Role of ER stress inhibitors in the management of diabetes

Endoplasmic Reticulum (ER) stress has been established to play a key pathophysiological role in developing metabolic diseases such as Diabetes Mellitus (DM). The complications of DM have been closely associated with deregulation of the unfolded protein response (UPR) signaling pathways, which are critically responsible for restoring homeostasis following ER stress. Chronic ER stress in the background of persistent hyperglycemia, as observed in DM, overwhelms the UPR signaling and commits the cells to apoptosis. The factors such as hyperglycemia, increased reactive oxygen species (ROS), disrupted calcium homeostasis, and overt inflammation serve as major UPR signal transduction pathways, including PKR like ER kinase (PERK), Activating transcription factor 6 alpha/beta (ATF6), and Inositol requiring enzyme1 alpha/beta (IRE1). The constantly developing understanding of these ER stress mediators has also unraveled their potential as therapeutic targets of small molecules termed ER stress inhibitors. A wide range of both naturally occurring and synthetic compounds have been screened and studied for their properties to inhibit ER stress in various experimental models. This review article elucidates the critical signaling pathways associated with response to ER stress. We shed light on the crosstalk between ER stress mediators with oxidative and inflammatory stress mediators in the background of DM. We extensively summarize the pieces of evidence sourced from preclinical and clinical research about the role of ER stress inhibitors and their pharmacological mechanism of action in alleviating ER stress in diabetes.

Automated summary

Endoplasmic reticulum stress plays a key role in the development of metabolic diseases like diabetes. The unfolded protein response signaling pathways are dysregulated in diabetes and contribute to the complications associated with the disease. Factors like hyperglycemia, oxidative stress, disrupted calcium homeostasis, and inflammation activate signaling pathways that overwhelm the endoplasmic reticulum's ability to restore homeostasis, leading to cell apoptosis. Understanding these signaling pathways has revealed potential therapeutic targets in the form of ER stress inhibitors, which have shown promise in alleviating ER stress in diabetes.