本文選題：利拉魯肽 + 艾塞那肽　； 參考：《新鄉(xiāng)醫(yī)學(xué)院》2017年碩士論文

【摘要】：背景糖尿病腎病(DN)是臨床上常見的糖尿病微血管并發(fā)癥之一,約30%-40%的糖尿病患者伴有不同程度腎臟的損傷,嚴(yán)重影響患者的生活質(zhì)量。胰高血糖素樣肽1(GLP-1)類似物是近年來運(yùn)用于臨床治療糖尿病的一種新型藥物,通過與其高親和力受體(GLP-1R)結(jié)合,能夠促進(jìn)胰島素分泌、降低胰高血糖素分泌,同時(shí)延緩胃排空、增強(qiáng)飽食感、抑制食欲、增加肝糖原合成、減少肝糖原分解等發(fā)揮降低血液中葡萄糖濃度的作用。GLP-1Rs廣泛存在于腎臟、心臟、肝臟等身體重要器官。近年來,大量研究表明GLP-1類似物在DN的發(fā)病過程中可通過減少炎癥反應(yīng)、抑制氧化應(yīng)激、改善晚期糖末終基化產(chǎn)物(AGEs)等多個(gè)方面起到除降糖作用外的腎臟保護(hù)作用。目前已在我國(guó)上市應(yīng)用的GLP-1類似物有利拉魯肽(liraglutide)和艾塞那肽(exenatide)兩種。利拉魯肽和艾塞那肽都可通過與GLP-1R結(jié)合延緩DN的發(fā)展,但兩者的合成來源、代謝途徑均不相同,兩者在DN患者中應(yīng)用的效果是否存在差異尚不清楚。目的探討驗(yàn)證GLP-1類似物治療DN的作用機(jī)制;對(duì)比利拉魯肽與艾塞那肽在DN發(fā)病過程中的對(duì)腎臟結(jié)構(gòu)和功能的保護(hù)作用是否存在差異。方法健康的雄性SD大鼠50只,完全隨機(jī)分出正常對(duì)照組(10只),另外40只大鼠飼以高糖高脂飼料6周誘導(dǎo)胰島素抵抗,聯(lián)合空腹腹腔注射小劑量鏈脲佐菌素(STZ)破壞胰島β細(xì)胞,形成胰島素抵抗伴胰島素分泌相對(duì)不足為特征的2型糖尿病,之后3天、7天各測(cè)一次晨空腹尾靜脈血糖,兩次血糖均≥16.9 mmol/L為DN模型成立。成模大鼠32只隨機(jī)分為模型組(10只)、利拉魯肽治療組(11只)和艾塞那肽治療組(11只)。正常對(duì)照組和模型組大鼠予皮下注射生理鹽水(10μL/Kg/12h);利拉魯肽治療組大鼠予皮下注射利拉魯肽(0.3 mg/Kg/12h);艾塞那肽治療組大鼠予皮下注射艾塞那肽(10μL/Kg/12h),共給藥8周。第8周末采集大鼠血液標(biāo)本,腎臟標(biāo)本。新鮮血液標(biāo)本離心后收集血清,之后使用全自動(dòng)生化分析儀測(cè)定大鼠BUN和Scr水平;腎臟標(biāo)本制作成蠟塊,采用HE染色和過碘酸雪夫染色(PAS)觀察腎臟組織結(jié)構(gòu)變化;免疫組織化學(xué)法檢測(cè)大鼠腎臟組織中TGF-β1和NOX 4的蛋白水平表達(dá)并使用Image-pro Plus軟件對(duì)TGF-β1和NOX 4在腎臟組織中蛋白水平表達(dá)進(jìn)行半定量分析;實(shí)時(shí)熒光定量PCR(RT-qPCR)定量分析各組腎臟組織中TGF-β1和NOX 4的mRNA水平表達(dá)情況。采用SPSS 19.0軟件進(jìn)行統(tǒng)計(jì)分析,所有計(jì)量資料結(jié)果采用均數(shù)±標(biāo)準(zhǔn)差(x±s)表示。多組間比較采用單因素方差分析,2組間比較采用t檢驗(yàn),檢驗(yàn)水準(zhǔn)α=0.05。結(jié)果與正常對(duì)照組比較,模型組和艾塞那肽治療組大鼠空腹血糖、BUN、Scr及腎組織中TGF-β1、NOX 4蛋白水平均顯著升高(P0.05);利拉魯肽治療組大鼠空腹血糖和腎組織中TGF-β1蛋白水平顯著升高(P0.05);模型組、利拉魯肽治療組和艾塞那肽治療組大鼠體質(zhì)量顯著降低(P0.05),腎組織形態(tài)學(xué)均顯示腎小球系膜明顯增厚,其中模型組增厚最明顯,利拉魯肽治療組最輕。與模型組比較,利拉魯肽治療組和艾塞那肽治療組大鼠BUN、Scr水平顯著降低(P0.05);利拉魯肽治療組大鼠腎組織中TGF-β1、NOX 4蛋白水平和mRNA水平顯著降低(P0.05);艾塞那肽治療組大鼠腎組織中TGF-β1、NOX 4蛋白水平和TGF-β1 m RNA水平顯著降低(P0.05)。利拉魯肽治療組大鼠Scr和腎組織中TGF-β1、NOX 4蛋白水平和m RNA水平顯著低于艾塞那肽治療組(P0.05)。結(jié)論1.GLP-1類似物可降低腎臟組織TGF-β1、NOX 4蛋白水平和mRNA水平的表達(dá),降低DN大鼠BUN、Scr水平,延緩大鼠DN的發(fā)展;2.DN大鼠短期內(nèi)使用GLP-1類似物,利拉魯肽較艾塞那肽能夠更好的減少DN模型大鼠腎臟組織中TGF-β1、NOX 4蛋白和mRNA水平的表達(dá),獲得更低的BUN、Scr水平。
[Abstract]:Background diabetic nephropathy (DN) is one of the most common diabetic microvascular complications. About 30%-40% diabetic patients with different degrees of kidney injury seriously affect the quality of life. Glucagon like peptide 1 (GLP-1) analogue is a new drug used in the clinical treatment of diabetes in recent years, through its high affinity. Force receptor (GLP-1R) binding, can promote insulin secretion, reduce glucagon secretion, delay gastric emptying, enhance satiety, inhibit appetite, increase liver glycogen synthesis, reduce liver glycogen decomposition, and reduce the concentration of glucose in the blood,.GLP-1Rs widely exists in important organs such as kidney, heart, liver and so on. A large number of studies have shown that GLP-1 analogues can play a role in renal protection by reducing inflammatory response, inhibiting oxidative stress and improving late end glycylation products (AGEs) in the pathogenesis of DN. The GLP-1 analogues in China are currently used in China, including liraglutide and exenat. IDE) two. Alralurin and alisenin can both delay the development of DN by combining with GLP-1R, but the source and metabolic pathways of both are different. The difference in the effect of the two in DN patients is not clear. The purpose is to verify the mechanism of GLP-1 analogues for the treatment of DN, and the pathogenesis of the GLP-1 in the DN. There were differences in the protection of renal structure and function in the process. Methods 50 healthy male SD rats were randomly divided into normal control group (10 rats), and 40 rats were fed with high glucose and high fat diet for 6 weeks to induce insulin resistance, and intraperitoneal injection of small dose streptozotocin (STZ) to destroy islet beta cells and form islets. In type 2 diabetes, which was characterized by relative deficiency of insulin secretion, 3 days after 3 days, every morning caudal vein blood glucose was measured on the 7 day, and two times of blood glucose more than 16.9 mmol/L were established. 