| Autor: |
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 |
| Jazyk: |
angličtina |
| Rok vydání: |
2012 |
| Předmět: |
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| Zdroj: |
PLoS ONE, Vol 7, Iss 10, p e46300 (2012) |
| Druh dokumentu: |
article |
| ISSN: |
1932-6203 |
| DOI: |
10.1371/journal.pone.0046300 |
| Popis: |
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). |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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