杨桃根环己二酮抗2型糖尿病的作用及其分子机制研究
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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。
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.
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。
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.
引文
[1]许曼音，陆广华，陈名道.耱尿病学[M].上海:上海科学技术出版社，2003.
[2] Porta M， Sjoelie A K， Chaturvedi N， et al. Risk factors for progression to proliferativediabetic retinopathy in the EURODIAB Prospective Complications Study[J]. Diabetologia，2001，44（12）:2203-2209.
[3] Basta G， Schmidt A M， De Caterina R. Advanced glycation end products and vascularinflammation: implications for accelerated atherosclerosis in diabetes[J]. Cardiovascularresearch，2004，63（4）:582-592.
[4] Tiedge M， Lortz S， Munday R， et al. Complementary action of antioxidant enzymesin the protection of bioengineered insulin-producing RINm5F cells against the toxicity ofreactive oxygen species[J]. Diabetes，1998，47（10）:1578-1585.
[5] Tiedge M， Lortz S， Drinkgern J， et al. Relation between antioxidant enzyme geneexpression and antioxidative defense status of insulin-producing cells[J]. Diabetes，1997，46（11）:1733-1742.
[6] Paz K， Hemi R， LeRoith D， et al. A molecular basis for insulin resistance Elevatedserine/threonine phosphorylation of IRS-1and IRS-2inhibits their binding to thejuxtamembrane region of the insulin receptor and impairs their ability to undergoinsulin-induced tyrosine phosphorylation[J]. Journal of Biological Chemistry，1997，272（47）:29911-29918.
[7] Kyriakis J M， Avruch J. Protein kinase cascades activated by stress and inflammatorycytokines[J]. Bioessays，1996，18（7）:567-577.
[8] Blair A S， Hajduch E， Litherland G J， et al. Regulation of glucose transport andglycogen synthesis in L6muscle cells during oxidative stress Evidence for cross-talk betweenthe insulin and SAPK2/p38mitogen-activated protein kinase signaling pathways[J]. Journalof Biological Chemistry，1999，274（51）:36293-36299.
[9] Aguirre V， Uchida T， Yenush L， et al. The c-Jun NH2-terminal kinase promotesinsulin resistance during association with insulin receptor substrate-1and phosphorylation ofSer307[J]. Journal of Biological Chemistry，2000，275（12）:9047-9054.
[10]李秀娟，刘福英，张焕铃，等.复肝春6号对H22荷瘤小鼠的抑瘤及免疫的调节作用[J].中国老年学杂志，2006，26（1）:92-93.
[11]殷立华.了解糖尿病现状，从自身做起[J].糖尿病新世界，2012（12）:76-76.
[12]黄桂红，贺敏，林兴，等.杨桃根醇提物对糖尿病模型小鼠的降血糖作用[J].中国医院药学杂志，2009（15）:1256-1258.
[13]黄桂红，黄纯真，黄仁彬.阳桃根多糖对糖尿病小鼠胰岛素及胸，脾指数的影响[J].中国药师，2009（7）:848-850.
[14]黄桂红，黄仁彬.阳桃根醇提物对糖尿病小鼠血糖及脂质过氧化反应的影响[J].时珍国医国药，2009，20（11）:2730-2731.
[15] Cazarolli L H， Folador P， Moresco H H， et al. Mechanism of action of the stimulatoryeffect of apigenin-6-C-（2″-O-α-l-rhamnopyranosyl）-β-l-fucopyranoside on14 C-glucose uptake[J]. Chemico-biological interactions，2009，17（92）:407-412.
[16] Cazarolli L H， Folador P， Moresco H H， et al. Stimulatory effect ofapigenin-6-C-β-L-fucopyranoside on insulin secretion and glycogen synthesis[J]. Europeanjournal of medicinal chemistry，2009，44（11）:4668-4673.
[17]宋立人.中华本草（第四册）[M].北京:科学出版社，1994.
[18] Bailey C J， Day C. Traditional plant medicines as treatments for diabetes[J]. Diabetescare，1989，12（8）:553-564.
[19]张玲芝，冯磊.灵芝多糖降血糖的机理探讨[J].福建医药杂志，2004，26（3）:137-140.
[20]罗少洪，杨红.灵芝多糖调节血糖作用的实验研究[J].广东药学院学报，2000，16（2）.
[21]徐珞珊，徐国钧，金蓉鸾.中国药材学[M].北京:中国医药科技出版社，1996.
[22]魏守蓉，薛存宽，何学斌，等.绞股蓝多糖降血糖作用的实验研究[J].中国老年学杂志，2005，25（4）:418-420.
[23]张朝云，叶红英，俞茂华，等.黄芪多糖对糖尿病大鼠心肌超微结构的影响[J].复旦学报（医学科学版），2001，28（6）:476-478.
[24]左绍远，万顺康.螺旋藻多糖降血糖活性实验研究[J].时珍国医国药，2000，11（8）:677-678.
[25]季峰，魏贤勇，刘广龙，等.玉竹多糖降血糖作用的实验研究[J].江苏中医药，2006，27（9）:70-71.
[26]王兵，黄巧娟.羊栖菜多糖降血糖作用的实验研究[J].中国海洋药物，2000，19（3）:33-35.
[27]王银萍，吴家祥.大豆皂甙和人参茎叶皂甙的抗糖尿病动脉粥样硬化作用[J].白求恩医科大学学报，1994，20（6）:551-554.
[28]柴瑞华，肖春莹，赵余庆.苦瓜总皂苷降血糖作用的研究[J].中草药，2007，38（2）:248-250.
[29]孙宝莹，孙宝全，张朝.苦瓜皂甙的药效学实验研究[J].河南中医药学刊，1994，9（6）:19-19.
[30]郭洁文，廖惠芳，潘竞锵，等.荔枝核皂苷对地塞米松致胰岛素抵抗糖尿病大鼠血糖血脂的影响[J].广东药学，2004，13（5）:32-35.
[31]戚向阳，陈维军，宋云飞，等.罗汉果提取物对糖尿病小鼠的降血糖作用[J].中国公共卫生，2003，19（10）:1226-1227.
[32]郝海平，许惠琴.山茱萸环烯醚萜总苷对由链脲佐菌素诱导的糖尿病血管并发症大鼠血清sICAM—1， TNF—α的影响[J].中药药理与临床，2002，18（4）:13-14.
[33]张一波.黄连素降血糖及防治糖尿病慢性并发症的作用和机制[J].中国中医药信息杂志，2003，10（1）:83-85.
[34]陈洪源，明智强，谢佳乐，等.小檗碱降血糖机制的研究进展[J].食品与药品，2008，10（2）:69-71.
[35]李宗友.胡芦巴的抗糖尿病和降胆固醇作用[J].国外医学:中医中药分册，1999，21（4）:9-14.
[36]钟正贤，覃洁萍.广西藤茶总黄酮降血糖的实验研究[J].中国中药杂志，2002，27（9）:687-689.
[37]钟正贤，周桂芬.黄杞总黄酮的实验研究[J].时珍国医国药，2000，11（6）:495-496.
[38]高荫榆，罗丽萍，王应想，等.薯蔓黄酮降血糖作用研究[J].食品科学，2005，26（3）:218-220.
[39]韩淑英，喇万英.荞麦种子总黄酮降血脂，血糖及抗脂质过氧化作用的研究[J].中国药理学通报，2001，17（6）:694-696.
[40] Gao Q， Qin W S， Jia Z H， et al. Rhein improves renal lesion and amelioratesdyslipidemia in db/db mice with diabetic nephropathy[J]. Planta medica，2010，76（01）:27-33.
[41]温庆伟，郑妮，陈春霞，等.阳桃根中化学成分类型的试验研究[J].中药与临床，2013（2）:4.
[42]王少华，段文若，杜冠华.内分泌代谢疾病合理用药[M].人民卫生出版社，2009.
[43] Eurich D T， McAlister F A， Blackburn D F， et al. Benefits and harms of antidiabeticagents in patients with diabetes and heart failure: systematic review[J]. Bmj，2007，335（7618）:497.
[44]陈其明，史顺娣，申竹芳，等.糖尿病KK小鼠生物特性的研究[J].中国医学科学院学报，1988，6:009.
[45] Simon M， Maresh J G， Harris S E， et al. Expression of bone morphogenetic protein-7mRNA in normal and ischemic adult rat kidney[J]. American Journal of Physiology-RenalPhysiology，1999，276（3）: F382-F389.
[46]郭清华，陆菊明，潘长玉.饮食能量对Kkay及Kk小鼠2型糖尿病发病的影响[J].军医进修学院学报，2005，26（2）:140-142.
[47]周桔，彭端，李明，等.钒对遗传性Ⅱ型糖尿病KK小鼠降糖作用的实验研究[J].中国科学院研究生院学报，2008，25（2）:192-196.
[48]王芬，何华亮，江南，等.糖耐康对自发性2型糖尿病KKAy小鼠胰岛素信号转导的影响[J].中国实验方剂学杂志，2008，14（1）:46-49.
[49]厉朝龙.生物化学与分子生物学实验技术[M].浙江，浙江大学出版社，2000.
[50]许曼音，陆广华，陈名道.耱尿病学[M].上海:上海科学技术出版社，2003.
[51] Bach J F. Insulin-dependent diabetes mellitus as an autoimmune disease[J]. Endocrinereviews，1994，15（4）:516-542.
[52] Tomkin G H. Targets for intervention in dyslipidemia in diabetes[J]. Diabetes Care，2008，31（Supplement2）: S241-S248.
[53] Demain A L. A new era of exploitation of microbial metabolites[C]//Biochemical Societysymposium.1982，48:117-132.
[54] Gupta S， Kataria M， Gupta P K， et al. Protective role of extracts of neem seeds indiabetes caused by streptozotocin in rats[J]. Journal of ethnopharmacology，2004，90（2）:185-189.
