- 學位論文
以動物模式評估梅精複方與梅精產品在抗代謝性疾病之作用：以糖尿病與高尿酸血症為例
Anti-metabolic disease effects of Mei-Gin Formulas and Mei-Gin Products in animal models of diabetes mellitus and hyperuricemia
摘要
代謝作用在廣義之定義為活體內所有參與能量產生與利用之過程總稱，而當代謝異常時，容易引發許多代謝疾病的發生，已知肥胖、飲食及遺傳因素都是導致代謝異常之原因。高尿酸血症及糖尿病為現今社會中常見之代謝疾病，並且常伴隨著許多併發症的發生。藥物是治療代謝疾病的有效方法，但是可能會導致許多副作用的發生，所以，近年來許多研究都在探討天然植物食品之抗代謝疾病之作用。因此，本研究將利用天然植物食品探討其在調節血糖及調節高尿酸血症之作用，並釐清其分子作用機轉，期望將其開發成具調節血糖與調節高尿酸血症之保健食品。內容主要分成兩部分：(一) 利用db/db糖尿病小鼠模式探討梅精複方調節血糖之研究 (二) 不同加工製程梅精產品對氧嗪酸鉀 (potassium oxonate, PO) 誘導SD大鼠高尿酸血症之影響。 (一) 本研究以梅精為基礎外加不同比例之青梅、黑蒜和仙草萃取物製成梅精複方 (Mei-Gin Formula, MGF)，評估不同劑量之梅精複方4號 (MGF-4) 與梅精複方7號 (MGF-7) 對db/db糖尿病小鼠之影響與分子作用機轉。結果顯示，給予MGF-4和MGF-7可顯著降低db/db糖尿病小鼠之空腹血糖、胰島素抗性指數及血清糖化血色素。給予MGF-4可降低db/db糖尿病小鼠之血清胰島素。由肌肉基因表現分析結果得知，給予db/db糖尿病小鼠MGF-4及MGF-7後，可顯著增加GLUT4及PFK-A之基因表現；給予MGF-4可額外提升其HK及PK2之基因表現。由肝臟基因分析結果得知，給予db/db糖尿病小鼠MGF-4及MGF-7後，可顯著增加GLUT2及AKT2之基因表現，並降低FOXO1、PEPCK及G6Pase之基因表現；給予MGF-4後，可額外增加GK及GYS2之基因表現。綜合上述結果得知，MGF-4及MGF-7確實有調節血糖之功能，其中MGF-4之作用最佳。 (二) 本研究利用PO誘導SD大鼠高尿酸血症模式，探討五種不同製程之梅精產品 (Mei-Gin Product, MGP) 對於高尿酸血症大鼠之影響與分子作用機轉。結果顯示，給予MGP-2、MGP-3、MGP-4及MGP-5可顯著降低高尿酸血症大鼠之血清尿酸含量及肝臟XOD之基因表現。給予MGP-3、MGP-4及MGP-5可顯著增加高尿酸血症大鼠之血清一氧化氮含量。給予MGP-3可顯著降低高尿酸血症大鼠之肝臟PRRS及PNP之基因表現。給予MGP-5可顯著降低高尿酸血症大鼠肝臟NT5E之基因表現，並增加肝臟APRT及HPRT之基因表現。此外，給予MGP-5可顯著增加高尿酸血症大鼠之尿液尿酸排泄。綜合上述結果得知，MGP-2、MGP-3、MGP-4及MGP-5確實有改善高尿酸血症之功能，其中以MGP-5之作用較佳。 以上結果證實，梅精複方具有調節血糖之作用，其可增加肌肉之葡萄萄轉運及糖解作用之相關基因，增加肝臟之葡萄萄轉運及肝醣合成作用之相關基因，並可降低肝臟之糖質新生作用之相關基因，達到調節血糖之作用。梅精產品具有改善高尿酸血症之作用，其可抑制肝臟之核苷酸合成、核苷酸分解、核苷分解及嘌呤分解作用之相關基因，並可增加肝臟之嘌呤再利用之相關基因，達到改善高尿酸血症之作用。綜合上述結果，未來可將梅精複方及梅精產品開發成調節血糖與改善高尿酸血症之保健食品。
並列摘要
Metabolism is broadly defined as the sum of all biochemical reaction that consists of anabolism and catabolism, which providing energy for life maintenance in living organism. A metabolic disorder occurs by an abnormal chemical process, can result from obesity, dietary habits, and inheritance. Metabolic disease is the most prevalent health disorder associated with social epidemic of diabetes mellitus and hyperuricemia. The synthetic medicines are generally considered to be an effective way to treat metabolic diseases. Concerning about drug-related side effects, emerging options of disease treatment have been conducted into pharmacological properties of nature plants products. In the present study, we aim to investigate the therapeutic potentials of nature occurring substances in improving uric acid and glucose dysregulation. The study designs are as follow: (part I) Anti-hyperglycemia effects of Mei-Gin Formulas in db/db diabetic mice; (part II) Anti-hyperuricemic effects of Mei-Gin Products with different processes in potassium oxonate-induced hyperuricemic SD (Sprague Dawley) rats. In part I, we investigated the hypoglycemia potential of Mei-Gin based plant extracts formulas (MGF) in db/db diabetic mice and also revealed the possible regulatory mechanisms. Administration of MGF-4 and MGF-7 significantly improved the levels of fasting blood