白藜芦醇改善高脂喂养大鼠胰岛素抵抗和肝脏脂毒性机制的研究
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摘要
第一部分大鼠正糖-高胰岛素钳夹术的改进
目的:在经典正糖-高胰岛素钳夹术基础上对插管技术进行改进,利用尾动静脉插管技术实施清醒状态下大鼠高胰岛素-正糖钳夹实验并对该技术进行评价。
方法:正常喂养和高脂喂养Wistar大鼠各5只,喂养4周后,清醒状态下鼠尾根局部麻醉,分别尾动静脉插管,由尾静脉输入胰岛素(速度0.25u/kg.h)和葡萄糖,尾动脉采血,进行高胰岛素-正糖钳夹实验。
结果:尾动静脉插管术后大鼠血糖在正常范围内,术后血糖无明显波动;高脂喂养组大鼠的葡萄糖输注率显著低于对照组(P＜0.01),表明高脂喂养的大鼠有胰岛素抵抗。
结论:尾动静脉插管技术基础上的高胰岛素-正糖钳夹实验是可行的,较传统插管技术,具有简便易行、缩短实验周期、大鼠死亡率低的优点。
第二部分白藜芦醇改善高脂喂养大鼠胰岛素抵抗、脂肪肝及其机制的研究
目的:观察白藜芦醇是否能够改善高脂喂养所导致大鼠的胰岛素抵抗和非酒精性脂肪肝(NAFLD)并探讨其机制。
方法:急性实验:10只Wistar大鼠分成两组(每组5只),对照组和白藜芦醇处理组,处理组白藜芦醇(100mg/kg.day)灌胃,对照组生理盐水灌胃,4小时后均处死,检测肝脏内AMPK磷酸化水平。慢性实验:30只Wistar大鼠平均分为3组(每组10只):正常对照组(标准饲料喂养),高脂组(高脂饲料喂养),和白藜芦醇组,其中白藜芦醇组全程高脂饲料喂养,并从第7周开始用白藜芦醇干预治疗(100mg/kg.day),各组均喂养16周。以正糖-高胰岛素钳夹技术评价大鼠IR,肝脏石蜡切片HE染色观察病理学改变,肝脏冰冻切片油红O染色观察肝细胞内脂质沉积状况,WesternBlot免疫印迹检测肝脏内AMPK磷酸化水平,RT-PCR检测肝脏固醇调节元件结合蛋白-1C(SREBP-1c)和脂肪酸合成酶(FAS)的mRNA基因表达。
结果:急性实验结果:白藜芦醇干预组肝脏组织内AMPK磷酸化水平增高到对照组的164.2%;慢性实验结果:高脂喂养组大鼠与对照组相比,内脏脂肪指数、肝指数增高(P＜0.05),空腹胰岛素水平增高、葡萄糖输注率下降(P＜0.01),光镜下肝脏出现明显脂肪变性,肝组织内AMPK磷酸化水平降低到对照组的45.8%(P＜0.01),同时脂质合成基因SREBP-1c和FAS的mRNA表达量显著增多;白藜芦醇治疗后的大鼠,内脏脂肪含量显著下降(P＜0.01),空腹胰岛素水平降低、葡萄糖输注率明显增加(P＜0.01),光镜下的肝脏脂肪变性得到明显改善,肝组织内的AMPK磷酸化水平提高到对照组的70.2%(P＜0.05),与此同时脂质合成基因SREBP-1c和FAS的mRNA表达量降低。
结论:白藜芦醇可以在体内促进肝脏内AMPK活性;白藜芦醇治疗可以改善高脂喂养大鼠的IR同时减少肝脏内脂质沉积从而改善脂肪肝,其机制是通过激活AMPK而抑制下游脂质合成途径。
第三部分白藜芦醇可通过激活AMPK途径减少肝细胞内脂质沉积
目的:观察白藜芦醇是否能够直接作用于肝细胞而减少肝细胞内的脂质沉积,并深入探讨其机制。
方法:HepG2细胞种植于6空板内,当细胞融合到80%单层贴壁细胞时血清饥饿过夜后,分别加入含0μM、10μM、25μM、50μM的白藜芦醇的低糖DMEM培养基孵育6小时和24小时后提取细胞蛋白检测细胞内AMPK水平;将HepG2培养于含25mmol/L葡萄糖和10nm/L的胰岛素培养基分别培养24小时诱导细胞脂肪变性模型,然后以50μM白藜芦醇浓度干预脂肪变性模型细胞24小时,提取蛋白后WesternBlot免疫印迹检测细胞内AMPK磷酸化水平;Trizol提取细胞内mRNA检测固醇调节元件结合蛋白-1C(SREBP-1c)和脂肪酸合成酶(FAS)的基因表达水平,同时油红O染色检测细胞内脂质沉积和提取细胞内脂质检测细胞内TG含量。
结果:白藜芦醇呈剂量、时间依赖性促进细胞内AMPKα磷酸化。HepG2细胞脂肪变性模型组出现明显的红色脂滴聚集(油红O染色显示),细胞内TG含量显著高于对照组(P＜0.01),AMPK磷酸化水平降低到对照组的33.5%,SREBP-1c、FAS基因表达量分别增高到对照组的182%和167%;白藜芦醇处理组HepG2油红O染色和细胞内TG定量均显示脂肪变性得到明显改善,AMPK磷酸化水平恢复到对照组的72.6%,而SREBP-1c和FAS的基因表达量也显著下降。
结论:白藜芦醇可以在体外提高肝细胞内AMPK活性;白藜芦醇可以直接作用于肝细胞减少肝细胞内TG沉积,其机制是激活AMPK后抑制下游的SREBP-1c、FAS的基因表达进而抑制脂质合成。
第四部分白藜芦醇改善高脂诱导胰岛素抵抗大鼠氧化应激
目的:观察白藜芦醇是否能够减轻高脂诱导IR模型大鼠体内氧化应激,并探讨氧化应激与IR关系。
方法:动物造模分组同本文第二部分,高胰岛素-正糖钳夹术检测胰岛素敏感性,试剂盒分别检测血清标本羟自由基、MDA水平和SOD活性,ELISA法检测血清TNF-α浓度。
结果:模型组大鼠血清羟自由基、MDA、TNF-α较对照组均显著增高,分别是对照组的1.2倍、2.1倍、1.69倍水平(P＜0.05或者0.01),SOD活性降低到对照组的86%(P＜0.01),且伴有胰岛素抵抗,提示模型组大鼠处于严重氧化应激和IR状态;经过白藜芦醇治疗后,羟自由基、MDA、TNF-α浓度降低,SOD活性恢复,IR也得到明显改善。
结论:IR和氧化应激关系密切,氧化应激是发生IR的重要原因之一,白藜芦醇的抗氧化应激效应是白藜芦醇改善IR的机制之一。
Aim To utilize tail arterial and vein catheterization technique to perform hyperinsulinemic-euglycemic clamp in conscious rats and evaluate this technique.
Methods Wistar rats were fed with standard chow diet or high-fat diet(two groups and five rats each group).Four weeks later,conscious rats received local anesthesia on the root of tail,then tail arterial and vein catheterization respectively.Tail vein was used to inject insulin(the infusion speed was 0.2 5u/kg.h) and tail arterial to obtain blood sample to perform hyperinsulinemic-euglycemic clamp.
Result The glucose infusion rate(GIR) of high-fat diet group was significantly lower than control group,suggesting that the high-fat diet fed rats was in insulin resistance state.
Conclusion Comparing with regularly jugular vein and carotid artery catheterization technique,hyperinsulinemic-euglycemic clamp in conscions rats based on tail arterial and vein catheterization technique has the advantages of stress-free,easy-to-perform,very low death rates of rats.
Aim:To observe the effect of resveratrol on IR and the nonalcoholic fatty liver disease (NAFLD) and tentatively explore the mechanism.
Methods Acute experiment:rats in fed state were orally administrated with RSV(100mg/kg) or saline(vehicle)(5 rats each group).Four hours after administration,the rats were sacrificed to determine the AMPK-αphosphorylation level;Chronic experiment:thirty Wistar rats were randomly allocated to three groups(10 rats for each group):normal control group(NC group,fed with standard chow),high fat feeding group(HF group,fed with high fat diet) and resveratrol treated group(HR group).The resveratrol-treated group was fed with high fat diet all the time and received resveratrol administration(100mg/kg.day) except the first 6 weeks.Each group rats were kept 16 weeks before killed.At the end of animal experiment,hyperinsulinemic-euglycemic clamp was performed to evaluate insulin sensitivity.Liver histology was detected by HE staining.Phosphorylation of AMP-activated protein kinase(AMPK) levels were determined by WesternBlot technique.SREBP-1c and FAS gene expressions,two key lipogenesis regulators,were detected by RT-PCR.
Results Compared to NC group,visceral fat index and liver mass index increased in HF group.Fasting serum insulin(FINS) was elevated and glucose infusion rate(GIR) decreased in HF group.Pathology observation by light microscope showed liver steatosis in HF group.Phosphorylation of AMPK levels in HF group decreased to 45.8%with the down regulation of SREBP-1c and FAS gene expressions.However,resveratrol administration greatly improved the visceral fat index,liver mass index,FINS,GIR as well as liver steatosis compared with HF group.Phosphorylation of AMPK was also elevated to 70.2% in HR group compared with NC group with the subsequent up-regulation of SREBP-1c and FAS gene expressions.
Conclusion Administration of RSV can promote AMPK activation in vivo;Resveratrol administration markedly improved high-fat feeding induced insulin resistance and liver fat accumulation,with the resultant improvement of NAFLD.Elevated phosphorylation of AMPK contributed to the improvement of NAFLD.
Aim:To investigate whether resveratrol(RSV) can directly improve steatosis in hepatocytes and try to find the possible mechanism.
Methods:HepG2 cells exposed to increasing concentrations of RSV for various times on 6-well plate after serum starvation overnight when they come to 80%cell confluence.A cell steatosis model were established by exposing HepG2 cells to a high concentration of glucose(25mmol/l) and insulin(100nm/L) and then were treated with resveratrol for 24 hours.Phosphorylation levels of AMPK were detected by WesternBlot analysis.Gene expression of SREBP-1c and FAS were determined by RT-PCR.Oil red O staining was performed and intracellular triglyceride contents were quantified to observe the lipid accumulation in cell steatosis model treated with or without RSV.
Results:RSV can promote AM PK phosphorylation in a dose and time dependent manner in HepG2 cells.Cell steatosis model was established,as confirmed by Oil red O staining and quantization of total intracellular TG contents.In the model,phosphorylation levels of AMPK were reduced to the 33.5%of the control cells;gene expression of SREBP-1c and FAS were elevated to the 182%and 167%of control,respectively.However,when challenged with RSV treatment,cell steatosis was greatly improved,as confirmed by Oil red O staining and quantization of total intracellular TG contents,phosphorylation levels of AMPK returned to the 72.6%of the control cells;gene expression of SREBP-1c and FAS were decreased,respectively.
Conclusion:RSV can stimulate AMPK in vitro in hepatocytes.RSV can directly act on hepatocytes to improve hepatic steatosis.The possible mechanism is that RSV can stimulate AMPK and prevent the lipogenesis process by inhibit its downstream key fators such as SREBP-1c and FAS.
Aim:To investigate whether resveratrol can ameliorate oxidative stress in the high fat induced insulin resistance(IR) rat model and explore the relationship between oxidative stress and IR.
Methods:The animal model was established according to the second part of this article. Hyperinsulinemic-euglycemic clamp was performed to evaluate the IR state.Serum hydroxy radical level,serum malondialdehyde(MDA)level and activity of superoxide dismutase(SOD) were measured.Serum TNF-αlevel was detected by ELISA.
Results:Compared with control group,serum hydroxy radical,MDA,TNF-αlevels of model rats increased significantly(P＜0.05 or 0.01),while activity of SOD decreased markedly.Beside,model rats developed IR.The indicators suggested that the model rats were in serious oxidative stress and IR state.However,resveratrol recovered the the indicators above,respectively.
Conclusion:There is a close relationship between IR and oxidative stress.Oxidative stress has a causal role in the development of IR.Antioxidant property of resveratrol contributed to the mechanism by which resveratrol improve IR.
