Role of placental insufficiency and intrauterine growth restriction on the activation of fetal hepatic glucose production

Abstract

Glucose is the major fuel for fetal oxidative metabolism. A positive maternal-fetal glucose gradient drives glucose across the placenta and is sufficient to meet the demands of the fetus, eliminating the need for endogenous hepatic glucose production (HGP). However, fetuses with intrauterine growth restriction (IUGR) from pregnancies complicated by placental insufficiency have an early activation of HGP. Furthermore, this activated HGP is resistant to suppression by insulin. Here, we present the data demonstrating the activation of HGP in animal models, mostly fetal sheep, and human pregnancies with IUGR. We also discuss potential mechanisms and pathways that may produce and support HGP and hepatic insulin resistance in IUGR fetuses.

Keywords: Fetus; Glucose; IUGR; Insulin resistance; Liver.

Figure 1. Potential role of FOXO1 on metabolic pathways in the IUGR fetal liver

The IUGR fetal liver has increased nuclear FOXO1. (A) We speculate that hypoxia may induce nuclear P-FOXO1 accumulation via HIF and/or JNK signaling at sites which prevent (B) insulin mediated FOXO1 inactivation via AKT and nuclear exclusion. This leads to insulin resistance and increased hepatic glucose production (PCK1), decreased glucose oxidation (PDK4), increased glycolysis (PFK1), and increased lactate production (LDHA).

Figure 2. Pathways and substrates for hepatic glucose production in the IUGR fetus

Blue labels and arrows highlight the potential substrate flux when PCK1 is used for glucose production. Red indicates other metabolic changes in the IUGR liver. Carbon substrates used for HGP may include lactate and amino acids (Gln, Glu). Increased PDK4 inhibits PDH and, with increased PC, favors conversion of pyruvate to oxaloacetate (OAA). OAA is shuttle to the cytosol where PCK1 catalyzes the rate limiting step in gluconeogenesis and the resulting phosphoenolpyruvate (PEP) is used to synthesize glucose. Increased PCK2 also may catalyze the mitochondrial conversion of OAA to PEP. Additionally, increased LDHA produces lactate and regenerates NAD+ to sustain increased glycolysis via increased PFK1 and maintain redox balance.