SHR3824, a novel selective inhibitor of renal sodium glucose cotransporter 2, exhibits antidiabetic efficacy in rodent models |
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Authors: | Pang-ke YAN Li-na ZHANG Ying FENG Hui QU Li QIN Lian-shan ZHANG Ying LENG |
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Affiliation: | [1]State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China [2]Shanghai Hengrui Pharmaceuticals Co, Ltd, Shanghai 200245, China |
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Abstract: | Aim: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.Methods: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.Results: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.Conclusion: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. |
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Keywords: | sodium glucose cotransporter 2 (SGLT2) SHR3824 dapagliflozin type 2 diabetes mellitus blood glucose insulin sensitivity β-cell function |
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