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

作者：Luo Jian; Swaminath Gayathri; Brown Sean P; Zhang Jane; Guo Qi; Chen Michael; Kathy Nguyen; Thanhvien Tran; Miao Lynn; Dransfield Paul J; Vimolratana Marc; Houze Jonathan B; Wong Simon; Toteva Maria; Shan Bei; Li Frank; Zhuang Run; Lin Daniel C H^*

来源：PLos One, 2012, 7(10): e46300.

DOI：10.1371/journal.pone.0046300

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 beta-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.

• 出版日期2012-10-9