The overall goal of these investigations is to determine the mechanism(s) responsible for insulin resistance among newborn dogs. We and others have demonstrated that the neonatal period is characterized by imprecise regulation of glucose metabolism as manifested by fasting hypoglycemia and alimented induced hyperglycemia. Using the euglycemic hyperinsulinemic clamp, we have demonstrated that neonatal insulin resistance in vivo is due to a postreceptor defect as demonstrated by a reduced maximum rate of insulin-mediated glucose uptake and by attenuated suppression of endogenous glucose production. These preliminary projects have led to further testable hypotheses related to mechanisms of insulin action due to immaturity, counterregulatory hormones, and FFA which may cause defects at the level of the insulin receptor tyrosine kinase activity, and the cellular uptake of glucose. Presently there is a paucity of studies which have simultaneously investigated the kinetic and postreceptor factors which may be responsible for neonatal insulin resistance. In addition to reduced peripheral tissue glucose uptake the newborn demonstrated the attenuated suppression of hepatic glucose production. We will investigate the relationship of this phenomenon with techniques to quantitate insulin's effect on the suppression of gluconeogenesis. This will be determined at the substrate flux level in addition to the enzyme activity and mRNA expression level. We hypothesize that ongoing gluconeogenesis is responsible for the poor suppression of hepatic glucose output in the newborn mammal. We also propose to employ the euglycemic hyperinsulinemic clamp in newborn dogs, combined with specific perturbations which are present during the neonatal period (e.g., epinephrine, FFA) and analyze alterations of insulin-mediated glucose uptake. In addition we will determine the suppression of endogenous glucose production, receptor binding characteristics, autophosphorylation of the insulin receptor, and phosphorylation of receptor-associated proteins. The insulin sensitive adult dog will serve as the appropriate control. It is anticipated that the results of the proposed investigations will increase our understanding of neonatal insulin resistance and further our knowledge about insulin physiology in general. The understanding of the relationship between insulin and glucose in animal models of human metabolic problems will enable more rational care for high-risk infants.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD020851-05
Application #
3319282
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Project Start
1985-12-01
Project End
1995-11-30
Budget Start
1991-12-01
Budget End
1992-11-30
Support Year
5
Fiscal Year
1992
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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