HIT Center for Life Sciences, School of Life Science and Technology, Harbin Institute of Technology, Harbin 150001, China.
Key Laboratory of Molecular Epigenetics of the Ministry of Education (MOE), School of Life Sciences, Northeast Normal University, Changchun 130024, China.
Mol Ther. 2020 Nov 4;28(11):2430-2441. doi: 10.1016/j.ymthe.2020.07.016. Epub 2020 Jul 21.
Islet β cell death has been proved to contribute to diabetes. Studies suggest that the activation of nuclear factor κB (NF-κB)-inducing kinase (NIK) is involved in the β cell dysfunction encountered in obesity. However, the pathological significance of NIK activation in diabetes remains largely unknown. Here, we report that β cell-specific overexpression of NIK (β-NIK-OE) results in spontaneous diabetes in male mice at a young age (≥10 weeks of age), which is likely due to insulin deficiency, β cell death, and insulitis. Importantly, inhibiting the kinase activation of NIK by the small molecule B022 prevents NIK- or HO-induced β cell death and also reduces streptozotocin (STZ)-induced β cell death while ameliorating hyperglycemia, suggesting that the kinase activity of NIK is essential in inducing islet inflammation, β cell death, and diabetes. In all, this study not only uncovers a role of NIK in β cell failure but also provides a potential therapeutic target for the treatment of diabetes.
胰岛 β 细胞死亡已被证明与糖尿病有关。研究表明，核因子 κB（NF-κB）诱导激酶（NIK）的激活参与了肥胖症中遇到的 β 细胞功能障碍。然而，NIK 激活在糖尿病中的病理意义在很大程度上仍然未知。在这里，我们报告称，β 细胞特异性过表达 NIK（β-NIK-OE）会导致雄性小鼠在年轻时（≥10 周龄）自发发生糖尿病，这可能是由于胰岛素缺乏、β 细胞死亡和胰岛炎。重要的是，小分子 B022 通过抑制 NIK 的激酶活性可防止 NIK 或 HO 诱导的 β 细胞死亡，并减少链脲佐菌素（STZ）诱导的 β 细胞死亡，同时改善高血糖症，表明 NIK 的激酶活性对于诱导胰岛炎症、β 细胞死亡和糖尿病是必需的。总之，这项研究不仅揭示了 NIK 在 β 细胞衰竭中的作用，而且为治疗糖尿病提供了一个潜在的治疗靶点。
