熊果酸对胰岛素抵抗大鼠糖、脂代谢及肝脏葡萄糖激酶的影响
|
摘要
第一部分高脂饲料诱导胰岛素抵抗大鼠模型的建立
目的：建立高脂饲料诱导的胰岛素抵抗大鼠模型。
方法：雄性Wistar大鼠60只,8周龄,体重180-200g。将大鼠随机分为正常对照组12只,喂以普通饲料；高脂饮食组48只,喂以高脂饲料。实验中称取体重,检测血脂(TC、TG、HDL-c、LDL-c)和血糖,采用葡萄糖耐量试验、胰岛素耐量试验判断大鼠糖代谢情况；酶联免疫吸附法测定血清胰岛素含量,计算胰岛素敏感指数和胰岛素抵抗指数评价胰岛素敏感性。
结果：高脂饮食组体重、TC、TG和LDL-c水平均明显高于正常饮食组(P<0.01),HDL-c、空腹血糖与正常饮食组比较无明显差异(P>0.05)；葡萄糖耐量试验和胰岛素耐量试验中,高脂饮食组负荷后血糖值和葡萄糖曲线下面积均高于正常饮食组(P<0.05或P<0.01)；同时该组空腹血清胰岛素、胰岛素抵抗指数均高于正常饮食组(P<0.05或P<0.01),胰岛素敏感指数低于正常饮食组(P<0.05)。
结论：通过高脂饲料喂养可成功建立胰岛素抵抗大鼠模型,该模型与人类肥胖所致胰岛素抵抗表现相似,适用于胰岛素抵抗的研究。
第二部分熊果酸对胰岛素抵抗大鼠糖、脂代谢及肝脏葡萄糖激酶的影响
目的：观察熊果酸对胰岛素抵抗大鼠糖、脂代谢及肝脏葡萄糖激酶的影响。
方法：高脂饮食组48只大鼠随机分为模型对照组(PBS溶液灌胃)、二甲双胍组(二甲双胍200mg/kg·d灌胃)、熊果酸高剂量组(熊果酸300mg／kg.d灌胃)、熊果酸低剂量组(150mg／kg.d灌胃),每组12只,均继续喂以高脂饲料。正常对照组12只继续喂以普通饲料并用PBS溶液灌胃。实验中称取体重,用药第4周及第8周检测血脂(TC、TG、HDL-c、LDL-c)和血糖；采用葡萄糖耐量试验、胰岛素耐量试验判断大鼠糖代谢情况；蒽酮法检测肝糖原含量；酶联免疫吸附法测定血清胰岛素含量,计算胰岛素敏感指数和胰岛素抵抗指数评价胰岛素敏感性；HE染色观察肝脏病理变化；酶联免疫吸附法测定葡萄糖激酶含量,实时荧光定量PCR法检测葡萄糖激酶mRNA表达,免疫组化法检测葡萄糖激酶蛋白表达。
结果：各用药组大鼠体重、TC、TG、LDL-c、负荷后血糖值、葡萄糖曲线下面积、空腹血清胰岛素、胰岛素抵抗指数均低于模型对照组(P<0.05或P<0.01),同时各用药组胰岛素敏感指数及肝糖原含量高于模型对照组(P<0.05或P<0.01)。各用药组部分肝脏接近正常,模型对照组肝脏脂肪变明显。各用药组葡萄糖激酶含量、蛋白表达及mRNA表达高于模型对照组(P<0.05或P<0.01)。
结论：熊果酸通过降低体重,改善糖、脂代谢,增加肝糖原、葡萄糖激酶含量及葡萄糖激酶mRNA及蛋白表达改善胰岛素抵抗。
Part I Rats of Insulin Resistance Model Induced by High-Fat-Fed
Objective:To establish insulin resistance rats model induced by high-fat-fed.
Methods:60 male Wistar rats, eight-week-old, body weight 180-200g, were randomly divided into two groups:normal control group (n=12) and high-fat diet group (n=48). Normal diet group rats were fed with basic feed and high-fat diet group rats were fed with high-fat feed. Before and in the experiment, the body weight, fasting blood glucose and serum TC, TG, HDL-L and LDL-L levels were measured; the regulatory function of glucose metabolism determined by the glucose tolerance test and insulin tolerance test; serum insulin levels determined by enzyme-linked immuno-sorbent assay; insulin sensitivity evaluated by the insulin sensitivity index and insulin resistance index.
Results:Compared with the normal diet group rats, the weight of high-fat diet group was improved obviously (P<0.01), the fasting blood glucose and HDL-c were no significant difference; the tolerance of glucose and insulin were impaired, the blood glucose levels after glucose load and glucose area under the curve were significantly higher than the normal diet group(P＜0.05 or P<0.01). Fasting serum insulin, insulin resistance index were significantly higher than the normal diet group (P＜0.05 or P＜0.01), and insulin sensitivity index was lower than the normal diet group (P<0.05).
Conclusion:Insulin resistance obesity rats model can be successfully established by 9-week high-fat diet feeding. The model's characteristics is similar to human insulin resistance caused by obesity and we think it is a economic and practical animal model for the study of obesity and insulin resistance.
Part II Effects of Ursolic Acid on Glucose, Lipid Metabolism and Glucokinase in
Insulin Resistance Rats
Objective:To observe the effects of ursolic acid on glucose, lipid metabolism and liver's glucokinase in insulin resistance rats.
