title: The effect of combined treatment with canagliflozin and teneligliptin on glucose intolerance in Zucker diabetic fatty rats.
abstract: To assess the impact of concomitant inhibition of sodium-glucose cotransporter (SGLT) 2 and dipeptidyl peptidase IV (DPP4) for the treatment of type 2 diabetes mellitus (T2DM), the effect of combined treatment with canagliflozin, a novel SGLT2 inhibitor, and teneligliptin, a DPP4 inhibitor, on glucose intolerance was investigated in Zucker diabetic fatty (ZDF) rats. Canagliflozin potently inhibited human and rat SGLT2 and moderately inhibited human and rat SGLT1 activities but did not affect DPP4 activity. In contrast, teneligliptin inhibited human and rat DPP4 activities but not SGLT activities. A single oral treatment of canagliflozin and teneligliptin suppressed plasma glucose elevation in an oral glucose tolerance test in 13 week-old ZDF rats. This combination of agents elevated plasma active GLP-1 levels in a synergistic manner, probably mediated by intestinal SGLT1 inhibition, and further improved glucose intolerance. In the combination-treated animals, there was no pharmacokinetic interaction of the drugs and no further inhibition of plasma DPP4 activity compared with that in the teneligliptin-treated animals. These results suggest that the inhibition of SGLT2 and DPP4 improves glucose intolerance and that combined treatment with canagliflozin and teneligliptin is a novel therapeutic option for glycemic control in T2DM.
authors.affiliation: Research Division, Mitsubishi Tanabe Pharma Corporation, Toda-shi, Saitama, 335-8505, Japan. Electronic address: oguma.takahiro@mx.mt-pharma.co.jp.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Oguma
authors.affiliation: Research Division, Mitsubishi Tanabe Pharma Corporation, Toda-shi, Saitama, 335-8505, Japan.
authors.forename: Chiaki
authors.initials: C
authors.lastname: Kuriyama
authors.affiliation: Research Division, Mitsubishi Tanabe Pharma Corporation, Toda-shi, Saitama, 335-8505, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Nakayama
authors.affiliation: Research Division, Mitsubishi Tanabe Pharma Corporation, Toda-shi, Saitama, 335-8505, Japan.
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Matsushita
authors.affiliation: Research Division, Mitsubishi Tanabe Pharma Corporation, Toda-shi, Saitama, 335-8505, Japan.
authors.forename: Kumiko
authors.initials: K
authors.lastname: Yoshida
authors.affiliation: Research Division, Mitsubishi Tanabe Pharma Corporation, Toda-shi, Saitama, 335-8505, Japan.
authors.forename: Satoko
authors.initials: S
authors.lastname: Kiuchi
authors.affiliation: Research Division, Mitsubishi Tanabe Pharma Corporation, Toda-shi, Saitama, 335-8505, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Ikenaga
authors.affiliation: Research Division, Mitsubishi Tanabe Pharma Corporation, Toda-shi, Saitama, 335-8505, Japan.
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Nakamaru
authors.affiliation: Research Division, Mitsubishi Tanabe Pharma Corporation, Toda-shi, Saitama, 335-8505, Japan.
authors.forename: Kumiko
authors.initials: K
authors.lastname: Hikida
authors.affiliation: Research Division, Mitsubishi Tanabe Pharma Corporation, Toda-shi, Saitama, 335-8505, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Saito
authors.affiliation: Research Division, Mitsubishi Tanabe Pharma Corporation, Toda-shi, Saitama, 335-8505, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Arakawa
authors.affiliation: Research Division, Mitsubishi Tanabe Pharma Corporation, Toda-shi, Saitama, 335-8505, Japan.
authors.forename: Kozo
authors.initials: K
authors.lastname: Oka
authors.affiliation: Research Division, Mitsubishi Tanabe Pharma Corporation, Toda-shi, Saitama, 335-8505, Japan.
authors.forename: Kiichiro
authors.initials: K
authors.lastname: Ueta
authors.affiliation: Research Division, Mitsubishi Tanabe Pharma Corporation, Toda-shi, Saitama, 335-8505, Japan.
authors.forename: Masaharu
authors.initials: M
authors.lastname: Shiotani
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000068896:Canagliflozin / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D052216:Glucagon-Like Peptide 1 / Q000097:blood; D018149:Glucose Intolerance / Q000188:drug therapy*; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D008297:Male; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D011924:Rats, Zucker; D051269:Sodium-Glucose Transporter 1 / Q000037:antagonists & inhibitors; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D053778:Thiazolidines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*
chemical_list: C579035:3-(4-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2-ylcarbonyl)thiazolidine; D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D011720:Pyrazoles; C495676:Slc5a1 protein, rat; C490300:Slc5a2 protein, rat; D051269:Sodium-Glucose Transporter 1; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D053778:Thiazolidines; D000068896:Canagliflozin; D052216:Glucagon-Like Peptide 1; C000602659:DPP4 protein, rat; D018819:Dipeptidyl Peptidase 4
keywords: Canagliflozin; Combination treatment; Glucagon-like peptide-1; Teneligliptin; Zucker diabetic fatty rats