【作者】 郑妮；

【导师】 黄仁彬；

【作者基本信息】 广西医科大学 ， 药理学， 2014， 博士

【摘要】 2型糖尿病是一组由于胰岛素抵抗和胰岛素分泌障碍所导致的糖、脂质、蛋白质代谢紊乱，以血糖升高为基本特征的代谢紊乱疾病。近年来，随着人们生活水平提高、饮食习惯改变、体力劳动减少以及人口肥胖率的增加等多种因素，全球糖尿病的发病率呈逐年上升趋势。糖尿病现成为与心脑血管疾病、肿瘤并列的严重危害人类健康的三大疾病之一。因此，寻找一些简单方便、安全可靠的防治糖尿病的方法变的十分紧迫。杨桃根，作为酢浆草科植物Averrhoa carambola L.的根。作为一种中药材已有悠久的应用历史，用于治疗糖尿病以及糖尿病肾病。2-十二烷基-6-甲氧基-2，5-二烯-1，4-环己二酮（2-dodecyl-6-methoxycyclohexa-2，5-diene-1，4-dione，DMDD）是从杨桃根中提取出来的有效活性成分。目的:研究DMDD对2型糖尿病KKAy小鼠的血糖血脂，肝脏糖脂代谢的影响以及对于由糖基化终产物所介导的肾脏损伤的保护作用，从而证明其对于糖尿病治疗的有效性。方法：KKAy小鼠给予DMDD（12.5，25，50毫克/公斤体重/天）或氨基胍（200毫克/公斤体重/天）灌胃8周。记录体重，死亡，空腹血糖，总胆固醇（TC），甘油三酯（TG），低密度脂蛋白胆固醇（LDL-C），高密度脂蛋白胆固醇（HDL-C），载脂蛋白（ApoAI，apoB），游离脂肪酸（FFA），总脂质酶，肿瘤坏死因子-α（TNF-α）。然后，将小鼠处死，将其肾脏标本进行组织病理学和免疫组织化学（RAGE，NF-κBβκ，TGF-β1，CML）分析。结果：2型糖尿病KKAy小鼠的空腹血糖，糖化血红蛋白，TG，TC，LDL-C，ApoB和FFA均显著高于C57BL/6J小鼠，而HDL-C、ApoAI水平则明显降低。DMDD显著降低血糖， TG，TC，LDL-C，ApoB的含量，增加HDL-C、ApoAI水平。DMDD增加糖尿病小鼠的肝脏糖原含量，而降低FFA、TG水平。DMDD升高SOD活性和降低MDA，显著降低FFA，而增加脂联素水平与总脂质酶，超氧化物歧化酶活性。DMDD显著降低肾脏AGES和相关蛋白的表达，如AGE受体，核因子-κB，转化生长因子-β1，NF-κBβκ。进行8周的治疗后DMDD显著改善了尿蛋白，血清肌酐，血清尿素氮和肌酐清除率，和肾小球系膜基肿胀。KKAy小鼠肾脏减少的超氧化物歧化酶和谷胱甘肽过氧化物酶也在DMDD治疗后有了显著提高。结论：这些研究结果表明，DMDD可抑制糖尿病肾病的进展，可能成为治疗糖尿病的药理学良好药物。更多还原

【Abstract】 Type2diabetes mellitus is a kind of metabolic disorder due to insulinresistance andinsulin-the glucose，lipid and protein metabolic disordersyndrome accompanying hyperlipidemia．In recent years，the morbidityof diabetes in the world is increasing year afteryear all over the worldbecause of the combination of elevated living standards，change in theeating habits，reduced manual labor and Increased rates of obesity.Diabete becomes oneof the mostserious illness threatening human healthafter cardiovascular and cerebrovascular disease and cancer.Therefore，itis urgent to look for some safe and effective methods toprevent and treatthe diabetes.The roots of Averrhoa carambola L.（Oxalidaceae） have a longhistory of medicaluse in traditional Chinese medicine for treatingdiabetes and diabetic nephropathy.2-dodecyl-6-methoxycyclohexa-2，5-diene-1，4-dione （DMDD） was isolated from thetuberous roots ofAverrhoa carambola L.Objective:The purpose of this study was to investigate the the effectsof DMDD on blood glucose，blood lipid，glucolipid metabolism in liverand beneficial effect of DMDD on the advanced glycationend-product-mediated renalinjury in type2diabetic KKAy mice with regard to prove its efficacy by local traditional practitioners in thetreatment of diabeties.Methods:KKAy micewere orally administrated DMDD （12.5，25，50mg/kg body weight/d） oraminoguanidine （200mg/kg bodyweight/d） for8weeks. The body weight， death， FBG， totalcholesterol（TC），triglyceride （TG）， low density，lipoprotein-cholesterol （LDL-C），high density lipoprotein-cholesterol（HDL-C），apolipoprotein（Apo）AI，ApoB，free fatty acid（FFA），total lipidase，tumor necrosis factor alpha（TNF-α）of the mice wererecorded during these days. Then， the mice were sacrificed， and theirkidneys were harvested for histopathological and immunohistochemical（RAGE，NF-κB， TGF-β1，CML） analysis.Results:Fasting blood glucose，HbAlc，TG，TC，LDL-C，ApoB andFFA in type2diabetic KKAy mice were all sjgnif!icantly higher thanthat of the C57BL/6J mice，while HDL-C and ApoAI levels weresignificantly lower． DMDD markedly decreased blood glucose，HbAlc，TG， TC，LDL-C，ApoB andFFA contents of type2diabetic KKAymice，while increased HDL-C and ApoAI1evels．DMDD increased thedeclined glycogen content in1iver of diabetic mice，while decreased theaugmented FFA and TG1evels in diabetic tissues． DMDD increasedSOD activity and decreased MDA content．DMDD significantly declinedFFA，MDA， SOD and TNF-α contents in serum and adipose tissue ofdiabetic mice， while increased adiponectin level and total lipidase，SOD activities．Renal AGE formation， and the expression of relatedproteins， such as the AGE receptor， nuclearfactor-κB， transforminggrowth factor-β1， and Nε-（carboxymethyl）lysine， were markedly decreased by DMDD. Diabetes-dependent alterations in proteinuria，serum creatinine， creatinine clearance， and serum urea-N andglomerular mesangial matrix expansion were attenuated after treatmentwith DMDD for8weeks. The activities of superoxide dismutase andglutathione peroxidase， which were reduced in the kidneys of KKAymice， were enhanced by DMDD.Conclusions: These findings suggest that DMDD may inhibit theprogression of diabetic nephropathy and may be a therapeutic agent forregulating several pharmacological targets in treating diabeties.更多还原