Islet-expressed circular RNAs are associated with type 2 diabetes status in human primary islets and in peripheral blood

Abstract

Background: 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. Despite their promise as biomarkers or future therapeutic targets, information on their expression and functionality in human pancreatic islets is a relatively unexplored subject. Methods: Here 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. Results: We 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. Conclusions: Our 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.

Circular RNAs as Novel Regulators of β-Cell Functions under Physiological and Pathological Conditions

“…However, their biological role in islet cells remains to be elucidated. A more recent study of the whole circRNA profile carried out in human islets of healthy donors and T2D patients, identified 2619 circRNAs expressed in islet donors [ 72 ]. Among them, 13 co-localized with the GWAS association signal for T2D.…”

“…Despite the number of circRNAs identified in this study is lower than in the previous one (10,830 circRNAs in Kaur et al), there was a considerable overlap between the two circRNA profiles, especially for the first top 100 abundantly expressed transcripts. Out of the five most abundant circRNAs present in the islet cells, CAMSAP1, CIRBP, RPH3AL, RHOBTB3, and ZKSCAN1, four of them were differentially expressed in the islets of T2D donors [ 72 ]. Moreover, the expression of two of them changed in palmitate-treated human EndoC-βH1 cells.…”

“…Moreover, the expression of two of them changed in palmitate-treated human EndoC-βH1 cells. Of note, the level of circCAMSAP1 in the peripheral blood of patients with T2D showed a negative association with the diabetes status and might have a future utility as a biomarker [ 72 ].…”

“…The level of circRNAs varies in different tissues and according to cellular conditions [ 7 , 80 ]. Moreover, as outlined in the previous chapters, the expression of some circRNAs is altered under disease states [ 7 , 8 , 9 , 10 , 11 ], including diabetes [ 72 , 73 , 81 ]. Finally, some circRNAs are secreted in the extracellular space and are abundant in body fluids (blood, saliva, urine, cerebrospinal fluid) and are detectable in liquid biopsies [ 82 , 83 ].…”

Plasma and local expressions of CircRNA CDR1as are linked with disease severity in patients with non-traumatic osteonecrosis of femoral head

“…Due to these characteristics, circRNAs have a great potential to serve as significant biomarkers to diagnose diseases. Recently, circulating circRNAs have been reported to be used as potential biomarkers for the diagnosis and prognosis of various diseases including cancer [12,13], essential hypertension [14], diabetes [15], and amyotrophic lateral sclerosis [16], etc.…”