A potent class of GPR40 full agonists engages the enteroinsular axis to promote glucose control in rodents

PLoS One. 2012;7(10):e46300. doi: 10.1371/journal.pone.0046300. Epub 2012 Oct 9.

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)NH(2).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Glucose / metabolism*
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Insulin / metabolism
  • Insulin Secretion
  • Mice
  • Mice, Knockout
  • Receptors, G-Protein-Coupled / agonists*
  • Receptors, G-Protein-Coupled / genetics
  • Second Messenger Systems

Substances

  • Blood Glucose
  • Ffar1 protein, mouse
  • Insulin
  • Receptors, G-Protein-Coupled

Grant support

This study was supported by Amgen Inc., which played a role in study design, data collection and analysis, decision to publish, and preparation of the manuscript.