Enhanced insulin secretion and insulin sensitivity in young lambs with placental insufficiency-induced intrauterine growth restriction

Abstract

Intrauterine growth restriction (IUGR) is associated with persistent metabolic complications, but information is limited for IUGR infants. We determined glucose-stimulated insulin secretion (GSIS) and insulin sensitivity in young lambs with placental insufficiency-induced IUGR. Lambs with hyperthermia-induced IUGR (n = 7) were compared with control lambs (n = 8). GSIS was measured at 8 ± 1 days of age, and at 15 ± 1 days, body weight-specific glucose utilization rates were measured with radiolabeled D-glucose during a hyperinsulinemic-euglycemic clamp (HEC). IUGR lambs weighed 23% less (P < 0.05) than controls at birth. Fasting plasma glucose and insulin concentrations were not different between IUGR and controls for either study. First-phase insulin secretion was enhanced 2.3-fold in IUGR lambs compared with controls. However, second-phase insulin concentrations, glucose- potentiated arginine-stimulated insulin secretion, and β-cell mass were not different, indicating that IUGR β-cells have an intrinsic enhancement in acute GSIS. Compared with controls, IUGR lambs had higher body weight-specific glucose utilization rates and greater insulin sensitivity at fasting (1.6-fold) and hyperinsulinemic periods (2.4-fold). Improved insulin sensitivity for glucose utilization was not due to differences in skeletal muscle insulin receptor and glucose transporters 1 and 4 concentrations. Plasma lactate concentrations during HEC were elevated in IUGR lambs compared with controls, but no differences were found for glycogen content or citrate synthase activity in liver and muscle. Greater insulin sensitivity for glucose utilization and enhanced acute GSIS in young lambs are predicted from fetal studies but may promote conditions that exaggerate glucose disposal and lead to episodes of hypoglycemia in IUGR infants.