二甲双胍与有氧运动对2型糖尿病大鼠血管氧化应激的影响
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摘要
目的评价二甲双胍、有氧运动及二甲双胍与有氧运动联合干预对2型糖尿病大鼠血管氧化应激的影响。方法采用高脂饮食、小剂量STZ诱导2型糖尿病模型,将大鼠分为5组:正常对照组(NC)、糖尿病对照组(DC)、糖尿病运动组(DS)、糖尿病二甲双胍干预组(DM)和糖尿病二甲双胍+运动联合干预组(DMS)。8周干预后,采用HE染色病理学检查、Western blotting和ELISA方法对大鼠血管形态、组织蛋白表达和血清指标进行检测。结果 DS、DM和DMS组空腹血糖和胰岛素均有不同程度的降低。与DC组相比,DS、DM和DMS组大鼠血管Nrf2和HO-1白表达增加,NOX4蛋白表达降低。DS和DMS组大鼠血管SOD活性升高,DM和DMS组MDA降低。DS、DM和DMS组大鼠血清VCAM-1和TNF-α浓度均存在不同程度的降低。结论二甲双胍与有氧运动可能通过调节Nrf2和NOX4平衡来降低2型糖尿病大鼠血管氧化应激。
Objective To investigate the effects of metformin,aerobic exercise alone or in combination on the vascular oxidative stress in type 2 diabetic rats.Methods Rat models of type 2 diabetes were established by feeding a high-fat diet combined with low dose streptozotocin(STZ).Rats were assigned into five groups:normal control(NC),diabetes control(DC),diabetes swimming(DS),diabetes metformin(DM),and diabetes metformin plus swimming(DMS).After undergoing the respective interventions for 8 weeks,indicators of vascular morphology,protein expression in the vascular tissue,and serum indicators were tested by histopathology using HE staining,western blotting,and ELISA.Results All the DS,DM,and DMS groups showed decrease to different degrees in fasting blood glucose and insulin levels.Compared with the DC group,the DS,DM,and DMS groups exhibited significant increases in the protein expression of Nrf2 and HO-1,and exhibited a clear decrease in the expression of NOX4.The activities of SOD in the DS and DMS groups were higher than in the DC group.MDA levels in the DM and DMS groups were lower than in the DC group.The concentrations of TNF-α and VCAM-1 were decreased to varying degrees in the DS,DM,and DMS groups.Conclusions Metformin and aerobic exercise may relieve vascular oxidative stress in type 2 diabetic rats,by regulating the balance between Nrf2 and NOX4.
Objective To investigate the effects of metformin,aerobic exercise alone or in combination on the vascular oxidative stress in type 2 diabetic rats.Methods Rat models of type 2 diabetes were established by feeding a high-fat diet combined with low dose streptozotocin(STZ).Rats were assigned into five groups:normal control(NC),diabetes control(DC),diabetes swimming(DS),diabetes metformin(DM),and diabetes metformin plus swimming(DMS).After undergoing the respective interventions for 8 weeks,indicators of vascular morphology,protein expression in the vascular tissue,and serum indicators were tested by histopathology using HE staining,western blotting,and ELISA.Results All the DS,DM,and DMS groups showed decrease to different degrees in fasting blood glucose and insulin levels.Compared with the DC group,the DS,DM,and DMS groups exhibited significant increases in the protein expression of Nrf2 and HO-1,and exhibited a clear decrease in the expression of NOX4.The activities of SOD in the DS and DMS groups were higher than in the DC group.MDA levels in the DM and DMS groups were lower than in the DC group.The concentrations of TNF-α and VCAM-1 were decreased to varying degrees in the DS,DM,and DMS groups.Conclusions Metformin and aerobic exercise may relieve vascular oxidative stress in type 2 diabetic rats,by regulating the balance between Nrf2 and NOX4.
引文
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[15]Sato N,Takasaka N,Yoshida M,et al.Metformin attenuates lung fibrosis development via NOX4 suppression[J].Respir Res,2016,17(1):107.
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[17]Muthusamy VR,Kannan S,Sadhaasivam K,et al.Acute exercise stress activates Nrf2/ARE signaling and promotes antioxidant mechanisms in the myocardium[J].Free Radic Biol Med,2012,52(2):366-376.
[18]Martin-montalvo A,Mercken EM,Mitchell SJ,et al.Metformin improves healthspan and lifespan in mice[J].Nat Commun,2013,4(7):2192.
[19]Zhou ZY,Ren LW,Zhan P,et al.Metformin exerts glucoselowering action in high-fat fed mice via attenuating endotoxemia and enhancing insulin signaling[J].Acta Pharmacol Sin,2016,37(8):1063-1075.
[20]Tafani M,Sansone L,Limana F,et al.The interplay of reactive oxygen species,hypoxia,inflammation,and sirtuins in cancer initiation and progression[J].Oxid Med Cell Longev,2016,2016(1):3907147.
[21]Nedeljkovic ZS,Gokce N,Loscalzo J.Mechanisms of oxidative stress and vascular dysfunction[J].Postgrad Med J,2003,79(930):195-199.
[22]Hopkins PN.Molecular biology of atherosclerosis[J].Physiol Rev,2013,93(3):1317-1542.
