KL 16 Abnormal glucose signaling in trophoblast biology

Abstract

Human trophoblast shows a peculiar carbohydrate metabolism during pregnancy with adaptive responses to systemic alterations that may occur during gestation. In fact, cells may adapt their metabolism to environmental changes driven by inflammatory cytokines, available nutrients and oxygen tension. An interesting adaptation of intracellular signaling occur in human trophoblast under healthy conditions throughout the pregnancy and in case of superimposed complications that alter the surrounding milieu. These modifications are not only passive responses but they may be considered as an active interaction and may be transferred to the mother through specific mediators as an attempt to modulate the maternal systemic reaction. In early gestation, trophoblast invades the endometrium (implantation) and gland secretions represent the initial form of nutrition for the conceptus (histiotrophic nutrition) prior to the complete development of the placenta. An alternative carbohydrate metabolism takes place in this setting that is characterized by low-oxygen tension, lipid and glycolipid secretion that represent the available nutrients, and high concentration of regulatory cytokines due to the immune system activation (fetal-placental interface). Inositol second messengers mediate this metabolic process of glucose non-oxidative use and storage and lipogenesis. Inositol phosphatides were shown to interact with leucocytes at membrane and intracellular level with a sort of reciprocal benefit during those weeks of rapid changes. Inositol phosphoglycans start to leak into maternal circulation to modulate physiological insulin resistance that occurs during healthy pregnancy. When an excessive systemic inflammation occurs like in preeclampsia, the fetal/placental unit pour out large amounts of D-chiro inositol mediators (IPG-P) into maternal circulation being favored by a more permissive placental membrane that show thinner glycocalyx and less tight junctions. These mediators were also shown to play a role in endothelial dysfunction, predisposition to seizures (eclampsia), and cardiovascular disease later in life.