Zhou Jinyi, Shi Yingying, Zhao Lishuang, Wang Rong, Luo Lan, Yin Zhimin
Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, China.
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China.
Toxicol Appl Pharmacol. 2025 Feb;495:117206. doi: 10.1016/j.taap.2024.117206. Epub 2024 Dec 17.
The impaired function of islet β-cell is associated with the pathogenesis of type 2 diabetes mellitus (T2DM). γ-glutamylcysteine (γ-GC), an immediate precursor of glutathione (GSH), has antioxidant and neuroprotective functions. Its level has been reported to be down-regulated in hyperglycemia. However, whether γ-GC has a protective effect on islet β-cell dysfunction remains elusive. Recently, we explore the molecular mechanism by which γ-GC protects islet β-cell from glucolipotoxicity-induced dysfunction.
In vivo mice models and in vitro cell models were established to examine the therapeutic effects and molecular mechanisms of γ-GC.
db mice develop impaired glucose-stimulated insulin secretion (GSIS) due to reduced islet number and damaged islet microstructure. Serious oxidative damage, apoptosis and lipid accumulation are also observed in β-cell stimulated by glucolipotoxicity. Mechanistic studies suggest that glucolipotoxicity inhibits PDX-1 nuclear translocation by inducing endoplasmic reticulum (ER) stress, which leads to impaired insulin (INS) secretion in β-cell. Nevertheless, γ-GC as an inhibitor of ER stress can alleviate the damage of islet microstructure in db mice. Importantly, γ-GC promotes INS gene expression and GSIS through driving nuclear translocation of PDX-1, thereby enhancing intracellular INS content. Moreover, treatment with γ-GC can also mitigate oxidative damage, apoptosis and lipid accumulation of β-cell, resulting in ameliorating islet β-cell dysfunction induced by glucolipotoxicity.
Our results support the use of γ-GC as an inhibitor of ER stress for prevention and treatment of T2DM in the future.
胰岛β细胞功能受损与2型糖尿病（T2DM）的发病机制相关。γ-谷氨酰半胱氨酸（γ-GC）是谷胱甘肽（GSH）的直接前体，具有抗氧化和神经保护功能。据报道，其水平在高血糖状态下会下调。然而，γ-GC是否对胰岛β细胞功能障碍具有保护作用仍不清楚。最近，我们探讨了γ-GC保护胰岛β细胞免受糖脂毒性诱导的功能障碍的分子机制。
建立体内小鼠模型和体外细胞模型，以研究γ-GC的治疗效果和分子机制。
db小鼠由于胰岛数量减少和胰岛微结构受损，出现葡萄糖刺激的胰岛素分泌（GSIS）受损。在糖脂毒性刺激的β细胞中也观察到严重的氧化损伤、细胞凋亡和脂质积累。机制研究表明，糖脂毒性通过诱导内质网（ER）应激抑制PDX-1核转位，从而导致β细胞胰岛素（INS）分泌受损。然而，γ-GC作为ER应激的抑制剂，可以减轻db小鼠胰岛微结构的损伤。重要的是，γ-GC通过驱动PDX-1核转位促进INS基因表达和GSIS，从而提高细胞内INS含量。此外，γ-GC治疗还可以减轻β细胞的氧化损伤、细胞凋亡和脂质积累，从而改善糖脂毒性诱导的胰岛β细胞功能障碍。
我们的结果支持未来将γ-GC作为ER应激抑制剂用于预防和治疗T2DM。
