【摘要】：目的：糖尿病在全球發(fā)病率逐年上升,呈現(xiàn)廣泛的流行趨勢。其中2型糖尿病占總糖尿病人數(shù)的90%左右,并且與肥胖的發(fā)生密切相關(guān)。Roux-en-Y胃繞道手術(shù)對重度肥胖合并糖尿病患者可起到體重減輕和血糖改善的顯著療效,并且這一效果可以長期保持。手術(shù)后代謝改善的明顯效果吸引了很多研究者探究其潛在的作用機制,然而其準確的作用機制尚不明確。本實驗的目的是采用基因分析所篩選出的藥物來模擬RYGB (Roux-en-Ygastric bypass)手術(shù)效果,探索改善糖尿病小鼠代謝癥狀的有效治療手段。方法：研究中我們綜合分析RYGB手術(shù)后大鼠腸道基因表達特性并且和Cmap中基因表達數(shù)據(jù)庫進行比對,獲得可能模擬RYGB手術(shù)效果的藥物。在本次研究中我們使用篩選出的藥物免疫抑制劑西羅莫司和抗菌藥物氨曲南,將它們應(yīng)用于HFD-STZ誘導(dǎo)的T2DM小鼠,期望能夠模擬出手術(shù)后體重減輕、血糖改善的有益效果�？紤]到西羅莫司能夠引起明確的高脂血癥,同時考慮到RYGB手術(shù)引起的膽汁路徑改變引起的食物和膽汁缺乏混合,我們在實驗藥物設(shè)計中增加了考來烯胺,用它來吸收膽汁酸以減少食物和膽汁酸混合,并改善血脂。實驗中糖尿病小鼠給藥量為西羅莫司(Sirolimus, SRL) 1mg/kg,氨曲南(Aztreonam, AZT)10mg/kg,每天一次灌胃給藥,持續(xù)10周�？紒硐┌�(Cofestyramine, CO)以20mg/g比例與高脂食物混合,給藥時間為10周。結(jié)果：SRL給藥組相比于對照組小鼠,體重減輕,附睪脂肪細胞減小,胰島素抵抗和血糖輕微改善且與對照組相比差異無顯著性,血清總甘油三酯(TG)含量減少,血清總膽固醇(TCHO)水平增加,胰島p細胞數(shù)量減少,以及葡萄糖耐量減低。氨曲南給藥組小鼠體重、附睪脂肪細胞大小、血漿TG、TCHO水平增加、血糖和血胰島素濃度增加�？紒硐┌方o藥組相比空白對照組體重減少、血糖和血脂降低、胰島素抵抗改善,并減弱氨曲南使用導(dǎo)致的不良反應(yīng)�？紒硐┌仿�(lián)合西羅莫司使用表現(xiàn)出藥物協(xié)同作用,西羅莫司和考來烯胺聯(lián)合給藥組小鼠血糖明顯改善,從23.42±1.39mmol/l降至14.42±1.90mmol/l (p 0.01),穩(wěn)態(tài)模型評估法-胰島素抵抗指數(shù)(HOMA-IR)相比對照組有明顯改善(p0.01)但是減重效果不明顯。西羅莫司、考來烯胺聯(lián)用給藥組小鼠給藥后第一周體重下降2.38±0.26g(p0.01),10周后體重改變0.84±0.44g(p0.1)。三聯(lián)給藥組小鼠血糖明顯改善,由25.18±1.00mmol/l下降至16.4±1.65mmol/l (p=0.014),體重改變由第一周下降1.30±0.55g,至10周末體重增加1.38±0.42g,體重改變無統(tǒng)計學(xué)意義。HOMA-IR相比對照組小鼠降低45.5%。結(jié)論：我們的研究提供了一個可能的治療方法,通過藥物作用重構(gòu)小腸的功能來模擬RYGB手術(shù)效果,然而最佳藥物組合和劑量有必要進一步研究,并且抗生素的作用需要被全面考慮。
[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 鹵1.39mmol/l to 14.42 鹵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 鹵0.26g (p0.01) in the first week and 0.84 鹵0.44g (p0.1) after 10 weeks. The blood glucose of mice in the triple administration group was significantly improved from 25.18 鹵1.00mmol/l to 16.4 鹵1.65mmol/l (p0. 014), and the body weight changed from 1. 30 鹵0. 55 g in the first week to 1. 38 鹵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.
【學(xué)位授予單位】：揚州大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2016
【分類號】：R587.1

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