有氧运动训练8周2型糖尿病模型大鼠骨骼肌磷脂酰肌醇3-激酶-蛋白激酶B信号转导通路的变化
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摘要
背景:目前普遍观点是2型糖尿病患者胰岛素信号传导中的信号分子磷脂酰肌醇3-激酶和蛋白激酶B相比于健康人群均出现异常,而运动后胰岛素敏感性的改善也与骨骼肌中胰岛素信号传导系统的蛋白表达和活性增强有关。目的:探究8周有氧运动对中龄2型糖尿病大鼠骨骼肌磷脂酰肌醇3-激酶-蛋白激酶B信号转导通路的影响。方法:10个月龄中年雌性SD大鼠75只,由成都达硕实验动物有限公司提供。实验方案经沈阳体育学院科学研究伦理委员会批准(批准号为2015006)。SD大鼠75只随机分成5组:正常对照组,给普通饲料;糖尿病对照1组、糖尿病运动1组,均于高脂饲料喂养8周后注射链脲佐菌素35 mg/kg,制备2型糖尿病模型,继续给予高脂饲料至16周;糖尿病对照2组、糖尿病运动2组,均于高脂饲料喂养16周后注射链脲佐菌素35 mg/kg,制备2型糖尿病模型;2个运动组均于第9周开始进行有氧运动,运动8周后测试血脂、血糖、胰岛素和腓肠肌磷脂酰肌醇3-激酶-蛋白激酶B的蛋白表达。结果与结论:①8周和16周的高糖高脂饮食结合小剂量的链脲佐菌素均可引发中龄SD大鼠出现骨骼肌磷脂酰肌醇3-激酶、PK蛋白表达下降,磷脂酰肌醇3-激酶-蛋白激酶B信号传导发生障碍,引起脂和糖代谢紊乱,胰岛素敏感性下降,诱发2型糖尿病;②与相对应的糖尿病对照组比较,糖尿病运动1组和糖尿病运动2组的体质量有上升趋势,脂肪量和脂体比有下降趋势,三酰甘油、总胆固醇、游离脂肪酸和低密度脂蛋白值均显著降低,空腹血糖、空腹胰岛素水平显著下降,磷脂酰肌醇3-激酶和蛋白激酶B活性均显著增高;③结果说明,在诱发糖尿病前后施加运动干预,能通过增加机体能量消耗,提高骨骼肌胰岛素信号传导通路磷脂酰肌醇3-激酶-蛋白激酶B磷酸化水平,增加机体胰岛素敏感性,改善脂代谢和糖代谢紊乱,最终对2型糖尿病的发生和发展起到了有效的改善/预防作用。
BACKGROUND: Abnormal phosphoinositide 3-kinase and protein kinase B occurs in insulin signaling transduction of type 2 diabetes, and improvement in insulin sensitivity post-exercise has been shown to be related to the increased protein expression and activity in insulin signaling transduction.OBJECTIVE: To investigate the effect of 8-week aerobic exercise on the phosphoinositide 3-kinase-protein kinase B signaling pathway in type 2 diabetic skeletal muscle of middle-aged rat models.METHODS: Seventy-five 10 month-old female Sprague-Dawley rats were provided by Chengdu Dashuo Experimental Animal Co., Ltd., and the study was approved by the Research Ethics Committee of Shenyang Sport University, approval number: 2015006. The rats were randomized into five groups: normal control group(common diet), diabetes control 1 group(8-week high fat diet prior to injection of 35 mg/kg streptozotocin; continue to give high fat feed to 16 weeks), diabetes exercise 1 group(8-week high fat diet prior to injection of 35 mg/kg streptozotocin+ aerobic exercise; continue to give high fat feed to 16 weeks), diabetes control 2 group(16-week high fat diet prior to injection of 35 mg/kg streptozotocin), and diabetes exercise 1 group(16-week high fat diet prior to injection of 35 mg/kg streptozotocin+ aerobic exercise). The aerobic exercise was undergone at the 9 th week. The blood lipid, blood glucose, insulin and gastrocnemius phosphoinositide3-kinase-protein kinase B expression levels were tested after 8 weeks of exercise.RESULTS AND CONCLUSION:(1) Both high-fat and high-fat diets at 8 and 16 weeks combined with low-dose streptozotocin could induce the decrease of phosphoinositide 3-kinase and protein kinase B protein expression in the rat skeletal muscle, and impaired phosphoinositide3-kinase-protein kinase B signal transduction caused lipid and glucose metabolism disorders, decreased insulin sensitivity, and induced type 2 diabetes.(2) Compared with the diabetes control groups, the body mass in the aerobic exercise groups was on a rise, fat mass and body fat rate were on a descent, triacylglycerol, total cholesterol, free fatty acid and low density lipoprotein were significantly decreased, fasting blood-glucose and fasting insulin levels were significantly decreased, and activities of phosphoinositide 3-kinase and protein kinase B were significantly increased.(3) These results indicate that exercise intervention before and after inducing diabetes can reverse/enhance the phosphoinositide 3-kinase-protein kinase B phosphorylation level in skeletal muscle, increase insulin sensitivity, improve lipid metabolism and disorder of glucose metabolism, and ultimately effectively improve and prevent the occurrence and development of type 2 diabetes.
