understanding the mechanisms of glutamine action in critically ill patients

Glutamine (Gln) is an important energy source and has been used as a supplementary energy substrate. Furthermore, Gln is an essential component for numerous metabolic functions, including acid-base homeostasis, gluconeogenesis, nitrogen transport and synthesis of proteins and nucleic acids. Therefore, glutamine plays a significant role in cell homeostasis and organ metabolism. This article aims to review the mechanisms of glutamine action during severe illnesses. In critically ill patients, the increase in mortality was associated with a decreased plasma Gln concentration. During catabolic stress, Gln consumption rate exceeds the supply, and both plasma and skeletal muscle pools of free Gln are severely reduced. The dose and route of Gln administration clearly influence its effectiveness: high-dose parenteral appears to be more beneficial than low-dose enteral administration. Experimental studies reported that Gln may protect cells, tissues, and whole organisms from stress and injury through the following mechanisms: attenuation of NF (nuclear factor)-kB activation, a balance between pro- and anti-inflammatory cytokines, reduction in neutrophil accumulation, improvement in intestinal integrity and immune cell function, and enhanced of heat shock protein expression. In conclusion, high-doses of parenteral Gln (>0.50 g/kg/day) demonstrate a greater potential to benefit in critically ill patients, although Gln pathophysiological mechanisms requires elucidation

Amino acid and protein turnover in human skeletal muscle [Elektronisk resurs]

Critically ill patients are characterised by a severe net protein catabolism. The rate of muscle protein loss is in the magnitude of 10% per week. A consequence of muscle wasting is increased weakness, which is associated with high rates of mortality and morbidity. Protein wasting is a result of either a decrease of protein synthesis or an increase of protein degradation or a combination of both. To understand the underlying mechanisms determinations of both protein synthesis and degradation on the tissue level are necessary, since the regulation of protein turnover is different between tissues. Protein synthesis on the tissue level can be measured quantitatively, however protein degradation is more difficult to measure quantitatively and the methods to study muscle protein breakdown in humans are not fully validated. One aim of this thesis was to descriptively study the amino acid and protein metabolism of skeletal muscle longitudinally in intensive care unit (ICU) patients. In a volunteer study endotoxin was used to obtain a human model of the initial phase of sepsis. To assess protein turnover in skeletal muscle, techniques to quantify synthesis as well as degradation in muscle tissue are required. Hence developing of new and accurate quantitative techniques to measure muscle protein breakdown are necessary. Another aim of the thesis was to develop and validate new and existing techniques to measure muscle protein breakdown rates which were validated in volunteers in the basal state and following endotoxin administration. The temporal pattern of amino acid net balances across the leg and plasma concentrations, in particular glutamine and glutamate, in long-staying ICU patients were investigated. Neither glutamine concentration nor net release from the leg changed significantly during the initial two weeks of ICU stay, despite a net release of phenylalanine indicating a progressive net loss of skeletal muscle proteins. In addition, the net uptake of glutamate across the leg muscle was not altered during this period. Studying of amino acid metabolism in the initial phase of illnesses in ICU patients is not possible. Therefore endotoxin administration was used as a human model of the early phase of sepsis to obtain information of the initial pattern of amino acid metabolism in skeletal muscle. Concentrations of all amino acids in plasma and skeletal muscle decreased after endotoxin administration and in addition the efflux of most amino acid from the leg increased. For studies of protein turnover at the tissue level, quantitatively accurate methods to measure protein kinetics are necessary. 3-Methylhistidine (3-MH) can be used as a marker of contractile protein degradation. Arterio-venous differences of 3-MH concentrations across limbs have been used to assess skeletal muscle protein degradation, but the methods to measure 3-MH net balances by HPLC techniques are not precise enough to measuring of the small arteriovenous concentration differences. The use of tracer techniques, employing 2H3-3-MH and 2 2H5-phenylalanine, enabled calculation of the rates of appearance for 3-MH and phenylalanine respectively. In the basal state these values were shown to be different from zero during the isotopic steady state. The effects of endotoxin on muscle protein metabolism were studied by three different models using tracer techniques. Whole body phenylalanine rate of appearance increased indicating an increase in whole body protein degradation. From the leg there was an increased efflux of phenylalanine indicating a net protein loss, but no alteration in 3-MH net balance or rate of appearance. A 3-compartment model for phenylalanine turnover was used, which showed a decreased muscle protein synthesis but an unchanged degradation. So endotoxin administration cause altered muscle protein synthesis but does not influence protein degradation, although whole body protein degradation increases. In summary alterations in amino acid metabolism in skeletal muscle are established early during the illnesses. During the initial two weeks of ICU stay no temporal changes in amino acid concentrations and net balances were seen, despite continuous protein loss from skeletal muscle. An endotoxin challenge decreased plasma and muscle amino acid concentrations and in addition the efflux of amino acids from the leg increased. Measurement of 3-MH rate of appearance from leg muscle using isotopically labelled 3-MH resulted in consistent and accurate values of contractile protein degradation rates. Endotoxin administration decreased human skeletal muscle synthesis rate while protein breakdown was not affected

Contractile protein breakdown in human leg skeletal muscle as estimated by [2H3]-3-methylhistidine: a new method

3-Methylhistidine urinary excretion and net balances across the leg or forearm have been used as markers of contractile protein breakdown in muscle tissue. Here we investigate whether infusion of labeled 3-methylhistidine and the measurement of the arteriovenous dilution of the tracer with unlabeled 3-methylhistidine will result in more consistent and precise measurements of 3-methylhistidine rates of appearance and consequently muscle contractile protein breakdown rates in comparison with conventional arteriovenous concentration difference measurements. Six healthy volunteers were studied in the postabsorptive state and received a primed continuous infusion of 3-[2H3-methyl]- methylhistidine and L-[ring-2H5]-phenylalanine for 4 hours. 2H3-3-methylhistidine reached an isotopic steady state after 210 minutes in all subjects. Arteriovenous differences of 3-methylhistidine, measured by high-performance liquid chromatography (HPLC), showed both uptake and release from skeletal muscle, which is theoretically not likely to occur. The enrichment of 2H3-3-methylhistidine was consistently lower in the femoral vein than in the artery, and therefore a constant net release of 3-methylhistidine from the leg was observed. The mean rates of appearance for 3-methylhistidine and phenylalanine were 0.44 +/- 0.30 nmol x min(-1) x 100 mL(-1) and 11.2 +/- 5.7 nmol x min(-1) x 100 mL(-1), respectively. In summary, arteriovenous difference measurement of 2H3-3-methylhistidine enrichment is more reliable than measurement of arteriovenous difference of unlabeled 3-methylhistidine. Consequently, measuring rates of appearance from leg muscle using labeled 3-methylhistidine resulted in more consistent and accurate values of contractile protein degradation rates in human skeletal muscle