為了協助糖尿病的改善，希望由古代藥方來研發出有效的治療用藥。因此，本研究將探討人蔘(Panax ginseng CA Meyer)的主要成分----人蔘皂苷 Rh2 (Ginsenoside Rh2, G-Rh2)----是藉由何種機制而達到降糖的效果。在體內(in vivo)試驗方面，經口投予人參粉至Wistar品系的正常大白鼠，產生了濃度遞增的降血糖作用。但是，給予streptozotocin (STZ) 誘導的胰島素依賴型糖尿病(insulin-dependent diabetes mellitus ; IDDM)大白鼠則看不到作用，表示這項降血糖作用與胰島素有關；同樣的，在正常大白鼠以尾靜脈注射G-Rh2 ，也產生了濃度遞增的降血糖作用。投予Atropine會解消G-Rh2降糖的作用。若給予Physostigmine則會增強G-Rh2降血糖的作用；表示G-Rh2的降血糖作用，與副交感神經有關。另外，給予Hemicholoninium-3，則G-Rh2 降血糖的作用也跟著減少；表示G-Rh2降血糖的作用與神經釋放Acetylcholine有關。若給予M3受體阻斷劑 4-DAMP mustard，會阻斷G-Rh2的降血糖作用；表示G-Rh2 降血糖的作用與M3受體有關。可是，給予Nicotinic receptor Antagonist- Hexamethonium或Pentolinium，卻不會解消G-Rh2 降血糖的效果，因此G-Rh2降血糖的作用與神經節的活化或Nicotinic receptor無關。由此可知，G-Rh2 降血糖的作用應是藉由副交感節後神經刺激acetylcholine釋放，使之作用在胰臟的M3受體，導致胰島素分泌來產生降血糖的作用。此外，人蔘也可藉由M3受體活化，導致胰島素釋放來產生降血糖作用。因此，以刺激胰島素釋放作用來看的話，人蔘的降糖作用應該與G-Rh2有關。
　　另一方面，以尾靜脈注射G-Rh2發現，在胰島素缺乏的糖尿病大白鼠身上，G-Rh2 以劑量相關的方式降低血糖。同時，在葡萄糖挑戰試驗，G-Rh2 會增加周邊組織對葡萄糖的利用率。在胰島素缺乏的大白鼠身上，可藉由藥物刺激腎上腺分泌b-endorphin來活化周邊組織嗎啡m型受體，進而產生降血糖作用。由於G-Rh2也能以劑量相關的方式增加IDDM大白鼠的血中b-endorphin含量。同時，G-Rh2的降糖作用會被嗎啡μ型受體阻斷劑Naloxone或Naloxonazineu依劑量相關方式阻斷掉。另外，在嗎啡μ型受體剔除的糖尿病小鼠，卻看不到G-Rh2降糖的作用；顯示在胰島素缺乏的糖尿病大白鼠身上，G-Rh2的降血糖作用與嗎啡μ型受體的活化有關。在streptozotocin (STZ) 誘導的糖尿病大白鼠，摘除兩側腎上腺(bilateral adrenalectomy)，G-Rh2降糖的作用消失，血中b-endorphin的含量也不會增加；可是在取自STZ糖尿病大白鼠的離體腎上腺(adrenal medulla)，G-Rh2卻沒有促進b-endorphin釋放的作用。由此可知，G-Rh2 並非直接作用在腎上腺來促使b-endorphin釋放。由於活化副交感神經Nicotinic receptor可促進b-endorphin的釋放，於是使用Nicotinic receptor antagonist的Hexamethonium與Pentolinum來前處理，它們皆會抑制G-Rh2在第一型糖尿病大白鼠所產生的降血糖作用及增加體內b-endorphin釋放的作用。由此可知，在胰島素缺乏的情況下，G-Rh2可透過體內活化Nicotinic receptor，促使腎上腺分泌b-endorphin。釋出的b-endorphin會活化周邊組織的嗎啡m型受體，增強第一型糖尿病大白鼠的骨骼肌對葡萄糖的利用，和減緩肝臟葡萄糖新生的速度，因而產生降血糖的作用。

　　In an attempt to develop agent with less side for handling of diabsts mellitus, the antihyperglycemic action and possible mechanism of ginsenoside Rh2 (G-Rh2) from Panax ginseng C.A. Meyer, was investigated in the present study. Oral administration of ginseng powder produced a dose-dependent hypoglycemic action in Wistar rats, but failed to lower plasma glucose in streptozocin (STZ) –induced diabetic rats. Thus, release of insulin seems responsible for the lowering of plasma glucose in Wistar rats by ginseng powder. G-Rh2 also produced a dose-dependent hypoglycemic action in Wistar rats after an intravenous injection (i.v.). Atropine produced a dose-depend inhibition of the G-Rh2-induced plasma glucose lowing effect in Wistar rats. Also, physostigmine increased the G-Rh2-induced plasma glucose lowing effect, indicating the mediation of parasympathetic nervous system. The plasma glucose lowering effect of G-Rh2 in Wistar rats was abolished by pretreatment of hemichoninium-3, indicating the release of acetylcholine. The action of G-Rh2 was also abolished by pretreatment 