A physiological increase in insulin suppresses gluconeogenic gene activation in fetal sheep with sustained hypoglycemia

Thorn SR, Sekar SM, Lavezzi JR, O'Meara MC, Brown LD, Hay Jr, WW, Rozance PJ. A physiological increase in insulin suppresses gluconeogenic gene activation in fetal sheep with sustained hypoglycemia. Am J Physiol Regul Integr Comp Physiol 303: R861-R869, 2012. First published August 29, 2012; doi:10.1152/ajpregu.00331.2012.-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.