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Insulinotropic and Antidiabetic Effects of 17{beta}-Estradiol and the GPR30 Agonist G-1 on Human Pancreatic Islets.

Kumar, Rajesh LU ; Balhuizen, Alexander LU ; Amisten, Stefan LU ; Lundquist, Ingmar LU and Salehi, S Albert LU (2011) In Endocrinology 152(7). p.2568-2579
Abstract
We have recently shown that 17β-estradiol (E2) and the synthetic G protein-coupled receptor 30 (GPR30) ligand G-1 have antiapoptotic actions in mouse pancreatic islets, raising the prospect that they might exert beneficial effects also in human islets. The objective of the present study was to identify the expression of GPR30 in human islets and clarify the role of GPR30 in islet hormone secretion and β-cell survival. GPR30 expression was analyzed by confocal microscopy, Western blot, and quantitative PCR in islets from female and male donors. Hormone secretion, phosphatidylinositol hydrolysis, cAMP content, and caspase-3 activity in female islets were determined with conventional methods and apoptosis with the annexin-V method. Confocal... (More)
We have recently shown that 17β-estradiol (E2) and the synthetic G protein-coupled receptor 30 (GPR30) ligand G-1 have antiapoptotic actions in mouse pancreatic islets, raising the prospect that they might exert beneficial effects also in human islets. The objective of the present study was to identify the expression of GPR30 in human islets and clarify the role of GPR30 in islet hormone secretion and β-cell survival. GPR30 expression was analyzed by confocal microscopy, Western blot, and quantitative PCR in islets from female and male donors. Hormone secretion, phosphatidylinositol hydrolysis, cAMP content, and caspase-3 activity in female islets were determined with conventional methods and apoptosis with the annexin-V method. Confocal microscopy revealed GPR30 expression in islet insulin, glucagon, and somatostatin cells. GPR30 mRNA and protein expression was markedly higher in female vs. male islets. An amplifying effect of G-1 or E2 on cAMP content and insulin secretion from isolated female islets was not influenced by the E2 genomic receptor (ERα and ERβ) antagonists ICI 182,780 and EM-652. Cytokine-induced (IL-1β plus TNFα plus interferon-γ) apoptosis in islets cultured for 24 h at 5 mmol/liter glucose was almost abolished by G-1 or E2 treatment and was not affected by the nuclear estrogen receptor antagonists. Concentration-response studies on female islets from healthy controls and type 2 diabetic subjects showed that both E2 and G-1 displayed important antidiabetic actions by improving glucose-stimulated insulin release while suppressing glucagon and somatostatin secretion. In view of these findings, we propose that small molecules activating GPR30 could be promising in the therapy of diabetes mellitus. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Endocrinology
volume
152
issue
7
pages
2568 - 2579
publisher
Endocrine Society
external identifiers
  • wos:000291925700006
  • pmid:21521748
  • scopus:79959457594
ISSN
0013-7227
DOI
10.1210/en.2010-1361
language
English
LU publication?
yes
id
0be2b1f6-d0c8-4c64-946c-75fbd96d466c (old id 1936666)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/21521748?dopt=Abstract
date added to LUP
2011-05-02 16:30:33
date last changed
2017-10-08 03:00:32
@article{0be2b1f6-d0c8-4c64-946c-75fbd96d466c,
  abstract     = {We have recently shown that 17β-estradiol (E2) and the synthetic G protein-coupled receptor 30 (GPR30) ligand G-1 have antiapoptotic actions in mouse pancreatic islets, raising the prospect that they might exert beneficial effects also in human islets. The objective of the present study was to identify the expression of GPR30 in human islets and clarify the role of GPR30 in islet hormone secretion and β-cell survival. GPR30 expression was analyzed by confocal microscopy, Western blot, and quantitative PCR in islets from female and male donors. Hormone secretion, phosphatidylinositol hydrolysis, cAMP content, and caspase-3 activity in female islets were determined with conventional methods and apoptosis with the annexin-V method. Confocal microscopy revealed GPR30 expression in islet insulin, glucagon, and somatostatin cells. GPR30 mRNA and protein expression was markedly higher in female vs. male islets. An amplifying effect of G-1 or E2 on cAMP content and insulin secretion from isolated female islets was not influenced by the E2 genomic receptor (ERα and ERβ) antagonists ICI 182,780 and EM-652. Cytokine-induced (IL-1β plus TNFα plus interferon-γ) apoptosis in islets cultured for 24 h at 5 mmol/liter glucose was almost abolished by G-1 or E2 treatment and was not affected by the nuclear estrogen receptor antagonists. Concentration-response studies on female islets from healthy controls and type 2 diabetic subjects showed that both E2 and G-1 displayed important antidiabetic actions by improving glucose-stimulated insulin release while suppressing glucagon and somatostatin secretion. In view of these findings, we propose that small molecules activating GPR30 could be promising in the therapy of diabetes mellitus.},
  author       = {Kumar, Rajesh and Balhuizen, Alexander and Amisten, Stefan and Lundquist, Ingmar and Salehi, S Albert},
  issn         = {0013-7227},
  language     = {eng},
  number       = {7},
  pages        = {2568--2579},
  publisher    = {Endocrine Society},
  series       = {Endocrinology},
  title        = {Insulinotropic and Antidiabetic Effects of 17{beta}-Estradiol and the GPR30 Agonist G-1 on Human Pancreatic Islets.},
  url          = {http://dx.doi.org/10.1210/en.2010-1361},
  volume       = {152},
  year         = {2011},
}