Article Figures & Data
Figures
- Fig. 1.
Pharmacokinetic studies of LX4211 in three preclinical species. (A) Chemical structure of LX4211. Plasma concentrations of LX4211 (mean ± S.D.) were measured at various times after (B) an intravenous dose of 1 mg/kg to each species, and (C) an oral dose of 10 mg/kg to mice and rats, and an oral dose of 3 mg/kg to dogs.
- Fig. 2.
LX4211 increases UGE in mice, rats, and dogs. UGE was measured over 24-hour intervals as described in Materials and Methods. In (A) mice, (C) rats, and (E) dogs, UGE was measured during the first 24 hours after treatment with vehicle or increasing doses of LX4211. After animals received a single dose of LX4211 on day 1, UGE was also measured in (B) mice during three successive 24-hour intervals; (D) rats during two to four successive 24-hour intervals; and (F) dogs during two successive 24-hour intervals. (A, C, and E) *P < 0.05; **P < 0.01; ***P < 0.001 versus the vehicle-treated group.
- Fig. 3.
LX4211 improves glucose homeostasis in KKAy diabetic mice: study 1. (A) Schematic outline of study design. BG, fed blood glucose; BW, body weight; FC, food consumption; Ins, fed serum insulin; UGE, 24-hour UGE measured in metabolic cages. (B) A time course of change in A1C levels. (C) A time course of fed blood glucose levels. (D) Blood glucose excursions from the week 9 OGTT data. (E) Change in serum insulin levels between the 0- and 30-minute time points of the week 9 OGTT. (F) Total pancreatic insulin: at necropsy, the pancreas of each mouse was isolated, and pancreatic insulin was extracted and measured as described in Materials and Methods. (G) Multiple 24-hour UGE measurements were made on mice in metabolic cages both before and after the start of LX4211 dosing. (B–G) *P < 0.05; **P < 0.01; ***P < 0.001 versus the vehicle-treated group.
- Fig. 4.
LX4211 improves glucose homeostasis in KKAy diabetic mice: study 2. (A) Schematic outline of study design. BW, body weight; FC, food consumption; Fed G, fed serum glucose; UGE, 24-hour UGE measured in metabolic cages. (B) Change in A1C levels between baseline (week 2) and week 6 of the study. (C) Fed serum glucose levels obtained at necropsy. (D) Blood glucose excursions from the week 6 OGTT data. (E) Change in serum insulin levels between the 0- and 30-minute time points of the week 6 OGTT data. (F) Total pancreatic insulin: at necropsy, the pancreas of each mouse was isolated, and pancreatic insulin was extracted and measured as described in Materials and Methods. (G) The mean value of two 24-hour UGE measurements made on consecutive days in mice acclimatized in metabolic cages during study week 7 or 8. (H) Total GLP-1 levels measured at necropsy, 2 hours after a 2 g/kg oral glucose bolus. (B–H) *P < 0.05; **P < 0.01; ***P < 0.001 versus the vehicle-treated group.
- Fig. 5.
The effect of LX4211 on body composition and food consumption in KKAy diabetic mice. In KKAy study 1, mice were evaluated for (A) change in body weight between the start of LX4211 treatment and necropsy; (B) change in body fat between QMR measurements made in week 1 and week 9; and (C) food consumption, reported as the mean daily intake measured during the 8 days that the mice were maintained in metabolic cages while receiving LX4211 or vehicle. In KKAy study 2, mice were evaluated for (D) change in body weight between measurements made on the first day of LX4211 or vehicle treatment and on multiple days during the first 6 weeks of treatment; (E) body fat measured by QMR during study week 9; and (F) food consumption, reported as the mean daily intake during the first 6 weeks of treatment with LX4211 or vehicle. (F) **P < 0.01; ***P < 0.001 versus the vehicle-treated group.
- Fig. 6.
Effects of LX4211 on body weight of lean rats and dogs. In rats, (A) change in body weight and (B) food consumption were measured during a 4-week toxicology study and then compared between the vehicle-treated group (N = 15) and pooled data from groups receiving LX4211 at doses of 10 (N = 10), 30 (N = 10), or 100 (N = 15) mg/kg per day. In dogs, (C) change in body weight and (D) food consumption were also measured during a 4-week toxicology study and then compared between the vehicle-treated group (N = 10) and pooled data from groups receiving LX4211 at doses of 30 (N = 6) or 100 (N = 10) mg/kg per day. In rats, (E) body weight and (F) food consumption were measured during a 13-week toxicology study and then compared between the vehicle-treated group (N = 15) and individual groups receiving LX4211 at doses of 3 (N = 10), 10 (N = 10), 30 (N = 15) or 100 (N = 15) mg/kg/d. The key for all groups in E and F is found in E. No statistically significant adverse effects of LX4211 treatment were observed at these doses in any of the three studies. (A–D) *P < 0.05; **P < 0.01; ***P < 0.001 versus the vehicle-treated group. (F) *P < 0.05 for vehicle versus all other groups; ^P < 0.05 for vehicle versus the 10, 30, and 100 mg/kg per day groups.
- Fig. 7.
Effects of LX4211 on OP-CD obese rats. (A) Schematic outline of study design. BW, body weight; FC, food consumption; UGE, 24-hour UGE measured in metabolic cages. (B) UGE, presented as mean 24-hour UGE values estimated from collections made on three consecutive days in metabolic cages. (C) Change in body weight between the start of LX4211 treatment and necropsy. (D) Body fat and (E) lean body mass, measured by QMR at the end of the study. (F) Food consumption, reported as the mean daily intake during the 25 days of treatment with LX4211 or vehicle. Cecal contents were isolated from fed rats at the time of necropsy and used to measure (G) cecal glucose, reported here as the total amount of glucose recovered, and (H) cecal pH, which represents a direct pH measurement of the cecal contents. (B–E, G, and H) *P < 0.05; ***P < 0.001 versus the vehicle-treated group.
Tables
Species N Half-Life AUC0–∞ CL Vss h nM*h ml/min/kg l/kg Dog 5 7.27 ± 1.39 8849 ± 1796 4.6 ± 0.9 1.98 ± 0.34 Rat 4 0.90 ± 0.09 1847 ± 132 21.3 ± 1.5 1.40 ± 0.07 Mouse 4 1.39 ± 0.45 1940 ± 331 20.6 ± 3.0 2.07 ± 0.14 CL, clearance; N, number of animals; Vss, volume at steady state.
Species N Dose Half-Life Tmax Cmax AUC0–∞ %F mg/kg h h nM nM*h Dog 5 3 7.38 ± 1.17 0.65 ± 0.34 2502 ± 325 18775 ± 4132 71 ± 16 Rat 4 10 ND 3.00 ± 1.15 1116 ± 378 ND ND Mouse 4 10 6.52 ± 0.82 0.31 ± 0.13 4373 ± 408 19079 ± 1580 98 ± 8 %F, % bioavailable; N, number of animals; ND, not determined.
Data Supplement
Files in this Data Supplement:
- Supplemental Tables - Table S1: Body composition of KKAy mice and OP-CD obese rats after long-term treatment with LX4211. Table S2: Body weight and food consumption of lean Sprague-Dawley rats treated with LX4211 for 13 weeks.
In this issue
Effect of LX4211 on Glucose Homeostasis and Body Composition
