有氧运动及膳食干预对胰岛素抵抗大鼠骨骼肌脂质代谢的影响
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摘要
目的通过建立高脂饲料喂养的胰岛素抵抗大鼠模型,观察胰岛素抵抗大鼠经过有氧运动和/或恢复普通饲料干预后,骨骼肌肌内甘油三酯(IMTG)、骨骼肌脂蛋白酯酶(LPL)、超氧化物歧化酶(SOD)、丙二醛(MDA)及解偶联蛋白3(UCP3)蛋白表达水平的变化；探讨有氧运动和/或恢复普通饲料对胰岛素抵抗大鼠骨骼肌脂质代谢的影响及改善胰岛素敏感性的可能作用机制。
方法7周龄雄性SD大鼠130只,普通饲料安静对照组10只,采用普通饲料喂养。高脂组大鼠采用高脂饲料喂养,共同喂养8周。选取高脂组体重上游的1/3大鼠40只,随机分为4组,即DIO高脂组、DIO运动干预组、DIO普通饲料组、DIO运动+普通饲料组,每组10只,检测大鼠空腹血糖(FBG)和血清胰岛素(FIN)浓度,行口服糖耐量试验(OGTT),计算胰岛素敏感指数(ISI),确定建模成功。普通饲料组采用基础饲料喂养,运动干预组进行中等强度的跑台有氧运动,共干预8周。最后一次运动结束后检测各组大鼠FBG、FIN浓度,行OGTT试验,试剂盒检测骨骼肌IMTG、MDA含量及LPL、SOD活性,应用Western blot检测骨骼肌UCP3蛋白表达的变化。
结果
1.8周高脂喂养后,高脂组大鼠体重明显高于对照组(P<0.01),ISI明显低于对照组(P<0.01)。
2.继续8周高脂喂养后,高脂组大鼠体重、骨骼肌IMTG、MDA明显高于对照组(P<0.01),ISI、LPL、SOD和UCP3明显低于对照组(P<0.05或P<0.01)。
3.运动或/和恢复普通饲料8周后,DIO普通饲料组、DIO运动+普通饲料组ISI与CON对照组相比差异无统计学意义(P>0.05)。DIO运动干预组、DIO普通饲料组、DIO运动+普通饲料组各组空腹血糖、空腹胰岛素与CON对照组差异无统计学意义(P>0.05)。
4.单纯有氧运动干预8周后,DIO大鼠IMTG、MDA明显低于DIO高脂组(P<0.01),SOD、UCP3明显高于DIO高脂组(P<0.05或P<0.01),LPL与DIO高脂组相比,差异无统计学意义(P>0.05)。与CON对照组相比,MDA、SOD和UCP3差异无统计学意义(P>0.05)。
5.单纯恢复普通饲料8周,DIO大鼠IMTG、MDA明显低于DIO高脂组(P<0.01),LPL和SOD活性、UCP。与DIO高脂组相比,差异无统计学意义(P>0.05)。与CON对照组相比,MDA、SOD、UCP3差异无统计学意义(P>0.05)。
6.有氧运动+恢复普通饲料8周,DIO大鼠IMTG、MDA明显低于DIO高脂组(P<0.01),LPL、SOD和UCP3明显高于DIO高脂组(P<0.01)。与CON对照组相比,IMTG和LPL、MDA和SOD、UCP3差异均无统计学意义(P>0.05)。
结论
1.高脂饲料喂养8周可诱导大鼠IR的形成。继续高脂饲料喂养8周,大鼠骨骼肌脂质沉积、脂质过氧化及IR加重。
2.有氧运动和/或恢复普通饲料均可改善IR及骨骼肌脂质代谢紊乱,大鼠骨骼肌脂质沉积减少、脂质氧化能力增强可能是运动和/或饮食改善IR状态的机制之一
Obejective To observe the effect of aerobic exercise and/or standard diet on the expression level of intramyocellular triglyceride (IMTG) and lipoprotein lipase (LPL)、uncoupling protein 3 (UCP3)、superoxide dismutase (SOD) and Malondialdehyde (MDA) in keletal muscle of insulin resistant (IR) rats fed with high fat. And to discuss the effects of aerobic exercise and/or standard diet on skeletal muscle lipid metabolism and the development of insulin resistant of rats and its possible mechanism.
Methods 40 male SD rats were modeled into IR rats by high fat diet for 8 weeks, while the 10 rats of control group were fed with standard diet. Then the 40 IR rats were randomly divided into 4 groups:DIO Group were given high fat diet for 8weeks; DIO-exercise Group and DIO-standard diet Group were respectively treated by aerobic exercise and standard diet; DIO-exercise&standard diet Group were treated by both aerobic exercise and standard diet.The groups were recorded at the beginning and the end of the treatment, including Fasting blood glucose (FBG)、Fasting insulin (FIN) and OGTT; and insulin sensitivity index(ISI) was calculated. Put rats to death after the completion of the 8-week training,and then detect the level of IMTG、LPL、SOD and MDA of skeletal muscles; Western blot was used to determine the expressions of UCP3.
Results 1. The body weight was obviously higher (P<0.01) and ISI was obviously lower (P<0.01) in the DIO Group than the control group after feeding high fat diet for 8 weeks.
2. The body weight, IMTG and MDA was obviously higher (P<0.01) and ISI, LPL, SOD and UCP3 was obviously lower (P<0.05 or P<0.01) in the DIO Group than the control group after feeding high fat diet for another 8 weeks.
