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A Potent Class of GPR40 Full Agonists Engages the EnteroInsular Axis to Promote Glucose Control in Rodents
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
Affiliation: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,
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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