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.
Pubmed ID: 22608007 RIS Download
Adenosine | Adenosine-5'-(N-ethylcarboxamide) | Animals | Blood Glucose | Cell Proliferation | Cell Survival | Diabetes Mellitus, Experimental | Drug Evaluation, Preclinical | Insulin-Secreting Cells | Larva | Mice | Pancreas | Purinergic P1 Receptor Agonists | Receptor, Adenosine A2A | Regeneration | Zebrafish | Zebrafish Proteins