3. After aerobic exercise and/or standard diet treatment for 8 weeks, the difference of ISI was not statistically significant between DIO-standard diet Group, DIO-exercise&standard diet Group and control group (P>0.05). The difference of FBG、FIN was not statistically significant between DIO-exercise Group, DIO-standard diet Group, DIO-exercise & standard diet Group and control group (P>0.05).
4. The IMTG, MDA was obviously lower (P<0.01) and SOD, UCP3 was obviously higher (P<0.01 or P<0.05) in the DIO-exercise Group than the DIO Group, but there is no significant difference between DIO-exercise and DIO Group (P>0.05). And there is no significant difference in the MDA, SOD and UCP3 contents between the DIO-exercise and the control group (P>0.05).
5. The IMTG, MDA was obviously lower (P<0.01) in the DIO-standard diet Group than the DIO Group, but there is no significant difference in the LPL, SOD and UCP3 between DIO-standard diet Group and DIO Group (P>0.05). And there is no significant difference in the MDA, SOD and UCP3 content between the DIO-exercise and the control group (P>0.05).
6. The IMTG, MDA was obviously lower (P<0.01) and LPL, SOD, UCP3 was obviously higher (P<0.01) in the DIO-exercise&standard diet Group than the DIO Group, but there is no significant difference between DIO-exercise&standard diet Group and DIO Group (P>0.05). And there is no significant difference in these indexes between the DIO-exercise&standard diet and the control group (P>0.05).
Conclusions 1. The rat model of IR was successfully established by feeding the SD rats 8 weeks with high fat diet. After feeding high fat diet for another 8 weeks, the lipid deposition, lipid peroxidation in skeletal muscle and IR were even more serious.
2. The aerobic exercise and/or standard diet treament can improve IR and the abnormal lipid metabolism of skeletal muscle. The reduction of lipid deposition and enhancement of capacity of lipid oxidation in Skeletal muscle may be one of mechanisms on aerobic exercise improving insulin resistance.
方法7周龄雄性SD大鼠130只,普通饲料安静对照组10只,采用普通饲料喂养。高脂组大鼠采用高脂饲料喂养,共同喂养8周。选取高脂组体重上游的1/3大鼠40只,随机分为4组,即DIO高脂组、DIO运动干预组、DIO普通饲料组、DIO运动+普通饲料组,每组10只,检测大鼠空腹血糖(FBG)和血清胰岛素(FIN)浓度,行口服糖耐量试验(OGTT),计算胰岛素敏感指数(ISI),确定建模成功。普通饲料组采用基础饲料喂养,运动干预组进行中等强度的跑台有氧运动,共干预8周。最后一次运动结束后检测各组大鼠FBG、FIN浓度,行OGTT试验,试剂盒检测骨骼肌IMTG、MDA含量及LPL、SOD活性,应用Western blot检测骨骼肌UCP3蛋白表达的变化。
结果
1.8周高脂喂养后,高脂组大鼠体重明显高于对照组(P<0.01),ISI明显低于对照组(P<0.01)。
2.继续8周高脂喂养后,高脂组大鼠体重、骨骼肌IMTG、MDA明显高于对照组(P<0.01),ISI、LPL、SOD和UCP3明显低于对照组(P<0.05或P<0.01)。
3.运动或/和恢复普通饲料8周后,DIO普通饲料组、DIO运动+普通饲料组ISI与CON对照组相比差异无统计学意义(P>0.05)。DIO运动干预组、DIO普通饲料组、DIO运动+普通饲料组各组空腹血糖、空腹胰岛素与CON对照组差异无统计学意义(P>0.05)。
4.单纯有氧运动干预8周后,DIO大鼠IMTG、MDA明显低于DIO高脂组(P<0.01),SOD、UCP3明显高于DIO高脂组(P<0.05或P<0.01),LPL与DIO高脂组相比,差异无统计学意义(P>0.05)。与CON对照组相比,MDA、SOD和UCP3差异无统计学意义(P>0.05)。
5.单纯恢复普通饲料8周,DIO大鼠IMTG、MDA明显低于DIO高脂组(P<0.01),LPL和SOD活性、UCP。与DIO高脂组相比,差异无统计学意义(P>0.05)。与CON对照组相比,MDA、SOD、UCP3差异无统计学意义(P>0.05)。
6.有氧运动+恢复普通饲料8周,DIO大鼠IMTG、MDA明显低于DIO高脂组(P<0.01),LPL、SOD和UCP3明显高于DIO高脂组(P<0.01)。与CON对照组相比,IMTG和LPL、MDA和SOD、UCP3差异均无统计学意义(P>0.05)。
结论
1.高脂饲料喂养8周可诱导大鼠IR的形成。继续高脂饲料喂养8周,大鼠骨骼肌脂质沉积、脂质过氧化及IR加重。
2.有氧运动和/或恢复普通饲料均可改善IR及骨骼肌脂质代谢紊乱,大鼠骨骼肌脂质沉积减少、脂质氧化能力增强可能是运动和/或饮食改善IR状态的机制之一
Obejective To observe the effect of aerobic exercise and/or standard diet on the expression level of intramyocellular triglyceride (IMTG) and lipoprotein lipase (LPL)、uncoupling protein 3 (UCP3)、superoxide dismutase (SOD) and Malondialdehyde (MDA) in keletal muscle of insulin resistant (IR) rats fed with high fat. And to discuss the effects of aerobic exercise and/or standard diet on skeletal muscle lipid metabolism and the development of insulin resistant of rats and its possible mechanism.
