线粒体解偶联可加速电子呼吸链传递促进糖脂分解代谢，以热量形式代替ATP生成，减少糖脂累积，从而改善代谢综合症。经典的线粒体解偶联剂DNP问世证实了线粒体解偶联的降糖降脂药理作用，但DNP使用中出现持续高热、高血钾、高乳酸症以及死亡等副作用限制了其发展与临床应用。丙酮酸脱氢酶复合物（PDC）是线粒体调控糖、脂代谢转换的关键复合物，其活性提高促使脂肪酸转变为葡萄糖氧化，抑制乳酸以及酮体生成。我们在充分调研基础上提出科学假设 “提高PDC活性可消除线粒体解偶联的副作用”，在前期研究中初步论证了细胞水平和动物水平上PDC激活剂DCA可消除DNP的促乳酸生成和致死毒性反应，并通过筛选与改造发现了具备双靶向的小分子调节剂，具有良好的降糖作用。本课题旨在验证线粒体解偶联和PDC双靶点策略可有效改善糖尿病，得到具有双靶点功能的小分子且安全有效改善高血糖，从而为治疗2型糖尿病提供新的靶向策略与先导化合物。

Type 2 diabetes and obesity are associated with glucose and lipid metabolism disorder. Numerous evidence showed that mitochondrial uncoupler performed a preferable hypoglycemic and hypolipidemic effects through accelerating mitochondrial electron respiratory chain, promoting glucose and lipid oxidation and replacing ATP by heat production. DNP, a classical mitochondrial uncoupler, exerted the hypoglycemic and hypolipidemic effect and was once applied in clinic but was withdrawn shortly because of a combination of hyperthermia, hyperkalemia, hyperlactatemia and the risk of death. The side effect of DNP was clarified to closely associated with excessive promotion of fatty acid oxidation leading to ketones body release and fever, and the compensatary ATP generation by glycolysis contribution to lactic acid release. Pyruvate dehydrogenase complex (PDC) is another key switch point of glucose and lipid metabolism. Increasing activity of PDC would promote glucose but not fatty acid oxidation, inhibit ketone generation and lactic acid release and result in a significant hypoglycemia. Based on the hypothesis, our preliminary research verified, the enhanced activity of PDC could partially reverse the side-effect inspired by DNP in vitro and vivo, and a novel series of backbone with mitochondria uncoupling and PDC activity were identified. In this project, we aim to prove the concept of dual targeting to mitochondria uncoupling and PDC activity for treatment of hyperglycemia, and will provide the novel strategy for drug discovery, and the potential candidates for type 2 diabetes.