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

J Physiol. 2017 Aug 1;595(15):5103-5113. doi: 10.1113/JP273324. Epub 2017 May 26.


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.

Publication types

  • Review
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Catecholamines / metabolism*
  • Female
  • Fetal Growth Retardation / metabolism
  • Fetus / metabolism*
  • Humans
  • Insulin / metabolism*
  • Insulin Secretion
  • Norepinephrine / metabolism
  • Placental Insufficiency / metabolism*
  • Pregnancy


  • Catecholamines
  • Insulin
  • Norepinephrine