Can Glutamine Enable the Critically Ill to Cope Better With Infection?

Hardy, Gil; Hardy, Ines

doi:10.1177/0148607108319796

Cited by 11 publications

(8 citation statements)

References 20 publications

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“…Studies demonstrate that GLN deficiency impairs immune functions, gut integrity and protein balance in skeletal muscle (Buchman 1999;Exner et al 2002;Hardy & Hardy 2008;Holecek & Sispera 2014). The BCAA are essential amino acids, which serve as an essential substrate and regulator in protein synthesis (Tischler et al 1982;Kimball & Jefferson 2001;Nair & Short 2005).…”

Section: Discussionmentioning

confidence: 99%

“…The BCAA are essential amino acids, which serve as an essential substrate and regulator in protein synthesis (Tischler et al 1982;Kimball & Jefferson 2001;Nair & Short 2005). Therefore, the decrease in GLN and BCAA levels after PB administration may lead to various adverse effects on the body, which may have disastrous consequences particularly in patients with severe illness, in which GLN concentrations in blood plasma are frequently low and BCAA catabolism is activated (Holecek et al 1997;Exner et al 2002;Hardy & Hardy 2008).…”

Section: Discussionmentioning

confidence: 99%

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Acute effects of phenylbutyrate on glutamine, branched‐chain amino acid and protein metabolism in skeletal muscles of rats

Holeček

Vodeničarovová

Šiman

2017

Int J Experimental Path

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Phenylbutyrate (PB) acts as chemical chaperone and histone deacetylase inhibitor, which is used to decrease ammonia in urea cycle disorders and has been investigated for use in the treatment of a number of lethal illnesses. We performed in vivo and in vitro experiments to examine the effects of PB on glutamine (GLN), branched-chain amino acid (BCAA; valine, leucine and isoleucine) and protein metabolism in rats. In the first study, animals were sacrificed one hour after three injections of PB (300mg/kg b.w.) or saline. In the second study, soleus (SOL, slow twitch) and extensor digitorum longus (EDL, fast twitch) muscles were incubated in a medium with or without PB (5 mM). L-[1- C] leucine was used to estimate protein synthesis and leucine oxidation, and 3-methylhistidine release was used to evaluate myofibrillar protein breakdown. PB treatment decreased GLN, BCAA and branched-chain keto acids (BCKAs) in blood plasma, decreased BCAA and increased GLN concentrations in muscles, and increased GLN synthetase activities in muscles. Addition of PB to incubation medium increased leucine oxidation (55% in EDL, 29% in SOL), decreased BCKA and increased GLN in medium of both muscles, increased GLN in muscles, decreased protein synthesis in SOL and increased proteolysis in EDL. It is concluded that PB decreases BCAA, BCKA and GLN in blood plasma, activates BCAA catabolism and GLN synthesis in muscle and exerts adverse effects on protein metabolism. The results indicate that BCAA and GLN supplementation is needed when PB is used therapeutically and that PB may be a useful prospective agent which could be effective in management of maple syrup urine disease.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Acute effects of phenylbutyrate on glutamine, branched‐chain amino acid and protein metabolism in skeletal muscles of rats

Holeček

Vodeničarovová

Šiman

2017

Int J Experimental Path

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“…Increased BCAA oxidation is coupled with increased synthesis of GLN, which is released from muscles and utilized, preferably by the immune system. Utilization of GLN often exceeds its synthesis, leading to a lack of GLN in blood and tissues [ 95 , 96 ]. Decreased GLN availability can become rate-limiting for key functions of immune cells, such as phagocytosis and antibody production.…”

Section: Conditions With Enhanced Bcaa Catabolism and Inconsistent Almentioning

confidence: 99%

Branched-chain amino acids in health and disease: metabolism, alterations in blood plasma, and as supplements