Methods:High-fat diet group (n=48) was randomly divided into four groups:model group (intragastric administration with PBS solution), metformin group (intragastric administration with metformin,200mg/kg-d), ursolic acid high-dose group (ursolic intragastric administration with ursolic acid,300mg/kg·d), and ursolic acid low-dose group (ursolic intragastric administration with ursolic acid,150mg/kg-d), each group was 12, and were fed with high-fat diet. Normal control group (intragastric administration with PBS solution), were fed with normal diet. At point 4 weeks and point 8 weeks after administration of each group, to observe the changes of weight, fasting blood glucose, fasting serum insulin, blood lipids, body weight, glucose tolerance, insulin tolerance, liver glycogen content and glucokinase; to calculate insulin sensitivity index and insulin resistance index; to observe the liver tissue pathological changes by light microscopy (HE staining); using enzyme-linked immuno-sorbent assay determined the content of glucokinase, RT-PCR assess the expression of glucokinase mRNA, Western Blot assess the expression of protein of glucokinase.
Results:Ursolic acid and metformin treatment can lower body weight, and reduce TC, TG, LDL-C, workload glucose, glucose area under the curve, serum FINS, insulin resistance index in insulin resistance rats (P<0.05 or P<0.01), also they can increase insulin sensitivity index and content of glycogen (P<0.05 or P<0.01).The livers of drug groups partly close to normal, and model control group's livers obviously changed to fatty.
Conclusion:Ursolic acid can reduce body weight, regulate glucose and lipid metabolism, increase the content of glycogen, glucokinase, the expression of glucokinase protein and mRNA to improve insulin resistance.
目的：建立高脂饲料诱导的胰岛素抵抗大鼠模型。
方法：雄性Wistar大鼠60只,8周龄,体重180-200g。将大鼠随机分为正常对照组12只,喂以普通饲料；高脂饮食组48只,喂以高脂饲料。实验中称取体重,检测血脂(TC、TG、HDL-c、LDL-c)和血糖,采用葡萄糖耐量试验、胰岛素耐量试验判断大鼠糖代谢情况；酶联免疫吸附法测定血清胰岛素含量,计算胰岛素敏感指数和胰岛素抵抗指数评价胰岛素敏感性。
结果：高脂饮食组体重、TC、TG和LDL-c水平均明显高于正常饮食组(P<0.01),HDL-c、空腹血糖与正常饮食组比较无明显差异(P>0.05)；葡萄糖耐量试验和胰岛素耐量试验中,高脂饮食组负荷后血糖值和葡萄糖曲线下面积均高于正常饮食组(P<0.05或P<0.01)；同时该组空腹血清胰岛素、胰岛素抵抗指数均高于正常饮食组(P<0.05或P<0.01),胰岛素敏感指数低于正常饮食组(P<0.05)。
结论：通过高脂饲料喂养可成功建立胰岛素抵抗大鼠模型,该模型与人类肥胖所致胰岛素抵抗表现相似,适用于胰岛素抵抗的研究。
第二部分熊果酸对胰岛素抵抗大鼠糖、脂代谢及肝脏葡萄糖激酶的影响
目的：观察熊果酸对胰岛素抵抗大鼠糖、脂代谢及肝脏葡萄糖激酶的影响。
方法：高脂饮食组48只大鼠随机分为模型对照组(PBS溶液灌胃)、二甲双胍组(二甲双胍200mg/kg·d灌胃)、熊果酸高剂量组(熊果酸300mg／kg.d灌胃)、熊果酸低剂量组(150mg／kg.d灌胃),每组12只,均继续喂以高脂饲料。正常对照组12只继续喂以普通饲料并用PBS溶液灌胃。实验中称取体重,用药第4周及第8周检测血脂(TC、TG、HDL-c、LDL-c)和血糖；采用葡萄糖耐量试验、胰岛素耐量试验判断大鼠糖代谢情况；蒽酮法检测肝糖原含量；酶联免疫吸附法测定血清胰岛素含量,计算胰岛素敏感指数和胰岛素抵抗指数评价胰岛素敏感性；HE染色观察肝脏病理变化；酶联免疫吸附法测定葡萄糖激酶含量,实时荧光定量PCR法检测葡萄糖激酶mRNA表达,免疫组化法检测葡萄糖激酶蛋白表达。
结果：各用药组大鼠体重、TC、TG、LDL-c、负荷后血糖值、葡萄糖曲线下面积、空腹血清胰岛素、胰岛素抵抗指数均低于模型对照组(P<0.05或P<0.01),同时各用药组胰岛素敏感指数及肝糖原含量高于模型对照组(P<0.05或P<0.01)。各用药组部分肝脏接近正常,模型对照组肝脏脂肪变明显。各用药组葡萄糖激酶含量、蛋白表达及mRNA表达高于模型对照组(P<0.05或P<0.01)。
结论：熊果酸通过降低体重,改善糖、脂代谢,增加肝糖原、葡萄糖激酶含量及葡萄糖激酶mRNA及蛋白表达改善胰岛素抵抗。
Part I Rats of Insulin Resistance Model Induced by High-Fat-Fed
Objective:To establish insulin resistance rats model induced by high-fat-fed.
Methods:60 male Wistar rats, eight-week-old, body weight 180-200g, were randomly divided into two groups:normal control group (n=12) and high-fat diet group (n=48). Normal diet group rats were fed with basic feed and high-fat diet group rats were fed with high-fat feed. Before and in the experiment, the body weight, fasting blood glucose and serum TC, TG, HDL-L and LDL-L levels were measured; the regulatory function of glucose metabolism determined by the glucose tolerance test and insulin tolerance test; serum insulin levels determined by enzyme-linked immuno-sorbent assay; insulin sensitivity evaluated by the insulin sensitivity index and insulin resistance index.
