Insulin injection in the fetal rat: Accelerated intrauterine growth and altered fetal and neonatal glucose homeostasis

Abstract

Fetal hyperinsulinemia is a well-known correlate of accelerated fetal growth; the consequences of fetal hyperinsulinemia upon fetal and neonatal glucoregulation are less well understood. We injected rat fetuses of a litter on day 18 of gestation with either 5 units of long acting insulin (I) or 154 mmol/L NaCl. Twelve hours after injection, the wet and dry mass of total body and liver of I fetuses significantly exceeded that of controls. At birth (day 21.5), newborn I pups weighed 5.86 ± .08 g, and controls, 5.48 ± .05 g, ( P < .001). On day 18, within one hour of injection, fetal plasma insulin concentrations were significantly elevated and remained so for 24 hours. Mothers of I fetuses had significant elevations of plasma insulin at 1, 3, and 6 hours, and they developed transient hypoglycemia. Plasma glucose concentrations in I fetuses were significantly diminished at 1, 3, and 6 hours and then achieved control levels by 12 hours. Fetal hypoglycemia resulted from an apparent direct effect of insulin upon fetal tissue and from the maternal hypoglycemia. Hypoglycemic I fetuses demonstrated a sluggish α-cell response; they failed to increase plasma glucagon one hour after insulin injection. Values were significantly increased three hours after injection. At birth, I pups became hypoglycemic relative to controls. This was, in part, due to their significantly elevated plasma insulin concentrations at 120 and 240 minutes (120 minutes, 43.8 ± 8 v 17.5 ± 6 μU/mL, P < .001). Plasma glucagon was significantly increased in I pups at 240 minutes. During the neonatal period, pups who had undergone intrauterine insulin injection did not mobilize glycogen or induce hepatic cytosolic phosphoenolpyruvate carboxykinase to the same extent as controls. Insulin injection to the fetus accelerates growth and causes fetal hypoglycemia by decreasing maternal glucose and increasing fetal tissue uptake of glucose. The intriguing observation of sustained neonatal hyperinsulinemia remains unexplained.