背景:有实验表明在胰岛素缺乏的糖尿病动物应用罗格列酮并未发现明显的增加胰岛素和降血糖作用,说明该药不刺激胰岛素分泌,其改善胰岛素抵抗的作用及对肝、肾脏功能的影响有待研究.目的:观察罗格列酮对高脂血症大鼠胰岛素抵抗是否有改善作用并分析其可能的作用机制.单位:广州市中医医院,广州市中医中药研究所.设计:分层随机对照动物实验.材料:选用64只SD大鼠,鼠龄6～8周,雌雄各半,体质量150～180 g,均购自广东省医用实验动物中心;基础饲料:总热量6.9 kJ/g(其中蛋白质占23%,碳水化合物占53%,脂肪占5%).高脂乳液:猪油200 g/L,胆固醇200 g/L,牛胆盐10 g/L,丙二醇200 g/L,吐温-80 200 g/L,总热量15.5 kJ/g.高脂肪-高糖-高热量饲料:基础饲料加100 g/L葡萄糖、200 g/L猪油和100 g/L蛋黄粉充分混匀后,制成饼块,烘干后用,总热量11.3 kJ/g(其中蛋白质占15%,碳水化合物占51%,脂肪占30%);罗格列酮片:葛兰素史克(天津)有限公司生产(5 mg/tab,批号:02110012);格列齐特片:法国施维雅药厂天津华津制药厂合作生产(100 mg/tab,批号:00232).方法:实验于2003-04/07在广州中医药大学完成.①按性别、体质量随机抽取16只大鼠作为空白对照组,喂饲普通饲料,共6周.其余大鼠按照参照文献方法灌服高脂乳液,取空腹血糖≥6.1 mmol/L或2 h血糖≥7.8 mmol/L的大鼠,按体质量和血糖值将大鼠分成3组:模型组、罗格列酮组和格列齐特组,每组16只.空白对照组大鼠不给予处理.罗格列酮组及格列齐特组大鼠分别灌胃给予罗格列酮(5 mg/kg)及格列齐特(100 mg/kg),模型组灌胃蒸馏水,同时分别继续喂饲高脂饲料,1次/d,共28 d,第21天开始同时灌服高脂乳液,1次/d,共7 d,末次给药后,禁食18 h,第29天采用血糖仪检测各组大鼠空腹血糖,按体质量分别灌胃2.78 mol/10 mL·kg葡萄糖溶液或葡萄糖-药物混合液10 mL/kg,2 h后测2 h血糖.②全部大鼠眼眶放血并分离血清,分别测定空腹血清血糖、胆固醇、三酰甘油、高密度脂蛋白胆固醇、低密度脂蛋白-胆固醇、丙氨酸氨基转移酶、天冬氨酸氨基转移酶、血清尿素氮、肌酐、肿瘤坏死因子α及胰岛素含量,同时按李光伟方法计算胰岛素敏感指数:胰岛素敏感指数=In[1/(空腹胰岛素浓度×空腹血糖浓度)].处死大鼠,制肝匀浆,测肝三酰甘油,超氧化物歧化酶,还原型谷胱甘肽和丙二醛水平.主要观察指标:①大鼠空腹血糖及2 h血糖检测结果.②大鼠血清大鼠血糖、血脂、肿瘤坏死因子α、胰岛素含量及胰岛素敏感指数检测结果.③大鼠肝细胞三酰甘油含量、还原型谷胱甘肽贮量、超氧化物歧化酶活性及丙二醛含量检测结果.④大鼠血清丙氨酸氨基转移酶,天冬氨酸氨基转移酶,血清尿素氮及肌酐检测结果.结果:①大鼠空腹血糖及2 h血糖检测结果:罗格列酮组大鼠空腹血糖及2 h血糖分别为(3.2±0.3),(6.3±1.2),mmol/L,低于模型对照组[(3.8±0.5),(8.1±2.1)mmol/L,P＜0.01].格列齐特组大鼠空腹血糖为(3.3±0.7)mmol/L,低于模型对照组.②大鼠血清血糖、血脂、肿瘤坏死因子α、胰岛素含量及胰岛素敏感指数检测结果:罗格列酮组大鼠空腹血糖、肿瘤坏死因子α及空腹胰岛素浓度分别为(4.2±1 2)mmol/L,(246±45)μg/L,(133±45)pmol/L,低于模型对照组[(6.6±1.5)mmol/L,(294±65)μg/L,(264±76)pmol/L,P＜0.05-0.01],胰岛素敏感指数高于模型对照组(-6.33±0.46,-7.46±0.95,P＜0.01).格列齐特组大鼠空腹血糖及肿瘤坏死因子α浓度分别为(4.1±1.1)mmol/L,(251±62)μg/L,低于模型对照组(P＜0.05-0.01).③大鼠肝细胞三酰甘油含量、还原型谷胱甘肽贮量、超氧化物歧化酶活性及丙二醛含量检测结果:罗格列酮组大鼠肝细胞三酰甘油、丙二醛含量分别为(1.00±0.38),(40±17)mmol/g,低于模型对照组[2.40±0.60],(171±63)mmol/g,p＜0.01],还原型谷胱甘肽贮量、超氧化物歧化酶活性分别为(51±14)mg/g,(583.45±50.01)nkat/g,高于模型对照组[(2.40±0.60)mg/g,(450.09±66.68)nkat/g,P＜0.05-0.01].格列齐特组大鼠肝细胞三酰甘油、丙二醛含量分别为(1.20±0.38),(100±30)mmol/g,低于模型对照组,还原型谷胱甘肽贮量(46±15)mg/g,高于模型对照组.④大鼠血清丙氨酸氨基转移酶,天冬氨酸氨基转移酶,血清尿素氮及肌酐检测结果:罗格列酮组大鼠血清尿素氮,肌酐含量分别为(14.3±3.8)mmol/L,(33±9)μmol/L,低于模型对照组[(19.2±5.6)mmol/L,(45±13)μmol/L,P＜0.05].结论:罗格列酮和格列齐特均能改善高脂饲养引发的胰岛素抵抗,罗格列酮在降低高脂病鼠高胰岛水平、降低血清尿素氮及肌酐含量、提高还原型谷胱甘肽贮量作用和增强超氧化物歧化酶活性的趋势方面优于格列齐特.
