PMID- 25892328 OWN - NLM STAT- MEDLINE DCOM- 20160314 LR - 20200826 IS - 1347-8648 (Electronic) IS - 1347-8613 (Linking) VI - 127 IP - 4 DP - 2015 Apr TI - The effect of combined treatment with canagliflozin and teneligliptin on glucose intolerance in Zucker diabetic fatty rats. PG - 456-61 LID - S1347-8613(15)00068-7 [pii] LID - 10.1016/j.jphs.2015.03.006 [doi] AB - 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. CI - Copyright (c) 2015 Mitsubishi Tanabe Pharma Corporation. Production and hosting by Elsevier B.V. All rights reserved. FAU - Oguma, Takahiro AU - Oguma T AD - Research Division, Mitsubishi Tanabe Pharma Corporation, Toda-shi, Saitama, 335-8505, Japan. Electronic address: oguma.takahiro@mx.mt-pharma.co.jp. FAU - Kuriyama, Chiaki AU - Kuriyama C AD - Research Division, Mitsubishi Tanabe Pharma Corporation, Toda-shi, Saitama, 335-8505, Japan. FAU - Nakayama, Keiko AU - Nakayama K AD - Research Division, Mitsubishi Tanabe Pharma Corporation, Toda-shi, Saitama, 335-8505, Japan. FAU - Matsushita, Yasuaki AU - Matsushita Y AD - Research Division, Mitsubishi Tanabe Pharma Corporation, Toda-shi, Saitama, 335-8505, Japan. FAU - Yoshida, Kumiko AU - Yoshida K AD - Research Division, Mitsubishi Tanabe Pharma Corporation, Toda-shi, Saitama, 335-8505, Japan. FAU - Kiuchi, Satoko AU - Kiuchi S AD - Research Division, Mitsubishi Tanabe Pharma Corporation, Toda-shi, Saitama, 335-8505, Japan. FAU - Ikenaga, Yuka AU - Ikenaga Y AD - Research Division, Mitsubishi Tanabe Pharma Corporation, Toda-shi, Saitama, 335-8505, Japan. FAU - Nakamaru, Yoshinobu AU - Nakamaru Y AD - Research Division, Mitsubishi Tanabe Pharma Corporation, Toda-shi, Saitama, 335-8505, Japan. FAU - Hikida, Kumiko AU - Hikida K AD - Research Division, Mitsubishi Tanabe Pharma Corporation, Toda-shi, Saitama, 335-8505, Japan. FAU - Saito, Akira AU - Saito A AD - Research Division, Mitsubishi Tanabe Pharma Corporation, Toda-shi, Saitama, 335-8505, Japan. FAU - Arakawa, Kenji AU - Arakawa K AD - Research Division, Mitsubishi Tanabe Pharma Corporation, Toda-shi, Saitama, 335-8505, Japan. FAU - Oka, Kozo AU - Oka K AD - Research Division, Mitsubishi Tanabe Pharma Corporation, Toda-shi, Saitama, 335-8505, Japan. FAU - Ueta, Kiichiro AU - Ueta K AD - Research Division, Mitsubishi Tanabe Pharma Corporation, Toda-shi, Saitama, 335-8505, Japan. FAU - Shiotani, Masaharu AU - Shiotani M AD - Research Division, Mitsubishi Tanabe Pharma Corporation, Toda-shi, Saitama, 335-8505, Japan. LA - eng PT - Journal Article DEP - 20150328 PL - Japan TA - J Pharmacol Sci JT - Journal of pharmacological sciences JID - 101167001 RN - 0 (3-(4-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2-ylcarbonyl)thiazolidine) RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) RN - 0 (Hypoglycemic Agents) RN - 0 (Pyrazoles) RN - 0 (Slc5a1 protein, rat) RN - 0 (Slc5a2 protein, rat) RN - 0 (Sodium-Glucose Transporter 1) RN - 0 (Sodium-Glucose Transporter 2) RN - 0 (Sodium-Glucose Transporter 2 Inhibitors) RN - 0 (Thiazolidines) RN - 0SAC974Z85 (Canagliflozin) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - EC 3.4.14.5 (DPP4 protein, rat) RN - EC 3.4.14.5 (Dipeptidyl Peptidase 4) SB - IM MH - Administration, Oral MH - Animals MH - Canagliflozin/administration & dosage/*pharmacology/*therapeutic use MH - Cells, Cultured MH - Cricetinae MH - Cricetulus MH - Diabetes Mellitus, Type 2/blood/*drug therapy MH - Dipeptidyl Peptidase 4/metabolism MH - Dipeptidyl-Peptidase IV Inhibitors/administration & dosage/pharmacology/*therapeutic use MH - Drug Therapy, Combination MH - Glucagon-Like Peptide 1/blood MH - Glucose Intolerance/*drug therapy MH - Humans MH - Hypoglycemic Agents/administration & dosage/*pharmacology/*therapeutic use MH - Male MH - Pyrazoles/administration & dosage/*pharmacology/*therapeutic use MH - Rats, Zucker MH - Sodium-Glucose Transporter 1/antagonists & inhibitors MH - Sodium-Glucose Transporter 2 MH - Sodium-Glucose Transporter 2 Inhibitors MH - Thiazolidines/administration & dosage/*pharmacology/*therapeutic use OTO - NOTNLM OT - Canagliflozin OT - Combination treatment OT - Glucagon-like peptide-1 OT - Teneligliptin OT - Zucker diabetic fatty rats EDAT- 2015/04/22 06:00 MHDA- 2016/03/15 06:00 CRDT- 2015/04/21 06:00 PHST- 2015/01/19 00:00 [received] PHST- 2015/03/02 00:00 [revised] PHST- 2015/03/22 00:00 [accepted] PHST- 2015/04/21 06:00 [entrez] PHST- 2015/04/22 06:00 [pubmed] PHST- 2016/03/15 06:00 [medline] AID - S1347-8613(15)00068-7 [pii] AID - 10.1016/j.jphs.2015.03.006 [doi] PST - ppublish SO - J Pharmacol Sci. 2015 Apr;127(4):456-61. doi: 10.1016/j.jphs.2015.03.006. Epub 2015 Mar 28.