DC260126, a small-molecule antagonist of GPR40, improves insulin tolerance

Xiaodong Zhang, Guirui Yan, Yiming Li, Weiliang Zhu, Heyao Wang

A B S T R A C T

GPR40 is a G-protein-coupled receptor specifically expressed in pancreatic islets, which maybe mediate
both acute and chronic effects of free fatty acids (FFAs) on b-cell function. However, it is still a matter of
debate whether GPR40 represents a novel therapeutic target for type 2 diabetes. To this aim, we
evaluated the effect of DC260126, a small-molecule antagonist of GPR40, on glucose and lipid
metabolism in obese Zucker rats. Rats were treated intraperitoneally with 6 mg/kg of DC260126 for 8
weeks. DC260126 could significantly decrease serum insulin levels, improve insulin tolerance and
increase Akt phosphorylation levels in liver, suggesting improved insulin sensitivity in DC260126-
treated rats. However, DC260126 did not affect food intake, body weight, blood glucose and lipids.
Throughout the experimental period, no significant difference in glucose tolerance was observed
between the vehicle and DC260126-treated rats. These results indicate that GPR40 antagonists may not
be beneficial for the treatment of type 2 diabetes, although GPR40 antagonists could improve insulin
tolerance and increase insulin signaling in vivo.