Methods 40 male SD rats were modeled into IR rats by high fat diet for 8 weeks, while the 10 rats of control group were fed with standard diet. Then the 40 IR rats were randomly divided into 4 groups:DIO Group were given high fat diet for 8weeks; DIO-exercise Group and DIO-standard diet Group were respectively treated by aerobic exercise and standard diet; DIO-exercise&standard diet Group were treated by both aerobic exercise and standard diet.The groups were recorded at the beginning and the end of the treatment, including Fasting blood glucose (FBG)、Fasting insulin (FIN) and OGTT; and insulin sensitivity index(ISI) was calculated. Put rats to death after the completion of the 8-week training,and then detect the level of IMTG、LPL、SOD and MDA of skeletal muscles; Western blot was used to determine the expressions of UCP3.
Results 1. The body weight was obviously higher (P<0.01) and ISI was obviously lower (P<0.01) in the DIO Group than the control group after feeding high fat diet for 8 weeks.
2. The body weight, IMTG and MDA was obviously higher (P<0.01) and ISI, LPL, SOD and UCP3 was obviously lower (P<0.05 or P<0.01) in the DIO Group than the control group after feeding high fat diet for another 8 weeks.
3. After aerobic exercise and/or standard diet treatment for 8 weeks, the difference of ISI was not statistically significant between DIO-standard diet Group, DIO-exercise&standard diet Group and control group (P>0.05). The difference of FBG、FIN was not statistically significant between DIO-exercise Group, DIO-standard diet Group, DIO-exercise & standard diet Group and control group (P>0.05).
4. The IMTG, MDA was obviously lower (P<0.01) and SOD, UCP3 was obviously higher (P<0.01 or P<0.05) in the DIO-exercise Group than the DIO Group, but there is no significant difference between DIO-exercise and DIO Group (P>0.05). And there is no significant difference in the MDA, SOD and UCP3 contents between the DIO-exercise and the control group (P>0.05).
5. The IMTG, MDA was obviously lower (P<0.01) in the DIO-standard diet Group than the DIO Group, but there is no significant difference in the LPL, SOD and UCP3 between DIO-standard diet Group and DIO Group (P>0.05). And there is no significant difference in the MDA, SOD and UCP3 content between the DIO-exercise and the control group (P>0.05).
6. The IMTG, MDA was obviously lower (P<0.01) and LPL, SOD, UCP3 was obviously higher (P<0.01) in the DIO-exercise&standard diet Group than the DIO Group, but there is no significant difference between DIO-exercise&standard diet Group and DIO Group (P>0.05). And there is no significant difference in these indexes between the DIO-exercise&standard diet and the control group (P>0.05).
Conclusions 1. The rat model of IR was successfully established by feeding the SD rats 8 weeks with high fat diet. After feeding high fat diet for another 8 weeks, the lipid deposition, lipid peroxidation in skeletal muscle and IR were even more serious.
2. The aerobic exercise and/or standard diet treament can improve IR and the abnormal lipid metabolism of skeletal muscle. The reduction of lipid deposition and enhancement of capacity of lipid oxidation in Skeletal muscle may be one of mechanisms on aerobic exercise improving insulin resistance.
引文
[1]Borkman M, Storlien LH, Pan DA, Jenkins AB, Chisholm DJ, Campbell LV. The relation between insulin sensitivity and the fatty-acid composition of skeletal-muscle phospholipids[J]. N Engl J Med,1993,328:238-44.
[2]Forouhi NG, Jenkinson G, Thomas EL, Mullick S, Mierisova S, Bhonsle U, McKeigue PM, Bell JD. Relation of triglyceride stores in skeletal muscle cells to central obesity and insulin sensitivity in European and South Asian men[J]. Diabetologia,1999,42:932-935.
[3]马丽超,张莉,刘利兵等.肝脏和肌肉脂肪异位沉积与空腹高胰岛素血.症的发生[J].第四军医大学学报,2007,28(8)：703-705.
[4]Poirier P, Marcell T, Huey PU, Schlaepfer IR, Owens GC, Jensen DR, Eckel RH. Increased intracellular triglyceride in C(2)C(12) muscle cells transfected with human lipoprotein lipase[J]. J Clin Endocrinol Metab,2000,270:997-1001.
[5]Kim JY, Hickner RC, Cortright RL, Dohm GL, Houmard JA. Lipid oxidation is reduced in obese human skeletal muscle[J]. Am J Physiol Endocrinol Metab,2000,279:E1039-E1044.
[6]许纲,丁树哲,高彩暇.解偶联蛋白3与运动适应[J].中国运动医学杂志,2004,23(3)：336-342.
[7]Kiens B. Skeletal muscle lipid metabolism in exercise and insulin resistance[J]. Physiol Rev, 2006,86:205-243.
[8]Boden G, Lebed B, Schatz M, Homko C, Lemieux S. Effects of acute changes of plasma free fatty acids on intramyocellular fat content and insulin resistance in healthy subjects[J]. Diabetes,2001,50:1612-1617.
[9]Hurley BF, Nemeth PM, Martin WHD, Hagberg JM, Dalsky GP, Holloszy JO. Muscle triglyceride utilization during exerciseeffect of training[J]. J Appl Physiol,1986,60:562-567.
[10]Simoneau JA, Colberg SR, Thaete FL, Kelley DE. Skeletal muscle glycolytic and oxidative enzyme capacities are determinants of insulin sensitivity and muscle composition in obese women[J]. FASEB J,1995,9:273-278.
