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 slc5a1 mice or with a potent dual inhibitor (compound 8; SGLT1 = 1.5 ± 0.5 nM 100-fold greater potency than phlorizin; SGLT2 = 0.4 ± 0.2 nM). C-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 C-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.

What does sodium‐glucose co‐transporter 1 inhibition add: Prospects for dual inhibition

“…As such, one might expect that changes in distal intestinal luminal glucose concentration as a result of SGLT1 inhibition might alter the gut microbiome. Surprisingly, treatment with a dual SGLT1/2 inhibitor did not affect relative abundance of bacterial orders or bacteria of interest in diabetic rodents . In contrast, in an adenine‐induced CKD mouse model, 2‐week canagliflozin treatment significantly altered microbiota composition in CKD mice .…”

Crosstalk between gut microbiota and antidiabetic drug action

“…SGLT1 transports glucose and galactose across the apical membrane of enterocytes, whereas SGLT2, and at some extent SGLT1, reabsorbs glucose in the renal tubule. SGLT2-selective inhibitors are a new class of treatment for T2D[82]. SGLT2 differs from other antidiabetic medications because it ameliorates vascular function and thus has advantageous effects on CVD.…”

“…The higher doses of SGLT1/2 inhibitor accelerated body weight gain and increased Bacteroidetes and decreased Firmicutes quantity, but the Akkermansia spp . was not modified[82]. SGLT1/2 inhibitors or SGLT2-selective drugs like canagliflozin guarantee intestinal SGLT1 inhibition in T2D[86].…”

Roles of Gut Microbial Metabolites in Diabetic Kidney Disease

“…Vildagliptin, a DPP4 inhibitor, has been reported to enrich SCFA-producing bacteria (163). Moreover, mice on HFD with DPP-4 inhibitor PKF-275-055 treatment showed enriched butyrate-producing Rumminococcus and of the acetogen Dorea (164). Some drugs for the treatment of DKD can increase the level of SCFA by enriching SCFA-producing microbiota.…”