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AMG 837: A Novel GPR40/FFA1 Agonist that Enhances Insulin Secretion and Lowers Glucose Levels in Rodents
Agonists of GPR40 (FFA1) have been proposed as a means to treat type 2 diabetes. Through lead optimization of a high throughput screening hit, we have identified a novel GPR40 agonist called AMG 837. The objective of these studies was to understand the preclinical pharmacological properties of AMG 8...
Autores principales: | , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2011
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3210765/ https://www.ncbi.nlm.nih.gov/pubmed/22087278 http://dx.doi.org/10.1371/journal.pone.0027270 |
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author | Lin, Daniel C.-H. Zhang, Jane Zhuang, Run Li, Frank Nguyen, Kathy Chen, Michael Tran, Thanhvien Lopez, Edwin Lu, Jenny Ying Lin Li, Xiaoyan Nina Tang, Liang Tonn, George R. Swaminath, Gayathri Reagan, Jeff D. Chen, Jin-Long Tian, Hui Lin, Yi-Jyun Houze, Jonathan B. Luo, Jian |
author_facet | Lin, Daniel C.-H. Zhang, Jane Zhuang, Run Li, Frank Nguyen, Kathy Chen, Michael Tran, Thanhvien Lopez, Edwin Lu, Jenny Ying Lin Li, Xiaoyan Nina Tang, Liang Tonn, George R. Swaminath, Gayathri Reagan, Jeff D. Chen, Jin-Long Tian, Hui Lin, Yi-Jyun Houze, Jonathan B. Luo, Jian |
author_sort | Lin, Daniel C.-H. |
collection | PubMed |
description | Agonists of GPR40 (FFA1) have been proposed as a means to treat type 2 diabetes. Through lead optimization of a high throughput screening hit, we have identified a novel GPR40 agonist called AMG 837. The objective of these studies was to understand the preclinical pharmacological properties of AMG 837. The activity of AMG 837 on GPR40 was characterized through GTPγS binding, inositol phosphate accumulation and Ca(2+) flux assays. Activity of AMG 837 on insulin release was assessed on isolated primary mouse islets. To determine the anti-diabetic activity of AMG 837 in vivo, we tested AMG 837 using a glucose tolerance test in normal Sprague-Dawley rats and obese Zucker fatty rats. AMG 837 was a potent partial agonist in the calcium flux assay on the GPR40 receptor and potentiated glucose stimulated insulin secretion in vitro and in vivo. Acute administration of AMG 837 lowered glucose excursions and increased glucose stimulated insulin secretion during glucose tolerance tests in both normal and Zucker fatty rats. The improvement in glucose excursions persisted following daily dosing of AMG 837 for 21-days in Zucker fatty rats. Preclinical studies demonstrated that AMG 837 was a potent GPR40 partial agonist which lowered post-prandial glucose levels. These studies support the potential utility of AMG 837 for the treatment of type 2 diabetes. |
format | Online Article Text |
id | pubmed-3210765 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-32107652011-11-15 AMG 837: A Novel GPR40/FFA1 Agonist that Enhances Insulin Secretion and Lowers Glucose Levels in Rodents Lin, Daniel C.-H. Zhang, Jane Zhuang, Run Li, Frank Nguyen, Kathy Chen, Michael Tran, Thanhvien Lopez, Edwin Lu, Jenny Ying Lin Li, Xiaoyan Nina Tang, Liang Tonn, George R. Swaminath, Gayathri Reagan, Jeff D. Chen, Jin-Long Tian, Hui Lin, Yi-Jyun Houze, Jonathan B. Luo, Jian PLoS One Research Article Agonists of GPR40 (FFA1) have been proposed as a means to treat type 2 diabetes. Through lead optimization of a high throughput screening hit, we have identified a novel GPR40 agonist called AMG 837. The objective of these studies was to understand the preclinical pharmacological properties of AMG 837. The activity of AMG 837 on GPR40 was characterized through GTPγS binding, inositol phosphate accumulation and Ca(2+) flux assays. Activity of AMG 837 on insulin release was assessed on isolated primary mouse islets. To determine the anti-diabetic activity of AMG 837 in vivo, we tested AMG 837 using a glucose tolerance test in normal Sprague-Dawley rats and obese Zucker fatty rats. AMG 837 was a potent partial agonist in the calcium flux assay on the GPR40 receptor and potentiated glucose stimulated insulin secretion in vitro and in vivo. Acute administration of AMG 837 lowered glucose excursions and increased glucose stimulated insulin secretion during glucose tolerance tests in both normal and Zucker fatty rats. The improvement in glucose excursions persisted following daily dosing of AMG 837 for 21-days in Zucker fatty rats. Preclinical studies demonstrated that AMG 837 was a potent GPR40 partial agonist which lowered post-prandial glucose levels. These studies support the potential utility of AMG 837 for the treatment of type 2 diabetes. Public Library of Science 2011-11-08 /pmc/articles/PMC3210765/ /pubmed/22087278 http://dx.doi.org/10.1371/journal.pone.0027270 Text en Lin 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 Lin, Daniel C.-H. Zhang, Jane Zhuang, Run Li, Frank Nguyen, Kathy Chen, Michael Tran, Thanhvien Lopez, Edwin Lu, Jenny Ying Lin Li, Xiaoyan Nina Tang, Liang Tonn, George R. Swaminath, Gayathri Reagan, Jeff D. Chen, Jin-Long Tian, Hui Lin, Yi-Jyun Houze, Jonathan B. Luo, Jian AMG 837: A Novel GPR40/FFA1 Agonist that Enhances Insulin Secretion and Lowers Glucose Levels in Rodents |
title | AMG 837: A Novel GPR40/FFA1 Agonist that Enhances Insulin Secretion and Lowers Glucose Levels in Rodents |
title_full | AMG 837: A Novel GPR40/FFA1 Agonist that Enhances Insulin Secretion and Lowers Glucose Levels in Rodents |
title_fullStr | AMG 837: A Novel GPR40/FFA1 Agonist that Enhances Insulin Secretion and Lowers Glucose Levels in Rodents |
title_full_unstemmed | AMG 837: A Novel GPR40/FFA1 Agonist that Enhances Insulin Secretion and Lowers Glucose Levels in Rodents |
title_short | AMG 837: A Novel GPR40/FFA1 Agonist that Enhances Insulin Secretion and Lowers Glucose Levels in Rodents |
title_sort | amg 837: a novel gpr40/ffa1 agonist that enhances insulin secretion and lowers glucose levels in rodents |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3210765/ https://www.ncbi.nlm.nih.gov/pubmed/22087278 http://dx.doi.org/10.1371/journal.pone.0027270 |
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