Emerging role of Unfolded Protein Response (UPR) mediated proteotoxic apoptosis in diabetes

Endoplasmic reticulum (ER) is a crucial single membrane organelle that acts as a quality control system for cellular proteins as it is intricately involved in their synthesis, folding and trafficking to the respective targets. Type 2 diabetes is characterized by enhanced blood glucose level that promotes insulin resistance and hampers cellular glucose metabolism. Hyperglycemia provokes mitochondrial ROS production and glycation of proteins which exert a tremendous load on ER for conventional refolding of misfolded/unfolded and nascent proteins that perturb ER homeostasis resulting in apoptotic cell death. Impairment in ER functions is suspected to be through specific ER membrane-bound proteins known as Unfolded Protein Response (UPR) sensor proteins. Conformational changes in these proteins induce oligomerization and cross-autophosphorylation which facilitate processes required for the restoration of ER homeostatic imbalance. Multiple studies have reported the involvement of UPR mediated autophagy and apoptotic pathways in the progression of metabolic disorders including diabetes, cardiac ischemia/reperfusion injury and hypoxia-mediated cell death. In this review, the involvement of UPR pathways in the progression of diabetes associated complications have been addressed, which underscores molecular crosstalks during neuropathy, nephropathy, hepatic injury and retinopathy. A better understanding of these molecular interventions may reveal advanced therapeutic approaches for preventing diabetic comorbidities. The article also highlights the importance of phytochemicals that are emerging as novel ER stress inhibitors and are being explored for targeted interaction in preventing cell death responses during diabetes.