PPARα/γ双激动剂GCP-02的抗糖尿病作用及其初步机制探讨
|
摘要
糖尿病是目前对人类健康威胁最大的常见疾病之一,其中90%以上是以胰岛素抵抗为主要病理特征的2型糖尿病。胰岛素抵抗不仅是2型糖尿病的病理基础,还与心血管疾病的发生密切相关。胰岛素抵抗常常伴随葡萄糖耐量异常、肥胖、脂质代谢紊乱、高血压,称为胰岛素抵抗综合征。贝特类PPARα激动剂具有良好的调脂作用,并能降低体重,改善炎症状态和血管机能。噻唑烷二酮类(TZDs)PPARγ激动剂具有胰岛素增敏作用,不但促进脂肪细胞分化、降低血糖和血胰岛素水平,还能降低血压、改善血管内皮功能和动脉粥样硬化,减轻心血管危险因子如TNFα等的损害,保护胰岛β细胞功能,在糖尿病和心血管疾病的治疗和预防方面取得了良好效果。但是部分病人出现的水肿和体重增加等副作用限制了TZDs的使用。GCP-02是本所合成的新型α-烷氧基苯丙酸衍生物,体外反向激活实验证实为PPARα/γ双激动剂,期望它能够保持PPARα和PPARγ两类激动剂的调脂和胰岛素增敏作用,同时减少和减轻副作用。
本研究采用胰岛素抵抗的肥胖MSG小鼠模型,以PPARγ激动剂罗格列酮为对照研究了GCP-02对胰岛素耐量、葡萄糖耐量、糖异生和血糖、血脂、血胰岛素水平等的影响,测定了肝脏、骨骼肌、心肌的脂质和糖原含量及心肌抗氧化能力,测定了肝脏与葡萄糖代谢相关基因的mRNA表达。为进一步探讨其作用机制,采用4种体外培养的细胞研究了GCP-02对葡萄糖转运、葡萄糖消耗、细胞活力和前脂肪细胞分化的影响,分别采用培养的人脐静脉内皮细胞和大鼠离体主动脉模型观察丁GCP-02对内皮细胞功能的影响。
结果1.GCP-02能够降低MSG小鼠非禁食血糖和空腹血糖,提高胰岛素敏感性,改善胰岛素耐量和葡萄糖耐量,抑制以左旋丙氨酸为底物的糖异生。2.GCP-02降低MSG小鼠体重,降低血胆固醇(Cho1)、甘油三酯(TG)和游离脂肪酸(FFA)水平。3.GCP-02降低MSG小鼠肝脏TG、FFA和糖原含量。4.GCP-02对血糖、胰岛素耐量、葡萄糖耐量、糖异生和肝脂、肝糖原的作用均强于阳性对照药罗格列酮。5.GCP-02降低骨骼肌糖原含量,降低心肌TG含量,提高心糞OD活性。6.GCP-02上调MSG小鼠肝脏IRS-2的mRNA表达。7.GCP-02促进HepG2细胞的葡萄糖消耗,促进HIRc-B细胞的葡萄糖消耗,促进3T3-L1前脂肪细胞的成熟分化,但不影响WB-F344细胞葡萄糖消耗。8.与HUVEC培养24小时,GCP-02对NO和ET-1合成分泌均无显著影响。9.GCP-02能降低去甲肾上腺素所致离体大鼠胸主动脉的收缩程度,其血管松弛作用与PGs和NO无关。
结论1.GCP-02增加胰岛素抵抗肥胖MSG小鼠的胰岛素敏感性、抑制糖异生、降低血糖,表明有PPARγ激动作用;有效降低血Cho1、TG和FFA,说明有PPARα激动作用。2.PPARα/γ双激动剂GCP-02的胰岛素增敏和对血糖、血脂的调节作用均强于PPARγ激动剂罗格列酮。3.GCP-02的作用可能与上调肝脏IRS-2的mRNA表达、促进葡萄糖消耗、促进脂肪细胞的分化有关。4.GCP-02抑制去甲肾上腺素性离体大鼠胸主动脉收缩,其血管松弛作用与NO和PGs无关。
Background and Objective Diabetes mellitus has become one of the main threats to human health in the 21 st century.The diabetes epidemic relates particularly to type 2 diabetes mellitus(T2DM),which accounts for 90%of cases globally.T2DM pathophysiologically arises from two defects:impaired insulin action and impairedβ-cell function/insulin secretion.Impaired insulin action,or insulin resistance,is not only the pathophysiologic basis for T2DM,but also associated closely with cardiovascular diseases.Insulin resistance often exsits together with obesity, dyslipidemia and hypertension,that are called insulin resistance syndrome.Fibrates PPARαagonists are hypolipidemic drugs by promoting fatty acid oxidation and can reduce lipid accumulation and body weight,but are not effective in blood glucose control.Thiazolidinediones(TZDs) PPARγagonists are a new class of anti-diabetic drugs with insulin-sensitizing properties.In addition to lowering blood glucose,TZDs may also benefit cardiovascular parameters,such as lipids,blood pressure, inflammatory biomarkers,endothelial function,and fibrinolytic status.However,side effects such as edema and weight gain restrict the use of TZDs in some patients.Then it's of interest to develop substances with combined PPARα/γeffects that could maintain the beneficial effects on insulin resistance and its associated atherogenic dyslipidemia while reducing the side effects.GCP-02,anα-ethoxy-phenyl-propionic acid derivative synthesized by the synthesis division of Institute of Materia Medica, Chinese Academy of Medical Sciences,has been identified by in vitro transactivation studies as a potent,selective dual activator of both PPARαand PPARγ.Here we report the primary study on the anti-diabetic effects and its mechanism of action of this compound.
Methods The research includes three parts.1.Monosodium glutamate-induced insulin resistant obese mice(MSG mice) were used to examine the action of GCP-02 in vivo.MSG mice were divided into four groups:MSG mice control group(Con), rosiglitazone group(7μmol·kg~(-1),RSG),high dose of GCP-02 group(7μmol·kg~(-1), GCP-02-H) and low dose of GCP-02 group(3.5μmol·kg~(-1),GCP-02-L).Agents were given orally once daily for 19 consecutive days,during which insulin tolerance test, oral glucose tolerance test and gluconeogenesis test were performed and in each test serum cholesterol(Chol),triglyceride(TG) and free fatty acids(FFA) were monitored. On day 19,mice were decapitated.Body length and body weight were measured. Serum was collected for the determination of insulin,alanine aminotransferase (ALT),and aspartate aminotransferase(AST).Intraperitoneal adipose,heart,liver were weighed.Liver,soleus muscle and myocardium were assayed for glycogen, Chol,TG and FFA contents.Myocardium superoxide dismutase(SOD) and malonaldehyde(MDA) were determined.The mRNA expressions of insulin receptor (IR),insulin receptor substrate 1 and -2(IRS-1,IRS-2),glucose transportor 1 and -2 (GLUT-1,GLUT-2),PPARαand PPARγ,in liver were analysed by reverse-transcription PCR.To further investigate the mechanism of action of GCP-02, 2.HepG2,HIRc-B and WB-F344 cells were used to test the effects of GCP-02 on glucose transportation,consumption and cell viability.3T3-L1 cells were used to test the effect of GCP-02 on adipocyte differentiation.3.Human umbilical vein endothelial cells(HUVEC) were cultured to test the effects of GCP-02 on NO and ET-1 secretion.The effect of GCP-02 on artery contractility was performed in rat aortic rings.
Results 1.In insulin resistant and obese MSG mice,GCP-02 improved insulin sensitivity,insulin tolerance and glucose tolerance,suppressed gluconeogenesis,the effects were more potent than RSG.2.GCP-02 prodeced more potent,rapid and stable effects than RSG in lowering serum Chol,TG and FFA.3.GCP-02 reduced body weight of MSG mice.4.GCP-02 significantly decreased glycogen,TG and FFA contents of liver,slightly decreased glycogen content of soleus muscle,reduced TG content of myocardium and increased myocardial SOD activity.5.The expression of IRS-2 mRNA in the liver was down-regulated in MSG mice and was up-regulated by GCP-02.6.GCP-02 promoted glucose consumption in both HepG2 and HIRc-B cells. 7.GCP-02 elicited similar promoting effect as RSG on 3T3-L1 cell differentiation.8. GCP-02 didn't affect NO and ET-1 production significantly in HUVEC after 24 hours of treatment.9.GCP-02 caused dose-dependent reduction of norepinephrine-induced aortic contraction by mechanisms independent of NO and PGs.
Conclusion 1.The effects on insulin sensitivity,insulin tolerance,glucose tolerance,blood glucose and gluconeogenesis indicate the activation of PPARγby GCP-02;the effects on serum Chol,TG,FFA and body weight indicate the activation of PPARαby GCP-02.2.PPARα/γdual agonist GCP-02 is more potent than PPARγagonist rosiglitazone in insulin sensitizing and in blood glucose,blood lipids controlling.3.The mechanism of GCP-02 action correlates possibly to the up-regulation of mRNA expression of IRS-2 in liver and the promotion of glucose consumption and pre-adipocyte differentiation.4.GCP-02 reduced norepinephrineinduced rat aortic contractilion by mechanisms independent of NO and PGs.
本研究采用胰岛素抵抗的肥胖MSG小鼠模型,以PPARγ激动剂罗格列酮为对照研究了GCP-02对胰岛素耐量、葡萄糖耐量、糖异生和血糖、血脂、血胰岛素水平等的影响,测定了肝脏、骨骼肌、心肌的脂质和糖原含量及心肌抗氧化能力,测定了肝脏与葡萄糖代谢相关基因的mRNA表达。为进一步探讨其作用机制,采用4种体外培养的细胞研究了GCP-02对葡萄糖转运、葡萄糖消耗、细胞活力和前脂肪细胞分化的影响,分别采用培养的人脐静脉内皮细胞和大鼠离体主动脉模型观察丁GCP-02对内皮细胞功能的影响。
结果1.GCP-02能够降低MSG小鼠非禁食血糖和空腹血糖,提高胰岛素敏感性,改善胰岛素耐量和葡萄糖耐量,抑制以左旋丙氨酸为底物的糖异生。2.GCP-02降低MSG小鼠体重,降低血胆固醇(Cho1)、甘油三酯(TG)和游离脂肪酸(FFA)水平。3.GCP-02降低MSG小鼠肝脏TG、FFA和糖原含量。4.GCP-02对血糖、胰岛素耐量、葡萄糖耐量、糖异生和肝脂、肝糖原的作用均强于阳性对照药罗格列酮。5.GCP-02降低骨骼肌糖原含量,降低心肌TG含量,提高心糞OD活性。6.GCP-02上调MSG小鼠肝脏IRS-2的mRNA表达。7.GCP-02促进HepG2细胞的葡萄糖消耗,促进HIRc-B细胞的葡萄糖消耗,促进3T3-L1前脂肪细胞的成熟分化,但不影响WB-F344细胞葡萄糖消耗。8.与HUVEC培养24小时,GCP-02对NO和ET-1合成分泌均无显著影响。9.GCP-02能降低去甲肾上腺素所致离体大鼠胸主动脉的收缩程度,其血管松弛作用与PGs和NO无关。
结论1.GCP-02增加胰岛素抵抗肥胖MSG小鼠的胰岛素敏感性、抑制糖异生、降低血糖,表明有PPARγ激动作用;有效降低血Cho1、TG和FFA,说明有PPARα激动作用。2.PPARα/γ双激动剂GCP-02的胰岛素增敏和对血糖、血脂的调节作用均强于PPARγ激动剂罗格列酮。3.GCP-02的作用可能与上调肝脏IRS-2的mRNA表达、促进葡萄糖消耗、促进脂肪细胞的分化有关。4.GCP-02抑制去甲肾上腺素性离体大鼠胸主动脉收缩,其血管松弛作用与NO和PGs无关。
Background and Objective Diabetes mellitus has become one of the main threats to human health in the 21 st century.The diabetes epidemic relates particularly to type 2 diabetes mellitus(T2DM),which accounts for 90%of cases globally.T2DM pathophysiologically arises from two defects:impaired insulin action and impairedβ-cell function/insulin secretion.Impaired insulin action,or insulin resistance,is not only the pathophysiologic basis for T2DM,but also associated closely with cardiovascular diseases.Insulin resistance often exsits together with obesity, dyslipidemia and hypertension,that are called insulin resistance syndrome.Fibrates PPARαagonists are hypolipidemic drugs by promoting fatty acid oxidation and can reduce lipid accumulation and body weight,but are not effective in blood glucose control.Thiazolidinediones(TZDs) PPARγagonists are a new class of anti-diabetic drugs with insulin-sensitizing properties.In addition to lowering blood glucose,TZDs may also benefit cardiovascular parameters,such as lipids,blood pressure, inflammatory biomarkers,endothelial function,and fibrinolytic status.However,side effects such as edema and weight gain restrict the use of TZDs in some patients.Then it's of interest to develop substances with combined PPARα/γeffects that could maintain the beneficial effects on insulin resistance and its associated atherogenic dyslipidemia while reducing the side effects.GCP-02,anα-ethoxy-phenyl-propionic acid derivative synthesized by the synthesis division of Institute of Materia Medica, Chinese Academy of Medical Sciences,has been identified by in vitro transactivation studies as a potent,selective dual activator of both PPARαand PPARγ.Here we report the primary study on the anti-diabetic effects and its mechanism of action of this compound.