目的:在经典正糖-高胰岛素钳夹术基础上对插管技术进行改进,利用尾动静脉插管技术实施清醒状态下大鼠高胰岛素-正糖钳夹实验并对该技术进行评价。
方法:正常喂养和高脂喂养Wistar大鼠各5只,喂养4周后,清醒状态下鼠尾根局部麻醉,分别尾动静脉插管,由尾静脉输入胰岛素(速度0.25u/kg.h)和葡萄糖,尾动脉采血,进行高胰岛素-正糖钳夹实验。
结果:尾动静脉插管术后大鼠血糖在正常范围内,术后血糖无明显波动;高脂喂养组大鼠的葡萄糖输注率显著低于对照组(P＜0.01),表明高脂喂养的大鼠有胰岛素抵抗。
结论:尾动静脉插管技术基础上的高胰岛素-正糖钳夹实验是可行的,较传统插管技术,具有简便易行、缩短实验周期、大鼠死亡率低的优点。
第二部分白藜芦醇改善高脂喂养大鼠胰岛素抵抗、脂肪肝及其机制的研究
目的:观察白藜芦醇是否能够改善高脂喂养所导致大鼠的胰岛素抵抗和非酒精性脂肪肝(NAFLD)并探讨其机制。
方法:急性实验:10只Wistar大鼠分成两组(每组5只),对照组和白藜芦醇处理组,处理组白藜芦醇(100mg/kg.day)灌胃,对照组生理盐水灌胃,4小时后均处死,检测肝脏内AMPK磷酸化水平。慢性实验:30只Wistar大鼠平均分为3组(每组10只):正常对照组(标准饲料喂养),高脂组(高脂饲料喂养),和白藜芦醇组,其中白藜芦醇组全程高脂饲料喂养,并从第7周开始用白藜芦醇干预治疗(100mg/kg.day),各组均喂养16周。以正糖-高胰岛素钳夹技术评价大鼠IR,肝脏石蜡切片HE染色观察病理学改变,肝脏冰冻切片油红O染色观察肝细胞内脂质沉积状况,WesternBlot免疫印迹检测肝脏内AMPK磷酸化水平,RT-PCR检测肝脏固醇调节元件结合蛋白-1C(SREBP-1c)和脂肪酸合成酶(FAS)的mRNA基因表达。
结果:急性实验结果:白藜芦醇干预组肝脏组织内AMPK磷酸化水平增高到对照组的164.2%;慢性实验结果:高脂喂养组大鼠与对照组相比,内脏脂肪指数、肝指数增高(P＜0.05),空腹胰岛素水平增高、葡萄糖输注率下降(P＜0.01),光镜下肝脏出现明显脂肪变性,肝组织内AMPK磷酸化水平降低到对照组的45.8%(P＜0.01),同时脂质合成基因SREBP-1c和FAS的mRNA表达量显著增多;白藜芦醇治疗后的大鼠,内脏脂肪含量显著下降(P＜0.01),空腹胰岛素水平降低、葡萄糖输注率明显增加(P＜0.01),光镜下的肝脏脂肪变性得到明显改善,肝组织内的AMPK磷酸化水平提高到对照组的70.2%(P＜0.05),与此同时脂质合成基因SREBP-1c和FAS的mRNA表达量降低。
结论:白藜芦醇可以在体内促进肝脏内AMPK活性;白藜芦醇治疗可以改善高脂喂养大鼠的IR同时减少肝脏内脂质沉积从而改善脂肪肝,其机制是通过激活AMPK而抑制下游脂质合成途径。
第三部分白藜芦醇可通过激活AMPK途径减少肝细胞内脂质沉积
目的:观察白藜芦醇是否能够直接作用于肝细胞而减少肝细胞内的脂质沉积,并深入探讨其机制。
方法:HepG2细胞种植于6空板内,当细胞融合到80%单层贴壁细胞时血清饥饿过夜后,分别加入含0μM、10μM、25μM、50μM的白藜芦醇的低糖DMEM培养基孵育6小时和24小时后提取细胞蛋白检测细胞内AMPK水平;将HepG2培养于含25mmol/L葡萄糖和10nm/L的胰岛素培养基分别培养24小时诱导细胞脂肪变性模型,然后以50μM白藜芦醇浓度干预脂肪变性模型细胞24小时,提取蛋白后WesternBlot免疫印迹检测细胞内AMPK磷酸化水平;Trizol提取细胞内mRNA检测固醇调节元件结合蛋白-1C(SREBP-1c)和脂肪酸合成酶(FAS)的基因表达水平,同时油红O染色检测细胞内脂质沉积和提取细胞内脂质检测细胞内TG含量。
结果:白藜芦醇呈剂量、时间依赖性促进细胞内AMPKα磷酸化。HepG2细胞脂肪变性模型组出现明显的红色脂滴聚集(油红O染色显示),细胞内TG含量显著高于对照组(P＜0.01),AMPK磷酸化水平降低到对照组的33.5%,SREBP-1c、FAS基因表达量分别增高到对照组的182%和167%;白藜芦醇处理组HepG2油红O染色和细胞内TG定量均显示脂肪变性得到明显改善,AMPK磷酸化水平恢复到对照组的72.6%,而SREBP-1c和FAS的基因表达量也显著下降。
结论:白藜芦醇可以在体外提高肝细胞内AMPK活性;白藜芦醇可以直接作用于肝细胞减少肝细胞内TG沉积,其机制是激活AMPK后抑制下游的SREBP-1c、FAS的基因表达进而抑制脂质合成。
第四部分白藜芦醇改善高脂诱导胰岛素抵抗大鼠氧化应激
目的:观察白藜芦醇是否能够减轻高脂诱导IR模型大鼠体内氧化应激,并探讨氧化应激与IR关系。
方法:动物造模分组同本文第二部分,高胰岛素-正糖钳夹术检测胰岛素敏感性,试剂盒分别检测血清标本羟自由基、MDA水平和SOD活性,ELISA法检测血清TNF-α浓度。
结果:模型组大鼠血清羟自由基、MDA、TNF-α较对照组均显著增高,分别是对照组的1.2倍、2.1倍、1.69倍水平(P＜0.05或者0.01),SOD活性降低到对照组的86%(P＜0.01),且伴有胰岛素抵抗,提示模型组大鼠处于严重氧化应激和IR状态;经过白藜芦醇治疗后,羟自由基、MDA、TNF-α浓度降低,SOD活性恢复,IR也得到明显改善。
结论:IR和氧化应激关系密切,氧化应激是发生IR的重要原因之一,白藜芦醇的抗氧化应激效应是白藜芦醇改善IR的机制之一。
Aim To utilize tail arterial and vein catheterization technique to perform hyperinsulinemic-euglycemic clamp in conscious rats and evaluate this technique.
Methods Wistar rats were fed with standard chow diet or high-fat diet(two groups and five rats each group).Four weeks later,conscious rats received local anesthesia on the root of tail,then tail arterial and vein catheterization respectively.Tail vein was used to inject insulin(the infusion speed was 0.2 5u/kg.h) and tail arterial to obtain blood sample to perform hyperinsulinemic-euglycemic clamp.
Result The glucose infusion rate(GIR) of high-fat diet group was significantly lower than control group,suggesting that the high-fat diet fed rats was in insulin resistance state.
Conclusion Comparing with regularly jugular vein and carotid artery catheterization technique,hyperinsulinemic-euglycemic clamp in conscions rats based on tail arterial and vein catheterization technique has the advantages of stress-free,easy-to-perform,very low death rates of rats.
Aim:To observe the effect of resveratrol on IR and the nonalcoholic fatty liver disease (NAFLD) and tentatively explore the mechanism.
Methods Acute experiment:rats in fed state were orally administrated with RSV(100mg/kg) or saline(vehicle)(5 rats each group).Four hours after administration,the rats were sacrificed to determine the AMPK-αphosphorylation level;Chronic experiment:thirty Wistar rats were randomly allocated to three groups(10 rats for each group):normal control group(NC group,fed with standard chow),high fat feeding group(HF group,fed with high fat diet) and resveratrol treated group(HR group).The resveratrol-treated group was fed with high fat diet all the time and received resveratrol administration(100mg/kg.day) except the first 6 weeks.Each group rats were kept 16 weeks before killed.At the end of animal experiment,hyperinsulinemic-euglycemic clamp was performed to evaluate insulin sensitivity.Liver histology was detected by HE staining.Phosphorylation of AMP-activated protein kinase(AMPK) levels were determined by WesternBlot technique.SREBP-1c and FAS gene expressions,two key lipogenesis regulators,were detected by RT-PCR.
Results Compared to NC group,visceral fat index and liver mass index increased in HF group.Fasting serum insulin(FINS) was elevated and glucose infusion rate(GIR) decreased in HF group.Pathology observation by light microscope showed liver steatosis in HF group.Phosphorylation of AMPK levels in HF group decreased to 45.8%with the down regulation of SREBP-1c and FAS gene expressions.However,resveratrol administration greatly improved the visceral fat index,liver mass index,FINS,GIR as well as liver steatosis compared with HF group.Phosphorylation of AMPK was also elevated to 70.2% in HR group compared with NC group with the subsequent up-regulation of SREBP-1c and FAS gene expressions.
Conclusion Administration of RSV can promote AMPK activation in vivo;Resveratrol administration markedly improved high-fat feeding induced insulin resistance and liver fat accumulation,with the resultant improvement of NAFLD.Elevated phosphorylation of AMPK contributed to the improvement of NAFLD.
Aim:To investigate whether resveratrol(RSV) can directly improve steatosis in hepatocytes and try to find the possible mechanism.
Methods:HepG2 cells exposed to increasing concentrations of RSV for various times on 6-well plate after serum starvation overnight when they come to 80%cell confluence.A cell steatosis model were established by exposing HepG2 cells to a high concentration of glucose(25mmol/l) and insulin(100nm/L) and then were treated with resveratrol for 24 hours.Phosphorylation levels of AMPK were detected by WesternBlot analysis.Gene expression of SREBP-1c and FAS were determined by RT-PCR.Oil red O staining was performed and intracellular triglyceride contents were quantified to observe the lipid accumulation in cell steatosis model treated with or without RSV.
Results:RSV can promote AM PK phosphorylation in a dose and time dependent manner in HepG2 cells.Cell steatosis model was established,as confirmed by Oil red O staining and quantization of total intracellular TG contents.In the model,phosphorylation levels of AMPK were reduced to the 33.5%of the control cells;gene expression of SREBP-1c and FAS were elevated to the 182%and 167%of control,respectively.However,when challenged with RSV treatment,cell steatosis was greatly improved,as confirmed by Oil red O staining and quantization of total intracellular TG contents,phosphorylation levels of AMPK returned to the 72.6%of the control cells;gene expression of SREBP-1c and FAS were decreased,respectively.
Conclusion:RSV can stimulate AMPK in vitro in hepatocytes.RSV can directly act on hepatocytes to improve hepatic steatosis.The possible mechanism is that RSV can stimulate AMPK and prevent the lipogenesis process by inhibit its downstream key fators such as SREBP-1c and FAS.
Aim:To investigate whether resveratrol can ameliorate oxidative stress in the high fat induced insulin resistance(IR) rat model and explore the relationship between oxidative stress and IR.
Methods:The animal model was established according to the second part of this article. Hyperinsulinemic-euglycemic clamp was performed to evaluate the IR state.Serum hydroxy radical level,serum malondialdehyde(MDA)level and activity of superoxide dismutase(SOD) were measured.Serum TNF-αlevel was detected by ELISA.
Results:Compared with control group,serum hydroxy radical,MDA,TNF-αlevels of model rats increased significantly(P＜0.05 or 0.01),while activity of SOD decreased markedly.Beside,model rats developed IR.The indicators suggested that the model rats were in serious oxidative stress and IR state.However,resveratrol recovered the the indicators above,respectively.
Conclusion:There is a close relationship between IR and oxidative stress.Oxidative stress has a causal role in the development of IR.Antioxidant property of resveratrol contributed to the mechanism by which resveratrol improve IR.
引文
[1]Kraegen E W,James D E,Bennett S P,et al.In vivo insulin sensitivity in the rat determined by euglycemic clamp.[J].Am J Physiol,1983,245(1):1-7.
[2]Monzillo L U,Hamdy O.Evaluation of insulin sensitivity in clinical practice and in research settings.[J].Nutr Rev,2003,61(12):397-412.
[3]Ferrannini E,Mari A.How to measure insulin sensitivity.[J].J Hypertens,1998,16(7):895-906.
[4]厉平,李玲,刘聪,et al.用葡萄糖钳夹技术评价各种简易胰岛素抵抗指数计算公式[J].中国糖尿病杂志,2007(12):708-710.
[5]Defronzo R A,Tobin J D,Andres R.Glucose clamp tectnique:a method for quantifying insulin secretion and resistance.[J].Am J Physiol,1979,237(3):214-223.
[6]Bergman R N,Ider Y Z,Bowden C R,et al.Quantitative estimation of insulin sensitivity.[J].Am J Physiol,1979,236(6):667-677.
[7]Matthews D R,Hosker J P,Rudenski A S,et al.Homeostasis model assessment:insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man.[J].Diabetologia,1985,28(7):412-410.
[8]Matsuda M,Defronzo R A.Insulin sensitivity indices obtained from oral glucose tolerance testing:comparison with the euglycemic insulin clamp.[J].Diabetes Care.1999,22(9):1462-1470.
[9]李光伟,潘孝仁,S L.检测人群胰岛素敏感性的一项新指数[J].中华内科杂志,1993.32(10):656-000
[10]李华,龚艳春,贾伟平,et al.三种简易胰岛素敏感性指数在糖耐量异常时的可靠性[J].高血压杂志,2004(03):204-200
[11]Mcauley K A,Williams S M,Mann J I,et al.Diagnosing insulin resistance in the general population.[J].Diabetes Care,2001,24(3):460-464.
[12]李光伟.个体胰岛素敏感性的临床评估出路在何方--兼谈2005年美国糖尿病学会年会的相关信[J].中华糖尿病杂志,2005(04):243-244.
[13]Andres R,Swerdloff R,Pozefsky T A C D.Manual feedback technique for the control of blood glucose concentration.In:Automation in Analytical Chemistry,edited by Skeggs LT Jr.[J].New York:Mediad,1966:486-491.
[14]Elahi D.In praise of the hyperglycemic clamp.A method for assessment of beta-cell sensitivity and insulin resistance.[J].Diabetes Care,1996,19(3):278-286.
[15]Sherwin R S.Evaluation of hypoglycemic counterregulation using a modification of the Andres glucose clamp.[J].Exp Gerontol,1993,28(4-5):371-380.
[16]Tappy L,Paquot N,Tounian P,et al.Assessment of glucose metabolism in humans with the simultaneous use of indirect calorimetry and tracer techniques.[J].Clin Physiol,1995,15(1):1-12.
[17]罗谋伦,郭欲晓,林志彬.大鼠正糖钳实验方法学[J].药学学报,1999(04).
[18]李晨钟,张素华,舒昌达,任伟.Wistar大鼠的正常血糖-高血浆胰岛素钳夹技术[J].重庆医科大学学报,1998,23(02):149-152.
[19]李玲.大鼠清醒和麻醉状态下胰岛素钳夹实验结果的比较[J].中国糖尿病杂志,2003(01).
[20]罗四川,李启富,刘红梅.清醒状犬态大鼠高胰岛素-正常血糖钳夹术的建立及其意义[J].重庆医科大学学报,2004(03).
[21]Frank P,Schoenhard G L,Burton E.A method for rapid and frequent blood collection from the rat tail vein.[J].J Pharmacol Methods,1991,26(3):233-238.
