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Dopamine-mediated autocrine inhibitory circuit regulating human insulin secretion in vitro

Norman Simpson1, Antonella Maffei, Matthew Freeby

  • 1Division of Endocrinology, Department of Medicine, Columbia University Medical College, 650 West 168th Street, BB 2006, New York, New York 10032, USA.

Molecular Endocrinology (Baltimore, Md.)
|August 24, 2012
PubMed

Insights

Dopamine (DA) released from human islet cells during glucose stimulation acts as a brake on insulin secretion. Blocking this dopamine signaling pathway enhances insulin release, potentially explaining side effects of certain medications.

Area of Science:

  • Endocrinology
  • Neuroscience
  • Cell Biology

Background:

  • Glucose-stimulated insulin secretion (GSIS) is crucial for maintaining glucose homeostasis.
  • Autocrine regulatory mechanisms within pancreatic beta cells fine-tune insulin release.
  • The role of neurotransmitters like dopamine in islet function is not fully elucidated.

Purpose of the Study:

  • To investigate the role of dopamine in regulating glucose-stimulated insulin secretion in human islets.
  • To identify the specific molecular players involved in dopamine signaling within beta cells.
  • To explore the potential link between islet dopamine signaling and metabolic side effects of medications.

Main Methods:

  • Purified human islets were used for in vitro experiments.
  • Chronoamperometry was employed to measure dopamine release.
  • In vitro glucose-stimulated insulin secretion assays were performed.
  • Pharmacological antagonism of dopamine receptors (D2R) was utilized.

Main Results:

  • Dopamine (DA) is released from human beta cells upon glucose stimulation.
  • DA is stored in secretory granules via vesicular monoamine transporter type 2 (VMAT2).
  • DA acts as a negative autocrine regulator of insulin secretion by binding to D2 receptors on beta cells.
  • Antagonism of D2 receptors significantly increased glucose-stimulated insulin secretion.

Conclusions:

  • A novel negative feedback loop involving dopamine in human islet autocrine regulation of insulin secretion has been identified.
  • This dopamine-D2 receptor pathway provides a brake on insulin release, modulated by glucose levels.
  • These findings offer insights into the metabolic consequences, such as increased adiposity, associated with atypical antipsychotic use, which can affect dopamine signaling.

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