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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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Related in: MedlinePlus

The effects of chronic SHR3824 treatment on glucose uptake in the soleus muscles of db/db mice. Mice were treated with SHR3824 (3.0 mg/kg) or vehicle for 43 d. The soleus muscles were isolated and 2-deoxyglucose uptake was measured at the end of the treatment. bP<0.05, cP<0.01 vs control. The data represent the mean±SEM. n=12.
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fig7: The effects of chronic SHR3824 treatment on glucose uptake in the soleus muscles of db/db mice. Mice were treated with SHR3824 (3.0 mg/kg) or vehicle for 43 d. The soleus muscles were isolated and 2-deoxyglucose uptake was measured at the end of the treatment. bP<0.05, cP<0.01 vs control. The data represent the mean±SEM. n=12.

Mentions: To determine whether SHR3824 improved hyperinsulinemia in type 2 diabetic mice, serum fasting insulin levels were measured pre-dose and on treatment d 38. As shown in Figure 6E, hyperinsulinemia was observed at the beginning of the experiment in all db/db mice compared with lean mice. Treatment with 3.0 mg/kg of SHR3824 significantly reduced the serum insulin levels by 21.1% (P<0.05), while treatment with 1.0 mg/kg BMS512148 resulted in a comparable decrease of 25.3%. These data suggest that chronic treatment with SHR3824 may improve the peripheral insulin sensitivity of db/db mice. To further study the insulin sensitivity of skeletal muscle, the soleus muscles were isolated from SHR3824 (3.0 mg/kg) treated and vehicle-treated control mice at the end of treatment for measuring 2-deoxyglucose uptake (Figure 7). Insulin incubation stimulated 2-deoxyglucose uptake in the soleus muscles. Chronic treatment with SHR3824 significantly enhanced the insulin-stimulated glucose uptake in the soleus muscles of db/db mice compared with vehicle-treated controls (P<0.05). The insulin-stimulated glucose uptake was increased by 43% in the soleus muscles of vehicle-treated control mice, whereas an 84% increase in the insulin-stimulated glucose uptake was observed in the soleus muscles of SHR3824 treated mice.


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 glucose uptake in the soleus muscles of db/db mice. Mice were treated with SHR3824 (3.0 mg/kg) or vehicle for 43 d. The soleus muscles were isolated and 2-deoxyglucose uptake was measured at the end of the treatment. bP<0.05, cP<0.01 vs control. The data represent the mean±SEM. n=12.
© Copyright Policy
Related In: Results  -  Collection

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

fig7: The effects of chronic SHR3824 treatment on glucose uptake in the soleus muscles of db/db mice. Mice were treated with SHR3824 (3.0 mg/kg) or vehicle for 43 d. The soleus muscles were isolated and 2-deoxyglucose uptake was measured at the end of the treatment. bP<0.05, cP<0.01 vs control. The data represent the mean±SEM. n=12.
Mentions: To determine whether SHR3824 improved hyperinsulinemia in type 2 diabetic mice, serum fasting insulin levels were measured pre-dose and on treatment d 38. As shown in Figure 6E, hyperinsulinemia was observed at the beginning of the experiment in all db/db mice compared with lean mice. Treatment with 3.0 mg/kg of SHR3824 significantly reduced the serum insulin levels by 21.1% (P<0.05), while treatment with 1.0 mg/kg BMS512148 resulted in a comparable decrease of 25.3%. These data suggest that chronic treatment with SHR3824 may improve the peripheral insulin sensitivity of db/db mice. To further study the insulin sensitivity of skeletal muscle, the soleus muscles were isolated from SHR3824 (3.0 mg/kg) treated and vehicle-treated control mice at the end of treatment for measuring 2-deoxyglucose uptake (Figure 7). Insulin incubation stimulated 2-deoxyglucose uptake in the soleus muscles. Chronic treatment with SHR3824 significantly enhanced the insulin-stimulated glucose uptake in the soleus muscles of db/db mice compared with vehicle-treated controls (P<0.05). The insulin-stimulated glucose uptake was increased by 43% in the soleus muscles of vehicle-treated control mice, whereas an 84% increase in the insulin-stimulated glucose uptake was observed in the soleus muscles of SHR3824 treated mice.

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