Results:Compared with the normal diet group rats, the weight of high-fat diet group was improved obviously (P<0.01), the fasting blood glucose and HDL-c were no significant difference; the tolerance of glucose and insulin were impaired, the blood glucose levels after glucose load and glucose area under the curve were significantly higher than the normal diet group(P＜0.05 or P<0.01). Fasting serum insulin, insulin resistance index were significantly higher than the normal diet group (P＜0.05 or P＜0.01), and insulin sensitivity index was lower than the normal diet group (P<0.05).
Conclusion:Insulin resistance obesity rats model can be successfully established by 9-week high-fat diet feeding. The model's characteristics is similar to human insulin resistance caused by obesity and we think it is a economic and practical animal model for the study of obesity and insulin resistance.
Part II Effects of Ursolic Acid on Glucose, Lipid Metabolism and Glucokinase in
Insulin Resistance Rats
Objective:To observe the effects of ursolic acid on glucose, lipid metabolism and liver's glucokinase in insulin resistance rats.
Methods:High-fat diet group (n=48) was randomly divided into four groups:model group (intragastric administration with PBS solution), metformin group (intragastric administration with metformin,200mg/kg-d), ursolic acid high-dose group (ursolic intragastric administration with ursolic acid,300mg/kg·d), and ursolic acid low-dose group (ursolic intragastric administration with ursolic acid,150mg/kg-d), each group was 12, and were fed with high-fat diet. Normal control group (intragastric administration with PBS solution), were fed with normal diet. At point 4 weeks and point 8 weeks after administration of each group, to observe the changes of weight, fasting blood glucose, fasting serum insulin, blood lipids, body weight, glucose tolerance, insulin tolerance, liver glycogen content and glucokinase; to calculate insulin sensitivity index and insulin resistance index; to observe the liver tissue pathological changes by light microscopy (HE staining); using enzyme-linked immuno-sorbent assay determined the content of glucokinase, RT-PCR assess the expression of glucokinase mRNA, Western Blot assess the expression of protein of glucokinase.
Results:Ursolic acid and metformin treatment can lower body weight, and reduce TC, TG, LDL-C, workload glucose, glucose area under the curve, serum FINS, insulin resistance index in insulin resistance rats (P<0.05 or P<0.01), also they can increase insulin sensitivity index and content of glycogen (P<0.05 or P<0.01).The livers of drug groups partly close to normal, and model control group's livers obviously changed to fatty.
Conclusion:Ursolic acid can reduce body weight, regulate glucose and lipid metabolism, increase the content of glycogen, glucokinase, the expression of glucokinase protein and mRNA to improve insulin resistance.
引文
[1]Stern MP.Diabetes and cardiovascular disease:the Common soil hypothesis.Diabetes,1995,44(4): 369-374
[2]Reaven GM.Banting lecture 1988:Role of insulin resistance in human disease.Diabetes,1997,13(1): 64
[3]Schrauwen P,Hesselink M.K.C.Oxidative capacity,lipotoxicity,and mitochondrial damage in type 2 diabets.Diabets.2002,53(6):1412-1417
[4]李秀钧.胰岛素抵抗及胰岛素抵抗综合征研究展望.中华内分泌代谢杂志,2000,16(5)：274-276
[5]于晓静,王晓梅,冯海娟.2型糖尿病合并脂肪肝危险因素临床分析.世界华人消化杂志,2006,14(30)：2977-2979
[6]Basu A,Shah P,Nielsen M,Basu R,Rizza RA.Effects of type 2 diabetes on the regulation of hepatic glucose metabolism.J Investig Med,2004,52:366-374
