"m6A mRNA methylation mediates glucose homeostasis through translational control of insulin"
In neurons where compartmentalization (cell body, axon, synapses) is so profound, the precise and dynamic regulation of localization, abundance, and translational state of mRNAs is essential for neuronal identity and function. As a model for the dynamic regulation of mRNAs, I discovered that N6-methyladenosine (m6A) is critical for the neuronal based fly insulin system to maintain glucose homeostasis. m6A is a pervasive messenger RNA modification that modulates the fate of RNAs although the specific roles for m6A over the insulin system remain unclear. I have found that when m6A methylation is inhibited, specifically in insulin-producing neurons, animals become hyperglycemic and develop diabetes. We found by m6A individual-nucleotide-resolution cross-linking and immunoprecipitation (mi-CLIP) that messenger RNAs important for the insulin system harbor m6A including insulin messenger RNA. Polysome profiling and in vivo mutational analysis demonstrated 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 mRNA is necessary to maintain adequate levels of insulin in insulin-producing neurons to respond to high levels of glucose. These insights uncover a new regulatory layer of the insulin system and a novel context in which m6A increases translation. The results underscore how the reduction of m6A, potentially through nutritional inputs, could lead to functional impairment of insulin-producing cells and ultimately diabetes
