Premium
Free fatty acid receptor 1 agonist, MR1704, lowers blood glucose levels in rats unresponsive to the sulfonylurea, glibenclamide
Author(s) -
Tsuda Naoto,
Kawaji Atsuko,
Takagi Mitsuhiro,
Higashi Chika,
Nakamura Masaki,
Hosaka Yoshitaka,
Sakaki Junichi
Publication year - 2018
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/ddr.21416
Subject(s) - glibenclamide , sulfonylurea , medicine , endocrinology , agonist , sulfonylurea receptor , diabetes mellitus , receptor , oral administration , fatty acid , chemistry , biochemistry
Preclinical Research & DevelopmentMR1704 is a selective G protein‐coupled receptor 40/free fatty acid receptor 1 agonist, which exhibited favorable pharmacokinetic profiles and glucose‐lowering effects in animal models. We studied the effects of MR1704 in a sulfonylurea‐desensitized Sprague–Dawley rat model and evaluated the risk of pancreatic β‐cell exhaustion compared to that of glibenclamide in Zucker fatty rats. Rats fed ad libitum a diet containing 0.03% glibenclamide exhibited lower non‐fasting blood glucose levels compared to those in rats fed a control diet during the first 6 days. However, the response to glibenclamide disappeared on day 9. In a rat oral glucose tolerance test (OGTT), MR1704 reduced the plasma glucose excursion, whereas glibenclamide did not show this effect. In Zucker fatty rats, oral administration of MR1704 reduced glucose excursion during the OGTT, and the effects of MR1704 were maintained after 2‐week treatment. In contrast, the glucose‐lowering effects of glibenclamide were diminished, and glucose tolerance was aggravated after 2‐week treatment. These results indicated that MR1704 provided more sustainable effects compared to those of the sulfonylurea, glibenclamide suggesting that MR1704 may be an attractive therapeutic option for diabetic patients who are unresponsive to sulfonylurea treatment.