[7]祝炼,袁莉.胰岛素信号转导与肝胰岛素抵抗.世界华人消化杂志,2004,12(10)：2420-2423
[8]李慧颖,崔广智,张岩.2型糖尿病胰岛素信号转导途径.长春中医药大学学报,2008,24(3)：325-326
[9]王洪涛,王韫秀,宋永喜.胰岛素信号转导障碍与糖尿病的关系.实用糖尿病杂志,2007,3(1)：57-59
[10]胡淑国,宋光耀,高宇,王敬,曲东明.罗格列酮对老年胰岛素抵抗大鼠肝脏脂肪酸代谢及胰岛素敏感性的影响.中国老年学杂志,2009,29(3)：304-306
[11]吴涛,季光.非酒精性脂肪性肝病的代谢发病机制.世界华人消化杂志,2009,17(28)：2908-2914
[12]周亚兵,朱德增,罗若茵,赵莉.酸味中药复方对2型糖尿病大鼠糖代谢的调节作用.成都中医药大学学报,2004,27(1)：13-16
[13]周亚兵,罗若茵,赵莉,朱德增.酸味中药复方对实验性2型糖尿病大鼠胰岛素抵抗的影响.中国中西医结合杂志,2005,25(5)：441-444
[14]曹玉莉,殷桂香,朱德增.酸味中药复方对2型糖尿病大鼠ET-1、NO及肾脏ICAM-1基因表达的影响.中国中西医结合肾病杂志,2009,5：400-403
[15]全山丛,邬旻,朱德增,原永芳,王忠壮.酸克糖颗粒的质量标准研究.药学服务与研究,2004；4(11)：36-38
[16]李晨钟,张素华,舒昌达.胰岛素抵抗的动物模型.国外医学：内分泌学分册,1998,18(3)：144-147
[17]李光伟,潘孝仁,Stephen Lillioja,Peter H.Bennett检测人群胰岛素敏感性的一项新指数.中华内科杂志,1993,32(10)：656-660
[18]刘永玉,毛良,莫启忠,方军.实验性NIDDM大鼠的胰岛素抵抗性.中国病理生理杂志,1991,7(4)：422-425
[19]Storlen LH,Pan DA,Kusunoki M,Cooney GJ.Effects of Benfluorex on in vivo patterns of insulin resistence induced by dite rich in fat or fructose.Diabetes Metab Rev,1993,9(Suppl 1):65S-72S
[20]De Fronzo RA,Tobin JD,Anadres R.Glucose clamp technique:a method for quantifying insulin secretion and resistance.Am J Physiol,1979,237:E214-E332
[21]Storlen LH,James DE,Burleighy KM,Chisholm DJ,Kraegen EW.Fat feeding causes widespread in vivo insulin resistance,decreased energy expenditure,and obesity in rats.Am J Physiol Endocrinol Metab,1986,251:E576-E583
[22]Oakes ND,Kennedy CJ,Jeninks AB,Laybutt DRmChisholm J,Kraegen EW.A new antidiabetic agent,BRL49653,reduces lipid availbility and improves insulin action and glucoregulation in the rats.Diabetes,1994,43(10):1203-1210
[23]Cederholm J,W ibell L.Insulin release and peripheral sensitivity at the oral glucose tolerance tes.Diabetes Res Clin Pract,1990;10:167-175
[22]李光伟.胰岛β细胞功能评估.国外医学内分泌学分册,2001,21：225-227
[23]Turner RC,HolmanRR,Matthews D,Hockaday TDR,Peto J.Insulin deficiency and insulin resistance interaction in diabetes,estimation of their relative contribution by feedback analysis from basal plasma insulin and glucose concentrations.Metabolism,1979,28(11):1086-1096
[24]Matthews DR,Hosker JP,Rudenski AS,Naylor BA,Treacher Df,Turner RC.Homeostasis model assessment:insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man.Diabetologia,1985,28(7):412-419
[25]Levy JC,Matthews DR,HennaIls MP.Correct homeostasis model assessment (HOMA) evaluation uses the computer program.Diabetes Care,1998,21 (12):2191-2192
[26]Wallace RM,Levy JC,Matthews DR.Use and abuse of HOMA modeling.Diabetes Care,2004,27(6): 1487-1495
[27]Cederholm J,Wibell L.Insulin release and peripheral sensitivity at the oral glucose tolerance test.Diabetes Res Clin Pract,1990,10(2):167-175
[28]Turner RC,HolmanRR,Matthews D,Hockaday TDR,Peto J.Insulin deficiency and insulin resistance interaction in diabetes,estimation of their relative contribution by feedback analysis from basal plasma insulin and glucose concentrations.Metabolism,1979,28(11):1086-1096
[29]Matthews DR,Hosker JP,Rudenski AS,Naylor BA,Treacher Df,Turner RC.Homeostasis model assessment:insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man.Diabetologia,1985,28(7):412-419
[30]Levy JC,Matthews DR,HennaIls MP.Correct homeostasis model assessment (HOMA) evaluation uses the computer program.Diabetes Care,1998,21(12):2191-2192
[31]Wallace RM,Levy JC,Matthews DR.Use and abuse of HOMA modeling.Diabetes Care,2004,27 (6):1487-1495
[32]李光伟,潘孝仁,Stephen Lillioja检测人群胰岛素敏感性的一项新指数.中华内科杂志,1993,32(10)：656-660
[33]张家庆,高从容,黄庆玲.用毛细血管法测胰岛素敏感性.中华内分泌代谢杂志.1997,13(2)：77-80
