本文選題：二甲雙胍 + 成纖維細胞生長因子19　； 參考：《山東大學》2017年碩士論文

【摘要】：研究目的近年來研究發(fā)現(xiàn)成纖維細胞生長因子19(FGF19)、成纖維細胞生長因子21(FGF21)通過與成纖維細胞生長因子受體(FGFRs)結合在糖脂代謝中發(fā)揮了重要作用,被認為新的代謝激素。此外,研究表明特異性活化纖維細胞生長因子受體1(FGFR1)可以改善糖脂代謝。二甲雙胍作為臨床一線用藥,主要通過抑制肝糖原輸出和增加外周組織胰島素敏感性發(fā)揮作用。我們研究二甲雙胍干預前后2型糖尿病模型中血清FGF19、FGF21,胰腺和脂肪組織FGFR1的表達水平及Akt的磷酸化水平的變化,進而探討二甲雙胍新的藥物靶點和器官靶點。研究方法給予8周齡健康雄性Wistar大鼠(n=60只)標準飲食,隨機分為正常對照組(Control group,Con)(n=20)和高脂飲食組(high fat diet group,HFD)(n=40),分別普通飼料和高脂飼料喂養(yǎng)。6w后,將HFD組大鼠腹腔注射鏈脲佐菌素(STZ)(35mg/kg)誘導糖尿病模型。誘導成模的大鼠隨機分為DM組和DM+METF組,DM+METF大鼠給予二甲雙胍(500 mg·kg-1·-d-1)。在24周末檢測血清生化學指標,酶聯(lián)免疫吸附法(ELISA)檢測FGF19和FGF21水平。蛋白免疫印跡(WB),免疫組化(IHC)檢測組織FGFR1的表達水平。WB檢測總的Akt(total Akt)及磷酸化的Akt(p-Akt)的變化。三組之間比較采用 one-way AN0VA。實驗結果1.各組大鼠一般觀察指標的比較糖尿病組(DM)大鼠在高脂飲食/STZ造模成功后,進食量和飲水量及體重顯著增加,高于正常對照組。二甲雙胍干預糖尿病組(DM+METF)大鼠的進食量,飲食量和體重也較正常組顯著增加,但是均明顯低于糖尿病組大鼠,差異具有統(tǒng)計學意義(P＜0.05)。2.各組大鼠的血清生化學指標比較在實驗末,糖尿病組(DM)大鼠的糖脂和膽汁酸代謝紊亂。2型糖尿病大鼠的糖耐量實驗提示胰島素釋放高峰延遲,整體胰島素曲線低平,兩小時末,胰島素水平仍高于正常對照組。二甲雙胍干預糖尿病組大鼠的FBG、FIN、TC、TG、LDL均較DM組大鼠降低,差異具有統(tǒng)計學意義。3.各組大鼠FGF19,FGF21,FGFR1和Akt磷酸化水平比較與正常對照組(Con)組大鼠比較,糖尿病組(DM)組大鼠血清FGF19水平顯著降低(P＜0.05);FGF21水平顯著升高(P＜0.05);脂肪組織和胰腺組織FGFR1表達異常增高,Akt的磷酸化水平(p-Akt/total-Akt)顯著降低(P＜0.05)。二甲雙胍干預大鼠的血清FGF21較DM組大鼠明顯升高(P0.05),而FGF19較DM組大鼠明顯減低(P0.05)。此外,胰腺FGFR1的表達水平接近正常組水平,而脂肪組織的FGFR1仍高于正常對照組和糖尿病組;兩組織的Akt的磷酸化水平(p-Akt/total-Akt)明顯高于糖尿病組大鼠。結論1.高脂飲食和小劑量鏈脲佐菌素(35mg/kg)可以誘導2型糖尿病模型,2型糖尿病大鼠的血脂和血糖代謝紊亂。2.二甲雙胍可以通過抑制攝食量改善體重。此外,還可以使膽固醇向膽汁酸轉化增多,并促進膽汁排泄。3.2型糖尿病大鼠FGF19和FGF21代謝出現(xiàn)紊亂,脂肪和胰腺組織FGFR1及Akt通路損傷。4.二甲雙胍干預可以使得DM大鼠的FGF19進一步降低,FGF21升高。但是可以逆轉Akt磷酸化水平的降低,這可能是通過FGFR1作用于Akt通路從而改善胰腺及脂肪組織功能。
[Abstract]:Research aims to find fibroblast growth factor 19 (FGF19), fibroblast growth factor 21 (FGF21), which plays an important role in glycolipid metabolism by combining with fibroblast growth factor receptor (FGFRs), and is considered as a new metabolic hormone. In addition, the study showed that specific activated fibroblast growth factor receptor 1 (FGFR). 1) can improve glycolipid metabolism. Metformin as a clinical first-line drug, mainly by inhibiting liver glycogen output and increasing peripheral tissue insulin sensitivity. We studied the expression level of serum FGF19, FGF21, pancreas and adipose tissue FGFR1 and the changes of phosphorylation level of Akt in type 2 diabetes mellitus model before and after metformin intervention. And then discuss the new drug target and organ target of metformin. The study method was given to 8 weeks old healthy male Wistar rats (n=60 only) standard diet and randomly divided into normal control group (Control group, Con) (n=20) and high fat diet group (high fat diet group, HFD) (n= 40). Streptozotocin (STZ) (35mg/kg) induced diabetes model was induced. The rats were randomly divided into DM group and DM+METF group. DM+METF rats were given metformin (500 mg. Kg-1. -d-1). Serum biochemical indexes were detected at the end of the 24 week, FGF19 and FGF21 levels were detected by enzyme linked immunosorbent assay (ELISA). Protein immunoblotting (WB) and immunohistochemical staining were detected. The expression level of FGFR1 was measured