Methods The research includes three parts.1.Monosodium glutamate-induced insulin resistant obese mice(MSG mice) were used to examine the action of GCP-02 in vivo.MSG mice were divided into four groups:MSG mice control group(Con), rosiglitazone group(7μmol·kg~(-1),RSG),high dose of GCP-02 group(7μmol·kg~(-1), GCP-02-H) and low dose of GCP-02 group(3.5μmol·kg~(-1),GCP-02-L).Agents were given orally once daily for 19 consecutive days,during which insulin tolerance test, oral glucose tolerance test and gluconeogenesis test were performed and in each test serum cholesterol(Chol),triglyceride(TG) and free fatty acids(FFA) were monitored. On day 19,mice were decapitated.Body length and body weight were measured. Serum was collected for the determination of insulin,alanine aminotransferase (ALT),and aspartate aminotransferase(AST).Intraperitoneal adipose,heart,liver were weighed.Liver,soleus muscle and myocardium were assayed for glycogen, Chol,TG and FFA contents.Myocardium superoxide dismutase(SOD) and malonaldehyde(MDA) were determined.The mRNA expressions of insulin receptor (IR),insulin receptor substrate 1 and -2(IRS-1,IRS-2),glucose transportor 1 and -2 (GLUT-1,GLUT-2),PPARαand PPARγ,in liver were analysed by reverse-transcription PCR.To further investigate the mechanism of action of GCP-02, 2.HepG2,HIRc-B and WB-F344 cells were used to test the effects of GCP-02 on glucose transportation,consumption and cell viability.3T3-L1 cells were used to test the effect of GCP-02 on adipocyte differentiation.3.Human umbilical vein endothelial cells(HUVEC) were cultured to test the effects of GCP-02 on NO and ET-1 secretion.The effect of GCP-02 on artery contractility was performed in rat aortic rings.
Results 1.In insulin resistant and obese MSG mice,GCP-02 improved insulin sensitivity,insulin tolerance and glucose tolerance,suppressed gluconeogenesis,the effects were more potent than RSG.2.GCP-02 prodeced more potent,rapid and stable effects than RSG in lowering serum Chol,TG and FFA.3.GCP-02 reduced body weight of MSG mice.4.GCP-02 significantly decreased glycogen,TG and FFA contents of liver,slightly decreased glycogen content of soleus muscle,reduced TG content of myocardium and increased myocardial SOD activity.5.The expression of IRS-2 mRNA in the liver was down-regulated in MSG mice and was up-regulated by GCP-02.6.GCP-02 promoted glucose consumption in both HepG2 and HIRc-B cells. 7.GCP-02 elicited similar promoting effect as RSG on 3T3-L1 cell differentiation.8. GCP-02 didn't affect NO and ET-1 production significantly in HUVEC after 24 hours of treatment.9.GCP-02 caused dose-dependent reduction of norepinephrine-induced aortic contraction by mechanisms independent of NO and PGs.
Conclusion 1.The effects on insulin sensitivity,insulin tolerance,glucose tolerance,blood glucose and gluconeogenesis indicate the activation of PPARγby GCP-02;the effects on serum Chol,TG,FFA and body weight indicate the activation of PPARαby GCP-02.2.PPARα/γdual agonist GCP-02 is more potent than PPARγagonist rosiglitazone in insulin sensitizing and in blood glucose,blood lipids controlling.3.The mechanism of GCP-02 action correlates possibly to the up-regulation of mRNA expression of IRS-2 in liver and the promotion of glucose consumption and pre-adipocyte differentiation.4.GCP-02 reduced norepinephrineinduced rat aortic contractilion by mechanisms independent of NO and PGs.
引文
1.Krssak M,Petersen KF,Dresner A,DiPietro L,Vogel SM,Rothman DL,Roden M,Shulman GI.Intramyocellular lipid concenrtationa are correlated with insulin sensitivity in humans:a 1H NMR spectroscopy study.Diabetelogia 1999;42:113-116
2.Bonow RO,Gheorghiade M.The diabetes epidemic:a national and global crisis.Am J Med 2004;116(Suppl.5A):2S-10S
3.吴多文,范华,肖晓艳.国内慢性病的现状、流行趋势及其应对策略.中国临床康复2005;9(47):126-128
4.Zimmet P,Alberti KGMM and Shaw J.Global and societal implications of the diabetes epidemic.Nature 2001;414:782-787
5. Zimmet P. Diabetes epidemiology as a trigger to diabetes research. Diabetologia 1999; 42: 499-518
6. Martens FM, Visseren FL, Lemay J, Koning EJ, Rabelink TJ. Metabolic and additional vascular effects of thiazolidinediones. Drugs 2002; 62(10): 1463-80
7. Masoudi FA, Wang Y, Inzucchi SE, Setaro JF, Havranek EP, Foody JM, Krumholz HM. Metformin and thiazolidinedione use in medicare patients with heart failure. JAMA 2003; 290: 81-85
8. Barry GS, William JH. Recent advances in peroxisome proliferator-activated receptor science. Curr Med Chem 2003; 10: 267-80
9. Kramer D, Shapiro R, Adler A, Bush E, Rondinone CM. Insulin-sensitizing effect of rosiglitazone (BRL-49653) by regulation of glucose transporters in muscle and fat of Zucker rats. Metabolism 2001; 50: 1294-1300
10. Nesto RW, Bell D, Bonow RO, Fonseca V, Grundy SM, Horton ES, Le Winter M, Porte D, Semenkovich CF, Smith S, Young LH, Kahn R. American Diabetes Association. Thiazolidinedione use, fluid retention, and congestive heart failure: a consensus statement from the American Heart Association and American Diabetes Association. Diabetes Care 2004; 27(1): 256-63
11. Brand CL, Sturis J, Gotfredsen CF, Fleckner J, Fledelius C, Hansen BF, Andersen B, Ye JM, Sauerberg P, Wassermann K. Dual PPARalpha /gamma activation provides enhanced improvement of insulin sensitivity and glycemic control in ZDF rats. Am J Physiol Endocrinol Metab 2003; 284(4): E841-854
12. Larsen PJ, Jensen PB, Sorensen RV, Larsen LK, Vrang N, Wulff EM, Wassermann K. Differential influences of peroxisome proliferator-activated receptors gamma and -alpha on food intake and energy homeostasis. Diabetes 2003; 52(9): 2249-59
13. Cai Z, Liu Q, Li PP, Guo ZR, Shen ZF. Synthesis and anti-diabetic activity of (RS)-2-ethoxy-3-{4-[2-(4-trifluoro-methanesulfonyloxy-phenyl)-ethoxy]-phenyl}-p ropionic acid. Acta Pharmacol Sin 2006; 27(5): 597-602
1.Zimmet P.Kelly West Lecture 1991.Challenges in diabetes epidemiology--from West to the rest.Diabetes Care 1992;15:232-252
2.Ruderman NB,Saha AK,Vavvas D,Witters LA.Malonyl-CoA,fuel sensing,and insulin sensitivity in humans.Am J Physiol 1999;276,E1-E18
3.丁世英,申竹芳,谢明智.MSG肥胖大鼠胰岛素抵抗特征的初步研究.中国药理学通报2001;17:181-185,
4.de Mello MA,de Souza CT,Braga LR,dos Santos JW,Ribeiro IA,Gobatto CA.Glucose tolerance and insulin action in monosodium glutamate(MSG) obese exercise-trained mice.Physiol Chem Phys Med NMR 2001;33:63-71
5.Macho L,Fickova M,Jezova D,Zorad S.Late effect of postnatal administration of monosodium glutamate on insulin action in adult mice.Physiol Res 2000;49 Suppl 1:S79-85
6.Wahli W,Braissant O,Desvergne B.Peroxisome proliferator activated receptors:transcriptional regulators of adipogenesis,lipid metabolism and more.Chem Biol 1995;2:261-6
7.孙素娟,申竹芳,陈跃腾等.结合亚油酸对胰岛素抵抗模型MSG肥胖小鼠的影响.药学学报2003;38(12):904-907
8.Barry GS,William JH.Recent advances in peroxisome proliferator-activated receptor science.Curr Med Chem 2003;10:267-80
9.Staels B and Fruchart JC.Therapeutic roles of peroxisome proliferator-activated receptor agonists.Diabetes 2005;54(8):2460-70
10.Barbier O,Torra IP,Duguay Y,Blanquart C,Fruchart JC,Glineur C,Staels B.Pleiotropic actions of peroxisome proliferator-activated receptors in lipid metabolism and atherosclerosis.Arterioscler Thromb Vasc Biol 2002;22(5):716-726
11.Kramer D,Shapiro R,Adler A,Bush E,Rondinone CM.Insulin-sensitizing effect of rosiglitazone(BRL-49653) by regulation of glucose transporters in muscle and fat of Zucker rats.Metabolism 2001;50:1294-1300
12.Bell DS.Beta-cell rejuvenation with thiazolidinediones.Am J Med 2003;115 Suppl 8A: 20S-23S
13. Mehendale HM. PPAR-alpha: a key to the mechanism of hepatoprotection by clofibrate. Toxicol Sci 2000; 57(2): 187-90
14. Nesto RW, Bell D, Bonow RO, Fonseca V, Grundy SM, Horton ES, Le Winter M, Porte D, Semenkovich CF, Smith S, Young LH, Kahn R. American Diabetes Association. Thiazolidinedione use, fluid retention, and congestive heart failure: a consensus statement from the American Heart Association and American Diabetes Association. Diabetes Care 2004; 27(1):256-63
15. Brand CL, Sturis J, Gotfredsen CF, Fleckner J, Fledelius C, Hansen BF, Andersen B, Ye JM, Sauerberg P, Wassermann K. Dual PPARalpha /gamma activation provides enhanced improvement of insulin sensitivity and glycemic control in ZDF rats. Am J Physiol Endocrinol Metab 2003; 284(4):E841-54
16. Fagerberg B, Edwards S, Halmos T, Lopatynski J, Schuster H, Stender S, Stoa-Birketvedt G, Tonstad S, Halldorsdottir S, Gause-Nilsson I. Tesaglitazar, a novel dual peroxisome proliferator-activated receptor alpha/gamma agonist, dose-dependently improves the metabolic abnormalities associated with insulin resistance in a non-diabetic population. Diabetologia 2005; 48(9): 1716-25
17. Kraegen EW, Cooney GJ, Ye J, Thompson AL.Triglyceride, fatty acids and insulin resistance—hyperinsulinemia. Exp Clin Endocrinol Diabetes 2001; 109(4): S516-26
18. Ye JM, Dzamko N, Cleasby ME, Hegarty BD, Furler SM, Cooney GJ, Kraegen EW. Direct demonstration of lipid sequestration as a mechanism by which rosiglitazone prevents fatty-acid-induced insulin resistance in the rat: comparison with metformin. Diabetologia 2004; 47(7):1306-13
19. Grimaldi PA. Regulatory role of peroxisome proliferator-activated receptor delta (PPAR delta) in muscle metabolism. A new target for metabolic syndrome treatment? Biochimie 2005; 87(1):5-8
20. Wyne KL. Free Fatty Acids and Type2 Diabetes Mellitus. Am J Med 2003; 115(8A):29S-36S
21. Mayerson AB., Hundal RS, Dufour S, Lebon V, Befroy D, Cline GW, Enocksson S, Inzucchi SE., Shulman GI., and Petersen KF. The effects of rosiglitazone on insulin sensitivity, lipolysis, and hepatic and skeletal muscle triglyceride content in patients with type 2 diabetes. Diabetes 2002; 51: 797-802
22. Guerre-Millo M, Gervois P, Raspe E, Madsen L, Poulain P, Derudas B, Herbert JM, Winegar DA, Willson TM, Fruchart JC, Berge RK, Staels B. Peroxisome proliferator-activated receptor alpha activators improve insulin sensitivity and reduce adiposity. J Biol Chem 2000; 275:16638 -16642
23. Sarafidis PA, Lasaridis AN, Nilsson PM, Pagkalos EM, Hitoglou-Makedou AD, Pliakaos CI, Kazakos KA, Yovos JG, Zebekakis PE, Tziolas IM, Tourkantonis AN. Ambulatory blood pressure reduction after rosiglitazone treatment in patients with type 2 diabetes and hypertension correlates with insulin sensitivity increase. J Hypertens 2004; 22(9): 1769-1777
24. Zhang J, Fu M, Cui T, Xiong C, Xu K, Zhong W, Xiao Y, Floyd D, Liang J, Li E, Song Q, Chen YE. Selective disruption of PPARgamma 2 impairs the development of adipose tissue and insulin sensitivity. Proc Natl Acad Sci USA 2004; 101(29): 10703-8
25. Hussein Z, Wentworth JM, Nankervis AJ, Proietto J, Colman PG.. Effectiveness and side effects of thiazolidinediones for type 2 diabetes: real-life experience from a tertiary hospital. Med J Aust 2004; 181(10): 536-9.
