Insulin Is a Key Modulator of Fetoplacental Endothelium Metabolic Disturbances in Gestational Diabetes Mellitus

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.

Low molecular weight heparin (nadroparin) improves placental permeability in rats with gestational diabetes mellitus via reduction of tight junction factors

“…TJs have been reported to be present in both trophoblast cells and in fetal vessel epithelium (5). Previous studies have suggested that placental dysfunction in patients with GdM is caused by hyperglycemia (6,7). in addition, other studies have identified that insulin therapy does not improve fetal or newborn metabolic outcomes (8), and that it can cause alterations in the placenta (9), indicating factors other than glucose may be involved in the pathophysiology of GdM.…”

Pro-angiogenic Role of Insulin: From Physiology to Pathology

“…For instance, insulin induces vasorelaxation, enhances endothelial uptake of amino acids (such as L-arginine) and increases survival and migration of endothelial cells (Dubó et al, 2016; Sobrevia et al, 2016). These actions, combined with the capacity of insulin to enhance expression of pro-angiogenic factors such as vascular endothelial growth factor (VEGF), as well as increase pericytes survival and reduce anti-angiogenic protein expression, have established the role of insulin in physiological and pathological angiogenesis (He et al, 2006).…”

Pharmacological targeting of adenosine receptor signaling

“…For example, as nicely reviewed by Eisenstein et al (Eisenstein et al, 2015) there are many opposing findings regarding the role of A 2B AR in metabolic pathologies since this receptor simultaneously and differently affects acute and chronic inflammation (macrophages), adipogenesis (adipose tissue), insulin release (pancreas) and gluconeogenesis as well as glycogenolysis (liver). Additionally, A 2A AR receptors seem essential in developing or maintaining endothelial dysfunction in the fetoplacental vasculature in diseases of pregnancy such as gestational diabetes mellitus or preeclampsia Sobrevia et al, 2016). However, the A 1 AR is required for the effect of insulin correcting the gestational diabetes mellitus-enhanced L-arginine transport in this vascular bed (Guzman-Gutierrez et al, 2016).…”