Sglt1 Inhibition Has Modest Gastrointestinal Consequences in Mice and Rats

In the small intestine glucose is transported apically across the enterocyte by sodium/glucose cotransporter 1 (SGLT1; slc5a1) and its inhibition lowers the post‐prandial blood glucose excursion; however, questions remain about the effect of altered luminal glucose in the intestine. Using 13 C6‐glucose LC/MS/MS detection we first quantified the inhibition of intestinal glucose uptake in SGLT1 −/− and −/+ mice in vivo, and pharmacologically by cmpd B (IC50 <20 nM for rSGLT1 & rSGLT2) in isolated rat jejunum mounted in Ussing chambers. After Cmpd B was dosed chronically, morphometric intestinal changes were assessed in Zucker Diabetic Fatty (ZDF) rats and cecal/fecal bacterial 16s RNA analysis performed in mice. A high fat diet In C57BL/6mice had variable effects on sglt1 mRNA expression (increased, decreased or not changed) in 3 separate experiments. Thus, there is no consistent impact of diet on SGLT1 mRNA expression. Jejunum mucosal SGLT1 mRNA expression was confirmed absent in −/− mice whereas +/− mice had ~ half the level of expression. After an oral 13 C6‐glucose tolerance test (oGTT) the AUC was similar in WT and SGLT1 +/− mice, and reduced to 25% of AUC in −/− mice (−/−3,851±384, P<0.05 by ANOVA compared to −/+ 18,682±3,277 and WT 14,674±1,616; n=7–8/group). Apically administered 13 C6‐glucose to rat isolated muscle‐stripped jejunum in the presence of cmpd B (1 μM) decreased the amount detected basolaterally (14.2 ± 1.8μM, n=16; versus 8.7 ± 1.3μM, n=12 after 90 mins). In ZDF rats treated daily with 0.3 or 1.0 mg/kg for up to 3 weeks, decreased HbA 1c , and total GLP‐1 during an oGTT increased after the higher dose. Analysis of GI tissue showed no difference in jejunum mucosal SGLT1 or GLUT2 mRNA relative expression, and no gross mucosal adaption (villus height, villus width or mucosal weight). In C57BL/6mice, high sucrose diet or cmpd B in mice fed normal chow (1.0 mg/kg p.o. daily for 5 days) alone did not change cecal glucose concentration but, when combined with high sucrose diet, cecal glucose was increased (30.6 ± 3.4 mg/dL versus 17.1 ± 4.7 mg/dL, n=8/group). Switching to high sucrose diet changed cecal/fecal bacterial diversity by day 2, with some differences in bacterial relative abundance; however, neither microbial diversity nor abundance was correlated with cecal glucose concentrations. In conclusion, SGLT1 inhibition or genetic ablation reduces intestinal glucose uptake (although glucose is still absorbed). but any remaining excess luminal glucose is not associated with intestinal adaptation or bacterial population changes during the time frames studied.