替米沙坦对高果糖饲养大鼠胰岛素抵抗及其脂肪组织PPARγ、IRS1、GLUT4、APN和AT1R表达的影响
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摘要
目的观察替米沙坦(Telmisartan,TM)对高果糖饲养大鼠胰岛素抵抗(Insulin resistance,IR)的影响,探讨其可能机制。
方法采用高果糖饲料饲养SD大鼠4周制备IR大鼠模型,实验动物分为4组:对照组(Contral,C);替米沙坦组(TM);高果糖组(High fructose diet ,HFD);高果糖+替米沙坦组(HFD+TM)。并检测以下指标:(1)于0,2,4,6,8,10,12周末,测量收缩压(Systolic Blood Pressure ,SBP)后,取尾部血样测空腹血糖(Fasting Blood Glucose,FBG)、空腹血胰岛素(Fasting Serum Insulin,FSI)并计算胰岛素敏感指数(Insulin Sensitive Index,ISI);(2)于4、12周末大鼠空腹过夜,进行腹腔注射葡萄糖耐量试验(Intraperitoneoclysis Glucose Tolerance Test,IPGTT)和胰岛素耐量实验(Insulin Tolerance Test,ITT);(3)第4、12周末取股动脉血测定血脂后,RT-PCR检测肾周脂肪中血管紧张素II 1型受体(Angiotensin II receptor-one,AT1R)、过氧化物酶体增殖活化受体γ( Peroxisome proliferator activated receptor-gamma,PPARγ)、胰岛素受体底物1 ( Insulin receptor substrate-one,IRS1)、葡萄糖转运体4(Glucose transporter-four,GLUT4)及脂联素(Adiponectin,APN)mRNA的表达;(4)第4、12周末免疫组化检测各组动物下腹脂肪中AT1R、IRS1、GLUT4的表达。
结果(1)替米沙坦降低IR大鼠的SBP、FBG、FSI,纠正血脂紊乱(P〈0.01);使IR大鼠糖耐量和胰岛素耐量曲线下移(P〈0.01)。(2)替米沙坦可显著上调IR大鼠肾周脂肪组织PPARγ以及IRS-1、GLUT4、APN mRNA的表达(P〈0.01),明显下调IR大鼠肾周脂肪组织AT1R mRNA的表达(P〈0.01)。(3)替米沙坦可显著增加IR大鼠下腹脂肪组织IRS1、GLUT4的蛋白表达(P〈0.01),显著减少IR大鼠下腹脂肪组织AT1R的蛋白表达(P〈0.01)。
结论
1.替米沙坦可有效改善高果糖饲料饲养SD大鼠的IR。
2.替米沙坦的抗IR作用可能与其下调脂肪组织AT1R表达,上调脂肪组织PPARγ、IRS1、GLUT4和APN的表达有关。
Aims The present study was to examine the effect of Telmisartan to insulin resistance of rats fed high fructose diet and to probe its mechanism.
Methods Male SD rats were fed with high fructose diet for 4 weeks to induce IR rats model.All rats were randomly divided into the following groups :C group, TM group,HFD group, HFD+TM group. Then tested the following indicators : (1) Systolic blood pressure(SBP)were measured after fasting overnight, subsequently,blood samples were withdrawn from the end of tails of animals for fasting blood glucose (FBG),fasting serum insulin (FSI)at the 0,2,4,6,8,10,12th weekend and insulin sensitive index (ISI) were calculated. (2) At the 4,12th weekend ,intraperitoneoclysis glucose tolerance test (IPGTT)、insulin tolerance test (ITT) were taken.(3) At the 4,12th weekend,fasting blood lipids were measured.RT-PCR detected PPARγ,AT1R,IRS-1,GLUT4 and APN mRNA expression in perirenal fat.(5) At the 4,12th weekend,Immunohistochemical detected AT1R,IRS-1,GLUT4 expression in the lower abdomen fat.
Results
1.Telmisartan can reduce the level of SBP, FBG ,FSI and improve IR、abnorm lipid metabolism and glucose tolerance test、insulin tolerance test ( P〈0.01 ) .