26. Reifel-Miller A, Otto K, Hawkins E, Barr R, Bensch WR, Bull C, Dana S, Klausing K, Martin JA, Rafaeloff-Phail R, Rafizadeh-Montrose C, Rhodes G, Robey R, Rojo I, Rungta D, Snyder D, Wilbur K, Zhang T, Zink R, Warshawsky A, Brozinick JT. A peroxisome proliferator-activated receptor alpha/gamma dual agonist with a unique in vitro profile and potent glucose and lipid effects in rodent models of type 2 diabetes and dyslipidemia.Mol Endocrinol 2005; 19(6): 1593-605
27. Doebber TW, Kelly LJ, Zhou G, Meurer R, Biswas C, Li Y, Wu MS, Ippolito MC, Chao YS, Wang PR, Wright SD, Moller DE, Berger JP. MK-0767, a novel dual PPARalpha/gamma agonist, displays robust antihyperglycemic and hypolipidemic activities. Biochem Biophys Res Commun 2004; 318(2): 323-8
28. Larsen PJ, Jensen PB, Sorensen RV, Larsen LK, Vrang N, Wulff EM, Wassermann K. Differential influences of peroxisome proliferator-activated receptors gamma and -alpha on food intake and energy homeostasis. Diabetes 2003; 52(9): 2249-59
29. Yajima K, Hirose H, Fujita H, Seto Y, Fujita H, Ukeda K, Miyashita K, Kawai T, Yamamoto Y, Ogawa T, Yamada T, Saruta T. Combination therapy with PPARgamma and PPARalpha agonists increases glucose-stimulated insulin secretion in db/db mice. Am J Physiol Endocrinol Metab 2003; 284(5): E966-71
30. Liu K, Xu L,Berger JP, Macnaul KL, Zhou G, Doebber TW, Forrest MJ, Moller DE, Jones AB. Discovery of a novel series of peroxisome proliferator-activated receptor alpha/gamma dual agonists for the treatment of type 2 diabetes and dyslipidemia. J Med Chem 2005; 48(7): 2262-5
31. Tan M, Johns D, Gonzalez Galvez G, Antunez O, Fabian G, Flores-Lozano F, Zuniga Guajardo S, Garza E, Morales H, Konkoy C, Herz M; GLAD Study Group. Effects of pioglitazone and glimepiride on glycemic control and insulin sensitivity in Mexican patients with type 2 diabetes mellitus: A multicenter, randomized, double-blind, parallel-group trial. Clin Ther 2004; 26(5):680-93
32. Zierath JR, Ryder JW, Doebber T, Woods J, Wu M, Ventre J, Li Z, McCrary C, Berger J, Zhang B, Moller DE. Role of skeletal muscle in thiazolidinedione insulin sensitizer (PPARγ agonist) action. Endocrinology 1998;139 (12): 5034-5041
33. Maggs DG, Buchanan TA, Burant CF, Cline G, Gumbiner B, Hsueh WA, Inzucchi S, Kelley D, Nolan J, Olefsky JM, Polonsky KS, Silver D, Valiquett TR, Shulman GI. Metabolic effects of troglitazone monotherapy in type 2 diabetes mellitus. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 1998; 128(3): 176-185
34. Brunmair B, Gras F, Neschen S, Roden M, Wagner L, Waldhausl W, and Furnsinn C. Direct thiazolidinedione action on isolated rat skeletal muscle fuel handling is independent of peroxisome proliferator-activated receptor-γ-mediated changes in gene expression. Diabetes 2001;50(10): 2309-2315
35. Balfour JA, McTavish D, HeelRC. Fenofibrate. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in dyslipidaemia. Drugs 1990; 40(2):260-90
1. Matsuoka M, Wispriyono B, Igisu H. Increased cytotoxicity of cadmium in fibroblasts lacking c-fos. Biochem Pharmacol 2000; 59(12):1573-1576
2. Zou C, Wang Y, Shen Z. 2-NBDG as a fluorescent indicator for direct glucose uptake measurement. J Biochem Biophys Methods 2005; 64(3): 207-215
3. Pak Y, Paule CR, Bao Y-D, Huang LC, Larner J. Insulin stimulates the biosynthesis of chiro-inositol-containing phospholipids in a rat fibroblast line expressing the human insulin receptor. Proc Natl Acad Sci USA 1993; 90: 7759-7763
4. Tsao MS, Smith JD, Nelson KG, Grisham JW. A diploid epithelial cell line from normal adult rat liver with phenotypic properties of 'oval' cells. Exp Cell Res 1984;154: 38-52
5. Usui I, Haruta T, Takata Y, Iwata M, Uno T, Takano A, Ueno E, Ishibashi O, Ishihara H, Wada T, Sasaoka T, Kobayashi M. Differential effects of palmitate on glucose uptake in rat-1 fibroblasts and 3T3-L1 adipocytes. Horm Metab Res 1999; 31(10):546-52
6. Kim S, Pak Y Caveolin-2 regulation of the cell cycle in response to insulin in Hirc-B fibroblast cells. Biochem Biophys Res Commun 2005; 330(1): 88-96
7. Machala M, Blaha L,Vondracek J, Trosko JE, Scott J, Upham BL. Inhibition of gap junctional intercellular communication by noncoplanar polychlorinated biphenyls: Inhibitory potencies and screening for potential mode(s) of action. Toxicol Sci 2003; 76: 102-111
1.Hsueh WA,Quinones ML.Role of endothelial dysfunction in insulin esistance.Am J Cardiol 2002;92(suppl):10J-17J
2.Hemandez-Pampaloni M,Quinones M,Chon Y,et al.Endothelial dysfunction is associated with subclinical atherosclerosis in insulin resistant patients.J Nucl Med 2002;80:140P
3.Dandona P,Aljada A.Endothelial dysfunction in patients with type 2 diabetes and the effects of thiazolidinedione antidiabetic agents.J Diabetes Complications 2004;18(2):91-102)
4.Mudaliar S,Chang AR,Henry RR.Thiazolidinediones,peripheral edema,and Type 2 Diabetes:incidence,pathophysiology,and clinical implications.Endocrine Practice 2003;9(5):406-416)
5.Swislocki A,Eason T,Kaysen GA.Oral administration of the nitric oxide biosynthesis inhibitor,N-Nitro-r-arginine Methyl Ester(L-NAME),causes hypertension,but not glucose intolerance or insulin resistance,in rats.Am J Hypertens 1995;8(10 Pt 1):1009-1014
6.严庆庵,王文霞,王凯,等.血管内皮细胞功能障碍性疾病的血清NO等改变.老年医学与保健2001;(4):222-224
7.Verbeuren T J,Bonhomme E,Laubie M,Simonet S.Evidence for induction of a non-endothelail NO synthase in aortae of cholesterol-fed rabbits.J Cardiovasc Pharmacol 1993;21(5):841-845
8.Schiffrin EL,Touyz RM.Vascular biology of endothelin.J Cardiovasc Pharmacol 1998;32(Suppl 3):S2-S13
9.朱雄翔,陈璧,汤朝武,徐明达,王小莉.培养HUNEC是研究炎症介质对血管EC黏附分子调节的可靠模型.第四军医大学学报(J Fourth Mil Med Univ)1998;19:394-397
10.Sarafidis PA,Lasaridis AN,Nilsson PM,Pagkalos EM,Hitoglou-Makedou AD,Pliakos CI,Kazakos KA,Yovos JG,Zebekakis PE,Tziolas IM,Tourkantonis AN.Ambulatory blood pressure reduction after rosiglitazone treatment in patients with type 2 diabetes and hypertension correlates with insulin sensitivity increase.J Hypertens.2004;22(9):1769-1777
11.Calnek DS,Mazzella L,Roser S,Roman J,Hart CM.Peroxisome proliferatoractivated receptor gamma ligands increase release of nitric oxide from endothelial cells.Arterioscler Thromb Vasc Biol 2003;23:52-57
12.St-Pierre P,Bouffard L,Maheux P.Rosiglitazone increases extravasation of macromolecules and endothelial nitric oxide synthase in skeletal muscles of the fructose-fed rat model.Biochem Pharmacol 2004;67(10):1997-2004
13.Vinik AI,Stansberry KB,Barlow PM.Rosiglitazone treatment increases nitric oxide production in human peripheral skin:a controlled clinical trial in patients with type 2 diabetes mellitus.J Diabetes Complications 2003;17(5):279-285
14.Song J,Knepper MA,Hu XQ,Verbalis JG,Ecelbarger CA.Rosiglitazone activates renal sodium- and water-reabsorptive pathways and lower blood pressure in normal rats.J Pharmacol Exp Ther 2003;308(2):426-433
15.Fujiwara T,Oshawa T,Miyamoto M,Ushiyama S,Matsuda K,Horikoshi H.Troglitazone(CS-045) actually increases skin blood flow in dexamethasoneinduced diabetic obese Zucker rats and normal rats(Abstract).Diabetes 1995;44(suppl.1):72A
16.Buchanan TA,Meehan WP,Jeng YY,Yang D,Chan TM,Nadler JL,Scott S,Rude RK,Hseuh WA.Blood pressure lowering by pioglitazone.Evidence for a direct vascular effect.J Clin Invest 1995;96(1):354-360.