[11]Bret H, Goodpaster, Jing HE, Simon Watkins, David E. Kelly. Skeletal Muscle Lipid Content and Insulin Resistance:Evidence for a Paradox in Endurance-Trained Athletes[J]. The Journal of Clinical Endocrinology & Metabolism,2000,86(12):5755-5761.
[12]谭正怀.脂蛋白酯酶的组织特异性表达及其调节[J].国外医学内分泌学分册,2000,20(6)：320-323.
[13]Maheux P, Azhar S, Kern PA, Chen YDI, Reaven GM. Relationship between insulin mediated glucose disposal and regulation of plasma and adipose tissue lipoprotein lipase[J]. Diabetologia, 1997,40: 850-858.
[14]Voshol PJ, Jong MC, Dahltnans VE, et al. In muscle-specific lipoproteinlipase-overexpressing mice, muscle triglyceride content is increased without inhibition of insulin-stimulated whole-body and muscle-specific glucose uptake[J]. Diabetes, 2001, 50(25): 85-90.
[15]胡瑞萍,吴毅,胡永善.运动对糖尿病骨骼肌胰岛素信号传递的影响[J].中国康复医学杂志,2004,19(9):716-718.
[16]Montell E, Turini M, Marotta M, et al. DAG accumulation from saturated fatty acidsdesensitizes insulin stimulation of glucose uptake in muscle cells[J]. Am J PhysiolEndocrinol Metab, 2001,280(E2): 29-37.
[17]Stratford S, Hoehn KL, Liu F, Summers SA. Regulation of insulin action by ceramide: dualmechanisms linking ceramide accumulation to the inhibition of Akt/protein kinase B[J]. JBiol Chem, 2004,279(36): 608-615.
[18]Morino K, Petersen KF, Dufour S, Befroy D, Frattini J, Shatzkes N,Neschen S, White MF,Bilz S, Sono S, Pypaert M, Shulman GI. Reduced mitochondrial density and increased IRS-1serine phosphorylation in muscle of insulin-resistant offspring of type 2 diabetic parents[J]. JClin Invest, 2005, 115: 3587-3593.
[19]Petersen KF, Befroy D, Dufour S, Dziura J, Ariyan C, Rothman DL, DiPietro L, Cline GW,Shulman GI. Mitochondrial dysfunction in the elderly: possible role in insulin resistance[J].Science, 2003,300:1140 -1142.
[20]杨璐.解偶联蛋白3与2型糖尿病[J].国际内科学杂志,2008,3(5)1:15-45
[21]Lin B, Coughlin S, Pilch PF. Bidirectional regulation of uncoupling protein-3 and GLUT-4mRNA in skeletal muscle by cold[J]. Am J Physiol, 1998,275: E386-E391.
[22]Himms-Hagen J and Harper ME. Physiological role of UCP_3 may be export of fatty acidsfrom mitochondria when fatty acid oxidation predominates: an hypothesis[J]. Exp BiolMed(Maywood), 2001,226: 78-84.
[23]Schrauwen P, Saris WH and Hesselink MK. An alternative function for human uncouplingprotein 3: protection of mitochondria against accumulation of nonesterified fatty acids insidethe mitochondria] matrix[J]. FASEB J, 2001, 15: 2497-2502.
[24]MacLellan JD, Gerrits MF, Gowing A, Smith PJ, Wheeler MB and Harper ME. Physiologicalincreases in uncoupling protein 3 augment fatty acid oxidation and decrease reactive oxygenspecies production without uncoupling respiration in muscle cells[J]. Diabetes, 2005, 54:2343-2350.
[25]Schrauwen P, Hesselink MK, Blaak EE, Borghouts LB, Schaart G, Saris WH, Keizer HA.Uncoupling protein 3 content is decreased in skeletal muscle of patients with type 2diabetes[J]. Diabetes, 2001, 50: 2870-2873.
[26]Pruchnic R, Katsiaras A, He J, et al. Exercise training increases intramyocellular lipid and oxidative capacity in older adults[J]. Am J Physiol Endocrinol Metab, 2004, 287: E857-E862.
[27]Tarnopolsky MA, Rennie CD, Robertshaw HA, et al. Influence of endurance exercise training and sex on intramyocellular lipid and mitochondrial ultrastructure, substrate use, and mitochondrial enzyme activity[J]. Am J Physiol, 2007,292: R1271-R1278.
[28]Tsuboyama-Kasaoka N, Tsunoda N, Maruyama K, Takahashi M, Kim H, Ikemoto S, and Ezaki O. Up-regulation of uncoupling protein 3 (UCP_3) mRNA by exercise training and down-regulation of UCP_3 by denervation in skeletal muscles[J]. Biochem Biophys Res Commun, 1998, 247:498-503.
[29]Richter EA, Garetto LP, Goodman MN, Ruderman NB. Muscle glucose metabolism following exercise in the rat: increased sensitivity to insulin[J]. J Clin Invest, 1982, 69:785-793.
[30]DiPietro L, Dziura J, Yeckel CW, Neufer PD. Exercise and improved insulin sensitivity in older women: evidence of the enduring benefits of higher intensity training[J]. J Appl Physiol,2006,100:142-149.
[31]Wojtaszewski JF, Nielsen JN, Richter EA. Invited review: effect of acute exercise on insulin signaling and action in humans [J]. J Appl Physiol, 2002, 93: 384-392.
[32]Menshikova EV, Ritov VB, Fairfull L, Ferrell RE, Kelley DE, Goodpaster BH. Effects of exercise on mitochondrial content and function in aging human skeletal muscle [J]. J Gerontol A Biol Sci Med Sci, 2006,61: 534-40.
