Reduced maternal
glucose supply to the fetus and resulting fetal
hypoglycemia and hypoinsulinemia activate fetal
glucose production as a means to maintain cellular
glucose uptake. However, this early activation of fetal
glucose production may be accompanied by hepatic
insulin resistance. We tested the capacity of a physiological increase in
insulin to suppress fetal hepatic gluconeogenic gene activation following sustained
hypoglycemia to determine whether hepatic
insulin sensitivity is maintained. Control fetuses (CON),
hypoglycemic fetuses induced by maternal
insulin infusion for 8 wk (HG), and 8 wk HG fetuses that received an isoglycemic
insulin infusion for the final 7 days (HG+INS) were studied.
Glucose and
insulin concentrations were 60% lower in HG compared with CON fetuses.
Insulin was 50% higher in HG+INS compared with CON and four-fold higher compared with HG fetuses. Expression of the hepatic gluconeogenic genes, PCK1, G6PC, FBP1, GLUT2, and PGC1A was increased in the HG and reduced in the HG+INS liver. Expression of the
insulin-regulated glycolytic and lipogenic genes, PFKL and FAS, was increased in the HG+INS liver. Total
FOXO1 protein expression, a gluconeogenic activator, was 60% higher in the HG liver. Despite low
glucose,
insulin, and IGF1 concentrations, phosphorylation of AKT and ERK was higher in the HG liver. Thus, a physiological increase in fetal
insulin is sufficient for suppression of gluconeogenic genes and activation of glycolytic and lipogenic genes in the HG fetal liver. These results demonstrate that fetuses exposed to sustained
hypoglycemia have maintained hepatic
insulin action in contrast to fetuses exposed to
placental insufficiency.