Critical role for adenosine receptor A2a in β-cell proliferation

Objective: Pharmacological activation of adenosine signaling has been shown to increase beta-cell proliferation and thereby beta-cell regeneration in zebrafish and rodent models of diabetes. However, whether adenosine has an endogenous role in regulating beta-cell proliferation is unknown. The objective of this study was to determine whether endogenous adenosine regulates beta-cell proliferation-either in the basal state or states of increased demand for insulin-and to delineate the mechanisms involved. Methods: We analyzed the effect of pharmacological adenosine agonists on beta-cell proliferation in in vitro cultures of mouse islets and in zebrafish models with beta- or delta-cell ablation. In addition, we performed physiological and histological characterization of wild-type mice and mutant mice with pancreas-or beta-cell-specific deficiency in Adora2a (the gene encoding adenosine receptor A2a). The mutant mice were used for in vivo studies on the role of adenosine in the basal state and during pregnancy (a state of increased demand for insulin), as well as for in vitro studies of cultured islets. Results: Pharmacological adenosine signaling in zebrafish had a stronger effect on beta-cell proliferation during beta-cell regeneration than in the basal state, an effect that was independent of the apoptotic microenvironment of the regeneration model. In mice, deficiency in Adora2a impaired glucose control and diminished compensatory beta-cell proliferation during pregnancy but did not have any overt phenotype in the basal state. Islets isolated from Adora2a-deficient mice had a reduced baseline level of beta-cell proliferation in vitro, consistent with our finding that UK432097, an A2a-specific agonist, promotes the proliferation of mouse beta-cells in vitro. Conclusions: This is the first study linking endogenously produced adenosine to beta-cell proliferation. Moreover, we show that adenosine signaling via the A2a receptor has an important role in compensatory beta-cell proliferation, a feature that could be harnessed pharmacologically for beta-cell expansion and future therapeutic development for diabetes. (C) 2016 The Author(s). Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).