揹景:有實驗錶明在胰島素缺乏的糖尿病動物應用囉格列酮併未髮現明顯的增加胰島素和降血糖作用,說明該藥不刺激胰島素分泌,其改善胰島素牴抗的作用及對肝、腎髒功能的影響有待研究.目的:觀察囉格列酮對高脂血癥大鼠胰島素牴抗是否有改善作用併分析其可能的作用機製.單位:廣州市中醫醫院,廣州市中醫中藥研究所.設計:分層隨機對照動物實驗.材料:選用64隻SD大鼠,鼠齡6～8週,雌雄各半,體質量150～180 g,均購自廣東省醫用實驗動物中心;基礎飼料:總熱量6.9 kJ/g(其中蛋白質佔23%,碳水化閤物佔53%,脂肪佔5%).高脂乳液:豬油200 g/L,膽固醇200 g/L,牛膽鹽10 g/L,丙二醇200 g/L,吐溫-80 200 g/L,總熱量15.5 kJ/g.高脂肪-高糖-高熱量飼料:基礎飼料加100 g/L葡萄糖、200 g/L豬油和100 g/L蛋黃粉充分混勻後,製成餅塊,烘榦後用,總熱量11.3 kJ/g(其中蛋白質佔15%,碳水化閤物佔51%,脂肪佔30%);囉格列酮片:葛蘭素史剋(天津)有限公司生產(5 mg/tab,批號:02110012);格列齊特片:法國施維雅藥廠天津華津製藥廠閤作生產(100 mg/tab,批號:00232).方法:實驗于2003-04/07在廣州中醫藥大學完成.①按性彆、體質量隨機抽取16隻大鼠作為空白對照組,餵飼普通飼料,共6週.其餘大鼠按照參照文獻方法灌服高脂乳液,取空腹血糖≥6.1 mmol/L或2 h血糖≥7.8 mmol/L的大鼠,按體質量和血糖值將大鼠分成3組:模型組、囉格列酮組和格列齊特組,每組16隻.空白對照組大鼠不給予處理.囉格列酮組及格列齊特組大鼠分彆灌胃給予囉格列酮(5 mg/kg)及格列齊特(100 mg/kg),模型組灌胃蒸餾水,同時分彆繼續餵飼高脂飼料,1次/d,共28 d,第21天開始同時灌服高脂乳液,1次/d,共7 d,末次給藥後,禁食18 h,第29天採用血糖儀檢測各組大鼠空腹血糖,按體質量分彆灌胃2.78 mol/10 mL·kg葡萄糖溶液或葡萄糖-藥物混閤液10 mL/kg,2 h後測2 h血糖.②全部大鼠眼眶放血併分離血清,分彆測定空腹血清血糖、膽固醇、三酰甘油、高密度脂蛋白膽固醇、低密度脂蛋白-膽固醇、丙氨痠氨基轉移酶、天鼕氨痠氨基轉移酶、血清尿素氮、肌酐、腫瘤壞死因子α及胰島素含量,同時按李光偉方法計算胰島素敏感指數:胰島素敏感指數=In[1/(空腹胰島素濃度×空腹血糖濃度)].處死大鼠,製肝勻漿,測肝三酰甘油,超氧化物歧化酶,還原型穀胱甘肽和丙二醛水平.主要觀察指標:①大鼠空腹血糖及2 h血糖檢測結果.②大鼠血清大鼠血糖、血脂、腫瘤壞死因子α、胰島素含量及胰島素敏感指數檢測結果.③大鼠肝細胞三酰甘油含量、還原型穀胱甘肽貯量、超氧化物歧化酶活性及丙二醛含量檢測結果.④大鼠血清丙氨痠氨基轉移酶,天鼕氨痠氨基轉移酶,血清尿素氮及肌酐檢測結果.結果:①大鼠空腹血糖及2 h血糖檢測結果:囉格列酮組大鼠空腹血糖及2 h血糖分彆為(3.2±0.3),(6.3±1.2),mmol/L,低于模型對照組[(3.8±0.5),(8.1±2.1)mmol/L,P＜0.01].格列齊特組大鼠空腹血糖為(3.3±0.7)mmol/L,低于模型對照組.②大鼠血清血糖、血脂、腫瘤壞死因子α、胰島素含量及胰島素敏感指數檢測結果:囉格列酮組大鼠空腹血糖、腫瘤壞死因子α及空腹胰島素濃度分彆為(4.2±1 2)mmol/L,(246±45)μg/L,(133±45)pmol/L,低于模型對照組[(6.6±1.5)mmol/L,(294±65)μg/L,(264±76)pmol/L,P＜0.05-0.01],胰島素敏感指數高于模型對照組(-6.33±0.46,-7.46±0.95,P＜0.01).格列齊特組大鼠空腹血糖及腫瘤壞死因子α濃度分彆為(4.1±1.1)mmol/L,(251±62)μg/L,低于模型對照組(P＜0.05-0.01).③大鼠肝細胞三酰甘油含量、還原型穀胱甘肽貯量、超氧化物歧化酶活性及丙二醛含量檢測結果:囉格列酮組大鼠肝細胞三酰甘油、丙二醛含量分彆為(1.00±0.38),(40±17)mmol/g,低于模型對照組[2.40±0.60],(171±63)mmol/g,p＜0.01],還原型穀胱甘肽貯量、超氧化物歧化酶活性分彆為(51±14)mg/g,(583.45±50.01)nkat/g,高于模型對照組[(2.40±0.60)mg/g,(450.09±66.68)nkat/g,P＜0.05-0.01].