Downregulation of the MA Reader Protein YTHDC1 Leads to Islet β-cell Failure and Diabetes

N6-methyladenosine (mA) methyltransferase writer proteins (METTL3/METTL14) have been shown to regulate β-cell function and diabetes. However, whether and which mA reader proteins regulate β-cell function and the pathogenesis of diabetes are largely unknown. In this study, we showed that YTHDC1 (YTH domain-containing protein 1), a key mA nuclear reader protein, plays an essential role in maintaining β-cell function. YTHDC1 is downregulated in islet β cells in type 2 diabetes, which is due to lipotoxicity and chronic inflammation. β-Cell specific deletion of Ythdc1 results in β-cell failure and diabetes, which is likely due to the decreased expression of β-cell specific transcription factors and insulin secretion-related genes. Taken together, YTHDC1 is required for maintaining β-cell function, and the downregulation of YTHDC1 leads to β-cell failure and diabetes.