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      Use of Stable Isotopes to Assess Protein and Amino Acid Metabolism in Children and Adolescents: A Brief Review

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          As protein accretion is a prerequisite for growth, studying the mechanisms by which nutrients and hormones promote protein gain is of the utmost relevance to paediatric endocrinology. Tracers are ideally suited for the assessment of protein and amino acid kinetics in vivo, as they provide an estimate of synthesis and turnover. Current tracer approaches in children and adolescents utilize stable isotopes, ‘heavier’ forms of elements that have one or several extra neutrons in the nucleus. Such isotopes are already present at low, but significant, levels in all tissues and foodstuffs, are not radioactive and are devoid of any known side-effects when present in small amounts. L-[1-<sup>13</sup>C] labelled leucine, given as a 4- to 6-h intravenous infusion, has become the method of choice to assess whole-body protein kinetics. After infusion, any <sup>13</sup>C-leucinethat is oxidized appears in the breath as <sup>13</sup>CO<sub>2</sub>, whereas the remainder is incorporated into body proteins through protein synthesis. The isotope enrichments are determined by isotope ratio mass spectrometry and gas chromatography mass spectrometry, and absolute rates of whole-body protein synthesis, oxidation, and breakdown can be extrapolated. This approach has been used extensively to investigate the regulation of protein kinetics by nutrients and by hormones. Attempts have also been made to measure amino acid/protein metabolism in selected body compartments, and to measure the kinetics of specific tissue proteins, for example, muscle, gut, or plasma proteins.

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          Most cited references 13

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          Is Glutamine a Conditionally Essential Amino Acid?

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            Blood glutathione synthesis rates in healthy adults receiving a sulfur amino acid-free diet.

            The availability of cysteine is thought to be the rate limiting factor for synthesis of the tripeptide glutathione (GSH), based on studies in rodents. GSH status is compromised in various disease states and by certain medications leading to increased morbidity and poor survival. To determine the possible importance of dietary cyst(e)ine availability for whole blood glutathione synthesis in humans, we developed a convenient mass spectrometric method for measurement of the isotopic enrichment of intact GSH and then applied it in a controlled metabolic study. Seven healthy male subjects received during two separate 10-day periods an L-amino acid based diet supplying an adequate amino acid intake or a sulfur amino acid (SAA) (methionine and cysteine) free mixture (SAA-free). On day 10, L-[1-(13)C]cysteine was given as a primed, constant i.v. infusion (3 micromol x kg(-1) x h(-1)) for 6 h, and incorporation of label into whole blood GSH determined by GC/MS selected ion monitoring. The fractional synthesis rate (mean +/- SD; day(-1)) of whole blood GSH was 0.65 +/- 0.13 for the adequate diet and 0.49 +/- 0.13 for the SAA-free diet (P 0.05), and the absolute rate of GSH synthesis was 747 +/- 216 and 579 +/- 135 micromol x liter(-1) x day(-1), respectively (P < 0.05). Thus, a restricted dietary supply of SAA slows the rate of whole blood GSH synthesis and diminishes turnover, with maintenance of the GSH concentration in healthy subjects.
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              Relationship of plasma leucine and alpha-ketoisocaproate during a L-[1-13C]leucine infusion in man: a method for measuring human intracellular leucine tracer enrichment.

              The keto analog of leucine, alpha-ketoisocaproate (KIC), is formed intracellularly from leucine and is released, in part, into the systemic circulation. Therefore. KIC can be used to estimate intracellular leucine tracer enrichment in man during labeled-leucine tracer experiments without requiring tissue biopsy samples. This approach was studied in young, healthy, male adults maintained on different dietary protein intakes from generous (1.5 g kg-1d-1) to deficient (0.0 g kg-1d-1) for 5-7 day periods. At the end of each dietary period, the volunteers were given a primed, continuous infusion of L-[1-13C]leucine either after an overnight fast (postabsorptive state) or while being fed hourly aliquots of the same diet. The plasma concentrations of all 3 branched-chain amino and keto acid pairs were measured from early morning blood samples taken from 4 subjects at 4 different levels of protein intake. Leucine concentration showed a weak correlation, and valine concentration showed a strong correlation with protein intake; isoleucine and the 3 keto acids did not. However, each branched-chain amino acid concentration was strongly correlated with its corresponding keto acid concentration. In plasma samples obtained during the L-[1-13C]leucine infusions, the ratio of [1-13C]KIC to [1-13C]leucine enrichment ratio remained relatively constant (77 +/- 1% over the wide range of dietary protein intakes and for both the fed and postabsorptive states. For the tissues from which the plasma KIC originates, the rate of plasma leucine into cells will account for approximately 77% of the intracellular leucine flux with the remaining 23% coming primarily from leucine release via protein breakdown. The constant nature of the plasma KIC to leucine 13C enrichment ratio implies that relative changes in leucine kinetics will appear the same under many dietary circumstances regardless of whether plasma leucine or KIC enrichments are used for the calculations.

                Author and article information

                Horm Res Paediatr
                Hormone Research in Paediatrics
                S. Karger AG
                February 2006
                27 January 2006
                : 64
                : Suppl 3
                : 32-37
                aINSERM U539, Human Nutrition Research Center, Nantes, France; bDivision of Endocrinology and Endocrine Research Laboratory, Nemours Children’s Clinic, Jacksonville, Fla., USA
                89315 Horm Res 2005;64:32–37
                © 2005 S. Karger AG, Basel

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                Page count
                Figures: 2, Tables: 1, References: 26, Pages: 6
                Insulin Sensitivity: Methods


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