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
Biology
Biomedical Research
α2-Adrenergic receptor
Bromocriptine
Dopamine receptor
INS-1E cells
Insulin secretion
Mice
alpha 2 adrenergic receptor
bromocriptine
cyclic AMP
domperidone
dopamine 2 receptor stimulating agent
G protein coupled receptor
glucose
insulin
placebo
yohimbine
analytic method
animal cell
animal experiment
article
cell line
cell membrane depolarization
cell membrane potential
controlled study
drug effect
glucose clamp technique
glucose tolerance test
hyperglycemia
in vitro study
in vivo study
inhibition kinetics
insulin release
male
mouse
nonhuman
pancreas islet beta cell
priority journal
Western blotting
Animals
Bromocriptine
Cell Line
Dopamine Agonists
Dose-Response Relationship, Drug
Glucose
Insulin
Insulin-Secreting Cells
Insulinoma
Male
Mice
Mice, Inbred C57BL
Rats
Receptors, Adrenergic, alpha
Receptors, 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