title: Beneficial effects of canagliflozin in combination with pioglitazone on insulin sensitivity in rodent models of obese type 2 diabetes.
abstract: BACKGROUND
  Despite its insulin sensitizing effects, pioglitazone may induce weight gain leading to an increased risk of development of insulin resistance. A novel sodium glucose co-transporter 2 (SGLT2) inhibitor, canagliflozin, provides not only glycemic control but also body weight reduction through an insulin-independent mechanism. The aim of this study was to investigate the combined effects of these agents on body weight control and insulin sensitivity.
  
  
  METHODS
  Effects of combination therapy with canagliflozin and pioglitazone were evaluated in established diabetic KK-Ay mice and prediabetic Zucker diabetic fatty (ZDF) rats.
  
  
  RESULTS
  In the KK-Ay mice, the combination therapy further improved glycemic control compared with canagliflozin or pioglitazone monotherapy. Furthermore, the combination significantly attenuated body weight and fat gain induced by pioglitazone and improved hyperinsulinemia. In the ZDF rats, early intervention with pioglitazone monotherapy almost completely prevented the progressive development of hyperglycemia, and no further improvement was observed by add-on treatment with canagliflozin. However, the combination significantly reduced pioglitazone-induced weight gain and adiposity and improved the Matsuda index, suggesting improved whole-body insulin sensitivity.
  
  
  CONCLUSIONS
  Our study indicates that combination therapy with canagliflozin and pioglitazone improves insulin sensitivity partly by preventing glucotoxicity and, at least partly, by attenuating pioglitazone-induced body weight gain in two different obese diabetic animal models. This combination therapy may prove to be a valuable option for the treatment and prevention of obese type 2 diabetes.
authors.affiliation: Pharmacology Research Laboratories II, Research Division, Mitsubishi Tanabe Pharma Corporation, Saitama, Japan; Department of Pharmacology, Saitama Medical University, Saitama, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Watanabe
authors.affiliation: Pharmacology Research Laboratories II, Research Division, Mitsubishi Tanabe Pharma Corporation, Saitama, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Nakayama
authors.affiliation: Pharmacology Research Laboratories II, Research Division, Mitsubishi Tanabe Pharma Corporation, Saitama, Japan.
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Taniuchi
authors.affiliation: Safety Research Laboratory, Research Division, Mitsubishi Tanabe Pharma Corporation, Saitama, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Horai
authors.affiliation: Pharmacology Research Laboratories II, Research Division, Mitsubishi Tanabe Pharma Corporation, Saitama, Japan.
authors.forename: Chiaki
authors.initials: C
authors.lastname: Kuriyama
authors.affiliation: Pharmacology Research Laboratories II, Research Division, Mitsubishi Tanabe Pharma Corporation, Saitama, Japan.
authors.forename: Kiichiro
authors.initials: K
authors.lastname: Ueta
authors.affiliation: Pharmacology Research Laboratories II, Research Division, Mitsubishi Tanabe Pharma Corporation, Saitama, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Arakawa
authors.affiliation: Department of Pharmacology, Saitama Medical University, Saitama, Japan.
authors.forename: Takaaki
authors.initials: T
authors.lastname: Senbonmatsu
authors.affiliation: Pharmacology Research Laboratories II, Research Division, Mitsubishi Tanabe Pharma Corporation, Saitama, Japan.
authors.forename: Masaharu
authors.initials: M
authors.lastname: Shiotani
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D000068896:Canagliflozin / Q000008:administration & dosage* / Q000627:therapeutic use; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D004359:Drug Therapy, Combination; D006946:Hyperinsulinism / Q000139:chemically induced / Q000188:drug therapy*; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D051379:Mice; D009765:Obesity / Q000139:chemically induced / Q000188:drug therapy*; D000077205:Pioglitazone; D051381:Rats; D011924:Rats, Zucker; D045162:Thiazolidinediones / Q000008:administration & dosage* / Q000627:therapeutic use
chemical_list: D007004:Hypoglycemic Agents; D045162:Thiazolidinediones; D000068896:Canagliflozin; D000077205:Pioglitazone