Abstract
Gestational diabetes mellitus (GDM) is a disease of the mother that associates with altered fetoplacental vascular function. GDM-associated maternal hyperglycaemia result in fetal hyperglycaemia, a condition that leads to fetal hyperinsulinemia and altered L-arginine transport and synthesis of nitric oxide, i.e., endothelial dysfunction. These alterations in the fetoplacental endothelial function are present in women with GDM that were under diet or insulin therapy. Since these women and their newborn show normal glycaemia at term, other factors or conditions could be altered and/or not resolved by restoring normal level of circulating D-glucose. GDM associates with metabolic disturbances, such as abnormal handling of the locally released vasodilator adenosine, and biosynthesis and metabolism of cholesterol lipoproteins, or metabolic diseases resulting in endoplasmic reticulum stress and altered angiogenesis. Insulin acts as a potent modulator of all these phenomena under normal conditions as reported in primary cultures of cells obtained from the human placenta; however, GDM and the role of insulin regarding these alterations in this disease are poorly understood. This review focuses on the potential link between insulin and endoplasmic reticulum stress, hypercholesterolemia, and angiogenesis in GDM in the human fetoplacental vasculature. Based in reports in primary culture placental endothelium we propose that insulin is a factor restoring endothelial function in GDM by reversing ERS, hypercholesterolaemia and angiogenesis to a physiological state involving insulin activation of insulin receptor isoforms and adenosine receptors and metabolism in the human placenta from GDM pregnancies.
Highlights
A large number of pregnant women are diagnosed with gestational diabetes mellitus (GDM), a disease that appears in pregnancy, courses with maternal hyperglycaemia and leads to fetal hyperglycaemia and hyperinsulinemia [American Diabetes Association (ADA), 2015]
It is reported that insulin via activation of insulin receptors forms A (IR-A) and/or IR-B modulates the expression and activity of hCAT isoform 1 (hCAT-1), endothelial NO synthase (eNOS), human equilibrative nucleoside transporter 1 (hENT1), and hENT2 in human umbilical vein endothelial cells (HUVECs) and human placental microvascular endothelial cells (hPMECs) (Table 1). These findings show that insulin modulates L-arginine and adenosine transport reversing the Gestational diabetes mellitus (GDM)-associated alterations in these mechanisms to values in human fetoplacental endothelium from normal pregnancies
Altered vascular function in GDM pregnancies is a critical condition leading to severe dysfunction of the human placenta and altered delivery of nutrients and signaling molecules from mother-to-fetus and vice-versa (Desoye et al, 2011; Leach, 2011; Herrera and Desoye, 2015; Sobrevia et al, 2015)
Summary
A large number of pregnant women are diagnosed with gestational diabetes mellitus (GDM), a disease that appears in pregnancy, courses with maternal hyperglycaemia and leads to fetal hyperglycaemia and hyperinsulinemia [American Diabetes Association (ADA), 2015]. Nothing is reported addressing the possibility of a potential differential expression and/or cell signaling of ARs accounting for these effects in the fetoplacental endothelium from normal pregnancies, or in mothers with GDM [Verier-Mine, 2010; American Diabetes Association (ADA), 2015; Sobrevia et al, 2015].
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