Adenosine Signaling Promotes Regeneration of Pancreatic β Cells In Vivo

Diabetes can be controlled with insulin injections, but a curative approach that restores the number of insulin-producing beta cells is still needed. Using a zebrafish model of diabetes, we screened 7,000 small molecules to identify enhancers of beta cell regeneration. The compounds we identified converge on the adenosine signaling pathway and include exogenous agonists and compounds that inhibit degradation of endogenously produced adenosine. The most potent enhancer of beta cell regeneration was the adenosine agonist 5'-N-ethylcarboxamidoadenosine (NECA), which, acting through the adenosine receptor A2aa, increased beta cell proliferation and accelerated restoration of normoglycemia in zebrafish. Despite markedly stimulating beta cell proliferation during regeneration, NECA had only a modest effect during development. The proliferative and glucose-lowering effect of NECA was confirmed in diabetic mice, suggesting an evolutionarily conserved role for adenosine in beta cell regeneration. With this whole-organism screen, we identified components of the adenosine pathway that could be therapeutically targeted for the treatment of diabetes.