In response to oxidative stress in
In response to oxidative stress in DM, antioxidant defence systems are activated in β-cells. Glutathione (GSH) is one of the most abundant antioxidants and has been shown to be expressed at lower concentrations in patients with DM , . Furthermore, plasma levels of glycine, which is a synthetic substrate of GSH, have been shown to be low in type 2 diabetes (T2D) patients , , whereas dietary supplementation with glycine restores GSH levels. Furthermore, glycine supplementation has been shown to raise plasma insulin levels in non-diabetic volunteers . Glycine therapy also has been shown to increase GSH levels in the optical lenses ,  of streptozotocin (STZ)-induced diabetic rats, and to ameliorate cataract formation and other diabetes complications. Glycine is widely accepted as an antioxidant and cytoprotective substance , , , , ; however, the mechanism of the glycine protective effect in β-cells is still unclear. Recent studies demonstrate that glycine cytoprotection for a variety of types of bardoxolone is activated through the glycine receptor (GlyR) and glycine transporter-1 (GlyT1) , , . Furthermore, these proteins have been shown to be expressed in human β-cells and that glycine-promoted insulin secretion might be associated with the GlyR pathway .
To explore the mechanism of glycine in protecting β-cells against damage induced by oxidative stress associated with diabetes, we performed a series of biochemical assays in STZ-induced diabetic rats and in INS-1 β-cells. Our results elucidate a pathway whereby glycine functions to decrease β-cell oxidative stress injury via GlyT1 and GlyR.
Materials and methods
Discussion Oxidative stress is one of the main pathogenic mechanisms of β-cell damage in DM. DM is known to be characterized by excessive ROS production and reduced antioxidative enzyme expression and capacity, which leads to β-cell damage and subsequent complications . Pancreatic β-cells are more sensitive to oxidative stress due to their low expression level of antioxidative enzymes . Many antioxidants used for diabetes treatment have been reported to protect β-cells via their ability to reduce oxidative stress levels , . As the main synthetic material of GSH, which is one of the most important internal antioxidants, glycine is widely accepted as an antioxidant , , , , . Circulating glycine concentrations are consistently low in T2D patients , and antioxidative effects of glycine have been characterized in the optical lenses and kidneys of diabetic rats , , , . Dietary supplementation with cysteine and glycine has also been reported to restore GSH synthesis and lower oxidative stress and oxidant damage in T2D patients . However, the effect of glycine in ameliorating oxidative stress in β-cells has not been directly characterized. The present work focused on characterizing the antioxidative effect of glycine on β-cells in reducing diabetes complications. We demonstrated that glycine reduces β-cell oxidative damage in diabetes, which provides evidence at the cellular and molecular level for its potential benefit in the treatment of DM. To assess the antioxidative effects of glycine at the level of the β-cell, we employed the STZ-induced diabetic rat model. Glycine therapy increased plasma insulin levels in diabetic rats, but had no significant effect on blood glucose levels. The glucose concentration in diabetic rats has previously been reported to be significantly reduced by supplemental glycine , , , . The reason for this discrepancy between our results and the previous findings is unknown, but could be related to the severity of the damage to the islet β-cells in our study. Nevertheless, glycine supplementation increased the plasma levels of GSH, CAT and SOD in the STZ-induced diabetic rats; and reduced the plasma level of 8-OHdG. Importantly, glycine administration also significantly increased the β-cell mass and improved the β-cell microstructure, increasing the number of mature insulin-secreting particles and reducing edema and degeneration of mitochondria. Glycine also decreased the elevated pancreatic expression of p22phox, which is a component of NADPH oxidase that is known to be involved in ROS generation and to be dysregulated in a variety of diseases . Our study, therefore, provides strong evidence that glycine directly reduces β-cell damage in diabetes through its antioxidative activity.