"m6A mRNA methylation mediates glucose homeostasis through translational control of insulin"
Regulation of the insulin system is critical for glucose homeostasis. N6-methyladenosine RNA (m6A) is a pervasive messenger RNA modification that modulates the fate of RNAs. As the generalized roles of m6A in RNA control are beginning to be unveiled, the specific roles for m6A over the insulin system remain unclear. RNA control plays an important yet understudied aspect of the dynamic regulation of the insulin system. Here we show that m6A is essential for proper glucose homeostasis. Insulin-producing cells monitor glucose levels and release the hormone insulin to stimulate the uptake of glucose and thus reduce circulating glucose. When m6A methylation is inhibited, specifically in insulin-producing cells, animals become hyperglycemic and develop diabetes. We found by miCLIP that messenger RNAs important for the insulin system harbor m6A including insulin messenger RNA. Furthermore, using direct RNA-sequencing combined with machine learning we identified the precise nucleotide that is methylated in the insulin transcript and m6A methylation of insulin is conserved in fly, fish, mouse, and human. Through polysome profiling and mutational analysis, we demonstrate that m6A enhances the translation of insulin messenger RNA but does not affect the stability of the message. Finally, our data reveal that methylation of the insulin RNA is necessary to maintain adequate levels of insulin in insulin-producing cells to respond to high levels of glucose. These insights uncover a new layer of regulation of the insulin system and a novel context in which m6A increases translation and underscore how the reduction of m6A could lead to functional impairment of insulin-producing cells and ultimately diabetes.