有氧运动对2型糖尿病大鼠糖脂代谢、骨骼肌炎症和自噬的影响

Effect of aerobic exercise on glycolipid metabolism,skeletal muscle inflammation and autophagy in type 2 diabetic rats

背景:肥胖及其导致的慢性低度炎症是诱发2型糖尿病的重要危险因素,这种炎症反应还将进一步累及骨骼肌,导致骨骼肌的分解代谢和自噬通量增加;有氧运动作为防治2型糖尿病的主流运动方式,对2型糖尿病骨骼肌也可能具有一定的保护作用。目的:探究有氧运动对2型糖尿病大鼠糖脂代谢、骨骼肌炎症和骨骼肌自噬的影响和调节机制。方法:通过8周高脂饲养联合链脲佐菌素注射建立2型糖尿病大鼠模型,将实验大鼠分为普通对照组、普通运动组、糖尿病对照组和糖尿病运动组,分别在4周有氧运动(跑速16 m/min,60 min/d,5 d/周)前后采用全自动生化分析仪检测各组大鼠血糖、血清高密度脂蛋白、低密度脂蛋白和三酰甘油水平,酶联免疫吸附法检测血清胰岛素水平,计算胰岛素抵抗指数和葡萄糖代谢曲线下面积;在4周有氧运动后采用酶联免疫吸附法测定比目鱼肌中白细胞介素6和肿瘤坏死因子α水平,免疫印迹法测定比目鱼肌中叉头框蛋白O3(forkhead box protein O3,FoxO3)、LC3和p62的蛋白表达水平。结果与结论:①与普通对照组相比,糖尿病对照组大鼠的糖耐量曲线下面积和胰岛素抵抗指数均显著升高(P<0.001,P=0.025),有氧运动能显著降低普通运动组(P<0.001,P=0.038)和糖尿病运动组(P<0.001,P=0.004)的糖耐量曲线下面积和胰岛素抵抗指数。②与普通对照组相比,糖尿病对照组大鼠的血清高密度脂蛋白水平显著降低(P=0.030)、低密度脂蛋白和三酰甘油水平显著升高(P=0.027,P=0.014),有氧运动能显著降低普通运动组的三酰甘油、低密度脂蛋白水平(P=0.019,P=0.008)以及糖尿病运动组的三酰甘油水平(P=0.022)。③与普通对照组相比,糖尿病对照组大鼠比目鱼肌的白细胞介素6和肿瘤坏死因子α水平均显著升高(P<0.001,P=0.007),有氧运动能显著降低糖尿病运动组的肿瘤坏死因子α水平(P=0.017)。④与普通对照组相比,糖尿病对照组大鼠比目鱼肌的LC3-Ⅱ/LC3-Ⅰ比值显著升高,有氧运动能显著提高普通运动组的LC3-Ⅱ/LC3-Ⅰ比值(P<0.001),降低糖尿病运动组的LC3-Ⅱ/LC3-Ⅰ比值、FoxO3和p62蛋白表达水平(P=0.026,P=0.050,P=0.048)。⑤结果表明,高脂饲养联合链脲佐菌素注射建立的2型糖尿病模型具有明显糖脂代谢障碍,同时累及并导致骨骼肌炎症反应和自噬过度激活;有氧运动可以改善2型糖尿病糖脂代谢,降低骨骼肌局部炎症并抑制骨骼肌自噬,从而对骨骼肌起到保护作用。

BACKGROUND:Obesity and its relevant chronic inflammation are important risk factors for inducing type 2 diabetes.This inflammatory response will further involve skeletal muscle,leading to an increase in catabolic and autophagic fluxes in skeletal muscle.Aerobic exercise is the mainstream mode of exercise in the prevention and treatment of type 2 diabetes,and may also has a certain protective effect on skeletal muscle.OBJECTIVE:To explore the effects and regulatory mechanisms of aerobic exercise on glucolipid metabolism,skeletal muscle inflammation and autophagy in type 2 diabetic rats.METHODS:Animal models of type 2 diabetes were established in rats by 8-week high-fat feeding combined with streptozotocin injection,and the experimental rats were then divided into normal control group,normal exercise group,diabetic control group and diabetic exercise group.The exercise group performed 4 weeks of aerobic exercise(16 m/min,60 min/d,5 d/wk).The levels of blood glucose,high-density lipoprotein,low-density lipoprotein and triglyceride in serum were measured by an automated biochemical analyzer.Serum insulin level was determined using enzyme-linked immunosorbent assay and the insulin resistance index and area under the glucose metabolism curve were calculated.The levels of interleukin 6 and tumor necrosis factorαin skeletal muscle were measured by enzyme-linked immunosorbent assay after 4 weeks of aerobic exercise,and the expression levels of forkhead box protein O3(FoxO3),LC3 and p62 in skeletal muscle were measured by western blot assay.RESULTS AND CONCLUSION:The area under the glucose tolerance curve and insulin resistance index both increased significantly in type 2 diabetic rats(P<0.001,P=0.025),and aerobic exercise significantly reduced the area under the glucose tolerance curve and insulin resistance index in the normal exercise group(P<0.001,P=0.038)and diabetic exercise group(P<0.001,P=0.004).Serum high-density lipoprotein significantly decreased(P=0.030),and low-density lipoprotein and triglyceride(P=0.027,P=0.014)levels significantly increased in the diabetic control group compared with the normal control group.Aerobic exercise significantly reduced triglyceride and low-density lipoprotein levels in the normal exercise group(P=0.019,P=0.008)as well as triglyceride levels in the diabetic exercise group(P=0.022).Both interleukin-6 and tumor necrosis factorαlevels were significantly increased in the skeletal muscle of type 2 diabetic rats compared with the normal control group(P<0.001,P=0.007),and aerobic exercise significantly reduced tumor necrosis factorαlevels in the diabetic exercise group(P=0.017).The LC3-II/LC3-I was significantly increased in the skeletal muscle of type 2 diabetic rats compared with the normal control group.Aerobic exercise significantly increased the LC3-II/LC3-I in the normal exercise group(P<0.001)and decreased the LC3-II/LC3-I,FoxO3 and p62 protein expression levels in the diabetic exercise group(P=0.026,P=0.050,P=0.048).To conclusion,type 2 diabetes model established by high-fat feeding combined with streptozotocin injection has obvious glycolipid metabolism disorder,and leads to inflammatory response and excessive activation of autophagy in skeletal muscle.Aerobic exercise can improve glycolipid metabolism,reduce local inflammation in skeletal muscle and inhibit autophagy,and finally play a protective role in skeletal muscle.