胰島素抗阻( insulin resistance )是第二型糖尿病的常見病徵且在出現糖尿病前就會發生。其形成的原因主要為周邊組織或器官喪失了對胰島素刺激的反應能力。Glucose transporter ( GLUT4 )對於胰島素刺激之下肌肉的葡萄糖攝取扮演著相當重要的角色，其功能好壞也與胰島素抗阻的關係密不可分。人參( Panax Ginseng C.A. Meyer )有廣泛的藥理作用，具有免疫、抗癌、代謝及神經方面及抗壓的優點；其有效成份為人參皂苷( ginsenosides )，例如Rh2。人參皂苷Rh2主要在韓國紅參根部被發現(以蒸氣萃取人參根)，文獻報導它可以改變癌細胞增生及干擾正常細胞的細胞週期。本實驗室之前研究已發現，Rh2在第一型糖尿病老鼠具有降血糖的效果。於是，本研究的目的是想探討Rh2是否也能改善胰島素抗阻，並了解其作用機轉。首先，使用C2C12細胞( myoblast cells )，進行葡萄糖攝取的實驗，觀察到Rh2能促進葡萄糖的攝取；這個作用在葡萄糖皮質類固醇受體( glucocorticoid receptor，GR )的阻斷劑RU486存在下會消失。另外，投予RNA合成的抑制劑actinomycin D ( Act D ) 及poly ( ADP- ribose ) polymerase ( PARP )的抑制劑，3-aminobenzamide ( 3-AB )或1,5-isoquinolinediol ( 1,5-ISO )，也會抑制Rh2所促進的葡萄糖攝取。使用西方墨點法，同樣變化也在C2C12細胞獲得證實：Rh2能有效增加GLUT4蛋白的表現，而處理RU486、Act D、 3-AB、1,5-ISO時，則GLUT4蛋白的表現會被抑制。另外，Rh2與胰島素同時處理細胞，可得到增強胰島素所促進葡萄糖的攝取。而且，以luciferase reporter assays，也看到Rh2能啟動glucocorticoid response element ( GRE )。由以上的結果顯示，Rh2會經由葡萄糖皮質類固醇受體的啟動來造成GLUT4表現，並促進葡萄糖的攝取。在活體實驗，使用遺傳性第二型糖尿病老鼠( Zucker rats )，以尾靜脈注射方式給予Rh2 ( 1 mg/kg )，每天三次，十九天後顯示，Rh2組Zucker rats有較低的HOMA IR指數、較好的葡萄糖耐受性，較佳的胰島素敏感性及葡萄糖-胰島素指數。然而，當RU486存在時，並不會抑制Rh2的這項作用。在肥胖Zucker rats離體骨骼肌， Rh2確實可增加胰島素的細胞內訊息傳遞：增加胰島素受體酪胺酸激酶( insulin receptor tyrosine kinase )及胰島素受體受質( insulin receptor substrate, IRS-1 )的磷酸化，活化phosphatidylinositol 3-kinase ( PI 3-Kinase )及Akt，並促進GLUT4蛋白的表現。可是，在Zucker rats肝臟，卻看不到Rh2降低PEPCK蛋白的表現。此外，檢測動物血液，看到Rh2在體內可轉換成其活性代謝物protopana- xadiol ( PPD )。以luciferase reporter assays，也看不到PPD能啟動GRE。可是，以PPD注射至動物體內，看到PPD也能降低Zucker rats的HOMA IR指數、增加葡萄糖耐受性、胰島素敏感度及有較佳的葡萄糖-胰島素指數。因此，由動物的實驗可知，Rh2在體內會經由轉換成活性代謝物( PPD )來達到改善胰島素抗阻。綜合這些結果，本研究證實Rh2可作為改善第二型糖尿病胰島素抗阻的參考物質。

　Insulin resistance ( IR ) is widely observed in patients with type 2 diabetes, even development before the induction of disease. IR is caused by the lower ability of peripheral target tissues to respond the circulating insulin. As one of the potential rate-controlling steps regulating insulin-stimulated glucose metabolism, glucose transporter ( GLUT4 ) has been implicated as the major parameters responsible for causing insulin resistance. Ginseng, Panax ginseng C.A. Meyer, has wide pharmacological actions, showing immunological, anti-cancer, metabolic, neurological benefits and anti-oxidant properties. Its primary active integrants are ginsenosides, such as Rh2. Ginsenoside Rh2 is contained in Korean red ginseng root ( steamed root of ginseng ) with ability to alter cancer cell proliferation and perturb normal cell cycle events. In our pervious studies, Rh2 was found to decrease the plasma glucose in STZ-diabetic rats. The aim of this study is to investigate the effect of Rh2 on insulin resistance. On C2C12 cells, glucose uptake was increased by Rh2 and this increase was reversed by glucocorticoid receptor ( GR ) anta- gonist, RU486 and RNA synthesis inhibitor, actinomycin D ( Act D ) and poly ( ADP-ribose ) polymerase ( PARP ) inhibitor, 3-aminobenzamide ( 3-AB ) and 1,5-isoquinolinediol ( 1,5-ISO ). GLUT4 proteins were also increased on C2C12 cells by Rh2, and this increase was inhibited by RU486, Act D, 3-AB and 1,5-ISO. Otherwise, combination of Rh2 with insulin-treated C2C12 cells produced better glucose uptake than insulin-treated only. In luciferase reporter assays, pGL2-GRE ( glucocorticoid response element ) promoter activity was increased by Rh2. Thus, Rh2 can increase GLUT4 expression and glucose uptake through GR via PARP-related pathway. Then, Zucker rats, the genetic type 2 diabetic rats, were treated with Rh2 ( 1 mg/kg., intravenously, tid, for 19 days ). Rh2-treated Zucker rats showed a lower HOMA IR index, and a better glucose tolerance, insulin sensitivity and glucose-insulin index than the control. This improvement was not reversed by RU486 ( 10 mg/kg, intraperitoneally, bid, for 19 days ). In the insulin signaling pathway of skeletal muscles, Rh2 treated-Zucker rats showed an increasing expression of tyrosine phosphorylation of insulin receptor and insulin receptor substrate ( IRS-1 ) and activation of phosphatidylinositol 3-kinase ( PI 3-Kinase ) and Akt and GLUT4 proteins. However, hepatic expression of Zucker rats was not influenced by Rh2. Moreover, Rh2 is changed to protopanaxadiol ( PPD ) in Zucker rats using assays of HPLC. In luciferase reporter assays, pGL2-GRE promoter activity was not raised by PPD. However, PPD-treated Zucker rats also showed lower HOMA IR index and better glucose tolerance or glucose-insulin index than the control. The obtained results indicate that Rh2 can improve the insulin resistance in type-2 like diabetic rats through the active metabolites of Rh2. Thus, Rh2 could be useful for insulin resistance in type 2 diabetes.

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