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Biomed Pharmacother. 2010 Nov;64(9):647-51. doi: 10.1016/j.biopha.2010.06.008.

DC260126, a small-molecule antagonist of GPR40, improves insulin tolerance but not glucose tolerance in obese Zucker rats.

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Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.


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 β-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.

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