glucose, HOMA-IR, and HbA1c in db/db diabetic mice. Serum insulin level remarkably decreased after the treatment of MGF-4. Next, to further clarify the hypoglycemia effects of MGF-4 and MGF-7 on glucose modulation gene expression, quantitative PCR was conducted. Actually, MGF-4 and MGF-7 significantly decreased mRNA expressions of GLUT4 and PFK-A; intake of MGF-4 significantly increased gene expressions of HK and PK2 in muscle of db/db diabetic mice. Furthermore, key enzymes of liver glucose metabolism are estimated by quantitative PCR. The gene expressions of GLUT2 and AKT2 were significantly increased, while the gene expressions of FOXO1, PEPCK and G6Pase were decreased after MGF-4 and MGF-7 treatment in db/db diabetic mice; treatment of MGF-4 significantly increased the gene expressions of GK and GYS2. These results indicated that glucose catabolism are drastically reduced in db/db diabetic mice, MGF-4 and MGF-7 administration significantly improved abnormal glucose metabolism of db/db diabetic mice. Moreover, MGF-4 was founded to exhibit optimal therapeutic efficacy against hyperglycemia. In part II, we examined the effect of five Mei-Gin Products (MGP) against hyperuricemia and the underlying molecular mechanism in potassium oxonate (PO)-induced hyperuricemic SD rats. Administration of MGP-2, MGP-3, MGP-4, and MGP-5 significantly decreased the serum uric acid level as well as the mRNA expression of hepatic XOD gene in PO-induced hyperuricemic rats. Administration of MGP-3, MGP-4, and MGP-5 significantly increased the serum nitric oxide level in PO-induced hyperuricemic rats. Administration of MGP-3 significantly decreased hepatic gene expressions of PRPS and PNP in PO-induced hyperuricemic rats. Administration of MGP-5 significantly decreased hepatic gene expression of NT5E in PO-induced hyperuricemic rats. Besides, administration of MGP-5 effectively increased hepatic gene expressions of APRT and HPRT and uric acid excretion in PO-induced hyperuricemic rats. These results indicated that MGP-2, MGP-3, MGP-4, and MGP-5 exhibit an anti-hyperuricemia property in vivo, especially in MGP-5 with optimal efficiency. In conclusion, this study demonstrated that Mei-Gin Formulas significantly increased the levels of muscle gene expressions of glucose transport and glycolysis; increased hepatic glucose transport and glycogen synthesis gene expressions; reduced hepatic gluconeogenesis gene expressions thereby ameliorated hyperglycemia in db/db diabetic mice. Mei-Gin Products significantly reduced the levels of hepatic gene expressions of nucleotide synthesis, nucleotide catabolism, nucleoside catabolism, and purine catabolism; increased hepatic purine salvage gene expressions in PO-induced .hyperuricemic rats. Therefore, Mei-Gin Formulas and Mei-Gin Products could be developed as anti-hyperglycemia and anti-hyperuricemic nutraceutical products.
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