格列齊特組大鼠肝細胞三酰甘油、丙二醛含量分彆為(1.20±0.38),(100±30)mmol/g,低于模型對照組,還原型穀胱甘肽貯量(46±15)mg/g,高于模型對照組.④大鼠血清丙氨痠氨基轉移酶,天鼕氨痠氨基轉移酶,血清尿素氮及肌酐檢測結果:囉格列酮組大鼠血清尿素氮,肌酐含量分彆為(14.3±3.8)mmol/L,(33±9)μmol/L,低于模型對照組[(19.2±5.6)mmol/L,(45±13)μmol/L,P＜0.05].結論:囉格列酮和格列齊特均能改善高脂飼養引髮的胰島素牴抗,囉格列酮在降低高脂病鼠高胰島水平、降低血清尿素氮及肌酐含量、提高還原型穀胱甘肽貯量作用和增彊超氧化物歧化酶活性的趨勢方麵優于格列齊特.
배경:유실험표명재이도소결핍적당뇨병동물응용라격렬동병미발현명현적증가이도소화강혈당작용,설명해약불자격이도소분비,기개선이도소저항적작용급대간、신장공능적영향유대연구.목적:관찰라격렬동대고지혈증대서이도소저항시부유개선작용병분석기가능적작용궤제.단위:엄주시중의의원,엄주시중의중약연구소.설계:분층수궤대조동물실험.재료:선용64지SD대서,서령6～8주,자웅각반,체질량150～180 g,균구자광동성의용실험동물중심;기출사료:총열량6.9 kJ/g(기중단백질점23%,탄수화합물점53%,지방점5%).고지유액:저유200 g/L,담고순200 g/L,우담염10 g/L,병이순200 g/L,토온-80 200 g/L,총열량15.5 kJ/g.고지방-고당-고열량사료:기출사료가100 g/L포도당、200 g/L저유화100 g/L단황분충분혼균후,제성병괴,홍간후용,총열량11.3 kJ/g(기중단백질점15%,탄수화합물점51%,지방점30%);라격렬동편:갈란소사극(천진)유한공사생산(5 mg/tab,비호:02110012);격렬제특편:법국시유아약엄천진화진제약엄합작생산(100 mg/tab,비호:00232).방법:실험우2003-04/07재엄주중의약대학완성.①안성별、체질량수궤추취16지대서작위공백대조조,위사보통사료,공6주.기여대서안조삼조문헌방법관복고지유액,취공복혈당≥6.1 mmol/L혹2 h혈당≥7.8 mmol/L적대서,안체질량화혈당치장대서분성3조:모형조、라격렬동조화격렬제특조,매조16지.공백대조조대서불급여처리.라격렬동조급격렬제특조대서분별관위급여라격렬동(5 mg/kg)급격렬제특(100 mg/kg),모형조관위증류수,동시분별계속위사고지사료,1차/d,공28 d,제21천개시동시관복고지유액,1차/d,공7 d,말차급약후,금식18 h,제29천채용혈당의검측각조대서공복혈당,안체질량분별관위2.78 mol/10 mL·kg포도당용액혹포도당-약물혼합액10 mL/kg,2 h후측2 h혈당.②전부대서안광방혈병분리혈청,분별측정공복혈청혈당、담고순、삼선감유、고밀도지단백담고순、저밀도지단백-담고순、병안산안기전이매、천동안산안기전이매、혈청뇨소담、기항、종류배사인자α급이도소함량,동시안리광위방법계산이도소민감지수:이도소민감지수=In[1/(공복이도소농도×공복혈당농도)].처사대서,제간균장,측간삼선감유,초양화물기화매,환원형곡광감태화병이철수평.주요관찰지표:①대서공복혈당급2 h혈당검측결과.②대서혈청대서혈당、혈지、종류배사인자α、이도소함량급이도소민감지수검측결과.③대서간세포삼선감유함량、환원형곡광감태저량、초양화물기화매활성급병이철함량검측결과.④대서혈청병안산안기전이매,천동안산안기전이매,혈청뇨소담급기항검측결과.결과:①대서공복혈당급2 h혈당검측결과:라격렬동조대서공복혈당급2 h혈당분별위(3.2±0.3),(6.3±1.2),mmol/L,저우모형대조조[(3.8±0.5),(8.1±2.1)mmol/L,P＜0.01].격렬제특조대서공복혈당위(3.3±0.7)mmol/L,저우모형대조조.②대서혈청혈당、혈지、종류배사인자α、이도소함량급이도소민감지수검측결과:라격렬동조대서공복혈당、종류배사인자α급공복이도소농도분별위(4.2±1 2)mmol/L,(246±45)μg/L,(133±45)pmol/L,저우모형대조조[(6.6±1.5)mmol/L,(294±65)μg/L,(264±76)pmol/L,P＜0.05-0.01],이도소민감지수고우모형대조조(-6.33±0.46,-7.46±0.95,P＜0.01).격렬제특조대서공복혈당급종류배사인자α농도분별위(4.1±1.1)mmol/L,(251±62)μg/L,저우모형대조조(P＜0.05-0.01).