title: Chronic exposure to elevated norepinephrine suppresses insulin secretion in fetal sheep with placental insufficiency and intrauterine growth restriction.
abstract: In this study, we examined chronic norepinephrine suppression of insulin secretion in sheep fetuses with placental insufficiency-induced intrauterine growth restriction (IUGR). Glucose-stimulated insulin secretion (GSIS) was measured with a square-wave hyperglycemic clamp in the presence or absence of adrenergic receptor antagonists phentolamine (alpha) and propranolol (beta). IUGR fetuses were hypoglycemic and hypoxemic and had lower GSIS responsiveness (P < or = 0.05) than control fetuses. IUGR fetuses also had elevated plasma norepinephrine (3,264 +/- 614 vs. 570 +/- 86 pg/ml; P < or = 0.05) and epinephrine (164 +/- 32 vs. 60 +/- 12 pg/ml; P < or = 0.05) concentrations. In control fetuses, adrenergic inhibition increased baseline plasma insulin concentrations (1.7-fold, P < or = 0.05), whereas during hyperglycemia insulin was not different. A greater (P < or = 0.05) response to adrenergic inhibition was found in IUGR fetuses, and the average plasma insulin concentrations increased 4.9-fold at baseline and 7.1-fold with hyperglycemia. Unlike controls, basal plasma glucose concentrations fell (P < or = 0.05) with adrenergic antagonists. GSIS responsiveness, measured by the change in insulin, was higher (8.9-fold, P < or = 0.05) in IUGR fetuses with adrenergic inhibition than controls (1.8-fold, not significant), showing that norepinephrine suppresses insulin secretion in IUGR fetuses. Strikingly, in IUGR fetuses, adrenergic inhibition resulted in a greater GSIS responsiveness, because beta-cell mass was 56% lower and the maximal stimulatory insulin response tended (P < 0.1) to be higher than controls. This persistent norepinephrine suppression appears to be partially explained by higher mRNA concentrations of adrenergic receptors alpha(1D), alpha(2A), and alpha(2B) in a cohort of fetuses that were naïve to the antagonists. Therefore, norepinephrine suppression of insulin secretion was maintained, in part, by upregulating adrenergic receptor expression, but the beta-cells also appeared to compensate with enhanced GSIS. These findings may begin to explain why IUGR infants have a propensity for increased glucose requirements if norepinephrine is suddenly decreased after birth.
authors.affiliation: Dept. of Animal Sciences, Univ. of Arizona, Tucson, 85719, USA.
authors.forename: Rafael A
authors.initials: RA
authors.lastname: Leos
authors.forename: Miranda J
authors.initials: MJ
authors.lastname: Anderson
authors.forename: Xiaochuan
authors.initials: X
authors.lastname: Chen
authors.forename: Juliana
authors.initials: J
authors.lastname: Pugmire
authors.forename: K Arbor
authors.initials: KA
authors.lastname: Anderson
authors.forename: Sean W
authors.initials: SW
authors.lastname: Limesand
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D001774:Blood Chemical Analysis; D001835:Body Weight / Q000187:drug effects; D002395:Catecholamines / Q000378:metabolism; D002469:Cell Separation; D005260:Female; D005317:Fetal Growth Retardation / Q000378:metabolism* / Q000473:pathology; D005333:Fetus / Q000187:drug effects / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D007329:Insulin Antagonists; D007515:Islets of Langerhans / Q000473:pathology; D009638:Norepinephrine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D009929:Organ Size / Q000187:drug effects; D010179:Pancreas / Q000473:pathology; D010646:Phentolamine / Q000494:pharmacology; D010927:Placental Insufficiency / Q000378:metabolism* / Q000473:pathology; D011247:Pregnancy; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011941:Receptors, Adrenergic / Q000096:biosynthesis; D012756:Sheep
chemical_list: D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D002395:Catecholamines; D007328:Insulin; D007329:Insulin Antagonists; D012333:RNA, Messenger; D011941:Receptors, Adrenergic; D005947:Glucose; D009638:Norepinephrine; D010646:Phentolamine