BACKGROUND: Abnormal phosphoinositide 3-kinase and protein kinase B occurs in insulin signaling transduction of type 2 diabetes, and improvement in insulin sensitivity post-exercise has been shown to be related to the increased protein expression and activity in insulin signaling transduction.OBJECTIVE: To investigate the effect of 8-week aerobic exercise on the phosphoinositide 3-kinase-protein kinase B signaling pathway in type 2 diabetic skeletal muscle of middle-aged rat models.METHODS: Seventy-five 10 month-old female Sprague-Dawley rats were provided by Chengdu Dashuo Experimental Animal Co., Ltd., and the study was approved by the Research Ethics Committee of Shenyang Sport University, approval number: 2015006. The rats were randomized into five groups: normal control group(common diet), diabetes control 1 group(8-week high fat diet prior to injection of 35 mg/kg streptozotocin; continue to give high fat feed to 16 weeks), diabetes exercise 1 group(8-week high fat diet prior to injection of 35 mg/kg streptozotocin+ aerobic exercise; continue to give high fat feed to 16 weeks), diabetes control 2 group(16-week high fat diet prior to injection of 35 mg/kg streptozotocin), and diabetes exercise 1 group(16-week high fat diet prior to injection of 35 mg/kg streptozotocin+ aerobic exercise). The aerobic exercise was undergone at the 9 th week. The blood lipid, blood glucose, insulin and gastrocnemius phosphoinositide3-kinase-protein kinase B expression levels were tested after 8 weeks of exercise.RESULTS AND CONCLUSION:(1) Both high-fat and high-fat diets at 8 and 16 weeks combined with low-dose streptozotocin could induce the decrease of phosphoinositide 3-kinase and protein kinase B protein expression in the rat skeletal muscle, and impaired phosphoinositide3-kinase-protein kinase B signal transduction caused lipid and glucose metabolism disorders, decreased insulin sensitivity, and induced type 2 diabetes.(2) Compared with the diabetes control groups, the body mass in the aerobic exercise groups was on a rise, fat mass and body fat rate were on a descent, triacylglycerol, total cholesterol, free fatty acid and low density lipoprotein were significantly decreased, fasting blood-glucose and fasting insulin levels were significantly decreased, and activities of phosphoinositide 3-kinase and protein kinase B were significantly increased.(3) These results indicate that exercise intervention before and after inducing diabetes can reverse/enhance the phosphoinositide 3-kinase-protein kinase B phosphorylation level in skeletal muscle, increase insulin sensitivity, improve lipid metabolism and disorder of glucose metabolism, and ultimately effectively improve and prevent the occurrence and development of type 2 diabetes.
引文
[1]况志彬.2型糖尿病合并非酒精性脂肪肝与胰岛素抵抗及心血管疾病的相关性[J].医学理论与实践.2018,31(5):667-669.
[2]Hu X,Wang S,Xu J,et al.Triterpenoid saponins from Stauntonia chinensis ameliorate insulin resistance via the AMP-activated protein kinase and IR/IRS-1/PI3K/Akt pathways in insulin-resistant HepG2 cells.Int J Mol Sci.2014;15(6):10446-10458.
[3]李斌,范源,李鑫.基于PI3K/Akt信号通路的中药改善2型糖尿病胰岛素抵抗研究进展[J],中成药,2017,39(1):151-154.
[4]章晓君,孙佳,赵新,等.6min步行试验对老年2型糖尿病患者干预效果分析[J].山西医药杂志,2015,44(4):420-422.
[5]李洪臣,邱玥,铁英,等.陈式太极拳功法对老年2型糖尿病患者血液生化指标和心肺功能的影响[J].中国老年学杂志, 2015,35(5):1293-1294.
[6]罗晓玲,李东锋,朱树贞.社区集体运动功能锻炼对老年2型糖尿病病人预后的影响[J].护理研究,2015,29(4):1196-1199.
