Puberty is a risk factor for increased incidence of childhood diabetes, for deteriorating metabolic control, and for increased prevalence of microvascular complications. Moreover, in patients with cystic fibrosis, insulin requiring diabetes develops around the time of puberty. It is now known that puberty is associated with resistance to insulin's action on glucose metabolism. Whether this insulin resistance primarily involves glucose oxidation or glucose storage is not known, and its mechanism(s) remains unknown. Furthermore, it is not known what the consequences of this insulin resistance are on protein, lipid and energy metabolism. The goals of this project are to characterize how puberty alters the hormonal control of energy metabolism in normal man, to define the mechanism(s) responsible for pubertal insulin resistance, and to investigate the consequences of insulin resistance and/or hyperinsulinemia on protein accretion and increased growth that is characteristic of puberty. To accomplish this, the technique of sequential hyperinsulinemic-euglycemic clamp will be used in conjunction with stable isotope tracers to study glucose, leucine (protein), glycerol/palmitate (lipid) turnover kinetics in vivo, and the role of insulin in regulating these pathways. Total net rates of glucose and fat oxidation will be calculated from indirect calorimetric measurements of gaseous exchange.
The specific aims are 1) to determine whether pubertal insulin resistance is limited to glucose or involves protein and fat metabolism, by a cross-sectional study of normal prepubertal, pubertal and postpubertal subjects. 2) To quantitate the relative contributions of glucose oxidation versus glucose storage to the overall decrease in insulin action. 3) To examine whether decrease insulin stimulation of glucose uptake is dependent on increased FFA availability and oxidation. 4) To evaluate whether increased GH during puberty is responsible for decreased insulin action. 5) To study whether pubertal increase in testosterone level plays a role in insulin resistance. Short normal children and patients with delayed puberty will be studied prospectively for aims 4 and 5, respectively. An understanding of the normal physiologic changes in hormonal regulation of energy metabolism that occur during puberty is essential for a thorough evaluation of the pathophysiologic alterations that lead to disease states.
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