The overall goal of this investigation is to determine the relationship between insulin action and glucose metabolism in the newborn mammal in vivo. We and others have demonstrated that the neonatal period is characterized by imprecise regulation of glucose metabolism as demonstrated by fasting hypoglycemia and alimented-induced hyperglycemia. Furthermore, considerable evidence suggests that the newborn mammal has a significant degree of insulin resistance. Compared to studies in adults, the neonate has diminished suppression of systemic glucose production and an attenuated uptake of amino acids by muscle in the presence of insulin. In contrast to the insulin resistance in normal newborn mammals, infants born to diabetic mothers or those with intrauterine growth retardation may be more sensitive to insulin, resulting in hypoglycemia. We have previously established canine animal models of these two aberrant metabolic neonatal human disease states. Presently, there is a paucity of data regarding the insulin sensitivity in newborn human infants as it would be dangerous to infuse insulin, and the resulting hypoglycemia would produce counter-regulatory hormone effects. We propose to study pups following normal, diabetic or growth retarding pregnancies with the euglycemic insulin clamp to avoid hypoglycemia. With the use of (6-3H) glucose we will determine the degree of systemic glucose suppression by insulin. In addition, we will determine the in vivo dose response curve to insulin. This curve will determine if insulin resistance is a defect in insulin receptors or in post-receptor mechanisms. Examination of hepatic and muscle tissue's regulatory enzymes and intermediates will help to explain the mechanisms of insulin mediated glucose utilization. Fasting hypoglycemia and alimented hyperglycemia continue to contribute to neonatal morbidity. The understanding of the relationship between insulin and glucose in these animal models of human metabolic problems will enable better care for these high risk neonates.
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