TAK-875, a GPR40/FFAR1 agonist, in combination with metformin prevents progression of diabetes and β-cell dysfunction in Zucker diabetic fatty rats

Background and PurposeTAK-875, a selective GPCR40/free fatty acid receptor 1 agonist, improves glycaemic control by increasing glucose-dependent insulin secretion. Metformin is a first-line drug for treatment of type 2 diabetes that improves peripheral insulin resistance. Based on complementary mechanism of action, combining these agents is expected to enhance glycaemic control. Here, we evaluated the chronic effects of TAK-875 monotherapy and combination therapy with metformin in diabetic rats. Experimental ApproachLong-term effects on glycaemic control and -cell function were evaluated using Zucker diabetic fatty (ZDF) rats, which develop diabetes with hyperlipidaemia and progressive -cell dysfunction. Key ResultsSingle doses of TAK-875 (3-10mgkg(-1)) and metformin (50-150mgkg(-1)) significantly improved both postprandial and fasting hyperglycaemia, and additive improvements were observed in their combination. Six-week treatment with TAK-875 (10mgkg(-1), b.i.d.) significantly decreased glycosylated Hb (GHb) by 1.7%, and the effect was additively enhanced by combination with metformin (50mgkg(-1), q.d.; GHb: -2.4%). This improvement in glycaemic control in the combination group was accompanied by significant 3.2-fold increase in fasting plasma insulin levels. Pancreatic insulin content was maintained at a level comparable to that in normal rats by combination treatment (vehicle: 26, combination: 67.1; normal lean: 69.1ngmg(-1) pancreas) without affecting pancreatic glucagon content. Immunohistochemical analyses revealed normal morphology, enhanced pancreas duodenum homeobox-1 expression and increased PCNA-positive cells in islets of the combination group. Conclusion and ImplicationsOur results indicate that combination therapy with TAK-875 and metformin could be a valuable strategy for glycaemic control and -cell preservation in type 2 diabetes.