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

Collins, Stephan C.; Do, Hyun Woong; Hastoy, Benoit; Hugill, Alison; Adam, Julie; Chibalina, Margarita V.; Galvanovskis, Juris LU ; Godazgar, Mahdieh; Lee, Sheena and Goldsworthy, Michelle, et al. (2016) In Diabetes 65(7). p.1952-1961
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... (More)

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.

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published
subject
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Diabetes
volume
65
issue
7
pages
10 pages
publisher
American Diabetes Association
external identifiers
  • Scopus:84975796009
  • WOS:000378463000022
ISSN
0012-1797
DOI
10.2337/db15-1489
language
English
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yes
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b939e4a2-45bd-43b7-a66d-d70c8530aa12
date added to LUP
2016-07-18 15:44:28
date last changed
2017-02-26 04:40:03
@article{b939e4a2-45bd-43b7-a66d-d70c8530aa12,
  abstract     = {<p>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 Ca<sup>2+</sup> 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.</p>},
  author       = {Collins, Stephan C. and Do, Hyun Woong and Hastoy, Benoit and Hugill, Alison and Adam, Julie and Chibalina, Margarita V. and Galvanovskis, Juris and Godazgar, Mahdieh and Lee, Sheena and Goldsworthy, Michelle and Salehi, S Albert and Tarasov, Andrei I. and Rosengren, Anders H. and Cox, Roger and Rorsman, Patrik},
  issn         = {0012-1797},
  language     = {eng},
  month        = {07},
  number       = {7},
  pages        = {1952--1961},
  publisher    = {American Diabetes Association},
  series       = {Diabetes},
  title        = {Increased expression of the diabetes gene SOX4 reduces insulin secretion by impaired fusion pore expansion},
  url          = {http://dx.doi.org/10.2337/db15-1489},
  volume       = {65},
  year         = {2016},
}