[55] Molitch M E. Management of dyslipidemias in patients with diabetes and chronic kidneydisease[J]. Clinical Journal of the American Society of Nephrology，2006，1（5）:1090-1099.
[56] Shoji T， Nishizawa Y， Kawagishi T， et al. Atherogenic lipoprotein changes in theabsence of hyperlipidemia in patients with chronic renal failure treated by hemodialysis[J].Atherosclerosis，1997，131（2）:229-236.
[57] Yang W S， Kim S B， Min W K， et al. Atherogenic lipid profile and lipoprotein （a）in relation to serum albumin in haemodialysis patients[J]. Nephrology DialysisTransplantation，1995，10（9）:1668-1671.
[58] Taskinen M R. Diabetic dyslipidemia[J]. Atherosclerosis Supplements，2002，3（1）:47-51.
[59]吕小虎.浅谈糖尿病发生机制的研究[J].中国现代实用医学杂志，2008，7（7）:37-39.
[60] He Z， King G L. Microvascular complications of diabetes[J]. Endocrinology andmetabolism clinics of North America，2004，33（1）:215-238.
[61] Fuller J H， Shipley M J， Rose G， et al. Coronary-heart-disease risk and impairedglucose tolerance The Whitehall Study[J]. The Lancet，1980，315（8183）:1373-1376.
[62]迟家敏.实用糖尿病学[M].北京:人民卫生出版社，2009.
[63]张均田.现代药理实验方法[M].北京医科大学，中国协和医科大学联合出版社，1998.
[64] Fry J R. Preparation of mammalian hepatocytes[J]. Methods in enzymology，1981，77:130.
[65] Lannoy V， Decaux J， Pierreux C， et al. Liver glucokinase gene expression iscontrolled by the onecut transcription factor hepatocyte nuclear factor-6[J]. Diabetologia，2002，45（8）:1136-1141.
[66] Kershaw E E， Flier J S. Adipose tissue as an endocrine organ[J]. Journal of ClinicalEndocrinology&Metabolism，2004，89（6）:2548-2556.
[67] Sethi J K， Hotamisligil G S. The role of TNFα in adipocyte metabolism[C].Seminars incell&developmental biology. Academic Press，1999，10（1）:19-29.
[68] Onozato M L， Tojo A， Goto A， et al. Oxidative stress and nitric oxide synthase in ratdiabetic nephropathy: effects of ACEI and ARB[J]. Kidney international，2002，61（1）:186-194.
[69]舒毅，钟历勇.氧化应激与糖尿病[J].东南大学学报:医学版，2005，24（1）:64-67.
[70]包蓓艳，沈汉超.谷胱甘肽抗氧化系统在早期糖尿病肾病中的变化[J].医师进修杂志，2005，28（2）:20-22.
[71]孙忠，吴蕴棠.锌对糖尿病大鼠血脂及脂质过氧化作用的影响[J].天津医科大学学报，2001，7（2）:171-173.
[72]牟忠卿.糖尿病大鼠不同组织中氧化应激的实验研究[D].山东大学:2005.
[73] Maeda K， Okubo K， Shimomura I， et al. cDNA cloning and expression of a noveladipose specific collagen-like factor， apM1（AdiPoseMost abundant Gene transcript1）[J]. Biochemical and biophysical research communications，1996，221（2）:286-289.
[74] Hotta K， Funahashi T， Arita Y， et al. Plasma concentrations of a novel，adipose-specific protein， adiponectin， in type2diabetic patients[J]. Arteriosclerosis，thrombosis， and vascular biology，2000，20（6）:1595-1599.
[75] Charles M A， Eschwege E， Thibult N， et al. The role of non-esterified fatty acids inthe deterioration of glucose tolerance in Caucasian subjects: results of the Paris ProspectiveStudy[J]. Diabetologia，1997，40（9）:1101-1106.
[76] Randle P J， Garland P B， Hales C N， et al. The glucose fatty-acid cycle its role ininsulin sensitivity and the metabolic disturbances of diabetes mellitus[J]. The Lancet，1963，281（7285）:785-789.
[77] Boden G. Role of fatty acids in the pathogenesis of insulin resistance and NIDDM[J].Diabetes，1997，46（1）:3-10.
[78]滕香宇，杨永年.游离脂肪酸与β细胞功能[J].中华内分泌代谢杂志，1999，15（6）:363-365.
[79] Simsolo R B， Ong J M， Saffari B， et al. Effect of improved diabetes control on theexpression of lipoprotein lipase in human adipose tissue[J]. Journal of lipid research，1992，33（1）:89-95.
[80] Boden G， Chen X. Effects of fat on glucose uptake and utilization in patients withnon-insulin-dependent diabetes[J]. Journal of Clinical Investigation，1995，96（3）:1261.
[81] Ricote M， Li A C， Willson T M， et al. The peroxisome proliferator-activatedreceptor-γ is a negative regulator of macrophage activation[J]. Nature，1998，391（6662）:79-82.
[82] Hotamisligil G S. The role of TNFα and TNF receptors in obesity and insulin resistance[J].Journal of internal medicine，1999，245（6）:621-625.
[83] Mishima Y， Kuyama A， Tada A， et al. Relationship between serum tumor necrosisfactor-α and insulin resistance in obese men with type2diabetes mellitus[J]. Diabetesresearch and Clinical practice，2001，52（2）:119-123.
[84] Moller D E. Potential role of TNF-α in the pathogenesis of insulin resistance and type2diabetes[J]. Trends in Endocrinology&Metabolism，2000，11（6）:212-217.
[85] Clarke S D， Gasperikova D， Nelson C， et al. Fatty acid regulation of geneexpression[J]. Annals of the New York Academy of Sciences，2002，967（1）:283-298.
[86] Shulman G I， Rothman D L， Jue T， et al. Quantitation of muscle glycogen synthesis innormal subjects and subjects with non-insulin-dependent diabetes by13C nuclear magneticresonance spectroscopy[J]. New England Journal of Medicine，1990，322（4）:223-228.
[87] Das U N. GLUT-4， tumour necrosis factor， essential fatty acids and daf-genes and theirrole in glucose homeostasis， insulin resistance， non-insulin dependent diabetesmellitus， and longevity[J]. The Journal of the Association of Physicians of India，1999，47（4）:431-435.
[88] Folks T M， Clouse K A， Justement J， et al. Tumor necrosis factor alpha inducesexpression of human immunodeficiency virus in a chronically infected T-cell clone[J].Proceedings of the National Academy of Sciences，1989，86（7）:2365-2368.
[89] Kern P A， Saghizadeh M， Ong J M， et al. The expression of tumor necrosis factor inhuman adipose tissue. Regulation by obesity， weight loss， and relationship to lipoproteinlipase[J]. Journal of Clinical Investigation，1995，95（5）:2111.
[90] Feingold K R， Grunfeld C. Role of cytokines in inducing hyperlipidemia[J]. Diabetes，1992，41（Supplement2）:97-101.
[91] Roden M， Price T B， Perseghin G， et al. Mechanism of free fatty acid-induced insulinresistance in humans[J]. Journal of Clinical Investigation，1996，97（12）:2859.
[92] Reaven G M. Role of insulin resistance in human disease[J]. Diabetes，1988，37（12）:1595-1607.
[93] Schmitz-Peiffer C. Signalling aspects of insulin resistance in skeletal muscle: mechanismsinduced by lipid oversupply[J]. Cellular signalling，2000，12（9）:583-594.
[94] Kraegen E W， Cooney G J， Ye J M， et al. The role of lipids in the pathogenesis ofmuscle insulin resistance and beta cell failure in type II diabetes and obesity[J]. Experimentaland Clinical Endocrinology&Diabetes，2001，109（Suppl2）: S189-S201.
[95] Chen N G， Reaven G M. Fatty acid inhibition of glucose-stimulated insulin secretion isenhanced in pancreatic islets from insulin-resistant rats[J]. Metabolism，1999，48（10）:1314-1317.
[96] Fasshauer M， Klein J， Neumann S， et al. Hormonal regulation of adiponectin geneexpression in3T3-L1adipocytes[J]. Biochemical and biophysical researchcommunications，2002，290（3）:1084-1089.
[97] Ridker P M， Rifai N， Rose L， et al. Comparison of C-reactive protein and low-densitylipoprotein cholesterol levels in the prediction of first cardiovascular events[J]. New Englandjournal of medicine，2002，347（20）:1557-1565.
[98] Carey A L， Bruce C R， Sacchetti M， et al. Interleukin-6and tumor necrosis factor-αare not increased in patients with type2diabetes: evidence that plasma interleukin-6isrelated to fat mass and not insulin responsiveness[J]. Diabetologia，2004，47（6）:1029-1037.
[99] Febbraio M A， Steensberg A， Starkie R L， et al. Skeletal muscle interleukin-6andtumor necrosis factor-α release in healthy subjects and patients with type2diabetes at restand during exercise[J]. Metabolism，2003，52（7）:939-944.
[100] Nakano Y， Tobe T， Choi-Miura N H， et al. Isolation and characterization ofGBP28， a novel gelatin-binding protein purified from human plasma[J]. Journal ofBiochemistry，1996，120（4）:803-812.
[101] Scherer P E， Williams S， Fogliano M， et al. A novel serum protein similar toC1q， produced exclusively in adipocytes[J]. Journal of Biological chemistry，1995，270（45）:26746-26749.
[102] Yamamoto Y， Hirose H， Saito I， et al. Correlation of the adipocyte-derivedprotein adiponectin with insulin resistance index and serum high-densitylipoprotein-cholesterol， independent of body mass index， in the Japanese population[J].Clinical Science，2002，103（2）:137-142.
[103] Rothenbacher D， Brenner H， M rz W， et al. Adiponectin， risk of coronaryheart disease and correlations with cardiovascular risk markers[J]. European Heart Journal，2005，26（16）:1640-1646.
