Dapagliflozin, a selective SGLT2 inhibitor, improves glucose homeostasis in normal and diabetic rats
Dapagliflozin, a selective SGLT2 inhibitor, improves glucose homeostasis in normal and diabetic rats
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DOI：
10.2337/db07-1472
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发表时间：
2008-06-01
期刊：
影响因子：
7.7
通讯作者：
Whaley, Jean M.
中科院分区：
文献类型：
--
作者：
Han, Songping;Hagan, Deborah L.;Whaley, Jean M.
抑制肠道和肾脏钠-葡萄糖协同转运蛋白（SGLT）已被提议作为治疗糖尿病的新治疗方法。我们已经确定了达格列净作为一种有效的和选择性的抑制剂的肾钠-葡萄糖协同转运蛋白SGLT 2在体外和其特点是在体外和体内pharmacology.Research设计和方法-细胞为基础的测定葡萄糖类似物的摄取被用来评估达格列净的能力，抑制钠依赖性和促进葡萄糖转运活动。在正常和糖尿病大鼠中进行了急性和多次给药研究，以评估达格列净改善进食和空腹血糖水平的能力。进行了高胰岛素-正葡萄糖钳夹研究，以评估达格列净在多次给药治疗后改善葡萄糖利用的能力。与人SGLT 1（肠道中葡萄糖的主要协同转运蛋白）相比，DAPGLIZTS-达格列净有效且选择性地抑制人SGLT 2，但不显著抑制人脂肪细胞中的促进性葡萄糖转运。在体内，单次口服0.1 - 1.0 mg/kg剂量后，达格列净可急性诱导正常和糖尿病大鼠的肾脏葡萄糖排泄，改善正常大鼠的葡萄糖耐量，降低Zucker糖尿病肥胖（ZDF）大鼠的高血糖。每日一次达格列净治疗超过2周显着降低空腹和餐后葡萄糖水平，剂量范围为0.1至1.0 mg/kg，并导致葡萄糖利用率的显着增加，伴随着显着减少葡萄糖productions.CONCLUSIONS-These数据表明，达格列净有可能是一种有效的治疗2型糖尿病。
OBJECTIVE-The inhibition of gut and renal sodium-glucose cotransporters (SGLTs) has been proposed as a novel therapeutic approach to the treatment of diabetes. We have identified dapagliflozin as a potent and selective inhibitor of the renal sodium-glucose cotransporter SGLT2 in vitro and characterized its in vitro and in vivo pharmacology.RESEARCH DESIGN AND METHODS-Cell-based assays measuring glucose analog uptake were used to assess dapagliflozin's ability to inhibit sodium-dependent and facilitative glucose transport activity. Acute and multi-dose studies in normal and diabetic rats were performed to assess the ability of dapagliflozin to improve fed and fasting plasma glucose levels. A hyperinsulinemic-euglycemic clamp study was performed to assess the ability of dapagliflozin to improve glucose utilization after multi-dose treatment.RESULTS-Dapagliflozin potently and selectively inhibited human SGLT2 versus human SGLT1, the major cotransporter of glucose in the gut, and did not significantly inhibit facilitative glucose transport in human adipocytes. In vivo, dapagliflozin acutely induced renal glucose excretion in normal and diabetic rats, improved glucose tolerance in normal rats, and reduced hyperglycemia in Zucker diabetic fatty (ZDF) rats after single oral doses ranging from 0.1 to 1.0 mg/kg. Once-daily dapagliflozin treatment over 2 weeks significantly lowered fasting and fed glucose levels at doses ranging from 0.1 to 1.0 mg/kg and resulted in a significant increase in glucose utilization rate accompanied by a significant reduction in glucose production.CONCLUSIONS-These data suggest that dapagliflozin has the potential to be an efficacious treatment for type 2 diabetes.