[33]Lauterio TJ, Bond JP, Ulman EA. Development and characrization of a purified diet to identify obesity-susceptible and resistant rat[J]. J Nutr, 1994, 124(11): 2172-2178.
[34]Bedford TG, Tipton CM, Wilson NC, et al. Maximum oxygen consumption of rats and its changes with various experimental procedures[J]. Journal of Applied Physiology, 1979, 47(6):1278-1283.
[35]李秀平,孙静,张俊权,李伟.慢性应急对大鼠葡萄糖耐量及胰岛素抵抗的影响[J].中国医药导报,2007,4(28):25-26.
[36]Khoursheed, Miles, K-M Gao, M-K Lee, AR Moossa and JM Olefsky. Metabolic effects of troglitazone on fat-induced insulin resistance in the rat[J]. Metabolism, 1995,44: 1489-1494.
[37]陈庆伟,刘丽华.肥胖、胰岛素抵抗与运动[J].吉林体育学院学报,2008,24(3):90-19.
[38]池脇克则等.代谢综合征与脂质代谢异常[J].日本医学介绍,2005,265(5):205-270.
[39]Holloszy JO. Exercise-induced increase in muscle insulin sensitivity[J]. J Appl Physiol, 2005,99:38-43.
[40]刘霞,曾凡星等.运动干预胰岛素抵抗的外周机制研究进展[J].北京体育大学学报,2005,1:23-25.
[41]Lindstrom J, Eriksson JG, Valle TT, et al. Prevention of diabetes mellitus in subjects with impaired glucose tolerance in the Finnish Diabetes Prevention Study: results from a randomized clinical trial[J]. J Am Soc Nephrol, 2003, 14: 8-13.
[42]GoodPaster BH,He J,Watkins S,Kelley DE.Skeletal muscle lipid content and insulin resistance: evidence for a paradox in endurancetrained athletes[J]. J Clin Endocrinol Metab,2001,86:5755-5761.
[43]Boden G, Lebed B, Schatz M, Homko C, Lemieux S. Effects of acute changes of plasma free fatty acids on intramyocellular fat content and insulin resistance in healthy subjects[J].Diabetes, 2001,50: 1612-1617.
[44]Bruce CR, Thrush AB, Mertz VA. et al. Endurance training in obese humans improves glucose tolerance and mitochondria! fatty acid oxidation and alters muscle lipid content[J]. Am J Physiol Endocrinol Metab, 2006,291: 99-107.
[45]Zechner R. The tissue-specific expression of lipoprotein lipase: implications for energy and lipoprotein metabolism[J]. Curr Opin Lipidol, 1997, 8:77-88.
[46]Picard F, Naimi N, Richard D, and Deshaies Y. Response of adipose tissue lipoprotein lipase to the cephalic phase of insulin secretion[J]. Diabetes, 1999,48: 452-459.
[47]Potts JL, Coppack SW, Fisher RM, Humphreys SM, Gibbons GF, and Frayn KN. Impaired postprandial clearance of triglycerol-rich lipoproteins in adipose tissue in obese subjects[J]. Am J Physiol Endocrinol Metab, 1995,268: E588-E594.
[48]漆正堂,丁树哲,贺杰.线粒体融合蛋白Mitoufsni在胰岛素抵抗发生与防治中的作用[J].生命科学,2008,20(4):599-603.
[49]Houstis N, Rosen ED, Lander ES. Reactive oxygen species have a causal role in multiple forms of insulin resistance[J]. Nature, 2006, 440:944-948.
[50]Imoto K, Kukidome D, Nishikawa T, Matsuhisa T, Sonoda K, Fujisawa K, Yano M, Motoshima H, Taguchi T, Tsuruzoe K, Matsumura T, Ichijo H, Araki E. Impact of mitochondrial reactive oxygen species and apoptosis signal-regulating kinase 1 on insulin signaling[J]. Diabetes, 2006, 55: 1197-1204.
[51]Couillard C, Ruel G, Archer WR, Pomerleau S, Bergeron J, Couture P, Lamarche B,Bergeron N. Circulating levels of oxidative stress markers and endothelial adhesion molecules in men with abdominal obesity[J]. J Clin Endocrinol Metab, 2005,90:6454-6459.
[52]Furukawa S, Fujita T, Shimabukuro M, Iwaki M, Yamada Y, Nakajima Y, Nakayama O, Makishima M, Matsuda M, Shimomura I. Increased oxidative stress in obesity and its impact on metabolic syndrome[J]. J Clin Invest, 2004,114: 1752-1761.
[53]Tauler P, Aguilo A, Fuentespina E, Tur J A&Pons A. Diet supplementation with Vitamin E, Vitamin C and beta-carotene cocktail enhances basal neutrophil antioxidant enzymes in athletes[J]. Pflugers Arch, 2002,443:791-797.
[54]Echtay KS, Esteves TC, Pakay JL, Jekabsons MB, Lambert AJ, Portero-Otin M, Pamplona R, Vidal-Puig AJ, Wang S, Roebuck SJ, Brand MD. A signalling role for 4-hydroxy-2-nonenal in regulation of mitochondrial uncoupIing[J]. Embo J, 2003,22: 4103-4110.
[55]Costford SR, Chaudhry SN, Salkhordeh M, Harper ME. Effects of the presence, absence, and overexpression of uncoupling protein-3 on adiposity and fuel metabolism in congenic mice[J]. Am J Physiol Endocrinol Metab, 2006, 290: E1304-E1312.
