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研究生:錢桂玉
研究生(外文):Kuie-Yu Chien
論文名稱:游泳運動對於果糖誘發胰島素阻抗鼠服用Metformin後之藥物動力學與葡萄糖代謝影響
論文名稱(外文):Effects of Swimming on the Pharmacokinetics and Glucose Metabolism of Metformin in Insulin- resistant Rats
指導教授:許美智許美智引用關係
指導教授(外文):Mei-Chich Hsu
學位類別:博士
校院名稱:國立體育學院
系所名稱:體育研究所
學門:教育學門
學類:專業科目教育學類
論文種類:學術論文
論文出版年:2008
畢業學年度:96
語文別:英文
論文頁數:60
中文關鍵詞:能量重新分配減脂口服降血糖藥吸收
外文關鍵詞:oral hypoglycemia agentabsorptionfat reductionenergy redistribution
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藥物治療合併生活型態改變是治療胰島素阻抗或糖尿病的典型策略,但至今對於服用Metformin (二甲双胍) 合併運動介入於藥物動力學、降血糖效果及其分子機轉影響的答案仍闕如。本論文以果糖誘發之胰島素阻抗鼠進行研究,第一部分探討單次45分鐘游泳運動對於Metformin之血糖濃度、胰島素分泌以及藥物動力學參數上的影響,第二部分則是探討游泳運動訓練以及服用Metformin對於葡萄糖代謝影響,並深入探討相關分子機轉之變化。研究結果顯示: (一) 服用Metformin之前進行單次45分鐘的游泳運動能使降血糖效果更好,並使服藥前空腹狀態之胰島素濃度降低。於藥物動力學參數部分則具有加速吸收,減少體內藥物之半衰期之效果,但並不影響其擬分佈體積、排除率以及整體藥物濃度之曲線下面積。(二) 運動訓練對於進食量、副睪脂肪量之減少以及肝臟G6Pase基因表現之增加具有加成作用。此外,僅服用Metformin二週即可減少體重、肝臟肝醣量以及空腹HOMA-IR指標 (HOMA-insulin resistance index),並增加股四頭之白肌肝醣量,此效應非經由增加肌肉之葡萄糖第一型(GLUT1)與第四型轉運體(GLUT4)之蛋白質含量來達成。本論文之獨創性發現為: (一) 服藥前進行運動能使服藥後2小時內之降血糖效果更好,此結果暗示了游泳運動或許在減少藥物的使用量下也可以達到相同的降血糖效果。(二)運動訓練合併Metformin的使用能減少脂肪與肝臟之能量儲存,並同時增加肌肉組織之肝醣含量,其顯示了能量使用之重新分配。
Drug therapy with life modification was the primary strategy to treatment type 2 diabetes or insulin resistance. However, the effects of swimming on the pharmacokinetics, glucose-lowering effects and its related mechanism are currently unclear. Fructose-induced insulin resistance rats were as animal model. There are two studies in this dissertation. The purpose of study one was to investigate the effects of swimming on the pharmacokinetic and glucose tolerance of metformin in rats with fructose-induced insulin resistance. After 12 h of fasting, a single dose of metformin-administered with a single bout of swimming group (MEa, n=8) swam for 45 min, while a single dose of metformin-administration group (Ma, n=8) were placed in 4-cm-deep water (34 ±1 °C) for the same time period. The first blood samples were withdrawn from the tail 60 min after the two groups had left the water. Metformin administration and an oral glucose tolerance test (OGTT) were performed after the first blood sample was taken. Blood samples were collected into test tubes at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, and 12 h. Serum metformin concentrations were determined by high-performance liquid chromatography (HPLC). A noncompartmental analysis was performed to estimate the pharmacokinetic parameters. Blood glucose levels, fasting insulin levels, the time to the maximum concentration, and the time to half life concentration in the MEa group were all lower than those in the Ma group (p<0.05). The maximum metformin concentration, the apparent volume of the distribution, the time-averaged total body clearance, and the area under the curve exhibited no significant differences between the two groups. The current study demonstrated that a single bout of 45 min swimming significantly enhanced the glucose-lowering effect and rate of metformin absorption. The purpose of study two was to evaluate the combined effects of metformin administration and swimming training on the insulin sensitivity in fructose-induced insulin-resistant rats. Fructose-induced insulin resistant rats were weight-matched and subdivided into following 4 groups: control group (C), exercise-trained group (E), metformin-treated group (M), exercise+metformin group (ME). Swimming training was performed 45 min a day, 5 days a week for 1 month. The tail weight load increased from 1% to 2% of total body weight. The M and the ME rats were orally treated with metformin (1350 mg • kg-1 • day-1) for 2 weeks. Metformin administration significantly decreased calories intake, body weight, and epididymal fat pad mass below the control level. We also observed metformin administration increased insulin sensitivity and this increase was paralleled with elevated glycogen in white quadriceps muscle without changed in GLUT4 protein levels. Liver glycogens were significantly lowered in the ME groups, concurrent with increased glucose-6-phosphatase (G6Pase) mRNA levels. Metformin administration induced a calories restriction (CR) mimetic effect, as shown by decreased HOMA-IR (insulin resistance) value, body weight, and increased hepatic G6Pase expression. Exercise training plus metformin treatment provides the best effect on lowering epidermal fat mass, but not for HOMA -IR Index. It was appeared implicated that the energy redistribution due to the increased of muscle glycogen storage and hepatic G6Pase gene expression, the reduction of liver glycogen and the loss of body fat in combined of metformin administration and swimming training.
Contents

Study One: Effects of swimming on the pharmacokinetics and glucose metabolism of metformin in insulin-resistant rats
1. Introduction ------------------------------------1
2. Materials and methods ---------------------------2
3. Results -----------------------------------------6
4. Discussion --------------------------------------7
5. Reference ---------------------------------------12


Study Two: Effects of metformin administration with swimming training in fructose induced insulin- resistant rats

1. Introduction ------------------------------------24
2. Materials and methods ---------------------------26
3. Results -----------------------------------------32
4. Discussion --------------------------------------35
5. Reference ---------------------------------------41
Study One: Effects of swimming on the pharmacokinetics and glucose metabolism of metformin in insulin-resistant rats
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Study Two: Effects of metformin administration with swimming training in fructose induced insulin- resistant rats
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