吡格列酮对自发性IGT-OLETF大鼠胰岛素抵抗的改善作用

目的研究胰岛素增敏剂吡格列酮（pioglitazone）对自发性IGT-OLETF大鼠胰岛素抵抗的改善作用。方法血糖测定采用葡糖氧化酶法，血胰岛素测定采用放射免疫法，游离脂肪酸（FFA）采用铜试剂显色法。结果 IGT-OLETF大鼠具有明显糖耐量、胰岛素耐量异常，脂代谢紊乱，胰岛素敏感指数显著降低等特征。吡格列酮可明显提高IGT-OLETF大鼠对外源性胰岛素的反应性，改善其高胰岛素血症，降低血甘油三酯（TG）、FFA水平，降低肝脂含量及骨骼肌TG含量，使胰岛素敏感指数基本恢复正常。结论吡格列酮可明显改善IGT-OLETF大鼠的胰岛素抵抗。     

吡格列酮改善高脂饮食导致的大鼠肝脏胰岛素抵抗

目的：观察大鼠肝脏中氧化应激以及胰岛素抵抗的发生并探讨吡咯列酮对高脂饮食导致的大鼠肝脏胰岛素抵抗的改善作用。方法：取4周龄雄性SD大鼠,实验分为4组：对照组,高脂组,吡咯列酮组、吡咯列酮＋高脂组。喂养12周后,称体重后断尾法留取空腹血标本,取血测定空腹血糖浓度、血清胰岛素,并计算胰岛素敏感指数;糖原检测试剂盒检测肝脏组织中糖原含量;DHE染色观察肝脏组织中的活性氧自由基水平。结果：正常大鼠的胰岛素敏感指数为-3.47±0.39,高脂饲料喂养12周后,大鼠空腹血糖水平上升,而胰岛素敏感指数降低为-6.29±0.54,吡咯列酮能降低血糖,增加胰岛素敏感指数为-4.54±0.33。蒽酮法的检测结果显示高脂饲料喂养大鼠肝组织糖原含量显著降低到（13.6±2.7）mg/g,吡咯列酮能促进肝脏糖原合成[（19.62±2.88）mg/g]。DHE染色显示肝组织活性氧自由基水平显著增加,吡咯列酮能降低氧化应激水平。结论：高脂饲料喂养SD大鼠胰岛素敏感指数降低,肝组织中活性氧自由基水平显著增加,糖原含量显著降低,吡咯列酮改善高脂饮食导致的大鼠肝脏胰岛素抵抗。     

胰岛素增敏剂的临床应用

2型糖尿病患者的一个重要病理生理改变为胰岛素抵抗，在肥胖和超重者尤为明显。使用某些能改善机体胰岛素敏感性的药物，能显著提高2型糖尿病患者的临床治疗效果，并阻止病情的发展。这些药物统称为胰岛素增敏剂，其中以噻唑烷二酮类的胰岛素增敏效果最为肯定，研究也最为深入。其代表药物有曲格列酮、罗格列酮和吡格列酮等。     

吡格列酮对高脂大鼠内脏肥胖与胰岛素抵抗的影响

目的：探讨环境因素引起的内脏性肥胖与胰岛素抵抗的关系,并观察吡格列酮对其的影响。方法：应用59%高脂饮食喂养大鼠4周制成胰岛素抵抗的动物模型后,给予吡格列酮干预4周,观察内脏肥胖对大鼠胰岛素敏感性的影响以及吡格列酮对其的干预。结果：经59%高脂饮食喂养8周后,模型对照组较正常对照组大鼠空腹血糖及胰岛素均明显增高,血脂、血清游离脂肪酸（FFA）亦明显增高。给予吡格列酮干预后药物干预组较模型对照组大鼠空腹血糖及胰岛素均明显减低,血脂、血清FFA亦明显减低。结论：高脂饮食可诱导内脏肥胖并导致胰岛素抵抗,而吡格列酮可干预此过程。     

