Free fatty acid receptor 1 agonist, MR1704, lowers blood glucose levels in rats unresponsive to the sulfonylurea, glibenclamide

Abstract

Preclinical Research & Development MR1704 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.

A FFAR1 full agonist restores islet function in models of impaired glucose-stimulated insulin secretion and diabetic non-human primates

“…In the last model of dysfunction tested, we sought to build upon a finding by Tsuda et al. who previously reported that a FFAR1 agonist enhanced glucose tolerance in sulfonylurea-desensitized normal and diabetic rats ( 23 ). While Tsuda showed that a GPR40 agonist was able to prevent the loss of glucose control associated with sulfonylurea (SU) secondary failure, here we expand on this finding by first establishing secondary failure before initiating treatment - akin to a treatment paradigm that would be used to treat humans with existing secondary failure.…”

Sulfonylurea and neuroprotection: The bright side of the moon

“…The main function of these receptors is to sense the intracellular levels of adenosine triphosphate (ATP) and adenosine diphosphate in response to the potassium channels, thus, K ATP channel and nonselective cation channel (NCCa-ATP) observes and sense the intracellular energy balance. [6]…”