Fetal Programming of Metabolic Disease: The Role of Catecholamines

Abstract

The objective of this dissertation research was to determine the chronic actions of catecholamines on insulin-stimulated glucose metabolism in the following models: 1) norepinephrine-infused ovine fetuses; 2) normal ovine fetuses with adrenal demedullation during an acute hypoxemic challenge; 3) adrenal demedullated ovine fetuses with placental insufficiency-induced intrauterine growth restriction (IUGR). To determine the effects of elevated catecholamine exposure on fetal glucose metabolism independent of other placental-related insufficiencies, we chronically infused norepinephrine into otherwise normal sheep fetuses near-term (NE-E; n=6). Weight-specific fluxes for oxygen, glucose and radiolabeled glucose were measured during a euinsulinemic-euglycemic clamp and hyperinsulinemic-euglycemic clamp (HEC). We found that chronic exposure to high plasma norepinephrine concentrations lowers glucose uptake rates in fetal tissues without affecting rates of glucose oxidation and production. Less fetal glucose uptake was independent of insulin, which indicates insulin resistance as a consequence of chronically elevated norepinephrine. This study validated that norepinephrine alone elicits adaptations in glucose metabolism. In order to determine the effects of hypoxia-induced norepinephrine secretion on fetal glucose metabolism, we performed surgical sham (intact; n=7) or adrenal demedullation (AD; n=6) at 0.65 gestation on normal, control fetuses. Weight-specific fluxes for oxygen, glucose and radiolabeled glucose were determined at baseline, HEC, and hypoxemic-HEC. During each period, umbilical blood flow was measured with 3H2O diffusion. We found that loss of normal adrenal medulla responsiveness lowered umbilical blood flow and caused placental insufficiency because net umbilical (fetal) uptake for oxygen and glucose were less in AD fetuses. The lower uptakes reduced arterial oxygen and glucose concentrations, which promoted glucose utilization and production rates in AD fetuses, independent of norepinephrine. To determine whether ablation of the chronic adrenergic stimulation enhances endogenous glucose utilization and production rates in IUGR fetuses, we performed surgical sham (IS; n=8) or adrenal demedullation (IA; n=6) at 0.65 gestation on IUGR fetuses that were compared to intact, control fetuses (n=9). Regardless of plasma catecholamine concentrations, glucose utilization rates were higher in IUGR fetuses despite lower umbilical glucose uptake due to the establishment of endogenous glucose production. Our findings show higher glucose utilization and production rates were independent of norepinephrine. Overall, these studies indicate that chronically high catecholamine concentrations do not solely contribute to the higher insulin sensitivity for glucose utilization or to the activation of glucose production previously shown as adaptations in IUGR fetuses with placental insufficiency. These data do confirm previous studies that show high concentrations of catecholamines lower insulin concentrations and contribute to the pathology of IUGR. In conclusion, insulin action on fetal glucose metabolism in the IUGR fetus is regulated by more complex mechanisms, and likely depends on the interplay between hypoglycemia and hypoxemia.