③대서간세포삼선감유함량、환원형곡광감태저량、초양화물기화매활성급병이철함량검측결과:라격렬동조대서간세포삼선감유、병이철함량분별위(1.00±0.38),(40±17)mmol/g,저우모형대조조[2.40±0.60],(171±63)mmol/g,p＜0.01],환원형곡광감태저량、초양화물기화매활성분별위(51±14)mg/g,(583.45±50.01)nkat/g,고우모형대조조[(2.40±0.60)mg/g,(450.09±66.68)nkat/g,P＜0.05-0.01].격렬제특조대서간세포삼선감유、병이철함량분별위(1.20±0.38),(100±30)mmol/g,저우모형대조조,환원형곡광감태저량(46±15)mg/g,고우모형대조조.④대서혈청병안산안기전이매,천동안산안기전이매,혈청뇨소담급기항검측결과:라격렬동조대서혈청뇨소담,기항함량분별위(14.3±3.8)mmol/L,(33±9)μmol/L,저우모형대조조[(19.2±5.6)mmol/L,(45±13)μmol/L,P＜0.05].결론:라격렬동화격렬제특균능개선고지사양인발적이도소저항,라격렬동재강저고지병서고이도수평、강저혈청뇨소담급기항함량、제고환원형곡광감태저량작용화증강초양화물기화매활성적추세방면우우격렬제특.
BACKGROUND: Some experiments indicated that applying rosiglitazone on diabetic animals lacking of insulin could not increase insulin and lower blood glucose obviously, which showed that rosiglitazone did not stimulate the excretion of rosiglitazone. The action of rosiglitazone in improving insulin resistance and the effects on the functions of liver and kidneys need more investigations.OBJECTIVE: To investigate whether rosiglitazone can improve the insulin resistance of rats with hyperlipemia, and analyze the possible mechanism.SETTINGS: Guangzhou Hospital of Traditional Chinese Medicine; Guangzhou Institute of Traditional Chinese Medicine and Materia MedicaDESIGN: A stratified randomized controlled animal trial.MATERIALS: Sixty-four Sprague-Dawley (SD) rats (Batch No. 2002A024), SPF grade, half male and half female,weighing 150 to 180 g, aged 6 to 8 weeks were purchased from Guangdong Medical Experimental Animal Center.Normal feed (total quantity of heat 6.9 kJ/g) was enriched with 23% protein, 53% carbohydrate and 5% fat. High fat emulsion (total quantity of heat 15.5 kJ/g) was enriched with 200 g/L lard, 200 g/L cholesterol, 10 g/L bile salt ox,200 g/L propylene glycol, 200 g/L tween-80. High fat and sugar feed (total quantity of heat 21.0 kJ/g) was enriched with 15% protein, 51% carbohydrate and 30% fat after adding 100 g/L glucose, 200 g/L lard and 100 g/L yolk powder then mixing and baking. Rosiglitazone was from GlaxoSmithKline Co Ltd. (Tianjin) (5 mg/tab, Batch No.02110012). Gliclazide was from Servier International and Tianjin Hua Jin Pharmaceutical Factory (100 mg/tab, Batch