Open AccessA selective GPR40 (FFAR1) agonist LY2881835 provides immediate and durable glucose control in rodent models of type 2 diabetes
Author(s) -
Chen Yanyun,
Song Min,
Riley Jonathan P.,
Hu Charlie C.,
Peng Xianbu,
Scheuner Donalyn,
Bokvist Krister,
Maiti Pranab,
Kahl Steven D.,
MontroseRafizadeh Chahrzad,
Hamdouchi Chafiq,
Miller Anne Reifel
Publication year - 2016
Publication title -
pharmacology research and perspectives
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.975
H-Index - 27
ISSN - 2052-1707
DOI - 10.1002/prp2.278
Subject(s) - free fatty acid receptor 1 , medicine , endocrinology , secretagogue , agonist , insulin , streptozotocin , diabetes mellitus , type 2 diabetes , islet , insulin resistance , in vivo , hypoglycemia , receptor , biology , microbiology and biotechnology
LY 2881835 is a selective, potent, and efficacious GPR 40 agonist. The objective of the studies described here was to examine the pharmacological properties of LY 2881835 in preclinical models of T2D. Significant increases in insulin secretion were detected when LY 2881835 was tested in primary islets from WT mice but not in islets from GPR 40 KO mice. Furthermore, LY 2881835 potentiated glucose stimulated insulin secretion in normal lean mice. Acute administration of LY 2881835 lowered glucose during OGTT s in WT mice but not in GPR 40 KO mice. These findings demonstrate that LY 2881835 induces GPR 40‐mediated activity ex vivo and in vivo. LY 2881835 was administered orally at 10 mg/kg to diet‐induced obese ( DIO ) mice (an early model of T2D due to insulin resistance) for 14 days. Statistically significant reductions in glucose were seen during OGTT s performed on days 1 and 15. When a study was done for 3 weeks in Zucker fa/fa rats, a rat model of insulin resistance, normalization of blood glucose levels equivalent to those seen in lean rats was observed. A similar study was performed in streptozotocin ( STZ )‐treated DIO mice to explore glucose control in a late model of T2D. In this model, pancreatic insulin content was reduced ~80% due to STZ ‐treatment plus the mice were insulin resistant due to their high fat diet. Glucose AUC s were significantly reduced during OGTT s done on days 1, 7, and 14 compared to control mice. In conclusion, these results demonstrate that LY 2881835 functions as a GPR 40‐specific insulin secretagogue mediating immediate and durable glucose control in rodent models of early‐ and late‐stage T2D.