High-throughput In Vivo Small Molecule Screen for Beta Cell Regeneration in Transgenic Zebrafish

Diabetes, characterized by elevated blood glucose levels due to insufficient insulin or insulin resistance, often results from the depletion of insulin-producing β cells. While diabetes can be controlled with insulin injections, a curative approach to restore β cell numbers is needed. This study used a zebrafish model of diabetes to screen approximately 7,000 small molecules, identifying enhancers of β cell regeneration that converge on the adenosine signaling pathway. These compounds included exogenous agonists and inhibitors of adenosine degradation. The most potent enhancer, the adenosine agonist 5′-N-ethylcarboxamidoadenosine (NECA), acting through the adenosine receptor A2aa, increased β cell proliferation and accelerated normoglycemia restoration in zebrafish. NECA’s effects were confirmed in diabetic mice, suggesting an evolutionarily conserved role for adenosine in β cell regeneration. Although NECA significantly stimulated β cell proliferation during regeneration, it had only a modest effect during development. This study’s whole-organism screen in diabetic mice identified adenosine pathway components that could be therapeutically targeted to treat diabetes, offering a potential approach to enhance β cell regeneration and improve patient outcomes.

Publication reference: Andersson, O. et al., Cell Metabolism, 2012, 15(6), 885-894.