ISG15 Mediates Oxidative Stress Modulation in T2DM Patients by Directly Targeting PIK3R2

Area of Science:

• Endocrinology and Metabolism
• Cellular and Molecular Biology
• Immunology

Background:

• Type 2 diabetes (T2DM) is linked to oxidative stress and pancreatic beta-cell dysfunction.
• The role of Interferon-stimulated gene 15 (ISG15) in T2DM pathogenesis is not well understood.
• ISG15 is a ubiquitin-like modifier involved in redox regulation.

Purpose of the Study:

• To investigate the role of ISG15 in T2DM pathogenesis.
• To identify novel bio-factors contributing to T2DM.
• To elucidate the molecular mechanisms underlying ISG15-mediated oxidative stress in T2DM.

Main Methods:

• Quantified ISG15 expression in peripheral blood mononuclear cells (PBMCs) and serum from T2DM patients and healthy controls.
• Assessed ISG15 expression in pancreatic islets of a T2DM mouse model.
• Utilized MIN6 pancreatic beta-cells exposed to hyperglycemic/hyperlipidemic (HG/PG) and hydrogen peroxide (H2O2) conditions.
• Performed protein-protein interaction assays and functional analyses after ISG15 genetic ablation.

Main Results:

• ISG15 expression was significantly higher in T2DM patients' PBMCs and serum compared to controls.
• T2DM mouse models showed increased ISG15 in islet beta-cells.
• In vitro studies demonstrated that HG/PG or H2O2 exposure increased ISG15, reduced cell viability, and elevated reactive oxygen species (ROS).
• ISG15 was found to directly interact with PIK3R2, inhibiting its activity and disrupting the PI3K/AKT/Nrf2 antioxidant pathway, leading to increased oxidative stress.

Conclusions:

• ISG15 is upregulated in T2DM and contributes to oxidative stress.
• ISG15 exacerbates T2DM by inhibiting the PIK3R2-dependent PI3K/AKT/Nrf2 pathway.
• ISG15 represents a potential therapeutic target for reducing oxidative damage in T2DM.