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

Journal article

The transcription factor Sox4 has been proposed to underlie the increased type-2 diabetes risk linked to an intronic SNP 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+) signalling and depolarization-evoked exocytosis. This paradox is explained by a 4-fold 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 only expands to a diameter of 2 nm that 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 GIIS 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 was reversed by silencing of STXBP6. These data suggest that increased SOX4 expression inhibits insulin secretion and increased diabetes risk by 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.

Authors: Collins, S; Do, H; Hastoy, B; Hugill, A; Adam, J

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: American Diabetes Association
• Journal: Diabetes
• Volume: 65
• Issue: 7
• Pages: 1952-1961
• Publication date: 2016-07-01
• Acceptance date: 2016-03-08
• DOI: 10.2337/db15-1489
• EISSN: 1939-327X
• ISSN: 0012-1797
• Language: English
• Keywords: SBTMR