Adenosine Signaling Promotes Regeneration of Pancreatic beta Cells In Vivo
- Authors
- Andersson, O., Adams, B.A., Yoo, D., Ellis, G.C., Gut, P., Anderson, R.M., German, M.S., and Stainier, D.Y.
- ID
- ZDB-PUB-120529-1
- Date
- 2012
- Source
- Cell Metabolism 15(6): 885-894 (Journal)
- Registered Authors
- Anderson, Ryan, Ellis, Greg, Gut, Philipp, Stainier, Didier, Yoo, Daniel
- Keywords
- none
- MeSH Terms
-
- Adenosine/metabolism
- Adenosine/physiology*
- Adenosine-5'-(N-ethylcarboxamide)/pharmacology*
- Adenosine-5'-(N-ethylcarboxamide)/therapeutic use
- Animals
- Blood Glucose
- Cell Proliferation/drug effects
- Cell Survival/drug effects
- Diabetes Mellitus, Experimental/drug therapy
- Diabetes Mellitus, Experimental/pathology
- Drug Evaluation, Preclinical
- Insulin-Secreting Cells/drug effects
- Insulin-Secreting Cells/metabolism*
- Insulin-Secreting Cells/physiology
- Larva/drug effects
- Mice
- Pancreas/drug effects
- Pancreas/pathology
- Pancreas/physiology
- Purinergic P1 Receptor Agonists/pharmacology*
- Purinergic P1 Receptor Agonists/therapeutic use
- Receptor, Adenosine A2A/metabolism
- Regeneration
- Zebrafish
- Zebrafish Proteins/metabolism
- PubMed
- 22608007 Full text @ Cell Metab.
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 52-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.