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    • To further investigate the molecular mechanisms that underli

    2021-12-06

    To further investigate the molecular mechanisms that underlie glycine's β-cell protective effects through its antioxidative activity in diabetes, we used a H2O2/high glucose-induced apoptosis cell model. Similar effects on ROS generation of high glucose and H2O2 support the in vivo results, suggesting that glucotoxicity leads to oxidative stress. Glycine reduced apoptosis of INS-1 cells, which was induced by high glucose and H2O2via inhibition of ROS generation and p22phox expression. Other tissue and cell studies have suggested that the mechanism of glycine antioxidant stress might be associated with GlyTs and the GlyR [24], [25], [32], [33], [34], [35], [36]. The GlyT system is unique because of its high substrate specificity and high affinity for glycine, which facilitates import of glycine into the cell via GlyTs on the basolateral membrane of intestinal epithelial Desformylflustrabromine hydrochloride [24]. However, in tissues such as the kidney, liver, vascular endothelium and myocardium, glycine cytoprotection appears to be associated with the activation of GlyR, independent of glutathione levels [37], [38], [39], [40]. A recent study first reported the expression of GlyR and GlyT on human islet β-cells [26], but the authors speculated that the expression of GlyR in β-cells may be specific to humans, as it has not been detected on mouse and rats islets [41]. Furthermore, rat pancreas α- and β-cells have been found to express GlyT2 but not GlyT1 [42]. In contrast to the latter findings, we detected GlyT1 and GlyR expression in rat pancreatic homogenate and in INS-1 rat insuloma cells. Using the GlyR inhibitor strychnine, we demonstrated a role for GlyR in the protection of β-cells against apoptosis and increased oxidative stress caused by p22phox. We also demonstrated that the GlyT1 inhibitor ALX5407 hydrochloride significantly inhibited the protective effect of glycine on INS-1 apoptosis, reduced intracellular GSH concentrations and elevated ROS levels, though no effect of ALX5407 hydrochloride was observed on p22phox expression. These results support the role of both GlyR and GlyT1 in glycine uptake and protection against oxidative stress in rat β-cells, but suggest that they may function at different levels in the oxidative stress pathway. Previous studies have described glycine involvement in the regulation of multiple cell signaling pathways, including NF-κB, p38, JNK and ERK MAPK signaling pathways [43], [44], [45], which are associated with cell apoptosis and oxidative stress. Moreover, glycine transporters are co-transporters of glycine with sodium and chloride, while glycine receptors are glycine-related pressure-gated chloride channels; both could regulate intracellular ion concentrations. Glycine is likely to regulate mitochondrial function in reducing ROS production from mitochondria indirectly by altering cytosolic ion balances, i.e. Na+, Cl- and Ca2+, via glycine receptors or transporters. The changes of ion balances would further affect mitochondrial membrane potential. Thus, the potential role of these pathways in mediating different aspects of the antioxidative effect of glycine merits further study. In summary, our study demonstrates that glycine reduces the ROS content in islet β-cells caused by hyperglycaemia, suggesting that glycine may serve as a potential therapeutic for ameliorating oxidative stress in diabetes. As shown in Fig. 6, glucotoxicity plays an important role in β-cells dysfunction and damage in diabetes, which is mediated mainly by mitochondrial injury and production of ROS via activation of NADPH oxidase. Our study suggests that the protective mechanisms of glycine include inhibition of ROS production by NOX inhibition via GlyR; and promotion of ROS consumption due to increase in the intracellular uptake of glycine and synthesis of GSH via GlyT1, both of which may contribute to its ability to ameliorate β-cell dysfunction and apoptosis by either inhibition of NADPH oxidase activity or increase in ROS degradation. In fact, there are already some animal experiments suggesting that the use of NADPH-oxidase inhibitors can bring beneficial effects to the treatment of diabetic complications. But further investigations, especially clinical studies, are needed to test if NADPH-oxidase inhibitors can serve as a plausible therapeutic strategy for treating diabetic complications. In our study, we found that glycine could reduce the expression of NADPH oxidase in β cells induced by high glucose, providing a new idea for reducing NADPH oxidase. Moreover, glycine is an endogenous antioxidant and is harmless. Thus, glycine can be used as a new treatment method for anti-oxidation treatment of diabetes. Despite the promising results of our study and other recent studies that characterize beneficial effects of glycine supplementation, high glycine concentrations in the brain can cause oxidative stress and nerve injury [46], and GlyT1 overexpression is associated with the occurrence of epilepsy [35]. Thus, further studies will be needed to determine the safest way to implement supplementation with glycine for amelioration of diabetes.