NNC 55-0396对db/db小鼠的降糖作用及其机制

Hypoglycemic effect and mechanism of NNC 55-0396 in db/db mice

目的探讨NNC 55-0396对db/db糖尿病小鼠的降糖作用及其机制。方法取8周龄雄性野生型非糖尿病小鼠及db/db糖尿病鼠各12只,分别按随机数字表法为2组,共4组:野生安慰剂组、野生NNC干预组、db/db安慰剂组及db/db NNC干预组(n=6)。NNC干预组均予30 mg/(kg.d)剂量NNC 55-0396腹腔注射,安慰剂组予等体积生理盐水腹腔注射,干预1周;比较实验动物药物干预前后血糖、体质量、胰岛素及总胆固醇的变化水平,并用免疫组织化学法及Western blot检测T型钙通道特异性亚基Cav3.1及Cav3.2表达水平。结果①与db/db安慰剂组比较,db/db NNC干预组空腹血糖水平显著下降(P<0.01),而野生安慰剂组和野生NNC干预组之间差异无统计学意义(P>0.05);②与db/db安慰剂组比较,db/db NNC干预组体质量、胰岛素及胆固醇水平均明显降低(P<0.05);③NNC 55-0396显著下调db/db糖尿病鼠Cav3.1及Cav3.2在肝脏及脑组织中的蛋白表达水平(P<0.05)。结论 NNC 55-0396通过调节小鼠体内钙离子水平产生降血糖作用。

Objective To explore the hypoglycemic effect and mechanism of NNC 55-0396 on db/db mice. Methods Twelve wild-type non-diabetic mice and 12 db/db mice were respectively separated into 4 groups by the stochastic indicator method including a wild-type control therapy group, a wild-type NNC group, a db/db control group and a db/db NNC group （6 mice per group）. The mice of both NNC groups were given intraperitoneal injection of NNC 55-0396 at a dose of 30 mg/（kg·d） for 7 d, while those of both control groups were given intraperitoneal injection of saline in an identical manner. Changes of plasma glucose, body weight, basal insulin and total cholesterol were compared after drug administration. Protein expression levels of T-type calcium channel subunits Cav3.1 and Cav3.2 were also eamined by immunohistochemistry and Western blotting. Results （1） Compared with the db/db control mice, the level of fasting blood glucose of diabetic db/db mice was significantly lowered （P〈0.01） after NNC 55-0396 treatment. No statistical difference was observed between the two wild type groups. （2） Compared with the db/db control mice, body weight and the levels of insulin and cholesterol of diabetic db/db mice were significantly lowered （P〈0.05） after NNC 55-0396 treatment. （3） NNC 55-0396 significantly decreased the protein expression of Cav3.1 and Cav3.2 in the liver and brain of db/db mice. Conclusion NNC 55-0396 lowers blood glucose by adjusting the level of Ca2＋ in vivo, providing a new mechanism for the treatment of diabetes.