Type 2 diabetes (T2DM), a chronic metabolic disorder characterized by pancreatic β-cell dysfunction and insulin resistance, is closely associated with oxidative stress. Interferon-stimulated gene 15 (ISG15), a ubiquitin-like modifier, has been implicated in redox regulation; however, its mechanistic role in T2DM progression remains unclear. To identify novel bio-factors contributing to T2DM, peripheral blood mononuclear cells (PBMCs) and serum samples were collected from T2DM patients and age-/BMI-matched healthy controls to quantify ISG15 expression. Complementary studies utilized a T2DM mouse model to assess β-cell-specific ISG15 expression within pancreatic islets. In parallel, MIN6 pancreatic β-cells were exposed to pathophysiological stressors, including hyperglycemic/hyperlipidemic (HG/PG) conditions and hydrogen peroxide (H2O2)-induced oxidative stress, to mimic the diabetic microenvironment. Protein-protein interactions were evaluated, and functional analyses were conducted following ISG15 genetic ablation. The results demonstrated that ISG15 expression was significantly elevated in PBMCs and serum from T2DM patients compared to healthy controls. Similarly, T2DM mouse models exhibited marked upregulation of ISG15 in islet β-cells. In vitro, exposure to HG/PG or H2O2 increased ISG15 levels, reduced MIN6 cell viability, and heightened reactive oxygen species (ROS) accumulation. Mechanistic studies revealed that ISG15 directly interacts with the PI3K regulatory subunit PIK3R2, suppressing its activity and thereby disrupting the PI3K/AKT/Nrf2 antioxidant signaling axis. This disruption led to exacerbated oxidative stress. Collectively, these findings indicate that ISG15 acts as a novel mediator of oxidative stress in T2DM by targeting and inhibiting the PIK3R2-dependent PI3K/AKT/Nrf2 pathway. These results uncover a previously unrecognized molecular mechanism driving β-cell dysfunction and identify ISG15 as a potential therapeutic target for mitigating oxidative damage in diabetes.
He et al. (Sun,) studied this question.