Dopamine-mediated autocrine inhibitory circuit regulating human insulin secretion in vitro.
We describe a negative feedback autocrine regulatory circuit for glucose-stimulated insulin secretion in purified human islets in vitro. Using chronoamperometry and in vitro glucose-stimulated insulin secretion measurements, evidence is provided that dopamine (DA), which is loaded into insulin-containing secretory granules by vesicular monoamine transporter type 2 in human β-cells, is released in response to glucose stimulation. DA then acts as a negative regulator of insulin secretion via its action on D2R, which are also expressed on β-cells. We found that antagonism of receptors participating in islet DA signaling generally drive increased glucose-stimulated insulin secretion. These in vitro observations may represent correlates of the in vivo metabolic changes associated with the use of atypical antipsychotics, such as increased adiposity.
Division of Endocrinology, Department of Medicine, Columbia University Medical College, 650 West 168th Street, BB 2006, New York, New York 10032, USA.
Norman
N
Simpson
Antonella
A
Maffei
Matthew
M
Freeby
Steven
S
Burroughs
Zachary
Z
Freyberg
Jonathan
J
Javitch
Rudolph L
RL
Leibel
Paul E
PE
Harris
D000328:Adult; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D019898:Autocrine Communication; D001569:Benzodiazepines / Q000494:pharmacology; D001786:Blood Glucose; D002478:Cells, Cultured; D003024:Clozapine / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism / Q000502:physiology*; D065127:Dopamine D2 Receptor Antagonists; D050483:Dopamine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D025461:Feedback, Physiological; D015870:Gene Expression; D005947:Glucose / Q000502:physiology; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism; D008297:Male; D000077152:Olanzapine; D010179:Pancreas / Q000166:cytology / Q000378:metabolism; D021381:Protein Transport; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000378:metabolism; D013747:Tetrabenazine / Q000494:pharmacology; D050493:Vesicular Monoamine Transport Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
D014150:Antipsychotic Agents; D001786:Blood Glucose; D065127:Dopamine D2 Receptor Antagonists; D050483:Dopamine Plasma Membrane Transport Proteins; D007328:Insulin; D017448:Receptors, Dopamine D2; C493452:SLC18A2 protein, human; C493214:SLC6A3 protein, human; D050493:Vesicular Monoamine Transport Proteins; D001569:Benzodiazepines; D005947:Glucose; D003024:Clozapine; D000077152:Olanzapine; D004298:Dopamine; D013747:Tetrabenazine