Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland.
Department of Medicine, Weill Cornell Medicine, 413 East 69th street, New York, NY, USA.
Nat Commun. 2020 Nov 5;11(1):5611. doi: 10.1038/s41467-020-19381-w.
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.
胰岛素分泌的微调对于维持血糖稳态至关重要。在这里，我们报告称，胰岛素基因第二个内含子的套索序列所包含的环状 RNA 可调控胰岛素分泌。胰岛中这种内含子环状 RNA 的沉默会导致β细胞分泌机制的关键成分表达减少，从而导致葡萄糖或 KCl 诱导的胰岛素释放和钙信号受损。环状 RNA 的作用发生在转录水平，并涉及与 RNA 结合蛋白 TAR DNA 结合蛋白 43 kDa（TDP-43）相互作用。这种环状化内含子的水平在啮齿动物糖尿病模型和 2 型糖尿病患者的胰岛中降低，这可能解释了它们分泌能力受损的原因。对这种和其他环状 RNA 的研究有助于理解糖尿病条件下β细胞功能障碍以及这种常见代谢紊乱的病因。