[104] Hotta K， Funahashi T， Bodkin N L， et al. Circulating concentrations of theadipocyte protein adiponectin are decreased in parallel with reduced insulin sensitivity duringthe progression to type2diabetes in rhesus monkeys[J]. Diabetes，2001，50（5）:1126-1133.
[105] Ruige J B， Ballaux D P， Funahashi T， et al. Resting metabolic rate is animportant predictor of serum adiponectin concentrations: potential implications forobesity-related disorders[J]. The American journal of clinical nutrition，2005，82（1）:21-25.
[106] Pilz S， Horejsi R， M ller R， et al. Early atherosclerosis in obese juveniles isassociated with low serum levels of adiponectin[J]. Journal of Clinical Endocrinology&Metabolism，2005，90（8）:4792-4796.
[107] Satoh N， Naruse M， Usui T， et al. Leptin-to-adiponectin ratio as a potentialatherogenic index in obese type2diabetic patients[J]. Diabetes care，2004，27（10）:2488-2490.
[108] Pajvani U B， Hawkins M， Combs T P， et al. Complex distribution， notabsolute amount of adiponectin， correlates with thiazolidinedione-mediated improvementin insulin sensitivity[J]. Journal of Biological Chemistry，2004，279（13）:12152-12162.
[109] Baribault H. Mouse models of type II diabetes mellitus in drug discovery[M]//MouseModels for Drug Discovery. Humana Press，2010:135-155.
[110]郝金成，穆振国，郭见光.晚期糖基化终末产物与糖尿病慢性并发症的关系[J].中国民康医学，2006，18（7）:594-595.
[111]郑永强，薛玲，李晓军，等.荞麦黄酮复方制剂对糖尿病大鼠肾损伤的抑制作用[J].时珍国医国药，2012，23（6）:1441-1444.
[112] Nakayama H， Mitsuhashi T， Kuwajima S， et al. Immunochemical detection ofadvanced glycation end products in lens crystallins from streptozocin-induced diabetic rat[J].Diabetes，1993，42（2）:345-350.
[113]庞玉萍.大鼠糖尿病肾脏病理改变以及罗格列酮对其病理改善的研究[D].浙江大学，2008.
[114] Sheetz M J， King G L. Molecular understanding of hyperglycemia's adverse effectsfor diabetic complications[J]. Jama，2002，288（20）:2579-2588.
[115] Hovind P， Rossing P， Tarnow L， et al. Progression of diabetic nephropathy[J].Kidney international，2001，59（2）:702-709.
[116] Parving H H， Lehnert H， Br chner-Mortensen J， et al. The effect of irbesartan onthe development of diabetic nephropathy in patients with type2diabetes[J]. New EnglandJournal of Medicine，2001，345（12）:870-878.
[117] Lea J， Greene T， Hebert L， et al. The relationship between magnitude ofproteinuria reduction and risk of end-stage renal disease: results of the African Americanstudy of kidney disease and hypertension[J]. Archives of Internal Medicine，2005，165（8）:947-953.
[118] Bohlender J M， Franke S， Stein G， et al. Advanced glycation end products andthe kidney[J]. American Journal of Physiology-Renal Physiology，2005，289（4）:F645-F659.
[119] Jiang T， Huang Z， Lin Y， et al. The protective role of Nrf2instreptozotocin-induced diabetic nephropathy[J]. Diabetes，2010，59（4）:850-860.
[120] Koya D， Hayashi K， Kitada M， et al. Effects of antioxidants in diabetes-inducedoxidative stress in the glomeruli of diabetic rats[J]. Journal of the American Society ofNephrology，2003，14（suppl3）: S250-S253.
[121] Prabhakar S， Starnes J， Shi S， et al. Diabetic nephropathy is associated withoxidative stress and decreased renal nitric oxide production[J]. Journal of the AmericanSociety of Nephrology，2007，18（11）:2945-2952.
[122] K dziora-Kornatowska K， Szram S， Kornatowski T， et al. The effect ofverapamil on the antioxidant defence system in diabetic kidney[J]. Clinica chimica acta，2002，322（1）:105-112.
[123] Reeves W B， Andreoli T E. Transforming growth factor β contributes to progressivediabetic nephropathy[J]. Proceedings of the National Academy of Sciences，2000，97（14）:7667-7669.
[124] Forbes J M， Fukami K， Cooper M E. Diabetic nephropathy: where hemodynamicsmeets metabolism[J]. Experimental and Clinical Endocrinology and Diabetes，2007，115（2）:69-84.
[125] Kanwar Y S， Wada J， Sun L， et al. Diabetic nephropathy: mechanisms of renaldisease progression[J]. Experimental Biology and Medicine，2008，233（1）:4-11.
[126] Daroux M， Prévost G， Maillard-Lefebvre H， et al. Advanced glycationend-products: implications for diabetic and non-diabetic nephropathies[J]. Diabetes&metabolism，2010，36（1）:1-10.
[127] Schleicher E D， Wagner E， Nerlich A G. Increased accumulation of theglycoxidation product N （epsilon）-（carboxymethyl） lysine in human tissues in diabetesand aging[J]. Journal of Clinical Investigation，1997，99（3）:457.
[128] Thomas M C， Forbes J M， Cooper M E. Advanced glycation end products anddiabetic nephropathy[J]. American journal of therapeutics，2005，12（6）:562-572.
[129] Yan S D， Schmidt A M， Anderson G M， et al. Enhanced cellular oxidant stressby the interaction of advanced glycation end products with their receptors/binding proteins[J].Journal of Biological Chemistry，1994，269（13）:9889-9897.
[130] Li J， Schmidt A M. Characterization and functional analysis of the promoter ofRAGE， the receptor for advanced glycation end products[J]. Journal of BiologicalChemistry，1997，272（26）:16498-16506.
[131] Wautier J L， Guillausseau P J. Advanced glycation end products， their receptorsand diabetic angiopathy[J].2008.
[132] Chappey O， Dosquet C， WAUTIER M P， et al. Advanced glycation endproducts， oxidant stress and vascular lesions[J]. European journal of clinicalinvestigation，1997，27（2）:97-108.
[133] Fu M X， Requena J R， Jenkins A J， et al. The advanced glycation end product，N-（carboxymethyl） lysine， is a product of both lipid peroxidation and glycoxidationreactions[J]. Journal of Biological Chemistry，1996，271（17）:9982-9986.
[134]倪海霞9任卫东.2型糖尿病患者治疗的效果观察与社区强化管理[J]。陕西医学杂志，2010，39（4）；504-505.
[135]王先远，金宏.苦瓜皂甙对衰老小鼠免疫功能的影响[J].营养学报，2001，23（3）:263-266.
[136] Hayase M， Ogawa Y， Katsuura G， et al. Regulation of obese gene expression inKK mice and congenic lethal yellow obese KKAy mice[J]. American Journal ofPhysiology-Endocrinology and Metabolism，1996，271（2）: E333-E339.
[137] Attie A D， Flowers M T， Flowers J B， et al. Stearoyl‐CoA DesaturaseDeficiency， Hypercholesterolemia， Cholestasis， and Diabetes[J]. Nutrition reviews，2007，65（s1）: S35-S38.
[138] Shaw JE，Sicree RA，Zimmet PZ．Global estimates of the preva-lenee of diabetesfor2010and2030[J1．Diabetes Res Clin Pract．2010，87（1）：4-14．
[139]邓尚平.糖尿病防治知识讲座[M].四川：四川科学技术出版社，2007.
[140]文世林.糖尿病流行的全球趋势和国内现状[J].河南诊断与治疗杂志，2002，16（1）:14-17.
[141] Yang W， Lu J， Weng J， et al. Prevalence of diabetes among men and women inChina[J]. New England Journal of Medicine，2010，362（12）:1090-1101.
[142]江济华，臧桐华.糖尿病及并发症与疾病负担[J].疾病控制杂志，2000，4（3）:259-262.
[143] Cryer P E. We are what we repeatedly do[J]. Diabetes，1998，47（2）:155-158.
[144] Olsson J， Persson U， Tollin C， et al. Comparison of excess costs of care andproduction losses because of morbidity in diabetic patients[J]. Diabetes Care，1994，17（11）:1257-1263.
[145] Neville S E， Boye K S， Montgomery W S， et al. Diabetes in Japan: a review ofdisease burden and approaches to treatment[J]. Diabetes/metabolism research and reviews，2009，25（8）:705-716.
[146] Kirigia J M， Sambo H B， Sambo L G， et al. Economic burden of diabetesmellitus in the WHO African region[J]. BMC international health and human rights，2009，9（1）:6.
[147]胡善联，刘国恩，许樟荣，等.我国糖尿病流行病学和疾病经济负担研究现状[J].中国卫生经济，2008，27（8）:5-8.
[148] Rovner A J， Nansel T R. Are children with type1diabetes consuming a healthfuldiet， A review of the current evidence and strategies for dietary change[J]. The DiabetesEducator，2009，35（1）:97-107.
[149] Ventura E E， Lane C J， Weigensberg M J， et al. Persistence of the metabolicsyndrome over3annual visits in overweight Hispanic children: association with progressiverisk for type2diabetes[J]. The Journal of pediatrics，2009，155（4）:535-541. e1.
[150] Rovner A J， Nansel T R， Gellar L. The effect of a low-glycemic diet vs a standarddiet on blood glucose levels and macronutrient intake in children with type1diabetes[J].Journal of the American Dietetic Association，2009，109（2）:303-307.
[151]付萍，满青青，张坚，等.中国5~17岁儿童青少年糖尿病流行情况分析[J].卫生研究，2008，36（6）:722-724.
[152]王立群.糖尿病低龄化成因分析及护理对策[J].航空航天医学杂志，2011，22（8）:1000-1002.
[153]许顺江，闫宝勇.儿童和青少年糖尿病患者的心理健康与护理[J].河北医药，2009，31（23）:72-73.
[154]马学毅.现代糖尿病诊断治疗学[M]，北京：人民军医出版社，2007.
