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SHR3824, a novel selective inhibitor of renal sodium glucose cotransporter 2, exhibits antidiabetic efficacy in rodent models.

Yan PK, Zhang LN, Feng Y, Qu H, Qin L, Zhang LS, Leng Y - Acta Pharmacol. Sin. (2014)

Bottom Line: 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.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).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.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.

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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The effects of chronic SHR3824 treatment on pancreatic insulin staining in db/db mice. The mice were treated with SHR3824 (3.0 mg/kg), BMS512148 (1.0 mg/kg), or vehicle for 43 d. Pancreases were isolated and pancreatic sections were stained with anti-insulin antibodies after 6 h of fasting. (A) Vehicle-treated lean mice. (B) Vehicle-treated db/db mice. (C) db/db mice treated with 3.0 mg/kg SHR3824. (D) db/db mice treated with 1.0 mg/kg BMS512148. The image magnification was ×40.
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fig8: The effects of chronic SHR3824 treatment on pancreatic insulin staining in db/db mice. The mice were treated with SHR3824 (3.0 mg/kg), BMS512148 (1.0 mg/kg), or vehicle for 43 d. Pancreases were isolated and pancreatic sections were stained with anti-insulin antibodies after 6 h of fasting. (A) Vehicle-treated lean mice. (B) Vehicle-treated db/db mice. (C) db/db mice treated with 3.0 mg/kg SHR3824. (D) db/db mice treated with 1.0 mg/kg BMS512148. The image magnification was ×40.

Mentions: To evaluate the chronic effects of SHR3824 treatment on pancreatic β-cell function, the pancreases of SHR3824 (3.0 mg/kg), BMS512148 (1.0 mg/kg), vehicle-treated control and lean control mice were isolated at the end of treatment and immunohistochemical analyses of insulin staining were performed. As shown in Figure 8, weak insulin staining with an irregular β-cell distribution was observed in the vehicle-treated db/db mice compared with vehicle-treated lean mice, indicating that β-cell function was impaired in the db/db mice. SHR3824 treatment for 43 d significantly increased insulin staining and enhanced insulin antigen positivity with regular distribution of β-cells, indicating that β-cell function was improved. The chronic BMS512148 treatment showed similar effects.


SHR3824, a novel selective inhibitor of renal sodium glucose cotransporter 2, exhibits antidiabetic efficacy in rodent models.

Yan PK, Zhang LN, Feng Y, Qu H, Qin L, Zhang LS, Leng Y - Acta Pharmacol. Sin. (2014)

The effects of chronic SHR3824 treatment on pancreatic insulin staining in db/db mice. The mice were treated with SHR3824 (3.0 mg/kg), BMS512148 (1.0 mg/kg), or vehicle for 43 d. Pancreases were isolated and pancreatic sections were stained with anti-insulin antibodies after 6 h of fasting. (A) Vehicle-treated lean mice. (B) Vehicle-treated db/db mice. (C) db/db mice treated with 3.0 mg/kg SHR3824. (D) db/db mice treated with 1.0 mg/kg BMS512148. The image magnification was ×40.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4814034&req=5

fig8: The effects of chronic SHR3824 treatment on pancreatic insulin staining in db/db mice. The mice were treated with SHR3824 (3.0 mg/kg), BMS512148 (1.0 mg/kg), or vehicle for 43 d. Pancreases were isolated and pancreatic sections were stained with anti-insulin antibodies after 6 h of fasting. (A) Vehicle-treated lean mice. (B) Vehicle-treated db/db mice. (C) db/db mice treated with 3.0 mg/kg SHR3824. (D) db/db mice treated with 1.0 mg/kg BMS512148. The image magnification was ×40.
Mentions: To evaluate the chronic effects of SHR3824 treatment on pancreatic β-cell function, the pancreases of SHR3824 (3.0 mg/kg), BMS512148 (1.0 mg/kg), vehicle-treated control and lean control mice were isolated at the end of treatment and immunohistochemical analyses of insulin staining were performed. As shown in Figure 8, weak insulin staining with an irregular β-cell distribution was observed in the vehicle-treated db/db mice compared with vehicle-treated lean mice, indicating that β-cell function was impaired in the db/db mice. SHR3824 treatment for 43 d significantly increased insulin staining and enhanced insulin antigen positivity with regular distribution of β-cells, indicating that β-cell function was improved. The chronic BMS512148 treatment showed similar effects.

Bottom Line: 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.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).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.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.

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.

Show MeSH
Related in: MedlinePlus