Restriction of placental growth in sheep impairs insulin secretion but not sensitivity before birth

Abstract

Restricted growth before birth is associated with impaired insulin secretion but with initially enhanced insulin sensitivity in early postnatal life, which then progresses to insulin resistance and impaired glucose homeostasis by adulthood. This suggests that prenatal restraint impairs insulin secretion, but increases insulin sensitivity, before birth. Poor placental growth and function are major causes of restricted fetal growth in humans. We have therefore investigated the effects of restricted placental growth and function on plasma glucose, alpha-amino nitrogen and insulin concentrations and glucose- and arginine-stimulated insulin secretion in the fetal sheep at 120 and 140 days gestational age, and on insulin sensitivity, measured by hyperinsulinaemic euglycaemic clamp, at 130 days gestational age. Placental restriction decreased fetal blood pH and oxygen content, and weight in late gestation by approximately 20%. Reduced fetal and placental weights and indices of poor placental function, in particular fetal hypoxia and hypoglycaemia, were associated with impaired glucose- and arginine-stimulated insulin secretion, but not with changes in insulin sensitivity in the fetal sheep. We conclude that the impaired insulin secretion capacity reported in children and adults after intrauterine growth restriction, and in the neonatal and young adult sheep which is small at birth, is present in utero and persists. Whether this reflects the actions of the adverse intrauterine environment or changes to intrinsic capacity is unclear, but in utero interventions may be necessary to improve postnatal insulin secretion in the infant who is growth-restricted before birth.

Figure 1

Flow diagram for experiments on fetal sheep

Figure 2

Placental restriction and fetal arterial blood parameters Blood pH (A), (B) and oxygen content (C) in control (○) and PR fetuses (•). Data are presented as means ±s.e.m., and were calculated from measures made at two-day intervals for all animals with at least one in vivo experiment, excluding measures taken on hypoxic fetuses immediately prior to killing. Where blood parameters on a single animal were measured twice during the 2 days, data from the earlier time point were included in calculations.

Figure 3

Placental restriction and fetal plasma cortisol Fetal plasma cortisol concentrations in control (open bars) and PR fetuses (filled bars). Data are presented as means ±s.e.m. Plasma cortisol was calculated as the mean of concentrations in two pre-experiment plasma samples for each animal and age. Cortisol was measured in plasma collected prior to glucose tolerance tests at 121 days mean gestational age (n = 11 control, 6 PR fetuses), prior to glucose tolerance tests at 139 days mean gestational age (n = 10 control, 6 PR fetuses), and before the hyperinsulinaemic euglycaemic clamp at 130 days mean gestational age (n = 9 control, 5 PR fetuses).

Figure 4

Plasma glucose and insulin concentrations in control and PR fetuses during glucose secretion tests at 121 and 139 days gestational age

Figure 5

Plasma α-amino nitrogen, glucose and insulin in control and PR fetuses during arginine secretion tests at 122 and 140 days gestational age