Estrogen and Serotonin – old dogs, new tricks, Implications for pancreatic beta-cell function
Author
Summary, in English
Estrogen and serotonin are circulating factors that bind to GPCRs. First, we studied the activation of GPER-1 in pancreatic islets using two agonists G-1 and Estrogen (E2). Both G-1 and E2 displayed a similar response in mouse and human islets even in the presence of estrogen receptor blockers, ICI 182, 720 and EM652. G-1 and E2 potentiated insulin secretion and inhibited glucagon and somatostatin secretion. G-1 induced cAMP generation, suggesting positive coupling to adenylate cyclase and a subsequent rise in insulin release. Furthermore both agonists protected pancreatic islets from cytokine-induced apoptosis via activation of anti-apoptotic signals, CREB, ERK1/2 and AKT and reduced phosphorylation of the pro-apoptotic signals SAPK/JNK and p38.
Second, we studied serotonin (5-HT) receptors in human islets and INS (832/13) cells. We detected 15 different 5-HT receptors and the 5-HT producing enzymes, TPH1 and TPH2 as well as DDC. Cellular localization for 5-HT1A, 5-HT1D and 5-HT2A were observed in both β- and α-cells; while 5-HT2B was only present in β-cells. Agonists targeting these four receptors were able to either inhibit or stimulate insulin secretion from human islets and INS (832/13) cells. In addition, 5-HT was quantified using GC/MS in INS (832/13) cells, rat islets and detected in human α and β-cells with immunohistochemistry.
Third, we investigated the peripheral role of a 5-HT2 receptor agonist, α-methyl serotonin maleate salt (AMS) in insulin resistance and β cell function. Long-term treatment with AMS in a high fat diet fed mouse model resulted in increased insulin sensitivity in vivo in high fat fed AMS treated mice. Moreover, insulin secretion from AMS treated control fed mice in vitro was decreased while plasma glucose levels were similar in vivo between AMS treated and untreated controls. In addition, AMS mediated protection from lipotoxicity in INS-1(832/13) cells.
In conclusion, this thesis contributes to increased understanding of how estrogen and peripheral 5-HT mediate their effects on islet function and overall glucose homeostasis.
Publishing year
2013
Language
English
Publication/Series
Lund University Faculty of Medicine Doctoral Dissertation Series
Volume
2013:123
Full text
Document type
Dissertation
Publisher
Diabetes and Celiac Unit
Topic
- Endocrinology and Diabetes
Keywords
- Diabetes
- Estrogen
- Serotonin
- Pancreatic islets
- Insulin resistance
- Beta-cell function
- GPCR
Status
Published
Research group
- Celiac Disease and Diabetes Unit
Supervisor
- Malin Fex
- Leif Groop
ISBN/ISSN/Other
- ISSN: 1652-8220
- ISBN: 978-91-87449-96-3
Defence date
15 November 2013
Defence time
09:00
Defence place
‘Lilla aulan’, Medicinskt Forskningscentrum, Jan Waldenströms gata 5, Malmö
Opponent
- Jens Høiriis Nielsen