1.Uwaifo GI,Ratner RE.The roles of insulin resistance,hyperinsulinemia,and thiazolidinediones in cardiovascular disease.Am J Med 2003;115 Suppl 8A:12S-19S
2.Mooradian AD.Cardiovascular disease in type 2 diabetes mellitus:current management guidelines.Arch Intern Med 2003;163:33-40
3.Willson TM,Brown PJ,Sternbach DD,Henke BR.The PPARs:from orphan receptors to drug discovery.J Med Chem 2000;43(4):527-550
4.Chinetti G,Fruchart JC,Staels B.Peroxisome proliferators-activated receptors (PPARs):nuclear receptors at the crossroads between lipid metabolism and inflammation.Inflamm Res 2000;49(10):497-505
5.Luquet S,Gaudel C,Holst D,Lopez-Soriano J,Jehl-Pietri C,Fredenrich A,Grimaldi PA.Roles of PPAR delta in lipid absorption and metabolism:a new target for the treatment of type 2 diabetes.Biochim Biophys Acta 2005;1740(2):313-317
6.Berger J,Wagner JA.Physiological and therapeutic roles of peroxisome proliferator- activated receptors.Diabetes Technol Ther 2002;4(2):163-174
7.Mohanty P,Aljada A,Ghanim H,Hofmeyer D,Tripathy D,Syed T,A1-Haddad W,Dhindsa S,Dandona P.Evidence for a potent antiinflammatory effect of osiglitazone.J Clin Endocrinol Metab 2004;89(6):2728-2735
8.Sakamoto J,Kimura H,Moriyama S,Odaka H,Momose Y,Sugiyama Y,Sawada H.Activation of human peroxisome proliferator- activated receptor(PPAR) subtypes by pioglitazone.Biochem Biophys Res Commun 2000;278(3):704-711
9.Petersen KF,Shulman GI.Pathogenesis of skeletal muscle insulin resistance in type 2 diabetes mellitus.Am J Cardiol 2002;90(5A):11G-18G
10.Roberts AW,Thomas A,Rees A,Evans M.Peroxisome proliferator-activated receptor-gamma agonists in atherosclerosis:current evidence and future directions.Curr Opin Lipidol 2003;14(6):567-573
11.Edelman SV.The role of the thiazolidinediones in the practical management of patients with type 2 diabetes and cardiovascular risk factors.Rev Cardiovasc Med 2003; 4 Suppl 6:S29-37
12. Miyazaki Y, Mahankali A, Wajcberg E, Bajaj M, Mandarino LJ, Defronzo RA. Effect of pioglitazone on circulating adipocytokine levels and insulin sensitivity in type 2 diabetic patients. J Clin Endocrinol Metab 2004; 89(9):4312-4319
13 Seufert J, Lubben G, Dietrich K, Bates PC. A comparison of the effects of thiazolidinediones and metformin on metabolic control in patients with type 2 diabetes mellitus. Clin Ther 2004; 26(6):805-818
14. Sarafidis PA, Lasaridis AN, Nilsson PM, Pagkalos EM, Hitoglou-Makedou AD, Pliakos CI, Kazakos KA, Yovos JG, Zebekakis PE, Tziolas IM, Tourkantonis AN. Ambulatory blood pressure reduction after rosiglitazone treatment in patients with type 2 diabetes and hypertension correlates with insulin sensitivity increase. J Hypertens 2004; 22(9): 1769-1777
15. Campbell IW. Long-term glycaemic control with pioglitazone in patients with type 2 diabetes. Int J Clin Pract 2004; 58(2): 192-200
16. Meriden T. Progress with thiazolidinediones in the management of type 2 diabetes mellitus. Clin Ther 2004; 26(2): 177-190
17. Smith U. Impaired ('diabetic') insulin signaling and action occur in fat cells long before glucose intolerance—is insulin resistance initiated in the adipose tissue? Int J Obes Relat Metab Disord 2002; 26(7):897-904
18. Ortmeyer HK, Bodkin NL, Haney J, Yoshioka S, Horikoshi H, Hansen BC. A thiazolidinedione improves in vivo insulin action on skeletal muscle glycogen synthase in insulin-resistant monkeys. Int J Exp Diabetes Res 2000; 1(3): 195-202
19. Kumar N, Kaul CL, Ishrath A, Dey CS. Combination of metformin and thiazolidindiones restore insulin signalling in insulin-resistant cultured myotubes. Life Sci 2004; 74(15): 1877-1888
20. Berger J, Biswas C, Hayes N, Ventre J, Wu M, Doebber TW. An antidiabetic thiazolidinedione potentiates insulin stimulation of glycogen synthase in rat adipose tissue. Endocrinology 1996; 137(5): 1984-1990
21. Gastaldelli A, Miyazaki Y, Pettiti M, Santini E, Ciociaro D, Defronzo RA, Ferrannini E. The effect of Rosiglitazone on the liver: decreased gluconeogenesis in patients with type 2 diabetes. J Clin Endocrinol Metab 2006; 91(3):806-812
22. Kraegen EW, Cooney GJ, Ye J, Thompson AL. Triglyceride, fatty acids and insulin resistance-hyperinsulinemia. Exp Clin Endocrinol Diabetes 2001; 109(4): S516-526
23. Krauss RM. Lipids and lipoproteins in patients with type 2 diabetes. Diabetes Care 2004;27(6): 1496-1504
24. Nieves DJ, Cnop M, Retzlaff B, Walden CE, Brunzell JD, Knopp RH, Kahn SE. The atherogenic lipoprotein profiles associated with obesity and insulin resistance is largely attributable to intra-abdominal fat. Diabetes 2003; 52: 172-179
25. Ovalle F, Bell DS. Lipoprotein effects of different thiazolidinediones in clinical practice. Endocr Pract 2002; 8(6):406-410
26. Fullert S, Schneider F, Haak E, Rau H, Badenhoop K, Lubben G, Usadel KH, Konrad T. Effects of pioglitazone in nondiabetic patients with arterial hypertension: a double-blind, placebo-controlled study. J Clin Endocrinol Metab 2002; 87(12):5503-5506
27. Kageyama H, Hirano T, Okada K, Ebara T, Kageyama A, Murakami T, Shioda S, Adachi M. Lipoprotein lipase mRNA in white adipose tissue but not in skeletal muscle is increased by pioglitazone through PPAR-gamma. Biochem Biophys Res Commun 2003; 305(1):22-27
28. Florkowski CM. Management of co-existing diabetes mellitus and dyslipidemia: defining the role of thiazolidinediones. Am J Cardiovasc Drugs 2002;(1): 15-21
29. Sidhu JS, Cowan D, Kaski JC. Effects of rosiglitazone on endothelial function in men with coronary artery disease without diabetes mellitus. Am J Cardiol 2004; 94(2):151-156.
30. Chaput E, Saladin R, Silvestre M, Edgar AD. Fenofibrate and rosiglitazone lower serum triglyceride with opposing effects on body weight. Biochem Biophys Res Commun 2000; 271(2):445-450
31. Ye JM, Dzamko N, Cleasby ME, Hegarty BD, Furler SM, Cooney GJ, Kraegen EW. Direct demonstration of lipid sequestration as a mechanism by which rosiglitazone prevents fatty-acid-induced insulin resistance in the rat: comparison with metformin. Diabetologia 2004; 47(7): 1306-1313
32. Miyazaki Y, Mahankali A, Matsuda M, Mahankali S, Hardies J, Cusi K, Mandarino LJ, Defronzo RA. Effect of pioglitazone on abdominal fat distribution and insulin sensitivity in type 2 diabetes patients. J Clin Endocrinol Metab 2002; 87: 2784-2791
33. Havel PJ. Update on adipocyte hormones: regulation of energy balance and carbohydrate/ lipid metabolism. Diabetes 2004;53 Suppl 1: S143-51
34. Guerre-Millo M. Adipose tissue and adipokines: for better or worse. Diabetes Metab 2004; 30(1):13-19
35. Willi SM, Kennedy A, Wallace P, Ganaway E, Rogers NL, Garvey WT. Troglitazone antagonizes metabolic effects of glucocorticoids in humans: effects on glucose tolerance, insulin sensitivity, suppression of free fatty acids, and leptin. Diabetes 2002; 51(10):2895-2902
36. Wellen KE,Uysal KT, Wiesbrock S, Yang Q, Chen H, Hotamisligil GS. Interaction of tumor necrosis factor-alpha- and thiazolidinedione-regulated pathways in obesity. Endocrinology 2004; 145(5):2214-2220
37. Murase K, Odaka H, Suzuki M, Tayuki N, Ikeda H. Pioglitazone time-dependently reduces tumour necrosis factor-alpha level in muscle and improves metabolic abnormalities in Wistar fatty rats. Diabetologia 1998; 41(3):257-264
38. Rebrin K, Steil GM, Getty L, Bergman RN. Free fatty acids as a link in the regulation of hepatic glucose output by peripheral insulin. Diabetes 1995; 44(9): 1038-1045
39. Michaud SE, Renier G. Direct regulatory effect of fatty acids on macrophage lipoprotein lipase: potential role of PPARs. Diabetes 2001; 50(3): 660-666
40. Kraegen EW, Cooney GJ, Ye JM, Thompson AL, Furler SM. The role of lipids in the pathogenesis of muscle insulin resistance and beta cell failure in type II diabetes and obesity. Exp Clin Endocrinol Diabetes 2001; 109 Suppl 2:S189-201
41. Diez JJ, Iglesias P. The role of the novel adipocyte-derived hormone adiponectin in human isease. Eur J Endocrinol 2003; 148(3):293-300
42. Yamauchi T, Kamon J, Waki H, Murakami K, Motojima K, Komeda, Ide, Kubota N,Terauchi Y,Tobe K,Miki H,Tsuchida A,Akanuma Y,Nagai R,Kimura S,Kadowaki T.The Mechanisms by which both heterozygous peroxisome proliferator-activated receptor γ(PPARγ) deficiency and PPARγ agonist improve insulin resistance.J Biol Chem 2001;276:41245-41254
43.Maeda N,Takahashi M,Funahashi T,Kihara S,Nishizawa H,Kishida K,Nagaretani H,Matsuda M,Komuro R,Ouchi N,Kuriyama H,Hotta K,Nakamura T,Shimomura I,Matsuzawa Y.PPARgamma ligands increase expression and plasma concentrations of adiponectin,an adipose-derived protein.Diabetes 2001;50(9):2094-2099
44.Lebovitz HE.Insulin secretagogues:old and new.Diabetes Reviews 1999;7:139-153
45.Bell DSH,Ovalle F.Tissue triglyceride levels in type 2 diabetes and the role of thiazolidinediones in reversing the effects of tisue hyperglyceridemia:review of the evidence in animals and humans.Endocr Pract 2001;7:135-138
46.Shimabukuro M,Ohneda M,Lee Y,Unger RH.Role of nitric oxide in obesity-induced β cell disease.J Clin Invest 1997;100:290-295
47.Butler AE,Janson J,Bonner-Weir S,Ritzel R,Rizza RA,Butler PC.Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes.Diabetes 2003;52:102-110
48.Mayerson AB,Hundal RS,Dufour S,Lebon V,Befroy D,Cline GW,Enocksson S,Inzucchi SE,Shulman GI,Petersen KF.The effects of rosiglitazone on insulin sensitivity,lipolysis,and hepatic and skeletal muscle triglyceride content in patients with type 2 diabetes.Diabetes 2002;51:797-802
49.Ovalle F,Bell DS.Clinical evidence of thiazolidinedione-induced improvevment of pancreatic β-cell function in patients with type 2 diabetes mellitus.Diabetes Obes Metab 2002;4:56-59
50.Brown AA,Hu FB.Dietary modulation of endithelial function:implications for cardiovascular disease.Am J Clin Nutr 2001;73(4):673-686
51.Hsueh WA,Quinones MJ.Role of endothelial dysfunction in insulin resistance.Am J Cardiol 2003;92(4A):10J-17J
52. Inoguchi T, Li P, Umeda F, HY Yu, Kakimoto M, Imamura M, Aoki T, Etoh T, Hashimoto T, Naruse M, Sano H, Utsumi H, Nawata H. High glucose level and free fatty acids stimulate reactive oxygen species production through protein kinase C-dependent activation of NAD(P)H oxidase in cultured vascular cells. Diabetes 2000; 49:1939-1945
53. Ridker PM. High-sensitivity C-reactive protein: potential adjunct for global risk accessment in the primary prevention of cardiovascular disease. Circulation 2001; 103(13):1813-1818
