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Br J Pharmacol. 2013 Oct;170(3):568-80. doi: 10.1111/bph.12297.

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

Author information

1
Cardiovascular and Metabolic Drug Discovery Unit, Takeda Pharmaceutical Company Limited, Kanagawa, Japan.

Abstract

BACKGROUND AND PURPOSE:

TAK-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 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.

KEYWORDS:

GPR40/FFAR1; TAK-875; Zucker diabetic fatty rats; glycaemic control; hyperlipidaemia; insulin secretion; metformin; β-cell preservation

PMID:
23848179
PMCID:
PMC3791995
DOI:
10.1111/bph.12297
[Indexed for MEDLINE]
Free PMC Article

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