[155]杨明功.糖尿病流行现状及防治对策[J].疾病控制杂志，2000，4（3）:193-196.
[156] Lind M， Garcia-Rodriguez L A， Booth G L， et al. Mortality trends in patientswith and without diabetes in Ontario， Canada and the UK from1996to2009: apopulation-based study[J]. Diabetologia，2013，56（12）:2601-2608.
[157] Zhang Y， Sun J， Pang Z， et al. Evaluation of two screening methods forundiagnosed diabetes in China: An cost-effectiveness study[J]. Primary care diabetes，2013，7（4）:275-282.
[158] Al-Qazaz H K， Hassali M A， Shafie A A， et al. The eight-item MoriskyMedication Adherence Scale MMAS: translation and validation of the Malaysian version[J].Diabetes research and clinical practice，2010，90（2）:216-221.
[159] Gu W， Huang Y， Zhang Y， et al. Adolescents and young adults with newlydiagnosed Type2diabetes demonstrate greater carotid intima‐media thickness than thosewith Type1diabetes[J]. Diabetic Medicine，2014，31（1）:84-91.
[160]向志雄，黄诚，彭新君，等.中药治疗糖尿病及其并发症研究进展[J].中西医结合学报，2006，4（3）：321-325.
[161] Park MY，LeeKS，SungMK.Effects of dietary mulberry，Korean red ginseng，andbanaba on glucose homeostasis in relationto PPAR-alpha，PPAR-gamma，and LPL mRNAexpressions[J]. LifeSci，2005，77（26）:3344-3354.
[162] Lee H，Gonzalez FJ，Yoon M.Ginsenoside Rf，a component of ginseng， regulateslipoprotein metabolism through peroxisome proliferator-activated receptor alpha[J]. BiochemBiophys Res Commun，2006，339（1）:196-203.
[163] Hou Z，Zhang Z，Wu H. Effect of Sanguis draxonis （a Chinese traditional herb）on the formation of insulin resistance in rats[J]. Diabetes Res Clin Pract，2005，68（1）:3-11.
[164] Xu ME，Xiao SZ，Sun YH，et al. The study of anti-metabolic syndrome effect ofpuerarin in vitro[J]. Life Sci，2005，77（25）:3183-3196.
[165] Ko BS，Choi SB，Park SK，et al. Insulin sensitizing and insulinotropic action ofberberine from Cortidis rhizoma[J].Biol Pharm Bull，2005，28（8）:1431-1437.
[166][2]Turner N，Li JY，Gosby A，et al．Berberine and its more biologically availablederivative，dihydroberberine，inhibit mitochondrial respiratory complex I：a mechanismfor the action of berberine to activate AMP—activated protein kinase and improve insulinaction．Diabetes．2008，57：1414-1418．
[167][3]Zhang Y，Li X，Zou D，et al．Treatment of type2diabetes and dyslipidemia withthe natural plant alkaloid berberine．J Clin Endocrinol Metab，2008，93：2559-2565．
[168][4]Kong W，Wei J，Abidi P，et al．Berberine is a liovel cholesterollowering dragworking through a unique mechanism distinct from statins． Nat Med，2004，10：1344-1351．
[169][5]Lu ss。Yu YL，Zhu ILl，et al．Berberine promotes ghcagon-like peptide-l（7-36）amide secretion in streptozotocin-induced diabetic rats． J Endocrinol，2009，200：159-165．
[170][6]Zhou L，Wang X，Shao L，et al．Berberine acutely inhibits insuhnsecretion frombeta． cells thmush3’，5’． cyclic adcnosine5’-monophosphate signalingpathway．Endocrinology，2008，149：4510-4518．
[171][7]Sotaniemi EA． Haapakeski E． Rantio A． Ginseng therapy innon-insulin-dependent diabetic patients．Diabetes Care，1995，18：1373-1375．
[172][8]Kim SH，Park KS．Effects of Panax ginseng extract on lipid metabolism inhumans．Phammcml Res，2003，48：511-513．
[173][9]Attele AS，Zhou YP。Xie JT．et al．Antidiabetie effects of Panax ginseng berrvextract and the identification of an effective component． Diabetes，2002．51：185l-1858．
[174][10]Zhang Z，Li X，Lv W，et al．Ginsenoside Re reduces insulinresistance throughinhibition of c-Jan NH2．terminal kinase and nuclear faetor-kappaB．Mol Endecrinol，2008，22：186-195．
[175][11]Wang H，Reaves LA，Edens NK．Ginseng extract inhibits lipolysis in ratadipocytes in vitro by activating phosphodiesterase．J Nutr，2006，136：337-342．
[176][12]Tan MJ，Ye JM，Tumet N，et al．Antidiabetic activities of triterpenoids isolatedfrom bitter melon associated with activation of the AMPK pathway．Chem Biol，2008，15：263-273．
[177][13]Kim EJ，Jung SN，Son KH，et al．Antidiabetes and antiobesity effect ofcryptotanshinone via activation of AMP-activated protein kinase．Mol Pharnlacol，2007，72：62-72．
[178][14]Gollg Z，Huang C，Sheng X，et al．The role of tanshinone II A in the treatmentof obesity through peroxisome proliferator-activated receptor gammaantagonism．Endocrinology，2009，150：104-113．
[179][15]Xu A，Wang H，Hoo RL，et aL．Selective elevation of adiponectin productionby the natural compounds derived from a medicinal herb alleviates insulin resistance andglucose intolerance in obese mice．Endocrinology，2009，150：625-633．
[180][16]Starke A，Grundy S，McGarry JD，et al．Correction of hyper-glycemia withphloridzin restores the ghcagon response to glucose in insulin-deficient dogs：implicationsfor human diabetes．Proc Natl Acad Sci，1985，82：1544-1546．
[181][17]Zhao H，Yakar S，Gavrilova O，et al．phloridzin improves hyperglycemia butnot hepatic insulin resistance in a transgenic mouse model of type2diabetes．Diabetes，2004．53：290l-2909．
[182][18]Stewart LK，Soileau JL，Ribnicky D，et al．Quereetin transiently increasesenergy expenditure but persistently decreases circufating markers of inflammation in C57BL／6J mice fed a high-fat diet．Metabolism，2008，57（7Suppl1）：S39-46．
[183][19]Strobel P， Allard C， Perez-Acle T， et al． Myricetin， quercetin andcatechin-gailate inhibit glucose uptake in isolmed rat adipocytes．Bioehem J，2005，386：471-478．
[184][20]Zhang CY，Parton LE．Ye CP，et al．Genipin inhibits UCP2-medlared protonleak and acutely reverses obesity-and high glucose-induced beta cell dysfunction in isolatedpancreatic islets．Cell Metab，2006，3：417-427．
[185][21]Liu D，Zhen W，Yang Z，et al．Genistein acutely stimulates insulinsecretion inpancreatic beta—ceils through a cAMP-dependent protein kinase pathway．Diabetes，2006．55：1043-1050．
[186][22]Morion MS，Arisaka0，Miyake N，et al．Phytoestrogen concentrations in serumfrom Japanese men and women over forty years of age．J Nutr．2002，132：3168-3171．
[187][23] Xu X，Harris KS，Wang HJ，et al．Bioavailability of soybean isoflavonesdepends upon gut microflom in women．J Nutr，1995，125：2307-2315．
[188][24] Xia M， Ling W， Zhu H， et al． Anthocyanin prevents CD40-activatedpminflammatory signaling in endothelial cells by regulating cholesteroldistribution．Arteriesder Thromb Vase Biol．2007，27：519-524．
[189][25] Tsuda T， Ueno Y， Aoki H， et al． Anthocyanin enhances adipocytokinesecretion and adipecyte-specific gene expression in isolated rat adipocytes． BiochemBiophys Res Commun，2004，316：149-157．
[190]廖彭莹，卢远飞，何俞勤，等.阳桃叶的化学成分预试验研究.中国医药导报.2010，7（19）:37-38.
[191] Luisa Helena Cazarolli， Poliane Folador， Henrique Hunger Moresco， et al.Mechanism of action of the stimulatory effect of apigenin-6-C-（2“-O-α-L-rhamnopyranosyl）-β-L-fucopyranoside on14C-glucose uptake.Chemico-Biological Interactions.2009，179（2）:407–412.
[192] Araho D.， Miyakoshi M.， Chou W.， et al. A new flavone C-glycoside from theleaves of Averrhoa carambola. Nat Med.2005，59（3）:113-116.
[193]黄桂红，黄仁彬.阳桃根醇提物对糖尿病小鼠血糖及脂质过氧化反应的影响.时珍国医国药.2009，20（11）:2730-2731.
[194]黄桂红，黄纯真，黄仁彬.阳桃根多糖对糖尿病小鼠胰岛素及胸、脾指数的影响.中国药师.2009，12（7）:848-850.
[195] Roseli Soncini， Michael B. Santiago， Lidiane Orlandi， et al. Hypotensive effectof aqueous extract of Averrhoa carambola L.（Oxalidaceae） in rats: An in vivo and in vitroapproach. Journal of Ethnopharmacology.2011，133（2）:353-357.
[196] C.M.L. Vasconcelos， M.S. Araújo， B.A. Silva， et al. Negative inotropic andchronotropic effects on the guinea pig atrium of extracts obtained from Averrhoa carambolaL. leaves. Brailian Journal of Medical and Biological Research.2005，（38）:1113-1122.
[197] Vuksan V，Stavre MP，Sievenpiper JL，et a1．Similar postprandial glycemicreductions with escalation of dose and administration time of American glnseng in type2diabetes．Diabetes Care。2000，23：122l-1226．
[198] Kunyan R，Rajendran R，Bantwal G，et a1． Effect of supplementation of Coceiniacordifolia extract on newly detected diabetic patients． Diabetes Care．2008，31：216-220．
[199] Ludvik B，Neuffer B，Pacini G．Efficacy of Ipomoea batatas （Caiapo） on diabetescontrol in type2diabetic subjects treated with diet．Diabetes Care．2004．27：436-440．
[2] Porta M， Sjoelie A K， Chaturvedi N， et al. Risk factors for progression to proliferativediabetic retinopathy in the EURODIAB Prospective Complications Study[J]. Diabetologia，2001，44（12）:2203-2209.
