The fetus secretes insulin appropriately in response to a number of stimuli, particularly alteration of circulating glucose levels. In some ways, fetal insulin secretory patterns are similar to those of the adult-onset diabetic. A possible role for prostaglandins in the inhibition of glucose-induced early phase insulin secretion has recently been demonstrated in the adult diabetic and may play a role in fetal insulin secretion as well. Prostaglandin synthesis inhibitors will be used to test this hypothesis. We are in process of testing the hypothesis also, that prolonged hyperglycemia in the fetus of the diabetic mother is the prime stimulant for the development of chronic fetal hyperinsulinism and subsequent macrosomia. Utilizing a twin fetal sheep infusion model we have been able to elevate the glucose concentrations in one twin 3 fold higher than the non-infused twin without producing fetal acidosis. Insulin secretory kinetics pre and post delivery are being assessed at present. A role for fetal glucagon secretion has yet to be delineated. We are also testing the hypothesis that fetal glucagon elevation (acute and chronic) may induce alterations in fetal metabolism. To date we have found that pharmacologic doses of glucagon (0.01 to 1.0 mg/kg) cause elevation in fetal plasma glucose 50-70% above baseline. A fall in the glucose V-A glucose difference and the glucose/O2 quotient suggests an acute fetal glycogenolytic response. Fetal ketone production post glucagon, unlike the adult, is unaltered. Chronic glucagon infusions to assess changes in fetal gluconeogenesis are planned.