Neonatal hypoglycemia is a significant and common complication of maternal diabetes. In the infant of diabetic mother (IDM), attenuated hepatic glucose production has been incriminated in the pathogenesis of this disorder. Chronic fetal hyperinsulinemia, characteristic of the IDM, may impede the normal perinatal hormonal induction of those hepatic enzymes involved in glucose hemeostasis. For the first three years of the project I intend to develop a model which simulates the hormonal and biochemical perturbations experienced by the liver of the IDM. Post delivery (17-19 day gestation) fetal rat liver explants will be cultured in a defined medium and the intermediary metabolism of these cells studied in detail. The endogenous and hormonally-stimulated production of ketones and glucose, both from glycogen and lactate, will be investigated. Specifically, the goals are to: a) develop an IDM liver model in which isolated fetal liver explants are cultured in a medium which can simulate the in vivo biochemical perturbations, viz., hyperglycemia and hyperinsulinemia. b) quantitate glycogenolysis, gluconeogenesis, and ketogenesis in both normal and IDM liver explants. c) study the effects of glucagon and epinephrine on (a, b). d) relate the ketogenic rates with the activity of carnitine palm itoyltransferase and the intracellular concentration of a feedback inhibitor, malonyl CoA. e) determine the perinatal development of hepatic ketogenesis and gluconeogenesis from fetal life (day 19 of gestation) through the newborn period. The remaining two years will be devoted to the study of basement membrane (BM) biochemistry and pathology in diabetes. Specifically, I am interested in the glycosylation of BM and the effect of this process on BM turnover, catabolism, and function. To conduct these studies with BM, I paln to develop a diabetic model of the renal glomeruli using isolated kidney explants in culture. Explants maintained in culture would be ideal models to preserve and study the pericellular environment. The work outlined above involves development biology, perinatal medicine, and biochemistry.