2.Telmisartan can significantly enhance PPARγ, IRS1,GLUT4,APN mRNA expression in perirenal adipose tissue of IR rats(P〈0.01),and reduct AT1R mRNA expression in perirenal adipose tissue of IR rats ( P〈0.01 ) .
3.Telmisartan can significantly enhance IRS1,GLUT4 expression in the lower abdomen fat of IR rats(P〈0.01),and reduct AT1R expression in the lower abdomen fat of IR rats(P〈0.01).
Conclusion
1.Telmisartan can effectively improve the insulin resistance of the rats fed with high-fructose diet.
2. The effects of telmisartan on insulin resistance may be about with it can reduct AT1R expression and increase the expression of PPARγ,IRS1, GLUT4 ,APN in adipose tissue.
方法采用高果糖饲料饲养SD大鼠4周制备IR大鼠模型,实验动物分为4组:对照组(Contral,C);替米沙坦组(TM);高果糖组(High fructose diet ,HFD);高果糖+替米沙坦组(HFD+TM)。并检测以下指标:(1)于0,2,4,6,8,10,12周末,测量收缩压(Systolic Blood Pressure ,SBP)后,取尾部血样测空腹血糖(Fasting Blood Glucose,FBG)、空腹血胰岛素(Fasting Serum Insulin,FSI)并计算胰岛素敏感指数(Insulin Sensitive Index,ISI);(2)于4、12周末大鼠空腹过夜,进行腹腔注射葡萄糖耐量试验(Intraperitoneoclysis Glucose Tolerance Test,IPGTT)和胰岛素耐量实验(Insulin Tolerance Test,ITT);(3)第4、12周末取股动脉血测定血脂后,RT-PCR检测肾周脂肪中血管紧张素II 1型受体(Angiotensin II receptor-one,AT1R)、过氧化物酶体增殖活化受体γ( Peroxisome proliferator activated receptor-gamma,PPARγ)、胰岛素受体底物1 ( Insulin receptor substrate-one,IRS1)、葡萄糖转运体4(Glucose transporter-four,GLUT4)及脂联素(Adiponectin,APN)mRNA的表达;(4)第4、12周末免疫组化检测各组动物下腹脂肪中AT1R、IRS1、GLUT4的表达。
结果(1)替米沙坦降低IR大鼠的SBP、FBG、FSI,纠正血脂紊乱(P〈0.01);使IR大鼠糖耐量和胰岛素耐量曲线下移(P〈0.01)。(2)替米沙坦可显著上调IR大鼠肾周脂肪组织PPARγ以及IRS-1、GLUT4、APN mRNA的表达(P〈0.01),明显下调IR大鼠肾周脂肪组织AT1R mRNA的表达(P〈0.01)。(3)替米沙坦可显著增加IR大鼠下腹脂肪组织IRS1、GLUT4的蛋白表达(P〈0.01),显著减少IR大鼠下腹脂肪组织AT1R的蛋白表达(P〈0.01)。
结论
1.替米沙坦可有效改善高果糖饲料饲养SD大鼠的IR。
2.替米沙坦的抗IR作用可能与其下调脂肪组织AT1R表达,上调脂肪组织PPARγ、IRS1、GLUT4和APN的表达有关。
Aims The present study was to examine the effect of Telmisartan to insulin resistance of rats fed high fructose diet and to probe its mechanism.
Methods Male SD rats were fed with high fructose diet for 4 weeks to induce IR rats model.All rats were randomly divided into the following groups :C group, TM group,HFD group, HFD+TM group. Then tested the following indicators : (1) Systolic blood pressure(SBP)were measured after fasting overnight, subsequently,blood samples were withdrawn from the end of tails of animals for fasting blood glucose (FBG),fasting serum insulin (FSI)at the 0,2,4,6,8,10,12th weekend and insulin sensitive index (ISI) were calculated. (2) At the 4,12th weekend ,intraperitoneoclysis glucose tolerance test (IPGTT)、insulin tolerance test (ITT) were taken.(3) At the 4,12th weekend,fasting blood lipids were measured.RT-PCR detected PPARγ,AT1R,IRS-1,GLUT4 and APN mRNA expression in perirenal fat.(5) At the 4,12th weekend,Immunohistochemical detected AT1R,IRS-1,GLUT4 expression in the lower abdomen fat.
