An increased incidence of congenital malformations has been shown to occur among offspring from diabetics such that these defects have become the leading cause of fetal wastage among this group. A broad spectrum of abnormalities occurs, including heart, neural tube, vertebral, and limb malformations, and is associated with retarded growth of the conceptus. Although a variety of factors characteristically altered in the diabetic state have been postulated to play a role in the origin of the malformations, only hyperketonemia, somatomedin inhibiting factors, and hyperglycemia have been independently shown to adversely affect embryonic growth and development in experimental models. Despite reports of the teratogenicity of these factors, their mechanism of action, i.e. biochemical alterations produced in the embryo following exposure to these substances, remains undefined. Using the system of whole embryo culture and radioactively labelled precursors, the biochemical effects of these factors will be characterized at critical stages of embryogenesis, i.e. organogenesis. Each factor will be analyzed separately and the rationale for each analysis will be based on results delineating the effects of these substances on fetal and adult tissues. Thus, for example, the ketone bodies, B-hydroxybutyrate and acetoacetate, will be investigated for their effects on glycolysis and de novo synthesis of pyrimidines. Both effects have been described in fetal brain and would represent a potential mechanism of teratogenesis for the developing embryo. Somatomedin inhibitors will be analyzed for their effects on embryonic growth and development by using isolated serum fractions of these factors. This is the first time that such fractions (as opposed to whole serum from diabetic animals) have been isolated and they represent an exciting new, potentially significant result in explaining the induction of malformations by diabetes. Finally, effects of hyperglycemia will be analyzed by monitoring two potentially detrimental processes that might adversely affect embryogenesis: 1) non-enzymatic glycosylation and modification of embryonic proteins; 2) altered glycosaminoglycan synthesis. In combination these studies will define the biochemical effects of these factors on embryogenesis, thereby providing a better understanding of the effects of maternal diabetes on the conceptus. These studies will also aid the clinician in counseling and managing the pregnant diabetic to produce a better outcome of pregnancy.
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