药物模拟Roux-en-Y手术对HFD-STZ诱导T2DM小鼠代谢影响的初步研究
发布时间：2018-11-17 19:18
【摘要】：目的：糖尿病在全球发病率逐年上升,呈现广泛的流行趋势。其中2型糖尿病占总糖尿病人数的90%左右,并且与肥胖的发生密切相关。Roux-en-Y胃绕道手术对重度肥胖合并糖尿病患者可起到体重减轻和血糖改善的显著疗效,并且这一效果可以长期保持。手术后代谢改善的明显效果吸引了很多研究者探究其潜在的作用机制,然而其准确的作用机制尚不明确。本实验的目的是采用基因分析所筛选出的药物来模拟RYGB (Roux-en-Ygastric bypass)手术效果,探索改善糖尿病小鼠代谢症状的有效治疗手段。方法：研究中我们综合分析RYGB手术后大鼠肠道基因表达特性并且和Cmap中基因表达数据库进行比对,获得可能模拟RYGB手术效果的药物。在本次研究中我们使用筛选出的药物免疫抑制剂西罗莫司和抗菌药物氨曲南,将它们应用于HFD-STZ诱导的T2DM小鼠,期望能够模拟出手术后体重减轻、血糖改善的有益效果。考虑到西罗莫司能够引起明确的高脂血症,同时考虑到RYGB手术引起的胆汁路径改变引起的食物和胆汁缺乏混合,我们在实验药物设计中增加了考来烯胺,用它来吸收胆汁酸以减少食物和胆汁酸混合,并改善血脂。实验中糖尿病小鼠给药量为西罗莫司(Sirolimus, SRL) 1mg/kg,氨曲南(Aztreonam, AZT)10mg/kg,每天一次灌胃给药,持续10周。考来烯胺(Cofestyramine, CO)以20mg/g比例与高脂食物混合,给药时间为10周。结果：SRL给药组相比于对照组小鼠,体重减轻,附睾脂肪细胞减小,胰岛素抵抗和血糖轻微改善且与对照组相比差异无显著性,血清总甘油三酯(TG)含量减少,血清总胆固醇(TCHO)水平增加,胰岛p细胞数量减少,以及葡萄糖耐量减低。氨曲南给药组小鼠体重、附睾脂肪细胞大小、血浆TG、TCHO水平增加、血糖和血胰岛素浓度增加。考来烯胺给药组相比空白对照组体重减少、血糖和血脂降低、胰岛素抵抗改善,并减弱氨曲南使用导致的不良反应。考来烯胺联合西罗莫司使用表现出药物协同作用,西罗莫司和考来烯胺联合给药组小鼠血糖明显改善,从23.42±1.39mmol/l降至14.42±1.90mmol/l (p 0.01),稳态模型评估法-胰岛素抵抗指数(HOMA-IR)相比对照组有明显改善(p0.01)但是减重效果不明显。西罗莫司、考来烯胺联用给药组小鼠给药后第一周体重下降2.38±0.26g(p0.01),10周后体重改变0.84±0.44g(p0.1)。三联给药组小鼠血糖明显改善,由25.18±1.00mmol/l下降至16.4±1.65mmol/l (p=0.014),体重改变由第一周下降1.30±0.55g,至10周末体重增加1.38±0.42g,体重改变无统计学意义。HOMA-IR相比对照组小鼠降低45.5%。结论：我们的研究提供了一个可能的治疗方法,通过药物作用重构小肠的功能来模拟RYGB手术效果,然而最佳药物组合和剂量有必要进一步研究,并且抗生素的作用需要被全面考虑。
[Abstract]:Objective: the incidence of diabetes in the world is increasing year by year, showing an extensive epidemic trend. Type 2 diabetes accounted for about 90% of the total diabetes mellitus, and was closely related to the occurrence of obesity. Roux-en-Y gastric bypass surgery can significantly reduce weight and improve blood sugar in patients with severe obesity and diabetes mellitus. And this effect can be maintained for a long time. The obvious effect of metabolic improvement after surgery has attracted many researchers to explore its potential mechanism, but its exact mechanism is not clear. The aim of this study was to use the drugs screened by gene analysis to simulate the effect of RYGB (Roux-en-Ygastric bypass) operation and to explore an effective therapeutic method to improve the metabolic symptoms of diabetic mice. Methods: in the study, we comprehensively analyzed the expression characteristics of gene in the intestine of rats after RYGB operation and compared it with the gene expression database in Cmap to obtain drugs that might mimic the effect of RYGB surgery. In this study, sirolimus and aztreonam were used as immunosuppressants to simulate the beneficial effects of weight loss and blood glucose improvement in HFD-STZ induced T2DM mice. Considering that sirolimus can cause explicit hyperlipidemia, and considering the lack of food and bile mixture due to changes in the bile pathway caused by RYGB surgery, we added colenamine to our experimental drug design. It is used to absorb bile acids to reduce the mixture of food and bile acids and to improve blood lipids. The diabetic mice were given sirolimus (Sirolimus, SRL) 1 mg / kg and aztreonam (Aztreonam, AZT) 10 mg / kg once a day for 10 weeks. Corelenamine (Cofestyramine, CO) was mixed with high fat food in 20mg/g ratio for 10 weeks. Results: compared with the control group, SRL group lost weight, decreased epididymal adipocytes, slightly improved insulin resistance and blood glucose, and decreased serum total triglyceride (TG) content. The level of serum total cholesterol (TCHO) increased, the number of islet p cells decreased, and glucose tolerance decreased. The body weight, size of epididymal adipocytes, plasma TG,TCHO level, blood glucose and insulin concentration were increased in aztreonam group. Compared with blank control group, Coolenamine group decreased body weight, blood glucose and blood lipid, improved insulin resistance, and weakened adverse reactions induced by aztreonam. Corelenamine combined with sirolimus showed synergistic effect. The blood glucose of mice treated with sirolimus and corelenamine was significantly improved from 23.42 卤1.39mmol/l to 14.42 卤1.90mmol/l (p0.01). The steady-state model assessment method-insulin resistance index (HOMA-IR) was significantly improved compared with the control group (p0.01), but the weight loss effect was not obvious. The mice in sirolimus combined with Coolenamine group lost 2.38 卤0.26g (p0.01) in the first week and 0.84 卤0.44g (p0.1) after 10 weeks. The blood glucose of mice in the triple administration group was significantly improved from 25.18 卤1.00mmol/l to 16.4 卤1.65mmol/l (p0. 014), and the body weight changed from 1. 30 卤0. 55 g in the first week to 1. 38 卤0. 42 g in the 10th week. There was no significant change in body weight. HOMA-IR decreased by 45. 5% compared with the control group. Conclusion: our study provides a possible therapeutic approach to mimic the effects of RYGB surgery by reconstructing the small intestine, but the optimal combination and dosage of drugs need to be further studied. And the role of antibiotics needs to be fully considered.
