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.

Chronic anemic hypoxemia increases plasma glucagon and hepatic PCK1 mRNA in late-gestation fetal sheep

“…Elevated fetal glucose concentrations in anemic fetuses were likely mediated by high fetal glucagon and cortisol concentrations. Even the slight, though not statistically significant, increase in mean fetal norepinephrine concentrations may have played a role (27,30,31). As the focus of the current study was on the factors that regulate fetal HGP, we did not determine the relative contribution of HGP and decreased fetal glucose utilization for the increase in fetal glucose concentrations.…”

Characterization of glucose-insulin responsiveness and impact of fetal number and sex difference on insulin response in the sheep fetus

“…Glucose and insulin concentrations were determined in samples representing the basal (euglycemia; Ϫ25 to 0 min) and hyperglycemic clamp (45-65 min) periods. Square-wave hyperglycemic clamp GSIS studies were conducted on 49 singleton (134 Ϯ 0.5 dGA) and 18 twin fetuses (132 Ϯ 0.8 dGA) from 10 ewes that were designated to be uncompromised control fetuses for previously published cohorts (25,26) and ongoing studies of fetal adaptations to nutritional insults. For the purposes of statistical analyses, data are expressed as means for the basal and hyperglycemic periods, and change in insulin and glucose during the clamp (hyperglycemicbasal) was calculated to indicate GSIS responsiveness.…”

“…Pancreas morphology data were collected from seven single and eight twin fetal sheep (from 4 ewes), a group of animals distinct from those used for the in vivo GSIS studies. These animals were also pooled from control, uncompromised animals from previously published (25,27,41) or recent unpublished studies that were designed to address different research questions. Ewes were euthanized with intravenous concentrated pentobarbital sodium (10 ml, Sleepaway; Fort Dodge Animal Health, Fort Dodge, IA).…”

Persistent hyperglycemia in a neonate: Is it a complication of therapeutic hypothermia?

“…O n e o f t h e m o s t c o m m o n c a u s e s o f hyperglycemia is increased circulating stressreactive hormones such as epinephrine and norepinephrine 7 . Circulating concentrations of epinephrine and norepinephrine also increase during infusion of dopamine and dobutamine by as much as two to six fold, either by enhanced endogenous secretion or reduced clearance (saturation of binding receptors) 8 .…”