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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 anti-diabetic effects of chronic SHR3824 treatment on random blood glucose levels (A), fasting blood glucose levels (B), HbA1c (C), body weight (D) and food intake (E) in GK rats. SHR3824, BMS512148 or vehicle was orally administered to GK rats once daily for 41 d. HbA1c levels were measured on treatment d 38. Fasting blood glucose levels, random blood glucose levels, body weight and food consumption were measured at fixed time intervals. bP<0.05, cP<0.01 vs control. The data represent the mean±SEM. n=12.
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fig4: The anti-diabetic effects of chronic SHR3824 treatment on random blood glucose levels (A), fasting blood glucose levels (B), HbA1c (C), body weight (D) and food intake (E) in GK rats. SHR3824, BMS512148 or vehicle was orally administered to GK rats once daily for 41 d. HbA1c levels were measured on treatment d 38. Fasting blood glucose levels, random blood glucose levels, body weight and food consumption were measured at fixed time intervals. bP<0.05, cP<0.01 vs control. The data represent the mean±SEM. n=12.

Mentions: SHR3824 (0.3, 1.0, or 3.0 mg/kg), BMS512148 (1.0 mg/kg) or vehicle was orally administered to GK rats once daily for 41 d. As shown in Figure 4A and 4B, the fasting and non-fasting glucose levels of GK rats were significantly higher than that of lean controls throughout treatment. The administration of SHR3824 caused significant reductions in the non-fasting and fasting blood glucose levels after 5 d of treatment compared with the vehicle-treated controls (P<0.01). This antihyperglycemic effect was sustained throughout treatment. After 38 d of treatment, GK rats treated with 0.3, 1.0, or 3.0 mg/kg of SHR3824 had HbA1c values of 5.47%±0.10%, 5.19%±0.09%, and 5.04%±0.07%, respectively, demonstrating a dose-dependent decrease compared with vehicle-treated controls (6.31%±0.11%) (P<0.01). SHR3824 affected neither the body weight nor the food intake during the treatment period (Figure 4D).


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 anti-diabetic effects of chronic SHR3824 treatment on random blood glucose levels (A), fasting blood glucose levels (B), HbA1c (C), body weight (D) and food intake (E) in GK rats. SHR3824, BMS512148 or vehicle was orally administered to GK rats once daily for 41 d. HbA1c levels were measured on treatment d 38. Fasting blood glucose levels, random blood glucose levels, body weight and food consumption were measured at fixed time intervals. 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

fig4: The anti-diabetic effects of chronic SHR3824 treatment on random blood glucose levels (A), fasting blood glucose levels (B), HbA1c (C), body weight (D) and food intake (E) in GK rats. SHR3824, BMS512148 or vehicle was orally administered to GK rats once daily for 41 d. HbA1c levels were measured on treatment d 38. Fasting blood glucose levels, random blood glucose levels, body weight and food consumption were measured at fixed time intervals. bP<0.05, cP<0.01 vs control. The data represent the mean±SEM. n=12.
Mentions: SHR3824 (0.3, 1.0, or 3.0 mg/kg), BMS512148 (1.0 mg/kg) or vehicle was orally administered to GK rats once daily for 41 d. As shown in Figure 4A and 4B, the fasting and non-fasting glucose levels of GK rats were significantly higher than that of lean controls throughout treatment. The administration of SHR3824 caused significant reductions in the non-fasting and fasting blood glucose levels after 5 d of treatment compared with the vehicle-treated controls (P<0.01). This antihyperglycemic effect was sustained throughout treatment. After 38 d of treatment, GK rats treated with 0.3, 1.0, or 3.0 mg/kg of SHR3824 had HbA1c values of 5.47%±0.10%, 5.19%±0.09%, and 5.04%±0.07%, respectively, demonstrating a dose-dependent decrease compared with vehicle-treated controls (6.31%±0.11%) (P<0.01). SHR3824 affected neither the body weight nor the food intake during the treatment period (Figure 4D).

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