基于DAG-PKC系统建立机制性药动/药效模型探究预测和改善胰岛素抵抗的新思路

项目名称： 基于DAG-PKC系统建立机制性药动/药效模型探究预测和改善胰岛素抵抗的新思路

项目编号： No.81503149

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 邱志霞

作者单位： 中国药科大学

项目金额： 17.9万元

中文摘要： 肥胖或高脂饮食条件下，脂肪组织脂解异常，游离脂肪酸(NEFA)异位转移激活DAG-PKC系统诱发机体产生胰岛素抵抗(IR)。以脂肪组织为靶组织，抑制其脂解改善IR，是目前抗糖尿病的新药研发和临床探索的前沿方向。本立项基于此机制，引入与IR直接相关标志因子-DAG，建立疾病进程模型(NEFA-DAG模型)，监控血浆NEFA来预测肝脏和骨骼肌DAG的变化，更准确地预测机体IR状态；基于上述模型，以脂肪组织为起点，牛磺熊去氧胆酸和姜黄素为干预药物，建立信号转导PK/PD模型(药物-NEFA-DAG模型)，评价药物通过抑制脂肪脂解降低肝脏和肌肉DAG，减弱DAG-PKC系统激活改善IR的程度。本立项突破传统上以血浆NEFA对IR的模糊判断(NEFA-IR)，以组织中DAG为靶标，预测机体IR状态(DAG-IR)，评价药物对基于上述机制的IR的干预程度，为临床准确预测、合理改善IR提供理论依据。

中文关键词： 胰岛素抵抗；脂肪脂解；DAG-PKC系统；游离脂肪酸；PK/PD；模型

英文摘要： Obesity or high-fat diet leads to adipose tissue dysfunction results in ectopic NEFA to over-activate DAG-PKC system, eventually causes IR. The strategy of targeting adipose tissue to reduce lipolysis and alleviate IR has become a much concerned forefront direction. Based on the mechanism of DAG-PKC induced IR, the disease progress model is put forward to investigate the connection between plasma NEFA and hepatic/intramuscular DAG, in order to directly predict the DAG dynamics and accurately predict IR status. Afterwards, the transduction PK/PD model is introduced to monitor the dynamics of plasma NEFA and DAG in target tissues after intervene by curcumin and TUDCA, in view of glucose-NEFA-insulin system. The adipose tissue as target to modify lipolysis is believed as a promising therapeutic strategy, which significantly reduces ectopic DAG accumulation in liver and muscle, to alleviate IR by weakening the DAG-PKC system activation. Breakthrough the ambiguous prediction of IR by NEFA, DAG is regarded as a more proper biomarker to predict IR. Consequently, the predicted amount of DAG in liver and skeletal muscle is applied to straightforward calculate the IR status, laying solid support to diagnosis and prognosis, treatment and prevent IR in clinical practice.

英文关键词： insulin resistance;adipolysis;DAG-PKC system;non-esterified fatty acid;PK/PD modeling