梓醇 (Catalpol)係純化自地黃所得的一種單類化合物。經由尾靜脈注射梓醇到streptozotocin (STZ)誘導的胰島素依賴型糖尿病(insulin-dependent diabetes mellitus ; IDDM)大白鼠，可產生濃度遞增性(dose-dependent)的降血糖作用。而且，對於外給葡萄糖所進行的葡萄糖挑戰試驗(glucose challenge test)，梓醇可增加正常老鼠對葡萄糖的利用率。在離體(in vitro)試驗方面，取STZ糖尿病老鼠的骨骼肌，梓醇會以劑量相關的方式來促進 [14C] 2-deoxy-glucose進入到骨骼肌內。另外，在STZ糖尿病老鼠的肝臟，梓醇對於肝糖的合成(glycogen synthesis)有顯著的刺激效果。
另一方面，以C2C12小鼠骨骼肌細胞株 (mouse myoblast cell line)進行實驗來了解梓醇的作用方式。結果梓醇能以劑量相關的形式增強C2C12小鼠肌母細胞對葡萄糖的吸回作用；而這項作用可被α1-adrenoceptor(α1-AR)阻斷劑prazosin及α1A-AR阻斷劑RS17053所解消。同時，梓醇隨著濃度的增加亦可逐漸取代α1-AR的[3H]prazosin在C2C12肌母細胞的結合。而且以phospholipase C (PLC) 的阻斷劑U73122，及protein kinase C (PKC) 的阻斷劑chelerythrine、GF109203X將α1-AR活化的訊息傳遞路徑阻斷後，亦可解消梓醇原先可增強C2C12肌母細胞對葡萄糖的吸回作用。另外，α1-AR的阻斷劑prazosin及α1A-AR阻斷劑RS17053會以劑量相關的形式阻斷梓醇原先在IDDM大白鼠所產生的降血糖效果。因此，在沒有胰島素的存在下，α1-AR的阻斷劑prazosin及α1A-AR阻斷劑RS17053的降血糖作用和α1A-AR有關。
使用enzyme-linked immunosorbent assay (ELISA)技術，檢測血中的腦內啡(β-endorphin)時，在IDDM大白鼠發現梓醇確實會促進血中β-endorphin的含量；這項作用會被α1-AR的阻斷劑prazosin及α1A-AR阻斷劑RS17053所解消。同時，嗎啡型受體阻斷劑naloxone及naloxonazine會依劑量相關性阻斷梓醇原先在IDDM大白鼠的降血糖作用。另外，在嗎啡型受體剔除(opioid -receptors knockout)的胰島素依賴型糖尿病小鼠，梓醇也無法再產生降血糖的作用。由此可知，梓醇對IDDM大白鼠所產生的降血糖作用與嗎啡型受體的活化有關。在去除腎上腺髓質(adrenal medulla)的IDDM大白鼠，梓醇無法再產生降血糖的現象。由此可知，梓醇乃藉由活化腎上腺的α1-AR，促使β-endorphin釋放而得到降血糖的效果。另一方面，利用靜脈注射給藥的方式，每日注射梓醇 0.1 mg/kg六次，處理兩天，取其老鼠的肝臟及骨骼肌，利用RT-PCR、Northern及Western immunoblotting來看糖尿病老鼠骨骼肌之葡萄糖第四型轉移蛋白(glucose transporter subtype 4 form; GLUT4)和與insulin signaling有關的Akt Ser473磷酸化及肝臟之解糖酵素 (phosphoenolpyruvate carboxykinase; PEPCK)的變化。結果發現，梓醇可增強IDDM大白鼠骨骼肌GLUT4和Akt Ser473磷酸化的表現，而且，IDDM大白鼠肝臟亢進的PEPCK基因也會受到抑制；以上三種作用皆可被naloxone所解消。
綜合以上的結果，在IDDM大白鼠，梓醇的降血糖作用主要是藉由活化位於腎上腺髓質的α1A-AR，加強腎上腺髓質釋放β-endorphin的能力，進而作用於週邊組織的嗎啡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，因而解消了糖尿病老鼠的高血糖現象。

Catalpol, a monoterpene compound ，was isolated from “Die-Huang”. Catalpol produced a dose-dependent hypoglycemic action in streptozotocin -induced diabetic rats after an intravenous injection (i.v.). Catalpol at the effective dose (0.1mg/kg) significantly attenuated the increase of plasma glucose induced by intravenous glucose challenge test in Wistar rats. In vitro, catalpol enhanced the uptake of 14C 2-deoxy-glucose (2-DG) into skeletal muscle in a concentration-dependent manner. In the hepatocytes isolated from diabetic rats, catalpol also increased the synthesis of glycogen.
Catalpol enhanced the uptake of radioactive glucose into mouse myoblast cell line C2C12 cells in a dose-dependent manner, which was abolished by α1-adrenoceptor(α1-AR) blocker prazosin and α1A-AR blocker RS17053 pretreatment. Effect of catalpol on α1-AR was further supported by the displacement of [3H] prazosin binding in C2C12 cells. The plasma glucose lowering effect of catalpol in the STZ-diabetic rats was also abolished by the pretreatment with prazosin and RS17053. Pharmacological inhibition of phospholipase C (PLC) by U73122 resulted in a concentration-dependent decrease in catalpol-stimulated uptake of radioactive glucose into C2C12 cells, although, the inactive congener, U73343, failed to block catalpol-stimulated glucose uptake. Moreover, chelerythrine diminished the action of catalpol at concentration sufficient to inhibit protein kinase C (PKC). The obtained data suggest that an activation of α1A-AR may play an important role in the plasma glucose lowering action of catalpol in the absence of insulin.
Injection of catalpol at the effective dose increased the plasma β-endorphin in STZ-diabetic rats that can be abolished by α1A-AR antagonists. The plasma glucose lowering effect of catalpol was also abolished by pretreatment with naloxone and naloxonazine at doses sufficient to block opioid -receptors. Plasma glucose lowering action of catalpol disappeared in opioid -receptors knockout mice, while the plasma glucose lowering response to catalpol was still observed in wild-type mice. Also, catalpol enhanced the β-endorphin release from the isolated adrenal medulla in a concentration-dependent manner. Bilateral adrenalectomy resulted in the loss of plasma glucose lowering effect of catalpol.
The mRNA and protein levels of glucose transporter subtype 4 form (GLUT4) in skeletal muscle was raised by catalpol after repeated treatment for three days in STZ-diabetic rats. Otherwise, similar repeated treatment with catalpol reversed the elevated mRNA and protein level of phosphoenolpyruvate carboxykinase (PEPCK) in liver of STZ-diabetic rats to the normal level. Also, the protein level of Akt Ser473 phosphorylation in skeletal muscle was raised by catalpol after similar repeated treatment. Pharmacological inhibition of opioid μ-receptors deleted these effects of catalpol. 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 catalpol through an activation of α1A-AR. Activation of opioid -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.

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