摘要
[目的]研究显示,在2型糖尿病的发病过程中,伴随着低度、慢性、全身性的炎症反应,上述炎症反应在2型糖尿病的发病过程中起着重要的作用。因此,具有抗炎作用的物质将有可能成为治疗2型糖尿病的潜在药物。益母草碱(SCM-198)是中药益母草中的一种生物碱。益母草在中国民间有百年以上的使用历史,其具有多种生物学效用。最近有报道指出益母草具有抗炎性质。于是,我们提出一个假设,即SCM-198可能对2型糖尿病有改善作用。基于这个假设,我们设计了本实验,旨在观察SCM-198对自发性2型糖尿病小鼠C57BLKS/J db/db小鼠糖尿病症状的改善效果,并探讨其可能的机制。
[方法]本实验将糖尿病小鼠db/db小鼠分为5组,分别为：阳性药组(盐酸吡格列酮,50 mg/kg, n=8); SCM-198低、中、高剂量组(50 mg/kg, 100 mg/kg,200 mg/kg, n=8-9), Vehicle组(n=9)。db/m小鼠作为正常对照(n=5)。吡格列酮和SCM-198溶解在新鲜配制的1%CMC-Na溶液中,制备成混悬液,每天灌胃给药一次。db/db Vehicle组和db/m组小鼠按同等体积灌胃1%CMC-Na溶液。实验周期为3周。实验期间,每周测定体重两次,监测12h空腹血糖一次。实验结束后,检测相关血浆指标,采用PCR的方法检测肝脏葡萄糖代谢酶：GK、G6paese、PEPCK,胰岛素信号通路分子：IR以及肝脏炎症介质：TNF-α、IL-6、IL-1β、COX-2、iNOS的表达,同时采用Western Blot的方法检测胰岛素信号通路关键分子p-IR、Akt、p-Akt和p-Foxol,以及炎症介质TNF-α蛋白的表达,NF-κB炎症通路中IκB-α的降解以及NF-κB p65 |的磷酸化。
[结果]经过3周的治疗后,SCM-198 (200 mg/kg)显著降低了糖尿病小鼠db/db小鼠的空腹血糖水平,并升高了空腹血浆胰岛素浓度,同时,SCM-198(200 mg/kg)还明显降低了血浆甘油三脂的浓度(TG),升高了血浆高密度脂蛋白(HDL-C)|的浓度。RT-PCR结果显示,SCM-198能上调肝脏葡萄糖代谢酶GK mRNA的表达,同时下调糖异生过程关键限速酶G6Paese和PEPCK mRNA的表达,Western Blot进一步的检测表明SCM-198能恢复肝脏IR和Akt磷酸化水平,同时促进Foxol的磷酸化。并且,本研究进一步发现SCM-198能够降低肝脏炎症介质TNF-α、IL-6、IL-1β、COX-2以及iNOS的基因表达,蛋白检测的结果显示,SCM-198能够降低TNF-α产生,抑制IκB-α的降解以及NF-κB p65的磷酸化。
[结论]本研究发现,SCM-198具有抗炎作用,它至少部分通过抑制NF-κB炎症通路,进而改善炎症状态,从而改善2型糖尿病小鼠db/db小鼠的糖尿病症状。因此,我们认为SCM-198可能成为防治2型糖尿病的潜在药物。
Background and purpose:There are reports of early evidence that suggested the involvement of chronic low-grade inflammation in the pathogenesis of type 2 diabetes, which plays a key role in type 2 diabetes. Thus, substances that have effects in reducing inflammation could be potential drugs for type 2 diabetes. Leonurine (SCM-198) is an alkaloid in Herba leonuri, which was reported to possess anti-inflammatory property. We hypothesize that SCM-198 may have beneficial effect on type 2 diabetes. In this study we attempted to test this hypothesis by evaluating the anti-diabetic effect of SCM-198 and the possible underlying mechanisms of its effects in db/db mice.
Experimental approach:SCM-198 (50,100,200 mg/kg body weight), pioglitazone (as positive control) (50 mg/kg body weight) and 1% sodium carboxymethyl cellulose (CMC-Na) were administered to the db/db or db/m mice once daily for 3 weeks.
Key results:After 3 weeks, SCM-198 (200 mg/kg) treatment significantly reduced the fasting blood glucose level and increased the plasma insulin concentration in the db/db mice, meanwhile it significantly lowered and increased the plasma triglyceride and HDL-cholesterol concentration respectively. Moreover, the disregulated transcription of the hepatic glucose metabolic enzymes was corrected, and the phosphoration of Akt and insulin receptor (IR) were recovered, with an increase of Foxol phosphorylations. The proinflammatory mediators (like TNF-α, IL-6, IL-1β, degradation of IκB-αand thereafter activation of NF-κB) were reversed by SCM-198 treatment in the db/db mice.
Conclusions and implications:The present study found that SCM-198 exhibited anti-inflammatory activity and has an ameliorating effect on diabetic symptoms involving inhibition of NF-κB/IKK pathway. Consequently, we suggested that SCM-198 may be a prospective agent for prevention and/or moderation of the progress of type 2 diabetes.
引文
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