γ-Glutamylcysteine restores glucolipotoxicity-induced islet β-cell apoptosis and dysfunction via inhibiting...

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.