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

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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.