Identification of islet-enriched long non-coding RNAs contributing to beta-cell failure in type 2 diabetes. Mus musculus

To study the contribution of long non-coding RNAs (lncRNAs) to beta-cell failure and the development of type 2 diabetes, we used RNA-sequencing coupled with de novo annotation to search for novel transcripts dysregulated in islets of diet-induced obese mice. We identified about 1500 novel lncRNAs, a number of which were differentially expressed in obese mice. The expression of two lncRNAs highly enriched in beta-cells, βlinc2 and βlinc3, correlated to body weight gain and glycaemia levels in obese mice and was also modified in diabetic db/db mice. The expression of both lncRNAs was also modulated in vitro in isolated islets cells by glucolipotoxic conditions. Moreover, the expression of the human orthologue of βlinc3 was altered in the islets of type 2 diabetic patients and was associated to the BMI of the donors. Modulation of the level of βlinc2 and βlinc3 by overexpression or downregulation in MIN6 and mouse islets cells, did not affect insulin secretion but increased beta-cell apoptosis. 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 beta-cell failure during the development of the disease. Overall design: Performed RNA sequencing coupled with de novo annotation to search for known (protein and long non coding RNAs) and novel transcripts (lncRNAs) dysregulated in pancreatic islets of diet-induced obesity mice versus mice fed a normal diet. (C57BL/6 mice 14 weeks old at sacrifice, fed for 8 weeks)