本文選題：糖尿病大鼠 + 利拉魯肽　； 參考：《皖南醫學院》2017年碩士論文

【摘要】：目的:觀察利拉魯肽與二甲雙胍聯合用藥對糖尿病大鼠血糖、血脂、胰島素抵抗的影響;對胸主動脈纖維化的影響及其可能機制。方法:隨機抽取SPF級SD雄性大鼠9只作為正常對照組(NG組,雙蒸水,5 ml·kg-1·d-1,i.g.),其余大鼠采用高糖高脂飼養加腹腔注射鏈脲佐菌素(STZ)35mg·kg-1誘導糖尿病大鼠模型。將造模成功的大鼠(空腹血糖≥11.1 mmol/L)隨機分為糖尿病模型對照組(DM組,雙蒸水,5 ml·kg-1·d-1,i.g.),二甲雙胍治療組(Met組,100 mg·kg-1·d-1,i.g.),利拉魯肽治療組(Lir組,0.2 mg·kg-1·d-1,i.p.),利拉魯肽聯用二甲雙胍治療組(Lir+Met組,0.1 mg·kg-1·d-1,i.p.+50 mg·kg-1·d-1,i.g.),格列齊特聯用二甲雙胍治療組(Gli+Met組,10 mg·kg-1·d-1+50 mg·kg-1·d-1,i.g.)。各組于每天早上8點-10點灌胃或腹腔注射給予相應藥物,連續給藥6周。期間每2周稱重一次、檢測大鼠空腹血糖(FBG)變化。于給藥6周末進行口服糖耐量(OGTT)實驗,計算曲線下面積(AUC)。腹主動脈取血,檢測大鼠血脂水平、糖化血紅蛋白(HbA1c)和空腹血清胰島素(FINS)水平,并計算胰島素抵抗指數(IR);測定血清中腫瘤壞死因子(TNF-α)、血管內皮生長因子(VEGF)、大鼠血管性血友病因子(VWF)含量;HE染色法觀察大鼠胸主動脈病理損傷;Masson染色法觀察大鼠胸主動脈膠原纖維變化;測算膠原容積(CVF);RT-PCR法檢測TNF-α、VEGF、絲裂原活化蛋白激酶p38(P38MAPK)mRNA表達。結果:(1)與正常組相比較,糖尿病模型組大鼠體重(BW)、高密度脂蛋白膽固醇(HDL-C)均顯著下降(P0.01),而FBG、FINS、TG、TC、LDL-C、HbA1c則顯著上升(P0.01或P0.05),提示出現明顯的胰島素抵抗;血清中TNF-α、VEGF、VWF含量升高(P0.01或P0.05);HE染色顯示胸主動脈內膜增厚,內皮細胞、平滑肌排列紊亂,炎性物質浸潤,產生明顯的病理損傷;Masson染色出現膠原纖維沉積,血管增厚,CVF顯著升高(P0.01);RT-PCR法檢測顯示TNF-α、VEGF和P38MAPK mRNA表達升高(P0.01或P0.05)。(2)與糖尿病模型組大鼠相比較,各給藥組大鼠BW、HDL-C有所上升(P0.01或P0.05),FBG、FINS、TG、LDL-C、HbA1c有不同程度的下降(P0.01或P0.05),HOMA-IR有所下降(P0.01或P0.05),且利拉魯肽聯合二甲雙胍用藥組效果優于二甲雙胍單用藥組;血清中TNF-α、VEGF、VWF有不同程度的降低(P0.01或P0.05),利拉魯肽聯合二甲雙胍組降低效果顯著(P0.01或P0.05);HE染色顯示各給藥組大鼠胸主動脈炎性浸潤、內膜增生等有不同程度改善,病理損傷減輕,且利拉魯肽聯合二甲雙胍用藥組效果優于單用藥組;Masson染色顯示各給藥組能減少胸主動脈膠原纖維沉積、血管增厚等現象,顯著降低CVF(P0.01),利拉魯肽聯合二甲雙胍降低CVF作用效果與聯用藥對照組相當;RT-PCR法顯示各給藥組TNF-α、VEGF和P38MAPK mRNA表達有所下降(P0.01或P0.05),而利拉魯肽聯用二甲雙胍在降低TNF-α、VEGF和P38MAPK mRNA表達方面效果更優。結論:(1)利拉魯肽與二甲雙胍聯合用藥作用于高糖高脂+STZ誘導的糖尿病模型大鼠,能顯著改善血糖、脂質代謝紊亂、胰島素抵抗等情況,能增加糖尿病大鼠的體質量,且效果優于二甲雙胍單用藥治療。(2)利拉魯肽與二甲雙胍聯合用藥作用于高糖高脂+STZ誘導的糖尿病模型大鼠,可降低血清中TNF-α、VEGF、VWF含量,且效果優于單用藥治療。(3)利拉魯肽與二甲雙胍聯合用藥作用于高糖高脂+STZ誘導的糖尿病模型大鼠,可降低胸主動脈膠原容積分數、改善血管內皮損傷,降低血管纖維化水平,其機制可能與下調TNF-α、VEGF、P38MAPK表達有關。
[Abstract]:Objective: To observe the effects of the combination of the combination of Li Lu Lu peptide and metformin on blood glucose, blood lipid and insulin resistance in diabetic rats and the effect on the thoracic aorta fibrosis and its possible mechanism. Methods: 9 SPF grade SD male rats were randomly selected as normal control group (group NG, double steam water, 5 ml. Kg-1. D-1, i.g.), and the other rats were fed high fat and high fat diet. The diabetic rat model was induced by intraperitoneal injection of streptozotocin (STZ) 35mg / kg-1. The rats were randomly divided into the diabetic model control group (DM group, double steam water, 5 ml kg-1. D-1, i.g.), the treatment group of metformin (Met group, 100 mg, kg-1.), and the treatment group (0.2). D-1, i.p.), the treatment group (group Lir+Met, 0.1 mg, kg-1, D-1, i.p.+50 mg, kg-1 D-1, i.g.), glitazide combined with metformin treatment group (Gli+Met group, 10) at 8 o'clock every morning or intraperitoneal injection for 6 weeks. Every 2 weeks. The rats were weighed once, and the rats' fasting blood glucose (FBG) changes were measured. The oral glucose tolerance (OGTT) test was conducted at the end of the 6 week. The area under the curve (AUC) was calculated. The abdominal aorta was taken from the abdominal aorta, the blood lipid level, the glycated hemoglobin (HbA1c) and the fasting serum insulin (FINS) level were measured, and the insulin resistance index (IR) was calculated, and the cause