[34]Mantin D,Meglasson,Franz M,Matschinsky.Discmination of glucose anomers by glucokinase from liver and transplantable insulinoma.J Biol Chem,1983,258:6705-6708
[35]朱德增,周松华,谷丽敏.“酸胜甘”法治疗糖尿病.中医杂志,1997,38(12)：725-726
[36]Zhang W,Hong D,Zhou Y,Zhang Y,Shen Q,Li JY,Hu LH,Li J.Ursolic acid and its derivative inhibit protein tyrosine phosphatase 1B,enhancing insulin receptor phosphorylation and stimulating glucose uptake.Biochim Biophys Act,2006,1760(10):1505-1512
[37]Chen CC,Hsu CY,Chen CY,Liu HK.Fructus Corni suppresses hepatic gluconeogenesis related gene transcription,enhances glucose responsiveness of pancreatic beta-cellls,and prevents toxin induced bet-cell death.Ethnopharmacol,2008,117(3):483-490
[38]Jang SM,Yee ST,Choi J. Ursolic acid enhances the cellular immune systerm and pancreatic beta-cell function in streptozotocinOinduced diabetic mice fed a high-fat diet.Int Immunopharmacol,2009,9 (1):113-119
[39]Jung SH,Ha YJ, Shim EK,Choi SY,Jin JL,Yun-Choi HS,Lee JR.Insulin-mimetic and insulin-sensitinzing activitives of a pentacyclic triterpenoid insulin receptor activator.Biochem J,2007,403 (2):243-250
[40]McLaughlin T,Abbasi F,Cheal K.Use of metabolic markers to identify overweight individuals who are insulin resistant.Ann Intern Med,2003,139:802-809
[41]Sandhofer A,Kaser S,Ritsch A.Cholesteryl ester transfer protein in metabolic syndrome.Obesity, 2006,14(5):812-818
[42]陈金仲,邵豪.脂代谢紊乱与胰岛素抵抗的相关研究进展.中国实用医药,2008,3(7)：147-149
[43]金顺福,金春花.黄连素的新用途.现代医药卫生,2007,23(20)：3099
[44]刘洪凤,杨勇,韩智学,包海花,聂颖,冯琴喜.黄芪多糖对2-DM胰岛素抵抗大鼠FINS及IR相关指数的影响.2007,28(6)：14-16
[45]刘月丽,吕俊华.红丝线草对胰岛素抵抗脂肪肝大鼠有关指标的影响.辽宁中医学院学报,2006,8(3)：4-6
[46]王佳珍,黄小明,陈秀芳,王秀娣,李安乐,周颖.月见草油和多烯康对糖尿病大鼠胰岛素抵抗的治疗作用.浙江医学,1998,20(1)：24-25
[47]Schuman GI,Rorhman DL,Jue T,Stein P, De Fronzo RA,Shulman RG.Quantitation of muscle glycogen synthses in normal subjects and subjects with non-insulin-dependent dibetes by 13C nuclear magnetic resonance spectrosropy.N Engl J Med,1990,322:223-228
[48]He J,Kelley DE.Muscle glycogen content in type 2 diabetes mellitus.Am J Physiol Endocrinol Metab,2004,287:E 1002-E1007
[49]Bischof MG,Bernroider E,Krssak M,Krebs M,Sting H,Nowotny P,YuC,Shulman GL, Waldhausl W,Roden M.Hepatic glycogen metabolism in type I diabetes after longterm near normoglycemia. Diabetes,2002,51(1);49-54
[50]Krssak M,Brehm A,Bernroider E,Anderwald C,Nowotony P,Dalla Man C,Cobelli C,Cline G W,Shulman GL, Waldhausl W,Roden M.Alterationsin postprandial hepatic Glycogen metabolism in type 2 diabetes.Diabetes,2004,53(12):3048-3056
[51]Mantin D,Meglasson,Franz M,Matschinsky.Discmination of glucose anomers by glucokinase from liver and transplantable insulinoma.J Biol Chem,1983,258:6705-6708
[52]Franz M.Matschinsky,Mark A.Magnuson,Dorothy Zelent,Tom L.Jetton,Nicolai Doliba,Yi Han, Rebecca Taub,Joseph Grimsby.The network of glucokinase-expressiong cells in glucose homeostasis and the potential ofglucokinase activators for diabete therapy.Diabetes,2006,55(1):1-12
[53]方亦斌,邹大进.葡萄糖激酶调节蛋白的研究进展.华夏医学,2003,16(3)：18-19
[54]郑宏庭,邓华聪.葡萄糖激酶与糖尿病的研究进展.中国组织工程研究与临床康复,2004,(27)：5960-5961
[55]高从容,张家庆,黄庆玲,等.黄连素增加胰岛素抵抗大鼠模型胰岛素敏感性的实验研究.中国中西医结合杂志,1997,17(3)：162-164
[56]曹莉,顾振纶,茅采萍.葛根素对糖尿病小鼠IR的影响.中草药,2006,37(6)：901-904
[57]徐梓辉,周世文,黄林青.薏苡仁多糖的分离提取及其降血糖作用的研究.第三军医大学学报,2000,22(6)：578-581
[58]徐梓辉,周世文,黄林青.薏苡仁多糖对四氧嘧啶致大鼠胰岛β细胞损伤的保护作用.中国药理学通报,2000,16(6)：639-642
[59]Zhiguo Zhang,Xiaoying Li,Wenshan Lv,Yisheng Yang,Hong Gao,Jun Yang,Yun Shen Guang Ning.Ginsenoside re reduces insulin resistance through inhibition of c-Jun NH2-terminal kinase and nuclear factor-κB.Molecular Endocrinology,2008,22(1):186-195
