Adenosine as a modulator of human islet function and hypoxic tolerance

Islet transplantation hold promises as a cell therapy for managing type 1 diabetes, but its effectiveness remains limited due to early graft loss caused by hypoxia and associated stressors. Identifying strategies to enhance islet resilience is imperative for improving clinical outcomes. We hypothesized that mitigating this injury requires shifting focus from augmenting oxygen supply to reducing the cellular metabolic demand. Adenosine (AD), an endogenous purine nucleoside with immunomodulatory and metabolic regulatory roles, emerges as a candidate to mitigate these challenges. This study evaluates the impact of AD on human islet (HI) viability, function, and metabolic suppression under hypoxic stress (1% O 2 ). Results demonstrated that AD at 1 mM induced a transient reduction in insulin content without impairing viability or functional indices (stimulation index, insulin secretion). These changes were reversible within 96 h of withdrawal. Preconditioning HI with 1 mM AD prior to 48-h hypoxia preserved both viability and glucose-stimulated insulin secretion, mitigating functional losses up to 48 h post-reperfusion. These findings establish AD preconditioning as an effective, reversible approach to reduce islet metabolic demand and enhance hypoxia tolerance during the early post-transplantation period. Furthermore, AD can be readily integrated into various stages of beta-cell replacement workflow, including islet culture, encapsulation, and 3D bioprinting. Overall, AD-mediated metabolic downregulation offers a novel strategy for mitigating ischemia-reperfusion injury, paving the way for more efficient and resilient cell-based therapies for beta-cell replacement.