title: Increased adrenergic signaling is responsible for decreased glucose-stimulated insulin secretion in the chronically hyperinsulinemic ovine fetus.
abstract: Insulin may stimulate its own insulin secretion and is a potent growth factor for the pancreatic β-cell. Complications of pregnancy, such as diabetes and intrauterine growth restriction, are associated with changes in fetal insulin concentrations, secretion, and β-cell mass. However, glucose concentrations are also abnormal in these conditions. The direct effect of chronic fetal hyperinsulinemia with euglycemia on fetal insulin secretion and β-cell mass has not been tested. We hypothesized that chronic fetal hyperinsulinemia with euglycemia would increase glucose-stimulated insulin secretion (GSIS) and β-cell mass in the ovine fetus. Singleton ovine fetuses were infused with iv insulin to produce high physiological insulin concentrations, or saline for 7-10 days. The hyperinsulinemic animals also received a direct glucose infusion to maintain euglycemia. GSIS, measured at 133 ± 1 days of gestation, was significantly attenuated in the hyperinsulinemic fetuses (P < .05). There was no change in β-cell mass. The hyperinsulinemic fetuses also had decreased oxygen (P < .05) and higher norepinephrine (1160 ± 438 vs 522 ± 106 pg/mL; P < .005). Acute pharmacologic adrenergic blockade restored GSIS in the hyperinsulinemic-euglycemic fetuses, demonstrating that increased adrenergic signaling mediates decreased GSIS in these fetuses.
authors.affiliation: Department of Obstetrics and Gynecology (S.E.A.), University of Colorado School of Medicine, Aurora, Colorado 80045; Perinatal Research Center (L.D.B., S.R.T., W.W.H., P.J.R.), Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado 80045; Center for Women's Health Research (L.D.B., P.J.R.), University of Colorado School of Medicine, Aurora, Colorado 80045; and School of Animal and Comparative Biomedical Sciences (S.W.L., M.D.), University of Arizona, Tucson, Arizona 85719.
authors.forename: Sasha E
authors.initials: SE
authors.lastname: Andrews
authors.forename: Laura D
authors.initials: LD
authors.lastname: Brown
authors.forename: Stephanie R
authors.initials: SR
authors.lastname: Thorn
authors.forename: Sean W
authors.initials: SW
authors.lastname: Limesand
authors.forename: Melissa
authors.initials: M
authors.lastname: Davis
authors.forename: William W
authors.initials: WW
authors.lastname: Hay
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Rozance
mesh_terms: D000818:Animals; D005260:Female; D005947:Glucose / Q000008:administration & dosage / Q000494:pharmacology*; D006946:Hyperinsulinism / Q000097:blood*; D007328:Insulin / Q000378:metabolism*; D008431:Maternal-Fetal Exchange; D010179:Pancreas / Q000166:cytology / Q000196:embryology; D011247:Pregnancy; D012756:Sheep / Q000196:embryology*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D007328:Insulin; D005947:Glucose