Fred Wilson School of Pharmacy, High Point University, High Point, North Carolina, USA.
Endocrinol Diabetes Metab. 2024 Mar;7(2):e00475. doi: 10.1002/edm2.475.
Sodium glucose-linked transporter 2 (SGLT2) inhibitors promote glucose, and therefore calorie, excretion in the urine. Patients taking SGLT2 inhibitors typically experience mild weight loss, but the amount of weight loss falls short of what is expected based on caloric loss. Understanding the mechanisms responsible for this weight loss discrepancy is imperative, as strategies to improve weight loss could markedly improve type 2 diabetes management and overall metabolic health.
Two mouse models of diet-induced obesity were administered the SGLT2 inhibitor empagliflozin in the food for 3 months. Urine glucose excretion, body weight, food intake and activity levels were monitored. In addition, serum hormone measurements were taken, and gene expression analyses were conducted.
In both mouse models, mice receiving empagliflozin gained the same amount of body weight as their diet-matched controls despite marked glucose loss in the urine. No changes in food intake, serum ghrelin concentrations or activity levels were observed, but serum levels of fibroblast growth factor 21 (FGF21) decreased after treatment. A decrease in the levels of deiodinase 2 (Dio2) was also observed in the white adipose tissue, a primary target tissue of FGF21.
These findings suggest that compensatory metabolic adaptations, other than increased food intake or decreased physical activity, occur in response to SGLT2 inhibitor-induced glycosuria that combats weight loss, and that reductions in FGF21, along with subsequent reductions in peripheral Dio2, may play a role.
钠-葡萄糖共转运蛋白 2（SGLT2）抑制剂可促进葡萄糖（进而使热量）从尿液中排出。服用 SGLT2 抑制剂的患者通常会出现轻度体重减轻，但体重减轻的幅度与根据热量损失所预期的幅度不符。了解导致这种体重减轻差异的机制至关重要，因为改善体重减轻的策略可能会显著改善 2 型糖尿病的管理和整体代谢健康。
两种饮食诱导肥胖的小鼠模型在食物中给予 SGLT2 抑制剂恩格列净治疗 3 个月。监测尿葡萄糖排泄、体重、食物摄入量和活动水平。此外，还进行了血清激素测量和基因表达分析。
在这两种小鼠模型中，尽管尿液中葡萄糖大量丢失，但接受恩格列净治疗的小鼠与饮食匹配的对照组相比，体重增加量相同。未观察到食物摄入量、血清胃饥饿素浓度或活动水平的变化，但治疗后血清成纤维细胞生长因子 21（FGF21）水平下降。还观察到白色脂肪组织中脱碘酶 2（Dio2）水平降低，而 FGF21 的主要靶组织正是白色脂肪组织。
这些发现表明，除了增加食物摄入或减少体力活动外，SGLT2 抑制剂诱导的糖尿还会引起代偿性代谢适应，从而对抗体重减轻，而 FGF21 的减少以及随后外周 Dio2 的减少可能发挥作用。