54. Fichtlscherer S, Rosenberger G, Walter DH, Breuer S, Dimmeler S, Zeiher AM. Elevated C-reactive protein levels and impaired endothelial vasoreactivity in patients with coronary artery disease. Circulation 2000; 102(9): 1000-1006
55. Moore KJ, Fitzgerald ML, Freeman MW. Peroxisome proliferator-activated receptors in macrophage biology: friend or foe? Curr Opin Lipidol 2001; 12(5): 519-527
56. Aitman TJ. CD36, insulin resistance, and coronary heart disease. Lancet 2001; 357(9257):651-652
57. Takada K, Ichiki T, Tokunou T, Funakoshi Y, Iino N, Hirano K, Kanaide H, Takeshita A. Peroxisome proliferator-activated receptor gamma activators downregulate angiotension II type 1 receptor in vascular smooth muscle cells. Circulation 2000; 102(15): 1834-1839
58. Buchanan TA, Meehan WP, Jeng YY, Yang D, Chan TM, Nadler JL, Scott S, Rude RK, Hsueh WA. Blood pressure lowering by pioglitazone. Evidence for a direct vascular effect. J Clin Invest 1995; 96(1): 354-360
59. Zhang F, Sowers JR, Ram JL, Standley PR, Peuler JD. Effects of pioglitazone on calcium channels in vascular smooth muscle. Hypertension 1994; 24: 170-175
60. Koshiyama H, Shimono D, Kuwamura N, Minamikawa J, Nakamura Y. Rapid communication: inhibitory effect of piogligatone on carotid arterial wall thickness in type 2 diabetes. J Clin Endocrinol Metab 2001; 86(7): 3452-3456
61. Howard G, O'Leary DH, Zaccaro D, Haffner S, Rewers M, Hamman R, Selby JV, Saad MF, Savage P, Bergman R. Insulin sensitivity and atherosclerosis. The insulin Resistance Atherosclerosis Study (IRAS) Investigation. Circulation 1996; 93(10): 1809-1817
62. Kato K, Satoh H, Endo Y, Yamada D, Midorikawa S, Sato W, Mizuno K, Fujita T, Tsukamoto k, Watanabe T. Thiazolidinediones down-regulate plasminogen activator inhibitor type 1 expression in human vascular endothelial cells: A possible role for PPARgamma in endothelial function. Biochem Biophys Res Commun 1999; 258(2):431-435
63. Kellerer M, Kroder G, Tippmer S, Berti L, Kiehn R, Mosthaf L, Haring H. Troglitazone prevents glucose-induced insulin resistance of insulin receptor in rat-1 fibroblasts. Diabetes 1994; 43(3):447-453
64. Ye JM, Frangioudakis G, Iglesias MA, Furler SM, Ellis B, Dzamko N, Cooney GJ, Kraegen EW. Prior thiazolidinedione treatment preserves insulin sensitivity in normal rats during acute fatty acid elevation: role of the liver. Endocrinology 2002; 143(12):4527-4535
65. Ishida H, Takizawa M, Ozawa S, Nakamichi Y, Yamaguchi S, Katsuta H, Tanaka t, Maruyama M, Katahira H, Yoshimoto K, Itagaki E, Nagamutsu S. Pioglitazone improves insulin secretory capacity and prevents the loss of beta-cell mass in obese diabetic db/db mice: Possible protection of beta cells from oxidative stress. Metabolism 2004; 53(4):488-494
66. Durbin RJ. Thiazolidinedione therapy in the prevention/delay of type 2 diabetes in patients with impaired glucose tolerance and insulin resistance. Diabetes Obes Metab 2004; 6(4):280-285
67. Buchanan TA, Xiang AH, Peters RK, Kjos SL, Marroquin A, Goico J, Ochoa C, Tan S, Berkowitz K, Hodis HN, Azen SP. Preservation of pancreatic beta-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk hispanic women. Diabetes 2002; 51(9):2796-2803
68. Palmer AJ, Roze S, Valentine WJ, Minshall ME, Lammert M, Oglesby A, Hayes C, Spinas GA. What impact would pancreatic beta-cell preservation have on life expectancy, quality-adjusted life expectancy and costs of complications in patients with type 2 diabetes? A projection using the CORE diabetes model. Curr Med Res Opin 2004;20(8 Suppl):59-66
69.Tettey JN,Maggs JL,Rapeport WG,Pirmohamed M,Park BK.Enzyme-induction dependent bioactivation of troglitazone and troglitazone quinone in vivo.Chem Res Toxicol 2001;14(8):965-974
70.Bonkovsky HL,Azar R,Bird S,Szabo G,Banner B.Severe cholestatic hepatitis caused by thiazolidinediones:risks associated with substituting rosiglitazone for troglitazone.Dig Dis Sci 2002;47(7):1632-1637
71.Dhawan M,Agrawal R,Ravi J,Gulati S,Silverman J,Nathan G,Raab S,Brodmerkel G Jr.Rosiglitazone-induced granulomatous hepatitis.J Clin Gastroenterol 2002;34(5):582-584
72.May LD,Lefkowitch JH,Kram MT,Rubin DE.Mixed hepatocellular-cholestatic liver injury after pioglitazone therapy.Ann Intern Med 2002;136(6):449-452
73.Mori Y,Murakawa Y,Okada K,Horikoshi H,Yokoyama J,Tajima N,Ikeda Y.Effect of troglitazone on body fat distribution in type 2 diabetic patients.Diabetes Care 1999;22(6):908-912
74.Ding SY Shen ZF,Xie MZ.Preliminary study of insulin resistance induced by neonatal monosodium treatment in normal Wistar rats.Chinese Pharmacological Bulletin(中国药理学通报)2001;17(2):181-185
75.Song J,Knepper MA,Hu X,Verbalis JG,Ecelbarger CA.Rosiglitazone activates renal sodium- and water-reabsorptive pathways and lower blood pressure in normal rats.J Pharmacol Exp Ther 2004;308(2):426-433
76.Mudaliar S,Chang AR,Henry RR.Thiazolidinediones,peripheral edema,and Type 2 Diabetes:incidence,pathophysiology,and clinical implications.Endocrine Practice 2003;9(5):406-416
77.Buch HN,Baskar V,Barton DM,Kamalakannan D,Akarca C,Singh BM.Combination of insulin and thiazolidinedione therapy in massively obese patients with Type 2 diabetes.Diabet Med 2002;19(7):572-574
78.Vinik AI,Stansberry KB,Barlow PM.Rosiglitazone treatment increases nitric oxide production in human peripheral skin:a controlled clinical trial in patients with type 2 diabetes mellitus.J Diabetes Complications 2003;17(5):279-285
79. Kermani A and Garg A. Thiazolidinedione-associated congestive heart failure and pulmonary edema. Mayo Clin Proc 2003; 78:1088-1091
80. Lygate CA, Hulbert K, Monfared M, Cole MA, Clarke K, Neubauer S. The PPARgamma-activator rosiglitazone does not alter remodeling but increases mortality in rats post-myocardial infarction. Cardiovasc Res 2003; 58(3): 632-637
81. Tan M, Johns D, Gonzalez GG, Antunez O, Fabian G, Flores-Lozano F, Zuniga Guajardo S, Garza E, Morales H, Konkoy C, Herz M; GLAD Study Group. Effects of pioglitazone and glimepiride on glycemic control and insulin sensitivity in Mexican patients with type 2 diabetes mellitus: A multicenter, randomized, double-blind, parallel-group trial. Clin Ther 2004; 26(5): 680-693
82. Dailey GE 3rd, Noor MA, Park JS, Bruce S, Fiedorek FT. Glycemic control with glyburide/ metformin tablets in combination with rosiglitazone in patients with type 2 diabetes: a randomized, double-blind trial. Am J Med 2004; 116(4): 223-229
2.Bonow RO,Gheorghiade M.The diabetes epidemic:a national and global crisis.Am J Med 2004;116(Suppl.5A):2S-10S
3.吴多文,范华,肖晓艳.国内慢性病的现状、流行趋势及其应对策略.中国临床康复2005;9(47):126-128
4.Zimmet P,Alberti KGMM and Shaw J.Global and societal implications of the diabetes epidemic.Nature 2001;414:782-787
5. Zimmet P. Diabetes epidemiology as a trigger to diabetes research. Diabetologia 1999; 42: 499-518
6. Martens FM, Visseren FL, Lemay J, Koning EJ, Rabelink TJ. Metabolic and additional vascular effects of thiazolidinediones. Drugs 2002; 62(10): 1463-80
7. Masoudi FA, Wang Y, Inzucchi SE, Setaro JF, Havranek EP, Foody JM, Krumholz HM. Metformin and thiazolidinedione use in medicare patients with heart failure. JAMA 2003; 290: 81-85
8. Barry GS, William JH. Recent advances in peroxisome proliferator-activated receptor science. Curr Med Chem 2003; 10: 267-80
9. Kramer D, Shapiro R, Adler A, Bush E, Rondinone CM. Insulin-sensitizing effect of rosiglitazone (BRL-49653) by regulation of glucose transporters in muscle and fat of Zucker rats. Metabolism 2001; 50: 1294-1300
10. Nesto RW, Bell D, Bonow RO, Fonseca V, Grundy SM, Horton ES, Le Winter M, Porte D, Semenkovich CF, Smith S, Young LH, Kahn R. American Diabetes Association. Thiazolidinedione use, fluid retention, and congestive heart failure: a consensus statement from the American Heart Association and American Diabetes Association. Diabetes Care 2004; 27(1): 256-63
11. Brand CL, Sturis J, Gotfredsen CF, Fleckner J, Fledelius C, Hansen BF, Andersen B, Ye JM, Sauerberg P, Wassermann K. Dual PPARalpha /gamma activation provides enhanced improvement of insulin sensitivity and glycemic control in ZDF rats. Am J Physiol Endocrinol Metab 2003; 284(4): E841-854
12. Larsen PJ, Jensen PB, Sorensen RV, Larsen LK, Vrang N, Wulff EM, Wassermann K. Differential influences of peroxisome proliferator-activated receptors gamma and -alpha on food intake and energy homeostasis. Diabetes 2003; 52(9): 2249-59
13. Cai Z, Liu Q, Li PP, Guo ZR, Shen ZF. Synthesis and anti-diabetic activity of (RS)-2-ethoxy-3-{4-[2-(4-trifluoro-methanesulfonyloxy-phenyl)-ethoxy]-phenyl}-p ropionic acid. Acta Pharmacol Sin 2006; 27(5): 597-602
1.Zimmet P.Kelly West Lecture 1991.Challenges in diabetes epidemiology--from West to the rest.Diabetes Care 1992;15:232-252
2.Ruderman NB,Saha AK,Vavvas D,Witters LA.Malonyl-CoA,fuel sensing,and insulin sensitivity in humans.Am J Physiol 1999;276,E1-E18
3.丁世英,申竹芳,谢明智.MSG肥胖大鼠胰岛素抵抗特征的初步研究.中国药理学通报2001;17:181-185,
4.de Mello MA,de Souza CT,Braga LR,dos Santos JW,Ribeiro IA,Gobatto CA.Glucose tolerance and insulin action in monosodium glutamate(MSG) obese exercise-trained mice.Physiol Chem Phys Med NMR 2001;33:63-71
5.Macho L,Fickova M,Jezova D,Zorad S.Late effect of postnatal administration of monosodium glutamate on insulin action in adult mice.Physiol Res 2000;49 Suppl 1:S79-85
6.Wahli W,Braissant O,Desvergne B.Peroxisome proliferator activated receptors:transcriptional regulators of adipogenesis,lipid metabolism and more.Chem Biol 1995;2:261-6
7.孙素娟,申竹芳,陈跃腾等.结合亚油酸对胰岛素抵抗模型MSG肥胖小鼠的影响.药学学报2003;38(12):904-907
8.Barry GS,William JH.Recent advances in peroxisome proliferator-activated receptor science.Curr Med Chem 2003;10:267-80
9.Staels B and Fruchart JC.Therapeutic roles of peroxisome proliferator-activated receptor agonists.Diabetes 2005;54(8):2460-70
10.Barbier O,Torra IP,Duguay Y,Blanquart C,Fruchart JC,Glineur C,Staels B.Pleiotropic actions of peroxisome proliferator-activated receptors in lipid metabolism and atherosclerosis.Arterioscler Thromb Vasc Biol 2002;22(5):716-726
11.Kramer D,Shapiro R,Adler A,Bush E,Rondinone CM.Insulin-sensitizing effect of rosiglitazone(BRL-49653) by regulation of glucose transporters in muscle and fat of Zucker rats.Metabolism 2001;50:1294-1300
12.Bell DS.Beta-cell rejuvenation with thiazolidinediones.Am J Med 2003;115 Suppl 8A: 20S-23S
13. Mehendale HM. PPAR-alpha: a key to the mechanism of hepatoprotection by clofibrate. Toxicol Sci 2000; 57(2): 187-90
