Placental Hormones and O-GlcNAcylation in Gestational Diabetes

PROJECT SUMMARY/ ABSTRACT Every year, about 18 million babies are born from mothers with gestational diabetes mellitus (GDM). While diabetic symptoms usually resolve after delivery, lasting complications can occur for both mother and child, including fetal overgrowth, type 2 diabetes (T2D), cardiovascular diseases, and obesity. While pathologically similar to type 2 diabetes, the rapidity of progression of GDM is unique to pregnancy, and likely arises from placental dysfunction. Increased blood glucose availability in a healthy pregnancy is vital for proper fetal development. A surge of placental hormones initiates a state of mild insulin resistance, which, combined with beta-cell dysfunction, likely causes GDM. Currently, effective treatments for GDM are limited or unsafe. Thus, an in-depth understanding of the pathophysiology of GDM becomes essential to prevent GDM and design innovative, non-toxic, and highly effective GDM treatments. Our research program aims to investigate GDM development by studying for the first time the role of nutrient-dependent O-GlcNAcylation on placental endocrine function. Directly dependent on plasma glucose levels, intracellular O-GlcNAcylation is a common dynamic post-translational modification that impacts numerous signaling pathways and diseases. Based on literature and preliminary data, we gathered that O-GlcNAcylation affects classical hormonal secretion (in non-pregnant animals), is critical for placental physiology, and impairs insulin signaling. Thus, we hypothesize that O-GlcNAcylation-dependent hormonal changes partly drive GDM. First, we will define the involvement of O-GlcNAcylated protein in physiological placenta endocrine secretion and, second, assess whether O-GlcNAc deregulations lead to GDM. We hope to propose novel molecular targets and signaling pathways involved in placental physiology and disease and advance the prevention and treatment of pregnancy metabolic diseases.