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.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-11302012-115134 |
| Date | 11 December 2012 |
| Creators | Ustione, Alessandro |
| Contributors | Aurelio Galli, Roger Colbran, Kevin Currie, Anne Kenworthy |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-11302012-115134/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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