[22]Storlien L H,Oakes N D,Pan D A,et al.Syndromes of insulin resistance in the rat.Inducement by diet and amelioration with benfluorex.[J].Diabetes,1993,42(3):457-402.
[23]何明,涂长春.Lee's指数用于评价成年大鼠肥胖程度的探讨[J].中国临床药理学与治疗学杂志,1997,2(3):177-179
[24]Ye J M,Frangioudakis G,Iglesias M A,et al.Prior thiazolidinedione treatment preserves insulin sensitivity in normal rats during acute fatty acid elevation:role of the liver.[J].Endocrinology,2002,143(12):4527-4535.
[1]Bunyan J,Murrell E A,Shah P P.The induction of obesity in rodents by means of monosodium glutamate.[J].Br J Nutr,1976,35(1):25-39.
[2]何明,涂长春.Lee‘s指数用于评价或年大鼠肥胖程度的探讨[J].中国临床药理学与治疗学杂志,1997,2(3):177-179.
[3]Lieber C S,Leo M A,Mak K M,et al.Model of nonalcoholic steatohepatitis.[J].Am J Clin Nutr,2004,79(3):502-509.
[4]Carmiel-haggai M,Cederbaum A I,Nieto N.A high-fat diet leads to the progression of non-alcoholic fatty liver disease in obese rats.[J].FASEB J,2005,19(1):136-138.
[5]Zou Y,Li J,Lu C,et al.High-fat emulsion-induced rat model of nonalcoholic steatohepatitis.[J].Life Sci,2006,79(11):1100-1107.
[6]Svegliati-baroni G,Candelaresi C,Saccomanno S,et al.A model of insulin resistance and nonalcoholic steatohepatitis in rats:role of peroxisome proliferator-activated receptor-alpha and n-3 polyunsaturated fatty acid treatment on liver injury.[J].Am J Pathol,2006,169(3):846-860.
[7]陈世清,刘杞,孙航,et al脂防肝胰岛素抵抗大鼠模型的建立[J].中华肝脏病杂志.2005,13(2):105-108
[8]Angulo P.Obesity and nonalcoholic fatty liver disease.[J].Nutr Rev,2007,65(6 Pt 2):57-63.
[9]Angulo P.Nonalcoholic fatty liver disease.[J].N Engl J Med,2002,346(16):1221-1231.
[10]Kelley D E,Mckolanis T M,Hegazi R A,et al.Fatty liver in type 2 diabetes mellitus:relation to regional adiposity,fatty acids,and insulin resistance.[J].Am J Physiol Endocrinol Metab,2003,285(4):906-916.
[11]Day C P,James O F.Steatohepatitis:a tale of two "hits"?[J].Gastroenterology,1998,114(4):842-845.
[12]Samuel V T,Liu Z X,Qu X,et al.Mechanism of hepatic insulin resistance in non-alcoholic fatty liver disease.[J].J Biol Chem,2004,279(31):32345-32353.
[13]Das D K,Manlik N.Resveratrol in cardioprotection:a therapeutic promise of alternative medicine.[J].Mol Interv,2006,6(1):36-47.
[14]Baur J A,Sinclair D A.Therapeutic potential of resveratrol:the in vivo evidence[J].Nat Rev Drug Discov,2006,5(6):493-506.
[15]Renaud S,De L M.Wine,alcohol,platelets,and the French paradox for coronary heart disease.[J].Lancet,1992,339(8808):1523-1526.
[16]Kopp P.Resveratrol,a phytoestrogen found in red wine.A possible explanation for the conundrum of the 'French paradox'?[J].Eur J Endocrinol,1998,138(6):619-620.
[17]Renaud S,Gueguen R.The French paradox and wine drinking.[J].Novartis Found Symp,1998,216:208-37352344.
[18]Shankar S,Singh G,Srivastava R K.Chemoprevention by resveratrol:molecular mechanisms and therapeutic potential.[J].Front Biosci,2007,12:4839-4854.
[19]Baur J A,Pearson K J,Price N L,et al.Resveratrol improves health and survival of mice on a high-calorie diet[J].Nature,2006,444(7117):337-342.
[20]Lagouge M,Argmann C,Gerhart-hines Z,et al.Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-lalpha[J].Cell,2006,127(6):1109-1122.
[21]Sun C,Zhang F,Ge X,et al.SIRT1 Improves Insulin Sensitivity under Insulin-Resistant Conditions by Repressing PTP1B.[J].Cell Metab,2007,6(4):307-319.
[22]Elchebly M,Payette P,Michaliszyn E,et al.Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene.[J].Science,1999,283(5407):1544-1548.
[23]Su H C,Hung L M,Chen J K.Resveratrol,a red wine antioxidant,possesses an insulin-like effect in streptozotocin-induced diabetic rats[J].Am J Physiol Endocrinol Metab,2006,290(6):1339-1346.
[24]Chi T C,Chen W P,Chi T L,et al.Phosphatidylinositol-3-kinase is involved in the antihyperglycemic effect induced by resveratrol in streptozotocin-induced diabetic rats.[J].Life Sci,2007,80(18):1713-1720.
[25]Arichi H,Kimura Y,Okuda H,et al.Effects of stilbene components of the roots of Polygonum cuspidatum Sieb.et Zucc.on lipid metabolism[J].Chem Pharm Bull (Tokyo),1982,30(5):1766-1770.
[26]Picard F,Kurtev M,Chung N,et al.Sirtl promotes fat mobilization in white adipocytes by repressing PPAR-gamma[J].Nature,2004,429(6993):771-776.
[27]Bujanda L,Garcia-barcina M,Gutierrez-de J V,et al.Effect of resveratrol on alcohol-induced mortality and liver lesions in mice.[J].BMC Gastroenterol,2006,6:35.
[28]Winder W W,Hardie D G.AMP-activated protein kinase,a metabolic master switch:possible roles in type 2 diabetes.[J].Am J Physiol,1999,277(1 Pt 1):1-10.
[29]Carling D.The AMP-activated protein kinase cascade--a unifying system for energy control.[J].Trends Biochem Sci,2004,29(1):18-24.
[30]Hardie D G,Hawley S A,Scott J W.AMP-activated protein kinase - development of the energy sensor concept[J].J Physiol The Journal of Physiology Online,2006,574(1):7-15.
[31]Misra P,Chakrabarti R.The role of AMP kinase in diabetes.[J].Indian J Med Res,2007,125(3):389-398.
[32]Towler M C,Hardie D G.AMP-activated protein kinase in metabolic control and insulin signaling.[J].Circ Res,2007,100(3):328-341.
[33]Viollet B,Foretz M,Guigas B,et al.Activation of AMP-actiwated protein kinase in the liver:a new strategy for the management of metabolic hepatic disorders.[J].J Physiol,2006,574(Pt 1):41-53.
[34]Wang M Y,Unger R H.Role of PP2C in cardiac lipid accumulation in obese rodents and its prevention by troglitazone.[J].Am J Physiol Endocrinol Metab,2005,288(1):216-221.
[35]Zang M,Xu S,Maitland-toolan K A,et al.Polyphenols Stimulate AMP-Activated Protein Kinase,Lower Lipids,and Inhibit Accelerated Atherosclerosis in Diabetic LDL Receptor-Deficient Mice[J].Diabetes,2006,55(8):2180-2101.
[36]Chen M B,Mcainch A J,Macaulay S L,et al.Impaired activation of AMP-kinase and fatty acid oxidation by globular adiponectin in cultured human skeletal muscle of obese type 2 diabetics.[J].J Clin Endocrinol Metab,2005,90(6):3665-3672.
[37]Dasgupta B,Milbrandt J.Resveratrol stimulates AMP kinase activity in neurons.[J].Proc Natl Acad Sci U S A,2007,104(17):7217-7222.
[38]Zhou G,Myers R,Li Y,et al.Role of AMP-activated protein kinase in mechanism of metformin action[J].J.Clin.Invest.,2001,108(8):1167-1174.
[39]Shimomura I,Bashmakov Y,Horton J D.Increased levels of nuclear SREBP-1c associated with fatty livers in two morose models of diabetes mellitus.[J].J Biol Chem,1999,274(42):30028-30032.
[40]Ahmed M H,Byrne C D.Modulation of sterol regulatory element binding proteins (SREBPs) as potential treatments for non-alcoholic fatty liver disease(NAFLD).[J].Drug Discov Today,2007,12(17-18):740-747.
[1]Utzschneider K M,Kahn S E.Review:The role of insulin resistance in nonalcoholic fatty liver disease.[J].J Clin Endocrinol Metab,2006,91(12):4753-4761.
[2]Qureshi K,Abrams G A.Metabolic liver disease of obesity and role of adipose tissue in the pathogenesis of nonalcoholic fatty liver disease.[J].World J Gastroenterol,2007,13(26):3540-3553.
[3]Palasciano G,Moschetta A,Palmieri V O,et al.Non-alcoholic fatty liver disease in the metabolic syndrome.[J].Curr Pharm Des,2007,13(21):2193-2198.
[4]Angulo P.Obesity and nonalcoholic fatty liver disease.[J].Nutr Rev,2007,65(6 Pt 2):57-63.
[5]Kotronen A,Yki-jarvinen H.Fatty liver:a novel component of the metabolic syndrome.[J].Arterioscler Thromb Vasc Biol,2008,28(1):27-38.
[6]Bugianesi E.Nonalcoholic fatty liver disease(NAFLD) and cardiac lipotoxicity:Another piece of the puzzle.[J].Hepatology,2008,47(1):2-4.
[7]Day C P,James O F.Steatohepatitis:a tale of two "hits"?[J].Gastroenterology,1998,114(4):842-845.
[8]Samuel V T,Liu Z X,Qu X,et al.Mechanism of hepatic insulin resistance in non-alcoholic fatty liver disease.[J].J Biol Chem,2004,279(31):32345-32353.
[9]Levin M C,Monetti M,Watt M J,et al.Increased lipid accumulation and insulin resistance in transgenic mice expressing DGAT2 in glycolytic(type Ⅱ) muscle.[J].Am J Physiol Endocrinol Metab,2007,293(6):1772-1781.
[10]Lagouge M,Argmann C,Gerhart-hines Z,et al.Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-lalpha[J].Cell,2006,127(6):1109-1122.
[11]Elchebly M,Payette P,Michaliszyn E,et al.Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene.[J].Science,1999,283(5407):1544-1548.
[12]Su H C,Hung L M,Chen J K.Resveratrol,a red wine antioxidant,possesses an insulin-like effect in streptozotocin-induced diabetic rats[J].An J Physiol Endocrinol Metab,2006,290(6):1339-1346.
[13]Foretz M,Guichard C,Ferre P,et al.Sterol regulatory element binding protein-1c is a major mediator of insulin action on the hepatic expression of glucoldnase and lipogenesis-related genes.[J].Proc Natl Acad Sci U S A,1999,96(22):12737-12742.
[14]Dasgupta B,Milbrandt J.Resveratrol stimulates AMP kinase activity in neurons.[J].Proc Natl Acad Sci U S A,2007,104(17):7217-7222.
[15]Towler M C,Hardie D G.AMP-activated protein kinase in metabolic control and insulin signaling.[J].Circ Res,2007,100(3):328-341.
[16]Hardie D G,Sakamoto K.AMPK:a key sensor of fuel and energy status in skeletal muscle.[J].Physiology(Bethesda),2006,21:48-60.
[17]Forcet C,Billaud M.Dialogue between LKB1 and AMPK:a hot topic at the cellular pole.[J].Sci STKE,2007,2007(404):pe51.
[18]Minokoshi Y,Kim Y B,Peroni O D,et al.Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase.[J].Nature,2002,415(6869):339-343.
[19]Yamaguchi N,Kukita T,Li Y J,et al.Adiponectin inhibits reduction of TNF-alpha/RANKL-stimulated NFATc1 via the AMPK signaling.[J].FEBS Lett,2008,582(3):451-456.
[20]Yamauchi T,Kamon J,Minokoshi Y,et al.Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase.[J].Nat Med,2002,8(11):1288-1295.
[21]Zhou G,Myers R,Li Y,et al.Role of AMP-activated protein kinase in mechanism of metformin action[J].J.Clin.Invest.,2001,108(8):1167-1174.
[22]Zang M,Zuccollo A,Hou X,et al.AMP-activated Protein Kinase Is Required for the Lipid-lowering Effect of Metformin in Insulin-resistant Human HepG2 Cells[J].J.Biol.Chem.,2004,279(46):47898-47905.
[23]Fryer L G,Parbu-patel A,Carling D.The Anti-diabetic drugs rosiglitazone and metformin stimulate AMP-activated protein kinase through distinct signaling pathways.[J].J Biol Chem,2002,277(28):25226-25232.
[24]To K,Yamaza H,Komatsu T,et al.Down-regulation of AMP-activated protein kinase by calorie restriction in rat liver.[J].Exp Gerontol,2007,42(11):1063-1071.
[25]Wang M Y,Unger R H.Role of PP2C in cardiac lipid accumulation in obese rodents and its prevention by troglitazone.[J].Am J Physiol Endocrinol Metab,2005,288(1):216-221.
[26]Liu Y,Wan Q,Guan Q,et al.High-fat diet feeding impairs both the expression and activity of AMPKa in rats' skeletal muscle[J].Biochem Biophys Res Commun,2006,339(2):701-707.
[27]Chen M B,Mcainch A J,Macaulay S L,et al.Impaired activation of AMP-kinase and fatty acid oxidation by globular adiponectin in cultured human skeletal muscle of obese type 2 diabetics.[J].J Clin Endocfinol Metab,2005,90(6):3665-3672.
[28]Viollet B,Mounier R,Leclerc J,et al.Targeting AMP-activated protein kinase as a novel therapeutic approach for the treatment of metabolic disorders.[J].Diabetes Metab,2007,33(6):395-402.