[7]牛衍龙,陈德明.运动治疗2型糖尿病训练学处方制定的分析[J].哈尔滨体育学院学报,2015,33(3):91-96.
[8]Palmer NO,Bakos HW, Owens JA,et al. Diet and exercise in an obese mouse fed a high-fat diet improve metabolic health and reverse perturbed sperm function.Am J Physiol Endocrinol Metab.2012;302(7):E768-E780.
[9]Srinivasan K,Viswanad B,Asrat L,et al.Combination of high-fat diet-fed and low-dose streptozotocin-treated rat:a model for type 2 diabetes and pharmacological screen-ing.Pharmacol Res. 2005;52(4):313-320.
[10]Zhang M,Lv XY,Li J,et al.The Characterization of High-Fat Diet and Multiple Low-Dose Streptozotocin Induced Type 2Diabetes Rat Model.Exp Diabetes Res.Exp Diabetes Res.2008;2008:704045.
[11]王子木,陈晓彤,慧梅.2型糖尿病患者的早期胰岛素强化改善[J].大连医科大学学报,2017,39(5):503-506.
[12]Sangeetha KN, Sujatha S, Muthusamy VS, et al.Current trends in small molecule discovery targeting key cellular signaling events towards the combined management of diabetes and obesity.Biomedical Informatics.2017;13(12):394-399
[13]中华医学会糖尿病学分会.中国2型糖尿病防治指南(2013年版)[J].中国糖尿病杂志,2014,22(8):后插2-后插42页.
[14]冯召岚,董爱武,谢鑫,等.运动干预对高脂饮食大鼠脂类代谢异常和胰岛素敏感性的影响[J].江苏医药,2018,44(2):125-128.
[15]Liang H,Tantiwong P,Sriwijitkamol A,et al. Effect of a sustained reduction in plasma free fatty acid concentration on insulin signalling and inflammation in skeletal muscle from human subjects.J Physiol.2013;591(11):2897-2909.
[16]Shibata E,Kanno T,Tsuchiya A,et al.Free fatty acids inhibit protein tyrosine phosphatase 1B and activate Akt. Cell Physiol Biochem.2013;32(4):871-879.
[17]Li HB,Yang YR,Mo ZJ,et al. Silibinin improves palmitate-induced insulin resistance in C2C12 myotubes by attenuating IRS-1/PI3K/Akt pathway inhibition.Braz J Med Biol Res.2015;48(5):440-446.
[18]Huri HZ,Makmor-Bakry M,Hashim R,et al. Optimisation of glycaemic control during episodes of severe/acute hyperglycaemia in patients with type 2 diabetes mellitus. Int J Clin Pharm. 2012;34(6):863-870.
[19]孙子林,刘莉莉.《中国糖尿病运动指南》解读[J].国际内分泌代谢杂志,2013,33(6):373-375, 378.
[20]Kjobsted R,Munk-Hansen N,Birk JB,et al. Enhanced Muscle Insulin Sensitivity After Contraction/Exercise Is Mediated by AMPK.Diabetes.2017;66(3):598-612.
[21]李艳辉,衣雪洁.有氧运动对2型糖尿病大鼠骨骼肌ERK1/2活性的影响[J].中国应用生理学杂志,2017, 33(1):33-37.
[22]赵金香,胡章云,李耀华,等.菊粉联合游泳训练对代谢综合征大鼠骨骼肌胰岛素受体底物1及葡萄糖转运子4表达的影响[J].中国糖尿病杂志, 2017,25(9):831-835.
[23]王月秋,王丽宏,车慧,等.微小RNA与胰岛素PI3K/AKT信号转导通路[J].新医学,2017,48(7):438-442.
[24]Winnay JN, Dirice E, Liew CW, et al. p85αdeficiency protectsβ-cells from endoplasmic reticulum stress-induced apoptosis.Proc Natl Acad Sci USA.2014;111(3):1192-1197.
[25]Nelson VL, Jiang YP, Dickman KG, et al. Adipose tissue insulin resistance due to loss of PI3K p110αleads to decreased energy expenditure and obesity.Am J Physiol EndocrinolMetab.2014;306(10):E1205-E1216.
[26]Sylow L,Kleinert M,Richter EA,et al.Exercise-stimulated glucose uptake-regulation and implications for glycaemic control. Nat Rev Endocrinol.2017;13(3):133-148.
[27]Zierath JR, Krook A, Wallberg-Henriksson H. Insulin action and insulin resistance in human skeletal muscle. Diabetologia.2000;43(7):821-35.
