Insulin therapy and fetoplacental vascular function in gestational diabetes mellitus

Abstract

New Findings r What is the topic of this review?This review focuses on the effects of insulin therapy on fetoplacental vasculature in gestational diabetes mellitus and the potentiating effects of adenosine on this therapy. r What advances does it highlight?This review highlights recent studies exploring a potential functional link between insulin receptors and their dependence on adenosine receptor activation (insulin-adenosine axis) to restore placental endothelial function in gestational diabetes mellitus.Gestational diabetes mellitus (GDM) is a disease that occurs during pregnancy and is associated with maternal and fetal hyperglycaemia. Women with GDM are treated via diet to control their glycaemia; however, a proportion of these patients do not achieve the recommended values of glycaemia and are subjected to insulin therapy until delivery. Even if a diet-treated GDM pregnancy leads to normal maternal and newborn glucose levels, fetoplacental vascular dysfunction remains evident. Thus, control of glycaemia via diet does not prevent GDM-associated fetoplacental vascular and metabolic alterations. We review the available information regarding insulin therapy in the context of its potential consequences for fetoplacental vascular function in GDM. We propose the possibility that insulin therapy to produce normoglycaemia in the mother and newborn may require additional therapeutic measures to restore the normal metabolic condition of the vascular network in GDM. A role for A 1 and A 2A adenosine receptors and insulin receptors A and B as well as a potential functional link in the cell signalling associated with the activation of these receptors is proposed. This possibility could be helpful for the planning of strategies, including adenosine receptor-improved insulin therapy, for the treatment of GDM patients, thereby promoting the wellbeing of the growing fetus, newborn and mother.

Intracellular acidification increases adenosine transport in human umbilical vein endothelial cells

“…2A). Incubation with 1 mmol/L NH 4 Cl increased hENT1-and hENT2-adenosine transport; however, the increase in hENT1-was higher than hENT2-mediated transport. Incubation of 175 cells with 5HT unaltered adenosine uptake.…”

“…1A) was lower in cells exposed to NH 4 Cl in a concentration-dependent manner, without altering the cell survival (Fig. 1B).…”

“…1B). NH 4 Cl increased the pHi value ( Fig. 1C), and NH 4 Cl removal caused rapid acidification (~1 second) recovering 155 to initial pHi value in ~7 minutes.…”

“…This phenomenon results from activation of adenosine receptors due to the extracellular accumulation of this nucleoside arising from a reduced uptake by the foetoplacental endothelium [8,10,11]. Thus, a proper function of membrane 65 transport mechanisms modulating the extracellular concentration of adenosine is critical to mantaining the physiological cell metabolism in this vascular bed [4,[8][9][10] as in other tissues [5,6].…”

“…These phenomena include the sodium (Na + )/H + exchanger 1 (NHE1) as the primary regulator of the pHi/pHo ratio. Uptake of metabolic substrates happens via different membrane transport systems in adult and foetoplacental endothelium [4,5]. Some of these transport systems depend on the pHo, such as those mediating adenosine and 5-hydroxytryptamine (5HT) [6].…”