Downregulation of the m6A reader protein YTHDC1 leads to islet β-cell failure and diabetes

N6-methyladenosine (m(6)A) methyltransferase writer proteins (METTL3/METTL14) have been shown to regulate beta-cell function and diabetes. However, whether and which m(6)A reader proteins regulate beta-cell function and the pathogenesis of diabetes are largely unknown. In this study, we showed that YTHDC1 (YTH domain-containing protein 1), a key m(6)A nuclear reader protein, plays an essential role in maintaining beta-cell function. YTHDC1 is downregulated in islet p cells in type 2 diabetes, which is due to lipotoxicity and chronic inflammation. beta-Cell specific deletion of Ythdc1 results in beta-cell failure and diabetes, which is likely due to the decreased expression of beta-cell specific transcription factors and insulin secretion-related genes. Taken together, YTHDC1 is required for maintaining beta-cell function, and the downregulation of YTHDC1 leads to beta-cell failure and diabetes.