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

Abstract

N6-methyladenosine (m6A) methyltransferase writer proteins (METTL3/METTL14) have been shown to regulate β-cell function and diabetes. However, whether and which m6A 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 m6A 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.