Coupled endoplasmic reticulum and oxidative stress in pancreatic β cells: mechanisms and therapeutic insights

Abstract

Pancreatic β cells maintain glycemic homeostasis through high-rate insulin synthesis and secretion, and their function depends on precise protein folding and the redox microenvironment. In diabetes, inflammation, chronic hyperglycemia, and lipotoxicity disrupt redox homeostasis, with increased reactive oxygen species and compromised antioxidant defenses that directly reduce secretory efficiency and endanger cell survival. Oxidative stress and endoplasmic reticulum stress are tightly coupled. Excessive oxidative load raises folding demand and chronically activates the unfolded protein response, which further perturbs calcium signaling and redox balance to form a vicious cycle. When endoplasmic reticulum stress shifts from adaptive to injurious outputs, β cells undergo a decline in the secretory phenotype, dedifferentiation, and apoptosis, leading to loss of β cell mass and function. As interventions, chemical chaperones and antioxidant strategies can jointly lower ER and oxidative burdens and improve islet function. Tauroursodeoxycholic acid and 4-phenylbutyric acid increase folding capacity and improve metabolic phenotypes across models. Overall, combination approaches centered on folding quality control and redox balance hold translational promise, yet optimal dose and timing, long-term safety, and compatibility with existing glucose-lowering therapies remain to be defined. This review summarizes these mechanistic links and therapeutic advances and discusses key challenges and prospects.