A novel free fatty acid receptor 1 (GPR40/FFAR1) agonist, MR1704, enhances glucose‐dependent insulin secretion and improves glucose homeostasis in rats

Abstract

Activation of G protein‐coupled receptor 40/Free fatty acid receptor 1 (GPR40/FFAR1), which is highly expressed in pancreatic β cells, is considered an important pharmacologic target for the treatment of type 2 diabetes mellitus. The aim of this study was to determine the effect of MR1704, a novel GPR40/FFAR1 agonist, on glucose homeostasis in rats. MR1704 is a highly potent and selective, orally bioavailable agonist with similar in vitro potencies among humans, mice, and rats. Treatment of rat islets with MR1704 increased glucose‐dependent insulin secretion. Augmentation of glucose‐dependent insulin secretion was abolished by adding a GPR40/FFAR1 antagonist. In mouse, insulinoma MIN6 cells, palmitic acid induced the activity of caspase 3/7 after a 72‐h exposure, while pharmacologically active concentrations of MR1704 did not. In an oral glucose tolerance test in normal Sprague‐Dawley rats, orally administered MR1704 (1–10 mg·kg−1) reduced plasma glucose excursion and enhanced insulin secretion, but MR1704 did not induce hypoglycemia, even at 300 mg·kg−1, in fasted Sprague‐Dawley rats. In addition, orally administered MR1704 reduced plasma glucose excursion and enhanced insulin secretion in diabetic Goto‐Kakizaki rats. Oral administration of MR1704 once daily to Goto‐Kakizaki rats reduced their blood glucose levels during a 5‐week treatment period without reducing pancreatic insulin content; as a result, hemoglobin A1C levels significantly decreased. These results suggest that MR1704 improves glucose homeostasis through glucose‐dependent insulin secretion with a low risk of hypoglycemia and pancreatic toxicity. MR1704 shows promise as a new, glucose‐lowering drug to treat type 2 diabetes mellitus.

Anthocyanins from purple corn activate free fatty acid-receptor 1 and glucokinase enhancing in vitro insulin secretion and hepatic glucose uptake

“…It has been found that the activation of FFAR1 ameliorates the fasting hyperglycemia and glucose tolerance in diabetic rats [ 24 ]. More importantly, no hypoglycemic effects and pancreatic toxicity were observed in normal rats, suggesting selective beneficial effects for type-2 diabetes patients [ 24 , 25 ]. GK, primarily expressed in pancreatic β-cells and liver hepatocytes, is known to play a crucial role in glucose homeostasis [ 26 ].…”

Evidence for NADPH oxidase activation by GPR40 in pancreatic β-cells

“…Activation of the NADPH oxidase complex generates ROS that may act as second messengers for GSIS [29,30,37]. In addition, GPR40 activation by FFAs or by agonist molecules also leads to the generation of additional second messengers such as DAG, Ca 2+ and cAMP, also culminating in the enhancement of insulin secretion [1,[6][7][8]38,39].…”

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

“…MR1704, a GPR40/FFAR1 agonist, exhibits favorable pharmacokinetic profiles and improves glucose homeostasis without the risk of hypoglycemia, pancreatic toxicity, or pancreatic b‐cell exhaustion (Tsuda et al, ). In the present study, we examined the effect of MR1704 in rats unresponsive to glibenclamide and determined the risk of secondary failure in ZF rats.…”

“…MR1704 is a highly potent, selective, orally bioavailable GPR40/FFAR1 agonist, which exhibited favorable pharmacokinetic profiles and pharmacological effects in several animal models, without causing hypoglycemia (Tsuda et al, ). Chronic treatment with MR1704 for 5 weeks decreased the glycated hemoglobin levels in Goto–Kakizaki rats, and its glucose‐lowering effect persisted during the study period.…”

“…Chronic treatment with MR1704 for 5 weeks decreased the glycated hemoglobin levels in Goto–Kakizaki rats, and its glucose‐lowering effect persisted during the study period. In addition, the improvement of glucose homeostasis was not associated with the reduction of the pancreatic insulin content (Tsuda et al, ), suggesting that MR1704 causes a low risk of pancreatic β ‐cell exhaustion.…”