小檗碱调控“胰岛素受体-Akt-eNOS”减轻糖尿病血管功能损害及其机制

项目名称： 小檗碱调控“胰岛素受体-Akt-eNOS”减轻糖尿病血管功能损害及其机制

项目编号： No.81470412

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 董玲

作者单位： 中国人民解放军第四军医大学

项目金额： 73万元

中文摘要： 胰岛素受体-Akt-eNOS 信号通路受损导致糖尿病血管功能损害。以往研究表明小檗碱降糖、降脂、抗炎与激活AMPK有关，但小檗碱改善糖尿病血管功能机制不清。我们前期研究表明小檗碱抗糖尿病大鼠心脏缺血再灌注损伤、减轻心肌细胞凋亡与激活AMPK以及Akt-eNOS有关。且新近发现小檗碱减轻糖尿病血管胰岛素抵抗、抑制血管内皮细胞凋亡、增加内皮细胞胰岛素受体、Akt和eNOS磷酸化。但小檗碱调控胰岛素受体-Akt-eNOS信号系统的关键靶点不清。据此提出问题：1）小檗碱能否调控胰岛素受体-Akt-eNOS减轻糖尿病血管功能损害？2）调控机制和关键靶点？拟通过血管功能测定、RNA干扰技术及血管内皮胰岛素受体基因敲除（VEIRKO）小鼠，探讨小檗碱对胰岛素受体-Akt-eNOS信号系统的调控及关键靶点，揭示小檗碱改善糖尿病血管功能的新机制。为小檗碱防治糖尿病血管并发症提供新资料。

中文关键词： 小檗碱；血管功能损害；胰岛素抵抗；AMPK；胰岛素受体

英文摘要： Diabetes are characterized by both insulin resistance and endothelial dysfunction that lead to substantial increases in cardiovascular morbidity and mortality. Studies demonstrate beneficial metabolic and cardiovascular health effects for berberine, an isoquinoline alkaloid used in Chinese medicine, exerts anti-diabetic effect by lowering blood glucose and regulating lipid metabolism. However, the molecular mechanisms of berberine beneficial effects are incompletely understood. Our previous findings demonstrate that berberine exerts anti-apoptotic effect and improves cardiac functional recovery following myocardial ischemia/reperfusion in diabetic rats via activating AMPK and Akt signaling.And the preliminary data showed that treatment of diabetic rats with berberine for 4 weeks dramatically restored the endothelium-dependent vasodilation and significantly improved insulin vasodilator actions. In addition, berberine elicited dose-dependent vasodilation in isolated conronay arteries, and this vasodilating effect of berberine was significantly enhanced combinded with insulin. More importantly, co-treatment of insulin, berberine significantly induced higher phosphorylation level of insulin receptor, Akt and eNOS in HUVECs. However, precise molecular mechanisms of action for berberine enhances insulin sensitivity and insulin-mediated coronary artery endothelial vasodilatation through activation of insulin receptor-Akt-eNOS signaling in diabetic rats are largely unknown.We aimed to investigate whether berberine has beneficial effects against endothelial dysfunction in diabetic rats and the underlying mechanisms.

英文关键词： Berberine;Vascular dysfunction;Insulin resistance;AMPK;Insulin receptor