[3] Basta G， Schmidt A M， De Caterina R. Advanced glycation end products and vascularinflammation: implications for accelerated atherosclerosis in diabetes[J]. Cardiovascularresearch，2004，63（4）:582-592.
[4] Tiedge M， Lortz S， Munday R， et al. Complementary action of antioxidant enzymesin the protection of bioengineered insulin-producing RINm5F cells against the toxicity ofreactive oxygen species[J]. Diabetes，1998，47（10）:1578-1585.
[5] Tiedge M， Lortz S， Drinkgern J， et al. Relation between antioxidant enzyme geneexpression and antioxidative defense status of insulin-producing cells[J]. Diabetes，1997，46（11）:1733-1742.
[6] Paz K， Hemi R， LeRoith D， et al. A molecular basis for insulin resistance Elevatedserine/threonine phosphorylation of IRS-1and IRS-2inhibits their binding to thejuxtamembrane region of the insulin receptor and impairs their ability to undergoinsulin-induced tyrosine phosphorylation[J]. Journal of Biological Chemistry，1997，272（47）:29911-29918.
[7] Kyriakis J M， Avruch J. Protein kinase cascades activated by stress and inflammatorycytokines[J]. Bioessays，1996，18（7）:567-577.
[8] Blair A S， Hajduch E， Litherland G J， et al. Regulation of glucose transport andglycogen synthesis in L6muscle cells during oxidative stress Evidence for cross-talk betweenthe insulin and SAPK2/p38mitogen-activated protein kinase signaling pathways[J]. Journalof Biological Chemistry，1999，274（51）:36293-36299.
[9] Aguirre V， Uchida T， Yenush L， et al. The c-Jun NH2-terminal kinase promotesinsulin resistance during association with insulin receptor substrate-1and phosphorylation ofSer307[J]. Journal of Biological Chemistry，2000，275（12）:9047-9054.
[10]李秀娟，刘福英，张焕铃，等.复肝春6号对H22荷瘤小鼠的抑瘤及免疫的调节作用[J].中国老年学杂志，2006，26（1）:92-93.
[11]殷立华.了解糖尿病现状，从自身做起[J].糖尿病新世界，2012（12）:76-76.
[12]黄桂红，贺敏，林兴，等.杨桃根醇提物对糖尿病模型小鼠的降血糖作用[J].中国医院药学杂志，2009（15）:1256-1258.
[13]黄桂红，黄纯真，黄仁彬.阳桃根多糖对糖尿病小鼠胰岛素及胸，脾指数的影响[J].中国药师，2009（7）:848-850.
[14]黄桂红，黄仁彬.阳桃根醇提物对糖尿病小鼠血糖及脂质过氧化反应的影响[J].时珍国医国药，2009，20（11）:2730-2731.
[15] Cazarolli L H， Folador P， Moresco H H， et al. Mechanism of action of the stimulatoryeffect of apigenin-6-C-（2″-O-α-l-rhamnopyranosyl）-β-l-fucopyranoside on14 C-glucose uptake[J]. Chemico-biological interactions，2009，17（92）:407-412.
[16] Cazarolli L H， Folador P， Moresco H H， et al. Stimulatory effect ofapigenin-6-C-β-L-fucopyranoside on insulin secretion and glycogen synthesis[J]. Europeanjournal of medicinal chemistry，2009，44（11）:4668-4673.
[17]宋立人.中华本草（第四册）[M].北京:科学出版社，1994.
[18] Bailey C J， Day C. Traditional plant medicines as treatments for diabetes[J]. Diabetescare，1989，12（8）:553-564.
[19]张玲芝，冯磊.灵芝多糖降血糖的机理探讨[J].福建医药杂志，2004，26（3）:137-140.
[20]罗少洪，杨红.灵芝多糖调节血糖作用的实验研究[J].广东药学院学报，2000，16（2）.
[21]徐珞珊，徐国钧，金蓉鸾.中国药材学[M].北京:中国医药科技出版社，1996.
[22]魏守蓉，薛存宽，何学斌，等.绞股蓝多糖降血糖作用的实验研究[J].中国老年学杂志，2005，25（4）:418-420.
[23]张朝云，叶红英，俞茂华，等.黄芪多糖对糖尿病大鼠心肌超微结构的影响[J].复旦学报（医学科学版），2001，28（6）:476-478.
[24]左绍远，万顺康.螺旋藻多糖降血糖活性实验研究[J].时珍国医国药，2000，11（8）:677-678.
[25]季峰，魏贤勇，刘广龙，等.玉竹多糖降血糖作用的实验研究[J].江苏中医药，2006，27（9）:70-71.
[26]王兵，黄巧娟.羊栖菜多糖降血糖作用的实验研究[J].中国海洋药物，2000，19（3）:33-35.
[27]王银萍，吴家祥.大豆皂甙和人参茎叶皂甙的抗糖尿病动脉粥样硬化作用[J].白求恩医科大学学报，1994，20（6）:551-554.
[28]柴瑞华，肖春莹，赵余庆.苦瓜总皂苷降血糖作用的研究[J].中草药，2007，38（2）:248-250.
[29]孙宝莹，孙宝全，张朝.苦瓜皂甙的药效学实验研究[J].河南中医药学刊，1994，9（6）:19-19.
[30]郭洁文，廖惠芳，潘竞锵，等.荔枝核皂苷对地塞米松致胰岛素抵抗糖尿病大鼠血糖血脂的影响[J].广东药学，2004，13（5）:32-35.
[31]戚向阳，陈维军，宋云飞，等.罗汉果提取物对糖尿病小鼠的降血糖作用[J].中国公共卫生，2003，19（10）:1226-1227.
[32]郝海平，许惠琴.山茱萸环烯醚萜总苷对由链脲佐菌素诱导的糖尿病血管并发症大鼠血清sICAM—1， TNF—α的影响[J].中药药理与临床，2002，18（4）:13-14.
[33]张一波.黄连素降血糖及防治糖尿病慢性并发症的作用和机制[J].中国中医药信息杂志，2003，10（1）:83-85.
[34]陈洪源，明智强，谢佳乐，等.小檗碱降血糖机制的研究进展[J].食品与药品，2008，10（2）:69-71.
[35]李宗友.胡芦巴的抗糖尿病和降胆固醇作用[J].国外医学:中医中药分册，1999，21（4）:9-14.
[36]钟正贤，覃洁萍.广西藤茶总黄酮降血糖的实验研究[J].中国中药杂志，2002，27（9）:687-689.
[37]钟正贤，周桂芬.黄杞总黄酮的实验研究[J].时珍国医国药，2000，11（6）:495-496.
[38]高荫榆，罗丽萍，王应想，等.薯蔓黄酮降血糖作用研究[J].食品科学，2005，26（3）:218-220.
[39]韩淑英，喇万英.荞麦种子总黄酮降血脂，血糖及抗脂质过氧化作用的研究[J].中国药理学通报，2001，17（6）:694-696.
[40] Gao Q， Qin W S， Jia Z H， et al. Rhein improves renal lesion and amelioratesdyslipidemia in db/db mice with diabetic nephropathy[J]. Planta medica，2010，76（01）:27-33.
[41]温庆伟，郑妮，陈春霞，等.阳桃根中化学成分类型的试验研究[J].中药与临床，2013（2）:4.
[42]王少华，段文若，杜冠华.内分泌代谢疾病合理用药[M].人民卫生出版社，2009.
[43] Eurich D T， McAlister F A， Blackburn D F， et al. Benefits and harms of antidiabeticagents in patients with diabetes and heart failure: systematic review[J]. Bmj，2007，335（7618）:497.
[44]陈其明，史顺娣，申竹芳，等.糖尿病KK小鼠生物特性的研究[J].中国医学科学院学报，1988，6:009.
[45] Simon M， Maresh J G， Harris S E， et al. Expression of bone morphogenetic protein-7mRNA in normal and ischemic adult rat kidney[J]. American Journal of Physiology-RenalPhysiology，1999，276（3）: F382-F389.
[46]郭清华，陆菊明，潘长玉.饮食能量对Kkay及Kk小鼠2型糖尿病发病的影响[J].军医进修学院学报，2005，26（2）:140-142.
[47]周桔，彭端，李明，等.钒对遗传性Ⅱ型糖尿病KK小鼠降糖作用的实验研究[J].中国科学院研究生院学报，2008，25（2）:192-196.
[48]王芬，何华亮，江南，等.糖耐康对自发性2型糖尿病KKAy小鼠胰岛素信号转导的影响[J].中国实验方剂学杂志，2008，14（1）:46-49.
[49]厉朝龙.生物化学与分子生物学实验技术[M].浙江，浙江大学出版社，2000.
[50]许曼音，陆广华，陈名道.耱尿病学[M].上海:上海科学技术出版社，2003.
[51] Bach J F. Insulin-dependent diabetes mellitus as an autoimmune disease[J]. Endocrinereviews，1994，15（4）:516-542.
[52] Tomkin G H. Targets for intervention in dyslipidemia in diabetes[J]. Diabetes Care，2008，31（Supplement2）: S241-S248.
[53] Demain A L. A new era of exploitation of microbial metabolites[C]//Biochemical Societysymposium.1982，48:117-132.
[54] Gupta S， Kataria M， Gupta P K， et al. Protective role of extracts of neem seeds indiabetes caused by streptozotocin in rats[J]. Journal of ethnopharmacology，2004，90（2）:185-189.
[55] Molitch M E. Management of dyslipidemias in patients with diabetes and chronic kidneydisease[J]. Clinical Journal of the American Society of Nephrology，2006，1（5）:1090-1099.
