Adenosine signaling promotes regeneration of pancreatic ß cells in vivo.

Diabetes can be controlled with insulin injections, but a curative approach that restores the number of insulin-producing ß cells is still needed. Using a zebrafish model of diabetes, we screened ~7,000 small molecules to identify enhancers of ß 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 ß cell regeneration was the adenosine agonist 5'-N-ethylcarboxamidoadenosine (NECA), which, acting through the adenosine receptor A2aa, increased ß cell proliferation and accelerated restoration of normoglycemia in zebrafish. Despite markedly stimulating ß 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 ß cell regeneration. With this whole-organism screen, we identified components of the adenosine pathway that could be therapeutically targeted for the treatment of diabetes.