TY - JOUR T1 - Effect of LX4211 on Glucose Homeostasis and Body Composition in Preclinical Models JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 232 LP - 242 DO - 10.1124/jpet.114.214304 VL - 350 IS - 2 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 Y1 - 2014/08/01 UR - http://jpet.aspetjournals.org/content/350/2/232.abstract N2 - Treatments that lower blood glucose levels and body weight should benefit patients with type 2 diabetes mellitus (T2DM). We developed LX4211 [(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol], an orally available small molecule that decreases postprandial glucose excursions by inhibiting intestinal sodium/glucose cotransporter 1 (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 that explored the ability of LX4211 to improve glycemic control and promote weight loss. We found that 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 mice, rats, and dogs; and 3) in the KK.Cg-Ay/J heterozygous (KKAy) mouse model of T2DM, LX4211 lowered A1C and postprandial glucose concentrations while increasing postprandial glucagon-like peptide 1 concentrations. Also, long-term LX4211 treatment 1) decreased oral glucose tolerance test (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. ER -