营养过剩压力诱导的代谢性炎症是糖尿病的重要致病机制，目前尚无靶向干预措施。我们前期发现糖脂毒性可直接激活β细胞TLR4信号通路从而诱导代谢性炎症反应，导致β细胞功能静默，但机制有待进一步明确。研究显示TMEM24是调节胰岛素脉冲性分泌的关键脂质转运蛋白，我们预实验发现诱导TMEM24过表达可削弱TLR4导致的β细胞功能障碍。为此，我们提出假说：糖脂毒性激活的TLR4可能通过调控TMEM24功能影响胰岛素囊泡分泌，导致β细胞功能静默的发生。为了验证这一假说，我们将通过构建饮食诱导的肥胖小鼠，糖尿病小鼠及糖脂毒性β细胞模型，采用过表达或组织特异性敲除TMEM24或TLR4基因，杂交获得不同基因型小鼠，并运用激动剂或抑制剂调控蛋白活性等手段，从分子、细胞、组织以及动物整体水平等多层面探讨TLR4是否通过调控TMEM24蛋白导致β细胞功能静默及机制，为靶向干预代谢性炎症相关药物的研发提供潜在靶点。

Nutrient-energy stress induced metainflammation was the important mechanism of diabetes, and was lack of specific targets for intervention. Our previous studies have demonstrated that glucolipotoxicity induced dysfunction in β cell through metainflammation by activating TLR4 signal way directly, but the underlying mechanismthe remained unresolved. New studies have shown that TMEM24 was a key lipid transport protein and it could regulate the impulsive secretion of insulin, and our preliminary experiments showed that induction of TMEM24 overexpression could attenuate TLR4 induced β cell dysfunction.Therefore, we presumed that the activating TLR4 induced by glucolipotoxicity may obstruct the secretion of insulin vesicles and lead β cell dysfunction by regulating TMEM24. To confirm our hypothesis, we will conduct the research from molecular, cell, tissue and animal holistic levels. We will establish the models of obese mice induced by high-fat diet, diabetic mice and glucolipotoxicity β-cell; induce TMEM24/TLR4 over-expression or conditional knockout TMEM24 /TLR4 gene; filter mice with different gene phenotypes by hybridization; and regulate the activity of proteins using agonists or inhibitors to investigated whether TLR4 can induce β cell dysfunction by regulating TMEM24 protein. This study will show the mechanism of sustained damage in β cell induced by metainflammation from the new viewpoint of TMEM24, and provide the intervention target for metainflammation and a novel therapeutic way for type 2 diabetes.