Abstract
BackgroundCircular RNAs are non-coding RNA molecules with gene regulatory potential that have been associated with several human diseases. They are stable and present in the circulation, making them excellent candidates for biomarkers of disease. Despite their promise as biomarkers or future therapeutic targets, information on their expression and functionality in human pancreatic islets is a relatively unexplored subject.MethodsHere we aimed to produce an enriched circRNAome profile for human pancreatic islets by CircleSeq, and to explore the relationship between circRNA expression, diabetes status, genotype at T2D risk loci and measures of glycaemia (insulin secretory index; SI and HbA1c) in human islet preparations from healthy control donors and donors with type 2 diabetes using ANOVA or linear regression as appropriate. We also assessed the effect of elevated glucose, cytokine and lipid and hypoxia on circRNA expression in the human beta cell line EndoC-βH1.ResultsWe identified over 2600 circRNAs present in human islets. Of the five most abundant circRNAs in human islets, four (circCIRBP, circZKSCAN, circRPH3AL and circCAMSAP1) demonstrated marked associations with diabetes status. CircCIRBP demonstrated an association with insulin secretory index in isolated human islets and circCIRBP and circRPH3AL displayed altered expression with elevated fatty acid in treated EndoC-βH1 cells. CircCAMSAP1 was also noted to be associated with T2D status in human peripheral blood. No associations between circRNA expression and genotype at T2D risk loci were identified in our samples.ConclusionsOur data suggest that circRNAs are abundantly expressed in human islets, and that some are differentially regulated in the islets of donors with type 2 diabetes. Some islet circRNAs are also expressed in peripheral blood and the expression of one, circCAMSAP1, correlates with diabetes status. These findings highlight the potential of circRNAs as biomarkers for T2D.
Highlights
Circular RNAs are non-coding RNA molecules with gene regulatory potential that have been associated with several human diseases
We identified 2619 circRNAs that were expressed in islet donors, 47 of which had not been previously identified in data from human tissues. 4/5 of the most abundant circRNA demonstrated differential expression in the islets of donors with type 2 diabetes (T2D), whilst 2/5 demonstrated dysregulated expression in response to elements of the diabetic microenvironment in the human beta cell line EndoC-βH1 in culture
The five circRNAs demonstrating the highest expression in human islets derived from the CAMSAP1, CIRBP, RPH3AL, RHOBTB3 and ZKSCAN1 loci
Summary
Circular RNAs are non-coding RNA molecules with gene regulatory potential that have been associated with several human diseases. They are stable and present in the circulation, making them excellent candidates for biomarkers of disease. Identifying people at risk of type 2 diabetes, or those likely to progress from impaired glucose tolerance to overt disease is an important aim. Over 80% of the human genome is predicted to display some degree of functionality [5], so it is likely that many of the diabetes-associated genetic variants may act via dysregulation of gene expression. Disruption of the activity or function of non-coding RNAs that moderate gene activity, such as microRNA (miRNA) or long non-coding RNA (lncRNA) may have particular relevance [6]
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