Perinatal Programming of Pancreatic Islets during Intrauterine Growth Restriction

Placental insufficiency and intrauterine growth restriction (IUGR) of the fetus is associated with short- and long-term disturbances in metabolism. In pregnant sheep, exposure to elevated ambient temperatures results in a small, defective placenta that restricts delivery of nutrients and oxygen to the fetus, resulting in IUGR. Fetal hypoxemia caused by placental insufficiency increases plasma catecholamine concentrations. We propose that the chronic elevation of catecholamines observed in the IUGR fetus produces developmental adaptations in pancreatic β-cells that impair β-cell proliferation and insulin secretion. Experimental evidence supporting this hypothesis shows that sustained high catecholamines in IUGR fetuses persistently inhibit insulin concentrations. However, a compensatory enhancement in insulin secretion responsiveness occurs following inhibition or cessation of adrenergic stimulation in IUGR fetuses. This finding has been replicated in normally grown sheep fetuses following a seven-day norepinephrine infusion. Together, these developmental adaptations will result in an imbalance between insulin secretion and insulin action in the lamb which suggests additional insults that impact the maturation of β-cell function.