PT  - JOURNAL ARTICLE
AU  - Takahiro Oguma
AU  - Keiko Nakayama
AU  - Chiaki Kuriyama
AU  - Yasuaki Matsushita
AU  - Kumiko Yoshida
AU  - Kumiko Hikida
AU  - Naoyuki Obokata
AU  - Minoru Tsuda-Tsukimoto
AU  - Akira Saito
AU  - Kenji Arakawa
AU  - Kiichiro Ueta
AU  - Masaharu Shiotani
TI  - Intestinal Sodium Glucose Cotransporter 1 Inhibition Enhances Glucagon-Like Peptide-1 Secretion in Normal and Diabetic Rodents
AID  - 10.1124/jpet.115.225508
DP  - 2015 Sep 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 279--289
VI  - 354
IP  - 3
4099  - http://jpet.aspetjournals.org/content/354/3/279.short
4100  - http://jpet.aspetjournals.org/content/354/3/279.full
SO  - J Pharmacol Exp Ther2015 Sep 01; 354
AB  - 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.