TAK-875, a GPR40 Agonist, in Combination with Metformin Improves Glycemic Control and β-Cell Function in Zucker Diabetic Fatty Rats
Abstract Number: 1002-P
Authors: RYO ITO, YOSHIYUKI TSUJIHATA, KAE NAGASUMI, NOBUYUKI NEGORO, KOJI TAKEUCHI
Institutions: Osaka, Japan
Results: GPR40, a G protein-coupled receptor highly expressed in pancreatic β-cells, mediates free fatty acid-induced insulin secretion. TAK-875 (TAK) is a selective and potent GPR40 agonist that lowers plasma glucose via stimulation of glucose-dependent insulin secretion. Metformin (MET) improves insulin resistance by pleiotropic action. Based on complementary mechanisms of action, the combination of TAK and MET is expected to enhance glycemic control vs either agent alone. In this study, we evaluated acute and chronic effects of TAK plus MET in combination in Zucker Diabetic Fatty (ZDF) rats, which spontaneously develop severe diabetes and progressive β-cell dysfunction. In the oral glucose tolerance test, oral administration of TAK (3 mg/kg) and MET (50 mg/kg) decreased glucose AUC by 21.0% and 15.4%, respectively, and TAK+MET additively decreased glucose AUC by 33.8%. In 19-week old ZDF rats with fasting hyperglycemia (ZDF: 234 mg/dL; lean: 101 mg/dL), combination treatment with TAK (10 mg/kg) and MET (150 mg/kg) additively decreased fasting plasma glucose. In a 6-week multiple dosing study, combination treatment with TAK (10 mg/kg, BID) and MET (50 mg/kg, QD) additively decreased glycosylated hemoglobin (TAK: -1.7; MET: -1.8; TAK+MET: -2.4%) and increased fasting plasma insulin (TAK: +7.4; MET: +8.3; TAK+MET: +13.2 ng/mL). In addition, in TAK+MET-treated ZDF rats, HOMA-β was 9.6-fold higher than in vehicle-treated ZDF rats and pancreatic insulin content was restored to a level comparable to that in lean rats (Vehicle: 26; TAK: 42.3; MET: 58.5; TAK+MET: 67.1; lean: 69.1 ng/mg pancreas). Finally, normal islet architecture was also maintained in TAK+MET-treated rats, as assessed by immunohistochemistry. These results suggest that combination treatment with TAK and MET has the potential to slow the progression of diabetes and β-cell dysfunction in ZDF rats, which may result from improvements in both postprandial and fasting hyperglycemia. Our results also suggest that TAK plus MET combination therapy may be a valuable strategy for glycemic control and β-cell preservation in patients with type 2 diabetes.