1754-P: Investigating the Interplay between T-Cell Infiltration, ROS Detoxification, and Pancreatic Beta-cell Dysfunction in Type 1 Diabetes Pathogenesis

Introduction & Objective: Reactive oxygen species (ROS), byproducts of cellular metabolism, are implicated in T1D progression, causing lipid, protein, and DNA damage, along with impaired β-cell function and apoptosis. Notably, at the onset of T1D, β-cells exhibit dysregulated glucose metabolism, resulting from decreased glucose uptake and impaired utilization. This metabolic perturbation diminishes NADPH production, a critical antioxidant cofactor from glycolysis and the pentose phosphate pathway (PPP). Consequently, islets in T1D individuals may exhibit compromised ROS-neutralizing abilities, heightening susceptibility to oxidative damage. The objective of this study is to determine glucose metabolism's role in β-cell antioxidant defense and T1D-related dysfunction. We hypothesize that insulitic islets in T1D are more vulnerable to damage from ROS compared to islets in individuals without diabetes and that diminished ROS detoxification contributes significantly to β-cell loss and dysfunction in T1D.

Methods: Islets in live pancreatic tissue slices from both nondiabetic and recent-onset diabetic donors were acutely challenged with hydrogen peroxide (H₂O₂), and palmitate, followed by glucose stimulations. Real-time monitoring of ROS levels, utilizing ROS biosensor GRX1-roGFP2 and chemical ROS indicators, were conducted.

Results & Conclusion: While it is generally the case that chronic hyperglycemia induces oxidative β-cell damage, our observations suggest that acute glucose stimulation reduces baseline ROS levels by promoting increased GSH in healthy β-cells. Following various ROS challenges including, high glucose stimulations quickly reverted their oxidative effects in healthy β-cells. These results support the concept that poor beta cell glucose responsiveness in T1D increases β-cell susceptibility to ROS.