Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adult
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Animals
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Antipsychotic Agents / pharmacology
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Autocrine Communication*
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Benzodiazepines / pharmacology
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Blood Glucose
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Cells, Cultured
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Clozapine / pharmacology
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Dopamine / metabolism
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Dopamine / physiology*
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Dopamine D2 Receptor Antagonists
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Dopamine Plasma Membrane Transport Proteins / antagonists & inhibitors
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Dopamine Plasma Membrane Transport Proteins / genetics
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Dopamine Plasma Membrane Transport Proteins / metabolism
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Feedback, Physiological
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Gene Expression
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Glucose / physiology
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Humans
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Insulin / genetics
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Insulin / metabolism*
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Insulin Secretion
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Insulin-Secreting Cells / drug effects
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Insulin-Secreting Cells / metabolism
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Male
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Olanzapine
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Pancreas / cytology
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Pancreas / metabolism
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Protein Transport
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Rats
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Rats, Sprague-Dawley
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Rats, Zucker
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Receptors, Dopamine D2 / genetics
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Receptors, Dopamine D2 / metabolism
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Tetrabenazine / pharmacology
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Vesicular Monoamine Transport Proteins / antagonists & inhibitors
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Vesicular Monoamine Transport Proteins / genetics
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Vesicular Monoamine Transport Proteins / metabolism
Substances
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Antipsychotic Agents
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Blood Glucose
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Dopamine D2 Receptor Antagonists
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Dopamine Plasma Membrane Transport Proteins
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Insulin
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Receptors, Dopamine D2
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SLC18A2 protein, human
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SLC6A3 protein, human
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Vesicular Monoamine Transport Proteins
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Benzodiazepines
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Glucose
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Clozapine
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Olanzapine
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Dopamine
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Tetrabenazine