The Role of Progesterone Membrane Receptors in the Development of Gestational Diabetes Mellitus; A Prospective Observational Case-Control Study

Gestational Diabetes Mellitus (GDM) is a medical condition characterized by glycemic intolerance that is detected at any time during pregnancy but was not present prior to it. It can lead to adverse health outcomes. Global data from 2021 indicate that 21.1 million live births involved women (aged 20-49) who experienced some form of diabetes during pregnancy (1). The fundamental mechanism underlying GDM pathophysiology is not yet fully understood; however, it generally results from pancreatic β-cell dysfunction arising from a state of chronic insulin resistance during pregnancy (2). Progesterone is a steroid that plays a central role in maintaining pregnancy; it suppresses uterine contractions and supports fetal immune tolerance (3). Progesterone exerts its effects not only through classical nuclear progesterone receptors but also via membrane-associated progesterone receptors (mPRs). These receptors include PGRMC1, PGRMC2, and the PAQR family (PAQR7, PAQR8, etc.) (4). Paula et al. demonstrated that the elimination of progesterone receptors in β-cells improved β-cell function and glucose tolerance in female mice during pregnancy and diet-induced insulin resistance (5). Furthermore, Picard et al. reported an improvement in glucose homeostasis-driven by β-cell proliferation-in progesterone receptor knockout mice (6). However, data regarding the expression levels of these receptors in the placentas of patients who develop gestational diabetes mellitus remain limited. In light of all this information, the scope of our study is to compare the expression levels of progesterone membrane receptors in placentas from pregnancies complicated by gestational diabetes mellitus and healthy pregnancies, and to determine the roles of these receptors in the pathophysiology of gestational diabetes mellitus.