[56] Shoji T， Nishizawa Y， Kawagishi T， et al. Atherogenic lipoprotein changes in theabsence of hyperlipidemia in patients with chronic renal failure treated by hemodialysis[J].Atherosclerosis，1997，131（2）:229-236.
[57] Yang W S， Kim S B， Min W K， et al. Atherogenic lipid profile and lipoprotein （a）in relation to serum albumin in haemodialysis patients[J]. Nephrology DialysisTransplantation，1995，10（9）:1668-1671.
[58] Taskinen M R. Diabetic dyslipidemia[J]. Atherosclerosis Supplements，2002，3（1）:47-51.
[59]吕小虎.浅谈糖尿病发生机制的研究[J].中国现代实用医学杂志，2008，7（7）:37-39.
[60] He Z， King G L. Microvascular complications of diabetes[J]. Endocrinology andmetabolism clinics of North America，2004，33（1）:215-238.
[61] Fuller J H， Shipley M J， Rose G， et al. Coronary-heart-disease risk and impairedglucose tolerance The Whitehall Study[J]. The Lancet，1980，315（8183）:1373-1376.
[62]迟家敏.实用糖尿病学[M].北京:人民卫生出版社，2009.
[63]张均田.现代药理实验方法[M].北京医科大学，中国协和医科大学联合出版社，1998.
[64] Fry J R. Preparation of mammalian hepatocytes[J]. Methods in enzymology，1981，77:130.
[65] Lannoy V， Decaux J， Pierreux C， et al. Liver glucokinase gene expression iscontrolled by the onecut transcription factor hepatocyte nuclear factor-6[J]. Diabetologia，2002，45（8）:1136-1141.
[66] Kershaw E E， Flier J S. Adipose tissue as an endocrine organ[J]. Journal of ClinicalEndocrinology&Metabolism，2004，89（6）:2548-2556.
[67] Sethi J K， Hotamisligil G S. The role of TNFα in adipocyte metabolism[C].Seminars incell&developmental biology. Academic Press，1999，10（1）:19-29.
[68] Onozato M L， Tojo A， Goto A， et al. Oxidative stress and nitric oxide synthase in ratdiabetic nephropathy: effects of ACEI and ARB[J]. Kidney international，2002，61（1）:186-194.
[69]舒毅，钟历勇.氧化应激与糖尿病[J].东南大学学报:医学版，2005，24（1）:64-67.
[70]包蓓艳，沈汉超.谷胱甘肽抗氧化系统在早期糖尿病肾病中的变化[J].医师进修杂志，2005，28（2）:20-22.
[71]孙忠，吴蕴棠.锌对糖尿病大鼠血脂及脂质过氧化作用的影响[J].天津医科大学学报，2001，7（2）:171-173.
[72]牟忠卿.糖尿病大鼠不同组织中氧化应激的实验研究[D].山东大学:2005.
[73] Maeda K， Okubo K， Shimomura I， et al. cDNA cloning and expression of a noveladipose specific collagen-like factor， apM1（AdiPoseMost abundant Gene transcript1）[J]. Biochemical and biophysical research communications，1996，221（2）:286-289.
[74] Hotta K， Funahashi T， Arita Y， et al. Plasma concentrations of a novel，adipose-specific protein， adiponectin， in type2diabetic patients[J]. Arteriosclerosis，thrombosis， and vascular biology，2000，20（6）:1595-1599.
[75] Charles M A， Eschwege E， Thibult N， et al. The role of non-esterified fatty acids inthe deterioration of glucose tolerance in Caucasian subjects: results of the Paris ProspectiveStudy[J]. Diabetologia，1997，40（9）:1101-1106.
[76] Randle P J， Garland P B， Hales C N， et al. The glucose fatty-acid cycle its role ininsulin sensitivity and the metabolic disturbances of diabetes mellitus[J]. The Lancet，1963，281（7285）:785-789.
[77] Boden G. Role of fatty acids in the pathogenesis of insulin resistance and NIDDM[J].Diabetes，1997，46（1）:3-10.
[78]滕香宇，杨永年.游离脂肪酸与β细胞功能[J].中华内分泌代谢杂志，1999，15（6）:363-365.
[79] Simsolo R B， Ong J M， Saffari B， et al. Effect of improved diabetes control on theexpression of lipoprotein lipase in human adipose tissue[J]. Journal of lipid research，1992，33（1）:89-95.
[80] Boden G， Chen X. Effects of fat on glucose uptake and utilization in patients withnon-insulin-dependent diabetes[J]. Journal of Clinical Investigation，1995，96（3）:1261.
[81] Ricote M， Li A C， Willson T M， et al. The peroxisome proliferator-activatedreceptor-γ is a negative regulator of macrophage activation[J]. Nature，1998，391（6662）:79-82.
[82] Hotamisligil G S. The role of TNFα and TNF receptors in obesity and insulin resistance[J].Journal of internal medicine，1999，245（6）:621-625.
[83] Mishima Y， Kuyama A， Tada A， et al. Relationship between serum tumor necrosisfactor-α and insulin resistance in obese men with type2diabetes mellitus[J]. Diabetesresearch and Clinical practice，2001，52（2）:119-123.
[84] Moller D E. Potential role of TNF-α in the pathogenesis of insulin resistance and type2diabetes[J]. Trends in Endocrinology&Metabolism，2000，11（6）:212-217.
[85] Clarke S D， Gasperikova D， Nelson C， et al. Fatty acid regulation of geneexpression[J]. Annals of the New York Academy of Sciences，2002，967（1）:283-298.
[86] Shulman G I， Rothman D L， Jue T， et al. Quantitation of muscle glycogen synthesis innormal subjects and subjects with non-insulin-dependent diabetes by13C nuclear magneticresonance spectroscopy[J]. New England Journal of Medicine，1990，322（4）:223-228.
[87] Das U N. GLUT-4， tumour necrosis factor， essential fatty acids and daf-genes and theirrole in glucose homeostasis， insulin resistance， non-insulin dependent diabetesmellitus， and longevity[J]. The Journal of the Association of Physicians of India，1999，47（4）:431-435.
[88] Folks T M， Clouse K A， Justement J， et al. Tumor necrosis factor alpha inducesexpression of human immunodeficiency virus in a chronically infected T-cell clone[J].Proceedings of the National Academy of Sciences，1989，86（7）:2365-2368.
[89] Kern P A， Saghizadeh M， Ong J M， et al. The expression of tumor necrosis factor inhuman adipose tissue. Regulation by obesity， weight loss， and relationship to lipoproteinlipase[J]. Journal of Clinical Investigation，1995，95（5）:2111.
[90] Feingold K R， Grunfeld C. Role of cytokines in inducing hyperlipidemia[J]. Diabetes，1992，41（Supplement2）:97-101.
[91] Roden M， Price T B， Perseghin G， et al. Mechanism of free fatty acid-induced insulinresistance in humans[J]. Journal of Clinical Investigation，1996，97（12）:2859.
[92] Reaven G M. Role of insulin resistance in human disease[J]. Diabetes，1988，37（12）:1595-1607.
[93] Schmitz-Peiffer C. Signalling aspects of insulin resistance in skeletal muscle: mechanismsinduced by lipid oversupply[J]. Cellular signalling，2000，12（9）:583-594.
[94] Kraegen E W， Cooney G J， Ye J M， et al. The role of lipids in the pathogenesis ofmuscle insulin resistance and beta cell failure in type II diabetes and obesity[J]. Experimentaland Clinical Endocrinology&Diabetes，2001，109（Suppl2）: S189-S201.
[95] Chen N G， Reaven G M. Fatty acid inhibition of glucose-stimulated insulin secretion isenhanced in pancreatic islets from insulin-resistant rats[J]. Metabolism，1999，48（10）:1314-1317.
[96] Fasshauer M， Klein J， Neumann S， et al. Hormonal regulation of adiponectin geneexpression in3T3-L1adipocytes[J]. Biochemical and biophysical researchcommunications，2002，290（3）:1084-1089.
[97] Ridker P M， Rifai N， Rose L， et al. Comparison of C-reactive protein and low-densitylipoprotein cholesterol levels in the prediction of first cardiovascular events[J]. New Englandjournal of medicine，2002，347（20）:1557-1565.
[98] Carey A L， Bruce C R， Sacchetti M， et al. Interleukin-6and tumor necrosis factor-αare not increased in patients with type2diabetes: evidence that plasma interleukin-6isrelated to fat mass and not insulin responsiveness[J]. Diabetologia，2004，47（6）:1029-1037.
[99] Febbraio M A， Steensberg A， Starkie R L， et al. Skeletal muscle interleukin-6andtumor necrosis factor-α release in healthy subjects and patients with type2diabetes at restand during exercise[J]. Metabolism，2003，52（7）:939-944.
[100] Nakano Y， Tobe T， Choi-Miura N H， et al. Isolation and characterization ofGBP28， a novel gelatin-binding protein purified from human plasma[J]. Journal ofBiochemistry，1996，120（4）:803-812.
[101] Scherer P E， Williams S， Fogliano M， et al. A novel serum protein similar toC1q， produced exclusively in adipocytes[J]. Journal of Biological chemistry，1995，270（45）:26746-26749.
[102] Yamamoto Y， Hirose H， Saito I， et al. Correlation of the adipocyte-derivedprotein adiponectin with insulin resistance index and serum high-densitylipoprotein-cholesterol， independent of body mass index， in the Japanese population[J].Clinical Science，2002，103（2）:137-142.
[103] Rothenbacher D， Brenner H， M rz W， et al. Adiponectin， risk of coronaryheart disease and correlations with cardiovascular risk markers[J]. European Heart Journal，2005，26（16）:1640-1646.
[104] Hotta K， Funahashi T， Bodkin N L， et al. Circulating concentrations of theadipocyte protein adiponectin are decreased in parallel with reduced insulin sensitivity duringthe progression to type2diabetes in rhesus monkeys[J]. Diabetes，2001，50（5）:1126-1133.
