||Effects of exercise training on serum insulin-like growth factor-1 and aortic apoptosis in type 1 diabetic rats
||Department of Physical Therapy
背景及目的：心血管疾病是造成糖尿病患產生併發症和高致死率的主要原因，在糖尿病血管病變發展過程中，血管平滑肌細胞凋亡是一個重要關鍵的因素。研究指出，第一型糖尿病之血清類胰島素生長因子-1(insulin-like growth factor-1, IGF-1)濃度會降低，而類胰島素生長因子-1可以抑制主動脈細胞凋亡的現象。因此，本研究的目的乃欲探討在第一型糖尿病鼠中，運動訓練對於血清類胰島素生長因子-1和主動脈細胞凋亡的影響，及其背後的原理機制。方法：將八週大雄性wistar大鼠隨機分為六組，分別是正常組(normal sedentary rats, NS)，正常組合併運動訓練（normal-exercised rats, NE），糖尿病組（streptozotocin-induced diabetic rats without exercise training, SS），糖尿病組合併運動訓練（streptozotocin-induced diabetic rats with exercise training, SE），糖尿病組合併胰島素治療（streptozotocin-induced diabetic rats without exercise training combine with insulin treatment, SS+IT），和糖尿病組合併運動訓練及胰島素治療（streptozotocin-induced diabetic rats with exercise training and insulin treatment, SE+IT）。運動訓練組會以鼠用跑步機進行四週的中度運動訓練，每週五天，每天六十分鐘，速度在15~21公尺／分鐘，在最後一次運動訓練結束後四十八小時，取下大鼠的血液樣本分析血清類胰島素生長因子-1的濃度，並分析胸主動脈phospho-Akt，phospho-Bad，active caspase-9和pro-caspase-3表現量以了解細胞凋亡的情形。結果：我們發現（1）在糖尿病組中，血清類胰島素生長因子-1的濃度是顯著比正常組低（P<0.05）。比較正常組和正常組合併運動訓練，發現運動訓練可以增加血清類胰島素生長因子-1的濃度（P<0.05），在糖尿病合併運動訓練組，運動訓練也可以增加血清類胰島素生長因子-1的濃度。（2）在糖尿病組中，主動脈細胞的phospho-Akt表現量明顯低於正常組(P<0.05)，經由運動訓練可以顯著增加正常組和糖尿組主動脈細胞的phospho-Akt表現量(P<0.05)。（3）在糖尿病組中，主動脈的phospho-Bad表現量明顯低於正常組(P<0.05)。（4）在糖尿病組中，主動脈的active caspase-9表現量顯著高於正常組(P<0.05)。運動訓練可以降低在糖尿病鼠主動脈之active caspase-9的表現量。（5）在糖尿病組中，主動脈細胞的pro-caspase-3表現量顯著比正常組低（P<0.05）。在正常組和糖尿病組中，經由運動訓練可以增加pro-caspase-3的表現量（P<0.05）。（6）胰島素治療可以增加糖尿病鼠血清類胰島素生長因子-1的濃度及主動脈細胞的phospho-Akt、phospho-Bad、pro-caspase-3表現量。結論：第一型糖尿病鼠血清中之類胰島素生長因子-1濃度較正常鼠低，而使其主動脈啟動較多的粒線體路徑之細胞凋亡。運動訓練和胰島素治療可以增加第一型糖尿病鼠中血清類胰島素生長因子-1，進而活化主動脈中phospho-Akt、抑制caspase-3的活化，達到減少糖尿病鼠之主動脈細胞凋亡。臨床意義：中度運動訓練和胰島素治療對於第一型糖尿病是有益處的。
Background and Purpose: Vascular diseases are the main causes of morbidity and mortality in diabetes. In the development of diabetic angiopathy, vascular smooth muscle cells apoptosis is a critical factor. Previous studies indicated that serum level of insulin-like growth factor-1(IGF-1) is decreased in type 1 diabetes, and IGF-1 was found to inhibit aortic apoptosis. Therefore, the purpose of this study was to investigate the effects of exercise training on serum IGF-1 and aortic apoptosis in type 1 diabetic rats. Methods: Eight weeks old male Wistar rats were divided into six groups: normal sedentary rats (NS), normal-exercised rats (NE), streptozotocin-induced diabetic rats without exercise training (SS), streptozotocin-induced diabetic rats with exercise training (SE), streptozotocin-induced diabetic rats without exercise training combine with insulin treatment (SS+IT), and streptozotocin-induced diabetic rats with exercise training and insulin treatment (SE+IT). Rats in the exercise group run on a treadmill 5 days/week, 60 min/day at 15~21 m/min for 4 weeks. Forty-eight hours after the last exercise session, blood samples were collected to determine the serum concentration of IGF-1 by ELISA. Phospho-Akt, phospho-Bad, active caspase-9 and pro-caspase-3 expression in aortic cells were also analyzed by western blotting. Results: We found that 1) Serum IGF-1 was reduced in diabetes (P<0.05). Exercise training could increase IGF-1 concentrations when comparing NE to NS (P<0.05) and could slightly increase IGF-1 concentrations when comparing SE to SS. 2) The expression of phospho-Akt in aortic cells of diabetes was significantly decreased (P<0.05). Exercise training could increase phospho-Akt expression in normal and diabetic rats (P<0.05). 3) The expression of phospho-Bad in aortic cells of diabetes was significantly decreased (P<0.05). 4) The expression of active caspase-9 in aortic cells of diabetes was significantly increased (P<0.05). Exercise training could slightly decrease the expression of active caspase-9 in diabetec rats. 5) The expression of pro-caspase-3 in aortic cells of diabetes was significantly decreased (P<0.05). Exercise training could increase pro-caspase-3 expression in normal and diabetic rats (P<0.05). 6) insulin treatment could increase IGF-1 concentrations, the expression of phospho-Akt, phospho-Bad and pro-caspase-3 in aortic cells (P<0.05). Conclusions: The serum level of IGF-1 was lower and the aortic mitochondrial-dependent apoptotic pathway was more activated in diabetic rats than in normal rats. Exercise training and insulin treatment could decrease the aortic apoptosis in diabetes through the increased concentration of serum IGF-1, activation of phospho-Akt and inhibition of caspase-3 activation. Clinical Relevance: These findings suggest physical exercise training and insulin treatment are beneficial for type 1 diabetes.
Abstract in Chinese-------------------------------------1
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Materials and methods ---------------------------------16
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