The maintenance of the pH homeostasis is maintained by several mechanisms including the
efflux of protons (H+) via membrane transporters expressed in almost all mammalian cells. Along these
membrane transporters the sodium/H+ exchangers (NHEs), mainly NHE isoform 1 (NHE1), plays a key
role in this phenomenon. NHE1 is under modulation by several environmental conditions (e.g. hyperglycaemia,
protein kinase C activity) as well as hormones, including insulin. NHE1 activation causes
intracellular alkalization in human endothelial cells leading to activation of the endothelial Nitric Oxide
Synthase (eNOS) to generate NO. Intracellular alkalization is a phenomenon that also results in upregulation
of the glucose transporter GLUT4 in cells that are responsive to insulin. A reduction in the removal
of the extracellular D-glucose is seen in states of insulin resistance, such as in diabetes mellitus
and obesity. Since insulin is a potent activator of eNOS in human endothelium, therefore causing vasodilation,
and its vascular effect is reduced in insulin resistance it is likely that a defective signal to activate
NHE1 in insulin target cells is expected. This phenomenon results in lower redistribution and activation
of GLUT4 leading to reduced uptake of D-glucose and hyperglycaemia. The general concept of a
role for NHE1, and perhaps other NHEs isoforms, in insulin resistance in the human vasculature is proposed.
Keywords: pH, insulin resistance, insulin, endothelium, diabetes, human, glucose.
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