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

2型糖尿病的特征在于由于胰腺中胰岛的胰岛素产生β细胞内的胰岛素生物合成和分泌不足而导致的相对胰岛素缺乏。肥胖引起的外周胰岛素抵抗是其主要原因。在糖尿病前期条件下，β细胞对细胞因子的暴露增强可导致细胞凋亡。只有β-细胞的失代偿及其功能和质量的丧失才导致临床上明显的糖尿病。其潜在的分子机制尚不清楚。我们自己的研究使用的模型的β细胞表明，双亮氨酸拉链激酶（DLK）减少β细胞的质量和功能，从而细胞因子诱导的DLK的核定位是诱导细胞凋亡所必需的。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质组发挥不同的功能。在本项目中，将在体内和体外研究DLK的亚细胞定位在糖尿病发病机制中的作用。这些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.