A potent class of GPR40 full agonists engages the enteroinsular axis to promote glucose control in rodents.
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).
Department of Metabolic Disorders, Amgen Inc., South San Francisco, California, USA.
Jian
J
Luo
Gayathri
G
Swaminath
Sean P
SP
Brown
Jane
J
Zhang
Qi
Q
Guo
Michael
M
Chen
Kathy
K
Nguyen
Thanhvien
T
Tran
Lynn
L
Miao
Paul J
PJ
Dransfield
Marc
M
Vimolratana
Jonathan B
JB
Houze
Simon
S
Wong
Maria
M
Toteva
Bei
B
Shan
Frank
F
Li
Run
R
Zhuang
Daniel C-H
DC
Lin
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D051379:Mice; D018345:Mice, Knockout; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000235:genetics; D015290:Second Messenger Systems
D001786:Blood Glucose; C473036:Ffar1 protein, mouse; D007328:Insulin; D043562:Receptors, G-Protein-Coupled