A potent class of GPR40 full agonists engages the enteroinsular axis to promote glucose control in rodents.
Type 2 diabetes is characterized by impaired glucose homeostasis due to defects in insulin secretion, insulin resistance and the incretin response. GPR40 (FFAR1 or FFA1) is a G-protein-coupled receptor (GPCR), primarily expressed in insulin-producing pancreatic β-cells and incretin-producing enteroe...
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2012
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oai:doaj.org-article:0849b9dfe7b244fab2862894d28691542021-11-18T08:12:44ZA potent class of GPR40 full agonists engages the enteroinsular axis to promote glucose control in rodents.1932-620310.1371/journal.pone.0046300https://doaj.org/article/0849b9dfe7b244fab2862894d28691542012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23056280/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Type 2 diabetes is characterized by impaired glucose homeostasis due to defects in insulin secretion, insulin resistance and the incretin response. GPR40 (FFAR1 or FFA1) is a G-protein-coupled receptor (GPCR), primarily expressed in insulin-producing pancreatic β-cells and incretin-producing enteroendocrine cells of the small intestine. Several GPR40 agonists, including AMG 837 and TAK-875, have been disclosed, but no GPR40 synthetic agonists have been reported that engage both the insulinogenic and incretinogenic axes. In this report we provide a molecular explanation and describe the discovery of a unique and potent class of GPR40 full agonists that engages the enteroinsular axis to promote dramatic improvement in glucose control in rodents. GPR40 full agonists AM-1638 and AM-6226 stimulate GLP-1 and GIP secretion from intestinal enteroendocrine cells and increase GSIS from pancreatic islets, leading to enhanced glucose control in the high fat fed, streptozotocin treated and NONcNZO10/LtJ mouse models of type 2 diabetes. The improvement in hyperglycemia by AM-1638 was reduced in the presence of the GLP-1 receptor antagonist Ex(9-39)NH(2).Jian LuoGayathri SwaminathSean P BrownJane ZhangQi GuoMichael ChenKathy NguyenThanhvien TranLynn MiaoPaul J DransfieldMarc VimolratanaJonathan B HouzeSimon WongMaria TotevaBei ShanFrank LiRun ZhuangDaniel C-H LinPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 10, p e46300 (2012) |
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DOAJ |
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Medicine R Science Q |
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Medicine R Science Q Jian Luo Gayathri Swaminath Sean P Brown Jane Zhang Qi Guo Michael Chen Kathy Nguyen Thanhvien Tran Lynn Miao Paul J Dransfield Marc Vimolratana Jonathan B Houze Simon Wong Maria Toteva Bei Shan Frank Li Run Zhuang Daniel C-H Lin A potent class of GPR40 full agonists engages the enteroinsular axis to promote glucose control in rodents. |
| description |
Type 2 diabetes is characterized by impaired glucose homeostasis due to defects in insulin secretion, insulin resistance and the incretin response. GPR40 (FFAR1 or FFA1) is a G-protein-coupled receptor (GPCR), primarily expressed in insulin-producing pancreatic β-cells and incretin-producing enteroendocrine cells of the small intestine. Several GPR40 agonists, including AMG 837 and TAK-875, have been disclosed, but no GPR40 synthetic agonists have been reported that engage both the insulinogenic and incretinogenic axes. In this report we provide a molecular explanation and describe the discovery of a unique and potent class of GPR40 full agonists that engages the enteroinsular axis to promote dramatic improvement in glucose control in rodents. GPR40 full agonists AM-1638 and AM-6226 stimulate GLP-1 and GIP secretion from intestinal enteroendocrine cells and increase GSIS from pancreatic islets, leading to enhanced glucose control in the high fat fed, streptozotocin treated and NONcNZO10/LtJ mouse models of type 2 diabetes. The improvement in hyperglycemia by AM-1638 was reduced in the presence of the GLP-1 receptor antagonist Ex(9-39)NH(2). |
| format |
article |
| author |
Jian Luo Gayathri Swaminath Sean P Brown Jane Zhang Qi Guo Michael Chen Kathy Nguyen Thanhvien Tran Lynn Miao Paul J Dransfield Marc Vimolratana Jonathan B Houze Simon Wong Maria Toteva Bei Shan Frank Li Run Zhuang Daniel C-H Lin |
| author_facet |
Jian Luo Gayathri Swaminath Sean P Brown Jane Zhang Qi Guo Michael Chen Kathy Nguyen Thanhvien Tran Lynn Miao Paul J Dransfield Marc Vimolratana Jonathan B Houze Simon Wong Maria Toteva Bei Shan Frank Li Run Zhuang Daniel C-H Lin |
| author_sort |
Jian Luo |
| title |
A potent class of GPR40 full agonists engages the enteroinsular axis to promote glucose control in rodents. |
| title_short |
A potent class of GPR40 full agonists engages the enteroinsular axis to promote glucose control in rodents. |
| title_full |
A potent class of GPR40 full agonists engages the enteroinsular axis to promote glucose control in rodents. |
| title_fullStr |
A potent class of GPR40 full agonists engages the enteroinsular axis to promote glucose control in rodents. |
| title_full_unstemmed |
A potent class of GPR40 full agonists engages the enteroinsular axis to promote glucose control in rodents. |
| title_sort |
potent class of gpr40 full agonists engages the enteroinsular axis to promote glucose control in rodents. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2012 |
| url |
https://doaj.org/article/0849b9dfe7b244fab2862894d2869154 |
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