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- Title
Increased Expression of the Diabetes Gene SOX4 Reduces Insulin Secretion by Impaired Fusion Pore Expansion.
- Authors
Collins, Stephan C.; Hyun Woong Do; Hastoy, Benoit; Hugill, Alison; Adam, Julie; Chibalina, Margarita V.; Galvanovskis, Juris; Godazgar, Mahdieh; Sheena Lee; Goldsworthy, Michelle; Salehi, Albert; Tarasov, Andrei I.; Rosengren, Anders H.; Cox, Roger; Rorsman, Patrik; Do, Hyun Woong; Lee, Sheena
- 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 Ca(2+) 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 kiss-and-run exocytosis at the expense of full fusion. We propose that pharmacological interventions promoting fusion pore expansion may be effective in diabetes therapy.
- Subjects
GENE expression; SINGLE nucleotide polymorphisms; DIABETES risk factors; EXOCYTOSIS; DNA microarrays; CALCIUM metabolism; PROTEIN metabolism; ANIMAL experimentation; BIOCHEMISTRY; CARRIER proteins; CELL lines; CELL physiology; GENES; INSULIN; ISLANDS of Langerhans; PHENOMENOLOGY; MICE; TYPE 2 diabetes; PROTEINS; RESEARCH funding
- Publication
Diabetes, 2016, Vol 65, Issue 7, p1952
- ISSN
0012-1797
- Publication type
journal article
- DOI
10.2337/db15-1489