TAK-875, a GPR40/FFAR1 agonist, in combination with metformin prevents progression of diabetes and ß-cell dysfunction in Zucker diabetic fatty rats.
Br J Pharmacol
; 170(3): 568-80, 2013 Oct.
Article
em En
| MEDLINE
| ID: mdl-23848179
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. EXPERIMENTALAPPROACH:
Long-term effects on glycaemic control and ß-cell function were evaluated using Zucker diabetic fatty (ZDF) rats, which develop diabetes with hyperlipidaemia and progressive ß-cell dysfunction. KEYRESULTS:
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 ß-cell preservation in type 2 diabetes.Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Sulfonas
/
Benzofuranos
/
Resistência à Insulina
/
Receptores Acoplados a Proteínas G
/
Diabetes Mellitus Tipo 2
/
Células Secretoras de Insulina
/
Hipoglicemiantes
/
Metformina
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article