882-P: Effects of YG1699 and Sotagliflozin on Intestinal Glucose Absorption and GLP-1 in Mice

Abstract

Background and Aims: YG1699, a dual inhibitor of SGLT1 and SGLT2, recently showed greater glucose reduction than dapagliflozin in patients with type 1 diabetes. This study examined whether YG1699 provides gastrointestinal SGLT1 inhibition. Materials and Methods: Male BALB/c mice (n=105) were randomly divided into five groups: vehicle, YG1699 at low (1mg/kg), medium (3mg/kg), and high doses (10mg/kg), and LX4211 (sotagliflozin) 10mg/kg by oral gavage. Animals received a 5g/kg glucose challenge 15 minutes after study drug. Animals were euthanized at various times to examine intestinal plasma GLP-1 and glucose content in small intestine, cecum, and colon. Differences between groups were evaluated by ANOVA. Results (See Table 1): Small intestinal glucose content 1 hour after glucose challenge increased in a dose-related fashion with YG1699 compared to vehicle (p<0.001 for each YG1699 group vs. vehicle). Similar results were found in cecum (p<0.05 for each YG1699 group vs. vehicle). Plasma GLP-1 and PYY concentrations at 1 hour were higher on YG1699 vs. vehicle. Intestinal glucose content in the sotagliflozin group was similar to vehicle and the plasma GLP-1 were only numerically increased in this group. Conclusion: YG1699 delays intestinal glucose absorption and induces an incretin response in BALB/c mice, indicating significant gastrointestinal SGLT1 inhibition. Disclosure J.Li: None. R.W.Xu: Consultant; Youngene Therapeutics. J.He: None. P.Lapuerta: Board Member; 4M Therapeutics, Consultant; Youngene Therapeutics, ViaCyte, Inc., Encuragen, Capsida, Provention Bio, Inc., Decibel Therapeutics, Crinetics, Next Phase Therapeutics.