[56]Huppertz C, Fischer BM, Kim YB, Kotani K, Vidal-Puig A, Slieker LJ, Sloop KW, Lowell BB, Kahn BB. Uncoupling protein 3 (UCP_3) stimulates glucose uptake in muscle cells through a phosphoinositide 3-kinase-dependent mechanism[J]. J Biol Chem, 2001, 276:12520-12529.
[57]Harper ME, Dent R, Monemdjou S, Bezaire V, Van Wyck L, Wells G, Kavaslar GN, Gauthier A, Tesson F, and McPherson R. Decreased mitochondrial proton leak and reduced expression of uncoupling protein 3 in skeletal muscle of obese diet-resistant women[J]. Diabetes,2002,51:2459-2466.
[58]Constable SH, Favier RJ, McLane JA, Fell RD, Chen M, Holloszy JO. Energy metabolism in contracting rat skeletal muscle:adaptation to exercise training[J]. Physiol,1987,253: C316-C322.
[59]Menshikova EV, Ritov VB, Toledo FG, Ferrell RE, Goodpaster BH, Kelley DE. Effects of weight loss and physical activity on skeletal muscle mitochondrial function in obesity[J]. Am J Physiol Endocrinol Metab,2005,288:E818-E825.
[60]Lopez-Lluch G, Hunt N, Jones B, Zhu M, Jamieson H, Hilmer S, Cascajo MV, Allard J, Ingram DK, Navas P, de Cabo R. Calorie restriction induces mitochondrial biogenesis and bioenergetic efficiency. Proc Natl Acad Sci USA,2006,103:1768-1773.
[2]Forouhi NG, Jenkinson G, Thomas EL, Mullick S, Mierisova S, Bhonsle U, McKeigue PM, Bell JD. Relation of triglyceride stores in skeletal muscle cells to central obesity and insulin sensitivity in European and South Asian men[J]. Diabetologia,1999,42:932-935.
[3]马丽超,张莉,刘利兵等.肝脏和肌肉脂肪异位沉积与空腹高胰岛素血.症的发生[J].第四军医大学学报,2007,28(8)：703-705.
[4]Poirier P, Marcell T, Huey PU, Schlaepfer IR, Owens GC, Jensen DR, Eckel RH. Increased intracellular triglyceride in C(2)C(12) muscle cells transfected with human lipoprotein lipase[J]. J Clin Endocrinol Metab,2000,270:997-1001.
[5]Kim JY, Hickner RC, Cortright RL, Dohm GL, Houmard JA. Lipid oxidation is reduced in obese human skeletal muscle[J]. Am J Physiol Endocrinol Metab,2000,279:E1039-E1044.
[6]许纲,丁树哲,高彩暇.解偶联蛋白3与运动适应[J].中国运动医学杂志,2004,23(3)：336-342.
[7]Kiens B. Skeletal muscle lipid metabolism in exercise and insulin resistance[J]. Physiol Rev, 2006,86:205-243.
[8]Boden G, Lebed B, Schatz M, Homko C, Lemieux S. Effects of acute changes of plasma free fatty acids on intramyocellular fat content and insulin resistance in healthy subjects[J]. Diabetes,2001,50:1612-1617.
[9]Hurley BF, Nemeth PM, Martin WHD, Hagberg JM, Dalsky GP, Holloszy JO. Muscle triglyceride utilization during exerciseeffect of training[J]. J Appl Physiol,1986,60:562-567.
[10]Simoneau JA, Colberg SR, Thaete FL, Kelley DE. Skeletal muscle glycolytic and oxidative enzyme capacities are determinants of insulin sensitivity and muscle composition in obese women[J]. FASEB J,1995,9:273-278.
[11]Bret H, Goodpaster, Jing HE, Simon Watkins, David E. Kelly. Skeletal Muscle Lipid Content and Insulin Resistance:Evidence for a Paradox in Endurance-Trained Athletes[J]. The Journal of Clinical Endocrinology & Metabolism,2000,86(12):5755-5761.
[12]谭正怀.脂蛋白酯酶的组织特异性表达及其调节[J].国外医学内分泌学分册,2000,20(6)：320-323.
[13]Maheux P, Azhar S, Kern PA, Chen YDI, Reaven GM. Relationship between insulin mediated glucose disposal and regulation of plasma and adipose tissue lipoprotein lipase[J]. Diabetologia, 1997,40: 850-858.
[14]Voshol PJ, Jong MC, Dahltnans VE, et al. In muscle-specific lipoproteinlipase-overexpressing mice, muscle triglyceride content is increased without inhibition of insulin-stimulated whole-body and muscle-specific glucose uptake[J]. Diabetes, 2001, 50(25): 85-90.
[15]胡瑞萍,吴毅,胡永善.运动对糖尿病骨骼肌胰岛素信号传递的影响[J].中国康复医学杂志,2004,19(9):716-718.
[16]Montell E, Turini M, Marotta M, et al. DAG accumulation from saturated fatty acidsdesensitizes insulin stimulation of glucose uptake in muscle cells[J]. Am J PhysiolEndocrinol Metab, 2001,280(E2): 29-37.
[17]Stratford S, Hoehn KL, Liu F, Summers SA. Regulation of insulin action by ceramide: dualmechanisms linking ceramide accumulation to the inhibition of Akt/protein kinase B[J]. JBiol Chem, 2004,279(36): 608-615.
