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 β cells is still needed. Using a zebrafish model of diabetes, we screened ∼7,000 small molecules to identify enhancers of β 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 β cell regeneration was the adenosine agonist 5′-N-ethylcarboxamidoadenosine (NECA), which, acting through the adenosine receptor A2aa, increased β cell proliferation and accelerated restoration of normoglycemia in zebrafish. Despite markedly stimulating β 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 β cell regeneration. With this whole-organism screen, we identified components of the adenosine pathway that could be therapeutically targeted for the treatment of diabetes. ► An in vivo screen identifies adenosine signaling as a promoter of β cell regeneration ► The adenosine agonist NECA stimulates proliferation of β cells in zebrafish and mouse ► NECA boosts β cell regeneration but only weakly affects β cell development ► Adenosine receptor A2aa mediates NECA-enhanced regeneration of β cells in zebrafish