Adenosine signaling promotes regeneration of pancreatic β cells in vivo

Cell Metab. 2012 Jun 6;15(6):885-94. doi: 10.1016/j.cmet.2012.04.018. Epub 2012 May 17.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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


  • Blood Glucose
  • Purinergic P1 Receptor Agonists
  • Receptor, Adenosine A2A
  • Zebrafish Proteins
  • Adenosine-5'-(N-ethylcarboxamide)
  • Adenosine