Role of the subcellular localization of the dual leucine zipper kinase in the pathogenesis of diabetes mellitus type 2

2型糖尿病的特点是由于胰腺朗格汉斯胰岛产生胰岛素的ß-细胞内的胰岛素生物合成和分泌不足而导致相对胰岛素缺乏。外周胰岛素抵抗作为肥胖引起的重要危险因素似乎是主要原因。糖尿病前期ß-细胞暴露于细胞因子的增强可导致细胞凋亡。只有β-细胞失代偿并丧失其功能和质量才会导致临床上明显的糖尿病。潜在的分子机制尚不清楚。我们自己使用ß-细胞模型的研究表明，双亮氨酸拉链激酶（DLK）减少ß-细胞的质量和功能，因此细胞因子诱导的DLK的核定位是诱导凋亡所必需的。这些发现表明DLK依赖于其亚细胞定位，通过不同的磷酸化蛋白组发挥不同的功能。本项目将在体内和体外研究DLK亚细胞定位在糖尿病发病机制中的作用。该结果可能为糖尿病的治疗确定新的治疗靶点。

Diabetes mellitus type 2 is characterized by a relative insulin deficiency due to inadequate insulin biosynthesis and secretion within the insulin producing ß-cells of the islets of Langerhans in the pancreas. Peripheral insulin resistance due to obesity as important risk factor seems to be the primary cause. The enhanced exposure of ß-cells to cytokines under prediabetic conditions can result in apoptosis. Only the decompensation of the β-cells with a loss of their function and mass result in clinically apparent diabetes mellitus. The underlying molecular mechanisms are unknown. Our own studies using a model of ß-cells show that the dual leucine zipper kinase (DLK) reduces ß-cell mass and function, whereby the nuclear localization of DLK induced by cytokines was required for induction of apoptosis. These findings suggest that DLK depending on its subcellular localization exerts distinct functions through a distinct phosphoproteom. In this project, the role of the subcellular localization of DLK for the pathogenesis of diabetes mellitus will be investigated in vivo and in vitro. The results may identify novel therapeutic targets for the treatment of diabetes.