In offspring of pregnancies complicated by poorly controlled diabetes mellitus, intrauterine growth retardation and premature delivery, perturbations in systemic perinatal glucose homeostasis may adversely affect the central nervous system (CNS) milieu, predisposing the neonate to CNS injury. The thesis of this proposal is that systemic hypoglycemia and hyperglycemia result in circulatory, metabolic, and blood-brain barrier permeability changes, which may place the fetus and neonate at higher risk for hypoxic-ischemic injury, and/or other CNS injury.
The specific aims of this proposal examine (1) the importance of prostanoids, (6-keto- prostaglandin F1alpha, thromboxane B2 and PGE2) to perinatal CNS circulation and metabolism during altered systemic glycemic states, (2) the importance of hypoglycemia to the development of ischemic CNS injury and (3) the importance of hyperglycemia to the development of ischemic CNS injury and (4) the effects of hyperglycemia on blood-brain barrier permeability in the early and late gestation fetus, cesarean-section delivered surfactant treated premature sheep and compare these findings to that of hyperglycemic full-term sheep. Studies will be performed in the chronically catheterized ovine fetus and neonate infused with insulin to induce hypoglycemia, glucose to induce hyperglycemia, insulin and glucose for a euglycemic hyperinsulinemic clamp and placebo for control fetuses. Fetal central nervous system blood flow (total and regional) will be measured with radionuclide-labelled microspheres, cerebral metabolism by the Fick principle, during steady- state conditions, by arterial-superior sagittal sinus differences of appropriate metabolites and blood-brain barrier permeability (total and regional) by the uni-directional influx of radiolabelled tracers (24Na, 14C-sucrose and 3H-mannitol) into brain. Pathophysiologic changes will be identified by comparing the results in the hypoglycemic or hyperglycemic fetuses to control, placebo-infused, fetal sheep. The overall goal of this proposal is to elucidate the CNS pathophysiology associated with perturbations in systemic glucose homeostasis.

Project Start
Project End
Budget Start
Budget End
Support Year
15
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Women and Infants Hospital-Rhode Island
Department
Type
DUNS #
069851913
City
Providence
State
RI
Country
United States
Zip Code
02905
Stonestreet, Barbara S; Sadowska, Grazyna B; Hanumara, R Choudary et al. (2012) Comparative effects of glucose- and mannitol-induced osmolar stress on blood-brain barrier function in ovine fetuses and lambs. J Cereb Blood Flow Metab 32:115-26
Stonestreet, Barbara S; Sadowska, Grazyna B; Leeman, Joanne et al. (2006) Effects of acute hyperosmolality on blood-brain barrier function in ovine fetuses and lambs. Am J Physiol Regul Integr Comp Physiol 291:R1031-9
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Stonestreet, Barbara S; Petersson, Katherine H; Sadowska, Grazyna B et al. (2004) Regulation of brain water during acute glucose-induced hyperosmolality in ovine fetuses, lambs, and adults. J Appl Physiol 96:553-60
Stonestreet, Barbara S; Oen-Hsiao, Joyce M; Petersson, Katherine H et al. (2003) Regulation of brain water during acute hyperosmolality in ovine fetuses, lambs, and adults. J Appl Physiol 94:1491-500
Vohr, B R; McGarvey, S T (1997) Growth patterns of large-for-gestational-age and appropriate-for-gestational-age infants of gestational diabetic mothers and control mothers at age 1 year. Diabetes Care 20:1066-72
Stonestreet, B S; Boyle, L D; Papparella, A et al. (1996) Circulatory and metabolic effects of alpha-adrenergic blockade in the hyperinsulinemic ovine fetus. J Soc Gynecol Investig 3:241-9
Meyers-Seifer, C H; Vohr, B R (1996) Lipid levels in former gestational diabetic mothers. Diabetes Care 19:1351-6
Sadeh, A; Dark, I; Vohr, B R (1996) Newborns' sleep-wake patterns: the role of maternal, delivery and infant factors. Early Hum Dev 44:113-26

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