Novel insights into the role of serotonin in control of β-cell fuction
Author
Summary, in English
A complete transcriptional mapping of 5-HT receptors in human islets of Langerhans revealed expression of fourteen 5-HT receptors, as well as the enzymes involved in the biosynthesis of 5-HT. Two 5-HT receptor genes (HTR1D and HTR2A) were over-expressed in type 2 diabetic (T2D) islet donors and while 5-HT inhibited both insulin and glucagon secretion in non-diabetic islet donors, 5-HT increased the release of insulin in response to glucose in diabetic T2D islet donors. When investigating the specific function of receptors 5-HT1d and 5-HT2a in non-diabetic islets, we found that a 5-HT1d receptor agonist inhibited insulin release, while a 5-HT1d antagonist potentiated insulin release. Similarly, a 5-HT2a receptor agonist significantly potentiated insulin release, and an antagonist blunted the response of insulin to glucose.
When stimulating human and mouse islets, as well as INS-1 (832/13) cells with a specific 5-HT2b receptor agonist GSIS was enhanced. Moreover, silencing Htr2b in INS-1 (832/13) cells resulted in a 30% reduction in GSIS. In addition, 5-HT2b receptor-activation produced robust, regular and sustained Ca2+ oscillations, paralleled with an increase in oxidative consumption rate in mouse islets.
In vivo studies showed that AMS significantly decreased the insulinogenic index in AMS treated HFD fed mice as compared to untreated mice. Moreover, isolated pancreatic islets from AMS-treated mice given a control diet secreted less insulin in response to glucose compared to islets from untreated control diet fed mice.
Taken together, we show that differential expression levels of 5-HT receptors have functional consequences on islet hormone secretion that may contribute to islet dysfunction as observed in T2D. Furthermore, we provide evidence for an important role of 5-HT2b receptor signaling in control of insulin secretion in vitro. In conclusion, our data suggests an important role for 5-HT signaling in control of islet hormone secretion.
Publishing year
2016
Language
English
Publication/Series
Lund University Faculty of Medicine Doctoral Dissertation Series
Volume
2016:11
Document type
Dissertation
Publisher
Unit of Diabetes and Celiac Disease
Topic
- Cell and Molecular Biology
Status
Published
Research group
- Celiac Disease and Diabetes Unit
Supervisor
ISBN/ISSN/Other
- ISSN: 1652-8220
- ISBN: 978-91-7619-237-5
Defence date
5 February 2016
Defence time
09:00
Defence place
Jubileumsaulan, MFC, Jan Waldenströms gata 5, Skånes Universitetssjukhus i Malmö.
Opponent
- Bryndis Birnir (Professor)