METTL3 is required for maintaining ß-cell function.

N6-methyladenosine (m6A) mRNA methylation has been shown to regulate obesity and type 2 diabetes. However, whether METTL3, the key methyltransferase for m6A mRNA methylation, regulates ß-cell failure in diabetes has not been fully explored. Here, we show that METTL3 is downregulated under the inflammatory and oxidative stress conditions, and islet ß-cell-specific deletion of Mettl3 induces ß-cell failure and hyperglycemia, which is likely due to decreased m6A modification and reduced expression of insulin secretion-related genes. Overall, METTL3 might be a potential drug target for the treatment of ß-cell failure in diabetes.

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

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