Elevated fetal plasma norepinephrine elicits perinatal adaptations in Beta-cell function

The objective of this dissertation research was to determine the specific actions of chronically elevated catecholamines on; 1.) fetal growth and ss-cell function during the third trimester in vivo in an ovine model of placental insufficiency-induced intrauterine growth restriction (PI-IUGR), and 2.) regulation of insulin secretion in vitro utilizing the mouse insulinoma cell line Min6.;At 0.7-gestation, fetal weights were not different but PI fetuses had lower (P<0.05) basal blood oxygen content, plasma glucose, IGF-1, and insulin concentrations and greater norepinephrine concentrations (891+/-211 vs. 292+/-65 pg/ml; P<0.05) compared to controls. Glucose-stimulated insulin secretion (GSIS) was lower in PI than control fetuses (0.34+/-0.03 vs. 1.08+/-0.06 ng/ml; P<0.05). ADR-block increased GSIS in PI fetuses (1.19+/-0.11) but decreased GSIS in controls (0.86+/-0.02 ng/ml). Insulin content per islet was not different between PI and control fetuses. We concluded that elevated fetal plasma norepinephrine, in PI fetuses at 0.7 gestation, precedes growth restriction and suppresses insulin concentrations, and ADR-block revealed compensatory beta-cells stimulus-secretion responsiveness.;Therefore, to determine the effects of chronic hypercatecholamine exposure on fetal growth and ss-cell function independent of hypoglycemia and hypoxemia, we performed surgical sham or adrenal demedullation (AD) at 0.65 gestation on control and IUGR fetuses (n= 5 Control-Sham, 5 Control-AD, 5 IUGR-Sham, 5 IUGR-AD fetuses). Studies commenced at 0.9 gestation under ambient conditions and steady-state reversal of arterial pO2 between IUGR and control fetuses. Plasma norepinephrine was 5-fold higher in IUGR-Sham vs. Control-Sham and reduced in IUGR-AD fetuses to concentrations not different from Control-Sham fetuses. Fetal mass was lower in IUGR vs. control fetuses but 92% greater in IUGR-AD compared to IUGR-Sham fetuses. Basal plasma glucose and arterial pO2 were lower in IUGR-Sham vs. Control-Sham, and IUGR-AD vs. Control-AD fetuses. Basal and glucose-stimulated insulin concentrations compared to Control-Sham were lower in IUGR-Sham and IUGR-AD and Control-AD fetuses. Oxygenation improved GSIS in IUGR-Sham and IUGR-AD fetuses. In conclusion, hypoglycemia, hypoxemia and norepinephrine interdependently and differentially regulate aspects of fetal growth and ss-cell function in the IUGR fetus.;In Min6 cells, we determined that GSIS responsiveness is enhanced and adrenergic receptor &agr;2A is desensitized cells following chronic exposure to epinephrine.