4-DAMP, indicating the activation of M3 receptor. But the plasma glucose lowering effect of G-Rh2 was not abolished by pretreatment with nicotinic receptor antagonist, either hexamethonium or pentolinum, indicating the activation of ganglion or nicotinic receptor can be ruled out. The results suggest that acetylcholine released from post-ganglion neuron of parasympathetic nerve to activate M3 receptor in pancreas seems responsible for the glucose-lowing effect of G-Rh2. Also, ginseng powder decreased plasma glucose in a way similar to G-Rh2 and stimulation of insulin secretion seems important for ginseng powder-induced glucose lowering effect.
　　Otherwise, G-Rh2 produced a dose-dependent hypoglycemic effect in diabetic rats lacking insulin after an intravenous injection. G-Rh2 at an effective dose significantly attenuated the increase of plasma glucose induced by intravenous glucose in Wistar rats indicating an increase of glucose utilization by G-Rh2. b-endorphin released from adrenal gland, to activate opioid m-receptor in the peripheral tissue, seems responsible for the hypoglycemic effect of G-Rh2 in rats lacking insulin. Because G-Rh2 produced a dose-dependent increase of the plasma b-endorphin level in the diabetic rats. The plasma glucose lowering effect of G-Rh2 was also abolished by naloxone or naloxonazine. Plasma glucose lowering action of G-Rh2 at the dose effective in diabetic rats was disappeared in opioid m-receptors knockout mice. The results suggest that activation of opioid m-receptor is responsible for the glucose-lowering effect of G-Rh2 in the rats lacking insulin. In G-Rh2 treated STZ-diabetic rats, bilateral adrenalectomy made the loss of the plasma glucose lowering effect of G-Rh2 and non-increase of plasma b-endorphin. However, G-Rh2 could not enhance the b-endorphin secretion from isolated adrenal medulla of STZ-diabetic rats. The results suggest that G-Rh2 did not directly enhance the b-endorphin secretion from adrenal medulla. Activation of nicotinic receptor could induce release of b-endorphin. The increase of plasma b-endorphin and the plasma glucose lowering effect by G-Rh2 were was also abolished by pretreatment with nicotinic receptor blockers-hexamethonium and pentolinum. These results suggest that release of b-endorphin from adrenal gland seems responsible for the lowering of plasma glucose in the insulin-deficient circumstances by G-Rh2 through an activation of nicotinic receptor. Action of opioid m-receptors by the released b-endorphin can increase the glucose utilization in skeletal muscle and decrease the hepatic gluconeogenesis to lower plasma glucose in diabetic rats lacking insulin.

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