AGEs-Induced and Endoplasmic Reticulum Stress/Inflammation-Mediated Regulation of GLUT4 Expression and Atherogenesis in Diabetes Mellitus.

Marisa Passarelli,Ubiratan Fabres Fabres Machado

doi:10.3390/cells11010104

Abstract

In recent decades, complex and exquisite pathways involved in the endoplasmic reticulum (ER) and inflammatory stress responses have been demonstrated to participate in the development and progression of numerous diseases, among them diabetes mellitus (DM). In those pathways, several players participate in both, reflecting a complicated interplay between ER and inflammatory stress. In DM, ER and inflammatory stress are involved in both the pathogenesis of the loss of glycemic control and the development of degenerative complications. Furthermore, hyperglycemia increases the generation of advanced glycation end products (AGEs), which in turn refeed ER and inflammatory stress, contributing to worsening glycemic homeostasis and to accelerating the development of DM complications. In this review, we present the current knowledge regarding AGEs-induced and ER/inflammation-mediated regulation of the expression of GLUT4 (solute carrier family 2, facilitated glucose transporter member 4), as a marker of glycemic homeostasis and of cardiovascular disease (CVD) development/progression, as a leading cause of morbidity and mortality in DM.

Highlights

Diabetes mellitus (DM) is a global public health burden, as the number of affected adults is expected to rise to 630 million by 2045 [1]
DM is a metabolic disorder characterized by inappropriate hyperglycemia and can be classified into type 1 DM (T1D), which primarily results from the lack of insulin secretion, and type 2 DM (T2D), which primarily results from insulin resistance (IR) [2]
Considering that advanced glycation end products (AGEs) can participate in both the impairment of glycemic homeostasis and the development/progression of chronic complications of DM, and considering that these effects involve endoplasmic reticulum (ER) stress- and inflammatory-mediated pathways, the present manuscript reviews these regulations upon the expression of solute carrier family 2, facilitated glucose transporter member 4 (GLUT4) expression, as a marker of altered glycemic homeostasis [11,12,13] and, upon atherogenesis, as an important inducer of the development/progression of cardiovascular disease (CVD) [7]

Summary

Introduction

Diabetes mellitus (DM) is a global public health burden, as the number of affected adults is expected to rise to 630 million by 2045 [1]. Considering that AGEs can participate in both the impairment of glycemic homeostasis and the development/progression of chronic complications of DM, and considering that these effects involve ER stress- and inflammatory-mediated pathways, the present manuscript reviews these regulations upon the expression of solute carrier family 2, facilitated glucose transporter member 4 (GLUT4) expression, as a marker of altered glycemic homeostasis [11,12,13] and, upon atherogenesis, as an important inducer of the development/progression of CVD [7]. Several disorders that course with IR have been considered as risk factors for the development of hypertension and CVD, including a high atherogenic lipoprotein profile (in its complexity), elevated plasma concentrations of plasminogen activator inhibitor-1, increased sympathetic nervous system activity and endothelial disfunction [17,18] Along with these risk factors, a pro-inflammatory profile and the activation of reticulum endoplasmic stress and oxidative stress are observed, in a complex relationship, creating a dangerous vicious circle [19,20]. In this manuscript, CVD (with special focus on atherogenesis) was chosen to be reviewed as the most important complication of DM

GLUT4 Expression and Glycemic Control

AGEs and GLUT4 Expression Regulation

Findings

Concluding Remarks