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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 effect of SHR3824 on urinary glucose excretion and blood glucose levels after acute and multiple dosing in GK rats. SHR3824, BMS512148, or vehicle was orally administered to GK rats once daily for 41 d. Urine volume, urinary glucose excretion and blood glucose levels were determined on treatment d 1 [(A) Urine volume; (B) urinary glucose excretion; and (C) blood glucose levels] and d 32 [(D) Urine volume; (E) urinary glucose excretion; and (F) blood glucose levels]. bP<0.05, cP<0.01 vs control. The data represent the mean±SEM. n=12.
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fig3: The effect of SHR3824 on urinary glucose excretion and blood glucose levels after acute and multiple dosing in GK rats. SHR3824, BMS512148, or vehicle was orally administered to GK rats once daily for 41 d. Urine volume, urinary glucose excretion and blood glucose levels were determined on treatment d 1 [(A) Urine volume; (B) urinary glucose excretion; and (C) blood glucose levels] and d 32 [(D) Urine volume; (E) urinary glucose excretion; and (F) blood glucose levels]. bP<0.05, cP<0.01 vs control. The data represent the mean±SEM. n=12.

Mentions: To assess whether acute administration and multiple doses of SHR3824 increased urinary glucose excretion by inhibiting renal glucose reabsorption, we orally administered SHR3824 (0.3, 1.0, or 3.0 mg/kg) to GK rats once daily for 41 d. The blood glucose, urine volume and urinary glucose excretion were measured on d 1 and 32 of treatment. As shown in Figure 3, the urine volume and urinary glucose excretion were increased by either acute or multiple oral administration of SHR3824 in a dose-dependent manner, and most of the glucose was excreted within 6 h of administration. On d 1 of treatment, 0.3, 1.0, or 3.0 mg/kg of SHR3824 increased the urinary glucose excretion during the first 6 h by 1.8-, 2.1-, and 2.2-fold compared with the vehicle-treated controls (P<0.01) while BMS512148 (1.0 mg/kg) increased the urinary glucose excretion by 3.0-fold (P<0.01). On d 32 of treatment, 0.3, 1.0, or 3.0 mg/kg of SHR3824 increased the urinary glucose excretion during the first 6 h by 1.6-, 1.8-, and 1.8-fold compared with the vehicle-treated controls (P<0.01) while BMS512148 (1.0 mg/kg) increased the urinary glucose excretion by 2.1-fold (P<0.01). Thus, SHR3824 was confirmed as a selective SGLT2 inhibitor capable of increasing urinary glucose excretion in a dose dependent manner. As shown in Figure 3C and 3F, GK rats exhibited hyperglycemia. The administration of SHR3824 or BMS512148 to GK rats produced a significant decrease in blood glucose levels. On d 1 of treatment, 0.3, 1.0, or 3.0 mg/kg of SHR3824 reduced the glucose AUC0–24 h values by 23.7%, 32.7%, and 36.5%, while 1.0 mg/kg of BMS512148 reduced the glucose AUC0–24 h levels by 46.5%. On d 32 of treatment, 0.3, 1.0, or 3.0 mg/kg of SHR3824 reduced the glucose AUC0–24 h values by 27.9%, 37.5%, and 42.4%, while 1.0 mg/kg of BMS512148 reduced the glucose AUC0–24 h values by 52.3%. The in vivo glucose lowering potency of SHR3824 on d 1 and 32 were comparable, suggesting that the multiple administration of SHR3824 did not exhibit tachyphylaxis with respect to its antidiabetic activity.


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 effect of SHR3824 on urinary glucose excretion and blood glucose levels after acute and multiple dosing in GK rats. SHR3824, BMS512148, or vehicle was orally administered to GK rats once daily for 41 d. Urine volume, urinary glucose excretion and blood glucose levels were determined on treatment d 1 [(A) Urine volume; (B) urinary glucose excretion; and (C) blood glucose levels] and d 32 [(D) Urine volume; (E) urinary glucose excretion; and (F) blood glucose levels]. bP<0.05, cP<0.01 vs control. The data represent the mean±SEM. n=12.
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Related In: Results  -  Collection

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fig3: The effect of SHR3824 on urinary glucose excretion and blood glucose levels after acute and multiple dosing in GK rats. SHR3824, BMS512148, or vehicle was orally administered to GK rats once daily for 41 d. Urine volume, urinary glucose excretion and blood glucose levels were determined on treatment d 1 [(A) Urine volume; (B) urinary glucose excretion; and (C) blood glucose levels] and d 32 [(D) Urine volume; (E) urinary glucose excretion; and (F) blood glucose levels]. bP<0.05, cP<0.01 vs control. The data represent the mean±SEM. n=12.
Mentions: To assess whether acute administration and multiple doses of SHR3824 increased urinary glucose excretion by inhibiting renal glucose reabsorption, we orally administered SHR3824 (0.3, 1.0, or 3.0 mg/kg) to GK rats once daily for 41 d. The blood glucose, urine volume and urinary glucose excretion were measured on d 1 and 32 of treatment. As shown in Figure 3, the urine volume and urinary glucose excretion were increased by either acute or multiple oral administration of SHR3824 in a dose-dependent manner, and most of the glucose was excreted within 6 h of administration. On d 1 of treatment, 0.3, 1.0, or 3.0 mg/kg of SHR3824 increased the urinary glucose excretion during the first 6 h by 1.8-, 2.1-, and 2.2-fold compared with the vehicle-treated controls (P<0.01) while BMS512148 (1.0 mg/kg) increased the urinary glucose excretion by 3.0-fold (P<0.01). On d 32 of treatment, 0.3, 1.0, or 3.0 mg/kg of SHR3824 increased the urinary glucose excretion during the first 6 h by 1.6-, 1.8-, and 1.8-fold compared with the vehicle-treated controls (P<0.01) while BMS512148 (1.0 mg/kg) increased the urinary glucose excretion by 2.1-fold (P<0.01). Thus, SHR3824 was confirmed as a selective SGLT2 inhibitor capable of increasing urinary glucose excretion in a dose dependent manner. As shown in Figure 3C and 3F, GK rats exhibited hyperglycemia. The administration of SHR3824 or BMS512148 to GK rats produced a significant decrease in blood glucose levels. On d 1 of treatment, 0.3, 1.0, or 3.0 mg/kg of SHR3824 reduced the glucose AUC0–24 h values by 23.7%, 32.7%, and 36.5%, while 1.0 mg/kg of BMS512148 reduced the glucose AUC0–24 h levels by 46.5%. On d 32 of treatment, 0.3, 1.0, or 3.0 mg/kg of SHR3824 reduced the glucose AUC0–24 h values by 27.9%, 37.5%, and 42.4%, while 1.0 mg/kg of BMS512148 reduced the glucose AUC0–24 h values by 52.3%. The in vivo glucose lowering potency of SHR3824 on d 1 and 32 were comparable, suggesting that the multiple administration of SHR3824 did not exhibit tachyphylaxis with respect to its antidiabetic activity.

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