title: Changes in glucose-induced plasma active glucagon-like peptide-1 levels by co-administration of sodium-glucose cotransporter inhibitors with dipeptidyl peptidase-4 inhibitors in rodents.
abstract: We investigated whether structurally different sodium-glucose cotransporter (SGLT) 2 inhibitors, when co-administered with dipeptidyl peptidase-4 (DPP4) inhibitors, could enhance glucagon-like peptide-1 (GLP-1) secretion during oral glucose tolerance tests (OGTTs) in rodents. Three different SGLT inhibitors-1-(β-d-Glucopyranosyl)-4-chloro-3-[5-(6-fluoro-2-pyridyl)-2-thienylmethyl]benzene (GTB), TA-1887, and canagliflozin-were examined to assess the effect of chemical structure. Oral treatment with GTB plus a DPP4 inhibitor enhanced glucose-induced plasma active GLP-1 (aGLP-1) elevation and suppressed glucose excursions in both normal and diabetic rodents. In DPP4-deficient rats, GTB enhanced glucose-induced aGLP-1 elevation without affecting the basal level, whereas metformin, previously reported to enhance GLP-1 secretion, increased both the basal level and glucose-induced elevation. Oral treatment with canagliflozin and TA-1887 also enhanced glucose-induced aGLP-1 elevation when co-administered with either teneligliptin or sitagliptin. These data suggest that structurally different SGLT2 inhibitors enhance plasma aGLP-1 elevation and suppress glucose excursions during OGTT when co-administered with DPP4 inhibitors, regardless of the difference in chemical structure. Combination treatment with DPP4 inhibitors and SGLT2 inhibitors having moderate SGLT1 inhibitory activity may be a promising therapeutic option for improving glycemic control in patients with type 2 diabetes mellitus.
authors.affiliation: Sohyaku. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Aoba-ku, Yokohama, Kanagawa, Japan; Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-ku, Sapporo, Japan. Electronic address: oguma.takahiro@mx.mt-pharma.co.jp.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Oguma
authors.affiliation: Sohyaku. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Aoba-ku, Yokohama, Kanagawa, Japan.
authors.forename: Chiaki
authors.initials: C
authors.lastname: Kuriyama
authors.affiliation: Sohyaku. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Aoba-ku, Yokohama, Kanagawa, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Nakayama
authors.affiliation: Sohyaku. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Aoba-ku, Yokohama, Kanagawa, Japan.
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Matsushita
authors.affiliation: Sohyaku. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Aoba-ku, Yokohama, Kanagawa, Japan.
authors.forename: Kumiko
authors.initials: K
authors.lastname: Hikida
authors.affiliation: Sohyaku. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Aoba-ku, Yokohama, Kanagawa, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Tsuda-Tsukimoto
authors.affiliation: Sohyaku. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Aoba-ku, Yokohama, Kanagawa, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Saito
authors.affiliation: Sohyaku. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Aoba-ku, Yokohama, Kanagawa, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Arakawa
authors.affiliation: Sohyaku. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Aoba-ku, Yokohama, Kanagawa, Japan.
authors.forename: Kiichiro
authors.initials: K
authors.lastname: Ueta
authors.affiliation: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-ku, Sapporo, Japan.
authors.forename: Masabumi
authors.initials: M
authors.lastname: Minami
authors.affiliation: Sohyaku. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Aoba-ku, Yokohama, Kanagawa, Japan.
authors.forename: Masaharu
authors.initials: M
authors.lastname: Shiotani
mesh_terms: D000818:Animals; D000068896:Canagliflozin / Q000494:pharmacology; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D052216:Glucagon-Like Peptide 1 / Q000097:blood*; D005951:Glucose Tolerance Test; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009005:Monosaccharides / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D000068900:Sitagliptin Phosphate / Q000494:pharmacology; D051269:Sodium-Glucose Transporter 1 / Q000037:antagonists & inhibitors; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D053778:Thiazolidines / Q000494:pharmacology
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; D009005:Monosaccharides; D011720:Pyrazoles; D011725:Pyridines; D051269:Sodium-Glucose Transporter 1; D000077203:Sodium-Glucose Transporter 2 Inhibitors; C586765:TA-3404; D053778:Thiazolidines; D000068896:Canagliflozin; D052216:Glucagon-Like Peptide 1; D000068900:Sitagliptin Phosphate
keywords: Canagliflozin; Combination treatment; DPP4 inhibitor; Glucagon-like peptide-1; SGLT2 inhibitor