LX2761 doses ≤0.15 mg/kg can decrease OGTT glucose excursions. (A) Schematic depiction of study design. Adult male mice fed HGD for 6 days prior to study were randomized into three or four treatment groups by body weight. All mice received 5 daily doses of either LX2761 or vehicle by oral gavage, and all mice were fed ad lib during the 15-hour interval between the final dose and the OGTT. (B) Glucose excursions from OGTTs performed on mice (4–5/group) that received either vehicle or LX2761 at a dose of 0.15, 0.015, or 0.009 mg/kg. (C) Glucose excursions from OGTTs performed on mice (8–9/group) that received either vehicle or LX2761 at a dose of 0.05 or 0.012 mg/kg. For (B) and (C), where glucose excursions among groups were compared as glucose AUC_{0–60 minutes} values, *P < 0.05 and ***P < 0.001 versus the vehicle-treated group.

The combination of LX2761 and sitagliptin synergistically increases aGLP-1 levels between 0 and 6 hours after an oral glucose challenge. Adult male mice (5/group) received 1 (A) or 14 (B) daily doses of either LX2761 (0.15 mg/kg), sitagliptin (30 mg/kg), the combination of LX2761 and sitagliptin (0.15 mg/kg + 30 mg/kg, respectively), or vehicle by oral gavage. Thirty minutes after the last dose, all mice received 4 g/kg glucose by oral gavage. Levels of aGLP-1 obtained at various times after the glucose challenge are plotted in the panels. For each treatment group, the aGLP-1 time-course data were converted to aGLP-1 AUC_{0–6 hours} values, which were then analyzed by two-way ANOVA. An interaction between the effects of LX2761 and sitagliptin on postprandial aGLP-1 levels was considered significant when P < 0.05.

LX2761 improves glycemic control in mice with early onset STZ-induced diabetes. Adult male mice (10–11/group) with early onset diabetes (fed blood glucose > 200 mg/dl required for entry; mean value = 287 mg/dl on day 1) received single daily doses of either vehicle or LX2761 (1.5 or 3 mg/kg) by oral gavage. (A) Schematic of study design. FBG = fasting blood glucose. (B) OGTT glucose excursions on day 21. Glucose excursions among groups were compared as glucose AUC_{0–120 minutes} values. (C) Fasting blood glucose levels on day 32. (D) Change in A1C levels on day 32 relative to baseline values. (E) Cecal glucose obtained at necropsy on day 39, reported as the total amount of glucose recovered. (F) Cecal pH obtained at necropsy on day 39, which represents a direct pH measurement of cecal contents. For panels (B)–(F), *P < 0.05, **P < 0.01, and ***P < 0.001 versus the vehicle-treated group.

LX2761 improves glycemic control in mice with well-established STZ-induced diabetes. Adult male mice (12–13/group at randomization) with well-established diabetes (A1C > 5.7% required for entry, mean = 9.4% on day 1) received single daily doses of vehicle or LX2761 (1.5 or 3 mg/kg) by oral gavage. (A) Schematic depiction of study design. (B) Kaplan and Meier survival curve for the three groups of study mice. (C) OGTT glucose excursions on day 20. Glucose excursions among groups were compared as glucose AUC_{0–120 minutes} values. (D) Change in A1C levels on day 32 relative to baseline values. On day 49, the final study day, samples were obtained to measure (E) fasting blood glucose; (F) plasma tGLP-1; (G) cecal glucose, reported as the total amount of glucose recovered; and (H) cecal pH, which represents a direct pH measurement of cecal contents. For panels (B)–(H), *P < 0.05, **P < 0.01, and ***P < 0.001 versus the vehicle-treated group.