γ-Glutamylcysteine restores glucolipotoxicity-induced islet β-cell apoptosis and dysfunction via inhibiting endoplasmic reticulum stress

• Published in: Toxicology and applied pharmacology 2025-02, Vol.495, p.117206, Article 117206
• Main Authors: Zhou, Jinyi, Shi, Yingying, Zhao, Lishuang, Wang, Rong, Luo, Lan, Yin, Zhimin
• Format: Article
• Language: English
• Subjects: Apoptosis; Endoplasmic reticulum stress; Islet β-cell; PDX-1; γ-glutamylcysteine
• ISSN: 0041-008X; 1096-0333; 1096-0333
• DOI: 10.1016/j.taap.2024.117206

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. [Display omitted] •γ-GC mitigates oxidative damage, apoptosis and lipid accumulation in islet β-cell.•γ-GC alleviates islet β-cell dysfunction induced by glucolipotoxicity.•γ-GC inhibits glucolipotoxicity-induced ER stress of islet β-cell.•γ-GC induces INS secretion through driving PDX-1 translocation into nucleus.