Results
1.Telmisartan can reduce the level of SBP, FBG ,FSI and improve IR、abnorm lipid metabolism and glucose tolerance test、insulin tolerance test ( P〈0.01 ) .
2.Telmisartan can significantly enhance PPARγ, IRS1,GLUT4,APN mRNA expression in perirenal adipose tissue of IR rats(P〈0.01),and reduct AT1R mRNA expression in perirenal adipose tissue of IR rats ( P〈0.01 ) .
3.Telmisartan can significantly enhance IRS1,GLUT4 expression in the lower abdomen fat of IR rats(P〈0.01),and reduct AT1R expression in the lower abdomen fat of IR rats(P〈0.01).
Conclusion
1.Telmisartan can effectively improve the insulin resistance of the rats fed with high-fructose diet.
2. The effects of telmisartan on insulin resistance may be about with it can reduct AT1R expression and increase the expression of PPARγ,IRS1, GLUT4 ,APN in adipose tissue.
引文
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2.Dandona P,Aljada A,Mohanty P,et al. Insulin inhibits intranuclear nuclear factor kB and stimulates IkB in mononuclear cells in obese sulrjects evidence for an anti-inflammation effect?J Clin Endocrinol Metab,2001,86:3257-3265.
3.Aljada A,Ghanim H,Saadeh R,et al.Insulin inhibits NF-κB and MCP-1 expression in human aortic endothelial cells.J Clin Endocrinol Metab,2001,86:450-453.
4.Juan J Di’ez and Pedro I.The role of the novel adipocyte-derived hormone adiponection..in human disease.Diabetes Care,2003,26(8):2442-2450.
5.Nakamura Y,Shimada K,Fukuda D,et al.Implications of plasma concentrations of adiponection in patients with coronary artery disease.Heart,2004,90:528-533.
6.Schoonjans K, Staels B, Auwerx J. The peroxisome proliferator activated receptors (PPARS) and their effects on lipid metabolism and adipocyte differentiation. Biochim Biophys Acta, 1996; 1302(2): 93-109.
7.Schoonjans K, Martin G, Staels B, et al. Peroxisome proliferators-activated recepors,orphans with ligands and functions. Curr Opin Lipidol,1997,8(3):159-66.
8.Olefsky JM.Treatment of insulin resistance with peroxisome proliferator-activated receptor gamma agonist. J Clin Invest,2000,106(4):467-472.
9.Nesto RW, Bell D, Bonow RO,et al.Thiazolidinedione use, fluid retention, and congestive heart failure: a consensus statement from the American Heart Association and American Diabetes Association. Diabetes Care 27:256 –263, 2004.
10.Opie LH. Renoprotection by angiotensin-receptor blockers and ACE inhibitors in hypertension. Lancet. 2001;358:1829 –1831.
11.Velloso LA, Folli F, Sun XJ, et al. Cross-talk between the insulin and angiotensin signaling systems. Proc Natl Acad Sci U S A. 1996; 93: 12490–12495.
12.Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001; 345: 861–869.
13.Parving HH, Lehnert H, Brochner-Mortensen J, et al. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med. 2001; 345: 870–878.
14.Lewis ED, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001; 345: 851–860.
15.Ortlepp JR, Breuer J, Eitner F, et al. Inhibition of the renin-angiotensin system ameliorates genetically determined hyperinsulinemia. Eur J Pharmacol. 2002; 436: 145–150. Halcox JP, Schenke WH, Zalos G, et al. Prognostic value of coronary vascular endothelial dysfunction. Circulation. 2002; 106: 653–658.
16.Julius S, Kjeldsen SE, Webel M, et al. Outcomes in hypertensive patients at high risk of cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial. Lanet. 2004; 363: 2022–2031.
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