[28]Uarvey WT,Huecksteadt TP,Matthaei S,et al. Role of glucose transporters in the cellular insulin resistance of type II non-insulin-dependent diabetes mellitus. J Clin Invest. 1988;81(5):1528-1536.
[29]Hohn P. Kirwanl,etc. Regular exercise enhacnes insulin activation of IRS-1-associated PI3-kinase in human skeletal muscle. J Appl Physiol 2000;88:793-803
[30]李常富.有氧运动对肥胖大鼠脂肪组织LC3泛素样系统相关蛋白表达的影响[D].北京体育大学,2017
[31]顾兰馨,王志法,殷强,等.有氧运动对CSD引起的大鼠IR的影响[J].心脏杂志,2017, 29(6):652-658.
[32]Chibalin AV, Yu M, Ryder JW, et al. Exercise-induced changes in epression and activity of proteins involved in insulin signal transduction skeletal muscle:differential effects on insulin receptor substrates 1 and Proc Natl Acad Sci USA.2000;97:38-43.
[33]Wojtaszewski JF, Nielsen P, Kiens B, et al.Regulation of Glycogen Synthase Kinase-3 in Human Skeletal Muscle:Effects of Food Intake and Bicycle Exercise. Diabetes.2001;50:265-269.
[34]Christ-Roberts CY, Pratipanawatr T,Pratipanawatr W,et al.Exercise training icnreases glycogen synthase activity and GLUT4 expression but not insulin signaling in overweight nondiabetic and type 2 diabetic subjects. Metabolism.2004;53(9):1233-1242.
[35]O'Gorman DJ, Karlsson HK, Mc Quaid S, et al. Exercise training icnreases insulin-stimulated glucose disposal and GLUT4(SLC2A4)protein content in patients with type 2diabetes. Diabetologia.2006;49(12):2983-2992.
[2]Hu X,Wang S,Xu J,et al.Triterpenoid saponins from Stauntonia chinensis ameliorate insulin resistance via the AMP-activated protein kinase and IR/IRS-1/PI3K/Akt pathways in insulin-resistant HepG2 cells.Int J Mol Sci.2014;15(6):10446-10458.
[3]李斌,范源,李鑫.基于PI3K/Akt信号通路的中药改善2型糖尿病胰岛素抵抗研究进展[J],中成药,2017,39(1):151-154.
[4]章晓君,孙佳,赵新,等.6min步行试验对老年2型糖尿病患者干预效果分析[J].山西医药杂志,2015,44(4):420-422.
[5]李洪臣,邱玥,铁英,等.陈式太极拳功法对老年2型糖尿病患者血液生化指标和心肺功能的影响[J].中国老年学杂志, 2015,35(5):1293-1294.
[6]罗晓玲,李东锋,朱树贞.社区集体运动功能锻炼对老年2型糖尿病病人预后的影响[J].护理研究,2015,29(4):1196-1199.
[7]牛衍龙,陈德明.运动治疗2型糖尿病训练学处方制定的分析[J].哈尔滨体育学院学报,2015,33(3):91-96.
[8]Palmer NO,Bakos HW, Owens JA,et al. Diet and exercise in an obese mouse fed a high-fat diet improve metabolic health and reverse perturbed sperm function.Am J Physiol Endocrinol Metab.2012;302(7):E768-E780.
[9]Srinivasan K,Viswanad B,Asrat L,et al.Combination of high-fat diet-fed and low-dose streptozotocin-treated rat:a model for type 2 diabetes and pharmacological screen-ing.Pharmacol Res. 2005;52(4):313-320.
[10]Zhang M,Lv XY,Li J,et al.The Characterization of High-Fat Diet and Multiple Low-Dose Streptozotocin Induced Type 2Diabetes Rat Model.Exp Diabetes Res.Exp Diabetes Res.2008;2008:704045.
[11]王子木,陈晓彤,慧梅.2型糖尿病患者的早期胰岛素强化改善[J].大连医科大学学报,2017,39(5):503-506.
[12]Sangeetha KN, Sujatha S, Muthusamy VS, et al.Current trends in small molecule discovery targeting key cellular signaling events towards the combined management of diabetes and obesity.Biomedical Informatics.2017;13(12):394-399
[13]中华医学会糖尿病学分会.中国2型糖尿病防治指南(2013年版)[J].中国糖尿病杂志,2014,22(8):后插2-后插42页.
[14]冯召岚,董爱武,谢鑫,等.运动干预对高脂饮食大鼠脂类代谢异常和胰岛素敏感性的影响[J].江苏医药,2018,44(2):125-128.
