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

Author:
  • Annika Axelsson
  • T Mahdi
  • H A Nenonen
  • Tania Singh
  • S Hänzelmann
  • A Wendt
  • Annika Bagge
  • T M Reinbothe
  • J Millstein
  • X Yang
  • B Zhang
  • E G Gusmao
  • L Shu
  • M Szabat
  • Y Tang
  • Jinling Wang
  • Sofia Salö
  • L Eliasson
  • I Artner
  • M Fex
  • J D Johnson
  • C B Wollheim
  • J M J Derry
  • B Mecham
  • P Spégel
  • H Mulder
  • Ivan G Costa
  • E Zhang
  • A H Rosengren
Publishing year: 2017-06-06
Language: English
Pages: 15652-15652
Publication/Series: Nature Communications
Volume: 8
Document type: Journal article
Publisher: Nature Publishing Group

Abstract english

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 Ca(2+)-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.

Keywords

  • Endocrinology and Diabetes
  • Journal Article

Other

Published
  • Islet patophysiology
  • Islet cell exocytosis
  • Molecular Metabolism
  • Diabetes and Celiac Unit
  • Diabetes and Endocrinology
  • ISSN: 2041-1723
Peter Spegel
E-mail: peter.spegel [at] chem.lu.se

Researcher

Centre for Analysis and Synthesis

1

Lund University Diabetes Centre, CRC, SUS Malmö, Entrance 72, House 91:12. SE-205 02 Malmö. Telephone: +46 40 39 10 00