32 rats were randomly divided into model group (10), lealaru treatment group (11) and alenenin group (11). Normal control group and model group. Rats were subcutaneously injected with saline (10 L/Kg/12h), and the rats in the learalu peptide group were given subcutaneous injection of Leila Lou (0.3 mg/Kg/12h), and the rats were given the subcutaneous injection of isinanpeptide (10 mu L/Kg/12h) for 8 weeks. The blood specimens of rats were collected at the end of the eighth week, and the kidney specimens were collected. The level of BUN and Scr in rats was measured with an automatic biochemical analyzer. The kidney specimens were made into wax blocks, HE staining and iodate Schiff staining (PAS) were used to observe the changes of renal tissue structure. The protein level of TGF- beta 1 and NOX 4 in the kidney tissues of rats was detected by immunohistochemistry and the Image-pro Plus software was used for the TGF- beta 1 and NOX 4 in the kidney. The expression of protein level in the tissue was analyzed by semi quantitative analysis; real-time quantitative PCR (RT-qPCR) was used to quantitatively analyze the mRNA level expression of TGF- beta 1 and NOX 4 in each group. SPSS 19 software was used for statistical analysis. The results of all measurement data were expressed with mean mean + standard deviation (x + s). A single factor analysis of variance was used in multiple groups, 2 Compared with the normal control group, the results of t test were compared with the normal control group. The level of fasting blood glucose, BUN, Scr, TGF- beta 1 and NOX 4 protein in the model group and the alennisin group were significantly increased (P0.05), and the level of the fasting blood glucose and the TGF- beta 1 protein in the renal tissue was significantly increased (P0.05) in the lealaru treatment group (P0.05); the model was significantly increased (P0.05). Group, the mass of the rats in the Leila Lou treatment group and the alsna peptide group decreased significantly (P0.05). The renal histomorphology showed the glomerular mesangial thickening. The thickening of the model group was the most obvious, and the lealulu treatment group was the lightest group. Compared with the model group, the level of BUN and Scr in the lialalu treatment group and the alsna peptide group were significantly lower (P0.05 TGF- beta 1, NOX 4 protein level and mRNA level in rat renal tissue were significantly decreased (P0.05), and the level of TGF- beta 1, NOX 4 protein and TGF- beta 1 m RNA decreased significantly (P0.05) in the renal tissue of the treatment group of alisin, and the TGF- beta 1 in the Scr and renal tissues of the lealaru treatment group was significantly lower than that of the kidney tissue. In the P0.05. Conclusion 1.GLP-1 analogues can reduce the expression of TGF- beta 1, NOX 4 protein and mRNA level in renal tissue, reduce BUN and Scr level in DN rats and delay the development of DN in rats; 2.DN rats use GLP-1 analogues in the short term, and Liraru peptide can reduce the beta 1 in kidney tissue of DN model rats better. The expression of NOX 4 protein and mRNA level showed a lower level of BUN and Scr.

【學(xué)位授予單位】：新鄉(xiāng)醫(yī)學(xué)院
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R587.2;R692.9;R-332

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