冬蟲夏草於糖尿病大鼠模式肌肉中降血糖機制之探討

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Title:	冬蟲夏草於糖尿病大鼠模式肌肉中降血糖機制之探討
Other Titles:	Studies on Mechanism of Anti-hyperglycemic Activity of Cordyceps sinensis in Muscle of Diabetic Rats
Authors:	黃鈺玲 Huang, Yu-Ling
Contributors:	盧錫祺 Lu, Hsi-Chi 東海大學食品科學系
Keywords:	糖尿病,降血糖,肌肉,冬蟲夏草
Date:	2008
Issue Date:	2011-03-11T06:07:34Z (UTC)
Abstract:	糖尿病是由於胰島素分泌不足或作用異常引起的內分泌疾病，全球盛行率持續攀升，且有年輕化的趨勢。患者於長期血糖調控異常下，衍生出多種併發症，而理想的血糖調控則能有效預防或是延緩糖尿病併發症的發生。於先前的研究中曾證實，天然的冬蟲夏草與其人工發酵產物在糖尿病大鼠動物模式中均在未提高胰島素分泌量下，顯著改善葡萄糖耐受性。在血糖恆定之調控上，除胰島素傳訊外，由脂肪細胞所分泌的脂泌素如脂聯素 (adiponectin) 等，亦具有調節胰島素敏感性的作用，且其傳訊逐漸受到重視。推測冬蟲夏草可能經由更有效率的胰島素傳訊或是經由其他傳訊，提高周邊組織的胰島素敏感性，達到血糖調降之目的。然而冬蟲夏草等中草藥之調節血糖功效與兩種訊息傳遞路徑的連結至今尚未完全建立。早先本研究室於肝臟中的實驗結果也初步證實此推測，冬蟲夏草可能增加IRS-1與Akt的表現量，透過更有效率的訊息傳遞，提高肝臟葡萄糖磷酸化及轉運效率，進而達到降血糖的效果。本研究接續前實驗，繼續探討肌肉於冬蟲夏草降血糖作用中所扮演的角色。?釐清冬蟲夏草的餵食是否導致胰島素與脂聯素傳訊之活化，本研究深入分析此二傳訊路徑之傳訊分子。以酵素免疫連結法分析血清，發現餵食冬蟲夏草的組別均能有效提高脂聯素的分泌量，顯示胰島素的敏感性可能獲得提升。進一步利用反轉錄同步定量聚合?連鎖反應於轉錄層次分析基因表現量，顯示冬蟲夏草能顯著提高胰島素受體基因轉錄效率，但不影響胰島素受體基質IRS-1與兩型脂聯素受體之基因轉錄。胰島素受體基質IRS-2之基因轉錄效率在餵食冬蟲夏草的組別反而下降，但血中三酸甘油酯與游離脂肪酸卻並未改變，顯示蟲草對於脂質代謝之調控尚待釐清。蛋白質層次之基因表現乃利用西方轉漬法進行分析。胰島素傳訊下游之Akt蛋白質表現量，以及脂聯素傳訊下游之AMPK蛋白質表現量、磷酸化量與其磷酸化程度於冬蟲夏草餵食組均有顯著的提升，顯示餵食冬蟲夏草能增強兩傳訊路徑。但冬蟲夏草卻對胰島素受體、胰島素受體基質IRS-1、磷酸化Akt之蛋白質表現量均無顯著之影響。餵食冬蟲夏草雖並未增加GLUT4之基因表現量，但卻能使其於胞膜上之蛋白質量顯著提高，可能代表轉位增加。本研究中初步證實，冬蟲夏草能提高血清中脂聯素濃度，於肌肉中增加AMPK蛋白質表現量、磷酸化量及其活性，增強肌肉細胞內之脂聯素傳訊；另一方面，冬蟲夏草則能提升胰島素受體轉錄效率、增加Akt蛋白質表現量，增強肌肉細胞內之胰島素傳訊。故冬蟲夏草可能透過增強肌肉細胞內胰島素與脂聯素傳訊，協同提高GLUT4之轉位與胰島素敏感性，改善糖尿病大鼠模式肌肉中葡萄糖之代謝調控。 Diabetes mellitus is a prevailing endocrine disease caused by a low level of insulin or insulin resistance, and is characterized by hyperglycemia. Hyperglycemia can result in many complications, which could be minimized through a better control of blood sugar. Previous studies have shown that both natural and cultured Cordyceps sinensis could ameliorate hyperglycemia in streptozotocin-induced diabetic rats, despite of an impaired insulin secretion. In addition to insulin signaling, signaling pathway mediated by adiponectin, an adipokine is secreted by adipocytes, may improve insulin sensitivity, which has received more and more attention in recent years. However, a direct link of anti-hyperglycemia activity of C. sinensis and these siganling pathways has not been estabolished. It is thought that C. sinensis may improve insulin sensitivity through more effective insulin and adiponectin signalings, and thereby lead to a hypoglycermic effect. We previously have found that ingestion of C. sinensis can increase protein expression of IRS-1 and Akt, and the efficency of signaling transduction to elevate the hepatic glucose phosphorylation and transprotation, and farther amilorate hyperglycemia. In current study, we futher to explore the roles of C. sinensis in alleviating the hyperglycemia in muscle of streptozotocin-induced diabetic rats. To clarify whether C. sinensis could activate insulin and adiponectin signaling in the muscle, molecules involved in these two signalings pathway were investigated. As shown by the enzyme-linked immunosorbent assay, serum adiponectin was significantly elevated in C. sinensis feeding groups, which suggests an improved insulin sensitivity. Reverse transcription real-time PCR showed that C. sinensis upregulated the mRNA expression of insulin receptor, but not insulin receptor substrate (IRS-1), adiponectin receptor 1 (AdipoR1) ,or adiponectin receptor 2 (AdipoR2). Reduced expression of insulin receptor substrate 2 (IRS-2) and unaltered serum concentration of triglycerol and free fatty acid in groups ingested with C. sinensis. C. sinensis in regulatory lipid metabolism are inconclusive. The result of Western blot analysis indicated that there were increased protein levels of Akt, AMPK, phospho-AMPK, and the ratio of phospho-AMPK/AMPK in the groups ingested with C. sinensis. Findings presumably reflected that tne increas in insulin and adiponectin signaling were mediated by the elevated protein expression of insulin receptor, insulin receptor substrate 1, and phospho-Akt. Ingestion of C. sinensis did not change the expression of glucose transproter 4 (GLUT4), but it can markly increase GLUT4 protein level in cell membrane, which can be interpreted as a result of increased GLUT4 translocation. Our results demonstrated that C. sinensis may increase the circulating adiponectin and the AMPK expression protein, phosphorylation, and activity, which may contribute to enhanced adiponectin signaling in the muscle. Insulin signaling in the muscle was also elvated in STZ-induced diabetic rats with C. sinensis, as revealed by the upregulation in insulin receptor transcription and Akt protein expression. To sum up, the antidiabetic activity of C. sinensis in part at least, is contributed by promoting GLUT4 translocation and improving insulin sensitivity by strengthening insulin and adiponectin signaling.
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