The perinatal mortality, in fetuses exposed to maternal hyperglycemia, is still unaceptably high despite intensive efforts toward maternal euglycemia. A major contributing factor to the adverse outcome in the progeny of diabetic parturiants is our general lack of knowledge concerning the developmental differences occurring in the fetus exposed to hyperglycemia in contrast to those residing in euglycemic milleu's. Investigators have been hindered in this area due to the lack of a reliable large animal model permitting chronic catheterization of the fetus and a consistent state of maternal hyperglycemia. Diabetes occurs spontaneously in several animals but is infrequent in occurrence. Streptozotocin, an antibiotic drug cytotoxic to the Beta-islet cells of the pancreas, is available commercially and reliably produces a hyperglycemic state with normal blood levels of ketones, free fatty acids. Streptozotocin, administered to the pregnant ewe intravenously, produces a consistent pattern of lateration in insulin secretion and carbohydrate metabolism occurring within 5-12 days depending on the degree of clinical severity required.
The specific aims of this grant is to: 1. Establish and extend our knowledge on the effects of fetal/maternal hyperglycemia, the observed alterations in the maternal ewe and its effect on fetal tissue composition and growth pattern. 2. Evaluate the endocrine/physiologic response in relation to the developing sympathetic nervous system of the fetus exposed to hyperglycemia in contrast to the euglycemic progeny. 3. Increase our understanding of the major factors contributing to the macrosomic growth observed clinically in the fetuses exposed to hyperglycemia.
These aims will be reached by utilizing the chronically catheterized pregnant ewe and fetus, a model well established in our laboratory. Birthweights and tissue composition will be assessed in the usual methods for DNA, RNA, lipid, and protein to confirm the type of organ/cellular growth. The catheters and volumes of samples allow assessment of changes in response to maternal hyperglycemia in fetal circulating glucose, insulin, MSA, catecholamines, and COMT without significant alterations in fetal blood volume. Blood flow alteration in response to stress of hyperglycemic offspring will be compared to the normal fetus by both blood flow probe measurements and radiolabelled microspheres. Lastly, systematic ablation of organ systems, known to produce intrauterine growth retardation in this model, will be utilized to expand our knowledge of their contribution in growth.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Human Embryology and Development Subcommittee 2 (HED)
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University of Mississippi Medical Center
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Dickinson, J E; Meyer, B A; Chmielowiec, S et al. (1991) Streptozocin-induced diabetes mellitus in the pregnant ewe. Am J Obstet Gynecol 165:1673-7
Dickinson, J E; Meyer, B A; Brath, P C et al. (1990) Placental thromboxane and prostacyclin production in an ovine diabetic model. Am J Obstet Gynecol 163:1831-5