LX4211 Improves Glycemic Control and Beta Cell Function in KKAy Diabetic Mice

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SAT 786-805-Diabetes & Obesity Therapeutics
Bench to Bedside
Saturday, June 15, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SAT-797
David R Powell*, Christopher M DaCosta, Lindsey Buhring, Zhi-Ming Ding, Melanie K Shadoan and Brian Zambrowicz
Lexicon Pharmaceuticals, Inc., The Woodlands, TX
There is a need for new anti-diabetic treatments that improve glycemic control while preserving pancreatic beta cell function. LX4211 is an orally available small molecule that improves glycemic control by the dual mechanism of inhibiting SGLT2-mediated renal glucose (Glu) reabsorption, which increases urinary Glu excretion (UGE), and by partially inhibiting SGLT1-mediated intestinal Glu absorption; in multiple clinical trials, LX4211 significantly improved glycemic control in patients with type 2 diabetes mellitus (T2DM). We tested if LX4211 improved glycemic control and beta cell function in the KKAy mouse model of T2DM. In a pilot study, 14-25 week-old KKAymice, individually housed in metabolic cages and fed 45% high fat diet (HFD), received vehicle (n=6), 1 mg/kg LX4211 (n=4) or 10 mg/kg LX4211 (n=5) once/day by oral gavage. During the 4 week study, the LX4211-treated groups had increased 24-hr UGE (p<0.001 for each), decreased fed blood Glu (p=0.052) and decreased HbA1c (p<0.05 for each) vs vehicle. The 3 groups did not differ significantly at baseline for any of these parameters.

Based on these data, we provided 10 week-old KKAymice with either vehicle (n=6) or 1 mg/kg/day LX4211 (n=6) mixed in HFD paste for 5 weeks. Results are presented as mean ± SD. In these mice, LX4211: 1) increased UGE vs vehicle, 1.0±0.2 vs 0.5±0.2 g/day during week 1 (p<0.001) and 2.1±0.5 vs 1.5±0.4 g/day during week 5 (p=0.055); 2) lowered fed Glu vs vehicle, 366±63 vs 565±61 mg/dL at week 1 (p<0.001) and 292±65 vs 581±31 mg/dL at week 5 (p<0.001); 3) decreased HbA1c vs vehicle, 8.7±0.6 vs 12.3±0.5 % at week 5 (p<0.001); 4) lowered Glu AUC vs vehicle during an oral Glu tolerance test (OGTT) performed during week 5, 34±5 vs 46±9 g/dl*min (p<0.05); and 5) increased the OGTT insulinogenic index (change in insulin from 0-30 minutes/change in Glu from 0-30 minutes) vs vehicle, 10.8±8.2 vs 1.9±1.0 ng insulin/mg Glu (p<0.05). The 2 groups did not differ significantly at baseline for any of these parameters.  Pancreata harvested on the last treatment day from LX4211-treated mice had twice the insulin content of pancreata from vehicle-treated mice, 63±17 vs 29±7 mg/g pancreas (p<0.01).

These data demonstrate that LX4211 improves glycemic control and pancreatic beta cell function in KKAy diabetic mice, and suggest that LX4211 may also improve beta cell function in humans with T2DM.

Disclosure: DRP: Employee, Lexicon Pharmaceuticals, Inc., Employee, Lexicon Pharmaceuticals, Inc., Employee, Lexicon Pharmaceuticals, Inc.. CMD: Employee, Lexicon Pharmaceuticals, Inc.. LB: Employee, Lexicon Pharmaceuticals, Inc.. ZMD: Employee, Lexicon Pharmaceuticals, Inc., Employee, Lexicon Pharmaceuticals, Inc., Employee, Lexicon Pharmaceuticals, Inc.. MKS: Employee, Lexicon Pharmaceuticals, Inc.. BZ: Employee, Lexicon Pharmaceuticals, Inc., Employee, Lexicon Pharmaceuticals, Inc., Employee, Lexicon Pharmaceuticals, Inc..

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm