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Identification of islet-enriched long non-coding RNAs contributing to β-cell failure in type 2 diabetes

Motterle, Anna; Gattesco, Sonia; Peyot, Marie Line; Esguerra, Jonathan Lou S. LU ; Ruiz-Gomez, Ana; Laybutt, D Ross; Gilon, Patrick; Burdet, Frédéric; Ibberson, Mark and Eliasson, Lena LU , et al. (2017) In Molecular Metabolism 6(11). p.1407-1418
Abstract

Objective: Non-coding RNAs constitute a major fraction of the β-cell transcriptome. While the involvement of microRNAs is well established, the contribution of long non-coding RNAs (lncRNAs) in the regulation of β-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 β-cell failure and in the development of the disease. Methods: Novel transcripts dysregulated in the islets of diet-induced obese mice were identified 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... (More)

Objective: Non-coding RNAs constitute a major fraction of the β-cell transcriptome. While the involvement of microRNAs is well established, the contribution of long non-coding RNAs (lncRNAs) in the regulation of β-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 β-cell failure and in the development of the disease. Methods: Novel transcripts dysregulated in the islets of diet-induced obese mice were identified 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 identified about 1500 novel lncRNAs, a number of which were differentially expressed in obese mice. The expression of two lncRNAs highly enriched in β-cells, βlinc2, and βlinc3, correlated to body weight gain and glycemia 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 islet 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 islet cells did not affect insulin secretion but increased β-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 β-cell failure during the development of the disease.

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Contribution to journal
publication status
published
subject
keywords
Diabetes, Gene expression, Insulin, Obesity, Pancreatic islet
in
Molecular Metabolism
volume
6
issue
11
pages
1407 - 1418
publisher
Elsevier GmbH
external identifiers
  • scopus:85028853623
ISSN
2212-8778
DOI
10.1016/j.molmet.2017.08.005
language
English
LU publication?
yes
id
6d08606c-3c60-4931-b822-268dc602e2c5
date added to LUP
2017-09-27 14:45:03
date last changed
2018-03-18 05:16:50
@article{6d08606c-3c60-4931-b822-268dc602e2c5,
  abstract     = {<p>Objective: Non-coding RNAs constitute a major fraction of the β-cell transcriptome. While the involvement of microRNAs is well established, the contribution of long non-coding RNAs (lncRNAs) in the regulation of β-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 β-cell failure and in the development of the disease. Methods: Novel transcripts dysregulated in the islets of diet-induced obese mice were identified 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 identified about 1500 novel lncRNAs, a number of which were differentially expressed in obese mice. The expression of two lncRNAs highly enriched in β-cells, βlinc2, and βlinc3, correlated to body weight gain and glycemia 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 islet 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 islet cells did not affect insulin secretion but increased β-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 β-cell failure during the development of the disease.</p>},
  author       = {Motterle, Anna and Gattesco, Sonia and Peyot, Marie Line and Esguerra, Jonathan Lou S. and Ruiz-Gomez, Ana and Laybutt, D Ross and Gilon, Patrick and Burdet, Frédéric and Ibberson, Mark and Eliasson, Lena and Prentki, Marc and Regazzi, Romano},
  issn         = {2212-8778},
  keyword      = {Diabetes,Gene expression,Insulin,Obesity,Pancreatic islet},
  language     = {eng},
  month        = {08},
  number       = {11},
  pages        = {1407--1418},
  publisher    = {Elsevier GmbH},
  series       = {Molecular Metabolism},
  title        = {Identification of islet-enriched long non-coding RNAs contributing to β-cell failure in type 2 diabetes},
  url          = {http://dx.doi.org/10.1016/j.molmet.2017.08.005},
  volume       = {6},
  year         = {2017},
}