A circular RNA generated from an intron of the insulin gene controls insulin secretion
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ABSTRACT:
PROVIDER: PRJNA556164 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR9734010.fastq.gz | Fastqsanger.gz | |||
| SRR9734005.fastq.gz | Fastqsanger.gz | |||
| SRR9734006.fastq.gz | Fastqsanger.gz | |||
| SRR9734007.fastq.gz | Fastqsanger.gz | |||
| SRR9734008.fastq.gz | Fastqsanger.gz |
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Project description: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.
2020-09-21 | GSE134699 | GEO
Project description: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.
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Project description:After the discovery of insulin a century ago, extensive work has been done to unravel the molecular network regulating insulin secretion. Here, we performed a chemical screen and identified AZD7762, a compound that potentiates glucose-stimulated insulin secretion (GSIS) of human β cell line, healthy and type 2 diabetic (T2D) human islets, and primary cynomolgus macaque islets. In vivo studies in diabetic mouse models and cynomolgus macaques demonstrated that AZD7762 enhances GSIS and improves glucose tolerance. Furthermore, genetic manipulation confirmed that ablation of CHEK2 in human β cells results in increased insulin secretion. Consistently, high-fat-diet fed Chk2-/- mice show elevated insulin secretion and improved glucose clearance. Finally, an untargeted metabolic profiling demonstrated the key role of the CHEK2-PP2A-PLK1-G6PD-PPP pathway in insulin secretion. This study successfully identifies a previously unknown insulin secretion regulating pathway that is conserved across rodents, cynomolgus macaques and human β cells in both healthy and T2D conditions.
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