Fuyong Du, Simon A Hinke, Cassandre Cavanaugh, David Polidori, Nathanial Wallace, Thomas Kirchner, Matthew Jennis, Wensheng Lang, Gee-Hong Kuo, Micheal D Gaul, James Lenhard, Keith Demarest, Nadim J Ajami, Yin Liang, Pamela J Hornby

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 in patients with Type 2 Diabetes; however, questions remain about altered gastrointestinal (GI) luminal glucose and tolerability. Therefore, this was evaluated in slc5a1-/- mice or using a potent dual inhibitor (cmpd 8; SGLT1 Ki = 1.5±0.5nM 100 fold > 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), GLP1 and HbA1c levels (Zucker Diabetic Fatty rats) were measured. intestinal adaptation and rRNA gene sequencing was analyzed (C57Bl/6 mice). Blood 13C6-glucose AUC was reduced in absence of SGLT1 by 75% (WT 245±6 vs slc5a1-/- 64±6 mg/dl.hr) and cmpd 8 inhibited its transport up to 50% in rat isolated jejunum. Compound 8 reduced the glucose excursion more than SGLT2-selective inhibition to (e.g. 1 mg/kg cmpd 8 AUC = 129±3 vs dapagliflozin 249±5 mg/dl.hr) with similar UGE but lower renal glucose excretion threshold. In ZDF rats, cmpd 8 decreased HbA1c and increased total GLP-1 without changes in jejunum SGLT1 expression, mucosal weight or villus length. Overall, cmpd 8 (1 mg/kg for 6 days) did not increase cecal glucose concentrations nor bacterial diversity in C57BL/6 mice. In conclusion, otent dual SGLT1/2 inhibition lowers blood glucose by reducing intestinal glucose absorption and renal glucose threshold, but minimally impacts the intestinal mucosa or luminal microbiota in chow-fed rodents.