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 homeostasis(1). N-6-methyladenosine (m(6)A) is the most abundant internal messenger RNA (mRNA) modification in mammals(2). Here, we report that the m(6)A landscape segregates human type 2 diabetes (T2D) islets from controls significantly better than the transcriptome and that m(6)A is vital for beta-cell biology. m(6)A 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 m(6)A levels in EndoC-beta H1 cells induces cell-cycle arrest and impairs insulin secretion by decreasing AKT phosphorylation and PDX1 protein levels. beta-cell-specific Mettl14 knockout mice, which display reduced m(6)A levels, mimic the islet phenotype in human T2D with early diabetes onset and mortality owing to decreased beta-cell proliferation and insulin degranulation. Our data underscore the significance of RNA methylation in regulating human beta-cell biology, and provide a rationale for potential therapeutic targeting of m(6)A modulators to preserve beta-cell survival and function in diabetes.