title: Enhanced insulin secretion responsiveness and islet adrenergic desensitization after chronic norepinephrine suppression is discontinued in fetal sheep.
abstract: Intrauterine growth-restricted (IUGR) fetuses experience prolonged hypoxemia, hypoglycemia, and elevated norepinephrine (NE) concentrations, resulting in hypoinsulinemia and β-cell dysfunction. Previously, we showed that acute adrenergic blockade revealed enhanced insulin secretion responsiveness in the IUGR fetus. To determine whether chronic exposure to NE alone enhances β-cell responsiveness afterward, we continuously infused NE into fetal sheep for 7 days and, after terminating the infusion, evaluated glucose-stimulated insulin secretion (GSIS) and glucose-potentiated arginine-induced insulin secretion (GPAIS). During treatment, NE-infused fetuses had greater (P < 0.05) plasma NE concentrations and exhibited hyperglycemia (P < 0.01) and hypoinsulinemia (P < 0.01) compared with controls. GSIS during the NE infusion was also reduced (P < 0.05) compared with pretreatment values. GSIS and GPAIS were approximately fourfold greater (P < 0.01) in NE fetuses 3 h after the 7 days that NE infusion was discontinued compared with age-matched controls or pretreatment GSIS and GPAIS values of NE fetuses. In isolated pancreatic islets from NE fetuses, mRNA concentrations of adrenergic receptor isoforms (α1D, α2A, α2C, and β1), G protein subunit-αi-2, and uncoupling protein 2 were lower (P < 0.05) compared with controls, but β-cell regulatory genes were not different. Our findings indicate that chronic exposure to elevated NE persistently suppresses insulin secretion. After removal, NE fetuses demonstrated a compensatory enhancement in insulin secretion that was associated with adrenergic desensitization and greater stimulus-secretion coupling in pancreatic islets.
authors.affiliation: College of Animal Science and Technology, Southwest University, Chongqing, China; and.
authors.forename: Xiaochuan
authors.initials: X
authors.lastname: Chen
authors.forename: Alice S
authors.initials: AS
authors.lastname: Green
authors.forename: Antoni R
authors.initials: AR
authors.lastname: Macko
authors.forename: Dustin T
authors.initials: DT
authors.lastname: Yates
authors.forename: Amy C
authors.initials: AC
authors.lastname: Kelly
authors.forename: Sean W
authors.initials: SW
authors.lastname: Limesand
mesh_terms: D000818:Animals; D001120:Arginine / Q000494:pharmacology; D001786:Blood Glucose / Q000032:analysis; D005260:Female; D005312:Fetal Blood / Q000737:chemistry; D005317:Fetal Growth Retardation; D005333:Fetus / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000196:embryology* / Q000378:metabolism; D009638:Norepinephrine / Q000097:blood / Q000494:pharmacology*; D011247:Pregnancy; D011941:Receptors, Adrenergic / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D012756:Sheep / Q000196:embryology*
chemical_list: D001786:Blood Glucose; D007328:Insulin; D011941:Receptors, Adrenergic; D001120:Arginine; D005947:Glucose; D009638:Norepinephrine
keywords: adrenergic receptor; catecholamines; intrauterine growth restriction; uncoupling protein 2; β-cell