title: Combination of TS-021 with metformin improves hyperglycemia and synergistically increases pancreatic β-cell mass in a mouse model of type 2 diabetes.
abstract: OBJECTIVE
  The objectives of this study were to elucidate the effects of a potent dipeptidyl peptidase (DPP)-IV inhibitor, TS-021, combined with/without metformin on glycemic control and pathological changes in pancreatic islets in high-fat diet and streptozotocin-induced (HFD-STZ) diabetic mice.
  
  
  METHODS
  The anti-diabetic effects of TS-021 and/or metformin in HFD-STZ mice were examined in both acute and chronic treatment studies. In addition, we performed immunohistochemical analysis after repeated administration of TS-021 and/or metformin to HFD-STZ mice twice a day for 5 weeks.
  
  
  RESULTS
  In the acute treatment study, TS-021 and/or metformin significantly improved glucose tolerance and glucagon-like peptide-1 (GLP-1) level, and TS-021 alone or in combination with metformin significantly increased the plasma insulin level after nutrient ingestion. In the chronic treatment study, TS-021 in combination with metformin significantly lowered the glycosylated hemoglobin level, plasma insulin level, and α-cell-to-β-cell area ratio in pancreatic islets. In particular, the combined treatment synergistically increased the insulin-positive area in pancreatic islets from 32.3% in diabetic mice treated with the vehicle to 51.1% (TS-021 alone, 35.3%; metformin alone, 30.6%).
  
  
  CONCLUSIONS
  The present study demonstrated that the coadministration of TS-021 and metformin synergistically improved the islet morphology by increasing the circulating level of biologically active GLP-1, which is thought to result from two different mechanisms (namely, an increase in GLP-1 secretion and DPP-IV inhibition). These findings strongly support the rationale for combined treatment with DPP-IV inhibitors plus metformin in clinical practice by clearly demonstrating an anti-diabetic effect associated with the remarkable improvement in pancreatic β-cell morphology.
authors.affiliation: Molecular Function and Pharmacology Laboratories, Taisho Pharmaceutical Co., Ltd., Saitama, Japan. atsushi.tajima@po.rd.taisho.co.jp
authors.forename: Atsushi
authors.initials: A
authors.lastname: Tajima
authors.forename: Takashi
authors.initials: T
authors.lastname: Hirata
authors.forename: Kazuo
authors.initials: K
authors.lastname: Taniguchi
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Kondo
authors.forename: Sota
authors.initials: S
authors.lastname: Kato
authors.forename: Masako
authors.initials: M
authors.lastname: Saito-Hori
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Ishimoto
authors.forename: Koji
authors.initials: K
authors.lastname: Yamamoto
mesh_terms: D000818:Animals; D001557:Benzenesulfonates / Q000494:pharmacology / Q000627:therapeutic use*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D004357:Drug Synergism; D052216:Glucagon-Like Peptide 1 / Q000097:blood; D006442:Glycated Hemoglobin / Q000032:analysis; D006943:Hyperglycemia / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D007328:Insulin / Q000097:blood; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008687:Metformin / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D011759:Pyrrolidines / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D001557:Benzenesulfonates; D018819:Dipeptidyl Peptidase 4; D052216:Glucagon-Like Peptide 1; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007328:Insulin; D008687:Metformin; D011759:Pyrrolidines; C558997:(2S,4S)-4-Fluoro-1-(((2-hydroxy-1,1-dimethylethyl)amino)acetyl)-pyrrolidine-2-carbonitrile monobenzenesulfonate