TAK-875, a GPR40/FFAR1 agonist, in combination with metformin prevents progression of diabetes and β-cell dysfunction in Zucker diabetic fatty rats
| Autor: | Ito, R, Tsujihata, Y, Matsuda-Nagasumi, K, Mori, I, Negoro, N, Takeuchi, K |
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| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Blood Glucose
Glycated Hemoglobin Homeodomain Proteins Male Time Factors Glucagon Research Papers Metformin Rats Rats Zucker Receptors G-Protein-Coupled Disease Models Animal Diabetes Mellitus Type 2 Insulin-Secreting Cells Proliferating Cell Nuclear Antigen Disease Progression Trans-Activators Animals Hypoglycemic Agents Insulin Drug Therapy Combination Sulfones Insulin Resistance Biomarkers Benzofurans |
| Popis: | 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.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.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.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. |
| Databáze: | OpenAIRE |
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