Drug Discovery Research, Astellas Pharma, Inc., Ibaraki 305-8585, Japan.
J Pharmacol Sci. 2012;120(1):36-44. doi: 10.1254/jphs.12089fp. Epub 2012 Aug 23.
Sodium-glucose cotransporter (SGLT) 2 plays an important role in renal glucose reabsorption, and inhibition of renal SGLT2 activity represents an innovative strategy for the treatment of hyperglycemia in diabetic patients. The present study investigated the antidiabetic effects of ipragliflozin, a SGLT2-selective inhibitor, in streptozotocin-nicotinamide-induced mildly diabetic mice, which exhibited a mild decline in glucose tolerance associated with the loss of early-phase insulin secretion. Oral administration of ipragliflozin increased urinary glucose excretion in a dose-dependent manner, an effect which was significant at doses of 0.3 mg/kg or higher and lasted over 12 h. In addition, ipragliflozin dose-dependently improved hyperglycemia and glucose intolerance with concomitant decreases in plasma insulin levels without causing hypoglycemia. Once-daily dosing of ipragliflozin (0.1 - 3 mg/kg) for 4 weeks attenuated hyperglycemia, glucose intolerance, and impaired insulin secretion. These results suggest that the SGLT2-selective inhibitor ipragliflozin increases urinary glucose excretion by inhibiting renal glucose reabsorption, improves hyperglycemia in streptozotocin-nicotinamide-induced mildly diabetic mice, and may be useful for treating type 2 diabetes.
钠-葡萄糖共转运蛋白 2（SGLT2）在肾脏葡萄糖重吸收中发挥重要作用，抑制肾脏 SGLT2 活性是治疗糖尿病患者高血糖的一种创新策略。本研究探讨了 SGLT2 选择性抑制剂伊格列净在链脲佐菌素-烟酰胺诱导的轻度糖尿病小鼠中的抗糖尿病作用，该模型表现出与早期胰岛素分泌丧失相关的轻度葡萄糖耐量下降。伊格列净口服给药呈剂量依赖性增加尿糖排泄，在 0.3mg/kg 或更高剂量时效果显著，持续超过 12 小时。此外，伊格列净还可剂量依赖性改善高血糖和葡萄糖耐量异常，同时降低血浆胰岛素水平，而不会引起低血糖。伊格列净（0.1-3mg/kg）每日一次给药 4 周可减轻高血糖、葡萄糖耐量异常和胰岛素分泌受损。这些结果表明，SGLT2 选择性抑制剂伊格列净通过抑制肾脏葡萄糖重吸收增加尿糖排泄，改善链脲佐菌素-烟酰胺诱导的轻度糖尿病小鼠的高血糖，并可能对治疗 2 型糖尿病有用。
