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Novel Zn(2+) Modulated GPR39 Receptor Agonists Do Not Drive Acute Insulin Secretion in Rodents

Type 2 diabetes (T2D) occurs when there is insufficient insulin release to control blood glucose, due to insulin resistance and impaired β-cell function. The GPR39 receptor is expressed in metabolic tissues including pancreatic β-cells and has been proposed as a T2D target. Specifically, GPR39 agoni...

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Autores principales: Fjellström, Ola, Larsson, Niklas, Yasuda, Shin-ichiro, Tsuchida, Takuma, Oguma, Takahiro, Marley, Anna, Wennberg-Huldt, Charlotte, Hovdal, Daniel, Fukuda, Hajime, Yoneyama, Yukimi, Sasaki, Kazuyo, Johansson, Anders, Lundqvist, Sara, Brengdahl, Johan, Isaacs, Richard J., Brown, Daniel, Geschwindner, Stefan, Benthem, Lambertus, Priest, Claire, Turnbull, Andrew
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4697807/
https://www.ncbi.nlm.nih.gov/pubmed/26720709
http://dx.doi.org/10.1371/journal.pone.0145849
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author Fjellström, Ola
Larsson, Niklas
Yasuda, Shin-ichiro
Tsuchida, Takuma
Oguma, Takahiro
Marley, Anna
Wennberg-Huldt, Charlotte
Hovdal, Daniel
Fukuda, Hajime
Yoneyama, Yukimi
Sasaki, Kazuyo
Johansson, Anders
Lundqvist, Sara
Brengdahl, Johan
Isaacs, Richard J.
Brown, Daniel
Geschwindner, Stefan
Benthem, Lambertus
Priest, Claire
Turnbull, Andrew
author_facet Fjellström, Ola
Larsson, Niklas
Yasuda, Shin-ichiro
Tsuchida, Takuma
Oguma, Takahiro
Marley, Anna
Wennberg-Huldt, Charlotte
Hovdal, Daniel
Fukuda, Hajime
Yoneyama, Yukimi
Sasaki, Kazuyo
Johansson, Anders
Lundqvist, Sara
Brengdahl, Johan
Isaacs, Richard J.
Brown, Daniel
Geschwindner, Stefan
Benthem, Lambertus
Priest, Claire
Turnbull, Andrew
author_sort Fjellström, Ola
collection PubMed
description Type 2 diabetes (T2D) occurs when there is insufficient insulin release to control blood glucose, due to insulin resistance and impaired β-cell function. The GPR39 receptor is expressed in metabolic tissues including pancreatic β-cells and has been proposed as a T2D target. Specifically, GPR39 agonists might improve β-cell function leading to more adequate and sustained insulin release and glucose control. The present study aimed to test the hypothesis that GPR39 agonism would improve glucose stimulated insulin secretion in vivo. A high throughput screen, followed by a medicinal chemistry program, identified three novel potent Zn(2+) modulated GPR39 agonists. These agonists were evaluated in acute rodent glucose tolerance tests. The results showed a lack of glucose lowering and insulinotropic effects not only in lean mice, but also in diet-induced obese (DIO) mice and Zucker fatty rats. It is concluded that Zn(2+) modulated GPR39 agonists do not acutely stimulate insulin release in rodents.
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spelling pubmed-46978072016-01-13 Novel Zn(2+) Modulated GPR39 Receptor Agonists Do Not Drive Acute Insulin Secretion in Rodents Fjellström, Ola Larsson, Niklas Yasuda, Shin-ichiro Tsuchida, Takuma Oguma, Takahiro Marley, Anna Wennberg-Huldt, Charlotte Hovdal, Daniel Fukuda, Hajime Yoneyama, Yukimi Sasaki, Kazuyo Johansson, Anders Lundqvist, Sara Brengdahl, Johan Isaacs, Richard J. Brown, Daniel Geschwindner, Stefan Benthem, Lambertus Priest, Claire Turnbull, Andrew PLoS One Research Article Type 2 diabetes (T2D) occurs when there is insufficient insulin release to control blood glucose, due to insulin resistance and impaired β-cell function. The GPR39 receptor is expressed in metabolic tissues including pancreatic β-cells and has been proposed as a T2D target. Specifically, GPR39 agonists might improve β-cell function leading to more adequate and sustained insulin release and glucose control. The present study aimed to test the hypothesis that GPR39 agonism would improve glucose stimulated insulin secretion in vivo. A high throughput screen, followed by a medicinal chemistry program, identified three novel potent Zn(2+) modulated GPR39 agonists. These agonists were evaluated in acute rodent glucose tolerance tests. The results showed a lack of glucose lowering and insulinotropic effects not only in lean mice, but also in diet-induced obese (DIO) mice and Zucker fatty rats. It is concluded that Zn(2+) modulated GPR39 agonists do not acutely stimulate insulin release in rodents. Public Library of Science 2015-12-31 /pmc/articles/PMC4697807/ /pubmed/26720709 http://dx.doi.org/10.1371/journal.pone.0145849 Text en © 2015 Fjellström et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Fjellström, Ola
Larsson, Niklas
Yasuda, Shin-ichiro
Tsuchida, Takuma
Oguma, Takahiro
Marley, Anna
Wennberg-Huldt, Charlotte
Hovdal, Daniel
Fukuda, Hajime
Yoneyama, Yukimi
Sasaki, Kazuyo
Johansson, Anders
Lundqvist, Sara
Brengdahl, Johan
Isaacs, Richard J.
Brown, Daniel
Geschwindner, Stefan
Benthem, Lambertus
Priest, Claire
Turnbull, Andrew
Novel Zn(2+) Modulated GPR39 Receptor Agonists Do Not Drive Acute Insulin Secretion in Rodents
title Novel Zn(2+) Modulated GPR39 Receptor Agonists Do Not Drive Acute Insulin Secretion in Rodents
title_full Novel Zn(2+) Modulated GPR39 Receptor Agonists Do Not Drive Acute Insulin Secretion in Rodents
title_fullStr Novel Zn(2+) Modulated GPR39 Receptor Agonists Do Not Drive Acute Insulin Secretion in Rodents
title_full_unstemmed Novel Zn(2+) Modulated GPR39 Receptor Agonists Do Not Drive Acute Insulin Secretion in Rodents
title_short Novel Zn(2+) Modulated GPR39 Receptor Agonists Do Not Drive Acute Insulin Secretion in Rodents
title_sort novel zn(2+) modulated gpr39 receptor agonists do not drive acute insulin secretion in rodents
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4697807/
https://www.ncbi.nlm.nih.gov/pubmed/26720709
http://dx.doi.org/10.1371/journal.pone.0145849
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