Developmental regulation of key gluconeogenic molecules in nonhuman primates

Abstract

Aberrant glucose regulation is common in preterm and full-term neonates leading to short and long-term morbidity/mortality; however, glucose metabolism in this population is understudied. The aim of this study was to investigate developmental differences in hepatic gluconeogenic pathways in fetal/newborn baboons. Fifteen fetal baboons were delivered at 125 day (d) gestational age (GA), 140d GA, and 175d GA (term = 185d GA) via cesarean section and sacrificed at birth. Term and healthy adult baboons were used as controls. Protein content and gene expression of key hepatic gluconeogenic molecules were measured: cytosolic and mitochondrial phosphoenolpyruvate carboxykinase (PEPCK-C and PEPCK-M), glucose-6-phosphatase-alpha (G6Pase-α), G6Pase-β, fructose-1,6-bisphosphatase (FBPase), and forkhead box-O1 (FOXO1). Protein content of PEPCK-M increased with advancing gestation in fetal baboons (9.6 fold increase from 125d GA to 175d GA, P < 0.001). PEPCK-C gene expression was consistent with these developmental differences. Phosphorylation of FOXO1 was significantly lower in preterm fetal baboons compared to adults, and gene expression of FOXO1 was lower in all neonates when compared to adults (10% and 62% of adults respectively, P < 0.05). The FOXO1 target gene G6Pase expression was higher in preterm animals compared to term animals. No significant differences were found in G6Pase-α, G6Pase-β, FOXO1, and FBPase during fetal development. In conclusion, significant developmental differences are found in hepatic gluconeogenic molecules in fetal and neonatal baboons, which may impact the responses to insulin during the neonatal period. Further studies under insulin-stimulated conditions are required to understand the physiologic impact of these maturational differences.