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    • Endoplasmic reticulum ER stress resulting from accumulation

    2023-09-15

    Endoplasmic reticulum (ER) stress resulting from accumulation of misfolded proteins in ER lumen stimulates a chain of adaptive responses termed as the unfolded protein response (UPR). Glucose related protein (GRP78/BiP), key ER chaperone essential for the activation of the ER-transmembrane signaling molecules. The three major transducers of ER stress-PKR-like endoplasmic reticulum kinase (PERK), activating transcription factor 6 (ATF6), and inositol-requiring enzyme 1 (IRE1) facilitate for sensing the presence of unfolded proteins and signal transduction to the cytosol or nucleus [37]. The UPR of pancreatic beta ochratoxin a is regulated by autophagy. It has been observed that the autophagy-deficient pancreatic cells are susceptible to ER stress that is involved in the progression of diabetes. The UPR machinery is compromised in autophagy-deficient beta cells making them prone to ER stress in vitro. The autophagy-deficient mice, when bred with obese mice to induce ER stress, were found to develop severe diabetes with the reduction in beta cell survival and accumulation of ROS as shown by nitrotyrosine staining [38]. For example, an increase in the ER stress and a defect in insulin signaling pathway have been found both in vivo and in vitro during the repression of Atg7 expression. While restoring the Atg7 expression, the ER stress was limited with the enhancement in the effect of insulin in obese mice [35]. Thus, autophagy is essential for UPR machinery, and autophagy-deficient cells can result in the development of diabetes from obesity. The expression of UPR genes Eif2α, Chop, Ero1α, Bip, Grp94, Erp72, Ubc7, Hrd1, Edem, Erdj4 was found to be significantly downregulated in autophagy deficient pancreatic beta cells compared to rat insulin promoter autophagy deficient mice, thereby suggesting that basal UPR is downregulated in autophagy deficient mice [38]. It was experimentally found that mice with only obesity or autophagy-deficient beta cells developed hyperglycemia but not diabetes. On the contrary, mice with both obesity and defective autophagy in pancreatic beta cells developed severe diabetes [38]. Recent investigations have found the role of autophagy in controlling insulin signaling and lipid metabolism. Improper processing of the lipid affects the functioning of the liver and may reduce the effect of insulin [39]. Whereas constitutive adipogenesis has been studied to be regulated by autophagy, suppressing the autophagic activity has an anti-obesity effect and is sensitive to insulin. Atg7 depletion in the adipose tissue of high-fat diet resulted in sensitivity toward insulin with the resistance to obesity [40]. Nevertheless, an increase in the accumulation of ubiquitinated protein aggregates was observed in INS-1 cells (a mouse insulinoma cell line) when they were treated with high glucose. Upon the inhibition of proteasome machinery, there was no alteration in the ubiquitinated proteins in INS-1 cells. When the cells were treated with an autophagic inhibitor 3-methyladenine (3-MA), the level of aggregated proteins increased in the presence of high glucose [36]. These observations, therefore, suggest that autophagy is the sole process for the regulation and degradation of ubiquitinated proteins in INS-1 cells. Similarly, the depletion of Atg7 causes accumulation of protein aggregates [41]. In an experiment, a type 2 diabetes drug, metformin, was shown to decrease the formation of autophagic vacuoles in type 2 diabetes as well as NEFA-treated beta cells. Metformin enhances AMP kinase activity that is known to inhibit mTOR pathway. Inhibition of mTOR pathway, in turn, leads to the removal of autophagic vacuoles. Therefore, metformin helps in the removal of autophagic vacuoles by inhibiting the action of mTOR on autophagy [42]. Similarly, exendin-4 that controls the level of glucose has also been found to regulate the autophagic markers, such as mTOR, LC3-II, LAMP1, parkin, Atg7, and p62, further validating the fact that autophagy plays a crucial role in regulating diabetes [43]. Another study put stress on the contribution of autophagy on diabetes where the lack of autophagy in skeletal muscles activated Atg4 that helped in the induction of Fgf21 expression. The activation of Fgf2 enhanced oxidation of fatty acids and therefore energy expenditure along with the white adipose tissue (WAT) browning. This resulted in resistance to high fat diet induced (HFD-induced) obesity. Therefore, the Atg7 mutant HFD-mice showed a decline in insulin concentration and better glucose homeostasis [44]. Interestingly, it has been investigated that exercise increases the autophagic turnover and mitochondrial fission in type 2 diabetes with an increase in the levels of Atg7 and p62/SQSTM1 and decrease in LC3-II protein [45].