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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism
  • Calcium Channels / metabolism
  • Chromatin / metabolism
  • Diabetes Mellitus, Experimental / metabolism*
  • Diabetes Mellitus, Type 2 / metabolism*
  • Exocytosis
  • Female
  • Gene Expression Regulation
  • Humans
  • Insulin / metabolism
  • Insulin-Secreting Cells / metabolism*
  • Islets of Langerhans / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Oligonucleotide Array Sequence Analysis
  • Phenotype
  • Phlorhizin / chemistry
  • RNA, Small Interfering / metabolism
  • Rats
  • SOXD Transcription Factors / metabolism*
  • Valproic Acid / chemistry

Substances

  • Calcium Channels
  • Chromatin
  • Insulin
  • RNA, Small Interfering
  • SOX5 protein, human
  • SOXD Transcription Factors
  • Sox5 protein, mouse
  • Valproic Acid
  • Phlorhizin
  • Calcium