本文選題：Exendin-4　切入點(diǎn)：糖尿病　出處：《濟(jì)南大學(xué)》2015年碩士論文　論文類型：學(xué)位論文

【摘要】：目的胰高糖素樣肽-1(GLP-1)受體激動(dòng)劑Exendin-4(EX-4)對(duì)2型糖尿病大鼠胰島α細(xì)胞形態(tài)和功能的影響目前尚不十分清楚。本研究通過不同濃度的GLP-1受體激動(dòng)劑EX-4對(duì)2型糖尿病大鼠模型進(jìn)行干預(yù),觀察EX-4對(duì)2型糖尿病大鼠胰島α細(xì)胞形態(tài)與功能的影響,從而為探討2型糖尿病的病理生理學(xué)和臨床應(yīng)用提供新的理論依據(jù)。方法采用高糖高脂喂養(yǎng)并聯(lián)合1%的STZ(35mg/kg)腹腔注射建立T2DM大鼠模型。40只雄性Wistar大鼠隨機(jī)分為正常對(duì)照(NC組,N=10)組和糖尿病組(n=30)。剔除造模失敗死亡的大鼠后將剩余25只納入本實(shí)驗(yàn)。分為糖尿病對(duì)照組(DC組,n=8),Exendin-4治療組(EX組,n=17),其中EX低劑量組(EXL組n=8),EX高劑量組(EXH組,n=9)。將Exendin-4溶于PBS溶液,EXL組左下腹腔注射5μg/kg,EXH組20μg/kg,每日定時(shí)兩次(上午9:00和下午5:00),NC、DC組注射PBS,治療8周。干預(yù)8周后,空腹12h,次日上午于給藥0h,1h,2h,3h,后分別頸靜脈抽血測血糖,取血清標(biāo)本用放射免疫法測定血清胰高糖素。剝離胰腺組織,置于中性福爾馬林液固定,然后石蠟包埋做切片備用。石蠟切片做HE染色以觀察形態(tài)學(xué)變化,免疫組化法染色觀察胰高糖素表達(dá)水平,觀察α細(xì)胞形態(tài)及數(shù)量變化。結(jié)果1.各組大鼠及血清胰高糖素水平干預(yù)前,DC組、EXL組及EXH組胰高糖素均較NC組明顯升高(P0.01)。干預(yù)8周后,EXL組及EXH胰高糖素水平較干預(yù)前下降(P0.05),EXH組下降較EXL組顯著(P0.05),且低于與同期DC組(P0.01)。2.干預(yù)后于末次給藥(0h,1h,2h,3h)監(jiān)測血糖,繪制血糖曲線圖DM組、EXH組、EXL組大鼠血糖明顯高于DC組,EXH組、EXL組血糖較DM組明顯下降(P0.01),EXH組下降幅度較EXL組大,且血糖隨時(shí)間點(diǎn)增加而下降。3.各組大鼠胰島α細(xì)胞免疫組化染色結(jié)果免疫組化法定位胰高糖素,Glucagon蛋白表達(dá)在細(xì)胞胞漿中,NC組Glucagon蛋白主要分布于胰島外周的α細(xì)胞,且量較少,DC組和EX組Glucagon蛋白除分布在胰島外周α細(xì)胞外,在胰島中央也多見表達(dá)。干預(yù)8周后,與NC組相比,DC組和EX組胰高糖素蛋白表達(dá)明顯增多,其中EX組表達(dá)量少于DC組。EXH組表達(dá)量少于EXL組。4.各組大鼠胰腺組織HE染色結(jié)果NC組胰島豐富形態(tài)飽滿,細(xì)胞核居中分布在均勻的胞漿中。內(nèi)分泌部胰島和外分泌部腺小葉清晰可見。在DC組及實(shí)驗(yàn)組中,胰島排列相對(duì)緊密,胰島間多見管腔內(nèi)存有紅細(xì)胞的毛細(xì)血管分布。胰島出現(xiàn)不同程度結(jié)構(gòu)破壞以及脂肪的浸潤和慢性炎癥的改變。在DC組,上述改變最為顯著。與DC組相比,EXL組EXH組上述改變有明顯改善,且EXH組改善情況優(yōu)于EXL組。結(jié)論GLP-1受體激動(dòng)劑Exendin-4能夠改善2型糖尿病大鼠胰島α細(xì)胞形態(tài),抑制過度增殖的大鼠胰島α細(xì)胞的數(shù)量,抑制其分泌胰高糖素,從而有效降低血糖水平。
[Abstract]:Objective the effect of Exendin-4 (EX-4) on the morphology and function of pancreatic islet 偽 cells in type 2 diabetic rats is not clear. In this study, different concentrations of GLP-1 receptor agonist EX-4 were used to interfere with type 2 diabetic rats. To observe the effect of EX-4 on the morphology and function of islet 偽 cells in type 2 diabetic rats. Therefore, this paper provides a new theoretical basis for the pathophysiology and clinical application of type 2 diabetes mellitus. Methods T2DM rat model. 40 male Wistar rats were randomly divided into normal rats by high glucose and high fat feeding combined with 1% STZ 35 mg / kg intraperitoneal injection. The remaining 25 rats were included in this experiment. The remaining 25 rats were divided into control group (DC group) and exendin-4 treatment group (EX group), among which the low dose group (ex group) and the low dose group (EXL group) were treated with n8EX group, the high dose group (EXH group) was divided into two groups: the control group, the control group, the control group, the control group and the diabetic group, and the remaining 25 rats were included in the experiment. The rats in the control group were divided into two groups: the control group, the DC group and the Exendin-4 treatment group. Exendin-4 dissolved in PBS solution was injected intraperitoneally into the left of the PBS group (5 渭 g / kg) and 20 渭 g / kg in the EXH group at regular intervals twice a day (9:00 in the morning and 5: 00pm in the control group) for 8 weeks. Blood glucose was measured by jugular vein blood sampling and serum samples were measured by radioimmunoassay. Pancreatic tissue was removed and fixed in neutral formalin solution. The paraffin sections were then embedded in paraffin for the preparation of sections. The paraffin sections were stained with HE to observe the morphological changes, and the expression of glucagon was observed by immunohistochemical staining. The changes of 偽 -cell morphology and quantity were observed. 1. The levels of glucagon in rats and serum glucagon in each group were significantly higher than those in NC group before intervention in DC group and EXH group. After 8 weeks of intervention, the levels of glucagon in exl group and EXH group were higher than those in NC group. 2. Compared with EXL group, the decrease of P0.05H group was significantly lower than that of EXL group, and was lower than that of DC group (P0.01U 路2.The blood glucose was monitored at 1 hour or 2 h after the last intervention). The blood glucose of the rats in the exh group was significantly higher than that in the DC group. The blood glucose in the exh group was significantly lower than that in the DM group. The decrease range of blood glucose in the exh group was higher than that in the EXL group. The results of immunohistochemical staining showed that the expression of glucagon protein in the cytoplasm of NC group was mainly distributed in the 偽 cells around the islets. The expression of Glucagon protein was also found in the center of the islet in addition to the peripheral 偽 cells in the DC group and ex group. After 8 weeks of intervention, the expression of glucagon protein in the DC group and ex group was significantly higher than that in the NC group. The expression of exh in the ex group was less than that in the DC group and the exh group was less than that in the EXL group. 4. The results of HE staining showed that the pancreatic islets in the NC group were rich in shape and full in shape. The nucleus was distributed in the uniform cytoplasm. The endocrine islets and the exocrine gland lobule were clearly visible. In DC group and experimental group, the islets were arranged relatively closely. The capillary distribution of red blood cells was found in the lumen of pancreatic islets. The islets were damaged to varying degrees, fat infiltrated and chronic inflammation were changed. Compared with DC group, the above changes in EXH group were significantly improved, and the improvement in EXH group was better than that in EXL group. Conclusion Exendin-4, a GLP-1 receptor agonist, can improve the morphology of islet 偽 cells in type 2 diabetic rats. Inhibiting the proliferation of rat islet 偽 cells and inhibiting the secretion of glucagon can effectively reduce the level of blood glucose.
【學(xué)位授予單位】：濟(jì)南大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2015
【分類號(hào)】：R587.1

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