| Summary: | 博士 === 高雄醫學大學 === 天然藥物研究所博士班 === 95 === It has been documented that Die-Huang-Wan showed an ability to lower the plasma glucose in normal rats via an increase of insulin secretion. Then, the herb of cornus (Cornus officinalis Sieb.) that is also called as San-Zu-Yee in Chinese has been indicated as a major factor for an increase of insulin secretion induced by Die-Huang-Wan. The present study was then conducted to understand the role of oleanolic acid from cornus (Cornus officinalis Sieb.) as an active principle responsible for the release of insulin. After an intraperitoneal injection into the fasting Wistar rats after 90 min, oleanolic acid (20 mg/kg) decreased the plasma glucose in a dose-dependent manner in parallel to an increase of plasma levels of insulin as well as C-peptide. The effects of oleanolic acid was reversed by a blockade of muscarinic receptors with atropine, but not affected by the ganglionic nicotinic antagonists, pentolinium or hexamethonium. Disruption of synaptic available acetylcholine (ACh) using an inhibitor of choline uptake, hemicholinium-3, or vesicular acetylcholine transport, vesamicol, negated this action of oleanolic acid. Also, physostigmine at concentration sufficient to inhibit acetylcholinesterase enhanced the action of oleanolic acid. Mediation of ACh release from the nerve terminals to enhance insulin secretion of oleanolic acid can thus be considered. Both the plasma glucose lowering action and the raised plasma levels of insulin and C-peptide by oleanolic acid were also inhibited by 4-diphenylacetoxy-N-methylpiperdine methiodide (4-DAMP), indicating the mediation of muscarinic M3 receptors. The results suggest that oleanolic acid can raise the release of ACh from nerve terminals, which stimulate muscarinic M3 receptors in the pancreatic cells and augment the insulin release resulting in a plasma glucose lowering action. Thus, oleanolic acid can be considered as one of the active principles for the increase of plasma insulin produced by cornus in normal rats.
In addition, administration of Die-Huang-Wan has been found to delay the formation of insulin resistance in rats. The major herb contained in Die-Huang-Wan for this action was also investigated. In rats with insulin resistance induced by fructose-rich food, dioscorea(4.2mg/kg) ( Dioscorea opposita Thunb.) named as San-Yaw in Chinese showed the plasma glucose lowering action (28.9 ± 7.6 % vs. 26.4 ± 4.6 %, n=8, p< 0.01)in a way similar to Die-Huang-Wan while another 5 herbs failed to produce same action. Also, deletion of dioscorea from Die-Huang-Wan negated the plasma glucose lowering action. Moreover, a similar action of dioscorea produced by Die-Huang-Wan was characterized using the reduction of glucose-insulin index. In STZ-induced diabetic rats, daily oral administration of Die-Huang-Wan caused an increase of response to exogenous insulin 7 days later, indicating an increase of insulin sensitivity. The present study found that oral administration of dioscorea can increase insulin sensitivity produced by Die-Huang-Wan and the absence of dioscorea in Die-Huang-Wan failed to produce this action. Thus, dioscorea can be considered as the major herb in Die-Huang-Wan for the improvement of insulin resistance.
In conclusion, now we found the mechanism(s) for two actions of Die-Huang-Wan in the regulation of plasma glucose in rats. Oleanolic acid was observed to be one of the active principles for the increase of plasma insulin produced by cornus which is the major herb in Die-Huang-Wan for increase of insulin secretion. The main herb in Die-Huang-Wan for improvement of insulin resistance was identified as dioscorea. Therefore, cornus and discorea may be used as an adjuvant for the handling of diabetic patients with insulin resistance in clinics.
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