of the bad cause of the tumor in the serum was measured. TNF- alpha, vascular endothelial growth factor (VEGF) and vascular hemophilia factor (VWF) in rats; HE staining was used to observe the pathological injury of thoracic aorta in rats; Masson staining method was used to observe the changes of collagen fiber in thoracic aorta and measure collagen volume (CVF); RT-PCR method was used to detect TNF- alpha, VEGF, mitogen activated protein kinase p38 (P38MAPK) mRNA expression. (1) compared with the normal group, the body weight (BW) and high density lipoprotein cholesterol (HDL-C) in the diabetic model group were significantly decreased (P0.01), while FBG, FINS, TG, TC, LDL-C, HbA1c increased significantly (P0.01 or P0.05), suggesting the emergence of significant insulin resistance. Thickening, endothelial cells, smooth muscle arrangement disorder, inflammatory infiltration, obvious pathological damage, Masson staining of collagen fibrous deposition, vascular thickening, CVF significantly increased (P0.01); RT-PCR assay showed that the expression of TNF- alpha, VEGF and P38MAPK mRNA increased (P0.01 or P0.05). (2) BW, H group rats BW, H DL-C increased (P0.01 or P0.05), FBG, FINS, TG, LDL-C, HbA1c had a different degree of decline (P0.01 or P0.05), HOMA-IR decreased (P0.01 or decreased), and the effect of alalu peptide combined with metformin was better than metformin single drug group. The effect of guanidine group was significant (P0.01 or P0.05); HE staining showed that the aorta arteritis of the rats in each group was improved, the hyperplasia of endometrium was improved, the pathological damage was reduced, and the effect of the drug group was better than that of the single drug group, and the Masson staining showed that the group could reduce the deposition of collagen fiber in the thoracic aorta and the blood vessels. The effect of thickening and other phenomena significantly decreased CVF (P0.01). The effect of alalup combined with metformin on the reduction of CVF was equivalent to that of the control group. The RT-PCR method showed that the expression of TNF- alpha, VEGF and P38MAPK mRNA decreased (P0.01 or P0.05) in each drug group, while the use of two metformin was better in reducing TNF- alpha. Conclusion: (1) the combination of L / M and metformin on diabetic rats induced by high glucose and high fat +STZ can significantly improve the blood glucose, lipid metabolism disorder, insulin resistance and so on. It can increase the body mass of diabetic rats, and the effect is better than metformin alone. (2) the effect of the combination of the use of Li Lu and metformin in combination with metformin. The diabetic rat model induced by high glucose and high fat +STZ can reduce the content of TNF- alpha, VEGF, and VWF in serum, and the effect is better than that of single drug treatment. (3) the combination of alalu and metformin on high glucose and high fat +STZ induced diabetic rats can reduce the volume fraction of collagen in the thoracic aorta, improve vascular endothelial damage and reduce vascular fiber. Its mechanism may be related to downregulation of TNF-, VEGF and P38MAPK expression.

【學位授予單位】：皖南醫學院
【學位級別】：碩士
【學位授予年份】：2017
【分類號】：R587.1

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