摘要
使用streptozotocin導致的糖尿病大白鼠(STZ糖尿病鼠)作為胰島素依賴型糖尿病(insulin-dependent diabetes mellitus ; IDDM)之動物模式研究紫丁香苷(syringin)產生降血糖作用的機轉，紫丁香苷是從刺五加(Eleutherococcus senticosus)根莖純化的一種物質。STZ糖尿病鼠靜脈注射30分鐘後會呈現濃度遞增性(concentration-dependent)的血糖降低與平行增加的β-endorphin。另外紫丁香苷會隨濃度的增加，從0.001到10 ?慆ol/l，促進β-endorphin從離體的腎上腺髓質釋放。在STZ糖尿病鼠進行雙側腎上腺切除消滅了紫丁香苷所引致血糖降低和血漿BER(??-endorphin-like immunoreactivity)濃度增加的作用。在嗎啡?搦洧?體拮抗劑存在下和或嗎啡?搦洧?體剔除(μ-opioid receptor knockout)的糖尿病小鼠，紫丁香苷也無法產生降血糖的作用。由此可知，在缺乏胰島素的糖尿病鼠，紫丁香苷能促進β-endorphin從腎上腺髓質釋放來興奮周邊嗎啡?搦洧?體而降低血糖。外給葡萄糖所進行的葡萄糖挑戰試驗(glucose challenge test)，紫丁香苷也可增加正常老鼠對葡萄糖的利用率。在離體實驗方面，STZ糖尿病鼠紫丁香苷以劑量相關的方式促進葡萄糖再攝入(glucose uptake)到骨骼肌。另外，在STZ糖尿病鼠肝細胞，紫丁香苷對肝糖的合成(glycogen synthesis)也有明顯增加作用。在pentobarbital麻醉下的正常大白鼠靜脈注射紫丁香苷(100 μg/kg) 60分鐘後，降血糖作用拌隨增加胰島素與C-peptide釋放，可是，紫丁香苷的作用在清醒大白鼠都無法出現，在腹腔注射guanethidine.進行交感神經阻斷時，紫丁香苷(100 μg/kg)的胰島素釋放與降血糖作用則可在清醒大白鼠出現。另外，先給予α1-AR阻斷劑prazosin時，紫丁香苷(100 μg/kg)的降血糖作用、促進胰島素與C-peptide分泌也會在清醒大白鼠出現；這些結果顯示，在清醒大白鼠，紫丁香苷促使胰島素釋放調控血糖的作用會減弱，然而，降低了交感神經活性如麻醉藥，則可幫助紫丁香苷的作用。在STZ糖尿病大白鼠，紫丁香苷的降血糖作用主要是藉由增加腎上腺髓質釋放β-endorphin 的能力，進而作用於週邊組織的嗎啡μ型受體，藉以增強糖尿病老鼠骨骼肌對葡萄糖的吸入作用，使過多的葡萄糖能有效地由細胞外進入細胞內儲存，同時，亦減緩糖尿病老鼠肝臟葡萄糖的新生，因此改善了糖尿病老鼠的高血糖現象。另外，在清醒大白鼠活化交感神經則會干擾紫丁香苷促進胰島素釋放的作用，降低交感神經活性則可促進紫丁香苷的作用。由此可知，紫丁香苷的作用會因動物的體內條件而異，於麻醉動物較易呈現效果。
並列摘要
In streptozotocin-induced diabetic rats (STZ-diabetic rats), the type-1 diabetes-like animal model, the mechanism(s) of antihyperglycemic action produced by syringin, an active principle purified from the rhizome part of Eleutherococcus senticosus (Araliaceae),was investigated . Bolus intravenous (i.v.) injection of syringin for 30 min dose-dependently decreased the plasma glucose of STZ-diabetic rats in a way parallel to the increase of plasma ??-endorphin-like immunoreactivity (BER). Syringin enhanced BER release from the isolated adrenal medulla of STZ-diabetic rat in a concentration-dependent manner from 0.001 to 10 ?慆ol/l. Bilateral adrenalectomy in STZ-diabetic rats eliminated the activities of syringin (1 mg/kg, i.v.) including the plasma glucose-lowering effect and the plasma BER-elevating effect. Also, syringin failed to lower plasma glucose in the presence of ??-opioid receptor antagonists and/or in the ??-opioid receptor knockout diabetic mice. The obtained results suggest that syringin can enhance the secretion of β-endorphin from adrenal medulla to stimulate peripheral ??-opioid receptors resulting in a decrease of plasma glucose in diabetic rats lacking insulin. Syringin at the effective dose (1.0 mg/kg) significantly attenuated the increase of plasma glucose induced by an intravenous glucose challenge test in normal rats. Stimulatory effect of syringin on the glucose uptake was also obtained in the soleus muscles isolated from STZ-diabetic rats in a concentration-dependent manner from 0.01 to 10.0 ?慆ol/l. The increase of glucose utilization by syringin was further characterized using the enhancement of glycogen synthesis in isolated hepatocytes of STZ-diabetic rats. These results suggest that syringin has an ability to enhance glucose utilization to lower plasma glucose in diabetic rats lacking insulin. Plasma glucose lowering effect accompanying with the increase of plasma insulin and C-peptide were obtained in pentobarbital anesthetized Wistar rats 60 min after an intravenous (i.v.) injection of syringin (100 μg/kg). However, neither the plasma glucose lowering action, nor the raised plasma levels of insulin and C-peptide can be observed in conscious rats received same syringin treatment. Otherwise, the insulin-releasing and plasma glucose lowering actions of syringin (100 μg/kg, i.v.) were appeared in conscious rats under chemical sympathectomy using an intraperitoneal injection of guanethidine. In addition, plasma glucose lowering action of syringin (100 μg/kg, i.v.) was observed in conscious rats received α1-adrenoceptor blockade with prazosin. The stimulatory actions of syringin on the secretion of plasma insulin and C-peptide were also obtained in prazosin-treated conscious rats. The obtained results suggest that and insulinotropic effect of syringin on the plasma glucose regulation is impaired in conscious rats with a regular sympathetic tone; decrease of sympathetic tone as observed in anesthetized animal is required for actions of syringin. These results suggest that release of β-endorphin from the adrenal gland seems responsible for the lowering of plasma glucose in STZ-diabetic rats by syringin Activation of opioid μ-receptors by the released β-endorphin can increase the utilization of glucose and decrease hepatic gluconeogenesis to lower plasma glucose in diabetic rats lacking insulin. However, insulinotropic effect of syringin was interfered with an increase of sympathetic activity in conscious animal; lowering of sympathetic tone might be helpful in the application of syringin.