title: TAK-875, a GPR40/FFAR1 agonist, in combination with metformin prevents progression of diabetes and β-cell dysfunction in Zucker diabetic fatty rats.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Cardiovascular and Metabolic Drug Discovery Unit, Takeda Pharmaceutical Company Limited, Kanagawa, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Ito
authors.forename: Y
authors.initials: Y
authors.lastname: Tsujihata
authors.forename: K
authors.initials: K
authors.lastname: Matsuda-Nagasumi
authors.forename: I
authors.initials: I
authors.lastname: Mori
authors.forename: N
authors.initials: N
authors.lastname: Negoro
authors.forename: K
authors.initials: K
authors.lastname: Takeuchi
mesh_terms: D000818:Animals; D001572:Benzofurans / Q000494:pharmacology*; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D018450:Disease Progression; D004359:Drug Therapy, Combination; D005934:Glucagon / Q000378:metabolism; D006442:Glycated Hemoglobin / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D051381:Rats; D011924:Rats, Zucker; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000378:metabolism; D013450:Sulfones / Q000494:pharmacology*; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism
chemical_list: D001572:Benzofurans; D015415:Biomarkers; D001786:Blood Glucose; D005934:Glucagon; D006442:Glycated Hemoglobin; D018398:Homeodomain Proteins; D007004:Hypoglycemic Agents; D007328:Insulin; D008687:Metformin; D018809:Proliferating Cell Nuclear Antigen; D043562:Receptors, G-Protein-Coupled; D013450:Sulfones; D015534:Trans-Activators; C473035:G-protein-coupled receptor 40, rat; C557331:TAK-875; C084010:pancreatic and duodenal homeobox 1 protein
keywords: GPR40/FFAR1; TAK-875; Zucker diabetic fatty rats; glycaemic control; hyperlipidaemia; insulin secretion; metformin; β-cell preservation