Macrosomia, profound postnatal hypoglycemia, acidosis, respiratory distress, brain damage, congenital deformities and ultimate demise are frequent perinatal abnormalities manifested by offspring of diabetic mothers (ODM). This study will be devoted to elucidation of the biochemical mechanisms underlying such developmental aberrancies. The effects of intra-uterine residence in the milieu of the diabetic mother on perinatal development and hormonal regulation of enzymes concerned with adaptation to extra-uterine life will be explored in the rat. Developmental courses of hepatic and lung enzymes, concerned with carbohydrate and phospholipid metabolism, respectively, will be compared in normal offspring and ODM. Enzymes will be chosen which are known to develop perinatally and/or be regulated by hormones related to diabetes. The development of regulatability of these enzymes by diabetes related hormones, e.g., glucocorticoids, glucagon, cAMP and insulin, will be compared in ODM and normal perinates. Exploration of possible abnormalities in the mechanisms by which these hormones influence enzyme development in the ODM will be initiated. Since it is known that the fetal ODM is hyperinsulinemic and that insulin regulates its own receptor, we plan to study perinatal development of insulin receptor sites in normal and ODM hepatic cell membranes; analogous studies may be undertaken on glucocorticoid and glucagon receptors. The roles of abnormal metabolite levels, transferred transplacentally to the fetus from the uncontrolled diabetic mother, and of fetal hyperinsulinemia in eliciting macrosomia and abnormal enzyme development and endocrine regulation in the ODM will be examined. The ultimate goal of these studies is aimed at the design of rational prophylaxis and/or therapy relevant to human infants of diabetic mothers.