Format

Send to

Choose Destination
Nat Commun. 2017 Jun 6;8:15652. doi: 10.1038/ncomms15652.

Sox5 regulates beta-cell phenotype and is reduced in type 2 diabetes.

Author information

1
Lund University Diabetes Center, CRC 91-11 SUS, Jan Waldenströms gata 35, SE-20502 Malmö, Sweden.
2
Medical Research Center, Hawler Medical University, 44001 Erbil, Iraq.
3
Institute of Biomedical Engineering, RWTH Aachen University Hospital, Pauwelstr 19, 52074 Aachen, Germany.
4
Sage Bionetworks, 1100 Fairview Avenue N, Seattle, Washington 98109, USA.
5
Department of Integrative Biology and Physiology, University of California, Los Angeles, 610 Charles E. Young Dr East, Los Angeles, California 90095, USA.
6
Department of Genetics and Genomic Sciences, Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, New York 10029, USA.
7
Diabetes Research Group, Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, 5358-2350 Health Sciences Mall, Vancouver, British Columbia, Canada V6T 1Z3.
8
Key Lab of Hormones and Development, Ministry of Health, Metabolic Diseases Hospital, Tianjin Medical University, Tianjin 300070, China.
9
Department of Emergency, Zhongshan Hospital, Xiamen University, Xiamen, Fujian 361004, China.
10
Department of Cell Physiology and Metabolism, University Medical Center, Rue Michel-Servet 1, 1206 Geneva, Switzerland.
11
Trialomics, 6310 12th Avenue NE, Seattle, Washington 98115, USA.
12
Centre for Analysis and Synthesis, Department of Chemistry, Lund University, SE-221 00 Lund, Sweden.
13
Department of Neuroscience and Physiology, University of Gothenburg, Box 100, SE-405 30 Gothenburg, Sweden.

Abstract

Type 2 diabetes (T2D) is characterized by insulin resistance and impaired insulin secretion, but the mechanisms underlying insulin secretion failure are not completely understood. Here, we show that a set of co-expressed genes, which is enriched for genes with islet-selective open chromatin, is associated with T2D. These genes are perturbed in T2D and have a similar expression pattern to that of dedifferentiated islets. We identify Sox5 as a regulator of the module. Sox5 knockdown induces gene expression changes similar to those observed in T2D and diabetic animals and has profound effects on insulin secretion, including reduced depolarization-evoked Ca2+-influx and β-cell exocytosis. SOX5 overexpression reverses the expression perturbations observed in a mouse model of T2D, increases the expression of key β-cell genes and improves glucose-stimulated insulin secretion in human islets from donors with T2D. We suggest that human islets in T2D display changes reminiscent of dedifferentiation and highlight SOX5 as a regulator of β-cell phenotype and function.

Comment in

PMID:
28585545
PMCID:
PMC5467166
DOI:
10.1038/ncomms15652
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center