This application is directed toward continuing studies exploring hormonal control of CHO metabolism in the perinatal period with particular emphasis on the roles of glucagon and insulin. The pregnant sheep preparation with surgically implanted chronic indwelling vascular catheters in fetal, maternal, placental and uterine compartments will be used for studies of net glucose utilization and production in each compartment through a combination of the Fick principle approach coupled with simultaneous infusion of differentially labeled isotopic glucose to fetus and mother for kinetic analysis of fetal glucose metabolis under the following conditions: Chronic provision of insulin, glucose or both, directly to the fetus so as to simulate the fetal environment of a diabetic pregnancy; acute infusion of ketones to mother to simulate in part maternal ketoacidosis; dose response effects of fetal epinephrine infusion; fetal response to chronic maternal undernutrition with emphasis on fetal initiation of gluconeogenesis; and the kinetics of fetal glucosefructose interconversion. Fetal hepatic glucagon/insulin receptors, number, affinity, structural characteristics via crosslinking or affinity labeling, polyacrylamide gel electrophoresis and autoradiography and functional linkage to post-receptor events such as cAMP production, glycogen synthase activity, acetate incorporation into lipid and amino acid uptake will be investigated in fetal rat hepatocytes. Structural characteristics of the insulin-somatomedin-C receptor will also be studied in fetal human liver supplied by the National Diabetes Research Interchange. Monoclonal antibodies to the glucagon receptor purified from adult rat liver will be developed as probes to study potential differences between fetal and adult glucagon receptors and their linkage to post-receptor events. These studies are based on established methodologies and should extend knowledge and understanding of glucose homeostasis and its disorders in the perinatal period.
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