Upregulation of GRP78 is accompanied by decreased antioxidant response and mitophagy promotion in streptozotocin-induced type 1 diabetes in rats

Endoplasmic reticulum stress, oxidative stress, and mitochondrial dysfunction are interconnected processes involved in the pathogenesis of diabetes mellitus (DM). In the present study, we demonstrate a distinct unfolded protein response (UPR) signaling pathways in two mammalian models of DM: β-TC-6 cell line and streptozotocin-induced type 1 diabetes model in rats. However, a feature common to both systems was the upregulation of the GRP78 protein. Moreover, in vivo studies showed the disruption of the antioxidant system and an escalation of mitophagy against the background of a depletion of the level of ATP in pancreatic cells. In conclusion, we suggest that glucotoxic conditions induced GRP78 upregulation, and next cause depletion of the antioxidant pool and disruption of the functioning of antioxidant defense enzymes and in consequence promote mitophagy in pancreatic cells. Therefore, GRP78 may be considered as a potential therapeutic factor in patients with diabetes. •PERK and IRE1α UPR-branches are involved in β-cells response to glucotoxicity in vitro.•GRP78 is a master regulator of β-cells proteostasis in vitro and in vivo.•Distinct unfolded protein response signaling in vitro and in vivo models of diabetes mellitus (DM).•GRP78 up-regulation decreased antioxidant capacity in streptozotocin-induced diabetes model.•GRP78 as a potential therapeutic factor in patients with diabetes.