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2017 ; 6
(11
): 1407-1418
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Identification of islet-enriched long non-coding RNAs contributing to ?-cell
failure in type 2 diabetes
#MMPMID29107288
Motterle A
; Gattesco S
; Peyot ML
; Esguerra JLS
; Gomez-Ruiz A
; Laybutt DR
; Gilon P
; Burdet F
; Ibberson M
; Eliasson L
; Prentki M
; Regazzi R
Mol Metab
2017[Nov]; 6
(11
): 1407-1418
PMID29107288
show ga
OBJECTIVE: Non-coding RNAs constitute a major fraction of the ?-cell
transcriptome. While the involvement of microRNAs is well established, the
contribution of long non-coding RNAs (lncRNAs) in the regulation of ?-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 ?-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 ?-cells, ?linc2, and ?linc3, 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
?linc3 was altered in the islets of type 2 diabetic patients and was associated
to the BMI of the donors. Modulation of the level of ?linc2 and ?linc3 by
overexpression or downregulation in MIN6 and mouse islet cells did not affect
insulin secretion but increased ?-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
?-cell failure during the development of the disease.
|Animals
[MESH]
|Diabetes Mellitus, Type 2/*genetics/metabolism
[MESH]