14. Nesto RW, Bell D, Bonow RO, Fonseca V, Grundy SM, Horton ES, Le Winter M, Porte D, Semenkovich CF, Smith S, Young LH, Kahn R. American Diabetes Association. Thiazolidinedione use, fluid retention, and congestive heart failure: a consensus statement from the American Heart Association and American Diabetes Association. Diabetes Care 2004; 27(1):256-63
15. Brand CL, Sturis J, Gotfredsen CF, Fleckner J, Fledelius C, Hansen BF, Andersen B, Ye JM, Sauerberg P, Wassermann K. Dual PPARalpha /gamma activation provides enhanced improvement of insulin sensitivity and glycemic control in ZDF rats. Am J Physiol Endocrinol Metab 2003; 284(4):E841-54
16. Fagerberg B, Edwards S, Halmos T, Lopatynski J, Schuster H, Stender S, Stoa-Birketvedt G, Tonstad S, Halldorsdottir S, Gause-Nilsson I. Tesaglitazar, a novel dual peroxisome proliferator-activated receptor alpha/gamma agonist, dose-dependently improves the metabolic abnormalities associated with insulin resistance in a non-diabetic population. Diabetologia 2005; 48(9): 1716-25
17. Kraegen EW, Cooney GJ, Ye J, Thompson AL.Triglyceride, fatty acids and insulin resistance—hyperinsulinemia. Exp Clin Endocrinol Diabetes 2001; 109(4): S516-26
18. Ye JM, Dzamko N, Cleasby ME, Hegarty BD, Furler SM, Cooney GJ, Kraegen EW. Direct demonstration of lipid sequestration as a mechanism by which rosiglitazone prevents fatty-acid-induced insulin resistance in the rat: comparison with metformin. Diabetologia 2004; 47(7):1306-13
19. Grimaldi PA. Regulatory role of peroxisome proliferator-activated receptor delta (PPAR delta) in muscle metabolism. A new target for metabolic syndrome treatment? Biochimie 2005; 87(1):5-8
20. Wyne KL. Free Fatty Acids and Type2 Diabetes Mellitus. Am J Med 2003; 115(8A):29S-36S
21. Mayerson AB., Hundal RS, Dufour S, Lebon V, Befroy D, Cline GW, Enocksson S, Inzucchi SE., Shulman GI., and Petersen KF. The effects of rosiglitazone on insulin sensitivity, lipolysis, and hepatic and skeletal muscle triglyceride content in patients with type 2 diabetes. Diabetes 2002; 51: 797-802
22. Guerre-Millo M, Gervois P, Raspe E, Madsen L, Poulain P, Derudas B, Herbert JM, Winegar DA, Willson TM, Fruchart JC, Berge RK, Staels B. Peroxisome proliferator-activated receptor alpha activators improve insulin sensitivity and reduce adiposity. J Biol Chem 2000; 275:16638 -16642
23. Sarafidis PA, Lasaridis AN, Nilsson PM, Pagkalos EM, Hitoglou-Makedou AD, Pliakaos CI, Kazakos KA, Yovos JG, Zebekakis PE, Tziolas IM, Tourkantonis AN. Ambulatory blood pressure reduction after rosiglitazone treatment in patients with type 2 diabetes and hypertension correlates with insulin sensitivity increase. J Hypertens 2004; 22(9): 1769-1777
24. Zhang J, Fu M, Cui T, Xiong C, Xu K, Zhong W, Xiao Y, Floyd D, Liang J, Li E, Song Q, Chen YE. Selective disruption of PPARgamma 2 impairs the development of adipose tissue and insulin sensitivity. Proc Natl Acad Sci USA 2004; 101(29): 10703-8
25. Hussein Z, Wentworth JM, Nankervis AJ, Proietto J, Colman PG.. Effectiveness and side effects of thiazolidinediones for type 2 diabetes: real-life experience from a tertiary hospital. Med J Aust 2004; 181(10): 536-9.
26. Reifel-Miller A, Otto K, Hawkins E, Barr R, Bensch WR, Bull C, Dana S, Klausing K, Martin JA, Rafaeloff-Phail R, Rafizadeh-Montrose C, Rhodes G, Robey R, Rojo I, Rungta D, Snyder D, Wilbur K, Zhang T, Zink R, Warshawsky A, Brozinick JT. A peroxisome proliferator-activated receptor alpha/gamma dual agonist with a unique in vitro profile and potent glucose and lipid effects in rodent models of type 2 diabetes and dyslipidemia.Mol Endocrinol 2005; 19(6): 1593-605
27. Doebber TW, Kelly LJ, Zhou G, Meurer R, Biswas C, Li Y, Wu MS, Ippolito MC, Chao YS, Wang PR, Wright SD, Moller DE, Berger JP. MK-0767, a novel dual PPARalpha/gamma agonist, displays robust antihyperglycemic and hypolipidemic activities. Biochem Biophys Res Commun 2004; 318(2): 323-8
28. Larsen PJ, Jensen PB, Sorensen RV, Larsen LK, Vrang N, Wulff EM, Wassermann K. Differential influences of peroxisome proliferator-activated receptors gamma and -alpha on food intake and energy homeostasis. Diabetes 2003; 52(9): 2249-59
29. Yajima K, Hirose H, Fujita H, Seto Y, Fujita H, Ukeda K, Miyashita K, Kawai T, Yamamoto Y, Ogawa T, Yamada T, Saruta T. Combination therapy with PPARgamma and PPARalpha agonists increases glucose-stimulated insulin secretion in db/db mice. Am J Physiol Endocrinol Metab 2003; 284(5): E966-71
30. Liu K, Xu L,Berger JP, Macnaul KL, Zhou G, Doebber TW, Forrest MJ, Moller DE, Jones AB. Discovery of a novel series of peroxisome proliferator-activated receptor alpha/gamma dual agonists for the treatment of type 2 diabetes and dyslipidemia. J Med Chem 2005; 48(7): 2262-5
31. Tan M, Johns D, Gonzalez Galvez G, Antunez O, Fabian G, Flores-Lozano F, Zuniga Guajardo S, Garza E, Morales H, Konkoy C, Herz M; GLAD Study Group. Effects of pioglitazone and glimepiride on glycemic control and insulin sensitivity in Mexican patients with type 2 diabetes mellitus: A multicenter, randomized, double-blind, parallel-group trial. Clin Ther 2004; 26(5):680-93
32. Zierath JR, Ryder JW, Doebber T, Woods J, Wu M, Ventre J, Li Z, McCrary C, Berger J, Zhang B, Moller DE. Role of skeletal muscle in thiazolidinedione insulin sensitizer (PPARγ agonist) action. Endocrinology 1998;139 (12): 5034-5041
33. Maggs DG, Buchanan TA, Burant CF, Cline G, Gumbiner B, Hsueh WA, Inzucchi S, Kelley D, Nolan J, Olefsky JM, Polonsky KS, Silver D, Valiquett TR, Shulman GI. Metabolic effects of troglitazone monotherapy in type 2 diabetes mellitus. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 1998; 128(3): 176-185
34. Brunmair B, Gras F, Neschen S, Roden M, Wagner L, Waldhausl W, and Furnsinn C. Direct thiazolidinedione action on isolated rat skeletal muscle fuel handling is independent of peroxisome proliferator-activated receptor-γ-mediated changes in gene expression. Diabetes 2001;50(10): 2309-2315
35. Balfour JA, McTavish D, HeelRC. Fenofibrate. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in dyslipidaemia. Drugs 1990; 40(2):260-90
1. Matsuoka M, Wispriyono B, Igisu H. Increased cytotoxicity of cadmium in fibroblasts lacking c-fos. Biochem Pharmacol 2000; 59(12):1573-1576
2. Zou C, Wang Y, Shen Z. 2-NBDG as a fluorescent indicator for direct glucose uptake measurement. J Biochem Biophys Methods 2005; 64(3): 207-215
3. Pak Y, Paule CR, Bao Y-D, Huang LC, Larner J. Insulin stimulates the biosynthesis of chiro-inositol-containing phospholipids in a rat fibroblast line expressing the human insulin receptor. Proc Natl Acad Sci USA 1993; 90: 7759-7763
4. Tsao MS, Smith JD, Nelson KG, Grisham JW. A diploid epithelial cell line from normal adult rat liver with phenotypic properties of 'oval' cells. Exp Cell Res 1984;154: 38-52
5. Usui I, Haruta T, Takata Y, Iwata M, Uno T, Takano A, Ueno E, Ishibashi O, Ishihara H, Wada T, Sasaoka T, Kobayashi M. Differential effects of palmitate on glucose uptake in rat-1 fibroblasts and 3T3-L1 adipocytes. Horm Metab Res 1999; 31(10):546-52
6. Kim S, Pak Y Caveolin-2 regulation of the cell cycle in response to insulin in Hirc-B fibroblast cells. Biochem Biophys Res Commun 2005; 330(1): 88-96
7. Machala M, Blaha L,Vondracek J, Trosko JE, Scott J, Upham BL. Inhibition of gap junctional intercellular communication by noncoplanar polychlorinated biphenyls: Inhibitory potencies and screening for potential mode(s) of action. Toxicol Sci 2003; 76: 102-111
1.Hsueh WA,Quinones ML.Role of endothelial dysfunction in insulin esistance.Am J Cardiol 2002;92(suppl):10J-17J
2.Hemandez-Pampaloni M,Quinones M,Chon Y,et al.Endothelial dysfunction is associated with subclinical atherosclerosis in insulin resistant patients.J Nucl Med 2002;80:140P
3.Dandona P,Aljada A.Endothelial dysfunction in patients with type 2 diabetes and the effects of thiazolidinedione antidiabetic agents.J Diabetes Complications 2004;18(2):91-102)
4.Mudaliar S,Chang AR,Henry RR.Thiazolidinediones,peripheral edema,and Type 2 Diabetes:incidence,pathophysiology,and clinical implications.Endocrine Practice 2003;9(5):406-416)
5.Swislocki A,Eason T,Kaysen GA.Oral administration of the nitric oxide biosynthesis inhibitor,N-Nitro-r-arginine Methyl Ester(L-NAME),causes hypertension,but not glucose intolerance or insulin resistance,in rats.Am J Hypertens 1995;8(10 Pt 1):1009-1014
6.严庆庵,王文霞,王凯,等.血管内皮细胞功能障碍性疾病的血清NO等改变.老年医学与保健2001;(4):222-224
7.Verbeuren T J,Bonhomme E,Laubie M,Simonet S.Evidence for induction of a non-endothelail NO synthase in aortae of cholesterol-fed rabbits.J Cardiovasc Pharmacol 1993;21(5):841-845
8.Schiffrin EL,Touyz RM.Vascular biology of endothelin.J Cardiovasc Pharmacol 1998;32(Suppl 3):S2-S13
9.朱雄翔,陈璧,汤朝武,徐明达,王小莉.培养HUNEC是研究炎症介质对血管EC黏附分子调节的可靠模型.第四军医大学学报(J Fourth Mil Med Univ)1998;19:394-397
10.Sarafidis PA,Lasaridis AN,Nilsson PM,Pagkalos EM,Hitoglou-Makedou AD,Pliakos CI,Kazakos KA,Yovos JG,Zebekakis PE,Tziolas IM,Tourkantonis AN.Ambulatory blood pressure reduction after rosiglitazone treatment in patients with type 2 diabetes and hypertension correlates with insulin sensitivity increase.J Hypertens.2004;22(9):1769-1777
11.Calnek DS,Mazzella L,Roser S,Roman J,Hart CM.Peroxisome proliferatoractivated receptor gamma ligands increase release of nitric oxide from endothelial cells.Arterioscler Thromb Vasc Biol 2003;23:52-57
12.St-Pierre P,Bouffard L,Maheux P.Rosiglitazone increases extravasation of macromolecules and endothelial nitric oxide synthase in skeletal muscles of the fructose-fed rat model.Biochem Pharmacol 2004;67(10):1997-2004
13.Vinik AI,Stansberry KB,Barlow PM.Rosiglitazone treatment increases nitric oxide production in human peripheral skin:a controlled clinical trial in patients with type 2 diabetes mellitus.J Diabetes Complications 2003;17(5):279-285
14.Song J,Knepper MA,Hu XQ,Verbalis JG,Ecelbarger CA.Rosiglitazone activates renal sodium- and water-reabsorptive pathways and lower blood pressure in normal rats.J Pharmacol Exp Ther 2003;308(2):426-433
15.Fujiwara T,Oshawa T,Miyamoto M,Ushiyama S,Matsuda K,Horikoshi H.Troglitazone(CS-045) actually increases skin blood flow in dexamethasoneinduced diabetic obese Zucker rats and normal rats(Abstract).Diabetes 1995;44(suppl.1):72A
16.Buchanan TA,Meehan WP,Jeng YY,Yang D,Chan TM,Nadler JL,Scott S,Rude RK,Hseuh WA.Blood pressure lowering by pioglitazone.Evidence for a direct vascular effect.J Clin Invest 1995;96(1):354-360.
