production, critical illness may be associated with either increased or decreased de novo synthesis. While tumor necrosis factor-alpha directly induces glutamine synthetase, the two major stress hormones, cortisol and epinephrine, have opposite effects on its synthesis. In addition, bed rest and hyponutrition may further decrease glutamine synthesis. In a recent study, we have determined, in skeletal muscle and during the post-absorptive state, glutamine synthesis de novo rate both in normal controls and in patients with severe burns during the “flow” phase after injury. We found that in burn patients, muscle glutamine synthesis was 50% lower than in healthy controls (Biolo, Fleming et al., 2000). Nonetheless, glutamine appearance rate was found either decreased (Jackson et al., 1999) or accelerated (Gore & Jahoor, 1994) when determined by stable isotopes at the whole body level. We may, therefore, speculate that, while glutamine synthesis is suppressed in muscle, it may be accelerated in other tissues. Evidence indicates infact that in lungs, glutamine synthesis is greatly accelerated after surgical stress (Herskowitz et al., 1991).

5. Clinical consequences of glutamine depletion
Glutamine depletion at whole body level may impair physiological functions of gut, liver and immune system (Newsholme et al., 2003), whereas intramuscular glutamine depletion may directly contribute to lean body mass wasting (Jepson, Bates, Broadbent, Pell, & Millward, 1988) (Table 1) and delayed recovery from illness.

6. Glutamine supplementation
Critical illness is characterized by increased glutamine utilization leading to depletion of the amino acid. Nonetheless, standard nutrition support solutions contain none (standard parenteral formulas) or very little glutamine (polymeric casein-derived enteral formulas). A lower plasma glutamine concentration (i.e., <0.420 mmol/l) is associated with a higher ICU mortality (60% versus 29%), supporting the hypothesis of a negative impact of glutamine depletion on clinical outcome of critically ill patients (Oudemans-van Straaten et al., 2001). In addition, there is evidence for a clear clinical benefit of glutamine supplementation in critically ill patients. A recent meta-analysis evaluated six randomized studies on glutamine supplementation in serious illness (Novak et al., 2002). The authors conclude that glutamine supplementation is associated with a strong trend toward a reduction in mortality, a lower infectious complication rate and a shorter hospitalization. More recently, four other randomized trials have been published. The results of the ten studies are summarized in Table 2 (Brantley & Pierce, 2000; Conejero et al., 2002, Garrel et al., 2003 and Goeters et al., 2002; Griffiths, Jones, & Palmer, 1997; Hall et al., 2003 and Houdijk et al., 1998; Jones, Palmer, & Griffiths, 1999; Powell-Tuck et al., 1999 and Wischmeyer et al., 2001). These studies show that survival is improved by glutamine supplementation only in high mortality rate settings. The effective daily supplementation dose ranged from 20 to 40 g. These glutamine administration rates approximately match the extent of the decrease in muscle glutamine de novo synthesis observed in burn patients (Biolo, Fleming et al., 2000). There is clear evidence that both enteral or parenteral supplementation can be effective in counteracting the systemic depletion glutamine. Enteral glutamine administration preferentially increases glutamine disposal in splanchnic tissues, whereas parenteral supplementation provides glutamine to the whole organism.
Glutamine supplementation was mostly ineffective in preventing muscle glutamine depletion in critically ill patients, because of the relative inability of this tissue in the uptake of the circulating amino acid. Intramuscular glutamine depletion should, therefore, be preferentially counteracted by promoting de novo glutamine synthesis. Clinical studies have shown that stimulation of pyruvate oxidation by dichloroacetate administration in burnt patients (Ferrando et al., 1998) and supplementation of ketoglutarate in post-surgical patients (Hammarqvist et al., 1991) may improve glutamine synthesis in skeletal muscle. In addition, branched chain amino acid administration may affect de novo muscle glutamine production rate by increasing nitrogen availability for ketoglutarate transamination (Darmaun & Dechelotte, 1991).

[Bane]

Originally Posted by Phosphate bond

I posted this one a few times in the many "glutamine" threads we have. It's interesting that they note that muscle uptake was not enhanced by systemic IV administration.

As far as their other findings, a meta-analysis is only as good as the author's interpretation skills. That burn victim study was a good example because nobody paid attention much to what glutamine was being compared to (glycine, rather than essential amino acids or complete protein)

After reading that whole thing, i still think that BCAAs are a far far far better option than Glutamine

[Phosphate bond]

Originally Posted by From Abstract posted

Muscle and plasma glutamine concentrations decrease proportionally to severity of diseases.

Yeah, no kidding. Glutamine sythesis is dependent on ATP. Do you think a critically ill person is making much ATP?

The relationship between the outcome and glutamine levels is probably due more to the ATP state of the tissues rather than any direct effect from glutamnine.

That's my take on it. It also explains why system administration can't increase skeletal glutamine levels. The Na/K pump that takes amino acids up is ATP dependent.

[Phosphate bond]

Originally Posted by Bane

After reading that whole thing, i still think that BCAAs are a far far far better option than Glutamine

My guess is that essential amino acids (with BCAAS) may be even better because of the essential nature EAAS play in energy production. NO ATP and glutamine levels will naturally drop.

[Bane]

Originally Posted by Phosphate bond

My guess is that essential amino acids (with BCAAS) may be even better because of the essential nature EAAS play in energy production. NO ATP and glutamine levels will naturally drop.

Agree here, though i consider you can get enough essential aminos from quality protein. Any supplement out there that contains only essential aminos?