[29]Misra P.AMP activated protein kinase:a next generation target for total metabolic control.[J].Expert Opin Ther Targets,2008,12(1):91-100.
[30]陈名道.脂毒性及其防治的一个关键靶点-AMPK[J].中华内分泌代谢杂志,2001,23(1):5-7.
[31]Tian W X.Inhibition of fatty acid synthase by polyphenols.[J].Curr Med Chem,2006,13(8):967-977.
[32]Eberle D,Hegarty B,Bossurd P,et al.SREBP transcription factors:master regulators of lipid homeostasis.[J].Biochimie,2004,86(11):830-848.
[33]Raghow R,Yellaturu C,Deng X,et al.SRBPs:the crossroads of physiological and pathological lipid homeostasis.[J].Trends Endocrinol Metab,2008,19(2):65-73.
[34]Shimomura I,Bashmakov Y,Horton J D.Increased levels of nuclear SREBP-1c associated with fatty livers in two mouse models of diabetes mellitus.[J].J Biol Chem,1000,274(42):30028-30032.
[35]Kakuma T,Lee Y,Higa M,et al.Leptin,troglitazone,and the expression of sterol regulatory element binding proteins in liver and pancreatic islets.[J].Proc Natl Acad Sci U S A,2000,97(15):8536-8541.
[36]Shimomura I,Matsuda M,Hammer R E,et al.Decreased IRS-2 and increased SREBP-1c lead to mixed insulin resistance and sensitivity in livers of lipodystrophic and ob/ob mice.[J].Mol Cell,2000,6(1):77-86.
[37]Ahmed M H.Byme C D.Modulation of sterol regulatory element binding proteins (SREBPs) as potential treatments for non-alcoholic fatty liver disease(NAFLD).[J].Drug Discov T oday,2007,12(17-18):740-747.
[38]Nadeau K J,Leitner J W,Gurerich I,et al.Insulin regulation of sterol regulatory element-binding protein-1 expression in L-6 muscle cells and 3T3 L1 adipocytes.[J].J Biol Chem,2004,279(33):34380-34387.
[39]Kohjima M,Higuchi N,Kato M,et al.SREBP-1c,regulated by the insulin and AMPK signaling pathways,plays a role in nonalcoholic fatty liver disease.[J].Int J Mol Med,2008,21(4):507-511.
[40]Pirola L,Frojdo S.Resveratrol:One molecule,many targets.[J].IUBMB Life,2008,60(5):323-332.
[41]Harikumar K B,Aggarwal B B.Resveratrol:A multitargeted agent for age-associated chronic diseases.[J].Cell Cycle,2008,7(8).
[42]Baur J A,Sinclair D A.Therapeutic potential of resveratrol:the in vivo evidence[J].Nat Rev Drug Discov,2006,5(6):493-506.
[1]Wittmann I,Nagy J.Are insulin resistance and atherosclerosis the consequences of oxidative stress?[J].Diabetologia,1996,39(8):1002-1003.
[2]Houstis N,Rosen E D,Lander E S.Reactive oxygen species have a causal role in multiple forms of insulin resistance.[J].Nature,2006,440(7086):944-948.
[3]Eriksson J W.Metabolic stress in insulin's target cells leads to ROS accumulation - a hypothetical common pathway causing insulin resistance.[J].FEBS Lett,2007,581(19):3734-3 742.
[4]Fridlyand L E,Philipson L H.Reactive species and early manifestation of insulin resistance in type 2 diabetes.[J].Diabetes Obes Metab,2006,8(2):136-145.
[5]Nishikawa T,Kukidome D,Sonoda K,et al.Impact of mitochondrial ROS production in the pathogenesis of insulin resistance.[J].Diabetes Res Clin Pract,2007,77 Suppl 1:161-164.
[6]Maddux B A,See W,Lawrence J C,et al.Protection against oxidative stress-induced insulin resistance in rat L6 muscle cells by mircomolar concentrations of alpha-lipoic acid.[J].Diabetes,2001,50(2):404-410.
[7]Evans J L,Goldfine I D,Maddux B A,et al.Oxidative stress and stress-activated signaling pathways:a unifying hypothesis of type 2 diabetes.[J].Endocr Rev,2002,23(5):599-622.
[8]De L C,Villegas I.Resveratrol as an antioxidant and pro-oxidant agent:mechanisms and clinical implications.[J].Biochem Soc Trans,2007,35(Pt 5):1156-1160.
[9]Orallo F.Comparative studies of the antioxidant effects of cis- and trans-resveratrol.[J].Curr Med Chem,2006,13(1):87-08.
[10]Shankar S,Singh G,Srivastava R K.Chemoprevention by resveratrol:molecular mechanisms and therapeutic potential.[J].Front Biosci,2007,12:4839-4854.
[11]Baur J A,Sinclair D A.Therapeutic potential of resveratrol:the in vivo evidence[J].Nat Rev Drug Discov,2006,5(6):493-506.
[12]Olas B,Saluk-juszczak J,Wachowicz B.D:-glucaro 1,4-lactone and resveratrol as antioxidants in blood platelets.[J].Cell Biol Toxicol,2008,24(2):180-100.
[13]陈瑗,周玫.自由基-炎症与衰老性疾病[M].北京:科学出版社,2007.1-2.
[14]Tirosh A,Potashnik R,Bashan N,et al.Oxidative stress disrupts insulin-induced cellular redistribution of insulin receptor substrate-1 and phosphatidylinositol 3-kinase in 3T3-L1 adipocytes.A putative cellular mechanism for impaired protein kinase B activation and GLUT4 translocation.[J].J Biol Chem,1999,274(15):10595-10602.
[15]Blair A S,Hajduch E,Litherland G J,et al.Regulation of glucose transport and glycogen synthesis in L6 muscle cells during oxidative stress.Evidence for cross-talk between the insulin and SAPK2/p38 mitogen-activated protein kinase signaling pathways.[J].J Biol Chem,1999,274(51):36293-36299.
[16]Lin Y,Berg A H,Iyengar P,et al.The hyperglycemia-induced inflammatory response in adipocytes:the role of reactive oxygen species.[J].J Biol Chem,2005,280(6):4617-4626.
[17]Furukawa S,Fujita T,Shimabukuro M,et al.Increased oxidative stress in obesity and its impact on metabolic syndrome.[J].J Clin Invest,2004,114(12):1752-1761.
[18]Urakawa H,Katsuki A,Sumida Y,et al.Oxidative stress is associated with adiposity and insulin resistance in men.[J].J Clin Endocrinol Metab,2003,88(10):4673-4676.
[19]Fujita K,Nishizawa H,Funahashi T,et al.Systemic oxidative stress is associated with visceral fat accumulation and the metabolic syndrome.[J].Circ J,2006,70(11):1437-1442.
[20]Martinez J,Moreno J J.Effect of resveratrol,a natural polyhenolic compound,on reactive oxygen species and prostaglandin production.[J].Biochem Pharmacol,2000,59(7):865-870.
[21]Leonard S S,Xia C,Jiang B H,et al.Resveratrol scavenges reactive oxygen species and effects radical-induced cellular responses.[J].Biochem Biophys Res Commun.2003.309(4):1017-1026.
[22]Zini R,Morin C,Bertelli A,et al.Effects of resveratrol on the rat brain respiratory chain.[J].Drugs Exp Clin Res,1999,25(2-3):87-97.
[23]Yen G C,Duh P D,Lin C W.Effects of resveratrol and 4-hexllresorcinol on hydrogen peroxide-induced oxidative DNA damage in human lymphocytes.[J].Free Radic Res,2003,37(5):509-514.
[24]Sun A Y,Sun G Y.Ethanol and oxidative mechanisms in the brain.[J].J Biomed Sci,2001,8(1):37-43.
[25]Ray P S,Maulik G,Cordis G A,et al.The red wine antioxidant resveratrol protects isolated rat hearts from ischemia reperfusion injury.[J].Free Radic Biol Med,1999,27(1-2):160-169.
[26]Sehirli O,Tozan A,Omurtag G Z,et al.Protective effect of resveratrol against naphthalene-induced oxidative stress in mice.[J].Ecotoxicol Environ Saf,2008.
[27]Gloire G,Legrand-poels S,Piette J.NF-kappaB activation by reactive oxygen species:fifteen years later.[J].Biochem Pharmacol,2006,72(11):1493-1505.
[28]Lagouge M,Argmann C,Gerhart-hines Z,et al.Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-lalpha[J].Cell,2006,127(6):1109-1122.
[29]Sun C,Zhang F,Ge X,et al.SIRT1 Improves Insulin Sensitivity under Insulin-Resistant Conditions by Repressing PTP1B.[J].Cell Metab,2007,6(4):307-319.
[30]Boily G,Seifert E L,Bevilacqua L,et al.SirT1 regulates energy metabolism and response to caloric restriction in mice.[J].PLoS ONE,2008,3(3):e1759.
[31]Hardie D G,Hawley S A,Scott J W.AMP-activated protein kinase - development of the energy sensor concept[J].J Physiol The Journal of Physiology Online,2006,574(1):7-15.
[32]Hardie D G,Sakamoto K.AMPK:a key sensor of fuel and energy status in skeletal mnscle.[J].Physiology(Bethesda),2006,21:48-60.
[33]Park I J,Hwang J T,Kim Y M,et al.Differential modulation of AMPK signaling pathways by low or high levels of exogenous reactive oxygen species in colon cancer cells.[J].Ann N Y Acad Sci,2006,1091:102-109.
[1]Scheen A J,Paquot N,Lefebvre P J.[Glucotoxicity and lipotoxicity,two implicated accomplices in the vicious circle of type 2 diabetes][J].Rev Med Liege,1999,54(6):535- 538.
[2]Durruty P,Garcia R M.[Glucotoxicity and lipotoxicity:factors in the pathogenesis and evolution of type 2 diabetes][J].Rev Med Chil,2001,129(6):671-679.
[3]Mcgarry J D.Banting lecture 2001:dysregulation of fatty acid metabolism in the etiology of type 2 diabetes.[J].Diabetes,2002,51(1):7-18.
[4]Lee Y,Hirose H,Ohneda M,et al.Beta-cell lipotoxicity in the pathogenesis of non-insulin-dependent diabetes mellitus of obese rats:impairment in adipocyte-beta-cell relationships.[J].Proc Natl Acad Sci U S A,1994,91(23):10878-10882.
[5]Unger R H.Lipotoxicity in the pathogenesis of obesity-dependent NIDDM.Genetic and clinical implications.[J].Diabetes,1995,44(8):863-870.
[6]Shang W,Yasuda K,Takahashi A,et al.Effect of high dietary fat on insulin secretion in genetically diabetic Goto-Kakizaki rats.[J].Pancreas,2002,25(41:393-399.
[7]Slawik M,Vidai-puig A J.Lipotoxicity,overnutrition and energy metabolism in aging.[J].Ageing Res Rev,2006,5(2):144-164.
[8]Defronzo R A.Dysfunctional fat cells,lipotoxicity and type 2 diabetes.[J].Int J Clin Pract Suppl,2004(143):9-21.
[9]Lewis G F,Carpentier A,Adeli K,et al.Disordered Fat Storage and Mobilization in the Pathogenesis of litsulin Resistance and Type 2 Diabetes[J].Endocr Rev Endocrine Reviews,2002,23(2):201-229.
[10]Hotamisligil G S,Arner P,Caro J F,et al.Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance.[J].J Clin Invest,1005,95(5):2409-2415.
[11]Hotamisligil G S,Shargill N S,Spiegelman B M.Adipose expression of tumor necrosis factor-alpha:direct role in obesity-linked insulin resistance.[J].Science,1003,250(5001):87-01.
[12]Fernandez-real J M,Vayreda M,Richart C,et al.Circulating interleukin 6 levels, blood pressure,and insulin sensitivity in apparently healthy men and women.[J].J Clin Endocrinol Metab,2001,86(3):1154-1159.
[13]Ronnemaa T,Pulkki K,Kaprio J.Serum soluble tumor necrosis factor-alpha receptor 2is elevated in obesity but is not related to insulin sensitivity:a study in identical twins discordant for obesity.[J].J Clin Endocrinol Metab,2000,85(8):2728-2732.
[14]Xu H,Barnes G T,Yang Q,et al.Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance.[J].J Clin Invest,2003,112(12):1821-1830.
[15]Weisberg S P,Mccann D,Desai M,et al.Obesity is associated with macrophage accumulation in adipose tissue.[J].J Clin Invest,2003,112(12):1796-1808.
[16]Wisse B E.The inflammatory syndrome:the role of adipose tissue cytokines in metabolic disorders linked to obesity.[J].J Am Soc Nephrol,2004,15(11):2792-2800.
[17]Schmidt M I,Duncan B B.Diabesity:an inflammatory metabolic condition.[J].Clin Chem Lab Med,2003,41(9):1120-1130.
[18]Ferrante A W.Obesity-induced inflammation:a metabolic dialogue in the language of inflammation.[J].J Intern Med,2007,262(4):408-414.
[19]Trayhurn P,Beattie J H.Physiological role of adipose tissue:white adipose tissue as an endocrine and secretory organ.[J].Proc Nutr Soc,2001,60(3):329-339.
[20]Gimeno R E,Klaman L D.Adipose tissue as an active endocrine organ:recent advances.[J].Curr Opin Pharmacol,2005,5(2):122-128.
[21]Matsuzawa Y.The metabolic syndrome and adipocytokines.[J].FEBS Lett,2006,580(12):2917-2921.
[22]Matsuzawa Y.Adipocytokines and metabolic syndrome.[J].Semin Vasc Med,2005,5(1):34-39.
[23]Faraj M,Lu H L,Cianflone K.Diabetes,lipids,and adipocyte secretagogues.[J].Biochem Cell Biol,2004,82(1):170-190.
[24]Moro C,Bajpeyi S,Smith S R.Determinants of intramyocellular triglyceride turnover:implications for insulin sensitivity.[J].Am J Physiol Endocrinol Metab,2008,294(2):203-213.
