Metabolic Diseases Biology, Bristol-Myers Squibb Co. Research and Development, Hopewell, NJ, USA.
Obesity (Silver Spring). 2012 Aug;20(8):1645-52. doi: 10.1038/oby.2012.59. Epub 2012 Mar 8.
Dapagliflozin is a potent and selective sodium glucose cotransporter-2 (SGLT2) inhibitor which promotes urinary glucose excretion and induces weight loss. Since metabolic compensation can offset a negative energy balance, we explored the potential for a compensatory physiological response to the weight loss induced by dapagliflozin. Dapagliflozin was administered (0.5-5 mpk; p.o.) to diet-induced obese (DIO) rats with or without ad libitum access to food for 38 days. Along with inducing urinary glucose excretion, chronic administration of dapagliflozin dose-dependently increased food and water intake relative to vehicle-treated controls. Despite this, it reduced body weight by 4% (relative to controls) at the highest dose. The degree of weight loss was increased by an additional 9% if hyperphagia was prevented by restricting food intake to that of vehicle controls. Neither oxygen consumption (vO2) or the respiratory exchange ratio (RER) were altered by dapagliflozin treatment alone. Animals treated with dapagliflozin and pair-fed to vehicle controls (5 mpk PF-V) showed a reduction in RER and an elevation in nonfasting β-hydroxybutyrate (BHBA) relative to ad libitum-fed 5 mpk counterparts. Fasting BHBA was elevated in the 1 mpk, 5 mpk, and 5 mpk PF-V groups. Serum glucose was reduced in the fasted, but not the unfasted state. Insulin was reduced in the non-fasted state. These data suggest that in rodents, the persistent urinary glucose excretion induced by dapagliflozin was accompanied by compensatory hyperphagia, which attenuated the weight loss induced by SGLT2 inhibition. Therefore, it is possible that dapagliflozin-induced weight loss could be enhanced with dietary intervention.
达格列净是一种强效且选择性的钠-葡萄糖协同转运蛋白 2（SGLT2）抑制剂，可促进尿糖排泄并诱导体重减轻。由于代谢补偿可以抵消负能平衡，我们探讨了达格列净诱导的体重减轻是否会引起代偿性生理反应的可能性。将达格列净（0.5-5mpk；口服）给予自由进食的饮食诱导肥胖（DIO）大鼠，连续给药 38 天。除了诱导尿糖排泄外，达格列净的慢性给药剂量依赖性地增加了相对于载体处理对照的食物和水的摄入。尽管如此，它在最高剂量时使体重减轻了 4%（相对于对照）。如果通过将食物摄入量限制为载体对照来防止过度进食，则体重减轻的程度会增加 9%。单独给予达格列净治疗不会改变耗氧量（vO2）或呼吸交换率（RER）。给予达格列净并与载体对照进行等热量喂养（5mpk PF-V）的动物的 RER 降低，非禁食β-羟丁酸（BHBA）升高，而自由进食的 5mpk 对应物则相反。1mpk、5mpk 和 5mpk PF-V 组的禁食 BHBA 升高。在禁食状态下血糖降低，但在非禁食状态下则不降低。胰岛素在非禁食状态下降低。这些数据表明，在啮齿动物中，达格列净持续诱导的尿糖排泄伴随着代偿性多食，从而减轻了 SGLT2 抑制引起的体重减轻。因此，通过饮食干预可能增强达格列净诱导的体重减轻。
