论文标题:实验性2型糖尿病大鼠大血管早期病变及药物干预研究
Early Macroangiopathy in Rat Model of Type 2 Diabetes Mellitus and Drugs Treatment
论文作者 王怡洁
论文导师 刘好文,论文学位 硕士,论文专业 神经病学
论文单位 河北医科大学,点击次数 87,论文页数 68页File Size5915k
2005-03-01论文网 http://www.lw23.com/lunwen_489162102/ 2 型糖尿病;大血管病变;核因子-κB;细胞间粘附分子-1;磺脲类药;他汀类药
Type 2 diabetes mellitus; Macroangiopathy; Nuclear factor-kappa B; Intercellar adhesion molecule-1; Sulfaurea; Statin
目的:脑卒中是国人死亡的重要原因之一。对脑卒中最好的治疗是预防,对其危险因素的有效治疗是预防的关键。作为四大可干预危险因素之一的糖尿病及其大血管病变动脉粥样硬化(Atherosclerosis,AS),在脑卒中的发病及转归中起着重要作用。关于糖尿病大血管并发症的发病机制不甚明确,新近有人提出慢性炎症机制,而核因子-κB(nuclear factor-kappaB,NF-κB)的激活及细胞间粘附分子(intercellar adhension molecule-1,ICAM-1)在内皮细胞的表达在炎症学说中倍受关注。对于糖尿病同时存在的各种代谢紊乱的治疗成为了阻止或延缓糖尿病动脉粥样硬化发生发展,从而预防脑卒中发病的重点。美吡达,又名格列吡嗪(Glipizide)属磺脲类药物,该药除了具有确切的降糖作用外,尚有增加外周组织对胰岛素的敏感性,调节血脂代谢紊乱及抑制血小板聚集等胰外作用。京必舒新属他汀(simvastatin)类药物,这类药物被认为是唯一可以稳定和阻止AS 进展的药物。这可能与其具有强力调脂作用,同时还存在恢复内皮功能完整性、抗炎、抑制氧化修饰、影响血小板功能等多种非调脂作用有关,但其分子机制不是十分明确。因此,本研究通过高糖高脂饮食诱导胰岛素抵抗, 再给予小剂量链脲佐菌素(streptozotocin,STZ)腹腔注射建立一种模拟人类2 型糖尿病发病过程的大鼠模型。在此基础上观察大血管早期病变,即
Objective:Stroke is the primary cause of death in China.The best treatment of stroke is prevention, and is the treatment of risk factors . As one of the four variable risk factors, diabetes mellitus and macroangiopathy atherosclerosis(AS) play a important role in the occurrence and prognosis of stroke. The pathological mechanism about diabetes macroangiopathy is not very explicit. Chronic inflammation may contribut to the pathologenesis. Many studies suggested the activation of nuclear factor-kappa B(NF-κB) and the expression of intercellar adhesion molecule-1(ICAM-1) in the endothelial cells are involed in diabetes macroangiopathy. The treatment of all kinds of metabolic disorders following with diabetes become the major point of preventing or delaying diabetes atherosclerosis occurrence and advance. Minidiab(Glipizide), an sulfaurea drug. Excepting for the definite role of reducing blood glucose, it has may exerts effects outside of pancreas,such as increases insulin sensitivity of outside tissue,regulating blood-lipid metablic disorders,inhibiting platelet clustering and so on. Simvastatin is regarded as the only drug that can stabilize and prevent the development of AS. It not only regulats blood-lipid but also has notregulating lipid effects: for example recovering endothelium function, resisting inflammation, inhibiting oxidization and influencing platelet function. Although it’s molecular mechanism is not very understanded. In present study, we establish a rat modes of type 2 diabetes mellitus by feeding high sugar and fat diet to inducing insulin resistance and subsequently injecting small dose streptozotocin (STZ). And investigated early macroangiopathy of and the expression of NF-κB and ICAM-1 in vascular wall. At the same time rats are fed on minidiab and simvastatin to explore their molecule mechanisms and clinical practical values in the prevention and treatment of diabetes macroangiopathy. Methods: Female Wister rats were randomly assigned into two groups: normal control group(A) and diabetic making group(B). group A was fed with the normal diet, group B was fed with the high sugar and fat diets including sucrose(20%,w/w) and lard (15%,w/w) for 4 weeks to induce insulin resistance. Then hyperglycemia was developed by intrapenitoneal injection STZ (30mg/kg)in these rats. At 8 weeks diabetic rats were defined according to FBG more than average value added 3 standard error and reducing insulin sensitive index(ISI). Diabetic rats were randomly devided into three groups: diabetic group(DM)、diabetic group treated with Minidiab (5mg/kg.d) (DG) and diabetic group treated with Minidiab (5mg/kg.d) and Simvastatin (2.5mg/kg.d) (DS). Body weight , fasting blood glucose (FBG) , fasting serum insulin (FINs) , serum triglyceride (TG) and serum cholesterol (TC) , low density lipidcholestrol (LDL-C) and high density lipid (HDL-C) were measured respectively after 4, 8 and 20 weeks. At the end of this study(20weeks), all rats were anesthetized by pentothal sodium(1%,w/w). Arotic tissues were revoved and were observed by light microscopy through hematoxylin-eosin stain(HE stain) and immuohischemisty statin of NF-κB and ICAM-1. Results:(1)In group B, fed with high sucrose and fat diet for 4 weeks, and body weight both were higher than group A(P<0.01, P<0.05); FINs、TC、TG and LDL-C significant increased levels(all P<0.01); ISI was lower (both P<0.01); But HDL-C was not clearly change. These results suggest insulin resistance in group B. (2) After injected a low dose of STZ intrapenitoneally for 4 weeks, group B rat’s FBG markedly increased compared with group A(P<0.01); FINs、TC、TG and LDL-C were still higher and ISI continued to reduce(P<0.01). (3)After 20 weeks, compared with DM there were significant decreases in FBG(P<0.01) in DG; FINs and ISI both increased(both P<0.01); TC decreased but still was higher than DS(P<0.01), others elements of blood lipid didn’t change obviously in DG(P>0.05). Compared with DM, there were obvious improvement of all indexs in DS (P<0.01). TC、TG、LDL-C and FINs were all lower in DS
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