[25]Goodpaster B H,Wolf D.Skeletal muscle lipid accumulation in obesity,insulin resistance,and type 2 diabetes.[J].Pediatr Diabetes,2004,5(4):219-226.
[26]Ye J M,Doyle P J,Iglesias M A,et al.Peroxisome proliferator-activated receptor (PPAR)-alpha activation lowers muscle lipids and improves insulin sensitivity in high fat-fed rats:comparison with PPAR-gamma activation.[J].Diabetes,2001,50(2):411-417.
[27]Griffin M E,Marcucci M J,Cline G W,et al.Free fatty acid-induced insulin resistance is associated with activation of protein kinase C theta and alterations in the insulin signaling cascade.[J].Diabetes,1999,48(6):1270-1274.
[28]Morris R T,Laye M J,Lees S J,et al.Exercise-induced attenuation of obesity,hyperinsulinemia,and skeletal muscle lipid peroxidation in the OLETF rat.[J].J Appl Physiol,2008,104(3).708-715.
[29]Krssak M,Falk P K,Dresner A,et al.Intramyocellular lipid concentrations are correlated with insulin sensitivity in humans:a 1H NMR spectroscopy study.[J].Diabetologia,1999,42(1):113-116.
[30]Pan D A,Lillioja S,Kriketos A D,et al.Skeletal muscle triglyceride levels are inversely related to insulin action.[J].Diabetes,199 7,46(6):983-988.
[31]Sinha R,Dufour S,Petersen K F,et al.Assessment of skeletal muscle triglyceride content by(1)H nuclear magnetic resonance spectroscopy in lean and obese adolescents:relationships to insulin sensitivity,total body fat,and central adiposity.[J].Diabetes,2002,51(4):1022-1027.
[32]Krssak M,Falk P K,Dresner A,et al.Intramyocellular lipid concentrations are correlated with insulin sensitivity in humans:a 1H NMR spectroscopy study.[J].Diabetologia,1999,42(1):113-116.
[33]St-onge M P,Newcoiner B R,Buchthal S,et al.Intramyocelhilar lipid content is lower with a low-fat diet than with high-fat diets,but that may not be relevant for health.[J].An J Clin Nutr,2007,86(5):1316-1322.
[34]Goodpaster B H,He J,Watkins S,et al.Skeletal muscle lipid content and insulin resistance:evidence for a paradox in endurance-trained athletes.[J].J Clin Endocrinol Metab,2001,86(12):5755-5761.
[35]Thamer C,Machann J,Bachmann O,et al.Intramyocelhilar lipids:anthropoinetric determinants and relationships with maximal aerobic capacity and insulin sensitivity.[J].J Clin Endocrinol Metab,2003,88(4):1785-1791.
[36]Nadeau K J,Ehlers L B,Aguirre L E,et al.Exercise training and calorie restriction increase SREBP-1 expression and intramuscular triglyceride in skeletal muscle.[J].Am J Physiol Endocrinol Metab,2006,291(1):90-98.
[37]Yu C,Chen Y,Cline G W,et al.Mechanism by which fatty acids inbit insulin activation of insulin receptor substrate- 1(IRS-1)-associated phosphatidylinositol 3-kinase activity in muscle.[J].J Biol Chem,2002,277(52):50230-50236.
[38]Thompson A L,Cooney G J.Acyl-CoA inhibition of hexokinase in rat and human skeletal muscle is a potential mechanism of lipid-indced iusulin resistance.[J].Diabetes,2000,49(11):1761-1765.
[39]Cooney G J,Thompson A L,Furlet S M,et al.Muscle long-chain acyl CoA esters and insulin resistance.[J].Ann N Y Acad Sci,2002,967:196-207.
[40]Levin M C,Monetti M,Watt M J,et al.Increased lipid accumulation and iusulin resistance in transgenic mice expressing DGAT2 in glycolytic(type Ⅱ) muscle.[J].Am J Physiol Endocrinol Metab,2007,293(6):1772-1781.
[41]Utzschneider K M,Kahn S E.Review:The role of iusulin resistance in nonalcoholic fatty liver disease.[J].J Clin Endocrinol Metab,2006,91(12):4753-4761.
[42]Qureshi K,Abrams G A.Metabolic liver disease of obesity and role of adipose tissue in the pathogenesis of nonalcoholic fatty liver disease.[J].World J Gastroenterol,2007,13(26):3540-3553.
[43]Palasciano G,Moschetta A,Palmeri V O,et al.Non-alcoholic fatty liver disease in the metabolic syndrome.[J].Curr Pham Des,200 7,13(21):2193-2198.
[44]Angulo P.Obesity and nonalcoholic fatty liver disese.[J].Nutr Rev,2007,65(6 Pt 2):57-03.
[45]Kotronen A,Yki-jarvinen H.Fatty liver:a novel component of the metabolic syndrome.[J].Arterioscler Thromb Vasc Biol,2008,28(1):27-38.
[46]Bugiannesi E.Nonalcoholic fatty liver disease(NAFLD) and cardiac lipotoxcity:Another piece of the puzzle.[J].Hepatology,2008,47(1):2-4.
[47]Angulo P.Nonalcoholic fatty liver disease.[J].N Engl J Med,2002,346(16):1221-1231.
[48]Kelley D E,Mckolanis T M,Hegazi R A,et al.Fatty liver in type 2 diabetes mellitus:relation to regional adiposity,fatty acids,and insulin resistance.[J].An J Physiol Endocrinol Metab,2003,285(4):603-916.
[49]Day C P,James O F.Steatohepatitis:a tale of two "hits"?[J]. Gastroenterology,1998,114(4):842-845.
[50]Samuel V T,Liu Z X,Qu X,et al.Mechanism of hepatic insulin resistance in non-alcoholic fatty liver disease.[J].J Biol Chem,2004,279(31):32345-32353.
[51]Liu H Y,Collins Q F,Xiong Y,et al.Prologed treatment of primary hepatocytes with oleate induces insulin resistance through p38 mitogen-activated protein kinase.[J].J Biol Chem,2007,282(19):14205-14212.
[52]Nagle C A,An J,Shiota M,et al.Hepatic overexpression of glycerol-sn-3-phosphate acyltransferase 1 in rats causes insulin resistance.[J].J Biol Chem,2007,282(20):14807-14815.
[53]Newgard C B,Mcgarry J D.Metabolic coupling factors in pancreatic beta-cell signal transduction.[J].Annu Rev Biochem,1995,64:689-719.
[54]Busch A K,Cordery D,Denyer G S,et al.Expression profiling of palmitate- and oleate-regulated genes provides novel insights into the effects of chronic lipid exposure on pancreatic beta-cell function.[J].Diabetes,2002,51(4):977-987.
[55]Randle P J,Garland P B,Hales C N,et al.The glucose fatty-acid cycle.Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus.[J].Lancet,1963,1(7285):785- 789.
[56]Zhou Y P,Grill V E.Long-term exposure of rat pancreatic islets to fatty acids inhibits glucose-induced insulin secretion and biosynthesis through a glucose fatty acid cycle.[J].J Clin Invest,1994,93(2):870-876.
[57]Mcgarry J D,Dobbins R L.Fatty acids,lipotoxicity and insulin secretion.[J].Diabetologia,1999,42(2):128-138.
[58]Yoshikawa H,Tajiri Y,Sako Y,et al.Effects of free fatty acids on beta-cell functions:a possible involvement of peroxisome proliferator-activated receptors alpha or pancreatic/duodenal homeobox.[J].Metabolism,2001,50(5):613-618.
[59]Tushuizen M E,Bunck M C,Pouwels P J,et al.Pancreatic fat content and beta-cell function in men with and without type 2 diabetes.[J].Diabetes Care,2007,30(11):2916-2921.
[60]Shimabukuro M,Zhou Y T,Lee Y,et al.Troglitazone lowers islet fat and restores beta cell function of Zucker diabetic fatty rats.[J].J Biol Chem,1998,273(6):3547-3550.
[61]Wang M Y.Koyalna K,Shimabukauro M,et al.OB-Rb gene transfer to leptin-resistant islets reverses diabetogenic phenotype[J].Proceedings of the National Academy of Sciences,1998,95(2):714.
[62]Man Z W,Hirashima T,Mori S,et al.Decrease in triglyceride accumulation in tissues by restricted diet and improvement of diabetes in Otsuka Long-Evans Tokushima fatty rats,a non-insulin-dependent diabetes model.[J].Metabolism,2000,49(1):108-114.
[63]Shimabukuro M,Zhou Y T,Levi M,et al.Fatty acid-induced beta cell apoptosis:a link between obesity and diabetes.[J].Proc Natl Acad Sci U S A,1998,95(5):2498-2502.
[64]Unger R H,Zhou Y T,Orci L.Regulation of fatty acid homeostasis in cells:novel role of leptin.[J].Proc Natl Acad Sci U S A,1999,96(5):2327-2332.
[65]Unger R H,Zhou Y T.Lipotoxcity of beta-cells in obesity and in other causes of fatty acid spillover.[J].Diabetes,2001,50 Suppl 1:118-121.
[66]Wrede C E,Dickson L M,Lingohr M K,et al.Fatty acid and phorbol ester-mediated interference of mitogenic signling via novel protein kinase C isoforms in pancreatic beta-cells(INS-1).[J].J Mol Endocrinol,2003,30(3):271-286.
[67]Eitel K,Staiger H,Rieger J,et al.Protein kinase C delta activation and translocafion to the nucleus are required for fatty acid-induced apoptosis of insulin-secreting cells.[J].Diabetes,2003,52(4):991-997.
[68]Kharroubi I,Ladriere L,Cardozo A K,et al.Free fatty acids and cytokines induce pancreatic beta-cell apoptosis by different mechanisms:role of nuclear factor-kappaB and enoplasinic reticulum stress.[J].Endocrinology,2004,145(11):5087-5096.
[69]Nozuki J,Kubota H,Yoshida H,et al.The endoplasmic reticulum stress response is stiinulated throgh the continuous activation of traibcription factors ATF6 and XBP1 in Ins2+/AAkita pancreatic beta cells.[J].Genes Cells,2004,9(3):261-270.
[70]Zhou Y T,Grayburn P,Karim A,et al.Lipotoxic heart disease in obese rats:implications for human obesity.[J].Proc Natl Acad Sci U S A,2000,97(4):1784-1789.
[71]Wang M Y,Unger R H.Role of PP2C in cardiac lipid accumulation in obese rodents and its prevention by troglitazone.[J].Am J Physiol Endocrinol Metab,2005,288(1):216-221.
[72]Szczepaniak L S,Dobbins R L,Metzger G J,et al.Myocardial triglycerides and systolic function in humans in vivo evaluation by localized proton spectroscopy and cardiac imaging.[J].Magn Reson Med,2003,49(3):417-423.
[73]Sharma S,Adrogue J V,Golfman L,et al.Intramyocardial lipid accumulation in the failing human heart resembles the lipotoxic rat heart.[J].FASEB J,2004,18(14):1692-1700.
[74]Lalani A P,Karma B,Joln J,et al.Abnormal signal-averaged electrocardiogram (SAECG) in obesity.[J].Obes Res,2000,8(1):20-28.
[75]Mcgavock J M,Lingvay I,Zib I,et al.Cardiac steatosis in diabetes mellitus:a 1H-magnetic resonance spectroscopy study.[J].Circulation,2007,116(10):1170-1175.
[76]Ruberg F L.Myocardial lipid accumulation in the diabetic heart.[J].Circulation,2007,116(10):1110-1112.
[77]Van H N,Schrauwen-hinderling V B.Lipid accumulation in non-adipose tissue and lipotoxicity.[J].Physiol Behav,2007.
[78]Moorhead J F,Chan M K,El-nahas M,et al.Lipid nephrotoxcity in chronic progressive glomerular and tubulo-interstitial disease.[J].Lancet,1982,2(8311):1309-1311.
[79]Wahba I M,Mak R H.Obesity and obesity-initiated metabolic syndrome:mechanistic links to chronic kidney disease.[J].Clin J Am Soc Nephrol,2007,2(3):550-562.
[80]Weinberg J M.Lipotoxicity.[J].Kidney Int,2006,70(9):1560-1566.
[2]Monzillo L U,Hamdy O.Evaluation of insulin sensitivity in clinical practice and in research settings.[J].Nutr Rev,2003,61(12):397-412.
[3]Ferrannini E,Mari A.How to measure insulin sensitivity.[J].J Hypertens,1998,16(7):895-906.
[4]厉平,李玲,刘聪,et al.用葡萄糖钳夹技术评价各种简易胰岛素抵抗指数计算公式[J].中国糖尿病杂志,2007(12):708-710.
[5]Defronzo R A,Tobin J D,Andres R.Glucose clamp tectnique:a method for quantifying insulin secretion and resistance.[J].Am J Physiol,1979,237(3):214-223.
[6]Bergman R N,Ider Y Z,Bowden C R,et al.Quantitative estimation of insulin sensitivity.[J].Am J Physiol,1979,236(6):667-677.
[7]Matthews D R,Hosker J P,Rudenski A S,et al.Homeostasis model assessment:insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man.[J].Diabetologia,1985,28(7):412-410.
[8]Matsuda M,Defronzo R A.Insulin sensitivity indices obtained from oral glucose tolerance testing:comparison with the euglycemic insulin clamp.[J].Diabetes Care.1999,22(9):1462-1470.
[9]李光伟,潘孝仁,S L.检测人群胰岛素敏感性的一项新指数[J].中华内科杂志,1993.32(10):656-000
[10]李华,龚艳春,贾伟平,et al.三种简易胰岛素敏感性指数在糖耐量异常时的可靠性[J].高血压杂志,2004(03):204-200
[11]Mcauley K A,Williams S M,Mann J I,et al.Diagnosing insulin resistance in the general population.[J].Diabetes Care,2001,24(3):460-464.
