Placental handling of glucose in the human - beyond the maternal-fetal glucose gradient

Glucose is the primary energy substrate for the human fetus, essential for brain development and overall growth. Traditionally, fetal glucose supply has been attributed to the maternal-fetal glucose gradient. However, emerging evidence indicates that the placenta plays an active role in regulating glucose availability through its own metabolic processes. This brief review aims to synthesize current knowledge on placental glucose handling in uncomplicated human pregnancies, emphasizing mechanisms beyond passive transfer and quantitative aspects. The placenta exhibits dynamic glucose metabolism, including consumption, storage, and endogenous production. Glycogen pools within placental cells are more likely endogenous sources of glucose than gluconeogenesis. Placental endogenous glucose may represent an auxiliary system that safeguards fetal glucose supply during maternal hypoglycemia and/or increased fetal demand. In vivo studies demonstrate that up to 70% of glucose released to the fetus can originate from placental sources at certain time points. Aerobic glycolysis (with lactate production) is a prominent feature of placental metabolism, with substantial lactate export to the maternal circulation. This energy loss is partly compensated for by uptake of maternal ketone bodies and acetate, highlighting the placenta's flexibility in substrate utilization. These adaptations underscore the placenta's dual role: maintaining its own structural and functional integrity while ensuring fetal oxygen and energy needs. Understanding these mechanisms is critical for defining the partition of energy between the placenta and fetus and its implications for fetal growth, particularly under conditions of maternal nutrient restriction. Insights into placental glucose metabolism may inform strategies for understanding and managing growth deviations and guide development of artificial placental systems.