[105] Ruige J B， Ballaux D P， Funahashi T， et al. Resting metabolic rate is animportant predictor of serum adiponectin concentrations: potential implications forobesity-related disorders[J]. The American journal of clinical nutrition，2005，82（1）:21-25.
[106] Pilz S， Horejsi R， M ller R， et al. Early atherosclerosis in obese juveniles isassociated with low serum levels of adiponectin[J]. Journal of Clinical Endocrinology&Metabolism，2005，90（8）:4792-4796.
[107] Satoh N， Naruse M， Usui T， et al. Leptin-to-adiponectin ratio as a potentialatherogenic index in obese type2diabetic patients[J]. Diabetes care，2004，27（10）:2488-2490.
[108] Pajvani U B， Hawkins M， Combs T P， et al. Complex distribution， notabsolute amount of adiponectin， correlates with thiazolidinedione-mediated improvementin insulin sensitivity[J]. Journal of Biological Chemistry，2004，279（13）:12152-12162.
[109] Baribault H. Mouse models of type II diabetes mellitus in drug discovery[M]//MouseModels for Drug Discovery. Humana Press，2010:135-155.
[110]郝金成，穆振国，郭见光.晚期糖基化终末产物与糖尿病慢性并发症的关系[J].中国民康医学，2006，18（7）:594-595.
[111]郑永强，薛玲，李晓军，等.荞麦黄酮复方制剂对糖尿病大鼠肾损伤的抑制作用[J].时珍国医国药，2012，23（6）:1441-1444.
[112] Nakayama H， Mitsuhashi T， Kuwajima S， et al. Immunochemical detection ofadvanced glycation end products in lens crystallins from streptozocin-induced diabetic rat[J].Diabetes，1993，42（2）:345-350.
[113]庞玉萍.大鼠糖尿病肾脏病理改变以及罗格列酮对其病理改善的研究[D].浙江大学，2008.
[114] Sheetz M J， King G L. Molecular understanding of hyperglycemia's adverse effectsfor diabetic complications[J]. Jama，2002，288（20）:2579-2588.
[115] Hovind P， Rossing P， Tarnow L， et al. Progression of diabetic nephropathy[J].Kidney international，2001，59（2）:702-709.
[116] Parving H H， Lehnert H， Br chner-Mortensen J， et al. The effect of irbesartan onthe development of diabetic nephropathy in patients with type2diabetes[J]. New EnglandJournal of Medicine，2001，345（12）:870-878.
[117] Lea J， Greene T， Hebert L， et al. The relationship between magnitude ofproteinuria reduction and risk of end-stage renal disease: results of the African Americanstudy of kidney disease and hypertension[J]. Archives of Internal Medicine，2005，165（8）:947-953.
[118] Bohlender J M， Franke S， Stein G， et al. Advanced glycation end products andthe kidney[J]. American Journal of Physiology-Renal Physiology，2005，289（4）:F645-F659.
[119] Jiang T， Huang Z， Lin Y， et al. The protective role of Nrf2instreptozotocin-induced diabetic nephropathy[J]. Diabetes，2010，59（4）:850-860.
[120] Koya D， Hayashi K， Kitada M， et al. Effects of antioxidants in diabetes-inducedoxidative stress in the glomeruli of diabetic rats[J]. Journal of the American Society ofNephrology，2003，14（suppl3）: S250-S253.
[121] Prabhakar S， Starnes J， Shi S， et al. Diabetic nephropathy is associated withoxidative stress and decreased renal nitric oxide production[J]. Journal of the AmericanSociety of Nephrology，2007，18（11）:2945-2952.
[122] K dziora-Kornatowska K， Szram S， Kornatowski T， et al. The effect ofverapamil on the antioxidant defence system in diabetic kidney[J]. Clinica chimica acta，2002，322（1）:105-112.
[123] Reeves W B， Andreoli T E. Transforming growth factor β contributes to progressivediabetic nephropathy[J]. Proceedings of the National Academy of Sciences，2000，97（14）:7667-7669.
[124] Forbes J M， Fukami K， Cooper M E. Diabetic nephropathy: where hemodynamicsmeets metabolism[J]. Experimental and Clinical Endocrinology and Diabetes，2007，115（2）:69-84.
[125] Kanwar Y S， Wada J， Sun L， et al. Diabetic nephropathy: mechanisms of renaldisease progression[J]. Experimental Biology and Medicine，2008，233（1）:4-11.
[126] Daroux M， Prévost G， Maillard-Lefebvre H， et al. Advanced glycationend-products: implications for diabetic and non-diabetic nephropathies[J]. Diabetes&metabolism，2010，36（1）:1-10.
[127] Schleicher E D， Wagner E， Nerlich A G. Increased accumulation of theglycoxidation product N （epsilon）-（carboxymethyl） lysine in human tissues in diabetesand aging[J]. Journal of Clinical Investigation，1997，99（3）:457.
[128] Thomas M C， Forbes J M， Cooper M E. Advanced glycation end products anddiabetic nephropathy[J]. American journal of therapeutics，2005，12（6）:562-572.
[129] Yan S D， Schmidt A M， Anderson G M， et al. Enhanced cellular oxidant stressby the interaction of advanced glycation end products with their receptors/binding proteins[J].Journal of Biological Chemistry，1994，269（13）:9889-9897.
[130] Li J， Schmidt A M. Characterization and functional analysis of the promoter ofRAGE， the receptor for advanced glycation end products[J]. Journal of BiologicalChemistry，1997，272（26）:16498-16506.
[131] Wautier J L， Guillausseau P J. Advanced glycation end products， their receptorsand diabetic angiopathy[J].2008.
[132] Chappey O， Dosquet C， WAUTIER M P， et al. Advanced glycation endproducts， oxidant stress and vascular lesions[J]. European journal of clinicalinvestigation，1997，27（2）:97-108.
[133] Fu M X， Requena J R， Jenkins A J， et al. The advanced glycation end product，N-（carboxymethyl） lysine， is a product of both lipid peroxidation and glycoxidationreactions[J]. Journal of Biological Chemistry，1996，271（17）:9982-9986.
[134]倪海霞9任卫东.2型糖尿病患者治疗的效果观察与社区强化管理[J]。陕西医学杂志，2010，39（4）；504-505.
[135]王先远，金宏.苦瓜皂甙对衰老小鼠免疫功能的影响[J].营养学报，2001，23（3）:263-266.
[136] Hayase M， Ogawa Y， Katsuura G， et al. Regulation of obese gene expression inKK mice and congenic lethal yellow obese KKAy mice[J]. American Journal ofPhysiology-Endocrinology and Metabolism，1996，271（2）: E333-E339.
[137] Attie A D， Flowers M T， Flowers J B， et al. Stearoyl‐CoA DesaturaseDeficiency， Hypercholesterolemia， Cholestasis， and Diabetes[J]. Nutrition reviews，2007，65（s1）: S35-S38.
[138] Shaw JE，Sicree RA，Zimmet PZ．Global estimates of the preva-lenee of diabetesfor2010and2030[J1．Diabetes Res Clin Pract．2010，87（1）：4-14．
[139]邓尚平.糖尿病防治知识讲座[M].四川：四川科学技术出版社，2007.
[140]文世林.糖尿病流行的全球趋势和国内现状[J].河南诊断与治疗杂志，2002，16（1）:14-17.
[141] Yang W， Lu J， Weng J， et al. Prevalence of diabetes among men and women inChina[J]. New England Journal of Medicine，2010，362（12）:1090-1101.
[142]江济华，臧桐华.糖尿病及并发症与疾病负担[J].疾病控制杂志，2000，4（3）:259-262.
[143] Cryer P E. We are what we repeatedly do[J]. Diabetes，1998，47（2）:155-158.
[144] Olsson J， Persson U， Tollin C， et al. Comparison of excess costs of care andproduction losses because of morbidity in diabetic patients[J]. Diabetes Care，1994，17（11）:1257-1263.
[145] Neville S E， Boye K S， Montgomery W S， et al. Diabetes in Japan: a review ofdisease burden and approaches to treatment[J]. Diabetes/metabolism research and reviews，2009，25（8）:705-716.
[146] Kirigia J M， Sambo H B， Sambo L G， et al. Economic burden of diabetesmellitus in the WHO African region[J]. BMC international health and human rights，2009，9（1）:6.
[147]胡善联，刘国恩，许樟荣，等.我国糖尿病流行病学和疾病经济负担研究现状[J].中国卫生经济，2008，27（8）:5-8.
[148] Rovner A J， Nansel T R. Are children with type1diabetes consuming a healthfuldiet， A review of the current evidence and strategies for dietary change[J]. The DiabetesEducator，2009，35（1）:97-107.
[149] Ventura E E， Lane C J， Weigensberg M J， et al. Persistence of the metabolicsyndrome over3annual visits in overweight Hispanic children: association with progressiverisk for type2diabetes[J]. The Journal of pediatrics，2009，155（4）:535-541. e1.
[150] Rovner A J， Nansel T R， Gellar L. The effect of a low-glycemic diet vs a standarddiet on blood glucose levels and macronutrient intake in children with type1diabetes[J].Journal of the American Dietetic Association，2009，109（2）:303-307.
[151]付萍，满青青，张坚，等.中国5~17岁儿童青少年糖尿病流行情况分析[J].卫生研究，2008，36（6）:722-724.
[152]王立群.糖尿病低龄化成因分析及护理对策[J].航空航天医学杂志，2011，22（8）:1000-1002.
[153]许顺江，闫宝勇.儿童和青少年糖尿病患者的心理健康与护理[J].河北医药，2009，31（23）:72-73.
[154]马学毅.现代糖尿病诊断治疗学[M]，北京：人民军医出版社，2007.
[155]杨明功.糖尿病流行现状及防治对策[J].疾病控制杂志，2000，4（3）:193-196.
