Yan Pang-ke, Zhang Li-na, Feng Ying, Qu Hui, Qin Li, Zhang Lian-shan, Leng Ying
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Shanghai Hengrui Pharmaceuticals Co, Ltd, Shanghai 200245, China.
Acta Pharmacol Sin. 2014 May;35(5):613-24. doi: 10.1038/aps.2013.196.
The sodium glucose cotransporter 2 (SGLT2) plays an important role in renal glucose reabsorption, thus serves as a new target for the treatment of diabetes. The purpose of this study was to evaluate SHR3824 as a novel selective SGLT2 inhibitor and to characterize its in vivo effects on glucose homeostasis. The effects of chronic administration of SHR3824 on peripheral insulin sensitivity and pancreatic β-cell function were also investigated.
The in vitro potency and selectivity of SHR3824 were assessed in HEK293 cells transfected with human SGLT2 or SGLT1. Acute and multi-dose studies were performed on ICR mice, GK rats and db/db mice to assess the ability of SHR3824 to enhance urinary glucose excretion and improve blood glucose levels. 2-Deoxyglucose uptake and insulin immunohistochemical staining were performed in the soleus muscle and pancreas, respectively, of db/db mice. A selective SGLT2 inhibitor BMS512148 (dapagliflozin) was taken as positive control.
SHR3824 potently inhibited human SGLT2 in vitro, but exerted much weak inhibition on human SGLT1 (the IC50 values of SHR3824 against human SGLT2 and SGLT1 were 2.38 and 4324 nmol/L, respectively). Acute oral administration of SHR3824 (0.3, 1.0, 3.0 mg/kg) dose-dependently improved glucose tolerance in ICR mice, and reduced hyperglycemia by increasing urinary glucose excretion in GK rats and db/db mice. Chronic oral administration of SHR3824 (0.3, 1.0, 3.0 mg·kg(-1)·d(-1)) dose-dependently reduced blood glucose and HbA1c levels in GK rats and db/db mice, and significantly increased insulin-stimulated glucose uptake in the soleus muscles and enhanced insulin staining in the islet cells of db/db mice.
SHR3824 is a potent and selective SGLT2 inhibitor and exhibits antidiabetic efficacy in several rodent models, suggesting its potential as a new therapeutic agent for the treatment of type 2 diabetes.
钠-葡萄糖协同转运蛋白2（SGLT2）在肾脏葡萄糖重吸收中起重要作用，因此成为糖尿病治疗的新靶点。本研究旨在评估SHR3824作为一种新型选择性SGLT2抑制剂，并表征其对体内葡萄糖稳态的影响。还研究了长期给予SHR3824对外周胰岛素敏感性和胰腺β细胞功能的影响。
在转染了人SGLT2或SGLT1的HEK293细胞中评估SHR3824的体外效力和选择性。对ICR小鼠、GK大鼠和db/db小鼠进行急性和多剂量研究，以评估SHR3824增强尿糖排泄和改善血糖水平的能力。分别在db/db小鼠的比目鱼肌和胰腺中进行2-脱氧葡萄糖摄取和胰岛素免疫组织化学染色。选用选择性SGLT2抑制剂BMS512148（达格列净）作为阳性对照。
SHR3824在体外能有效抑制人SGLT2，但对人SGLT1的抑制作用较弱（SHR3824对人SGLT2和SGLT1的IC50值分别为2.38和4324 nmol/L）。急性口服SHR3824（0.3、1.0、3.0 mg/kg）剂量依赖性地改善了ICR小鼠的糖耐量，并通过增加GK大鼠和db/db小鼠的尿糖排泄降低了高血糖。长期口服SHR3824（0.3、1.0、3.0 mg·kg⁻¹·d⁻¹）剂量依赖性地降低了GK大鼠和db/db小鼠的血糖和糖化血红蛋白水平，并显著增加了比目鱼肌中胰岛素刺激的葡萄糖摄取，增强了db/db小鼠胰岛细胞中的胰岛素染色。
SHR3824是一种有效且选择性的SGLT2抑制剂，在几种啮齿动物模型中显示出抗糖尿病疗效，表明其作为治疗2型糖尿病新治疗药物的潜力。