No.00232).METHODS: The experiment was carried out in Guangzhou University of Traditional Chinese Medicine from April to July in 2003. ① Sixty-four Sprague-Dawley rats, 16 of which were randomly sampled as the normal control group and had been fed with normal feed for 6 weeks. The others were modeled after medical literatures, each one was administered with high fat emulsion (10 mL/kg) by gavage once a day for 14 days. Rats whose FBG≥6.1 mmol/L or 2hBG≥7.8 mmol/L were selected, randomized into 3 groups according to body mass and blood glucose, i.e., negative control (model)group, rosiglitazone group and gliclazide group, there were 16 rats in each group. Except the normal control group, rats in the rosiglitazone group and gliclazide group were gavaged with rosiglitazone for 5 mg/kg and gliclazide for 100 mg/kg respectively, and those in the model group were gavaged with distilled water. All of the rats were fed with high-fat feed once a day for 28 days. From the 21st day, high fat emulsion was added once a day for 7 days. After fasting for 18 hours from the last administration, all the rats were recorded for FBG and administered dextrose 2.78 mol/10 mL .kg or dextrose and drug mixture 10 mL/kg by body mass. Two hours'later, 2hBG was recorded. ② Blood samples were collected from orbital plexus and serum was prepared for detecting the biochemical indexes and immunological indexes in serum, i.e., fasting serum glucose(FSG), total cholesterol (TC), triglyceride (TG), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), alanine aminotransferase (ALT), aspartate aminotransferase (AST),blood urea nitrogen (BUN), creatinine (Cr), tumor necrosis factor alpha (TNF-α) and fasting insulin (FINS). The insulin sensitivity index (ISI) was calculated: ISI=ln [1/ (FINS content×FBG content)]. After the rats were killed, their liver suspension was prepared for measuring the levels of TG, superoxide dismutase (SOD), glutathione (GSH) and malondialdehyde (MDA).MAIN OUTCOME MEASURES: ① FBG and 2hBG; ② FSG, blood lipids, TNF-α, FINS and ISI in serum; ③ TG, GSH, SOD and MDA in liver cells; ④ ALT, AST, BUN and Cr in serum. RESULTS: ① Results of FBG and 2hBG: The FBG and 2hBG in the rosiglitazone group [(3.2±0.3), (6.3±1.2) mmol/L]were lower than those in the modelcontrol group [(3.8±0.5), (8.1±2.1) mmol/L, P ＜ 0.01]. The FBG in the gliclazide group [(3.3±0.7) mmol/L] was lower than that in the model control group. ② Results of FSG, blood lipids, TNF-α, FINS and ISI: The FSG, TNF-α and FINS in the rosiglitazone group were (4.2±1.2) mmol/L, (246±45) μg/L and (133±45) pmol/L respectively, which were lower than those in the model control group [(6.6±1.5) mmol/L, (294±65) μg/L, (264±76) pmol/L,P ＜ 0.05-0.01], whereas ISI was higher than that in the model control group (-6.33±0.46, -7.46±0.95, P ＜ 0.01). The FSG and TNF-α in the gliclazide group [(4.1±1.1) mmol/L, (251±62) μg/L] were lower than those in the model control group (P ＜ 0.05-0.01). ③ Results of TG content, GSH deposit, SOD activity and MDA content in liver cells: The TG and MDA contents in liver cells in the rosiglitazone group [(1.00±0.38), (40±17) mmol/g] were lower than those in the model control group [(2.40±0.60), (171±63) mmol/g, P＜ 0.01], the GSH deposit and SOD activity [(51±14) mg/g, (583.45±50.01 ) nkat/g] were higher than those in the model control group [(2.40±0.60) mg/g, (450.09±66. 68) nkat/g, P ＜ 0.05-0.01].The TG and MDA contents in the gliclazide group [(1.20±0.38), (100±30) mmol/g] were lower than those in the model control group, whereas the GSH deposit [(46±15) mg/g] was higher than that in the model control group. ④ Results of ALT, AST, BUN and Cr in serum: The serum contents of BUN and Cr in the rosiglitazone group [(14.3±3.8) mmol/L,(33±9) μmol/L] were lower than those in the model control group [(19.2±5.6) mmol/L, (45±13) μmol/L, P ＜ 0.05].CONCLUSION: Both rosiglitazone and gliclazide can improve the insulin resistance induced by high fat feed.Rosiglitazone is superior to gliclazide in decreasing the high insulin level, decreaseing serum levels of BUN and Cr,improving reduced GSH deposit and enhancing SOD activity.