吡格列酮在2型糖尿病肥胖患者中的应用

目的 :了解肥胖的 2型糖尿病患者应用胰岛素增敏剂吡格列酮的临床疗效。方法 :选择 30例 2型糖尿病患者 ,体重指数≥ 2 5kg/m2 ,观察服药前后血糖、糖化血红蛋白、胰岛素、胰岛素抵抗指数、胰岛 β细胞功能及体重指数的变化。结果 :服药后血糖、糖化血红蛋白、餐后胰岛素、胰岛素抵抗指数均明显下降 (P <0 .0 5 ) ,胰岛素 β细胞功能明显改善 (P <0 .0 5 )。结论 :吡格列酮是治疗肥胖 2型糖尿病理想的口服降糖药。     

上海市儿童肥胖症原因分析

目的探讨肥胖儿童青少年血脂异常、瘦隶抵抗与胰岛索抵抗的关系。方法检测201例肥胖无糖代谢异常儿童，40例肥胖伴糖代谢异常儿童和230例正常体重儿童的空腹血糖、空腹血胰岛素、血脂、血瘦素水平，以胰岛紊抵抗指数评价胰岛素抵抗。结果肥胖无糖代谢异常组空腹血糖、瘦素显著高于对照组；血甘油三脂、载脂蛋白B、低密度脂蛋白．胆固醇水平以及空腹血胰岛素水平、胰岛素抵抗指数在对照组、肥胖无糖代谢异常组、肥胖伴耱代谢异常组三组间均呈显著上升趋势；甘油三脂、瘦素与胰岛素抵抗指数呈显著正相关。结论肥胖儿童青少年具有明显的脂代谢紊乱、高瘦素血症和瘦素抵抗状态，并与胰岛素抵抗密切相关。     

高脂喂养法建立大鼠胰岛素抵抗模型

目的建立大鼠胰岛素抵抗模型。方法采用高脂饲料喂养雄性SD大鼠,6周后分别进行葡萄糖耐量试验和胰岛素耐量试验,并测定血清胰岛素、总胆固醇及甘油三脂含量,求算胰岛素敏感性指数。结果与正常对照组相比,3周后喂以高脂饲料的大鼠体重显著增加（P〈0．05,n=15）,6周后葡萄糖耐量和胰岛素耐量明显异常,胰岛素水平显著升高（P〈0．01,n=15）,胰岛素敏感性明显下降（P〈0．01,n=15）,但空腹血糖、血清中总胆固醇和甘油三脂含量无显著改变（P〈0．05,n=8）。结论高脂饲料喂养大鼠6周可出现明显的胰岛素抵抗特征。     

罗格列酮的胰岛素增敏作用和胰岛素抵抗改善作用

目的　观察罗格列酮的胰岛素增敏作用和胰岛素抵抗改善作用。方法　大鼠尾静脉注射链佐菌素 (5 0mg·kg-1)制备IDDM模型 ,观察单用罗格列酮、单用小剂量胰岛素 (皮下注射 2 5U·鼠 -1)、罗格列酮并用小剂量胰岛素的降糖作用 ;大鼠尾静脉注射卡介苗 (10mg·鼠 -1)制备免疫性胰岛素抵抗模型 ,观察罗格列酮对模型的葡萄糖输注速率的回升作用。结果　罗格列酮 1,3 ,10 μmol·kg-13个剂量组连续灌胃给药 8d ,均未能降低正常大鼠血糖 ,也未能降低链佐菌素所致糖尿病大鼠血糖 ;但在并用小剂量胰岛素条件下 ,罗格列酮 3 ,10 μmol·kg-1连续灌胃给药 8d ,能降低链佐菌素所致糖尿病大鼠血糖 ;罗格列酮 10 μmol·kg-1连续灌胃给药 8d后 ,用正糖钳技术检测 ,免疫性胰岛素抵抗模型亚极高和极高胰岛素状态下的葡萄糖输注速率均得到回升。结论　罗格列酮具有胰岛素增敏作用和胰岛素抵抗改善作用     

