Abstract
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.
Adenosine-treated human islets (1mM for 24h) were then subjected to 48h of hypoxia (1% O2), followed by 2h of reperfusion (culturing in full oxygenated medium, 21% O2), and then directly analyzed for viability (confocal imaging) and function by glucose-stimulated insulin secretion (GSIS) index (an index>2 suggested functional islets).
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).
Adenosine preconditioning can protect human islets from the impact of hypoxia. These findings provide a strong support for incorporating adenosine preconditioning in bioengineered islet grafts for cell therapy in diabetes, to protect islets from necrosis that often occurs early during the engraftment period due to insufficient oxygen supply.