title: Intestinal Sodium Glucose Cotransporter 1 Inhibition Enhances Glucagon-Like Peptide-1 Secretion in Normal and Diabetic Rodents.
abstract: The sodium glucose cotransporter (SGLT) 1 plays a major role in glucose absorption and incretin hormone release in the gastrointestinal tract; however, the impact of SGLT1 inhibition on plasma glucagon-like peptide-1 (GLP-1) levels in vivo is controversial. We analyzed the effects of SGLT1 inhibitors on GLP-1 secretion in normoglycemic and hyperglycemic rodents using phloridzin, CGMI [3-(4-cyclopropylphenylmethyl)-1-(β-d-glucopyranosyl)-4-methylindole], and canagliflozin. These compounds are SGLT2 inhibitors with moderate SGLT1 inhibitory activity, and their IC50 values against rat SGLT1 and mouse SGLT1 were 609 and 760 nM for phloridzin, 39.4 and 41.5 nM for CGMI, and 555 and 613 nM for canagliflozin, respectively. Oral administration of these inhibitors markedly enhanced and prolonged the glucose-induced plasma active GLP-1 (aGLP-1) increase in combination treatment with sitagliptin, a dipeptidyl peptidase-4 (DPP4) inhibitor, in normoglycemic mice and rats. CGMI, the most potent SGLT1 inhibitor among them, enhanced glucose-induced, but not fat-induced, plasma aGLP-1 increase at a lower dose compared with canagliflozin. Both CGMI and canagliflozin delayed intestinal glucose absorption after oral administration in normoglycemic rats. The combined treatment of canagliflozin and a DPP4 inhibitor increased plasma aGLP-1 levels and improved glucose tolerance compared with single treatment in both 8- and 13-week-old Zucker diabetic fatty rats. These results suggest that transient inhibition of intestinal SGLT1 promotes GLP-1 secretion by delaying glucose absorption and that concomitant inhibition of intestinal SGLT1 and DPP4 is a novel therapeutic option for glycemic control in type 2 diabetes mellitus.
authors.affiliation: Research Division, Mitsubishi Tanabe Pharma Corporation, Toda-shi, Saitama, Japan 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, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Nakayama
authors.affiliation: Research Division, Mitsubishi Tanabe Pharma Corporation, Toda-shi, Saitama, Japan.
authors.forename: Chiaki
authors.initials: C
authors.lastname: Kuriyama
authors.affiliation: Research Division, Mitsubishi Tanabe Pharma Corporation, Toda-shi, Saitama, Japan.
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Matsushita
authors.affiliation: Research Division, Mitsubishi Tanabe Pharma Corporation, Toda-shi, Saitama, Japan.
authors.forename: Kumiko
authors.initials: K
authors.lastname: Yoshida
authors.affiliation: Research Division, Mitsubishi Tanabe Pharma Corporation, Toda-shi, Saitama, Japan.
authors.forename: Kumiko
authors.initials: K
authors.lastname: Hikida
authors.affiliation: Research Division, Mitsubishi Tanabe Pharma Corporation, Toda-shi, Saitama, Japan.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Obokata
authors.affiliation: Research Division, Mitsubishi Tanabe Pharma Corporation, Toda-shi, Saitama, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Tsuda-Tsukimoto
authors.affiliation: Research Division, Mitsubishi Tanabe Pharma Corporation, Toda-shi, Saitama, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Saito
authors.affiliation: Research Division, Mitsubishi Tanabe Pharma Corporation, Toda-shi, Saitama, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Arakawa
authors.affiliation: Research Division, Mitsubishi Tanabe Pharma Corporation, Toda-shi, Saitama, Japan.
authors.forename: Kiichiro
authors.initials: K
authors.lastname: Ueta
authors.affiliation: Research Division, Mitsubishi Tanabe Pharma Corporation, Toda-shi, Saitama, Japan.
authors.forename: Masaharu
authors.initials: M
authors.lastname: Shiotani
mesh_terms: D000818:Animals; D016466:CHO Cells; D003412:Cricetulus; D003921:Diabetes Mellitus, Experimental / Q000097:blood* / Q000188:drug therapy / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy / Q000378:metabolism; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000097:blood*; D005947:Glucose / Q000378:metabolism; D006801:Humans; D006943:Hyperglycemia / Q000097:blood / Q000188:drug therapy / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007408:Intestinal Absorption / Q000187:drug effects; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker; D051269:Sodium-Glucose Transporter 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D051297:Sodium-Glucose Transporter 2 / Q000378:metabolism
chemical_list: D007004:Hypoglycemic Agents; D051269:Sodium-Glucose Transporter 1; D051297:Sodium-Glucose Transporter 2; D052216:Glucagon-Like Peptide 1; D018819:Dipeptidyl Peptidase 4; D005947:Glucose