[60]Claudia Soto,Recoba Rosa,Hector Barron,Carlos Alvarez,Liliana favari.Silymarin increases antioxidant enzymes in alloxan-induced diabetes in rat pancreas.Comparative Biochemistry and Physiology Part C:Toxicology Pharmacology,2003,136(3):205-212
[61]Soto C,Mena R,Luna J,Cerbon M,Larrieta E,Vital P,Uria E,Sanchez M,Recola R,Barron H, Favari L,Lara A.Silymarin induces recovery of pancreatic function after alloxan damage in rats.Life Sci,2004, 75(18):2167-2180
[62]于丽萍,张雪,王玉芝.单剂卷柏对FFR胰岛素敏感性的影响.中成药,2001,23(4)：291-292
[63]陆灏.三黄煎对2型糖尿病大鼠的胰岛素分泌功能的影响.辽宁中医药杂志,2000,27(6)：281-283
[64]熊曼琪,林安忠,朱志章,蔡文就,何敏,郑高飞,陈芝喜,沈慧婷,钟春宁,贾可亮.加味桃核承气汤对II型糖尿病大鼠胰岛素抵抗的影响.中国中西医结合杂志,1997,17(3)：165-168
[65]徐丽君,曾凡鹏,陆付耳,杨明炜,王开富.补肾通脉方对Ⅱ型糖尿病大鼠骨骼肌胰岛素受体表达的影响.中国医药学杂志,2003,23(4)：201-203
[66]黄献平,袁肇凯,卢芳国,田松,谢梦洲,胡志希,姚湘玲.养心通脉片对胰岛素抵抗综合征病人红细胞胰岛素受体的影响.中西医结合心脑血管病杂志,2003,1(7)：373-375
[67]王凌,李秋贵,浦信行,东圃胜浩,村上英之,富坚信彦,岛本和明.参地降糖颗粒对高果糖大鼠胰岛素抵抗的影响.中医杂志,2001,42(11)：686-688
[68]张琦,冯凭.金芪降糖片对高脂胰岛素抵抗鼠PAI-1和t-PA活性的影响.天津中医药,2004,21(4)：328-331
[69]郭盛,何丽,刘昌玉.活血化瘀法对营养性肥胖大鼠胰岛素敏感指数及脂肪组织中肿瘤坏死因子-α的影响.现代中西医结合杂志,2004,13(16)：2127-2128
[70]朱志章.三黄降糖方对2型糖尿病患者外周胰岛素抵抗的影响.中国中西医结合杂志,1997,17(10)：590-593
[71]于健.葛根素治疗2型糖尿病患者胰岛素抵抗的临床研究.山东中医杂志,2001,20(12)：727-729
[72]黄琦,许家鸾.麦冬多糖对2型糖尿病血糖及胰岛素抵抗的影响.浙江中西医结合杂志,2002,12(2)：81
[73]黄全海.水蛭素对2型糖尿病胰岛素抵抗的影响.浙江中医学院学报,2005,29(4)：18-19
[74]叶励民.养阴降糖片治疗2型糖尿病胰岛素抵抗的临床观察.中国民族民间医药,2009,18(19)：74
[75]朱颖玲.中西医结合治疗2型糖尿病胰岛素抵抗30例临床研究.江苏中医药,2009,10：27-28
[76]王亚丽.血府逐瘀汤加减对代谢综合征胰岛素抵抗的影响.浙江中西医结合杂志,2009,19(8)：491-492
[77]刘志伟,安淑华.疏肝理气法对糖耐量减低肥胖者胰岛素抵抗及血清C-RP的影响.江苏中医药,2009,41(8)：32-33
[2]Reaven GM.Banting lecture 1988:Role of insulin resistance in human disease.Diabetes,1997,13(1): 64
[3]Schrauwen P,Hesselink M.K.C.Oxidative capacity,lipotoxicity,and mitochondrial damage in type 2 diabets.Diabets.2002,53(6):1412-1417
[4]李秀钧.胰岛素抵抗及胰岛素抵抗综合征研究展望.中华内分泌代谢杂志,2000,16(5)：274-276
[5]于晓静,王晓梅,冯海娟.2型糖尿病合并脂肪肝危险因素临床分析.世界华人消化杂志,2006,14(30)：2977-2979
[6]Basu A,Shah P,Nielsen M,Basu R,Rizza RA.Effects of type 2 diabetes on the regulation of hepatic glucose metabolism.J Investig Med,2004,52:366-374
[7]祝炼,袁莉.胰岛素信号转导与肝胰岛素抵抗.世界华人消化杂志,2004,12(10)：2420-2423
[8]李慧颖,崔广智,张岩.2型糖尿病胰岛素信号转导途径.长春中医药大学学报,2008,24(3)：325-326
[9]王洪涛,王韫秀,宋永喜.胰岛素信号转导障碍与糖尿病的关系.实用糖尿病杂志,2007,3(1)：57-59
[10]胡淑国,宋光耀,高宇,王敬,曲东明.罗格列酮对老年胰岛素抵抗大鼠肝脏脂肪酸代谢及胰岛素敏感性的影响.中国老年学杂志,2009,29(3)：304-306
[11]吴涛,季光.非酒精性脂肪性肝病的代谢发病机制.世界华人消化杂志,2009,17(28)：2908-2914
[12]周亚兵,朱德增,罗若茵,赵莉.酸味中药复方对2型糖尿病大鼠糖代谢的调节作用.成都中医药大学学报,2004,27(1)：13-16
[13]周亚兵,罗若茵,赵莉,朱德增.酸味中药复方对实验性2型糖尿病大鼠胰岛素抵抗的影响.中国中西医结合杂志,2005,25(5)：441-444
[14]曹玉莉,殷桂香,朱德增.酸味中药复方对2型糖尿病大鼠ET-1、NO及肾脏ICAM-1基因表达的影响.中国中西医结合肾病杂志,2009,5：400-403
[15]全山丛,邬旻,朱德增,原永芳,王忠壮.酸克糖颗粒的质量标准研究.药学服务与研究,2004；4(11)：36-38
[16]李晨钟,张素华,舒昌达.胰岛素抵抗的动物模型.国外医学：内分泌学分册,1998,18(3)：144-147
[17]李光伟,潘孝仁,Stephen Lillioja,Peter H.Bennett检测人群胰岛素敏感性的一项新指数.中华内科杂志,1993,32(10)：656-660
[18]刘永玉,毛良,莫启忠,方军.实验性NIDDM大鼠的胰岛素抵抗性.中国病理生理杂志,1991,7(4)：422-425
[19]Storlen LH,Pan DA,Kusunoki M,Cooney GJ.Effects of Benfluorex on in vivo patterns of insulin resistence induced by dite rich in fat or fructose.Diabetes Metab Rev,1993,9(Suppl 1):65S-72S
[20]De Fronzo RA,Tobin JD,Anadres R.Glucose clamp technique:a method for quantifying insulin secretion and resistance.Am J Physiol,1979,237:E214-E332
[21]Storlen LH,James DE,Burleighy KM,Chisholm DJ,Kraegen EW.Fat feeding causes widespread in vivo insulin resistance,decreased energy expenditure,and obesity in rats.Am J Physiol Endocrinol Metab,1986,251:E576-E583
[22]Oakes ND,Kennedy CJ,Jeninks AB,Laybutt DRmChisholm J,Kraegen EW.A new antidiabetic agent,BRL49653,reduces lipid availbility and improves insulin action and glucoregulation in the rats.Diabetes,1994,43(10):1203-1210
