PT  - JOURNAL ARTICLE
AU  - Fuyong Du
AU  - Simon A. Hinke
AU  - Cassandre Cavanaugh
AU  - David Polidori
AU  - Nathanial Wallace
AU  - Thomas Kirchner
AU  - Matthew Jennis
AU  - Wensheng Lang
AU  - Gee-Hong Kuo
AU  - Micheal D. Gaul
AU  - James Lenhard
AU  - Keith Demarest
AU  - Nadim J. Ajami
AU  - Yin Liang
AU  - Pamela J. Hornby
TI  - Potent Sodium/Glucose Cotransporter SGLT1/2 Dual Inhibition Improves Glycemic Control Without Marked Gastrointestinal Adaptation or Colonic Microbiota Changes in Rodents
AID  - 10.1124/jpet.118.248575
DP  - 2018 Jun 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 676--687
VI  - 365
IP  - 3
4099  - http://jpet.aspetjournals.org/content/365/3/676.short
4100  - http://jpet.aspetjournals.org/content/365/3/676.full
SO  - J Pharmacol Exp Ther2018 Jun 01; 365
AB  - The sodium/glucose cotransporters (SGLT1 and SGLT2) transport glucose across the intestinal brush border and kidney tubule. Dual SGLT1/2 inhibition could reduce hyperglycemia more than SGLT2-selective inhibition in patients with type 2 diabetes. However, questions remain about altered gastrointestinal (GI) luminal glucose and tolerability, and this was evaluated in slc5a1−/− mice or with a potent dual inhibitor (compound 8; SGLT1 Ki = 1.5 ± 0.5 nM 100-fold greater potency than phlorizin; SGLT2 Ki = 0.4 ± 0.2 nM). 13C6-glucose uptake was quantified in slc5a1−/− mice and in isolated rat jejunum. Urinary glucose excretion (UGE), blood glucose (Sprague-Dawley rats), glucagon-like peptide 1 (GLP-1), and hemoglobin A1c (HbA1c) levels (Zucker diabetic fatty rats) were measured. Intestinal adaptation and rRNA gene sequencing was analyzed in C57Bl/6 mice. The blood 13C6-glucose area under the curve (AUC) was reduced in the absence of SGLT1 by 75% (245 ± 6 vs. 64 ± 6 mg/dl⋅h in wild-type vs. slc5a1−/− mice) and compound 8 inhibited its transport up to 50% in isolated rat jejunum. Compound 8 reduced glucose excursion more than SGLT2-selective inhibition (e.g., AUC = 129 ± 3 vs. 249 ± 5 mg/dl⋅h for 1 mg/kg compound 8 vs. dapagliflozin) with similar UGE but a lower renal glucose excretion threshold. In Zucker diabetic fatty rats, compound 8 decreased HbA1c and increased total GLP-1 without changes in jejunum SGLT1 expression, mucosal weight, or villus length. Overall, compound 8 (1 mg/kg for 6 days) did not increase cecal glucose concentrations or bacterial diversity in C57BL/6 mice. In conclusion, potent dual SGLT1/2 inhibition lowers blood glucose by reducing intestinal glucose absorption and the renal glucose threshold but minimally impacts the intestinal mucosa or luminal microbiota in chow-fed rodents.