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Hyperglycemia associated ER stress has been found as a critical contributor in the pathogenesis of type 2 diabetes mellitus. However, reports regarding molecular mechanisms involved are limited. This study was aimed to identify the role of ER stress in regulating hepatic glucose metabolism and its link with oxidative stress. Further, this study explores the novel role of Morin, a flavonol, in modulating ER stress in STZ/nicotinamide induced type 2 diabetic male Wistar rats. Results demonstrate that hyperglycemia induced ER stress in rats and significantly lowered the expression of glucose transporter proteins resulting in impaired glucose metabolism during diabetes. Morin was found to downregulate PERK-eIF2α-ATF4 pathway by interacting with PERK protein as confirmed through pull-down assay. Additionally, Morin maintained the reducing environment in ER and enhanced PDI activity compared to diabetic rats. Morin prevented cell death by suppressing the expression of PERK dependent pro-apoptotic proteins including ATF4 and CHOP. Findings from this study affirm the role of ER stress in hyperglycemia induced gluco-metabolic aberrations and liver injury as confirmed by ISRIB, a standard chemical ER stress inhibitor. Notably, Morin promoted deactivation of UPR sensors and upregulated PDI activity endorsing its anti-ER stress potential which may allow the development of new therapeutic avenues to target hyperglycemic hepatotoxicity. Unlabelled Image • PERK-eIF2α-ATF4 pathway plays a critical role in the progression of diabetic hepatotoxicity. • Inhibition of PERK-eIF2α-ATF4 pathway enhances gluco-metabolism in diabetic liver. • Morin prevents proteotoxic cell death by selectively down-regulating PERK response pathway. • Morin shows ER stress inhibitory potential that improves glucose metabolism and prevents liver injury during diabetes. [ABSTRACT FROM AUTHOR]

Abstract 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. Graphical abstract Unlabelled Image [ABSTRACT FROM AUTHOR]

Endoplasmic reticulum (ER) dysfunction contributes greatly to the pathophysiology of hyperglycemic nephrotoxicity. This study unravels the critical role of Tribbles 3 (TRB3)-Forkhead box O1 (FoxO1) signaling pathway during hyperglycemic renal toxicity. It also uncovers the novel role of Naringenin, a flavanone, in regulating ER stress in proximal tubular cells, NRK 52E, and kidneys of streptozotocin/nicotinamide induced experimental diabetic Wistar rats. Results demonstrate that expression of ER stress marker proteins including phosphorylated protein kinase ER like kinase (p-PERK), phosphorylated eukaryotic Initiation Factor 2α (p-eIF2α), X Box Binding Protein 1 spliced (XBP1s), Activating Transcription Factor 4 (ATF4) and C/EBP Homologous Protein (CHOP) were upregulated in diabetic kidneys indicating the activation of ER stress response due to nephrotoxicity. Treatment with Naringenin reduced the expression of TRB3, an ER stress-inducible pseudokinase, both in vitro and in vivo. Gene silencing of TRB3 enhanced Akt and FoxO1 phosphorylation and alleviated FoxO1 mediated apoptosis during hyperglycemic nephrotoxicity. Notably, TRB3 gene silencing effects were comparable to the response with Naringenin treatment. Prevention of nuclear colocalization of ATF4 and CHOP in Naringenin treated cells was evident. Naringenin also reduced insulin resistance, apoptosis and glycogen accumulation along with enhancement of glucose tolerance in diabetic rats. Prevention of ultrastructural aberrations in the ER of hyperglycemic renal cells by Naringenin confirmed its anti-ER stress effects. These findings affirm that activation of TRB3-FoxO1 signaling is critical in the pathogenesis of hyperglycemia-induced renal toxicity and protective effect of Naringenin via modulation of ER stress may be exploited as a novel approach for its management. [Display omitted] • UPR sensor proteins were upregulated indicating ER stress during hyperglycemia. • Aberrant ER stress response induces TRB3 expression in vitro and in vivo. • Gene silencing of TRB3 prevented renal cell death during hyperglycemic nephrotoxicity. • Anti-ER stress effects of Naringenin were comparable to effects of TRB3 gene silencing. • Naringenin attenuated ER stress and TRB3-FoXO1 dependent responses. [ABSTRACT FROM AUTHOR]