[12]李光伟.个体胰岛素敏感性的临床评估出路在何方--兼谈2005年美国糖尿病学会年会的相关信[J].中华糖尿病杂志,2005(04):243-244.
[13]Andres R,Swerdloff R,Pozefsky T A C D.Manual feedback technique for the control of blood glucose concentration.In:Automation in Analytical Chemistry,edited by Skeggs LT Jr.[J].New York:Mediad,1966:486-491.
[14]Elahi D.In praise of the hyperglycemic clamp.A method for assessment of beta-cell sensitivity and insulin resistance.[J].Diabetes Care,1996,19(3):278-286.
[15]Sherwin R S.Evaluation of hypoglycemic counterregulation using a modification of the Andres glucose clamp.[J].Exp Gerontol,1993,28(4-5):371-380.
[16]Tappy L,Paquot N,Tounian P,et al.Assessment of glucose metabolism in humans with the simultaneous use of indirect calorimetry and tracer techniques.[J].Clin Physiol,1995,15(1):1-12.
[17]罗谋伦,郭欲晓,林志彬.大鼠正糖钳实验方法学[J].药学学报,1999(04).
[18]李晨钟,张素华,舒昌达,任伟.Wistar大鼠的正常血糖-高血浆胰岛素钳夹技术[J].重庆医科大学学报,1998,23(02):149-152.
[19]李玲.大鼠清醒和麻醉状态下胰岛素钳夹实验结果的比较[J].中国糖尿病杂志,2003(01).
[20]罗四川,李启富,刘红梅.清醒状犬态大鼠高胰岛素-正常血糖钳夹术的建立及其意义[J].重庆医科大学学报,2004(03).
[21]Frank P,Schoenhard G L,Burton E.A method for rapid and frequent blood collection from the rat tail vein.[J].J Pharmacol Methods,1991,26(3):233-238.
[22]Storlien L H,Oakes N D,Pan D A,et al.Syndromes of insulin resistance in the rat.Inducement by diet and amelioration with benfluorex.[J].Diabetes,1993,42(3):457-402.
[23]何明,涂长春.Lee's指数用于评价成年大鼠肥胖程度的探讨[J].中国临床药理学与治疗学杂志,1997,2(3):177-179
[24]Ye J M,Frangioudakis G,Iglesias M A,et al.Prior thiazolidinedione treatment preserves insulin sensitivity in normal rats during acute fatty acid elevation:role of the liver.[J].Endocrinology,2002,143(12):4527-4535.
[1]Bunyan J,Murrell E A,Shah P P.The induction of obesity in rodents by means of monosodium glutamate.[J].Br J Nutr,1976,35(1):25-39.
[2]何明,涂长春.Lee‘s指数用于评价或年大鼠肥胖程度的探讨[J].中国临床药理学与治疗学杂志,1997,2(3):177-179.
[3]Lieber C S,Leo M A,Mak K M,et al.Model of nonalcoholic steatohepatitis.[J].Am J Clin Nutr,2004,79(3):502-509.
[4]Carmiel-haggai M,Cederbaum A I,Nieto N.A high-fat diet leads to the progression of non-alcoholic fatty liver disease in obese rats.[J].FASEB J,2005,19(1):136-138.
[5]Zou Y,Li J,Lu C,et al.High-fat emulsion-induced rat model of nonalcoholic steatohepatitis.[J].Life Sci,2006,79(11):1100-1107.
[6]Svegliati-baroni G,Candelaresi C,Saccomanno S,et al.A model of insulin resistance and nonalcoholic steatohepatitis in rats:role of peroxisome proliferator-activated receptor-alpha and n-3 polyunsaturated fatty acid treatment on liver injury.[J].Am J Pathol,2006,169(3):846-860.
[7]陈世清,刘杞,孙航,et al脂防肝胰岛素抵抗大鼠模型的建立[J].中华肝脏病杂志.2005,13(2):105-108
[8]Angulo P.Obesity and nonalcoholic fatty liver disease.[J].Nutr Rev,2007,65(6 Pt 2):57-63.
[9]Angulo P.Nonalcoholic fatty liver disease.[J].N Engl J Med,2002,346(16):1221-1231.
[10]Kelley D E,Mckolanis T M,Hegazi R A,et al.Fatty liver in type 2 diabetes mellitus:relation to regional adiposity,fatty acids,and insulin resistance.[J].Am J Physiol Endocrinol Metab,2003,285(4):906-916.
[11]Day C P,James O F.Steatohepatitis:a tale of two "hits"?[J].Gastroenterology,1998,114(4):842-845.
[12]Samuel V T,Liu Z X,Qu X,et al.Mechanism of hepatic insulin resistance in non-alcoholic fatty liver disease.[J].J Biol Chem,2004,279(31):32345-32353.
[13]Das D K,Manlik N.Resveratrol in cardioprotection:a therapeutic promise of alternative medicine.[J].Mol Interv,2006,6(1):36-47.
[14]Baur J A,Sinclair D A.Therapeutic potential of resveratrol:the in vivo evidence[J].Nat Rev Drug Discov,2006,5(6):493-506.
[15]Renaud S,De L M.Wine,alcohol,platelets,and the French paradox for coronary heart disease.[J].Lancet,1992,339(8808):1523-1526.
[16]Kopp P.Resveratrol,a phytoestrogen found in red wine.A possible explanation for the conundrum of the 'French paradox'?[J].Eur J Endocrinol,1998,138(6):619-620.
[17]Renaud S,Gueguen R.The French paradox and wine drinking.[J].Novartis Found Symp,1998,216:208-37352344.
[18]Shankar S,Singh G,Srivastava R K.Chemoprevention by resveratrol:molecular mechanisms and therapeutic potential.[J].Front Biosci,2007,12:4839-4854.
[19]Baur J A,Pearson K J,Price N L,et al.Resveratrol improves health and survival of mice on a high-calorie diet[J].Nature,2006,444(7117):337-342.
[20]Lagouge M,Argmann C,Gerhart-hines Z,et al.Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-lalpha[J].Cell,2006,127(6):1109-1122.
[21]Sun C,Zhang F,Ge X,et al.SIRT1 Improves Insulin Sensitivity under Insulin-Resistant Conditions by Repressing PTP1B.[J].Cell Metab,2007,6(4):307-319.
[22]Elchebly M,Payette P,Michaliszyn E,et al.Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene.[J].Science,1999,283(5407):1544-1548.
[23]Su H C,Hung L M,Chen J K.Resveratrol,a red wine antioxidant,possesses an insulin-like effect in streptozotocin-induced diabetic rats[J].Am J Physiol Endocrinol Metab,2006,290(6):1339-1346.
[24]Chi T C,Chen W P,Chi T L,et al.Phosphatidylinositol-3-kinase is involved in the antihyperglycemic effect induced by resveratrol in streptozotocin-induced diabetic rats.[J].Life Sci,2007,80(18):1713-1720.
[25]Arichi H,Kimura Y,Okuda H,et al.Effects of stilbene components of the roots of Polygonum cuspidatum Sieb.et Zucc.on lipid metabolism[J].Chem Pharm Bull (Tokyo),1982,30(5):1766-1770.
[26]Picard F,Kurtev M,Chung N,et al.Sirtl promotes fat mobilization in white adipocytes by repressing PPAR-gamma[J].Nature,2004,429(6993):771-776.
[27]Bujanda L,Garcia-barcina M,Gutierrez-de J V,et al.Effect of resveratrol on alcohol-induced mortality and liver lesions in mice.[J].BMC Gastroenterol,2006,6:35.
[28]Winder W W,Hardie D G.AMP-activated protein kinase,a metabolic master switch:possible roles in type 2 diabetes.[J].Am J Physiol,1999,277(1 Pt 1):1-10.
[29]Carling D.The AMP-activated protein kinase cascade--a unifying system for energy control.[J].Trends Biochem Sci,2004,29(1):18-24.
[30]Hardie D G,Hawley S A,Scott J W.AMP-activated protein kinase - development of the energy sensor concept[J].J Physiol The Journal of Physiology Online,2006,574(1):7-15.
[31]Misra P,Chakrabarti R.The role of AMP kinase in diabetes.[J].Indian J Med Res,2007,125(3):389-398.
[32]Towler M C,Hardie D G.AMP-activated protein kinase in metabolic control and insulin signaling.[J].Circ Res,2007,100(3):328-341.
[33]Viollet B,Foretz M,Guigas B,et al.Activation of AMP-actiwated protein kinase in the liver:a new strategy for the management of metabolic hepatic disorders.[J].J Physiol,2006,574(Pt 1):41-53.
[34]Wang M Y,Unger R H.Role of PP2C in cardiac lipid accumulation in obese rodents and its prevention by troglitazone.[J].Am J Physiol Endocrinol Metab,2005,288(1):216-221.
[35]Zang M,Xu S,Maitland-toolan K A,et al.Polyphenols Stimulate AMP-Activated Protein Kinase,Lower Lipids,and Inhibit Accelerated Atherosclerosis in Diabetic LDL Receptor-Deficient Mice[J].Diabetes,2006,55(8):2180-2101.
[36]Chen M B,Mcainch A J,Macaulay S L,et al.Impaired activation of AMP-kinase and fatty acid oxidation by globular adiponectin in cultured human skeletal muscle of obese type 2 diabetics.[J].J Clin Endocrinol Metab,2005,90(6):3665-3672.
[37]Dasgupta B,Milbrandt J.Resveratrol stimulates AMP kinase activity in neurons.[J].Proc Natl Acad Sci U S A,2007,104(17):7217-7222.
[38]Zhou G,Myers R,Li Y,et al.Role of AMP-activated protein kinase in mechanism of metformin action[J].J.Clin.Invest.,2001,108(8):1167-1174.
[39]Shimomura I,Bashmakov Y,Horton J D.Increased levels of nuclear SREBP-1c associated with fatty livers in two morose models of diabetes mellitus.[J].J Biol Chem,1999,274(42):30028-30032.
[40]Ahmed M H,Byrne C D.Modulation of sterol regulatory element binding proteins (SREBPs) as potential treatments for non-alcoholic fatty liver disease(NAFLD).[J].Drug Discov Today,2007,12(17-18):740-747.
[1]Utzschneider K M,Kahn S E.Review:The role of insulin resistance in nonalcoholic fatty liver disease.[J].J Clin Endocrinol Metab,2006,91(12):4753-4761.
[2]Qureshi K,Abrams G A.Metabolic liver disease of obesity and role of adipose tissue in the pathogenesis of nonalcoholic fatty liver disease.[J].World J Gastroenterol,2007,13(26):3540-3553.
[3]Palasciano G,Moschetta A,Palmieri V O,et al.Non-alcoholic fatty liver disease in the metabolic syndrome.[J].Curr Pharm Des,2007,13(21):2193-2198.
[4]Angulo P.Obesity and nonalcoholic fatty liver disease.[J].Nutr Rev,2007,65(6 Pt 2):57-63.
[5]Kotronen A,Yki-jarvinen H.Fatty liver:a novel component of the metabolic syndrome.[J].Arterioscler Thromb Vasc Biol,2008,28(1):27-38.
[6]Bugianesi E.Nonalcoholic fatty liver disease(NAFLD) and cardiac lipotoxicity:Another piece of the puzzle.[J].Hepatology,2008,47(1):2-4.
[7]Day C P,James O F.Steatohepatitis:a tale of two "hits"?[J].Gastroenterology,1998,114(4):842-845.
[8]Samuel V T,Liu Z X,Qu X,et al.Mechanism of hepatic insulin resistance in non-alcoholic fatty liver disease.[J].J Biol Chem,2004,279(31):32345-32353.
[9]Levin M C,Monetti M,Watt M J,et al.Increased lipid accumulation and insulin resistance in transgenic mice expressing DGAT2 in glycolytic(type Ⅱ) muscle.[J].Am J Physiol Endocrinol Metab,2007,293(6):1772-1781.
[10]Lagouge M,Argmann C,Gerhart-hines Z,et al.Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-lalpha[J].Cell,2006,127(6):1109-1122.
[11]Elchebly M,Payette P,Michaliszyn E,et al.Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene.[J].Science,1999,283(5407):1544-1548.
[12]Su H C,Hung L M,Chen J K.Resveratrol,a red wine antioxidant,possesses an insulin-like effect in streptozotocin-induced diabetic rats[J].An J Physiol Endocrinol Metab,2006,290(6):1339-1346.
[13]Foretz M,Guichard C,Ferre P,et al.Sterol regulatory element binding protein-1c is a major mediator of insulin action on the hepatic expression of glucoldnase and lipogenesis-related genes.[J].Proc Natl Acad Sci U S A,1999,96(22):12737-12742.
[14]Dasgupta B,Milbrandt J.Resveratrol stimulates AMP kinase activity in neurons.[J].Proc Natl Acad Sci U S A,2007,104(17):7217-7222.
[15]Towler M C,Hardie D G.AMP-activated protein kinase in metabolic control and insulin signaling.[J].Circ Res,2007,100(3):328-341.
[16]Hardie D G,Sakamoto K.AMPK:a key sensor of fuel and energy status in skeletal muscle.[J].Physiology(Bethesda),2006,21:48-60.
[17]Forcet C,Billaud M.Dialogue between LKB1 and AMPK:a hot topic at the cellular pole.[J].Sci STKE,2007,2007(404):pe51.
[18]Minokoshi Y,Kim Y B,Peroni O D,et al.Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase.[J].Nature,2002,415(6869):339-343.
[19]Yamaguchi N,Kukita T,Li Y J,et al.Adiponectin inhibits reduction of TNF-alpha/RANKL-stimulated NFATc1 via the AMPK signaling.[J].FEBS Lett,2008,582(3):451-456.
[20]Yamauchi T,Kamon J,Minokoshi Y,et al.Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase.[J].Nat Med,2002,8(11):1288-1295.
[21]Zhou G,Myers R,Li Y,et al.Role of AMP-activated protein kinase in mechanism of metformin action[J].J.Clin.Invest.,2001,108(8):1167-1174.
