二甲双胍对糖皮质激素引起的代谢紊乱的改善作用的研究

发布时间：2018-08-24 08:45

【摘要】：背景：地塞米松(Dex)等糖皮质激素是临床上经常使用的一类抗炎和免疫抑制药物,广泛用于多种疾病的治疗。当长期或大剂量使用时,往往会引起一系列明显的代谢副作用,例如：胰岛素抵抗、高血糖、血脂紊乱、肌肉萎缩等。目的：(1)构建外源性Dex引起的代谢类疾病模型,(2)研究二甲双胍(Met)对糖皮质激素引起的代谢副作用的治疗作用。方法：使用Dex构建糖皮质激素引起的代谢紊乱模型：(1)急性大剂量Dex实验：喂食8周高脂饲料(HFD)后,对大鼠连续注射1周高剂量Dex(0.5mg/kg)及Met (100 mg/kg,200 mg/kg);(2)慢性低剂量Dex实验：腹腔注射8周低剂量Dex(0.05mg/kg)后,对大鼠进行2周的Met (100 mg/kg,200 mg/kg)治疗。我们主要通过大鼠的体重、空腹血糖、摄食量、胰岛素耐受、糖耐量及甘油三酯(TG)水平等指标对Dex所引起的代谢副作用进行全面评价。结果：通过急性高剂量Dex模型的建立,我们发现：(1)喂食8周HFD的大鼠与正常对照组相比,体重(p0.01)及TG含量(p0.01)出现了明显的上升,并且出现了一定的胰岛素抵抗现象；(2)连续7天连续注射Dex 0.5 mg/kg后,大鼠出现了明显的体重(p0.01)和摄食量(p0.01)下降、血糖(p0.01)升高并且胰岛素抵抗症状更为严重的现象；(3)使用Met进行治疗后,发现Met (200 mg/kg)具有明显的降低血糖(p0.05)、降低血脂(p0.05)及改善胰岛素抵抗的症状。而与之相反,Met (100 mg/kg)对大剂量Dex引起的代谢副作用的治疗效果不佳。通过慢性低剂量Dex模型建立,发现：(1)连续8周注射Dex (0.05 mg/kg)后,Dex组大鼠与正常对照组相比,体重和摄食量明显下降(p0.01),血清中TG(p0.01),及胰岛素的含量(p0.01)均升高,胰岛素敏感指数(ISI)降低(p0.01),出现了一定的胰岛素抵抗症状；(2)使用Met进行治疗后,发现100mg/kg及200mg/kg的Met均能起到有效地降低TG(p0.01)、降低血清中胰岛素含量(p0.05)、提高机体胰岛素敏感性(p0.05)及改善胰岛素抵抗的作用。但是Met(200 mg/kg)表现出明显的副作用,具体表现为体重下降(p0.01)及摄食量的减少(p0.05)。结论：本研究通过使用Dex成功构建了急性高剂量Dex引起的高血糖模型和慢性低剂量Dex引起的具有高血脂、胰岛素抵抗等代谢副作用的大鼠模型。研究也发现Met在抗高血糖、改善机体胰岛素抵抗和改善脂质代谢紊乱方面具有显著作用,表明Met是临床上治疗糖皮质激素引起的代谢紊乱的有效药物。
[Abstract]:Background: dexamethasone (Dex) and other glucocorticoids are often used in clinical use of anti-inflammatory and immunosuppressive drugs widely used in the treatment of many diseases. A series of obvious metabolic side effects, such as insulin resistance, hyperglycemia, dyslipidemia, muscle atrophy and so on, are often caused by long-term or high-dose use. Objective: (1) to establish a metabolic disease model induced by exogenous Dex and (2) to study the therapeutic effect of metformin (Met) on glucocorticoid induced metabolic side effects. Methods: the metabolic disorder model induced by glucocorticoid was established by using Dex. (1) Acute high-dose Dex test: after 8 weeks of high fat diet (HFD), Chronic low dose Dex (0.5mg/kg) and Met (100 mg/kg,200 mg/kg); (2) chronic low dose Dex were administered to rats for 1 week. Met (100 mg/kg,200 mg/kg) was given to rats for 2 weeks after 8 weeks of low dose Dex (0.05mg/kg) injection. The metabolic side effects induced by Dex were evaluated by weight, fasting blood glucose, intake, insulin resistance, glucose tolerance and triglyceride (TG) levels in rats. Results: through the establishment of acute high-dose Dex model, we found that: (1) compared with the control group, the rats fed with HFD for 8 weeks showed significant increase in body weight (p0.01) and TG content (p0.01), and a certain phenomenon of insulin resistance; (2) after continuous injection of Dex 0.5 mg/kg for 7 days, the weight (p0.01) and food intake (p0.01) decreased significantly, the blood glucose (p0.01) increased and the symptoms of insulin resistance became more serious in rats. (3) after treatment with Met, the symptoms of insulin resistance were more serious. It was found that Met (200 mg/kg) could significantly reduce blood glucose, reduce blood lipid and improve insulin resistance. On the contrary, Met (100 mg/kg) was not effective in the treatment of metabolic side effects caused by high dose Dex. The chronic low dose Dex model was established. The results showed that: (1) after 8 weeks of injection of Dex (0. 05 mg/kg), the body weight and food intake of rats in the Dexi group were significantly lower than those in the normal control group (p0. 01), and the serum TG (p0. 01) and insulin content (p0. 01) were increased. The insulin sensitivity index (ISI) was decreased (p0.01) and the symptoms of insulin resistance appeared. (2) after treatment with Met, It was found that both Met of 100mg/kg and 200mg/kg could effectively reduce TG (p0.01), decrease serum insulin content (p0.05), increase insulin sensitivity (p0.05) and improve insulin resistance. But Met (200 mg/kg) showed obvious side effects, such as weight loss (p0.01) and food intake decrease (p0.05). Conclusion: the model of high blood glucose induced by acute high dose Dex and rat model of chronic low dose Dex with metabolic side effects such as hyperlipidemia and insulin resistance were successfully constructed by using Dex. It is also found that Met plays a significant role in anti-hyperglycemia, improving insulin resistance and improving lipid metabolic disorder, indicating that Met is an effective drug in the treatment of glucocorticoid induced metabolic disorder.
【学位授予单位】：南京大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R965

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