Kotte, A.; Marcuccio, F.; Masante, L.; von Wiegen, N.; Prandi, L.; Silva, R. S.; Pracana, R.; Zasso, J.; Soskic, B.; Zappulo, A.; Legnini, I.

Insulin is an essential regulator of glucose homeostasis in vertebrates, and impairment of its synthesis or action leads to diabetes with severe health complications in humans. It is therefore essential to understand how beta cells control insulin synthesis and secretion, including the transcription, translation and decay of its messenger RNA. Using sequencing-based poly(A) tail length profiling from human tissue, genetic evidence for type 2 diabetes, bulk and single-cell transcriptomics and perturbation experiments, here we find that the insulin mRNA is stabilized by the activity of noncanonical poly(A) polymerases of the Tent5 family. We show that Tent5 activity is specific, promoted by both localization at the endoplasmic reticulum and regulatory sequences within the insulin mRNA and regulated by glucose. Overall, our findings provide a mechanistic link between the dynamic control of insulin production by beta cells and the direct regulation of insulin mRNA metabolism.