[22]Zang M,Zuccollo A,Hou X,et al.AMP-activated Protein Kinase Is Required for the Lipid-lowering Effect of Metformin in Insulin-resistant Human HepG2 Cells[J].J.Biol.Chem.,2004,279(46):47898-47905.
[23]Fryer L G,Parbu-patel A,Carling D.The Anti-diabetic drugs rosiglitazone and metformin stimulate AMP-activated protein kinase through distinct signaling pathways.[J].J Biol Chem,2002,277(28):25226-25232.
[24]To K,Yamaza H,Komatsu T,et al.Down-regulation of AMP-activated protein kinase by calorie restriction in rat liver.[J].Exp Gerontol,2007,42(11):1063-1071.
[25]Wang M Y,Unger R H.Role of PP2C in cardiac lipid accumulation in obese rodents and its prevention by troglitazone.[J].Am J Physiol Endocrinol Metab,2005,288(1):216-221.
[26]Liu Y,Wan Q,Guan Q,et al.High-fat diet feeding impairs both the expression and activity of AMPKa in rats' skeletal muscle[J].Biochem Biophys Res Commun,2006,339(2):701-707.
[27]Chen M B,Mcainch A J,Macaulay S L,et al.Impaired activation of AMP-kinase and fatty acid oxidation by globular adiponectin in cultured human skeletal muscle of obese type 2 diabetics.[J].J Clin Endocfinol Metab,2005,90(6):3665-3672.
[28]Viollet B,Mounier R,Leclerc J,et al.Targeting AMP-activated protein kinase as a novel therapeutic approach for the treatment of metabolic disorders.[J].Diabetes Metab,2007,33(6):395-402.
[29]Misra P.AMP activated protein kinase:a next generation target for total metabolic control.[J].Expert Opin Ther Targets,2008,12(1):91-100.
[30]陈名道.脂毒性及其防治的一个关键靶点-AMPK[J].中华内分泌代谢杂志,2001,23(1):5-7.
[31]Tian W X.Inhibition of fatty acid synthase by polyphenols.[J].Curr Med Chem,2006,13(8):967-977.
[32]Eberle D,Hegarty B,Bossurd P,et al.SREBP transcription factors:master regulators of lipid homeostasis.[J].Biochimie,2004,86(11):830-848.
[33]Raghow R,Yellaturu C,Deng X,et al.SRBPs:the crossroads of physiological and pathological lipid homeostasis.[J].Trends Endocrinol Metab,2008,19(2):65-73.
[34]Shimomura I,Bashmakov Y,Horton J D.Increased levels of nuclear SREBP-1c associated with fatty livers in two mouse models of diabetes mellitus.[J].J Biol Chem,1000,274(42):30028-30032.
[35]Kakuma T,Lee Y,Higa M,et al.Leptin,troglitazone,and the expression of sterol regulatory element binding proteins in liver and pancreatic islets.[J].Proc Natl Acad Sci U S A,2000,97(15):8536-8541.
[36]Shimomura I,Matsuda M,Hammer R E,et al.Decreased IRS-2 and increased SREBP-1c lead to mixed insulin resistance and sensitivity in livers of lipodystrophic and ob/ob mice.[J].Mol Cell,2000,6(1):77-86.
[37]Ahmed M H.Byme C D.Modulation of sterol regulatory element binding proteins (SREBPs) as potential treatments for non-alcoholic fatty liver disease(NAFLD).[J].Drug Discov T oday,2007,12(17-18):740-747.
[38]Nadeau K J,Leitner J W,Gurerich I,et al.Insulin regulation of sterol regulatory element-binding protein-1 expression in L-6 muscle cells and 3T3 L1 adipocytes.[J].J Biol Chem,2004,279(33):34380-34387.
[39]Kohjima M,Higuchi N,Kato M,et al.SREBP-1c,regulated by the insulin and AMPK signaling pathways,plays a role in nonalcoholic fatty liver disease.[J].Int J Mol Med,2008,21(4):507-511.
[40]Pirola L,Frojdo S.Resveratrol:One molecule,many targets.[J].IUBMB Life,2008,60(5):323-332.
[41]Harikumar K B,Aggarwal B B.Resveratrol:A multitargeted agent for age-associated chronic diseases.[J].Cell Cycle,2008,7(8).
[42]Baur J A,Sinclair D A.Therapeutic potential of resveratrol:the in vivo evidence[J].Nat Rev Drug Discov,2006,5(6):493-506.
[1]Wittmann I,Nagy J.Are insulin resistance and atherosclerosis the consequences of oxidative stress?[J].Diabetologia,1996,39(8):1002-1003.
[2]Houstis N,Rosen E D,Lander E S.Reactive oxygen species have a causal role in multiple forms of insulin resistance.[J].Nature,2006,440(7086):944-948.
[3]Eriksson J W.Metabolic stress in insulin's target cells leads to ROS accumulation - a hypothetical common pathway causing insulin resistance.[J].FEBS Lett,2007,581(19):3734-3 742.
[4]Fridlyand L E,Philipson L H.Reactive species and early manifestation of insulin resistance in type 2 diabetes.[J].Diabetes Obes Metab,2006,8(2):136-145.
[5]Nishikawa T,Kukidome D,Sonoda K,et al.Impact of mitochondrial ROS production in the pathogenesis of insulin resistance.[J].Diabetes Res Clin Pract,2007,77 Suppl 1:161-164.
[6]Maddux B A,See W,Lawrence J C,et al.Protection against oxidative stress-induced insulin resistance in rat L6 muscle cells by mircomolar concentrations of alpha-lipoic acid.[J].Diabetes,2001,50(2):404-410.
[7]Evans J L,Goldfine I D,Maddux B A,et al.Oxidative stress and stress-activated signaling pathways:a unifying hypothesis of type 2 diabetes.[J].Endocr Rev,2002,23(5):599-622.
[8]De L C,Villegas I.Resveratrol as an antioxidant and pro-oxidant agent:mechanisms and clinical implications.[J].Biochem Soc Trans,2007,35(Pt 5):1156-1160.
[9]Orallo F.Comparative studies of the antioxidant effects of cis- and trans-resveratrol.[J].Curr Med Chem,2006,13(1):87-08.
[10]Shankar S,Singh G,Srivastava R K.Chemoprevention by resveratrol:molecular mechanisms and therapeutic potential.[J].Front Biosci,2007,12:4839-4854.
[11]Baur J A,Sinclair D A.Therapeutic potential of resveratrol:the in vivo evidence[J].Nat Rev Drug Discov,2006,5(6):493-506.
[12]Olas B,Saluk-juszczak J,Wachowicz B.D:-glucaro 1,4-lactone and resveratrol as antioxidants in blood platelets.[J].Cell Biol Toxicol,2008,24(2):180-100.
[13]陈瑗,周玫.自由基-炎症与衰老性疾病[M].北京:科学出版社,2007.1-2.
[14]Tirosh A,Potashnik R,Bashan N,et al.Oxidative stress disrupts insulin-induced cellular redistribution of insulin receptor substrate-1 and phosphatidylinositol 3-kinase in 3T3-L1 adipocytes.A putative cellular mechanism for impaired protein kinase B activation and GLUT4 translocation.[J].J Biol Chem,1999,274(15):10595-10602.
[15]Blair A S,Hajduch E,Litherland G J,et al.Regulation of glucose transport and glycogen synthesis in L6 muscle cells during oxidative stress.Evidence for cross-talk between the insulin and SAPK2/p38 mitogen-activated protein kinase signaling pathways.[J].J Biol Chem,1999,274(51):36293-36299.
[16]Lin Y,Berg A H,Iyengar P,et al.The hyperglycemia-induced inflammatory response in adipocytes:the role of reactive oxygen species.[J].J Biol Chem,2005,280(6):4617-4626.
[17]Furukawa S,Fujita T,Shimabukuro M,et al.Increased oxidative stress in obesity and its impact on metabolic syndrome.[J].J Clin Invest,2004,114(12):1752-1761.
[18]Urakawa H,Katsuki A,Sumida Y,et al.Oxidative stress is associated with adiposity and insulin resistance in men.[J].J Clin Endocrinol Metab,2003,88(10):4673-4676.
[19]Fujita K,Nishizawa H,Funahashi T,et al.Systemic oxidative stress is associated with visceral fat accumulation and the metabolic syndrome.[J].Circ J,2006,70(11):1437-1442.
[20]Martinez J,Moreno J J.Effect of resveratrol,a natural polyhenolic compound,on reactive oxygen species and prostaglandin production.[J].Biochem Pharmacol,2000,59(7):865-870.
[21]Leonard S S,Xia C,Jiang B H,et al.Resveratrol scavenges reactive oxygen species and effects radical-induced cellular responses.[J].Biochem Biophys Res Commun.2003.309(4):1017-1026.
[22]Zini R,Morin C,Bertelli A,et al.Effects of resveratrol on the rat brain respiratory chain.[J].Drugs Exp Clin Res,1999,25(2-3):87-97.
[23]Yen G C,Duh P D,Lin C W.Effects of resveratrol and 4-hexllresorcinol on hydrogen peroxide-induced oxidative DNA damage in human lymphocytes.[J].Free Radic Res,2003,37(5):509-514.
[24]Sun A Y,Sun G Y.Ethanol and oxidative mechanisms in the brain.[J].J Biomed Sci,2001,8(1):37-43.
[25]Ray P S,Maulik G,Cordis G A,et al.The red wine antioxidant resveratrol protects isolated rat hearts from ischemia reperfusion injury.[J].Free Radic Biol Med,1999,27(1-2):160-169.
[26]Sehirli O,Tozan A,Omurtag G Z,et al.Protective effect of resveratrol against naphthalene-induced oxidative stress in mice.[J].Ecotoxicol Environ Saf,2008.
[27]Gloire G,Legrand-poels S,Piette J.NF-kappaB activation by reactive oxygen species:fifteen years later.[J].Biochem Pharmacol,2006,72(11):1493-1505.
[28]Lagouge M,Argmann C,Gerhart-hines Z,et al.Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-lalpha[J].Cell,2006,127(6):1109-1122.
[29]Sun C,Zhang F,Ge X,et al.SIRT1 Improves Insulin Sensitivity under Insulin-Resistant Conditions by Repressing PTP1B.[J].Cell Metab,2007,6(4):307-319.
[30]Boily G,Seifert E L,Bevilacqua L,et al.SirT1 regulates energy metabolism and response to caloric restriction in mice.[J].PLoS ONE,2008,3(3):e1759.
[31]Hardie D G,Hawley S A,Scott J W.AMP-activated protein kinase - development of the energy sensor concept[J].J Physiol The Journal of Physiology Online,2006,574(1):7-15.
[32]Hardie D G,Sakamoto K.AMPK:a key sensor of fuel and energy status in skeletal mnscle.[J].Physiology(Bethesda),2006,21:48-60.
[33]Park I J,Hwang J T,Kim Y M,et al.Differential modulation of AMPK signaling pathways by low or high levels of exogenous reactive oxygen species in colon cancer cells.[J].Ann N Y Acad Sci,2006,1091:102-109.
[1]Scheen A J,Paquot N,Lefebvre P J.[Glucotoxicity and lipotoxicity,two implicated accomplices in the vicious circle of type 2 diabetes][J].Rev Med Liege,1999,54(6):535- 538.
[2]Durruty P,Garcia R M.[Glucotoxicity and lipotoxicity:factors in the pathogenesis and evolution of type 2 diabetes][J].Rev Med Chil,2001,129(6):671-679.
[3]Mcgarry J D.Banting lecture 2001:dysregulation of fatty acid metabolism in the etiology of type 2 diabetes.[J].Diabetes,2002,51(1):7-18.
[4]Lee Y,Hirose H,Ohneda M,et al.Beta-cell lipotoxicity in the pathogenesis of non-insulin-dependent diabetes mellitus of obese rats:impairment in adipocyte-beta-cell relationships.[J].Proc Natl Acad Sci U S A,1994,91(23):10878-10882.
[5]Unger R H.Lipotoxicity in the pathogenesis of obesity-dependent NIDDM.Genetic and clinical implications.[J].Diabetes,1995,44(8):863-870.
[6]Shang W,Yasuda K,Takahashi A,et al.Effect of high dietary fat on insulin secretion in genetically diabetic Goto-Kakizaki rats.[J].Pancreas,2002,25(41:393-399.
[7]Slawik M,Vidai-puig A J.Lipotoxicity,overnutrition and energy metabolism in aging.[J].Ageing Res Rev,2006,5(2):144-164.
[8]Defronzo R A.Dysfunctional fat cells,lipotoxicity and type 2 diabetes.[J].Int J Clin Pract Suppl,2004(143):9-21.
[9]Lewis G F,Carpentier A,Adeli K,et al.Disordered Fat Storage and Mobilization in the Pathogenesis of litsulin Resistance and Type 2 Diabetes[J].Endocr Rev Endocrine Reviews,2002,23(2):201-229.
[10]Hotamisligil G S,Arner P,Caro J F,et al.Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance.[J].J Clin Invest,1005,95(5):2409-2415.
[11]Hotamisligil G S,Shargill N S,Spiegelman B M.Adipose expression of tumor necrosis factor-alpha:direct role in obesity-linked insulin resistance.[J].Science,1003,250(5001):87-01.
[12]Fernandez-real J M,Vayreda M,Richart C,et al.Circulating interleukin 6 levels, blood pressure,and insulin sensitivity in apparently healthy men and women.[J].J Clin Endocrinol Metab,2001,86(3):1154-1159.
[13]Ronnemaa T,Pulkki K,Kaprio J.Serum soluble tumor necrosis factor-alpha receptor 2is elevated in obesity but is not related to insulin sensitivity:a study in identical twins discordant for obesity.[J].J Clin Endocrinol Metab,2000,85(8):2728-2732.
[14]Xu H,Barnes G T,Yang Q,et al.Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance.[J].J Clin Invest,2003,112(12):1821-1830.