[18]Morino K, Petersen KF, Dufour S, Befroy D, Frattini J, Shatzkes N,Neschen S, White MF,Bilz S, Sono S, Pypaert M, Shulman GI. Reduced mitochondrial density and increased IRS-1serine phosphorylation in muscle of insulin-resistant offspring of type 2 diabetic parents[J]. JClin Invest, 2005, 115: 3587-3593.
[19]Petersen KF, Befroy D, Dufour S, Dziura J, Ariyan C, Rothman DL, DiPietro L, Cline GW,Shulman GI. Mitochondrial dysfunction in the elderly: possible role in insulin resistance[J].Science, 2003,300:1140 -1142.
[20]杨璐.解偶联蛋白3与2型糖尿病[J].国际内科学杂志,2008,3(5)1:15-45
[21]Lin B, Coughlin S, Pilch PF. Bidirectional regulation of uncoupling protein-3 and GLUT-4mRNA in skeletal muscle by cold[J]. Am J Physiol, 1998,275: E386-E391.
[22]Himms-Hagen J and Harper ME. Physiological role of UCP_3 may be export of fatty acidsfrom mitochondria when fatty acid oxidation predominates: an hypothesis[J]. Exp BiolMed(Maywood), 2001,226: 78-84.
[23]Schrauwen P, Saris WH and Hesselink MK. An alternative function for human uncouplingprotein 3: protection of mitochondria against accumulation of nonesterified fatty acids insidethe mitochondria] matrix[J]. FASEB J, 2001, 15: 2497-2502.
[24]MacLellan JD, Gerrits MF, Gowing A, Smith PJ, Wheeler MB and Harper ME. Physiologicalincreases in uncoupling protein 3 augment fatty acid oxidation and decrease reactive oxygenspecies production without uncoupling respiration in muscle cells[J]. Diabetes, 2005, 54:2343-2350.
[25]Schrauwen P, Hesselink MK, Blaak EE, Borghouts LB, Schaart G, Saris WH, Keizer HA.Uncoupling protein 3 content is decreased in skeletal muscle of patients with type 2diabetes[J]. Diabetes, 2001, 50: 2870-2873.
[26]Pruchnic R, Katsiaras A, He J, et al. Exercise training increases intramyocellular lipid and oxidative capacity in older adults[J]. Am J Physiol Endocrinol Metab, 2004, 287: E857-E862.
[27]Tarnopolsky MA, Rennie CD, Robertshaw HA, et al. Influence of endurance exercise training and sex on intramyocellular lipid and mitochondrial ultrastructure, substrate use, and mitochondrial enzyme activity[J]. Am J Physiol, 2007,292: R1271-R1278.
[28]Tsuboyama-Kasaoka N, Tsunoda N, Maruyama K, Takahashi M, Kim H, Ikemoto S, and Ezaki O. Up-regulation of uncoupling protein 3 (UCP_3) mRNA by exercise training and down-regulation of UCP_3 by denervation in skeletal muscles[J]. Biochem Biophys Res Commun, 1998, 247:498-503.
[29]Richter EA, Garetto LP, Goodman MN, Ruderman NB. Muscle glucose metabolism following exercise in the rat: increased sensitivity to insulin[J]. J Clin Invest, 1982, 69:785-793.
[30]DiPietro L, Dziura J, Yeckel CW, Neufer PD. Exercise and improved insulin sensitivity in older women: evidence of the enduring benefits of higher intensity training[J]. J Appl Physiol,2006,100:142-149.
[31]Wojtaszewski JF, Nielsen JN, Richter EA. Invited review: effect of acute exercise on insulin signaling and action in humans [J]. J Appl Physiol, 2002, 93: 384-392.
[32]Menshikova EV, Ritov VB, Fairfull L, Ferrell RE, Kelley DE, Goodpaster BH. Effects of exercise on mitochondrial content and function in aging human skeletal muscle [J]. J Gerontol A Biol Sci Med Sci, 2006,61: 534-40.
[33]Lauterio TJ, Bond JP, Ulman EA. Development and characrization of a purified diet to identify obesity-susceptible and resistant rat[J]. J Nutr, 1994, 124(11): 2172-2178.
[34]Bedford TG, Tipton CM, Wilson NC, et al. Maximum oxygen consumption of rats and its changes with various experimental procedures[J]. Journal of Applied Physiology, 1979, 47(6):1278-1283.
[35]李秀平,孙静,张俊权,李伟.慢性应急对大鼠葡萄糖耐量及胰岛素抵抗的影响[J].中国医药导报,2007,4(28):25-26.
[36]Khoursheed, Miles, K-M Gao, M-K Lee, AR Moossa and JM Olefsky. Metabolic effects of troglitazone on fat-induced insulin resistance in the rat[J]. Metabolism, 1995,44: 1489-1494.
[37]陈庆伟,刘丽华.肥胖、胰岛素抵抗与运动[J].吉林体育学院学报,2008,24(3):90-19.
[38]池脇克则等.代谢综合征与脂质代谢异常[J].日本医学介绍,2005,265(5):205-270.
[39]Holloszy JO. Exercise-induced increase in muscle insulin sensitivity[J]. J Appl Physiol, 2005,99:38-43.
[40]刘霞,曾凡星等.运动干预胰岛素抵抗的外周机制研究进展[J].北京体育大学学报,2005,1:23-25.
[41]Lindstrom J, Eriksson JG, Valle TT, et al. Prevention of diabetes mellitus in subjects with impaired glucose tolerance in the Finnish Diabetes Prevention Study: results from a randomized clinical trial[J]. J Am Soc Nephrol, 2003, 14: 8-13.
