TS-071, a Novel, Potent and Selective SGLT2 Inhibitor, Induces Weight Loss and a Reduction in Adipocyte Size in Diet-Induced Obese Rats
Abstract Number: 1000-P
Authors: SAEKO UCHIDA, TEISUKE TAKAHASHI, HIDEKI TOMOIKE, EMI GUNJI, NAOKI KOJIMA, NAMIKO FUKUHARA, KAHORI TAKANO, TAKASHI NAKAYAMA, KENZO TAKAHASHI
Institutions: Saitama, Japan
Results: We have discovered a novel sodium-dependent glucose co-transporter 2 (SGLT2) inhibitor, TS-071 (TS), which is currently under clinical development for the treatment of type 2 diabetes (T2DM). TS is a potent SGLT2 inhibitor with an IC50 value of 2.26 nM, and exhibits 1765-fold selectivity for inhibition of SGLT2 over SGLT1. TS competitively inhibited SGLT2 activity with a Ki value of 1.10 nM. The aim of this study is to evaluate the effect of TS on urinary glucose excretion, body weight and metabolic parameters in diet-induced obese (DIO) rats. We also examined the effects of TS on the white adipose tissue mass and the adipocyte size in visceral and subcutaneous fat. Sprague-Dawley rats were made obesity by free access to high-sucrose/ high-fat diet for 11 weeks and were given orally either vehicle (VEH) or TS (3 and 10 mg/kg) once daily for 4 weeks. TS significantly increased urinary glucose excretion (VEH = 3.1±0.2 mg/day, TS 3 mg/kg = 2548±144 mg/day***, TS 10 mg/kg = 4938±261 mg/day***, ***p < 0.001 vs. VEH) and reduced body weight gain (% change from baseline body weight: VEH = 10.5±1.6%, TS 3 mg/kg = 5.9±0.8%*, TS 10 mg/kg = 2.2±0.9%***, *p < 0.05, ***p < 0.001 vs. VEH). In addition, TS (10 mg/kg) significantly improved hyperinsulinemia, hypertriglyceridemia and hyperleptinemia in DIO rats. In the pair-feeding experiment, TS (10 mg/kg) induced the marked body weight loss (% change from baseline body weight: VEH 8.9±1.1% vs. TS -1.3±0.7%, p < 0.001). TS significantly reduced the white adipose tissue mass in both visceral fat (VEH 89.9±7.0 g vs. TS 66.5±4.2 g, p < 0.05) and subcutaneous fat (VEH 96.8±5.4 g vs. TS 67.8±7.7 g, p < 0.05). The distribution of the visceral adipocyte size in TS-treated DIO rats was similar to that in lean rats, and TS significantly reduced the average adipocyte size (VEH 9904±883 μm2 vs TS 7249±282 μm2, p < 0.05). In summary, the decrease in body weight by TS is accompanied by a loss of fat mass and a reduction in adipocyte size, including visceral compartment. These findings suggest that TS exhibits the potential effect for inducing meaningful body weight loss in addition to treating T2DM.