by.WB, the total Akt (total Akt) and phosphorylation of Akt (p-Akt). The comparison between the three groups was compared with the results of one-way AN0VA. experiment 1., the general observation index of rats in each group was compared with the diabetic group (DM) rats. After the high fat diet /STZ model was successful, the food intake and the amount of drinking water and body weight were significantly increased, higher than normal. Control group. Metformin intervention in diabetic group (DM+METF) rats intake, diet and weight was also significantly higher than the normal group, but all significantly lower than the diabetic rats, the difference was statistically significant (P < 0.05) the serum biochemical indexes of rats in.2. groups were compared at the end of the experiment, glucose and bile acid metabolism in diabetic group (DM) rats The glucose tolerance test of type.2 diabetic rats showed that the peak of insulin release was delayed, the overall insulin curve was low, and the insulin level was still higher than that of the normal control group at the end of two hours. The FBG, FIN, TC, TG, LDL of the diabetic rats were lower than those in the DM group, and the difference was statistically significant in FGF19, FGF21, FGFR1 in each group of.3. rats. Compared with the normal control group (Con), the level of serum FGF19 in the diabetic group (DM) was significantly lower (P < 0.05), the level of FGF21 increased significantly (P < 0.05), the expression of FGFR1 in the adipose tissue and pancreatic tissue was increased, and the phosphorylation level of Akt (P < 0.05) was significantly decreased (P < 0.05). The intervention of metformin in the DM group was significantly lower. The serum FGF21 of rats was significantly higher than that of the DM group (P0.05), while FGF19 was significantly lower than that in the DM group (P0.05). In addition, the expression level of the pancreas FGFR1 was close to that of the normal group, but the FGFR1 of the adipose tissue was still higher than that of the normal control group and the diabetic group; the phosphorylation level of Akt (p-Akt/total-Akt) in two tissues was significantly higher than that of the diabetic rats. Conclusion 1 High fat diet and small dose of streptozotocin (35mg/kg) can induce type 2 diabetes model. The blood lipid and blood glucose metabolism disorder.2. metformin in type 2 diabetic rats can improve the body weight by inhibiting the intake of food. In addition, it can also increase the conversion of cholesterol to bile acid, and promote the bile excretion of the FGF19 and FGF21 generation of type.3.2 diabetic rats. The metabolic disorder of FGFR1 and Akt pathway in fat and pancreatic tissue damage.4. metformin intervention can further reduce FGF19 in DM rats and increase FGF21. But it can reverse the decrease in the level of Akt phosphorylation, which may be through the action of FGFR1 on the Akt pathway to improve the function of the pancreas and fat tissue.
【學位授予單位】：山東大學
【學位級別】：碩士
【學位授予年份】：2017
【分類號】：R587.1

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