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Title page for ETD etd-11302012-115134


Type of Document Dissertation
Author Ustione, Alessandro
URN etd-11302012-115134
Title Dopaminergic regulation of insulin secretion from the pancreatic islet
Degree PhD
Department Molecular Physiology and Biophysics
Advisory Committee
Advisor Name Title
Aurelio Galli Committee Chair
Anne Kenworthy Committee Member
Kevin Currie Committee Member
Roger Colbran Committee Member
Keywords
  • pancreatic islet
  • dopamine
  • dopamine receptor
  • dopamine transporter
  • diabetes
  • insulin secretion
Date of Defense 2012-10-25
Availability unrestricted
Abstract
Insulin secretion is the natural response to hyperglycemia, and it is crucial to maintain glucose homeostasis in healthy individuals. Impairment in this regulation eventually results in Type-2 diabetes. From the perspective of finding new drug targets, it is fundamental to investigate stimuli other than glucose that regulate insulin secretion. I focused my study on dopamine, based on previous literature that showed its role as an inhibitor of insulin secretion. I tested the hypothesis that the islets synthesize dopamine from the circulating precursor L dopa. I observed a dose-dependent inhibition of glucose-stimulated insulin secretion (GSIS) by combining L-dopa and glucose. The inhibition was attributed to increased intracellular dopamine content. I measured a dose dependent decrease in the frequency of the [Ca2+]i oscillations when the islets were treated with dopamine. Also, I investigated which dopamine receptor (DR) is active in the islets. The data show that while DRD2 and DRD3 are both present in the islets, only the antagonism of DRD3 abolished the effects of dopamine, enhanced GSIS in untreated islets, and increased the frequency of [Ca2+]i oscillations. I verified that dopamine transporter also is expressed in the islets, and its pharmacological inhibition impairs GSIS.

These results depict a dopaminergic negative feedback acting on insulin secretion. Blocking this dopaminergic feedback increases GSIS. Therefore DRD3 is a potential target for new drugs for the treatment of type 2 diabetes.

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