Adrenergic modulation of pancreatic hormone secretion in utero: Studies in fetal sheep

To assess the functional maturity of adrenergic modulation of plasma concentration of glucose, as well as immunoreactive glucagon (IRG) and immunoreactive insulin (IRI) secretion in utero, adrenergic agonists with or without β (propranolol) or α (phentolamine) antagonists were infused to the chronically catheterized sheep fetus (n=35) late in the third trimester. Mean ± S.E. days at study was 129.5 ± 1.5; term is 150 days. In 9 separate studies at gestational age 129 ± 1 days, the infusion of saline for 3 hr was not associated with significant changes in the basal levels of glucose, IRG, or IRI. With epinephrine, 6 μg/min (n=6) glucose rose from 16.7 ± 3.6 to 41.9 ± 9.7 mg/dl, IRG rose from 75 ± 8 to 219 ± 45 pg/ml, and IRI fell from 22.6 ± 1.7 to 12.7 ± 3.5 microunits/ml (P<0.05 for each). Propranolol alone (n=4) did not alter basal glucose or IRG but significantly suppressed IRI. Propranolol did, however, markedly attentuate the rise in glucose and IRG while exaggerating the fall in IRI during epinephrine infusion. Qualitatively similar but smaller responses were obtained with epinephrine, 0.4 μg/min (n=10). Similarly, elevation of glucose and suppression of IRI was obtained with norepinephrine, 2 μ/min (n=5), but IRG levels did not rise significantly. α-Adrenergic blockade alone augmented IRI from 18 ± 3 to 38 ± 5 microunits/ml without affecting glucose or IRG concentrations; during α blockade, norepinephrine infusion failed to induce the rise in glucose, IRG remained unchanged, and IRI remained elevated (n=5). 2-Deoxy-D-glucose, 200 mg IV over 30 min, did not affect glucose, IRG, or IRI (n=5). Thus, appropriate adrenergic modulation of plasma concentrations of glucose, and of IRG and IRI secretion is established in the third trimester. Many of the metabolic adaptations that characterize the transition from intrauterine to extrauterine energy homeostasis are suggestive of a catecholamine effect. These changes include a surge in plasma immunoreactive glucagon concentrations, low immunoreactive insulin levels, an initial fall followed by stabilization of blood glucose, and a rapid rise in free fatty acid levels. An abrupt but brief increase in arterial plasma concentrations of epinephrine and norepinephrine also occurs at births. In the present studies, infusion of epinephrine in utero simulated those changes that usually occur after birth, thereby suggesting that catecholamines are a major trigger for neonatal energy adaptations that involve insulin and glucagon secretion.