[15]Liang H,Tantiwong P,Sriwijitkamol A,et al. Effect of a sustained reduction in plasma free fatty acid concentration on insulin signalling and inflammation in skeletal muscle from human subjects.J Physiol.2013;591(11):2897-2909.
[16]Shibata E,Kanno T,Tsuchiya A,et al.Free fatty acids inhibit protein tyrosine phosphatase 1B and activate Akt. Cell Physiol Biochem.2013;32(4):871-879.
[17]Li HB,Yang YR,Mo ZJ,et al. Silibinin improves palmitate-induced insulin resistance in C2C12 myotubes by attenuating IRS-1/PI3K/Akt pathway inhibition.Braz J Med Biol Res.2015;48(5):440-446.
[18]Huri HZ,Makmor-Bakry M,Hashim R,et al. Optimisation of glycaemic control during episodes of severe/acute hyperglycaemia in patients with type 2 diabetes mellitus. Int J Clin Pharm. 2012;34(6):863-870.
[19]孙子林,刘莉莉.《中国糖尿病运动指南》解读[J].国际内分泌代谢杂志,2013,33(6):373-375, 378.
[20]Kjobsted R,Munk-Hansen N,Birk JB,et al. Enhanced Muscle Insulin Sensitivity After Contraction/Exercise Is Mediated by AMPK.Diabetes.2017;66(3):598-612.
[21]李艳辉,衣雪洁.有氧运动对2型糖尿病大鼠骨骼肌ERK1/2活性的影响[J].中国应用生理学杂志,2017, 33(1):33-37.
[22]赵金香,胡章云,李耀华,等.菊粉联合游泳训练对代谢综合征大鼠骨骼肌胰岛素受体底物1及葡萄糖转运子4表达的影响[J].中国糖尿病杂志, 2017,25(9):831-835.
[23]王月秋,王丽宏,车慧,等.微小RNA与胰岛素PI3K/AKT信号转导通路[J].新医学,2017,48(7):438-442.
[24]Winnay JN, Dirice E, Liew CW, et al. p85αdeficiency protectsβ-cells from endoplasmic reticulum stress-induced apoptosis.Proc Natl Acad Sci USA.2014;111(3):1192-1197.
[25]Nelson VL, Jiang YP, Dickman KG, et al. Adipose tissue insulin resistance due to loss of PI3K p110αleads to decreased energy expenditure and obesity.Am J Physiol EndocrinolMetab.2014;306(10):E1205-E1216.
[26]Sylow L,Kleinert M,Richter EA,et al.Exercise-stimulated glucose uptake-regulation and implications for glycaemic control. Nat Rev Endocrinol.2017;13(3):133-148.
[27]Zierath JR, Krook A, Wallberg-Henriksson H. Insulin action and insulin resistance in human skeletal muscle. Diabetologia.2000;43(7):821-35.
[28]Uarvey WT,Huecksteadt TP,Matthaei S,et al. Role of glucose transporters in the cellular insulin resistance of type II non-insulin-dependent diabetes mellitus. J Clin Invest. 1988;81(5):1528-1536.
[29]Hohn P. Kirwanl,etc. Regular exercise enhacnes insulin activation of IRS-1-associated PI3-kinase in human skeletal muscle. J Appl Physiol 2000;88:793-803
[30]李常富.有氧运动对肥胖大鼠脂肪组织LC3泛素样系统相关蛋白表达的影响[D].北京体育大学,2017
[31]顾兰馨,王志法,殷强,等.有氧运动对CSD引起的大鼠IR的影响[J].心脏杂志,2017, 29(6):652-658.
[32]Chibalin AV, Yu M, Ryder JW, et al. Exercise-induced changes in epression and activity of proteins involved in insulin signal transduction skeletal muscle:differential effects on insulin receptor substrates 1 and Proc Natl Acad Sci USA.2000;97:38-43.
[33]Wojtaszewski JF, Nielsen P, Kiens B, et al.Regulation of Glycogen Synthase Kinase-3 in Human Skeletal Muscle:Effects of Food Intake and Bicycle Exercise. Diabetes.2001;50:265-269.
[34]Christ-Roberts CY, Pratipanawatr T,Pratipanawatr W,et al.Exercise training icnreases glycogen synthase activity and GLUT4 expression but not insulin signaling in overweight nondiabetic and type 2 diabetic subjects. Metabolism.2004;53(9):1233-1242.
[35]O'Gorman DJ, Karlsson HK, Mc Quaid S, et al. Exercise training icnreases insulin-stimulated glucose disposal and GLUT4(SLC2A4)protein content in patients with type 2diabetes. Diabetologia.2006;49(12):2983-2992.
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