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Sox5 regulates beta-cell phenotype and is reduced in type 2 diabetes.
Axelsson, A S; Mahdi, T; Nenonen, H A; Singh, T; Hänzelmann, S; Wendt, A; Bagge, A; Reinbothe, T M; Millstein, J; Yang, X; Zhang, B; Gusmao, E G; Shu, L; Szabat, M; Tang, Y; Wang, J; Salö, S; Eliasson, L; Artner, I; Fex, M; Johnson, J D; Wollheim, C B; Derry, J M J; Mecham, B; Spégel, P; Mulder, H; Costa, I G; Zhang, E; Rosengren, A H.
Afiliação
  • Axelsson AS; Lund University Diabetes Center, CRC 91-11 SUS, Jan Waldenströms gata 35, SE-20502 Malmö, Sweden.
  • Mahdi T; Lund University Diabetes Center, CRC 91-11 SUS, Jan Waldenströms gata 35, SE-20502 Malmö, Sweden.
  • Nenonen HA; Medical Research Center, Hawler Medical University, 44001 Erbil, Iraq.
  • Singh T; Lund University Diabetes Center, CRC 91-11 SUS, Jan Waldenströms gata 35, SE-20502 Malmö, Sweden.
  • Hänzelmann S; Lund University Diabetes Center, CRC 91-11 SUS, Jan Waldenströms gata 35, SE-20502 Malmö, Sweden.
  • Wendt A; Institute of Biomedical Engineering, RWTH Aachen University Hospital, Pauwelstr 19, 52074 Aachen, Germany.
  • Bagge A; Lund University Diabetes Center, CRC 91-11 SUS, Jan Waldenströms gata 35, SE-20502 Malmö, Sweden.
  • Reinbothe TM; Lund University Diabetes Center, CRC 91-11 SUS, Jan Waldenströms gata 35, SE-20502 Malmö, Sweden.
  • Millstein J; Lund University Diabetes Center, CRC 91-11 SUS, Jan Waldenströms gata 35, SE-20502 Malmö, Sweden.
  • Yang X; Sage Bionetworks, 1100 Fairview Avenue N, Seattle, Washington 98109, USA.
  • Zhang B; Sage Bionetworks, 1100 Fairview Avenue N, Seattle, Washington 98109, USA.
  • Gusmao EG; Department of Integrative Biology and Physiology, University of California, Los Angeles, 610 Charles E. Young Dr East, Los Angeles, California 90095, USA.
  • Shu L; Sage Bionetworks, 1100 Fairview Avenue N, Seattle, Washington 98109, USA.
  • Szabat M; 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.
  • Tang Y; Institute of Biomedical Engineering, RWTH Aachen University Hospital, Pauwelstr 19, 52074 Aachen, Germany.
  • Wang J; Department of Integrative Biology and Physiology, University of California, Los Angeles, 610 Charles E. Young Dr East, Los Angeles, California 90095, USA.
  • Salö S; 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.
  • Eliasson L; Lund University Diabetes Center, CRC 91-11 SUS, Jan Waldenströms gata 35, SE-20502 Malmö, Sweden.
  • Artner I; Key Lab of Hormones and Development, Ministry of Health, Metabolic Diseases Hospital, Tianjin Medical University, Tianjin 300070, China.
  • Fex M; Lund University Diabetes Center, CRC 91-11 SUS, Jan Waldenströms gata 35, SE-20502 Malmö, Sweden.
  • Johnson JD; Department of Emergency, Zhongshan Hospital, Xiamen University, Xiamen, Fujian 361004, China.
  • Wollheim CB; Lund University Diabetes Center, CRC 91-11 SUS, Jan Waldenströms gata 35, SE-20502 Malmö, Sweden.
  • Derry JMJ; Lund University Diabetes Center, CRC 91-11 SUS, Jan Waldenströms gata 35, SE-20502 Malmö, Sweden.
  • Mecham B; Lund University Diabetes Center, CRC 91-11 SUS, Jan Waldenströms gata 35, SE-20502 Malmö, Sweden.
  • Spégel P; Lund University Diabetes Center, CRC 91-11 SUS, Jan Waldenströms gata 35, SE-20502 Malmö, Sweden.
  • Mulder H; 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.
  • Costa IG; Lund University Diabetes Center, CRC 91-11 SUS, Jan Waldenströms gata 35, SE-20502 Malmö, Sweden.
  • Zhang E; Department of Cell Physiology and Metabolism, University Medical Center, Rue Michel-Servet 1, 1206 Geneva, Switzerland.
  • Rosengren AH; Sage Bionetworks, 1100 Fairview Avenue N, Seattle, Washington 98109, USA.
Nat Commun ; 8: 15652, 2017 06 06.
Article em En | MEDLINE | ID: mdl-28585545
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 ß-cell exocytosis. SOX5 overexpression reverses the expression perturbations observed in a mouse model of T2D, increases the expression of key ß-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 ß-cell phenotype and function.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Diabetes Mellitus Experimental / Diabetes Mellitus Tipo 2 / Células Secretoras de Insulina / Fatores de Transcrição SOXD Idioma: En Ano de publicação: 2017 Tipo de documento: Article
Texto completo
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Diabetes Mellitus Experimental / Diabetes Mellitus Tipo 2 / Células Secretoras de Insulina / Fatores de Transcrição SOXD Idioma: En Ano de publicação: 2017 Tipo de documento: Article