[42]GoodPaster BH,He J,Watkins S,Kelley DE.Skeletal muscle lipid content and insulin resistance: evidence for a paradox in endurancetrained athletes[J]. J Clin Endocrinol Metab,2001,86:5755-5761.
[43]Boden G, Lebed B, Schatz M, Homko C, Lemieux S. Effects of acute changes of plasma free fatty acids on intramyocellular fat content and insulin resistance in healthy subjects[J].Diabetes, 2001,50: 1612-1617.
[44]Bruce CR, Thrush AB, Mertz VA. et al. Endurance training in obese humans improves glucose tolerance and mitochondria! fatty acid oxidation and alters muscle lipid content[J]. Am J Physiol Endocrinol Metab, 2006,291: 99-107.
[45]Zechner R. The tissue-specific expression of lipoprotein lipase: implications for energy and lipoprotein metabolism[J]. Curr Opin Lipidol, 1997, 8:77-88.
[46]Picard F, Naimi N, Richard D, and Deshaies Y. Response of adipose tissue lipoprotein lipase to the cephalic phase of insulin secretion[J]. Diabetes, 1999,48: 452-459.
[47]Potts JL, Coppack SW, Fisher RM, Humphreys SM, Gibbons GF, and Frayn KN. Impaired postprandial clearance of triglycerol-rich lipoproteins in adipose tissue in obese subjects[J]. Am J Physiol Endocrinol Metab, 1995,268: E588-E594.
[48]漆正堂,丁树哲,贺杰.线粒体融合蛋白Mitoufsni在胰岛素抵抗发生与防治中的作用[J].生命科学,2008,20(4):599-603.
[49]Houstis N, Rosen ED, Lander ES. Reactive oxygen species have a causal role in multiple forms of insulin resistance[J]. Nature, 2006, 440:944-948.
[50]Imoto K, Kukidome D, Nishikawa T, Matsuhisa T, Sonoda K, Fujisawa K, Yano M, Motoshima H, Taguchi T, Tsuruzoe K, Matsumura T, Ichijo H, Araki E. Impact of mitochondrial reactive oxygen species and apoptosis signal-regulating kinase 1 on insulin signaling[J]. Diabetes, 2006, 55: 1197-1204.
[51]Couillard C, Ruel G, Archer WR, Pomerleau S, Bergeron J, Couture P, Lamarche B,Bergeron N. Circulating levels of oxidative stress markers and endothelial adhesion molecules in men with abdominal obesity[J]. J Clin Endocrinol Metab, 2005,90:6454-6459.
[52]Furukawa S, Fujita T, Shimabukuro M, Iwaki M, Yamada Y, Nakajima Y, Nakayama O, Makishima M, Matsuda M, Shimomura I. Increased oxidative stress in obesity and its impact on metabolic syndrome[J]. J Clin Invest, 2004,114: 1752-1761.
[53]Tauler P, Aguilo A, Fuentespina E, Tur J A&Pons A. Diet supplementation with Vitamin E, Vitamin C and beta-carotene cocktail enhances basal neutrophil antioxidant enzymes in athletes[J]. Pflugers Arch, 2002,443:791-797.
[54]Echtay KS, Esteves TC, Pakay JL, Jekabsons MB, Lambert AJ, Portero-Otin M, Pamplona R, Vidal-Puig AJ, Wang S, Roebuck SJ, Brand MD. A signalling role for 4-hydroxy-2-nonenal in regulation of mitochondrial uncoupIing[J]. Embo J, 2003,22: 4103-4110.
[55]Costford SR, Chaudhry SN, Salkhordeh M, Harper ME. Effects of the presence, absence, and overexpression of uncoupling protein-3 on adiposity and fuel metabolism in congenic mice[J]. Am J Physiol Endocrinol Metab, 2006, 290: E1304-E1312.
[56]Huppertz C, Fischer BM, Kim YB, Kotani K, Vidal-Puig A, Slieker LJ, Sloop KW, Lowell BB, Kahn BB. Uncoupling protein 3 (UCP_3) stimulates glucose uptake in muscle cells through a phosphoinositide 3-kinase-dependent mechanism[J]. J Biol Chem, 2001, 276:12520-12529.
[57]Harper ME, Dent R, Monemdjou S, Bezaire V, Van Wyck L, Wells G, Kavaslar GN, Gauthier A, Tesson F, and McPherson R. Decreased mitochondrial proton leak and reduced expression of uncoupling protein 3 in skeletal muscle of obese diet-resistant women[J]. Diabetes,2002,51:2459-2466.
[58]Constable SH, Favier RJ, McLane JA, Fell RD, Chen M, Holloszy JO. Energy metabolism in contracting rat skeletal muscle:adaptation to exercise training[J]. Physiol,1987,253: C316-C322.
[59]Menshikova EV, Ritov VB, Toledo FG, Ferrell RE, Goodpaster BH, Kelley DE. Effects of weight loss and physical activity on skeletal muscle mitochondrial function in obesity[J]. Am J Physiol Endocrinol Metab,2005,288:E818-E825.
[60]Lopez-Lluch G, Hunt N, Jones B, Zhu M, Jamieson H, Hilmer S, Cascajo MV, Allard J, Ingram DK, Navas P, de Cabo R. Calorie restriction induces mitochondrial biogenesis and bioenergetic efficiency. Proc Natl Acad Sci USA,2006,103:1768-1773.