肥胖性胰岛素抵抗MSG大鼠肝脏蛋白质组学初步研究

代谢综合征是一组与糖尿病、心血管疾病密切相关的疾病，是近年来国内外关注的热点问题。代谢综合征主要包括四个方面即糖耐量异常、肥胖、脂质代谢紊乱、高血压，其主要病理基础是机体胰岛素抵抗。实验已证明我们实验室建立的肥胖性胰岛素抵抗MSG大鼠具有胰岛素抵抗特征，胰岛素耐量异常、胰岛素敏感指数（ISI）明显降低、     

罗格列酮在胰岛素抵抗糖尿病患者中的应用

目的探讨罗格列酮在胰岛素抵抗糖尿病患者中的临床疗效。方法选择对胰岛素强化治疗无效的胰岛素抵抗患者39例,采用罗格列酮增敏配合胰岛素强化治疗,观察治疗前后空腹血糖（FBG）、餐后2h血糖（2hPG）水平并比较。结果采用增敏法治疗后FBG与2hPG水平均明显改善,差异有统计学意义（P〈0.01）。结论采用罗格列酮增敏胰岛素强化治疗胰岛素抵抗的糖尿病患者,血糖控制效果满意。     

吡格列酮对高脂喂养大鼠骨骼肌组织脂质异位沉积的影响

目的:观察吡格列酮(Pio)对高脂喂养大鼠骨骼肌组织脂质异位沉积的影响。方法:30只Wistar大鼠平均分为对照组、胰岛素抵抗组和吡格列酮干预组,对照组给予基础饲料,其余2组均给予高脂饲料喂养,其中吡格列酮干预组同时给予吡格列酮20 mg·kg^-1·d^-1灌胃,各组均喂养16周后检测各组大鼠血游离脂肪酸(FFA)水平及骨骼肌组织中三酰甘油(TG)含量,同时应用蛋白免疫印迹法检测骨骼肌组织一磷酸腺苷活化蛋白激酶α(AMPKα)磷酸化水平。结果:与对照组比较,胰岛素抵抗组大鼠胰岛素敏感性显著降低,血FFA水平及骨骼肌组织TG含量增高,骨骼肌组织中AMPKα磷酸化水平降至对照组水平的52.9%;与胰岛素抵抗组比较,吡格列酮干预组大鼠胰岛素敏感性明显提高,血FFA水平及骨骼肌组织TG含量显著下降,骨骼肌组织中AMPKα磷酸化水平显著提高至对照组的81.3%。但是与对照组比较,吡格列酮干预组大鼠血FFA水平及骨骼肌组织TG含量仍然较高,而且胰岛素敏感性及骨骼肌组织中AMPKα磷酸化水平仍然显著降低。结论:高脂饮食诱导胰岛素抵抗,吡格列酮干预可以通过降低血FFA水平及减轻骨骼肌组织脂质异位沉积改善其胰岛素抵抗。     

Pioglitazone can ameliorate insulin resistance in low-dose streptozotocin and high sucrose-fat diet induced obese rats

Aim: To investigate the effect of the peroxisome proliferator-activator receptor (PPAR)-γ agonist, pioglitazone, on insulin resistance in low-dose streptozotocin and high sucrose-fat diet induced obese rats. Methods: Normal female Wistar rats were injected intraperitoneally with low-dose streptozotocin (STZ, 30mg/kg) and fed with a high sucrose-fat diet for 8 weeks. Pioglitazone (20mg/kg) was administered orally to the obese and insulin-resistant rats for 28d. Intraperitoneal glucose tolerance tests, insulin tolerance tests and gluconeogenesis tests were car ried out over the last 14d. At the end of d 28 of the treatment, serums were collected for biochemical analysis. Glucose transporter 4 (GLUT4) and insulin receptor substrate-1 (IRS-1) protein expression in the liver and skeletal muscle were detected using Western blotting. Results: Significant insulin resistance and obesity were observed in low-dose STZ and high sucrose-fat diet induced obese rats. Pioglitazone (20mg/kg) treatment significantly decreased serum insulin,triglyceride and free fatty acid levels, and elevated high density lipoprotein-cholesterol (HDL-C) levels. Pioglitazone also lowered the lipid contents in the liver and muscles of rats undergoing treatment. Gluconeogenesis was inhibited and insulin sensitivity was improved markedly. The IRS-1 protein contents in the liver and skeletal muscles and the GLUT4 contents in skeletal muscle were elevated significantly. Conclusion: The data suggest that treatment with pioglitazone improves insulin sensitivity in low-dose STZ and high sucrose-fat diet induced obese rats. The insulin sensitizing effect may be associated with ameliorating lipid metabolism, reducing hyperinsulinemia, inhibiting gluconeogenesis, and increasing IRS-1 and GLUT4 protein expression in insulin-sensitive tissues.     

