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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

Authors

  • Andersson O
  • Adams BA
  • Yoo D
  • Ellis GC
  • Gut P
  • Anderson RM
  • German MS
  • Stainier DY

Journal

Cell metabolism

Publication Data

June 6, 2012

Associated Grants

  • Agency: NIDDK NIH HHS, Id: R01 DK075032
  • Agency: NIDDK NIH HHS, Id: R01DK075032
  • Agency: NIDDK NIH HHS, Id: T32 DK007418
  • Agency: NIDDK NIH HHS, Id: U01 DK089541
  • Agency: NIDDK NIH HHS, Id: U01DK089541

Mesh Terms

  • 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