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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD012613-09
Application #
3311933
Study Section
Metabolism Study Section (MET)
Project Start
1978-07-01
Project End
1990-06-30
Budget Start
1987-07-01
Budget End
1988-06-30
Support Year
9
Fiscal Year
1987
Total Cost
Indirect Cost
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
Menon, R K; Chernausek, S D; Sperling, M A (1991) Ontogeny of insulin-like growth factor I and insulin receptor kinase activity in rat liver. J Dev Physiol 16:87-97
Cutfield, W S; Bergman, R N; Menon, R K et al. (1990) The modified minimal model: application to measurement of insulin sensitivity in children. J Clin Endocrinol Metab 70:1644-50
Menon, R K; Cohen, R M; Sperling, M A et al. (1990) Transplacental passage of insulin in pregnant women with insulin-dependent diabetes mellitus. Its role in fetal macrosomia. N Engl J Med 323:309-15
Menon, R K; Bloch, C A; Sperling, M A (1990) Estimation of glucose kinetics in fetal-maternal studies: potential errors, solutions, and limitations. Am J Physiol 258:E1006-13
Low, L; Chernausek, S D; Sperling, M A (1989) Acromegaloid patients with type A insulin resistance: parallel defects in insulin and insulin-like growth factor-I receptors and biological responses in cultured fibroblasts. J Clin Endocrinol Metab 69:329-37
Artal, R; Doug, N; Wu, P et al. (1988) Circulating catecholamines and glucagon in infants of strictly controlled diabetic mothers. Biol Neonate 53:121-5
Bloch, C A; Menon, R K; Sperling, M A (1988) Effects of somatostatin and glucose infusion on glucose kinetics in fetal sheep. Am J Physiol 255:E87-93
Bloch, C A; Sperling, M A (1988) Sources and disposition of fetal glucose: studies in the fetal lamb. Am J Perinatol 5:344-52
Menon, R K; Sperling, M A (1988) Carbohydrate metabolism. Semin Perinatol 12:157-62
Chernausek, S D; Beach, D C; Banach, W et al. (1987) Characteristics of hepatic receptors for somatomedin-C/insulin-like growth factor I and insulin in the developing human. J Clin Endocrinol Metab 64:737-43

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