title: Adenosine signaling promotes regeneration of pancreatic β cells in vivo.
abstract: 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.
authors.affiliation: Department of Biochemistry and Biophysics, Program in Developmental and Stem Cell Biology and Program in Genetics and Human Genetics, Diabetes Center, Institute for Regeneration Medicine and Liver Center, University of California, San Francisco, 1550 4th Street, San Francisco, CA 94158, USA. olov.andersson@ki.se
authors.forename: Olov
authors.initials: O
authors.lastname: Andersson
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Adams
authors.forename: Daniel
authors.initials: D
authors.lastname: Yoo
authors.forename: Gregory C
authors.initials: GC
authors.lastname: Ellis
authors.forename: Philipp
authors.initials: P
authors.lastname: Gut
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Anderson
authors.forename: Michael S
authors.initials: MS
authors.lastname: German
authors.forename: Didier Y R
authors.initials: DY
authors.lastname: Stainier
mesh_terms: D000241:Adenosine / Q000378:metabolism / Q000502:physiology*; D019830:Adenosine-5'-(N-ethylcarboxamide) / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001786:Blood Glucose; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000473:pathology; D004353:Drug Evaluation, Preclinical; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D007814:Larva / Q000187:drug effects; D051379:Mice; D010179:Pancreas / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D058906:Purinergic P1 Receptor Agonists / Q000494:pharmacology* / Q000627:therapeutic use; D043705:Receptor, Adenosine A2A / Q000378:metabolism; D012038:Regeneration; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D058906:Purinergic P1 Receptor Agonists; D043705:Receptor, Adenosine A2A; D029961:Zebrafish Proteins; D019830:Adenosine-5'-(N-ethylcarboxamide); D000241:Adenosine