Potent sodium/glucose cotransporter SGLT1/2 dual inhibition improves glycemic control without marked gastrointestinal adaptation or colonic microbiota changes in rodents

Abstract

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 slc5a12/2 mice or with a potent dual inhibitor (compound 8; SGLT1 Ki 5 1.5 6 0.5 nM 100-fold greater potency than phlorizin; SGLT2 Ki 5 0.4 6 0.2 nM). 13C6-glucose uptake was quantified in slc5a12/2 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-glu-cose area under the curve (AUC) was reduced in the absence of SGLT1 by 75% (245 6 6 vs. 64 6 6 mg/dl×h in wild-type vs. slc5a12/2 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 5 129 6 3 vs. 249 6 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.