[23]Hyun B,Shin S,Lee A,et al.Metformin down-regulates TNF-αsecretion via suppression of scavenger receptors in macrophages[J].Immune Netw,2013,13(4):123-132.
[24]李俊,王少兵,许桂清,等.有氧运动和二甲双胍对糖尿病大鼠血清IL-1β、TNF-α和MCP-1的影响[J].中国体育科技,2017,53(3):41-47.
[25]Codellar R,Luzi L,Inverardi L,et al.The anti-inflammatory effects of exercise in the syndromic thread of diabetes and autoimmunity[J].Eur Rev Med Pharmacol Sci,2015,19(19):3709-3722.
[2]潘小康.二甲双胍降糖机制研究进展[J].中国糖尿病杂志,2016,24(7):665-668.
[3]Golbidi S,Laher I.Exercise and the aging endothelium[J].JDiabetes Res,2013,2013(22):1-12.
[4]陈永欣,韦锦斌.链脲佐菌素诱导大鼠2型糖尿病并发症模型研究进展[J].中国比较医学杂志,2013,23(3):63-66.
[5]Fu X,Song B,Tian GW,et al.The effects of the waterextraction of Astragali radix and Lycopi herba on the pathway of TGF-smads-UPP in a rat model of diabetic nephropathy[J].Pharmacogn Mag,2014,10(40):491-496.
[6]Linden MA,Fletcher JA,Morris EM,et al.Combining metformin and aerobic exercise training in the treatment of type 2diabetes and NAFLD in OLETF rats[J].Am J Physiol Endocrinol Metab,2013,306:300-310.
[7]龚云,张鑫.运动对糖尿病大鼠胰岛的影响及其机制探讨[J].中国比较医学杂志,2017,27(8):22-27.
[8]Colberg SR,Sigal RJ,Yardley JE,et al.Physical activity/exercise and diabetes:a position statement of the American Diabetes Association[J].Diabetes Care,2016,39(11):2065-2079.
[9]Colberg SR,Hermandez MJ,Shahzad F.Blood glucose responses to type,intensity,duration,and timing of exercise[J].Diabetes care,2013,36(10):e177.
[10]Shaban N,Kenno KA,Milne KJ.The effects of a 2 week modified high intensity interval training program on the homeostatic model of insulin resistance(HOMA-IR)in adults with type 2 diabetes[J].J Sports Med Phys Fitness,2014,54(2):203-209.
[11]美国糖尿病协会.美国糖尿病协会糖尿病完全指南[M].北京:北京科学技术出版社,2014.
[12]Pattamaprapanont P,Muanprasat C,Soodvilai S,et al.Effect of exercise training on signaling of interleukin-6 in skeletal muscles of type 2 diabetic rats[J].Rev Diabet Stud,2016,13(2-3):197-206.
[13]Schramm A,Matusik P,Osmenda G,et al.Targeting NADPHoxidases in vascular pharmacology[J].Vascul Pharmacol,2012,56(5-6):216-231.
[14]Wang W,Wu QH,Sui Y,et al.Rutin protects endothelial dysfunction by disturbing Nox4 and ROS-sensitive NLRP3inflammasome[J].Biomed Pharmacother,2017,86:32-40.
[15]Sato N,Takasaka N,Yoshida M,et al.Metformin attenuates lung fibrosis development via NOX4 suppression[J].Respir Res,2016,17(1):107.
[16]Keum YS,Choi BY.Molecular and chemical regulation of the Keap1-Nrf2 signaling pathway[J].Molecules,2014,19:10074-10089.
[17]Muthusamy VR,Kannan S,Sadhaasivam K,et al.Acute exercise stress activates Nrf2/ARE signaling and promotes antioxidant mechanisms in the myocardium[J].Free Radic Biol Med,2012,52(2):366-376.
[18]Martin-montalvo A,Mercken EM,Mitchell SJ,et al.Metformin improves healthspan and lifespan in mice[J].Nat Commun,2013,4(7):2192.
[19]Zhou ZY,Ren LW,Zhan P,et al.Metformin exerts glucoselowering action in high-fat fed mice via attenuating endotoxemia and enhancing insulin signaling[J].Acta Pharmacol Sin,2016,37(8):1063-1075.
[20]Tafani M,Sansone L,Limana F,et al.The interplay of reactive oxygen species,hypoxia,inflammation,and sirtuins in cancer initiation and progression[J].Oxid Med Cell Longev,2016,2016(1):3907147.
[21]Nedeljkovic ZS,Gokce N,Loscalzo J.Mechanisms of oxidative stress and vascular dysfunction[J].Postgrad Med J,2003,79(930):195-199.
[22]Hopkins PN.Molecular biology of atherosclerosis[J].Physiol Rev,2013,93(3):1317-1542.
[23]Hyun B,Shin S,Lee A,et al.Metformin down-regulates TNF-αsecretion via suppression of scavenger receptors in macrophages[J].Immune Netw,2013,13(4):123-132.
[24]李俊,王少兵,许桂清,等.有氧运动和二甲双胍对糖尿病大鼠血清IL-1β、TNF-α和MCP-1的影响[J].中国体育科技,2017,53(3):41-47.
[25]Codellar R,Luzi L,Inverardi L,et al.The anti-inflammatory effects of exercise in the syndromic thread of diabetes and autoimmunity[J].Eur Rev Med Pharmacol Sci,2015,19(19):3709-3722.