Identification of islet-enriched long non-coding RNAs contributing to Î²-cell failure in type 2 diabetes.
Objective: Non-coding RNAs constitute a major fraction of the Î²-cell transcriptome. While the involvement of microRNAs is well established, the contribution of long non-coding RNAs (lncRNAs) in the regulation of Î²-cell functions and in diabetes development remains poorly understood. The aim of this study was to identify novel islet lncRNAs differently expressed in type 2 diabetes models and to investigate their role in Î²-cell failure and in the development of the disease. Methods: Novel transcripts dysregulated in the islets of diet-induced obese mice were identiï¬ed by high throughput RNA-sequencing coupled with de novo annotation. Changes in the level of the lncRNAs were assessed by real time PCR. The functional role of the selected lncRNAs was determined by modifying their expression in MIN6 cells and primary islet cells. Results: We identiï¬ed about 1500 novel lncRNAs, a number of which were differentially expressed in obese mice. The expression of two lncRNAs highly enriched in Î²-cells, Î²linc2, and Î²linc 3, correlated to body weight gain and glycemia levels in obese mice and was also modiï¬ed in diabetic dbl/dbmice. The expression of both lncRNAs was also modulated in vitro in isolated islet cells by glucolipotoxic conditions. Moreover, the expression of the human of the human ologue of Î²linc3 was altered in the islets of type 2 diabetic patients and was associated to the BMI of the donors. Modulation of the level of Î²linc2 and Î²linc3 by overexpression or downregulation in MIN6 and mouse islet cells did not affect insulin secretion but increased Î² -cell apoptosis. Conclusions: Taken together, the data show that lncRNAs are modulated in a model of obesity associated type 2 diabetes and that variations in the expression of some of them may contribute to Î² -cell failure during the development of the disease.
|Authors||Motterle, A, Gattesco, S, Peyot, M-L, Esguerra, J.L.S, Gomez-Ruiz, A, Laybutt, D.R, Gilon, P, Burdet, F, Ibberson, M, Eliasson, L, Prentki, M, Regazzi, R.|
|Responsible Garvan Author|
|Publisher Name||Molecular Metabolism|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/14200|