Print Email Facebook Twitter The dopamine receptor D2 agonist bromocriptine inhibits glucose-stimulated insulin secretion by direct activation of the α2-adrenergic receptors in beta cells Title The dopamine receptor D2 agonist bromocriptine inhibits glucose-stimulated insulin secretion by direct activation of the α2-adrenergic receptors in beta cells Author de Leeuw van Weenen, J.E. Parlevliet, E.T. Maechler, P. Havekes, L.M. Romijn, J.A. Ouwens, D.M. Pijl, H. Guigas, B. TNO Kwaliteit van Leven Publication year 2010 Abstract Treatment with the dopamine receptor D2 (DRD2) agonist bromocriptine improves metabolic features in obese patients with type 2 diabetes by a still unknown mechanism. In the present study, we investigated the acute effect of bromocriptine and its underlying mechanism(s) on insulin secretion both in vivo and in vitro. For this purpose, C57Bl6/J mice were subjected to an intraperitoneal glucose tolerance test (ipGTT) and a hyperglycemic (HG) clamp 60. min after a single injection of bromocriptine or placebo. The effects of bromocriptine on glucose-stimulated insulin secretion (GSIS), cell membrane potential and intracellular cAMP levels were also determined in INS-1E beta cells. We report here that bromocriptine increased glucose levels during ipGTT in vivo, an effect associated with a dose-dependent decrease in GSIS. During the HG clamp, bromocriptine reduced both first-phase and second-phase insulin response. This inhibitory effect was also observed in INS-1E beta cells, in which therapeutic concentrations of bromocriptine (0.5-50. nM) decreased GSIS. Mechanistically, neither cellular energy state nor cell membrane depolarization was affected by bromocriptine whereas intracellular cAMP levels were significantly reduced, suggesting involvement of G-protein-coupled receptors. Surprisingly, the DRD2 antagonist domperidone did not counteract the effect of bromocriptine on GSIS, whereas yohimbine, an antagonist of the α2-adrenergic receptors, completely abolished bromocriptine-induced inhibition of GSIS. In conclusion, acute administration of bromocriptine inhibits GSIS by a DRD2-independent mechanism involving direct activation of the pancreatic α2-adrenergic receptors. We suggest that treatment with bromocriptine promotes beta cells rest, thereby preventing long-lasting hypersecretion of insulin and subsequent beta cell failure. © 2010 Elsevier Inc. Subject BiologyBiomedical Researchα2-Adrenergic receptorBromocriptineDopamine receptorINS-1E cellsInsulin secretionMicealpha 2 adrenergic receptorbromocriptinecyclic AMPdomperidonedopamine 2 receptor stimulating agentG protein coupled receptorglucoseinsulinplaceboyohimbineanalytic methodanimal cellanimal experimentarticlecell linecell membrane depolarizationcell membrane potentialcontrolled studydrug effectglucose clamp techniqueglucose tolerance testhyperglycemiain vitro studyin vivo studyinhibition kineticsinsulin releasemalemousenonhumanpancreas islet beta cellpriority journalWestern blottingAnimalsBromocriptineCell LineDopamine AgonistsDose-Response Relationship, DrugGlucoseInsulinInsulin-Secreting CellsInsulinomaMaleMiceMice, Inbred C57BLRatsReceptors, Adrenergic, alphaReceptors, Dopamine D2 To reference this document use: http://resolver.tudelft.nl/uuid:f868c2bb-e03c-4511-b8f2-fb6d63feb87a TNO identifier 408475 ISSN 0006-2952 Source Biochemical Pharmacology, 79 (12), 1827-1836 Document type article Files To receive the publication files, please send an e-mail request to TNO Library.