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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
1R01HD020851-01
Application #
3319273
Study Section
Human Embryology and Development Subcommittee 2 (HED)
Project Start
1985-12-01
Project End
1988-11-30
Budget Start
1985-12-01
Budget End
1986-11-30
Support Year
1
Fiscal Year
1986
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Feng, B C; Li, J; Kliegman, R M (1997) Transcription of the amylin gene in newborn dogs. Biochem Mol Med 61:192-7
Feng, B C; Li, J; Kliegman, R M (1997) Insulin resistance and the transcription of the glucose-6-phosphatase gene in newborn dogs. Biochem Mol Med 60:134-41
Feng, B; Li, J; Kliegman, R M (1997) Developmental aspects of transcription of fructose-1,6-bisphosphatase in newborn dogs. Biochem Mol Med 60:174-81
Feng, B C; Li, J; Kliegman, R M (1996) Transcription of hepatic cytosolic phosphoenolpyruvate carboxykinase gene in newborn dogs. Biochem Mol Med 59:13-9
Feng, B C; Li, J; Kliegman, R M (1996) Effects of insulin, epinephrine, and glucose on regulation of transcription of the serine dehydratase gene in newborn dogs. Biochem Mol Med 57:91-6
Feng, B; Li, J; Kliegman, R M (1996) Differential effects of insulin-like growth factor-1 on neonatal canine gene expression. Biochem Mol Med 59:154-60
Johnston, V; Frazzini, V; Davidheiser, S et al. (1991) Insulin receptor number and binding affinity in newborn dogs. Pediatr Res 29:611-4
Kliegman, R M; Clapp, D W; Berger, M (1990) Targeted immunoglobulin therapy for the prevention of neonatal infections. Rev Infect Dis 12 Suppl 4:S443-55;discussion S455-6
Kliegman, R; Trindade, C; Huang, M et al. (1989) Effect of euglycemic hyperinsulinemia on neonatal canine hepatic and muscle metabolism. Pediatr Res 25:124-9
Hulman, S E; Kliegman, R M (1989) Assessment of insulin resistance in newborn beagles with the euglycemic hyperinsulinemic clamp. Pediatr Res 25:219-23

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