A Potent Class of GPR40 Full Agonists Engages the EnteroInsular Axis to Promote Glucose Control in Rodents |
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Authors: | 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 |
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Institution: | 1. Department of Metabolic Disorders, Amgen Inc., South San Francisco, California, United States of America.; 2. Department of Therapeutic Discovery, Amgen Inc., South San Francisco, California, United States of America.; 3. Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., South San Francisco, California, United States of America.; 4. Department of Pharmaceutics, Amgen Inc., South San Francisco, California, United States of America.; University of British Columbia, Canada, |
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Abstract: | 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)NH2. |
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