Involvement of Intracellular pH in Vascular Insulin Resistance

Abstract

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 (v.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.

Towards an Integral Therapeutic Protocol for Breast Cancer Based upon the New H+-Centered Anticancer Paradigm of the Late Post-Warburg Era

“…High glucose loads, with or without insulin, also stimulate Na + /H + activity, cell cycle progression and the activation of oncogene expression [ 144 ]. These effects are associated with BC carcinogenicity and progression [ 11 ], justifying the fact that hyperinsulinemia and obesity are protumoral factors that increase the incidence of BC [ 145 , 146 , 147 ]. On the contrary, antidiabetic drugs of the sulfonylurea family, known to stimulate the pancreatic secretion of INS, appear to have a negative impact on BC growth, also increasing BC risk [ 148 , 149 , 150 ].…”

“…On the contrary, antidiabetic drugs of the sulfonylurea family, known to stimulate the pancreatic secretion of INS, appear to have a negative impact on BC growth, also increasing BC risk [ 148 , 149 , 150 ]. Furthermore, the overexpression of insulin and/or the insulin growth factor 1 gene are associated with a decrease in the length of the life of women with BC, while their suppression increases life span and decreases tumorigenesis [ 28 , 103 , 142 , 143 , 145 , 146 , 147 , 151 , 152 , 153 , 154 , 155 , 156 , 157 ]. Hyperinsulinemia has also been considered an important factor in a wide array of human malignancies, while insulin inhibition has been proposed to decrease their growth [ 158 , 159 ].…”

A New and Integral Approach to the Etiopathogenesis and Treatment of Breast Cancer based upon its Hydrogen Ion Dynamics

“…INS presents a direct effect in raising pHi, which is probably related to its known tumor-stimulating properties [130]. This is reasonable since hyperinsulinemia and obesity have been associated with an increased incidence of BC [125,126] ( shown that insulin resistance might be a secondary effect of an abnormal NHE-1 signaling pathway [128] (Table 1).…”

Towards An Integral Therapeutic Protocol for Breast Cancer based upon the New H+-Centered Anticancer Paradigm of the Late Post-Warburg Era

“…High glucose loads, with or without insulin, also stimulate Na + /H + activity, cell cycle progression and activation of oncogene expression [133]. These effects are associated with BC carcinogenicity and progression [10], justifying the fact that hyperinsulinemia and obesity are protumoral factors that increase the incidence of BC [134][135][136]. On the contrary, antidiabetic drugs of the sulfonylurea family, known to stimulate the pancreatic secretion of INS, appear to have a negative impact on BC growth, also increasing BC risk [137][138][139].…”

“…On the contrary, antidiabetic drugs of the sulfonylurea family, known to stimulate the pancreatic secretion of INS, appear to have a negative impact on BC growth, also increasing BC risk [137][138][139]. Furthermore, the overexpression of INS and/or the IGF-1 gene are associated with a decrease in the length of life of women with BC, while their suppression increases life span and decreases tumorigenesis [27,91,131,132,[134][135][136][140][141][142][143][144][145][146]. Hyperinsulinemia has also been considered an important factor in a wide array of human malignancies, while insulin inhibition has been proposed to decrease their growth [147,148].…”