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 involved in cell-cycle progression, insulin secretion, and the Insulin/IGF1-AKT-PDX1 pathway. Depletion of m⁶A levels in EndoC-βH1 induces cell-cycle arrest and impairs insulin secretion by decreasing AKT phosphorylation and PDX1 protein levels. β-cell specific Mettl14 knock-out mice, which display reduced m⁶A levels, mimic the islet phenotype in human T2D with early diabetes onset and mortality due 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.