Journal Article Dopamine D2 Receptor-Mediated Regulation of Pancreatic β Cell Mass

Sakano, Daisuke  ,  Choi, Sungik  ,  Kataoka, Masateru  ,  Shiraki, Nobuaki  ,  Uesugi, Motonari  ,  Kume, Kazuhiko  ,  Kume, Shoen

7 ( 1 )  , pp.95 - 109 , 2016-07-12 , Elsevier BV
Understanding the molecular mechanisms that regulate β cell mass and proliferation is important for the treatment of diabetes. Here, we identified domperidone (DPD), a dopamine D2 receptor (DRD2) antagonist that enhances β cell mass. Over time, islet β cell loss occurs in dissociation cultures, and this was inhibited by DPD. DPD increased proliferation and decreased apoptosis of β cells through increasing intracellular cAMP. DPD prevented β cell dedifferentiation, which together highly contributed to the increased β cell mass. DRD2 knockdown phenocopied the effects of domperidone and increased the number of β cells. Drd2 overexpression sensitized the dopamine responsiveness of β cells and increased apoptosis. Further analysis revealed that the adenosine agonist 5′-N-ethylcarboxamidoadenosine, a previously identified promoter of β cell proliferation, acted with DPD to increase the number of β cells. In humans, dopamine also modulates β cell mass through DRD2 and exerts an inhibitory effect on adenosine signaling.

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