Background: Islet transplantation is an effective cell therapy for treating type 1 diabetes. However, a high therapeutic dose is required to achieve optimal glycemic control, as a significant proportion of islets is destroyed shortly post-transplantation due to oxidative stresses. Adenosine has been shown to decrease the metabolism of rat islets and, also to provide protection against ischemia-reperfusion injury. Therefore, the objective was to assess the impact of adenosine in preventing hypoxia-associated adverse effects on human islets viability and function.

Methods: This study investigates the effect of adenosine on human islet (HI) metabolism, function, and survival under hypoxic conditions (1% O2). HI were exposed to adenosine (1 mM and 10 µM) for 24h, followed by assessments of viability, insulin secretion, and hypoxia resilience. 

Results: Results demonstrated that adenosine at 1 mM significantly reduced insulin content, an effect that was reversible within 96h, without impairing islet viability or functionality (stimulation index, and insulin secretion in response to glucose). Furthermore, preconditioning of human islets with adenosine was able to prevent the deleterious effects of hypoxia. Hypoxia reduced islet viability compared to non-hypoxic control (72.7±6.8% vs. 91.4±0.3%, p<0.01), but adenosine treatment prevented the reduction in viability (81.5±5.3%, p<0.01 vs. hypoxia). Hypoxia also decreased the GSIS index compared to the control (0.68±0.42 vs. 4.80±1.98, p < 0.01), and adenosine prevented this reduction in the GSIS index (3.41±0.80, p<0.01 vs. hypoxia).

Conclusions/perspectives: These findings suggest that adenosine preconditioning offers a simple and effective strategy to enhance HI survival and function during the transplantation process, by downregulating islet metabolism and insulin content, enhancing resistance to hypoxia. This approach holds potential for integration into various stages of beta-cell replacement therapies, including islet culture, encapsulation, and 3D bioprinting. It also presents opportunities for improving outcomes in alternative transplantation sites, such as the subcutaneous space. In conclusion, adenosine preconditioning represents a promising avenue for mitigating ischemia-reperfusion injuries in cell therapies for type 1 diabetes, paving the way for more efficient and resilient beta-cell replacement strategies.