[23]Cederholm J,W ibell L.Insulin release and peripheral sensitivity at the oral glucose tolerance tes.Diabetes Res Clin Pract,1990;10:167-175
[22]李光伟.胰岛β细胞功能评估.国外医学内分泌学分册,2001,21：225-227
[23]Turner RC,HolmanRR,Matthews D,Hockaday TDR,Peto J.Insulin deficiency and insulin resistance interaction in diabetes,estimation of their relative contribution by feedback analysis from basal plasma insulin and glucose concentrations.Metabolism,1979,28(11):1086-1096
[24]Matthews DR,Hosker JP,Rudenski AS,Naylor BA,Treacher Df,Turner RC.Homeostasis model assessment:insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man.Diabetologia,1985,28(7):412-419
[25]Levy JC,Matthews DR,HennaIls MP.Correct homeostasis model assessment (HOMA) evaluation uses the computer program.Diabetes Care,1998,21 (12):2191-2192
[26]Wallace RM,Levy JC,Matthews DR.Use and abuse of HOMA modeling.Diabetes Care,2004,27(6): 1487-1495
[27]Cederholm J,Wibell L.Insulin release and peripheral sensitivity at the oral glucose tolerance test.Diabetes Res Clin Pract,1990,10(2):167-175
[28]Turner RC,HolmanRR,Matthews D,Hockaday TDR,Peto J.Insulin deficiency and insulin resistance interaction in diabetes,estimation of their relative contribution by feedback analysis from basal plasma insulin and glucose concentrations.Metabolism,1979,28(11):1086-1096
[29]Matthews DR,Hosker JP,Rudenski AS,Naylor BA,Treacher Df,Turner RC.Homeostasis model assessment:insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man.Diabetologia,1985,28(7):412-419
[30]Levy JC,Matthews DR,HennaIls MP.Correct homeostasis model assessment (HOMA) evaluation uses the computer program.Diabetes Care,1998,21(12):2191-2192
[31]Wallace RM,Levy JC,Matthews DR.Use and abuse of HOMA modeling.Diabetes Care,2004,27 (6):1487-1495
[32]李光伟,潘孝仁,Stephen Lillioja检测人群胰岛素敏感性的一项新指数.中华内科杂志,1993,32(10)：656-660
[33]张家庆,高从容,黄庆玲.用毛细血管法测胰岛素敏感性.中华内分泌代谢杂志.1997,13(2)：77-80
[34]Mantin D,Meglasson,Franz M,Matschinsky.Discmination of glucose anomers by glucokinase from liver and transplantable insulinoma.J Biol Chem,1983,258:6705-6708
[35]朱德增,周松华,谷丽敏.“酸胜甘”法治疗糖尿病.中医杂志,1997,38(12)：725-726
[36]Zhang W,Hong D,Zhou Y,Zhang Y,Shen Q,Li JY,Hu LH,Li J.Ursolic acid and its derivative inhibit protein tyrosine phosphatase 1B,enhancing insulin receptor phosphorylation and stimulating glucose uptake.Biochim Biophys Act,2006,1760(10):1505-1512
[37]Chen CC,Hsu CY,Chen CY,Liu HK.Fructus Corni suppresses hepatic gluconeogenesis related gene transcription,enhances glucose responsiveness of pancreatic beta-cellls,and prevents toxin induced bet-cell death.Ethnopharmacol,2008,117(3):483-490
[38]Jang SM,Yee ST,Choi J. Ursolic acid enhances the cellular immune systerm and pancreatic beta-cell function in streptozotocinOinduced diabetic mice fed a high-fat diet.Int Immunopharmacol,2009,9 (1):113-119
[39]Jung SH,Ha YJ, Shim EK,Choi SY,Jin JL,Yun-Choi HS,Lee JR.Insulin-mimetic and insulin-sensitinzing activitives of a pentacyclic triterpenoid insulin receptor activator.Biochem J,2007,403 (2):243-250
[40]McLaughlin T,Abbasi F,Cheal K.Use of metabolic markers to identify overweight individuals who are insulin resistant.Ann Intern Med,2003,139:802-809
[41]Sandhofer A,Kaser S,Ritsch A.Cholesteryl ester transfer protein in metabolic syndrome.Obesity, 2006,14(5):812-818
[42]陈金仲,邵豪.脂代谢紊乱与胰岛素抵抗的相关研究进展.中国实用医药,2008,3(7)：147-149
[43]金顺福,金春花.黄连素的新用途.现代医药卫生,2007,23(20)：3099
[44]刘洪凤,杨勇,韩智学,包海花,聂颖,冯琴喜.黄芪多糖对2-DM胰岛素抵抗大鼠FINS及IR相关指数的影响.2007,28(6)：14-16