结合亚油酸对胰岛素抵抗模型MSG肥胖小鼠的影响结合亚油酸对胰岛素抵抗模型MSG肥胖小鼠的影响

目的研究结合亚油酸对胰岛素抵抗模型MSG肥胖小鼠的胰岛素抵抗是否有改善作用。方法建立胰岛素抵抗模型后分为模型、结合亚油酸和罗格列酮组,观察结合亚油酸对MSG小鼠肥胖、葡萄糖代谢、胰岛素抗性、血及脂肪组织中TNF-α含量等的影响。结果结合亚油酸使MSG小鼠体重增长减少,体型明显改变,但对MSG小鼠异常的胰岛素和葡萄糖耐量、高胰岛素血症及脂肪组织中TNF-α含量升高均无改善,使胰岛素敏感指数明显降低。结论结合亚油酸对MSG小鼠有一定减肥作用,对MSG小鼠的胰岛素抵抗无改善作用。     

Thiazolidinediones improve hepatic fibrosis in rats with non‐alcoholic steatohepatitis by activating the adenosine monophosphate‐activated protein kinase signalling pathway

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Reversal of glucose intolerance by by pioglitazone in high fat diet-fed rats

The present study was undertaken to determine the effect of pioglitazone (3, 10 and 30 mg/kg p.o.), an insulin sensitizer, on glucose intolerance in high fat diet- (HFD) fed rats (a nongenetic model of insulin resistance). In addition, the effect of pioglitazone (3, 10 and 30 mg/kg p.o.) on diet-induced changes in body weight, plasma glucose, insulin, triglyceride and total cholesterol levels were also determined. The feeding of HFD for 4 weeks produced a significant increase in body weight, total fat pad weight, basal/fasting plasma glucose, insulin, basal triglyceride (TG) and total cholesterol (TC) levels in male rats. Furthermore, the rats fed HFD exhibited fasting hyperglycemia and hyperinsulinemia as well as enhanced glycemic response to exogenously administered glucose (2 g/kg p.o.) during an oral glucose tolerance test (OGTT) at the end of 4 weeks of dietary manipulation, indicating that the rats had developed insulin resistance and glucose intolerance. Treatment with pioglitazone (10 and 30 mg/kg p.o.) once daily for 2 weeks significantly diminished the elevated basal plasma insulin and TG levels in HFD-fed rats. In addition, a statistically significant reduction in TC level was observed only with the high dose of pioglitazone (30 mg/kg p.o.). However, pioglitazone had no significant effect on body weight, total fat pad weight and basal plasma glucose level. Pioglitazone (10 and 30 mg/kg p.o.) significantly reduced fasting hyperglycemia and reversed oral glucose intolerance to normal in HFD-fed rats compared with control normal rats. The above findings suggest that pioglitazone has potent insulin-sensitizing and lipid-lowering properties in a HFD-fed rat model. In conclusion, the present study demonstrates that the adult male rats on a HFD for 4 weeks exhibited the characteristic features of obesity, insulin resistance and glucose intolerance, namely increased body weight, increased total fat pad weight, mild basal/fasting hyperglycemia, hyperinsulinemia, hypertriglyceridemia, hypercholesterolemia and impaired oral glucose tolerance, that closely resemble the human prediabetic obese insulin-resistant and glucose-intolerant state. Further treatment with pioglitazone once daily for 2 weeks significantly ameliorated changes in basal plasma insulin, TG and TC, and reversed oral glucose intolerance to normal in HFD-fed rats, suggesting its potential in the treatment of insulin resistance and glucose intolerance associated with abnormal lipid metabolism.     