2018

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Branched-chain amino acids (BCAAs; valine, leucine, and isoleucine) are essential amino acids with protein anabolic properties, which have been studied in a number of muscle wasting disorders for more than 50 years. However, until today, there is no consensus regarding their therapeutic effectiveness.In the article is demonstrated that the crucial roles in BCAA metabolism play: (i) skeletal muscle as the initial site of BCAA catabolism accompanied with the release of alanine and glutamine to the blood; (ii) activity of branched-chain keto acid dehydrogenase (BCKD); and (iii) amination of branched-chain keto acids (BCKAs) to BCAAs. Enhanced consumption of BCAA for ammonia detoxification to glutamine in muscles is the cause of decreased BCAA levels in liver cirrhosis and urea cycle disorders. Increased BCKD activity is responsible for enhanced oxidation of BCAA in chronic renal failure, trauma, burn, sepsis, cancer, phenylbutyrate-treated subjects, and during exercise. Decreased BCKD activity is the main cause of increased BCAA levels and BCKAs in maple syrup urine disease, and plays a role in increased BCAA levels in diabetes type 2 and obesity. Increased BCAA concentrations during brief starvation and type 1 diabetes are explained by amination of BCKAs in visceral tissues and decreased uptake of BCAA by muscles.The studies indicate beneficial effects of BCAAs and BCKAs in therapy of chronic renal failure. New therapeutic strategies should be developed to enhance effectiveness and avoid adverse effects of BCAA on ammonia production in subjects with liver cirrhosis and urea cycle disorders. Further studies are needed to elucidate the effects of BCAA supplementation in burn, trauma, sepsis, cancer and exercise. Whether increased BCAA levels only markers are or also contribute to insulin resistance should be known before the decision is taken regarding their suitability in obese subjects and patients with type 2 diabetes.It is concluded that alterations in BCAA metabolism have been found common in a number of disease states and careful studies are needed to elucidate their therapeutic effectiveness in most indications.

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“…During stress illness the body’s requirements for GLN frequently exceed the individual’s ability to synthesize sufficient amounts of this amino acid (Hardy and Hardy 2008; Wernerman 2011). Therefore, GLN is classified as a “conditionally essential” amino acid in the critically ill, the replacement of which is a rational therapeutic approach in GLN-deficient states.…”

Section: Gln and Ammonia Metabolism In The Physiological Statementioning

confidence: 99%

Evidence of a vicious cycle in glutamine synthesis and breakdown in pathogenesis of hepatic encephalopathy–therapeutic perspectives

Holeček

2013

Metab Brain Dis

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There is substantial clinical and experimental evidence that ammonia is a major factor in the pathogenesis of hepatic encephalopathy. In the article is demonstrated that in hepatocellular dysfunction, ammonia detoxification to glutamine (GLN) in skeletal muscle, brain, and likely the lungs, is activated. In addition to ammonia detoxification, enhanced GLN production may exert beneficial effects on the immune system and gut barrier function. However, enhanced GLN synthesis may exert adverse effects in the brain (swelling of astrocytes or altered neurotransmission) and stimulate catabolism of branched-chain amino acids (BCAA; valine, leucine, and isoleucine) in skeletal muscle. Furthermore, the majority of GLN produced is released to the blood and catabolized in enterocytes and the kidneys to ammonia, which due to liver injury escapes detoxification to urea and appears in peripheral blood. As only one molecule of ammonia is detoxified in GLN synthesis whereas two molecules may appear in GLN breakdown, these events can be seen as a vicious cycle in which enhanced ammonia concentration activates synthesis of GLN leading to its subsequent catabolism and increase in ammonia levels in the blood. These alterations may explain why therapies targeted to intestinal bacteria have only a limited effect on ammonia levels in patients with liver failure and indicate the needs of new therapeutic strategies focused on GLN metabolism. It is demonstrated that each of the various treatment options targeting only one the of the ammonia-lowering mechanisms that affect GLN metabolism, such as enhancing GLN synthesis (BCAA), suppressing ammonia production from GLN breakdown (glutaminase inhibitors and alpha-ketoglutarate), and promoting GLN elimination (phenylbutyrate) exerts substantial adverse effects that can be avoided if their combination is tailored to the specific needs of each patient.

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Can Glutamine Enable the Critically Ill to Cope Better With Infection?

Cited by 11 publications

References 20 publications

Acute effects of phenylbutyrate on glutamine, branched‐chain amino acid and protein metabolism in skeletal muscles of rats

Acute effects of phenylbutyrate on glutamine, branched‐chain amino acid and protein metabolism in skeletal muscles of rats

Branched-chain amino acids in health and disease: metabolism, alterations in blood plasma, and as supplements

Evidence of a vicious cycle in glutamine synthesis and breakdown in pathogenesis of hepatic encephalopathy–therapeutic perspectives

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