[Estopell]

Originally Posted by Bane

Agree here, though i consider you can get enough essential aminos from quality protein. Any supplement out there that contains only essential aminos?

http://www.bodybuilding.com/store/ergo/all.html

[Phosphate bond]

Originally Posted by Bane

Agree here, though i consider you can get enough essential aminos from quality protein. Any supplement out there that contains only essential aminos?

Agreed. That is why I question replacing whole protein intake with large amounts of glutamine.

[Phosphate bond]

Originally Posted by Estopell

http://www.bodybuilding.com/store/ergo/all.html

Unfortunately it's missing Trytophan, but that's not Pat Arnold's fault. (FDA banned tryptophan in 1989)

Still seems like a good product. Even has vitargo in it.

[Bane]

Maybe I'll try it sometime. Anyone here that can find out what downregulates-upregulates the glutamine synthetase enzyme in humans? Unfortunately browsing through gene libraries was never my forte

[Bane]

Forget it, i found it
http://ajpendo.physiology.org/cgi/co...ll/276/6/E1136
Seems interesting that glucocorticoids enhance GS expression

[Phosphate bond]

Originally Posted by Bane

Forget it, i found it
http://ajpendo.physiology.org/cgi/co...ll/276/6/E1136
Seems interesting that glucocorticoids enhance GS expression

Good work. I'll have to go through and read that later.

[Bane]

http://ajpendo.physiology.org/cgi/c...ull/276/6/E1136

The most interesting thing that comes out of this is that for acute stress, it is Glucucorticoids(like cortisone) which increase GS expression, leading to Glutamine synthesis. You know what this means? THAT ALL THESE ANTICORTISOL SUPPLEMENTS(if we accept that they work) are WORTHLESS P.W.O. since they will inhibit glutamine reformation.
It also becomes more clear that Glutamine supplementation is verry much worthless. Even glutamine free diets didn't affect the GS expression.
Edit:Uploaded the pdf to bb.com server

[Big_r]

Hey Bane. The top link to the PDF file is dead.
Could you please make a new one....

Pretty please

[Bane]

I have already done so. See the post right above yours :P

[Big_r]

Originally Posted by Bane

I have already done so. See the post right above yours :P

Shame on me for my short vision.... Thanx!
Will defenitely study it. Aways nice to learn more.

You must spread some Reputation around before giving it to Bane again.

[Bane]

Who cares about rep anyway? It's the thanks that counts. Does anyone knows if the forum poses a limit on the size of files you can upload? There are many nice full studies I have access to at the university.

[Big_r]

Originally Posted by Bane

Does anyone knows if the forum poses a limit on the size of files you can upload? There are many nice full studies I have access to at the university.

Yummy. There are some studies i'd love to get my hands on but i don't have access here.
Feel free to post as much as you've got.....

[Bane]

Just PM me what full study you'd like and when i hit the library again I'll see what I can do. Meanwhile you can check the other posted study here:
http://forum.bodybuilding.com/showth...ighlight=study

[Big_r]

Originally Posted by Bane

Just PM me what full study you'd like and when i hit the library again I'll see what I can do. Meanwhile you can check the other posted study here:
http://forum.bodybuilding.com/showth...ighlight=study

Great! I read the study in this thread, and will go on to the arginine/ornithine study.

I know of 1 study adding leucine to a protein/carb mix. It concludes adding leucine increases protein synthesis even more.
But i'm very curious about the amounts used....

Since most people (including you and me) advertise BCAA supplementation, this might be an interesting one:
http://www.ncbi.nlm.nih.gov/entrez/q...251&query_hl=6

[Bane]

I am working on BCAAs studies right now

[Bane]

The presence of inflammation significantly affects glutamine concentrations and gut permeability, in contrast to the presence of depletion of body cell mass per se. On the other hand, villus morphology is not influenced by changes in systemic inflammatory activity whereas nutritional status possibly does affect villus height.

[Big_r]

Look at this one Bane:

A protein rich meal (3 g/kg lean beef) in 7 healthy sujects increases AAs from the splanchic bed. BCAAs accounted for more than half of total splanchic AA output. Arterial BCAA concentrations incremented 100-200%. Leg exchange of most AAs reverted from a basal net output to a net uptake which was most marked for the BCAAs. Glutamine was continuously taken up by the splanchic tissues and released by the leg tissues after the protein meal, although their rate of output from the leg declined transiently at 30-60 min.
After protein ingestion within 30-60 min. net uptake of the leg was observed for valine, leucine and isoleucine, and to a lesser extent for threonine, serine, glycine, tyrosine, phenylalanine, lysine, histidine, and arginine. The uptake of the BCAAs accounted for more than half of total leg AA uptake at 30-60 min, and for virtually all of the AA uptake at 90-180 min. Throughout the 3-h period of observation after protein intake, a continuous net release of alanine and glutamine was observed.
It is thus clear that the BCAAs are the major source for repletion of muscle nitrogen after protein intake.

http://www.pubmedcentral.gov/pageren...geindex=1#page

[PatsFan75BC]

Post the cliff notes. No one is going to read all that and people who do and act like they understand it all, are just trying to make themselves look smart.


This has been another post in the series, "Patsfan tells it like it is"

Thank you

[Bane]

Originally Posted by PatsFan75BC

Post the cliff notes. No one is going to read all that and people who do and act like they understand it all, are just trying to make themselves look smart.


This has been another post in the series, "Patsfan tells it like it is"

Thank you

People must learn someday that they cannot be really knowledgable if they don't have the patience to open a pdf and read a full study
And for anyone who is really bored, he can simply read the abstract on the top and the conclusions at the end. Sheesh,i search, find and post, i don't have to paste too!

[kingcarlos]

so u have posted all the info already? thanx man cuz the site u posted is not working anymore and im reali interested on some supple reads