m6A mRNA methylation regulates human β-cell biology in physiological states and in type 2 diabetes

The regulation of islet cell biology is critical for glucose homeostasis1. N6-methyladenosine (m6A) is the most abundant internal messenger RNA (mRNA) modification in mammals2. Here, we report that the m6A landscape segregates human type 2 diabetes (T2D) islets from controls significantly better than the transcriptome and that m6A is vital for β-cell biology. m6A sequencing in human T2D islets reveals several hypomethylated transcripts that are involved in cell-cycle progression, insulin secretion, and the insulin/IGF1–AKT–PDX1 pathway. Depletion of m6A levels in EndoC-βH1 cells induces cell-cycle arrest and impairs insulin secretion by decreasing AKT phosphorylation and PDX1 protein levels. β-cell-specific Mettl14 knockout mice, which display reduced m6A levels, mimic the islet phenotype in human T2D with early diabetes onset and mortality owing to decreased β-cell proliferation and insulin degranulation. Our data underscore the significance of RNA methylation in regulating human β-cell biology, and provide a rationale for potential therapeutic targeting of m6A modulators to preserve β-cell survival and function in diabetes. m6A mRNA methylation regulates several cellular processes, including cancer progression and stem cell maintenance. Here, De Jesus and colleagues demonstrate that the m6A landscape segregates human type 2 diabetic islets from controls and that m6A is fundamental for human β-cell biology.