Activation of NF-κB-Inducing Kinase in Islet β Cells Causes β Cell Failure and Diabetes

Islet beta cell death has been proved to contribute to diabetes. Studies suggest that the activation of nuclear factor kappa B (NF-kappa B)-inducing kinase (NIK) is involved in the beta cell dysfunction encountered in obesity. However, the pathological significance of NIK activation in diabetes remains largely unknown. Here, we report that beta cell-specific overexpression of NIK (beta-NIK-OE) results in spontaneous diabetes in male mice at a young age (>= 10 weeks of age), which is likely due to insulin deficiency, beta cell death, and insulitis. Importantly, inhibiting the kinase activation of NIK by the small molecule B022 prevents NIK- or H2O2-induced beta cell death and also reduces streptozotocin (STZ)-induced beta cell death while ameliorating hyperglycemia, suggesting that the kinase activity of NIK is essential in inducing islet inflammation, beta cell death, and diabetes. In all, this study not only uncovers a role of NIK in beta cell failure but also provides a potential therapeutic target for the treatment of diabetes.