In this study we determined
body weight-specific fetal (umbilical)
glucose uptake (UGU), utilization (
GUR), and production rates (GPR) and
insulin action in intrauterine growth-restricted (IUGR) fetal sheep. During basal conditions, UGU from the placenta was 33% lower in IUGR fetuses, but
GUR was not different between IUGR and control fetuses. The difference between
glucose utilization and UGU rates in the IUGR fetuses demonstrated the presence and rate of fetal GPR (41% of
GUR). The
mRNA concentrations of the gluconeogenic
enzymes glucose-6-phophatase and PEPCK were higher in the livers of IUGR fetuses, perhaps in response to CREB activation, as phosphorylated CREB/total CREB was increased 4.2-fold. A hyperglycemic clamp resulted in similar rates of
glucose uptake and utilization in IUGR and control fetuses. The nearly identical GURs in IUGR and control fetuses at both basal and high
glucose concentrations occurred at mean plasma
insulin concentrations in the IUGR fetuses that were approximately 70% lower than controls, indicating increased
insulin sensitivity. Furthermore, under basal conditions,
hepatic glycogen content was similar, skeletal muscle
glycogen was increased 2.2-fold, the fraction of fetal
GUR that was oxidized was 32% lower, and GLUT1 and GLUT4 concentrations in liver and skeletal muscle were the same in IUGR fetuses compared with controls. These results indicate that
insulin-responsive fetal tissues (liver and skeletal muscle) adapt to the
hypoglycemic-hypoinsulinemic IUGR environment with mechanisms that promote
glucose utilization, particularly for
glucose storage, including increased
insulin action,
glucose production, shunting of
glucose utilization to
glycogen production, and maintenance of
glucose transporter concentrations.