Increased expression of the diabetes gene SOX4 reduces insulin secretion by impaired fusion pore expansion

Research output: Contribution to journalArticle

Abstract

The transcription factor Sox4 has been proposed to underlie the increased type 2 diabetes risk linked to an intronic single nucleotide polymorphism in CDKAL1. In a mouse model expressing a mutant form of Sox4, glucose-induced insulin secretion is reduced by 40% despite normal intracellular Ca2+ signaling and depolarization-evoked exocytosis. This paradox is explained by a fourfold increase in kiss-and-run exocytosis (as determined by single-granule exocytosis measurements) in which the fusion pore connecting the granule lumen to the exterior expands to a diameter of only 2 nm, which does not allow the exit of insulin. Microarray analysis indicated that this correlated with an increased expression of the exocytosis-regulating protein Stxbp6. In a large collection of human islet preparations (n = 63), STXBP6 expression and glucose-induced insulin secretion correlated positively and negatively with SOX4 expression, respectively. Overexpression of SOX4 in the human insulin-secreting cell EndoC-βH2 interfered with granule emptying and inhibited hormone release, the latter effect reversed by silencing STXBP6. These data suggest that increased SOX4 expression inhibits insulin secretion and increased diabetes risk by the upregulation of STXBP6 and an increase in kissand-run exocytosis at the expense of full fusion. We propose that pharmacological interventions promoting fusion pore expansion may be effective in diabetes therapy.

Details

Authors
  • Stephan C. Collins
  • Hyun Woong Do
  • Benoit Hastoy
  • Alison Hugill
  • Julie Adam
  • Margarita V. Chibalina
  • Juris Galvanovskis
  • Mahdieh Godazgar
  • Sheena Lee
  • Michelle Goldsworthy
  • S Albert Salehi
  • Andrei I. Tarasov
  • Anders H. Rosengren
  • Roger Cox
  • Patrik Rorsman
Organisations
External organisations
  • University of Oxford
  • Mary Lyon Centre Pathology
  • University of Gothenburg
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Endocrinology and Diabetes
Original languageEnglish
Pages (from-to)1952-1961
Number of pages10
JournalDiabetes
Volume65
Issue number7
Publication statusPublished - 2016 Jul 1
Publication categoryResearch
Peer-reviewedYes