米非司酮基于糖皮质激素受体调节糖尿病大鼠高血糖的作用机制

Mifepristone Improves Hyperglycemia in Diabetic Rats by Regulating Glucocorticoid Receptor Expression

目的观察米非司酮（MIF）对2型糖尿病大鼠血浆中促肾上腺皮质激素释放激素（CRH）、促肾上腺皮质激素（ACTH）、皮质酮（CORT）、胰岛素（INS）、醛甾酮（ALD）的水平和海马组织中糖皮质激素受体（GR）mRNA表达的影响,探讨MIF对2型糖尿病高血糖的调节作用及其可能机制。方法采用高脂饲料加小剂量链脲佐菌素（30 mg·kg^-1）腹腔注射诱导2型糖尿病模型。随机分为正常对照组、模型对照组、阳性对照组（给予二甲双胍200 mg·kg^-1·d^-1）、米非司酮小剂量组（10 mg·kg^-1·d^-1）、米非司酮中剂量组（25 mg·kg^-1·d^-1）、米非司酮大剂量组（50 mg·kg^-1·d^-1）,正常对照组和模型对照组给予纯化水。每周测定大鼠空腹血糖,给药5周后断头处死,计算脏器指数,测定血浆中CRH、ACTH、CORT、INS、ALD水平,采用实时荧光定量PCR技术测定大鼠海马组织中GR mRNA的表达。结果与正常对照组比较,模型对照组大鼠体质量明显降低（P〈0.01）,空腹血糖升高（P〈0.01）,脏器指数增加（P〈0.05）,CRH、ACTH、CORT、INS、ALD水平升高;糖尿病大鼠海马组织中GRmRNA的表达降低（P〈0.01）。与模型对照组比较,米非司酮中剂量组和大剂量组给药14 d体质量有所增加（P〈0.01）;给药第1～4周,米非司酮中剂量组空腹血糖水平有所降低,且在第4周差异有统计学意义（P〈0.05）;米非司酮中剂量组和大剂量组肾指数减小（P〈0.01或P〈0.05）;米非司酮小剂量组CRH、ACTH、CORT增加,ALD降低,米非司酮中和大剂量组CRH、ACTH、CORT、ALD降低,INS升高,但均差异无统计学意义（P〉0.05）。米非司酮小剂量组、中剂量组、大剂量组GR mRNA的相对表达均有所增加（均P〈0.01）。结论 MIF对2型糖尿病的高血糖有缓解作用,其机制可能与MIF基于GR拮抗调节HPA轴功能有关。

Objective To observe the effect of mifepristone（ MIF） on the level of corticotropin releasing hormone（CRH）,adrenocorticotropic hormone（ACTH）,corticosterone（CORT）,insulin（INS） and aldosterone（ALD） in plasma and expression of glucocorticoid receptor（GR） mRNA in hippocampus in type 2 diabetic rats and to discuss the effect and mechanism by which mifepristone improves hyperglycemia. Methods Type 2 diabetes mellitus model was induced by high-fat diet plus intragastric administration of low dose streptozotocin（30 mg·kg^-1）.Rats were randomly divided into normal control group,model control group,positive control（ MET）（ metformin hydrochloride 200 mg·kg^-1·d^-1） group,mifepristone low dose（MIF-L）（10 mg·kg^-1·d^-1）,medium dose（MIF-M）（25 mg·kg^-1·d^-1） and high dose（MIF-H）（50 mg·kg^-1·d^-1） groups.The normal control group and model control group were given distilled water. Fasting blood glucose（FBG） was measured once a week.The rats were decapitated after five weeks. Organ index,corticotropin release hormone（ CRH）,adrenocorticotropic hormone（ACTH）,corticosterone（CORT）,insulin（INS） and aldosterone（ALD）levels were measured. The expression of GR mRNA in hippocampus was measured by using real-time PCR. Results Compared with the normal control group,body weight was decreased significantly（P〈0. 01）,FBG was increased significantly（ P〈 0. 01）,organ index was increased significantly（ P〈 0. 05）,CRH,ACTH,CORT,INS and ALD were increased and the expression of GR mRNA in hippocampus was decreased（P 〈0.01） in the model control group. Compared with model control group,body weight increased in MIF-M and MIF-H groups after administration for 14 days（ P〈 0. 01）. FBG was decreased in MIF-M group 1 to 4 weeks after administration,with significant difference（P〈 0. 05） at 4th week. The kidney index was decreased in MIF-M and MIF-H groups（P 〈0. 01,P〈 0. 05）. CRH,ACTH and CORT were increased,ALD level was decreased in MIF-L group,CRH,ACTH,CORT and ALD were decreased,INS level was increased in MIF-M and MIF-H groups,without statistically significant differences（ P 〉0. 05）. Relative expression of GR mRNA was significantly increased in MIF-L,MIF-M and MIF-H groups（all P〈 0. 01）. Conclusion Hyperglycemia in type 2diabetic rats can be improved by MIF. The possible mechanism may be related to regulating the HPA axis through inhibiting GR.