[15]Weisberg S P,Mccann D,Desai M,et al.Obesity is associated with macrophage accumulation in adipose tissue.[J].J Clin Invest,2003,112(12):1796-1808.
[16]Wisse B E.The inflammatory syndrome:the role of adipose tissue cytokines in metabolic disorders linked to obesity.[J].J Am Soc Nephrol,2004,15(11):2792-2800.
[17]Schmidt M I,Duncan B B.Diabesity:an inflammatory metabolic condition.[J].Clin Chem Lab Med,2003,41(9):1120-1130.
[18]Ferrante A W.Obesity-induced inflammation:a metabolic dialogue in the language of inflammation.[J].J Intern Med,2007,262(4):408-414.
[19]Trayhurn P,Beattie J H.Physiological role of adipose tissue:white adipose tissue as an endocrine and secretory organ.[J].Proc Nutr Soc,2001,60(3):329-339.
[20]Gimeno R E,Klaman L D.Adipose tissue as an active endocrine organ:recent advances.[J].Curr Opin Pharmacol,2005,5(2):122-128.
[21]Matsuzawa Y.The metabolic syndrome and adipocytokines.[J].FEBS Lett,2006,580(12):2917-2921.
[22]Matsuzawa Y.Adipocytokines and metabolic syndrome.[J].Semin Vasc Med,2005,5(1):34-39.
[23]Faraj M,Lu H L,Cianflone K.Diabetes,lipids,and adipocyte secretagogues.[J].Biochem Cell Biol,2004,82(1):170-190.
[24]Moro C,Bajpeyi S,Smith S R.Determinants of intramyocellular triglyceride turnover:implications for insulin sensitivity.[J].Am J Physiol Endocrinol Metab,2008,294(2):203-213.
[25]Goodpaster B H,Wolf D.Skeletal muscle lipid accumulation in obesity,insulin resistance,and type 2 diabetes.[J].Pediatr Diabetes,2004,5(4):219-226.
[26]Ye J M,Doyle P J,Iglesias M A,et al.Peroxisome proliferator-activated receptor (PPAR)-alpha activation lowers muscle lipids and improves insulin sensitivity in high fat-fed rats:comparison with PPAR-gamma activation.[J].Diabetes,2001,50(2):411-417.
[27]Griffin M E,Marcucci M J,Cline G W,et al.Free fatty acid-induced insulin resistance is associated with activation of protein kinase C theta and alterations in the insulin signaling cascade.[J].Diabetes,1999,48(6):1270-1274.
[28]Morris R T,Laye M J,Lees S J,et al.Exercise-induced attenuation of obesity,hyperinsulinemia,and skeletal muscle lipid peroxidation in the OLETF rat.[J].J Appl Physiol,2008,104(3).708-715.
[29]Krssak M,Falk P K,Dresner A,et al.Intramyocellular lipid concentrations are correlated with insulin sensitivity in humans:a 1H NMR spectroscopy study.[J].Diabetologia,1999,42(1):113-116.
[30]Pan D A,Lillioja S,Kriketos A D,et al.Skeletal muscle triglyceride levels are inversely related to insulin action.[J].Diabetes,199 7,46(6):983-988.
[31]Sinha R,Dufour S,Petersen K F,et al.Assessment of skeletal muscle triglyceride content by(1)H nuclear magnetic resonance spectroscopy in lean and obese adolescents:relationships to insulin sensitivity,total body fat,and central adiposity.[J].Diabetes,2002,51(4):1022-1027.
[32]Krssak M,Falk P K,Dresner A,et al.Intramyocellular lipid concentrations are correlated with insulin sensitivity in humans:a 1H NMR spectroscopy study.[J].Diabetologia,1999,42(1):113-116.
[33]St-onge M P,Newcoiner B R,Buchthal S,et al.Intramyocelhilar lipid content is lower with a low-fat diet than with high-fat diets,but that may not be relevant for health.[J].An J Clin Nutr,2007,86(5):1316-1322.
[34]Goodpaster B H,He J,Watkins S,et al.Skeletal muscle lipid content and insulin resistance:evidence for a paradox in endurance-trained athletes.[J].J Clin Endocrinol Metab,2001,86(12):5755-5761.
[35]Thamer C,Machann J,Bachmann O,et al.Intramyocelhilar lipids:anthropoinetric determinants and relationships with maximal aerobic capacity and insulin sensitivity.[J].J Clin Endocrinol Metab,2003,88(4):1785-1791.
[36]Nadeau K J,Ehlers L B,Aguirre L E,et al.Exercise training and calorie restriction increase SREBP-1 expression and intramuscular triglyceride in skeletal muscle.[J].Am J Physiol Endocrinol Metab,2006,291(1):90-98.
[37]Yu C,Chen Y,Cline G W,et al.Mechanism by which fatty acids inbit insulin activation of insulin receptor substrate- 1(IRS-1)-associated phosphatidylinositol 3-kinase activity in muscle.[J].J Biol Chem,2002,277(52):50230-50236.
[38]Thompson A L,Cooney G J.Acyl-CoA inhibition of hexokinase in rat and human skeletal muscle is a potential mechanism of lipid-indced iusulin resistance.[J].Diabetes,2000,49(11):1761-1765.
[39]Cooney G J,Thompson A L,Furlet S M,et al.Muscle long-chain acyl CoA esters and insulin resistance.[J].Ann N Y Acad Sci,2002,967:196-207.
[40]Levin M C,Monetti M,Watt M J,et al.Increased lipid accumulation and iusulin resistance in transgenic mice expressing DGAT2 in glycolytic(type Ⅱ) muscle.[J].Am J Physiol Endocrinol Metab,2007,293(6):1772-1781.
[41]Utzschneider K M,Kahn S E.Review:The role of iusulin resistance in nonalcoholic fatty liver disease.[J].J Clin Endocrinol Metab,2006,91(12):4753-4761.
[42]Qureshi K,Abrams G A.Metabolic liver disease of obesity and role of adipose tissue in the pathogenesis of nonalcoholic fatty liver disease.[J].World J Gastroenterol,2007,13(26):3540-3553.
[43]Palasciano G,Moschetta A,Palmeri V O,et al.Non-alcoholic fatty liver disease in the metabolic syndrome.[J].Curr Pham Des,200 7,13(21):2193-2198.
[44]Angulo P.Obesity and nonalcoholic fatty liver disese.[J].Nutr Rev,2007,65(6 Pt 2):57-03.
[45]Kotronen A,Yki-jarvinen H.Fatty liver:a novel component of the metabolic syndrome.[J].Arterioscler Thromb Vasc Biol,2008,28(1):27-38.
[46]Bugiannesi E.Nonalcoholic fatty liver disease(NAFLD) and cardiac lipotoxcity:Another piece of the puzzle.[J].Hepatology,2008,47(1):2-4.
[47]Angulo P.Nonalcoholic fatty liver disease.[J].N Engl J Med,2002,346(16):1221-1231.
[48]Kelley D E,Mckolanis T M,Hegazi R A,et al.Fatty liver in type 2 diabetes mellitus:relation to regional adiposity,fatty acids,and insulin resistance.[J].An J Physiol Endocrinol Metab,2003,285(4):603-916.
[49]Day C P,James O F.Steatohepatitis:a tale of two "hits"?[J]. Gastroenterology,1998,114(4):842-845.
[50]Samuel V T,Liu Z X,Qu X,et al.Mechanism of hepatic insulin resistance in non-alcoholic fatty liver disease.[J].J Biol Chem,2004,279(31):32345-32353.
[51]Liu H Y,Collins Q F,Xiong Y,et al.Prologed treatment of primary hepatocytes with oleate induces insulin resistance through p38 mitogen-activated protein kinase.[J].J Biol Chem,2007,282(19):14205-14212.
[52]Nagle C A,An J,Shiota M,et al.Hepatic overexpression of glycerol-sn-3-phosphate acyltransferase 1 in rats causes insulin resistance.[J].J Biol Chem,2007,282(20):14807-14815.
[53]Newgard C B,Mcgarry J D.Metabolic coupling factors in pancreatic beta-cell signal transduction.[J].Annu Rev Biochem,1995,64:689-719.
[54]Busch A K,Cordery D,Denyer G S,et al.Expression profiling of palmitate- and oleate-regulated genes provides novel insights into the effects of chronic lipid exposure on pancreatic beta-cell function.[J].Diabetes,2002,51(4):977-987.
[55]Randle P J,Garland P B,Hales C N,et al.The glucose fatty-acid cycle.Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus.[J].Lancet,1963,1(7285):785- 789.
[56]Zhou Y P,Grill V E.Long-term exposure of rat pancreatic islets to fatty acids inhibits glucose-induced insulin secretion and biosynthesis through a glucose fatty acid cycle.[J].J Clin Invest,1994,93(2):870-876.
[57]Mcgarry J D,Dobbins R L.Fatty acids,lipotoxicity and insulin secretion.[J].Diabetologia,1999,42(2):128-138.
[58]Yoshikawa H,Tajiri Y,Sako Y,et al.Effects of free fatty acids on beta-cell functions:a possible involvement of peroxisome proliferator-activated receptors alpha or pancreatic/duodenal homeobox.[J].Metabolism,2001,50(5):613-618.
[59]Tushuizen M E,Bunck M C,Pouwels P J,et al.Pancreatic fat content and beta-cell function in men with and without type 2 diabetes.[J].Diabetes Care,2007,30(11):2916-2921.
[60]Shimabukuro M,Zhou Y T,Lee Y,et al.Troglitazone lowers islet fat and restores beta cell function of Zucker diabetic fatty rats.[J].J Biol Chem,1998,273(6):3547-3550.
[61]Wang M Y.Koyalna K,Shimabukauro M,et al.OB-Rb gene transfer to leptin-resistant islets reverses diabetogenic phenotype[J].Proceedings of the National Academy of Sciences,1998,95(2):714.
[62]Man Z W,Hirashima T,Mori S,et al.Decrease in triglyceride accumulation in tissues by restricted diet and improvement of diabetes in Otsuka Long-Evans Tokushima fatty rats,a non-insulin-dependent diabetes model.[J].Metabolism,2000,49(1):108-114.
[63]Shimabukuro M,Zhou Y T,Levi M,et al.Fatty acid-induced beta cell apoptosis:a link between obesity and diabetes.[J].Proc Natl Acad Sci U S A,1998,95(5):2498-2502.
[64]Unger R H,Zhou Y T,Orci L.Regulation of fatty acid homeostasis in cells:novel role of leptin.[J].Proc Natl Acad Sci U S A,1999,96(5):2327-2332.
[65]Unger R H,Zhou Y T.Lipotoxcity of beta-cells in obesity and in other causes of fatty acid spillover.[J].Diabetes,2001,50 Suppl 1:118-121.
[66]Wrede C E,Dickson L M,Lingohr M K,et al.Fatty acid and phorbol ester-mediated interference of mitogenic signling via novel protein kinase C isoforms in pancreatic beta-cells(INS-1).[J].J Mol Endocrinol,2003,30(3):271-286.
[67]Eitel K,Staiger H,Rieger J,et al.Protein kinase C delta activation and translocafion to the nucleus are required for fatty acid-induced apoptosis of insulin-secreting cells.[J].Diabetes,2003,52(4):991-997.
[68]Kharroubi I,Ladriere L,Cardozo A K,et al.Free fatty acids and cytokines induce pancreatic beta-cell apoptosis by different mechanisms:role of nuclear factor-kappaB and enoplasinic reticulum stress.[J].Endocrinology,2004,145(11):5087-5096.
[69]Nozuki J,Kubota H,Yoshida H,et al.The endoplasmic reticulum stress response is stiinulated throgh the continuous activation of traibcription factors ATF6 and XBP1 in Ins2+/AAkita pancreatic beta cells.[J].Genes Cells,2004,9(3):261-270.
[70]Zhou Y T,Grayburn P,Karim A,et al.Lipotoxic heart disease in obese rats:implications for human obesity.[J].Proc Natl Acad Sci U S A,2000,97(4):1784-1789.
[71]Wang M Y,Unger R H.Role of PP2C in cardiac lipid accumulation in obese rodents and its prevention by troglitazone.[J].Am J Physiol Endocrinol Metab,2005,288(1):216-221.
[72]Szczepaniak L S,Dobbins R L,Metzger G J,et al.Myocardial triglycerides and systolic function in humans in vivo evaluation by localized proton spectroscopy and cardiac imaging.[J].Magn Reson Med,2003,49(3):417-423.
[73]Sharma S,Adrogue J V,Golfman L,et al.Intramyocardial lipid accumulation in the failing human heart resembles the lipotoxic rat heart.[J].FASEB J,2004,18(14):1692-1700.
[74]Lalani A P,Karma B,Joln J,et al.Abnormal signal-averaged electrocardiogram (SAECG) in obesity.[J].Obes Res,2000,8(1):20-28.
[75]Mcgavock J M,Lingvay I,Zib I,et al.Cardiac steatosis in diabetes mellitus:a 1H-magnetic resonance spectroscopy study.[J].Circulation,2007,116(10):1170-1175.
[76]Ruberg F L.Myocardial lipid accumulation in the diabetic heart.[J].Circulation,2007,116(10):1110-1112.
[77]Van H N,Schrauwen-hinderling V B.Lipid accumulation in non-adipose tissue and lipotoxicity.[J].Physiol Behav,2007.
[78]Moorhead J F,Chan M K,El-nahas M,et al.Lipid nephrotoxcity in chronic progressive glomerular and tubulo-interstitial disease.[J].Lancet,1982,2(8311):1309-1311.
[79]Wahba I M,Mak R H.Obesity and obesity-initiated metabolic syndrome:mechanistic links to chronic kidney disease.[J].Clin J Am Soc Nephrol,2007,2(3):550-562.
[80]Weinberg J M.Lipotoxicity.[J].Kidney Int,2006,70(9):1560-1566.