1,25-二羟维生素D3改善骨骼肌胰岛素抵抗新作用及机制研究

项目名称： 1,25-二羟维生素D3改善骨骼肌胰岛素抵抗新作用及机制研究

项目编号： No.81200630

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 医学二处

项目作者： 郑超

作者单位： 温州医科大学

项目金额： 23万元

中文摘要： 近年来维生素D的骨外作用研究备受重视。临床试验和基础研究证实1,25-二羟维生素D3（1,25(OH)2D3）能改善机体胰岛素抵抗（IR）状态，但机制不明。针对骨骼肌是外周IR的主要靶器官，本研究将在前期工作的基础上，采用对照增强超声，胰岛素钳夹实验和RNA干扰技术，从骨骼肌微循环的角度来探讨1,25(OH)2D3作用IR大鼠后骨骼肌微血管开放的程度，胰岛素跨内皮细胞转运，骨骼肌胰岛素信号通路及对葡萄糖的摄取能力等方面的影响，明确1,25(OH)2D3对骨骼肌IR的改善作用，同时在细胞水平探讨1,25(OH)2D3对血管内皮PI3K/Akt/eNOS通路及NO合成的影响，明确1,25(OH)2D3改善骨骼肌IR的直接靶细胞。通过这一原创性研究，将有助于进一步揭示骨骼肌IR的发病机制，为1,25(OH)2D3治疗IR及相关疾病提供崭新视角，理论基础和实验依据。

中文关键词： 胰岛素抵抗；1;25-二羟维生素D3；代谢综合症；骨骼肌微循环；

英文摘要： Insulin resistance (IR) constitutes a common and broadly prevalent metabolic disorder, which seems to govern the pathophysiology of diabetes mellitus, metabolic syndrome, and obesity.Evidence has showed that IR causes endothelial dysfunction and impairs insulin-mediated increases in total muscle blood flow.1,25-dihydroxy-vitamin D3 （1,25(OH)2D3）is the most active metabolite of vitamin D and plays a pivotal role in reducing IR and improving endothelium function. However,the underlying mechanisms remain poorly understood.This proposal will focus on the effect of 1,25(OH)2D3 on skeletal muscle(SM) microvasculature.The hypothesis is that 1,25(OH)2D3 improves IR by increase SM microvascular volume and glucose uptake. 1,25(OH)2D3 binding the receptor (VDR) may activate IRS/PI3-K/Akt/eNOS pathway,lead to increased endothelial nitric oxide (NO) production,increased SM capillary recruitment,insulin transmembrane transportation , insulin-mediated GLUT4 plasma membrane translocation and glucose uptake. By employing a series of biochemical, molecular and cellular methodologies, and new state-of-the-art technologies including RNA interference, hyperinsulinemic-euglycemic clamp,contrast-enhanced ultrasound and isotope tracer technology,the hypothesis will be tested by pursuing two specific aims.Aim 1 is to assess the effects

英文关键词： Insulin Resistance；1;25-dihydroxy-vitamin D3；Metabolic Syndrome；skeletal muscle microcirculation；