[156] Lind M， Garcia-Rodriguez L A， Booth G L， et al. Mortality trends in patientswith and without diabetes in Ontario， Canada and the UK from1996to2009: apopulation-based study[J]. Diabetologia，2013，56（12）:2601-2608.
[157] Zhang Y， Sun J， Pang Z， et al. Evaluation of two screening methods forundiagnosed diabetes in China: An cost-effectiveness study[J]. Primary care diabetes，2013，7（4）:275-282.
[158] Al-Qazaz H K， Hassali M A， Shafie A A， et al. The eight-item MoriskyMedication Adherence Scale MMAS: translation and validation of the Malaysian version[J].Diabetes research and clinical practice，2010，90（2）:216-221.
[159] Gu W， Huang Y， Zhang Y， et al. Adolescents and young adults with newlydiagnosed Type2diabetes demonstrate greater carotid intima‐media thickness than thosewith Type1diabetes[J]. Diabetic Medicine，2014，31（1）:84-91.
[160]向志雄，黄诚，彭新君，等.中药治疗糖尿病及其并发症研究进展[J].中西医结合学报，2006，4（3）：321-325.
[161] Park MY，LeeKS，SungMK.Effects of dietary mulberry，Korean red ginseng，andbanaba on glucose homeostasis in relationto PPAR-alpha，PPAR-gamma，and LPL mRNAexpressions[J]. LifeSci，2005，77（26）:3344-3354.
[162] Lee H，Gonzalez FJ，Yoon M.Ginsenoside Rf，a component of ginseng， regulateslipoprotein metabolism through peroxisome proliferator-activated receptor alpha[J]. BiochemBiophys Res Commun，2006，339（1）:196-203.
[163] Hou Z，Zhang Z，Wu H. Effect of Sanguis draxonis （a Chinese traditional herb）on the formation of insulin resistance in rats[J]. Diabetes Res Clin Pract，2005，68（1）:3-11.
[164] Xu ME，Xiao SZ，Sun YH，et al. The study of anti-metabolic syndrome effect ofpuerarin in vitro[J]. Life Sci，2005，77（25）:3183-3196.
[165] Ko BS，Choi SB，Park SK，et al. Insulin sensitizing and insulinotropic action ofberberine from Cortidis rhizoma[J].Biol Pharm Bull，2005，28（8）:1431-1437.
[166][2]Turner N，Li JY，Gosby A，et al．Berberine and its more biologically availablederivative，dihydroberberine，inhibit mitochondrial respiratory complex I：a mechanismfor the action of berberine to activate AMP—activated protein kinase and improve insulinaction．Diabetes．2008，57：1414-1418．
[167][3]Zhang Y，Li X，Zou D，et al．Treatment of type2diabetes and dyslipidemia withthe natural plant alkaloid berberine．J Clin Endocrinol Metab，2008，93：2559-2565．
[168][4]Kong W，Wei J，Abidi P，et al．Berberine is a liovel cholesterollowering dragworking through a unique mechanism distinct from statins． Nat Med，2004，10：1344-1351．
[169][5]Lu ss。Yu YL，Zhu ILl，et al．Berberine promotes ghcagon-like peptide-l（7-36）amide secretion in streptozotocin-induced diabetic rats． J Endocrinol，2009，200：159-165．
[170][6]Zhou L，Wang X，Shao L，et al．Berberine acutely inhibits insuhnsecretion frombeta． cells thmush3’，5’． cyclic adcnosine5’-monophosphate signalingpathway．Endocrinology，2008，149：4510-4518．
[171][7]Sotaniemi EA． Haapakeski E． Rantio A． Ginseng therapy innon-insulin-dependent diabetic patients．Diabetes Care，1995，18：1373-1375．
[172][8]Kim SH，Park KS．Effects of Panax ginseng extract on lipid metabolism inhumans．Phammcml Res，2003，48：511-513．
[173][9]Attele AS，Zhou YP。Xie JT．et al．Antidiabetie effects of Panax ginseng berrvextract and the identification of an effective component． Diabetes，2002．51：185l-1858．
[174][10]Zhang Z，Li X，Lv W，et al．Ginsenoside Re reduces insulinresistance throughinhibition of c-Jan NH2．terminal kinase and nuclear faetor-kappaB．Mol Endecrinol，2008，22：186-195．
[175][11]Wang H，Reaves LA，Edens NK．Ginseng extract inhibits lipolysis in ratadipocytes in vitro by activating phosphodiesterase．J Nutr，2006，136：337-342．
[176][12]Tan MJ，Ye JM，Tumet N，et al．Antidiabetic activities of triterpenoids isolatedfrom bitter melon associated with activation of the AMPK pathway．Chem Biol，2008，15：263-273．
[177][13]Kim EJ，Jung SN，Son KH，et al．Antidiabetes and antiobesity effect ofcryptotanshinone via activation of AMP-activated protein kinase．Mol Pharnlacol，2007，72：62-72．
[178][14]Gollg Z，Huang C，Sheng X，et al．The role of tanshinone II A in the treatmentof obesity through peroxisome proliferator-activated receptor gammaantagonism．Endocrinology，2009，150：104-113．
[179][15]Xu A，Wang H，Hoo RL，et aL．Selective elevation of adiponectin productionby the natural compounds derived from a medicinal herb alleviates insulin resistance andglucose intolerance in obese mice．Endocrinology，2009，150：625-633．
[180][16]Starke A，Grundy S，McGarry JD，et al．Correction of hyper-glycemia withphloridzin restores the ghcagon response to glucose in insulin-deficient dogs：implicationsfor human diabetes．Proc Natl Acad Sci，1985，82：1544-1546．
[181][17]Zhao H，Yakar S，Gavrilova O，et al．phloridzin improves hyperglycemia butnot hepatic insulin resistance in a transgenic mouse model of type2diabetes．Diabetes，2004．53：290l-2909．
[182][18]Stewart LK，Soileau JL，Ribnicky D，et al．Quereetin transiently increasesenergy expenditure but persistently decreases circufating markers of inflammation in C57BL／6J mice fed a high-fat diet．Metabolism，2008，57（7Suppl1）：S39-46．
[183][19]Strobel P， Allard C， Perez-Acle T， et al． Myricetin， quercetin andcatechin-gailate inhibit glucose uptake in isolmed rat adipocytes．Bioehem J，2005，386：471-478．
[184][20]Zhang CY，Parton LE．Ye CP，et al．Genipin inhibits UCP2-medlared protonleak and acutely reverses obesity-and high glucose-induced beta cell dysfunction in isolatedpancreatic islets．Cell Metab，2006，3：417-427．
[185][21]Liu D，Zhen W，Yang Z，et al．Genistein acutely stimulates insulinsecretion inpancreatic beta—ceils through a cAMP-dependent protein kinase pathway．Diabetes，2006．55：1043-1050．
[186][22]Morion MS，Arisaka0，Miyake N，et al．Phytoestrogen concentrations in serumfrom Japanese men and women over forty years of age．J Nutr．2002，132：3168-3171．
[187][23] Xu X，Harris KS，Wang HJ，et al．Bioavailability of soybean isoflavonesdepends upon gut microflom in women．J Nutr，1995，125：2307-2315．
[188][24] Xia M， Ling W， Zhu H， et al． Anthocyanin prevents CD40-activatedpminflammatory signaling in endothelial cells by regulating cholesteroldistribution．Arteriesder Thromb Vase Biol．2007，27：519-524．
[189][25] Tsuda T， Ueno Y， Aoki H， et al． Anthocyanin enhances adipocytokinesecretion and adipecyte-specific gene expression in isolated rat adipocytes． BiochemBiophys Res Commun，2004，316：149-157．
[190]廖彭莹，卢远飞，何俞勤，等.阳桃叶的化学成分预试验研究.中国医药导报.2010，7（19）:37-38.
[191] Luisa Helena Cazarolli， Poliane Folador， Henrique Hunger Moresco， et al.Mechanism of action of the stimulatory effect of apigenin-6-C-（2“-O-α-L-rhamnopyranosyl）-β-L-fucopyranoside on14C-glucose uptake.Chemico-Biological Interactions.2009，179（2）:407–412.
[192] Araho D.， Miyakoshi M.， Chou W.， et al. A new flavone C-glycoside from theleaves of Averrhoa carambola. Nat Med.2005，59（3）:113-116.
[193]黄桂红，黄仁彬.阳桃根醇提物对糖尿病小鼠血糖及脂质过氧化反应的影响.时珍国医国药.2009，20（11）:2730-2731.
[194]黄桂红，黄纯真，黄仁彬.阳桃根多糖对糖尿病小鼠胰岛素及胸、脾指数的影响.中国药师.2009，12（7）:848-850.
[195] Roseli Soncini， Michael B. Santiago， Lidiane Orlandi， et al. Hypotensive effectof aqueous extract of Averrhoa carambola L.（Oxalidaceae） in rats: An in vivo and in vitroapproach. Journal of Ethnopharmacology.2011，133（2）:353-357.
[196] C.M.L. Vasconcelos， M.S. Araújo， B.A. Silva， et al. Negative inotropic andchronotropic effects on the guinea pig atrium of extracts obtained from Averrhoa carambolaL. leaves. Brailian Journal of Medical and Biological Research.2005，（38）:1113-1122.
[197] Vuksan V，Stavre MP，Sievenpiper JL，et a1．Similar postprandial glycemicreductions with escalation of dose and administration time of American glnseng in type2diabetes．Diabetes Care。2000，23：122l-1226．
[198] Kunyan R，Rajendran R，Bantwal G，et a1． Effect of supplementation of Coceiniacordifolia extract on newly detected diabetic patients． Diabetes Care．2008，31：216-220．
[199] Ludvik B，Neuffer B，Pacini G．Efficacy of Ipomoea batatas （Caiapo） on diabetescontrol in type2diabetic subjects treated with diet．Diabetes Care．2004．27：436-440．