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TAK ‐875, a GPR 40/ FFAR 1 agonist, in combination with metformin prevents progression of diabetes and β ‐cell dysfunction in Z ucker diabetic fatty rats
Author(s) -
Ito R,
Tsujihata Y,
MatsudaNagasumi K,
Mori I,
Negoro N,
Takeuchi K
Publication year - 2013
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.12297
Subject(s) - metformin , endocrinology , medicine , postprandial , type 2 diabetes , diabetes mellitus , insulin , agonist , glucagon like peptide 1 , receptor
Background and Purpose TAK ‐875, a selective GPCR 40/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 Approach Long‐term effects on glycaemic control and β ‐cell function were evaluated using Zucker diabetic fatty ( ZDF ) rats, which develop diabetes with hyperlipidaemia and progressive β ‐cell dysfunction. Key Results Single doses of TAK ‐875 (3–10 mg·kg −1 ) and metformin (50–150 mg·kg −1 ) significantly improved both postprandial and fasting hyperglycaemia, and additive improvements were observed in their combination. Six‐week treatment with TAK ‐875 (10 mg·kg −1 , b.i.d.) significantly decreased glycosylated Hb ( GHb ) by 1.7%, and the effect was additively enhanced by combination with metformin (50 mg·kg −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: 69.1 ng·mg −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 Implications Our results indicate that combination therapy with TAK ‐875 and metformin could be a valuable strategy for glycaemic control and β ‐cell preservation in type 2 diabetes.