1.Uwaifo GI,Ratner RE.The roles of insulin resistance,hyperinsulinemia,and thiazolidinediones in cardiovascular disease.Am J Med 2003;115 Suppl 8A:12S-19S
2.Mooradian AD.Cardiovascular disease in type 2 diabetes mellitus:current management guidelines.Arch Intern Med 2003;163:33-40
3.Willson TM,Brown PJ,Sternbach DD,Henke BR.The PPARs:from orphan receptors to drug discovery.J Med Chem 2000;43(4):527-550
4.Chinetti G,Fruchart JC,Staels B.Peroxisome proliferators-activated receptors (PPARs):nuclear receptors at the crossroads between lipid metabolism and inflammation.Inflamm Res 2000;49(10):497-505
5.Luquet S,Gaudel C,Holst D,Lopez-Soriano J,Jehl-Pietri C,Fredenrich A,Grimaldi PA.Roles of PPAR delta in lipid absorption and metabolism:a new target for the treatment of type 2 diabetes.Biochim Biophys Acta 2005;1740(2):313-317
6.Berger J,Wagner JA.Physiological and therapeutic roles of peroxisome proliferator- activated receptors.Diabetes Technol Ther 2002;4(2):163-174
7.Mohanty P,Aljada A,Ghanim H,Hofmeyer D,Tripathy D,Syed T,A1-Haddad W,Dhindsa S,Dandona P.Evidence for a potent antiinflammatory effect of osiglitazone.J Clin Endocrinol Metab 2004;89(6):2728-2735
8.Sakamoto J,Kimura H,Moriyama S,Odaka H,Momose Y,Sugiyama Y,Sawada H.Activation of human peroxisome proliferator- activated receptor(PPAR) subtypes by pioglitazone.Biochem Biophys Res Commun 2000;278(3):704-711
9.Petersen KF,Shulman GI.Pathogenesis of skeletal muscle insulin resistance in type 2 diabetes mellitus.Am J Cardiol 2002;90(5A):11G-18G
10.Roberts AW,Thomas A,Rees A,Evans M.Peroxisome proliferator-activated receptor-gamma agonists in atherosclerosis:current evidence and future directions.Curr Opin Lipidol 2003;14(6):567-573
11.Edelman SV.The role of the thiazolidinediones in the practical management of patients with type 2 diabetes and cardiovascular risk factors.Rev Cardiovasc Med 2003; 4 Suppl 6:S29-37
12. Miyazaki Y, Mahankali A, Wajcberg E, Bajaj M, Mandarino LJ, Defronzo RA. Effect of pioglitazone on circulating adipocytokine levels and insulin sensitivity in type 2 diabetic patients. J Clin Endocrinol Metab 2004; 89(9):4312-4319
13 Seufert J, Lubben G, Dietrich K, Bates PC. A comparison of the effects of thiazolidinediones and metformin on metabolic control in patients with type 2 diabetes mellitus. Clin Ther 2004; 26(6):805-818
14. Sarafidis PA, Lasaridis AN, Nilsson PM, Pagkalos EM, Hitoglou-Makedou AD, Pliakos CI, Kazakos KA, Yovos JG, Zebekakis PE, Tziolas IM, Tourkantonis AN. Ambulatory blood pressure reduction after rosiglitazone treatment in patients with type 2 diabetes and hypertension correlates with insulin sensitivity increase. J Hypertens 2004; 22(9): 1769-1777
15. Campbell IW. Long-term glycaemic control with pioglitazone in patients with type 2 diabetes. Int J Clin Pract 2004; 58(2): 192-200
16. Meriden T. Progress with thiazolidinediones in the management of type 2 diabetes mellitus. Clin Ther 2004; 26(2): 177-190
17. Smith U. Impaired ('diabetic') insulin signaling and action occur in fat cells long before glucose intolerance—is insulin resistance initiated in the adipose tissue? Int J Obes Relat Metab Disord 2002; 26(7):897-904
18. Ortmeyer HK, Bodkin NL, Haney J, Yoshioka S, Horikoshi H, Hansen BC. A thiazolidinedione improves in vivo insulin action on skeletal muscle glycogen synthase in insulin-resistant monkeys. Int J Exp Diabetes Res 2000; 1(3): 195-202
19. Kumar N, Kaul CL, Ishrath A, Dey CS. Combination of metformin and thiazolidindiones restore insulin signalling in insulin-resistant cultured myotubes. Life Sci 2004; 74(15): 1877-1888
20. Berger J, Biswas C, Hayes N, Ventre J, Wu M, Doebber TW. An antidiabetic thiazolidinedione potentiates insulin stimulation of glycogen synthase in rat adipose tissue. Endocrinology 1996; 137(5): 1984-1990
21. Gastaldelli A, Miyazaki Y, Pettiti M, Santini E, Ciociaro D, Defronzo RA, Ferrannini E. The effect of Rosiglitazone on the liver: decreased gluconeogenesis in patients with type 2 diabetes. J Clin Endocrinol Metab 2006; 91(3):806-812
22. Kraegen EW, Cooney GJ, Ye J, Thompson AL. Triglyceride, fatty acids and insulin resistance-hyperinsulinemia. Exp Clin Endocrinol Diabetes 2001; 109(4): S516-526
23. Krauss RM. Lipids and lipoproteins in patients with type 2 diabetes. Diabetes Care 2004;27(6): 1496-1504
24. Nieves DJ, Cnop M, Retzlaff B, Walden CE, Brunzell JD, Knopp RH, Kahn SE. The atherogenic lipoprotein profiles associated with obesity and insulin resistance is largely attributable to intra-abdominal fat. Diabetes 2003; 52: 172-179
25. Ovalle F, Bell DS. Lipoprotein effects of different thiazolidinediones in clinical practice. Endocr Pract 2002; 8(6):406-410
26. Fullert S, Schneider F, Haak E, Rau H, Badenhoop K, Lubben G, Usadel KH, Konrad T. Effects of pioglitazone in nondiabetic patients with arterial hypertension: a double-blind, placebo-controlled study. J Clin Endocrinol Metab 2002; 87(12):5503-5506
27. Kageyama H, Hirano T, Okada K, Ebara T, Kageyama A, Murakami T, Shioda S, Adachi M. Lipoprotein lipase mRNA in white adipose tissue but not in skeletal muscle is increased by pioglitazone through PPAR-gamma. Biochem Biophys Res Commun 2003; 305(1):22-27
28. Florkowski CM. Management of co-existing diabetes mellitus and dyslipidemia: defining the role of thiazolidinediones. Am J Cardiovasc Drugs 2002;(1): 15-21
29. Sidhu JS, Cowan D, Kaski JC. Effects of rosiglitazone on endothelial function in men with coronary artery disease without diabetes mellitus. Am J Cardiol 2004; 94(2):151-156.
