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Estrogen and Serotonin – old dogs, new tricks, Implications for pancreatic beta-cell function

Author

  • Alexander Balhuizen

Summary, in English

Islet hormone secretion is tightly regulated by metabolic status as well as local and circulating factors. These factors can activate different receptors on the pancreatic islet cells, for instance G-protein coupled receptors (GPCRs). When activated, these receptors are able to fine-tune islet hormone secretion and regulate overall β-cell function.

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

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

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