替米沙坦对OLETF大鼠脂肪细胞因子网膜素、视黄醇结合蛋白4及内脂素的影响

目的：研究血管紧张素Ⅱl型(AT1)受体阻滞剂替米沙坦对改善OLETF大鼠胰岛素抵抗(IR)的作用及其机制。方法：肥胖自发2型糖尿病雄性OLETF大鼠47只,高脂喂养22周诱导建立胰岛素抵抗大鼠模型。随机分为5组,胰岛素抵抗对照组（OLETF）大鼠给予高脂饮食,替米沙坦组(L)高脂饮食加替米沙坦,二甲双胍组（MET）高脂饮食加二甲双胍,吡格列酮组（P）高脂饮食加吡格列酮,低剂量替米沙坦组(VL) 高脂饮食加低剂量替米沙坦,干预26周后测定空腹血糖、空腹胰岛素、游离脂肪酸、血脂、网膜素、视黄醇结合蛋白4、内脂素水平。结果：替米沙坦具有改善OLETF自发胰岛素抵抗大鼠的胰岛素抵抗和糖、脂代谢的作用,药物干预组与胰岛素抵抗对照组比较,血清网膜素表达水平明显升高(F=6.888,P<0.001), 血清视黄醇结合蛋白4表达水平明显降低(F=7.236,P<0.001),血清内脂素表达水平明显降低(F=4.165,P=0.003),血脂水平和胰岛素抵抗得到明显改善。结论：替米沙坦可能通过提高血清网膜素表达、降低血清视黄醇结合蛋白4及内脂素表达,调节血脂水平,改善胰岛素抵抗。     

益气养阴清热液对高血糖肥胖大鼠胰岛素抵抗的影响

目的观察益气养阴清热液(YYQ)对高血糖肥胖大鼠胰岛素抵抗的改善作用。方法采用高脂饲料加小剂量链脲佐菌素(STZ)诱导高血糖肥胖大鼠胰岛素抵抗,用YYQ治疗4wk。检测空腹血糖(FBG)、葡萄糖耐量(OGT)、血清胰岛素(INS)、总胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白(LDL-C)、高密度脂蛋白(HDL-C)、游离脂肪酸(FFA)、红细胞膜胰岛素受体(INSR)、胰岛素钳夹实验下的葡萄糖输注率(GIR);测定肾周、附睾周围脂肪垫重量。同时测定YYQ对肝组织中IR-1、IRS-1mRNA表达的影响。结果YYQ治疗4wk后,大鼠血清中TC、TG、LDL-C、INS、FFA降低,OGT改善,而血清中HDL-C和GIR明显升高,INSR高、低亲和力受体数目均明显增多,肝组织中IR、IRS-1mRNA表达升高,各项指标均与模型组大鼠差异有显著性。结论YYQ对高血糖肥胖大鼠胰岛素抵抗有治疗作用,通过增加胰岛素受体数目而提高其胰岛素敏感性可能是其作用机制之一。     

Crocetin prevents dexamethasone-induced insulin resistance in rats

The main objective of the study was to examine whether crocetin, a natural product from Gardenia jaminoides Ellis, has beneficial effects on the state of insulin resistance induced by dexamethasone in a rat model. Measured using the oral glucose tolerance tests (OGTT), male Wistar rats treated with subcutaneous dexamethasone (0.08 mg/kg/d) for 6 weeks exhibited reduced insulin sensitivity at weeks 2 and 4 and impaired glucose tolerance at week 4. In the dexamethasone-treated group, serum insulin, free fatty acids (FFA), triglyceride (TG) and tumor necrosis factor (TNF)-alpha levels were significantly increased at the end of the study. In addition, the hepatic glycogen content was reduced as indicated by periodic acid-Schiff (PAS) staining, and pancreatic islet beta cells showed compensatory hyperactivity suggested by immunohistochemical (IHC) staining using an antibody against insulin. Treatment with crocetin (40 mg/kg/d) significantly attenuated all the described effects of dexamethasone. These results suggest that crocetin might prevent the development of dexamethasone-induced insulin resistance and related abnormalities in rats.