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.
Highlights
Fine-tuning of insulin release from pancreatic β-cells is essential to maintain blood glucose homeostasis
To circumvent this problem and obtain a comprehensive picture of all circRNAs present in islet cells, we used a two-algorithm computational approach to de novo annotate potential circular transcripts detectable in highthroughput RNA-sequencing data from mouse islets (GEO accession GSE92602)[10]. This computational approach led to the prediction of 15,925 putative circRNAs, which included circRNAs generated from key β-cell genes such as Ins[1], Ins[2], Chga, Chgb, Gck, Glp1r, Pcsk[1], Pcsk[2], and Slc30a85,11 (Supplementary Table 1)
Because of the essential role played by insulin in β-cell function and blood glucose homeostasis[5], we decided to focus on circRNAs originating from the insulin genes
Summary
Fine-tuning of insulin release from pancreatic β-cells is essential to maintain blood glucose homeostasis. 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 (TDP43) 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 level of this circRNA is decreased in the islets of rodents and humans with type 2 diabetes, suggesting that it may contribute to the development of the disease
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
