Effects of maternal diabetes on trophoblast cells

Abstract

Diabetes mellitus (DM) is a health condition characterized by hyperglycemia over a prolonged period. There are three main types of DM: DM type 1 (DM1), DM2 and gestational DM (GDM). Maternal diabetes, which includes the occurrence of DM1 and DM2 during pregnancy or GDM, increases the occurrence of gesttional complications and adverse fetal outcomes. The hyperglycemic intrauterine environment affects not only the fetus but also the placental development and function in humans and experimental rodents. The underlying mechanisms are still unclear, but some evidence indicates alterations in trophoblast proliferation, apoptosis and cell cycle control in diabetes. A proper coordination of trophoblast proliferation, differentiation and invasion is required for placental development. Initially, increased expression of proliferative markers in junctional and labyrinth zones of rat placentas and villous cytotrophoblast, syncytiotrophoblast, stromal cells and fetal endothelial cells in human placentas is reported among diabetics. Moreover, reduced apoptotic index and expression of some apoptotic genes are described in placentas of GDM women. In addition, cell cycle regulators including cyclins and cyclin-dependent kinase inhibitors seem to be affected by the hyperglycemic environment. More studies are necessary to check the balance between proliferation, apoptosis and differentiation in trophoblast cells during maternal diabetes.

Keywords: Apoptosis; Diabetes; Differentiation; Placenta; Proliferation; Trophoblast.

Figure 1

Schematic representation of eukaryotic cell cycle and key regulatory proteins which allow the transition from one cell cycle phase to another. CDKs inhibitors, such as p15, p16, p18, p19 (INK4 group), p21, p27 and p57 (CIP/KIP class) and proliferative markers are also showed. The arrows in red indicate increased or decreased expression of some trophoblast key regulatory proteins, CDKs inhibitors and proliferative markers in maternal diabetes. G1: Gap 1 phase; S: synthesis phase; G2: Gap 2 phase; M: Mitosis; CDKs: Cyclin-dependent kinases; PCNA: Proliferating cell nuclear antigen; p53: Tumor protein p53.

Figure 2

Schematic representation of trophoblast apoptosis findings in maternal diabetes. Reduced expression of apoptotic components from both intrinsic and extrinsic pathways, caspase-3 and poly (ADP-ribose) polymerase (PARP) are reported by some works. FasR: Fas receptor; FasL: Fas ligand; MCL1: Myeloid cell leukemia 1; BCL2: B-cell lymphoma 2; BCL2L1: BCL2-like 1; XIAP: X-linked inhibitor of apoptosis; BCL2L2: BCL2-like 2.