[45]刘月丽,吕俊华.红丝线草对胰岛素抵抗脂肪肝大鼠有关指标的影响.辽宁中医学院学报,2006,8(3)：4-6
[46]王佳珍,黄小明,陈秀芳,王秀娣,李安乐,周颖.月见草油和多烯康对糖尿病大鼠胰岛素抵抗的治疗作用.浙江医学,1998,20(1)：24-25
[47]Schuman GI,Rorhman DL,Jue T,Stein P, De Fronzo RA,Shulman RG.Quantitation of muscle glycogen synthses in normal subjects and subjects with non-insulin-dependent dibetes by 13C nuclear magnetic resonance spectrosropy.N Engl J Med,1990,322:223-228
[48]He J,Kelley DE.Muscle glycogen content in type 2 diabetes mellitus.Am J Physiol Endocrinol Metab,2004,287:E 1002-E1007
[49]Bischof MG,Bernroider E,Krssak M,Krebs M,Sting H,Nowotny P,YuC,Shulman GL, Waldhausl W,Roden M.Hepatic glycogen metabolism in type I diabetes after longterm near normoglycemia. Diabetes,2002,51(1);49-54
[50]Krssak M,Brehm A,Bernroider E,Anderwald C,Nowotony P,Dalla Man C,Cobelli C,Cline G W,Shulman GL, Waldhausl W,Roden M.Alterationsin postprandial hepatic Glycogen metabolism in type 2 diabetes.Diabetes,2004,53(12):3048-3056
[51]Mantin D,Meglasson,Franz M,Matschinsky.Discmination of glucose anomers by glucokinase from liver and transplantable insulinoma.J Biol Chem,1983,258:6705-6708
[52]Franz M.Matschinsky,Mark A.Magnuson,Dorothy Zelent,Tom L.Jetton,Nicolai Doliba,Yi Han, Rebecca Taub,Joseph Grimsby.The network of glucokinase-expressiong cells in glucose homeostasis and the potential ofglucokinase activators for diabete therapy.Diabetes,2006,55(1):1-12
[53]方亦斌,邹大进.葡萄糖激酶调节蛋白的研究进展.华夏医学,2003,16(3)：18-19
[54]郑宏庭,邓华聪.葡萄糖激酶与糖尿病的研究进展.中国组织工程研究与临床康复,2004,(27)：5960-5961
[55]高从容,张家庆,黄庆玲,等.黄连素增加胰岛素抵抗大鼠模型胰岛素敏感性的实验研究.中国中西医结合杂志,1997,17(3)：162-164
[56]曹莉,顾振纶,茅采萍.葛根素对糖尿病小鼠IR的影响.中草药,2006,37(6)：901-904
[57]徐梓辉,周世文,黄林青.薏苡仁多糖的分离提取及其降血糖作用的研究.第三军医大学学报,2000,22(6)：578-581
[58]徐梓辉,周世文,黄林青.薏苡仁多糖对四氧嘧啶致大鼠胰岛β细胞损伤的保护作用.中国药理学通报,2000,16(6)：639-642
[59]Zhiguo Zhang,Xiaoying Li,Wenshan Lv,Yisheng Yang,Hong Gao,Jun Yang,Yun Shen Guang Ning.Ginsenoside re reduces insulin resistance through inhibition of c-Jun NH2-terminal kinase and nuclear factor-κB.Molecular Endocrinology,2008,22(1):186-195
[60]Claudia Soto,Recoba Rosa,Hector Barron,Carlos Alvarez,Liliana favari.Silymarin increases antioxidant enzymes in alloxan-induced diabetes in rat pancreas.Comparative Biochemistry and Physiology Part C:Toxicology Pharmacology,2003,136(3):205-212
[61]Soto C,Mena R,Luna J,Cerbon M,Larrieta E,Vital P,Uria E,Sanchez M,Recola R,Barron H, Favari L,Lara A.Silymarin induces recovery of pancreatic function after alloxan damage in rats.Life Sci,2004, 75(18):2167-2180
[62]于丽萍,张雪,王玉芝.单剂卷柏对FFR胰岛素敏感性的影响.中成药,2001,23(4)：291-292
[63]陆灏.三黄煎对2型糖尿病大鼠的胰岛素分泌功能的影响.辽宁中医药杂志,2000,27(6)：281-283
[64]熊曼琪,林安忠,朱志章,蔡文就,何敏,郑高飞,陈芝喜,沈慧婷,钟春宁,贾可亮.加味桃核承气汤对II型糖尿病大鼠胰岛素抵抗的影响.中国中西医结合杂志,1997,17(3)：165-168
[65]徐丽君,曾凡鹏,陆付耳,杨明炜,王开富.补肾通脉方对Ⅱ型糖尿病大鼠骨骼肌胰岛素受体表达的影响.中国医药学杂志,2003,23(4)：201-203
[66]黄献平,袁肇凯,卢芳国,田松,谢梦洲,胡志希,姚湘玲.养心通脉片对胰岛素抵抗综合征病人红细胞胰岛素受体的影响.中西医结合心脑血管病杂志,2003,1(7)：373-375
[67]王凌,李秋贵,浦信行,东圃胜浩,村上英之,富坚信彦,岛本和明.参地降糖颗粒对高果糖大鼠胰岛素抵抗的影响.中医杂志,2001,42(11)：686-688
[68]张琦,冯凭.金芪降糖片对高脂胰岛素抵抗鼠PAI-1和t-PA活性的影响.天津中医药,2004,21(4)：328-331
[69]郭盛,何丽,刘昌玉.活血化瘀法对营养性肥胖大鼠胰岛素敏感指数及脂肪组织中肿瘤坏死因子-α的影响.现代中西医结合杂志,2004,13(16)：2127-2128
[70]朱志章.三黄降糖方对2型糖尿病患者外周胰岛素抵抗的影响.中国中西医结合杂志,1997,17(10)：590-593
[71]于健.葛根素治疗2型糖尿病患者胰岛素抵抗的临床研究.山东中医杂志,2001,20(12)：727-729
[72]黄琦,许家鸾.麦冬多糖对2型糖尿病血糖及胰岛素抵抗的影响.浙江中西医结合杂志,2002,12(2)：81
[73]黄全海.水蛭素对2型糖尿病胰岛素抵抗的影响.浙江中医学院学报,2005,29(4)：18-19
[74]叶励民.养阴降糖片治疗2型糖尿病胰岛素抵抗的临床观察.中国民族民间医药,2009,18(19)：74
[75]朱颖玲.中西医结合治疗2型糖尿病胰岛素抵抗30例临床研究.江苏中医药,2009,10：27-28
[76]王亚丽.血府逐瘀汤加减对代谢综合征胰岛素抵抗的影响.浙江中西医结合杂志,2009,19(8)：491-492
[77]刘志伟,安淑华.疏肝理气法对糖耐量减低肥胖者胰岛素抵抗及血清C-RP的影响.江苏中医药,2009,41(8)：32-33