A circular RNA generated from an intron of the insulin gene controls insulin secretion
Lisa Stoll, Adriana Rodriguez‐Trejo, Claudiane Guay, Flora Brozzi, Mustafa Bilal Bayazit, Sonia Gattesco, Véronique Menoud, Jonathan Sobel, Ana Claudia Marques, Morten T. Venø, Jonathan L.S. Esguerra, Mohammad Barghouth, Mara Suleiman, Lorella Marselli, Jørgen Kjems, Lena Eliasson, Erik Renström, Karim Bouzakri, M. Pinget, Piero Marchetti, Romano Regazzi
Abstract
Fine-tuning of insulin release from pancreatic β-cells is essential to maintain blood glucose homeostasis. Here, we report that insulin secretion is regulated by a circular RNA containing the lariat sequence of the second intron of the insulin gene. Silencing of this intronic circular RNA in pancreatic islets leads to a decrease in the expression of key components of the secretory machinery of β-cells, resulting in impaired glucose- or KCl-induced insulin release and calcium signaling. The effect of the circular RNA is exerted at the transcriptional level and involves an interaction with the RNA-binding protein TAR DNA-binding protein 43 kDa (TDP-43). The level of this circularized intron is reduced in the islets of rodent diabetes models and of type 2 diabetic patients, possibly explaining their impaired secretory capacity. The study of this and other circular RNAs helps understanding β-cell dysfunction under diabetes conditions, and the etiology of this common metabolic disorder.