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

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

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.

MeSH terms

  • Animals
  • Benzofurans / pharmacology*
  • Biomarkers / blood
  • Blood Glucose / drug effects
  • Blood Glucose / metabolism
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / pathology
  • Diabetes Mellitus, Type 2 / physiopathology
  • Disease Models, Animal
  • Disease Progression
  • Drug Therapy, Combination
  • Glucagon / metabolism
  • Glycated Hemoglobin A / metabolism
  • Homeodomain Proteins / metabolism
  • Hypoglycemic Agents / pharmacology*
  • Insulin / blood
  • Insulin Resistance*
  • Insulin-Secreting Cells / drug effects*
  • Insulin-Secreting Cells / metabolism
  • Insulin-Secreting Cells / pathology
  • Male
  • Metformin / pharmacology*
  • Proliferating Cell Nuclear Antigen / metabolism
  • Rats
  • Rats, Zucker
  • Receptors, G-Protein-Coupled / agonists*
  • Receptors, G-Protein-Coupled / metabolism
  • Sulfones / pharmacology*
  • Time Factors
  • Trans-Activators / metabolism

Substances

  • Benzofurans
  • Biomarkers
  • Blood Glucose
  • G-protein-coupled receptor 40, rat
  • Glycated Hemoglobin A
  • Homeodomain Proteins
  • Hypoglycemic Agents
  • Insulin
  • Proliferating Cell Nuclear Antigen
  • Receptors, G-Protein-Coupled
  • Sulfones
  • TAK-875
  • Trans-Activators
  • pancreatic and duodenal homeobox 1 protein
  • Glucagon
  • Metformin