In the current grant we will investigate the metabolic reasons for variations in acute nitrogen responses to growth hormone, and study mechanisms of adaptation to growth hormone treatment which cause a return to pretreatment growth rates on chronic growth hormone treatment. Specifically, we plan: 1) To quantify the contribution of body protein turnover to resting, postprandial, and total daily energy expenditure in mid-childhood and test the hypothesis that these relationships are altered in children with short stature. 2) To measure short childrens' sensitivity to insulin and test the hypothesis that nitrogen retention to acute growth hormone challenge is directly proportional to glucose and amino acid sensitivity to insulin. 3) To determine the relationships between nitrogen kinetics, amino acid oxidation, and daily energy expenditure in short children treated with growth hormone on a long-term basis and test the hypotheses that: a. Protein turnover, protein synthesis, and energy expenditure increase in a commensurate fashion while amino acid oxidation declines proportionately during the period of rapid growth. b. Total daily energy expenditure declines and protein turnover and synthesis represent a reduced fraction of daily energy expenditure in those children whose height velocity declines on continued treatment. c. Development of attenuated height velocity response to continued treatment with recombinant human growth hormone is associated with the degree of resistance developed to insulin's actions on glucose and amino acid metabolism.
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