TAK-875, a GPR40/FFAR1 agonist, in combination with metformin prevents progression of diabetes and β-cell dysfunction in Zucker diabetic fatty rats
| Autor: | Yoshiyuki Tsujihata, Ryo Ito, N Negoro, I Mori, Koji Takeuchi, K Matsuda-Nagasumi |
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| Rok vydání: | 2013 |
| Předmět: |
Pharmacology
Agonist medicine.medical_specialty Combination therapy business.industry medicine.drug_class Type 2 diabetes medicine.disease Metformin medicine.anatomical_structure Postprandial Endocrinology Diabetes mellitus Internal medicine Free fatty acid receptor 1 medicine Pancreas business medicine.drug |
| Zdroj: | British Journal of Pharmacology. 170:568-580 |
| ISSN: | 0007-1188 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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