PT  - JOURNAL ARTICLE
AU  - David R Powell
AU  - Christopher M DaCosta
AU  - Melinda Smith
AU  - Deon Doree
AU  - Angela Harris
AU  - Lindsey Buhring
AU  - William Heydorn
AU  - Amr Nouraldeen
AU  - Wendy Xiong
AU  - Padmaja Yalamanchili
AU  - Faika Mseeh
AU  - Alan Wilson
AU  - Melanie Shadoan
AU  - Brian Zambrowicz
AU  - Zhi-Ming Ding
TI  - Effect of LX4211 on Glucose Homeostasis and Body Composition in Preclinical Models
AID  - 10.1124/jpet.114.214304
DP  - 2014 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - jpet.114.214304
4099  - http://jpet.aspetjournals.org/content/early/2014/05/21/jpet.114.214304.short
4100  - http://jpet.aspetjournals.org/content/early/2014/05/21/jpet.114.214304.full
AB  - Treatments which lower blood glucose levels and body weight should benefit patients with type 2 diabetes mellitus (T2DM). We developed LX4211, an orally available small molecule that decreases postprandial glucose excursions by inhibiting intestinal SGLT1 and increases urinary glucose excretion (UGE) by inhibiting renal SGLT2. In clinical studies of patients with T2DM, LX4211 appears to act through dual SGLT1/SGLT2 inhibition to improve glycemic control and promote weight loss. Here, we present preclinical studies which explored the ability of LX4211 to improve glycemic control and promote weight loss. We found: 1) LX4211 inhibited in vitro glucose transport mediated by mouse, rat and dog SGLT1 and SGLT2; 2) a single daily LX4211 dose markedly increased UGE for > 24 hours in mouse, rat and dog; and 3) in the KKAy mouse model of T2DM, LX4211 lowered A1C and postprandial glucose concentrations while increasing postprandial GLP-1 concentrations. Also, long-term LX4211 treatment: 1) decreased OGTT glucose excursions, increased OGTT 30 minute insulin concentrations and increased pancreatic insulin content in KKAy mice; and 2) decreased weight gain in dogs and rats but not in KKAy mice, while increasing food consumption in dogs, rats and KKAy mice; in these KKAy mice, calories lost through UGE were completely offset by calories gained through hyperphagia. These findings suggest that LX4211 improves glycemic control by dual SGLT1/SGLT2 inhibition in mice as in humans, and that the LX4211-mediated weight loss observed in patients with T2DM may be attenuated by LX4211-mediated hyperphagia in some of these individuals.