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

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.

Advances in the therapeutic application and pharmacological properties of kinsenoside against inflammation and oxidative stress-induced disorders

“…Previous studies have determined the importance of insulin resistance in the Frontiers in Pharmacology frontiersin.org development of type II DM. Specifically, inflammatory factors decrease the activities of insulin receptor in hepatocytes, muscle cells, and adipocytes, accompanied by insulin receptor substanceinduced intracellular signaling transduction inhibition, glucose transporter generation and translocation suppression, and glucose uptake and metabolism disruption (Passarelli and Machado, 2021;Xiao et al, 2022). A hyperglycemic environment facilitates the occurrence of inflammation and oxidative stress, which exacerbate vascular and myocardial complications and enhance the risks of diabetic disability and mortality (Lu et al, 2021;Semwal et al, 2021;Yu et al, 2022).…”

Ligament Alteration in Diabetes Mellitus

“…AGEs create intra- and extracellular cross-links with proteins, sometimes lipids and nucleic acids, which participate in the progression of diabetic complications. They cause disruption in the molecular conformation, rearrange enzymatic activity, and disorganise molecule-receptor functioning [ 4 , 11 , 12 ]. The investigation of cellular receptors for AGEs (RAGE) revealed the pathophysiological bases for the alteration of intracellular signalling as well as expression of important genes, pro-inflammatory molecules, and free-radical release [ 6 ].…”

“…The investigation of cellular receptors for AGEs (RAGE) revealed the pathophysiological bases for the alteration of intracellular signalling as well as expression of important genes, pro-inflammatory molecules, and free-radical release [ 6 ]. The activated RAGE promotes the chain reaction of reactive oxygen species and triggers the transcription of factor NF-κB [ 4 , 13 ]. Cross-link formation in collagen fibres dictates the development of pro-inflammatory molecules, which then accelerate the creation of a disorganised cell phenotype [ 14 , 15 , 16 ].…”

“…Altered glucose metabolism impacts on all the basic processes taking place in the organism and remains the reason for impaired body functioning and regenerative abilities [ 2 ]. DM is a complex metabolic disorder, which has several direct and indirect effects on multiple processes, starting from simple to more complex: chemotaxis, phagocytosis, bacterial killing, heat shock, protein expression, antioxidant synthesis, oxygen-free-radical generation, growth factor depletion, glucocorticoid concentration, cell proliferation, up-regulation of apoptosis, and extracellular matrix (ECM) synthesis [ 3 , 4 ]. The cellular and molecular background for those changes and irreversible degradation are further evaluated and, so far, the pathophysiology of tendinopathies has been clarified comprehensively.…”

Diabetes Mellitus Promotes the Development of Atherosclerosis: The Role of NLRP3

“…The coexistence of high glucose levels and persistent oxidative stress leads to the formation of advanced glycation end products (AGEs). AGEs, through their receptor interactions (RAGEs), play an important role in the vascular complications of diabetes ( 14 ). AGEs can upregulate inflammatory signaling pathways and induce reactive oxygen species production and apoptosis.…”