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

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

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Lund University Diabetes Center, CRC 91-11 SUS, Jan Waldenströms gata 35, SE-20502 Malmö, Sweden.
Medical Research Center, Hawler Medical University, 44001 Erbil, Iraq.
Institute of Biomedical Engineering, RWTH Aachen University Hospital, Pauwelstr 19, 52074 Aachen, Germany.
Sage Bionetworks, 1100 Fairview Avenue N, Seattle, Washington 98109, USA.
Department of Integrative Biology and Physiology, University of California, Los Angeles, 610 Charles E. Young Dr East, Los Angeles, California 90095, USA.
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.
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.
Key Lab of Hormones and Development, Ministry of Health, Metabolic Diseases Hospital, Tianjin Medical University, Tianjin 300070, China.
Department of Emergency, Zhongshan Hospital, Xiamen University, Xiamen, Fujian 361004, China.
Department of Cell Physiology and Metabolism, University Medical Center, Rue Michel-Servet 1, 1206 Geneva, Switzerland.
Trialomics, 6310 12th Avenue NE, Seattle, Washington 98115, USA.
Centre for Analysis and Synthesis, Department of Chemistry, Lund University, SE-221 00 Lund, Sweden.
Department of Neuroscience and Physiology, University of Gothenburg, Box 100, SE-405 30 Gothenburg, Sweden.


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.

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