We investigated the plasma glucose-lowering mechanism(s) of Rh2, a ginsenoside derived from Panax ginseng, in rats with streptozotocin-induced diabetes (STZ-diabetic rats). After intravenous injection over 120 min into fasting STZ-diabetic rats, Rh2 decreased plasma glucose in a dose-dependent manner. In parallel to the lowering of plasma glucose, an increase of plasma β-endorphin-like immunoreactivity was observed. In addition, naloxone and naloxonazine at doses sufficient to block opioid μ-receptors inhibited the plasma glucose-lowering action of Rh2 in genetically wild-type, diabetic mice. In contrast, Rh2 failed to lower plasma glucose in opioid μ-receptor knockout diabetic mice. An increase in gene expression at both the mRNA and protein levels of glucose transporter subtype 4 (GLUT 4) was observed in soleus muscle obtained from STZ-diabetic rats treated with Rh2 three times daily for one day; this increase in expression was absent when opioid μ-receptors were blocked. In conclusion, our results suggest that ginsenoside Rh2 may lower plasma glucose in STZ-diabetic rats based on an increase in β-endorphin secretion that activates opioid μ-receptors thereby resulting in an increased expression of GLUT 4.
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