30. Chaput E, Saladin R, Silvestre M, Edgar AD. Fenofibrate and rosiglitazone lower serum triglyceride with opposing effects on body weight. Biochem Biophys Res Commun 2000; 271(2):445-450
31. Ye JM, Dzamko N, Cleasby ME, Hegarty BD, Furler SM, Cooney GJ, Kraegen EW. Direct demonstration of lipid sequestration as a mechanism by which rosiglitazone prevents fatty-acid-induced insulin resistance in the rat: comparison with metformin. Diabetologia 2004; 47(7): 1306-1313
32. Miyazaki Y, Mahankali A, Matsuda M, Mahankali S, Hardies J, Cusi K, Mandarino LJ, Defronzo RA. Effect of pioglitazone on abdominal fat distribution and insulin sensitivity in type 2 diabetes patients. J Clin Endocrinol Metab 2002; 87: 2784-2791
33. Havel PJ. Update on adipocyte hormones: regulation of energy balance and carbohydrate/ lipid metabolism. Diabetes 2004;53 Suppl 1: S143-51
34. Guerre-Millo M. Adipose tissue and adipokines: for better or worse. Diabetes Metab 2004; 30(1):13-19
35. Willi SM, Kennedy A, Wallace P, Ganaway E, Rogers NL, Garvey WT. Troglitazone antagonizes metabolic effects of glucocorticoids in humans: effects on glucose tolerance, insulin sensitivity, suppression of free fatty acids, and leptin. Diabetes 2002; 51(10):2895-2902
36. Wellen KE,Uysal KT, Wiesbrock S, Yang Q, Chen H, Hotamisligil GS. Interaction of tumor necrosis factor-alpha- and thiazolidinedione-regulated pathways in obesity. Endocrinology 2004; 145(5):2214-2220
37. Murase K, Odaka H, Suzuki M, Tayuki N, Ikeda H. Pioglitazone time-dependently reduces tumour necrosis factor-alpha level in muscle and improves metabolic abnormalities in Wistar fatty rats. Diabetologia 1998; 41(3):257-264
38. Rebrin K, Steil GM, Getty L, Bergman RN. Free fatty acids as a link in the regulation of hepatic glucose output by peripheral insulin. Diabetes 1995; 44(9): 1038-1045
39. Michaud SE, Renier G. Direct regulatory effect of fatty acids on macrophage lipoprotein lipase: potential role of PPARs. Diabetes 2001; 50(3): 660-666
40. Kraegen EW, Cooney GJ, Ye JM, Thompson AL, Furler SM. The role of lipids in the pathogenesis of muscle insulin resistance and beta cell failure in type II diabetes and obesity. Exp Clin Endocrinol Diabetes 2001; 109 Suppl 2:S189-201
41. Diez JJ, Iglesias P. The role of the novel adipocyte-derived hormone adiponectin in human isease. Eur J Endocrinol 2003; 148(3):293-300
42. Yamauchi T, Kamon J, Waki H, Murakami K, Motojima K, Komeda, Ide, Kubota N,Terauchi Y,Tobe K,Miki H,Tsuchida A,Akanuma Y,Nagai R,Kimura S,Kadowaki T.The Mechanisms by which both heterozygous peroxisome proliferator-activated receptor γ(PPARγ) deficiency and PPARγ agonist improve insulin resistance.J Biol Chem 2001;276:41245-41254
43.Maeda N,Takahashi M,Funahashi T,Kihara S,Nishizawa H,Kishida K,Nagaretani H,Matsuda M,Komuro R,Ouchi N,Kuriyama H,Hotta K,Nakamura T,Shimomura I,Matsuzawa Y.PPARgamma ligands increase expression and plasma concentrations of adiponectin,an adipose-derived protein.Diabetes 2001;50(9):2094-2099
44.Lebovitz HE.Insulin secretagogues:old and new.Diabetes Reviews 1999;7:139-153
45.Bell DSH,Ovalle F.Tissue triglyceride levels in type 2 diabetes and the role of thiazolidinediones in reversing the effects of tisue hyperglyceridemia:review of the evidence in animals and humans.Endocr Pract 2001;7:135-138
46.Shimabukuro M,Ohneda M,Lee Y,Unger RH.Role of nitric oxide in obesity-induced β cell disease.J Clin Invest 1997;100:290-295
47.Butler AE,Janson J,Bonner-Weir S,Ritzel R,Rizza RA,Butler PC.Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes.Diabetes 2003;52:102-110
48.Mayerson AB,Hundal RS,Dufour S,Lebon V,Befroy D,Cline GW,Enocksson S,Inzucchi SE,Shulman GI,Petersen KF.The effects of rosiglitazone on insulin sensitivity,lipolysis,and hepatic and skeletal muscle triglyceride content in patients with type 2 diabetes.Diabetes 2002;51:797-802
49.Ovalle F,Bell DS.Clinical evidence of thiazolidinedione-induced improvevment of pancreatic β-cell function in patients with type 2 diabetes mellitus.Diabetes Obes Metab 2002;4:56-59
50.Brown AA,Hu FB.Dietary modulation of endithelial function:implications for cardiovascular disease.Am J Clin Nutr 2001;73(4):673-686
51.Hsueh WA,Quinones MJ.Role of endothelial dysfunction in insulin resistance.Am J Cardiol 2003;92(4A):10J-17J
52. Inoguchi T, Li P, Umeda F, HY Yu, Kakimoto M, Imamura M, Aoki T, Etoh T, Hashimoto T, Naruse M, Sano H, Utsumi H, Nawata H. High glucose level and free fatty acids stimulate reactive oxygen species production through protein kinase C-dependent activation of NAD(P)H oxidase in cultured vascular cells. Diabetes 2000; 49:1939-1945
53. Ridker PM. High-sensitivity C-reactive protein: potential adjunct for global risk accessment in the primary prevention of cardiovascular disease. Circulation 2001; 103(13):1813-1818
54. Fichtlscherer S, Rosenberger G, Walter DH, Breuer S, Dimmeler S, Zeiher AM. Elevated C-reactive protein levels and impaired endothelial vasoreactivity in patients with coronary artery disease. Circulation 2000; 102(9): 1000-1006
55. Moore KJ, Fitzgerald ML, Freeman MW. Peroxisome proliferator-activated receptors in macrophage biology: friend or foe? Curr Opin Lipidol 2001; 12(5): 519-527
56. Aitman TJ. CD36, insulin resistance, and coronary heart disease. Lancet 2001; 357(9257):651-652
57. Takada K, Ichiki T, Tokunou T, Funakoshi Y, Iino N, Hirano K, Kanaide H, Takeshita A. Peroxisome proliferator-activated receptor gamma activators downregulate angiotension II type 1 receptor in vascular smooth muscle cells. Circulation 2000; 102(15): 1834-1839
58. Buchanan TA, Meehan WP, Jeng YY, Yang D, Chan TM, Nadler JL, Scott S, Rude RK, Hsueh WA. Blood pressure lowering by pioglitazone. Evidence for a direct vascular effect. J Clin Invest 1995; 96(1): 354-360
59. Zhang F, Sowers JR, Ram JL, Standley PR, Peuler JD. Effects of pioglitazone on calcium channels in vascular smooth muscle. Hypertension 1994; 24: 170-175
60. Koshiyama H, Shimono D, Kuwamura N, Minamikawa J, Nakamura Y. Rapid communication: inhibitory effect of piogligatone on carotid arterial wall thickness in type 2 diabetes. J Clin Endocrinol Metab 2001; 86(7): 3452-3456
61. Howard G, O'Leary DH, Zaccaro D, Haffner S, Rewers M, Hamman R, Selby JV, Saad MF, Savage P, Bergman R. Insulin sensitivity and atherosclerosis. The insulin Resistance Atherosclerosis Study (IRAS) Investigation. Circulation 1996; 93(10): 1809-1817
62. Kato K, Satoh H, Endo Y, Yamada D, Midorikawa S, Sato W, Mizuno K, Fujita T, Tsukamoto k, Watanabe T. Thiazolidinediones down-regulate plasminogen activator inhibitor type 1 expression in human vascular endothelial cells: A possible role for PPARgamma in endothelial function. Biochem Biophys Res Commun 1999; 258(2):431-435
63. Kellerer M, Kroder G, Tippmer S, Berti L, Kiehn R, Mosthaf L, Haring H. Troglitazone prevents glucose-induced insulin resistance of insulin receptor in rat-1 fibroblasts. Diabetes 1994; 43(3):447-453
64. Ye JM, Frangioudakis G, Iglesias MA, Furler SM, Ellis B, Dzamko N, Cooney GJ, Kraegen EW. Prior thiazolidinedione treatment preserves insulin sensitivity in normal rats during acute fatty acid elevation: role of the liver. Endocrinology 2002; 143(12):4527-4535
65. Ishida H, Takizawa M, Ozawa S, Nakamichi Y, Yamaguchi S, Katsuta H, Tanaka t, Maruyama M, Katahira H, Yoshimoto K, Itagaki E, Nagamutsu S. Pioglitazone improves insulin secretory capacity and prevents the loss of beta-cell mass in obese diabetic db/db mice: Possible protection of beta cells from oxidative stress. Metabolism 2004; 53(4):488-494
66. Durbin RJ. Thiazolidinedione therapy in the prevention/delay of type 2 diabetes in patients with impaired glucose tolerance and insulin resistance. Diabetes Obes Metab 2004; 6(4):280-285
67. Buchanan TA, Xiang AH, Peters RK, Kjos SL, Marroquin A, Goico J, Ochoa C, Tan S, Berkowitz K, Hodis HN, Azen SP. Preservation of pancreatic beta-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk hispanic women. Diabetes 2002; 51(9):2796-2803
68. Palmer AJ, Roze S, Valentine WJ, Minshall ME, Lammert M, Oglesby A, Hayes C, Spinas GA. What impact would pancreatic beta-cell preservation have on life expectancy, quality-adjusted life expectancy and costs of complications in patients with type 2 diabetes? A projection using the CORE diabetes model. Curr Med Res Opin 2004;20(8 Suppl):59-66
69.Tettey JN,Maggs JL,Rapeport WG,Pirmohamed M,Park BK.Enzyme-induction dependent bioactivation of troglitazone and troglitazone quinone in vivo.Chem Res Toxicol 2001;14(8):965-974
70.Bonkovsky HL,Azar R,Bird S,Szabo G,Banner B.Severe cholestatic hepatitis caused by thiazolidinediones:risks associated with substituting rosiglitazone for troglitazone.Dig Dis Sci 2002;47(7):1632-1637
71.Dhawan M,Agrawal R,Ravi J,Gulati S,Silverman J,Nathan G,Raab S,Brodmerkel G Jr.Rosiglitazone-induced granulomatous hepatitis.J Clin Gastroenterol 2002;34(5):582-584
72.May LD,Lefkowitch JH,Kram MT,Rubin DE.Mixed hepatocellular-cholestatic liver injury after pioglitazone therapy.Ann Intern Med 2002;136(6):449-452
73.Mori Y,Murakawa Y,Okada K,Horikoshi H,Yokoyama J,Tajima N,Ikeda Y.Effect of troglitazone on body fat distribution in type 2 diabetic patients.Diabetes Care 1999;22(6):908-912
74.Ding SY Shen ZF,Xie MZ.Preliminary study of insulin resistance induced by neonatal monosodium treatment in normal Wistar rats.Chinese Pharmacological Bulletin(中国药理学通报)2001;17(2):181-185
75.Song J,Knepper MA,Hu X,Verbalis JG,Ecelbarger CA.Rosiglitazone activates renal sodium- and water-reabsorptive pathways and lower blood pressure in normal rats.J Pharmacol Exp Ther 2004;308(2):426-433
76.Mudaliar S,Chang AR,Henry RR.Thiazolidinediones,peripheral edema,and Type 2 Diabetes:incidence,pathophysiology,and clinical implications.Endocrine Practice 2003;9(5):406-416
77.Buch HN,Baskar V,Barton DM,Kamalakannan D,Akarca C,Singh BM.Combination of insulin and thiazolidinedione therapy in massively obese patients with Type 2 diabetes.Diabet Med 2002;19(7):572-574
78.Vinik AI,Stansberry KB,Barlow PM.Rosiglitazone treatment increases nitric oxide production in human peripheral skin:a controlled clinical trial in patients with type 2 diabetes mellitus.J Diabetes Complications 2003;17(5):279-285
79. Kermani A and Garg A. Thiazolidinedione-associated congestive heart failure and pulmonary edema. Mayo Clin Proc 2003; 78:1088-1091
80. Lygate CA, Hulbert K, Monfared M, Cole MA, Clarke K, Neubauer S. The PPARgamma-activator rosiglitazone does not alter remodeling but increases mortality in rats post-myocardial infarction. Cardiovasc Res 2003; 58(3): 632-637
81. Tan M, Johns D, Gonzalez GG, Antunez O, Fabian G, Flores-Lozano F, Zuniga Guajardo S, Garza E, Morales H, Konkoy C, Herz M; GLAD Study Group. Effects of pioglitazone and glimepiride on glycemic control and insulin sensitivity in Mexican patients with type 2 diabetes mellitus: A multicenter, randomized, double-blind, parallel-group trial. Clin Ther 2004; 26(5): 680-693
82. Dailey GE 3rd, Noor MA, Park JS, Bruce S, Fiedorek FT. Glycemic control with glyburide/ metformin tablets in combination with rosiglitazone in patients with type 2 diabetes: a randomized, double-blind trial. Am J Med 2004; 116(4): 223-229