Adrenal Demedullation and Oxygen Supplementation Independently Increase Glucose-Stimulated Insulin Concentrations in Fetal Sheep With Intrauterine Growth Restriction

Authors

Antoni R. Macko, The University of Arizona
Dustin T. Yates, University of Nebraska Lincoln & The University of ArizonaFollow
Xiaochuan Chen, The University of Arizona
Leslie A. Shelton, The University of Arizona
Amy C. Kelly, The University of Arizona
Melissa A. Davis, The University of ArizonaFollow
Leticia E. Camacho, The University of Arizona
Miranda J. Anderson, The University of Arizona
Sean W. Limesand, The University of ArizonaFollow

Document Type

Article

Date of this Version

3-3-2016

Citation

2016 by the Endocrine Society

Comments

doi: 10.1210/en.2015-1850

Abstract

In pregnancies complicated by placental insufficiency and intrauterine growth restriction (IUGR), fetal glucose and oxygen concentrations are reduced, whereas plasma norepinephrine and epinephrine concentrations are elevated throughout the final third of gestation. Here we study the effects of chronic hypoxemia and hypercatecholaminemia on β-cell function in fetal sheep with placental insufficiency-induced IUGR that is produced by maternal hyperthermia. IUGR and control fetuses underwent a sham (intact) or bilateral adrenal demedullation (AD) surgical procedure at 0.65 gestation. As expected, AD-IUGR fetuses had lower norepinephrine concentrations than intact-IUGR fetuses despite being hypoxemic and hypoglycemic. Placental insufficiency reduced fetal weights, but the severity of IUGR was less with AD. Although 2 basal plasma insulin concentrations were lower in intact-IUGR and AD-IUGR fetuses compared with intact-controls, glucose-stimulated insulin concentrations were greater in AD-IUGR fetuses compared with intact-IUGR fetuses. Interestingly, AD-controls had lower glucose- and arginine-stimulated insulin concentrations than intact-controls, but AD-IUGR and AD-control insulin responses were not different. To investigate chronic hypoxemia in the IUGR fetus, arterial oxygen tension was increased to normal levels by increasing the maternal inspired oxygen fraction. Oxygenation of IUGR fetuses enhanced glucose-stimulated insulin concentrations 3.3-fold in intact-IUGR and 1.7-fold in AD-IUGR fetuses but did not lower norepinephrine and epinephrine concentrations. Together these findings show that chronic hypoxemia and hypercatecholaminemia have distinct but complementary roles in the suppression of β-cell responsiveness in IUGR fetuses. Placental insufficiency restricts the supply of oxygen and nutrients to the fetus and causes intrauterine growth restriction (IUGR) (1, 2). The resulting fetal hypoxemia and hypoglycemia provoke endocrine responses that lower plasma insulin concentrations (3,–5). High norepinephrine and epinephrine concentrations are a hallmark of both human and animal IUGR fetuses (6,–11). These high concentrations of catecholamines inhibit insulin secretion from pancreatic β-cells and may contribute to very low insulin concentrations in the IUGR fetus (12, 13). In addition, chronic elevation of norepinephrine has been shown to slow fetal growth and induce asymmetric growth of fetal tissues (14, 15).