Fetal adaptations in insulin secretion result from high catecholamines during placental insufficiency

Abstract

Placental insufficiency and intrauterine growth restriction (IUGR) of the fetus affects approximately 8% of all pregnancies and is associated with short- and long-term disturbances in metabolism. In pregnant sheep, experimental models with a small, defective placenta that restricts delivery of nutrients and oxygen to the fetus result in IUGR. Low blood oxygen concentrations increase fetal plasma catecholamine concentrations, which lower fetal insulin concentrations. All of these observations in sheep models with placental insufficiency are consistent with cases of human IUGR. We propose that sustained high catecholamine concentrations observed in the IUGR fetus produce developmental adaptations in pancreatic β-cells that impair fetal insulin secretion. Experimental evidence supporting this hypothesis shows that chronic elevation in circulating catecholamines in IUGR fetuses persistently inhibits insulin concentrations and secretion. Elevated catecholamines also allow for maintenance of a normal fetal basal metabolic rate despite low fetal insulin and glucose concentrations while suppressing fetal growth. Importantly, a compensatory augmentation in insulin secretion occurs following inhibition or cessation of catecholamine signalling in IUGR fetuses. This finding has been replicated in normally grown sheep fetuses following a 7-day noradrenaline (norepinephrine) infusion. Together, these programmed effects will potentially create an imbalance between insulin secretion and insulin-stimulated glucose utilization in the neonate which probably explains the transient hyperinsulinism and hypoglycaemia in some IUGR infants.

Keywords: developmental programming; epinephrine; intrauterine growth restriction; norepinephrine; β-cell.

Figure 1. Comparison of insulin secretion defects in sheep models of IUGR

Two sheep models of IUGR, placental insufficiency and maternal insulin infusion‐induced chronic hypoglycaemia, exhibit reduced glucose‐stimulated insulin secretion (GSIS) in vivo. Isolated islets from these treatments distinguish alternative defects that are responsible for the β‐cell dysfunction.

Figure 2. Adrenergic programming of insulin secretion in PI‐IUGR fetuses

The proposed actions and responses for placental insufficiency leading to decreased glucose‐stimulated insulin secretion (GSIS) are depicted. Experimental approaches used to disrupt the proposed actions of catecholamines are indicated along with the major conclusions for the induction of hyper‐responsiveness in insulin secretion.

Figure 3. Translation of adrenergic programming in IUGR infants

Normal placental transfer of oxygen and nutrients to the growing fetus is presented in black. Placental insufficiency, represented in red, reduces the delivery of oxygen and nutrients to the fetuses resulting in IUGR. Fetal hypoxaemia raises plasma catecholamine concentrations and subsequently lowers insulin secretion. The chronic elevation in plasma catecholamines causes β‐cell adaptations. Loss of the sustained adrenergic signalling following parturition exposes β‐cell hyper‐responsiveness, which is represented in green. It is hypothesized that hyperinsulinism and hypoglycaemia develop following delivery and stabilization of the neonate that experienced perinatal stress.