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Mol Metab. 2017 Jan 26;6(4):340-351. doi: 10.1016/j.molmet.2017.01.009. eCollection 2017 Apr.

Molecular phenotyping of multiple mouse strains under metabolic challenge uncovers a role for Elovl2 in glucose-induced insulin secretion.

Author information

1
Unité de Biologie Fonctionnelle et Adaptative, Sorbonne Paris Cité, CNRS UMR 8251, Université Paris Diderot, Paris, France.
2
INSERM U1016, Université Paris-Descartes, Institut Cochin, Paris, France.
3
Centre for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland.
4
Discovery Sciences, Innovative Medicines & Early Development Biotech Unit, AstraZeneca, Cambridge Science Park, Milton Road, Cambridge CB4 0WG, UK.
5
Vital-IT Group, SIB Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland.
6
Recherche de Découverte, PIT Métabolisme, IdRS, 11 rue des Moulineaux, 92150 Suresnes, France.
7
Boehringer Ingelheim Pharma GmbH & Co, KG 88400 Biberach, Germany.
8
Section of Cell Biology and Functional Genomics, Department of Medicine, Imperial College London, London W120NN, UK.
9
Unité de Biologie Fonctionnelle et Adaptative, Sorbonne Paris Cité, CNRS UMR 8251, Université Paris Diderot, Paris, France; I2BC - UMR 9198 Université Paris Sud, Gif sur Yvette, France.
10
Unité de Biologie Fonctionnelle et Adaptative, Sorbonne Paris Cité, CNRS UMR 8251, Université Paris Diderot, Paris, France. Electronic address: christophe.magnan@univ-paris-diderot.fr.
11
Vital-IT Group, SIB Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland. Electronic address: mark.ibberson@sib.swiss.

Abstract

OBJECTIVE:

In type 2 diabetes (T2D), pancreatic β cells become progressively dysfunctional, leading to a decline in insulin secretion over time. In this study, we aimed to identify key genes involved in pancreatic beta cell dysfunction by analyzing multiple mouse strains in parallel under metabolic stress.

METHODS:

Male mice from six commonly used non-diabetic mouse strains were fed a high fat or regular chow diet for three months. Pancreatic islets were extracted and phenotypic measurements were recorded at 2 days, 10 days, 30 days, and 90 days to assess diabetes progression. RNA-Seq was performed on islet tissue at each time-point and integrated with the phenotypic data in a network-based analysis.

RESULTS:

A module of co-expressed genes was selected for further investigation as it showed the strongest correlation to insulin secretion and oral glucose tolerance phenotypes. One of the predicted network hub genes was Elovl2, encoding Elongase of very long chain fatty acids 2. Elovl2 silencing decreased glucose-stimulated insulin secretion in mouse and human β cell lines.

CONCLUSION:

Our results suggest a role for Elovl2 in ensuring normal insulin secretory responses to glucose. Moreover, the large comprehensive dataset and integrative network-based approach provides a new resource to dissect the molecular etiology of β cell failure under metabolic stress.

KEYWORDS:

Beta cell dysfunction; Diabetes; Metabolic stress; Molecular phenotyping; Network analysis; Pancreas

PMID:
28377873
PMCID:
PMC5369210
DOI:
10.1016/j.molmet.2017.01.009
[Indexed for MEDLINE]
Free PMC Article

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