Deficiency of WTAP in islet beta cells results in beta cell failure and diabetes in mice

Aims/hypothesis: N⁶-methyladenosine (m⁶A) mRNA methylation and m⁶A-related proteins (methyltransferase-like 3 [METTL3], methyltransferase-like 14 [METTL14] and YTH domain containing 1 [YTHDC1]) have been shown to regulate islet beta cell function and the pathogenesis of diabetes. However, whether Wilms’ tumour 1-associating protein (WTAP), a key regulator of the m⁶A RNA methyltransferase complex, regulates islet beta cell failure during pathogenesis of diabetes is largely unknown. The present study aimed to investigate the role of WTAP in the regulation of islet beta cell failure and diabetes. Methods: Islet beta cell-specific Wtap-knockout and beta cell-specific Mettl3-overexpressing mice were generated for this study. Blood glucose, glucose tolerance, serum insulin, glucose-stimulated insulin secretion (both in vivo and in vitro), insulin levels, glucagon levels and beta cell apoptosis were examined. RNA-seq and MeRIP-seq were performed, and the data were well analysed. Results: WTAP was downregulated in islet beta cells in type 2 diabetes, due to lipotoxicity and chronic inflammation, and islet beta cell-specific deletion of Wtap (Wtap-betaKO) induced beta cell failure and diabetes. Wtap-betaKO mice showed severe hyperglycaemia (above 20 mmol/l [360 mg/dl]) from 8 weeks of age onwards. Mechanistically, WTAP deficiency decreased m⁶A mRNA modification and reduced the expression of islet beta cell-specific transcription factors and insulin secretion-related genes by reducing METTL3 protein levels. Islet beta cell-specific overexpression of Mettl3 partially reversed the abnormalities observed in Wtap-betaKO mice. Conclusions/interpretation: WTAP plays a key role in maintaining beta cell function by regulating m⁶A mRNA modification depending on METTL3, and the downregulation of WTAP leads to beta cell failure and diabetes. Data availability: The RNA-seq and MeRIP-seq datasets generated during the current study are available in the Gene Expression Omnibus database repository (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE215156; https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE215360). Graphical abstract: [Figure not available: see fulltext.].