Liu I-Min, Chen Wang-Chuan, Cheng Juei-Tang
Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan City, Taiwan 70101, Republic of China.
J Pharmacol Exp Ther. 2003 Dec;307(3):1196-204. doi: 10.1124/jpet.103.053900. Epub 2003 Sep 15.
We investigated the mechanism(s) by which isoferulic acid lowers plasma glucose levels in streptozotocin-induced diabetic rats (STZ-diabetic rats). In STZ-diabetic rats, isoferulic acid dose dependently lowered plasma glucose concentrations and increased plasma beta-endorphin-like immunoreactivity (BER). Both of these effects of isoferulic acid were abolished by pretreatment of rats with tamsulosin or 2-[2,6-dimethoxyphenoxyethyl]aminomethyl-1,4-benzodioxane hydrochloride (WB 4101) at doses sufficient to block alpha1-adrenoceptors. Also, isoferulic acid enhanced BER release from isolated rat adrenal medulla in a concentration-dependent manner that could be abolished by treatment with alpha1-adrenoceptor antagonists. Moreover, bilateral adrenalectomy in STZ-diabetic rats eliminated the activities of isoferulic acid, including the plasma glucose-lowering effect and the plasma BER-elevating effect. Naloxone and naloxonazine inhibited the plasma glucose-lowering activity of isoferulic acid at doses sufficient to block opioid mu-receptors. In contrast with the effect in wild-type diabetic mice, isoferulic acid failed to lower plasma glucose levels in opioid mu-receptor knockout diabetic mice. Treatment of STZ-diabetic rats with isoferulic acid three times in 1 day resulted in an increase in the expression of the glucose transporter subtype 4 form in soleus muscle. This effect was blocked by alpha1-adrenoceptor or opioid mu-receptor antagonists. The reduction of elevated mRNA or protein level of hepatic phosphoenolpyruvate carboxykinase was also impeded in the same groups of STZ-diabetic rats. In conclusion, our results suggest that isoferulic acid may activate alpha1-adrenoceptors to enhance the secretion of beta-endorphin, which can stimulate the opioid mu-receptors to increase glucose use or/and reduce hepatic gluconeogenesis, resulting in a decrease of plasma glucose in STZ-diabetic rats.
我们研究了异阿魏酸降低链脲佐菌素诱导的糖尿病大鼠（STZ糖尿病大鼠）血糖水平的机制。在STZ糖尿病大鼠中，异阿魏酸剂量依赖性地降低血糖浓度，并增加血浆β-内啡肽样免疫反应性（BER）。用足以阻断α1肾上腺素能受体的剂量的坦索罗辛或2-[2,6-二甲氧基苯氧基乙基]氨基甲基-1,4-苯并二恶烷盐酸盐（WB 4101）预处理大鼠后，异阿魏酸的这两种作用均被消除。此外，异阿魏酸以浓度依赖性方式增强离体大鼠肾上腺髓质的BER释放，而这种作用可被α1肾上腺素能受体拮抗剂处理所消除。此外，STZ糖尿病大鼠双侧肾上腺切除消除了异阿魏酸的活性，包括降低血糖作用和升高血浆BER的作用。纳洛酮和纳洛嗪在足以阻断阿片μ受体的剂量下抑制异阿魏酸降低血糖的活性。与野生型糖尿病小鼠的作用相反，异阿魏酸未能降低阿片μ受体敲除糖尿病小鼠的血糖水平。在一天内用异阿魏酸处理STZ糖尿病大鼠三次导致比目鱼肌中葡萄糖转运蛋白4亚型的表达增加。这种作用被α1肾上腺素能受体或阿片μ受体拮抗剂阻断。在同一组STZ糖尿病大鼠中，肝磷酸烯醇式丙酮酸羧激酶升高的mRNA或蛋白水平的降低也受到阻碍。总之，我们的结果表明，异阿魏酸可能激活α1肾上腺素能受体以增强β-内啡肽的分泌，β-内啡肽可刺激阿片μ受体以增加葡萄糖利用或/和减少肝糖异生，从而导致STZ糖尿病大鼠的血糖降低。
