Increased hepatic glucose production with lower oxidative metabolism in the growth-restricted fetus.

Fetuses with growth restriction (FGR) have an early activation of hepatic glucose production (HGP), a hallmark of type 2 diabetes (T2D). Here we used fetal hepatic catheterization to directly measure HGP and substrate flux in an FGR sheep model. We hypothesized that FGR fetuses would have increased hepatic lactate and amino acid uptake to support increased HGP. Indeed, FGR compared to normal (CON) fetuses had increased HGP and activation of gluconeogenic genes. Unexpectedly, hepatic pyruvate output was increased while hepatic lactate and gluconeogenic amino acid uptake rates were decreased in FGR fetal liver. Hepatic oxygen consumption and total substrate uptake rates were lower. In FGR liver tissue, metabolite abundance, 13C-metabolite labeling, enzyme activity, and gene expression support decreased pyruvate oxidation and increased lactate production. Isolated hepatocytes from FGR fetuses had greater intrinsic capacity for lactate-fueled glucose production. FGR livers also had lower energy (ATP) and redox state (NADH:NAD+). Thus, reduced hepatic oxidative metabolism may make carbons available for increased HGP but also produces nutrient and energetic stress in FGR fetal liver. Intrinsic programming of these pathways regulating HGP in the FGR fetus may underlie increased HGP and T2D risk postnatally.