【学位授予单位】：扬州大学
【学位级别】：硕士
【学位授予年份】：2016
【分类号】：R587.1
本文编号：2338803
[Abstract]:Objective: the incidence of diabetes in the world is increasing year by year, showing an extensive epidemic trend. Type 2 diabetes accounted for about 90% of the total diabetes mellitus, and was closely related to the occurrence of obesity. Roux-en-Y gastric bypass surgery can significantly reduce weight and improve blood sugar in patients with severe obesity and diabetes mellitus. And this effect can be maintained for a long time. The obvious effect of metabolic improvement after surgery has attracted many researchers to explore its potential mechanism, but its exact mechanism is not clear. The aim of this study was to use the drugs screened by gene analysis to simulate the effect of RYGB (Roux-en-Ygastric bypass) operation and to explore an effective therapeutic method to improve the metabolic symptoms of diabetic mice. Methods: in the study, we comprehensively analyzed the expression characteristics of gene in the intestine of rats after RYGB operation and compared it with the gene expression database in Cmap to obtain drugs that might mimic the effect of RYGB surgery. In this study, sirolimus and aztreonam were used as immunosuppressants to simulate the beneficial effects of weight loss and blood glucose improvement in HFD-STZ induced T2DM mice. Considering that sirolimus can cause explicit hyperlipidemia, and considering the lack of food and bile mixture due to changes in the bile pathway caused by RYGB surgery, we added colenamine to our experimental drug design. It is used to absorb bile acids to reduce the mixture of food and bile acids and to improve blood lipids. The diabetic mice were given sirolimus (Sirolimus, SRL) 1 mg / kg and aztreonam (Aztreonam, AZT) 10 mg / kg once a day for 10 weeks. Corelenamine (Cofestyramine, CO) was mixed with high fat food in 20mg/g ratio for 10 weeks. Results: compared with the control group, SRL group lost weight, decreased epididymal adipocytes, slightly improved insulin resistance and blood glucose, and decreased serum total triglyceride (TG) content. The level of serum total cholesterol (TCHO) increased, the number of islet p cells decreased, and glucose tolerance decreased. The body weight, size of epididymal adipocytes, plasma TG,TCHO level, blood glucose and insulin concentration were increased in aztreonam group. Compared with blank control group, Coolenamine group decreased body weight, blood glucose and blood lipid, improved insulin resistance, and weakened adverse reactions induced by aztreonam. Corelenamine combined with sirolimus showed synergistic effect. The blood glucose of mice treated with sirolimus and corelenamine was significantly improved from 23.42 卤1.39mmol/l to 14.42 卤1.90mmol/l (p0.01). The steady-state model assessment method-insulin resistance index (HOMA-IR) was significantly improved compared with the control group (p0.01), but the weight loss effect was not obvious. The mice in sirolimus combined with Coolenamine group lost 2.38 卤0.26g (p0.01) in the first week and 0.84 卤0.44g (p0.1) after 10 weeks. The blood glucose of mice in the triple administration group was significantly improved from 25.18 卤1.00mmol/l to 16.4 卤1.65mmol/l (p0. 014), and the body weight changed from 1. 30 卤0. 55 g in the first week to 1. 38 卤0. 42 g in the 10th week. There was no significant change in body weight. HOMA-IR decreased by 45. 5% compared with the control group. Conclusion: our study provides a possible therapeutic approach to mimic the effects of RYGB surgery by reconstructing the small intestine, but the optimal combination and dosage of drugs need to be further studied. And the role of antibiotics needs to be fully considered.
【学位授予单位】：扬州大学
【学位级别】：硕士
【学位授予年份】：2016
【分类号】：R587.1
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