title: Increased Expression of the Diabetes Gene SOX4 Reduces Insulin Secretion by Impaired Fusion Pore Expansion.
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.
authors.affiliation: Oxford Centre for Diabetes, Endocrinology & Metabolism, Radcliffe Department of Medicine, Oxford, U.K. Université de Bourgogne Franche-Comté, Burgundy, France collinss@igbmc.fr.
authors.forename: Stephan C
authors.initials: SC
authors.lastname: Collins
authors.affiliation: Oxford Centre for Diabetes, Endocrinology & Metabolism, Radcliffe Department of Medicine, Oxford, U.K.
authors.forename: Hyun Woong
authors.initials: HW
authors.lastname: Do
authors.affiliation: Oxford Centre for Diabetes, Endocrinology & Metabolism, Radcliffe Department of Medicine, Oxford, U.K.
authors.forename: Benoit
authors.initials: B
authors.lastname: Hastoy
authors.affiliation: Mammalian Genetics Unit, MRC Harwell, Oxfordshire, U.K.
authors.forename: Alison
authors.initials: A
authors.lastname: Hugill
authors.affiliation: Oxford Centre for Diabetes, Endocrinology & Metabolism, Radcliffe Department of Medicine, Oxford, U.K.
authors.forename: Julie
authors.initials: J
authors.lastname: Adam
authors.affiliation: Oxford Centre for Diabetes, Endocrinology & Metabolism, Radcliffe Department of Medicine, Oxford, U.K.
authors.forename: Margarita V
authors.initials: MV
authors.lastname: Chibalina
authors.affiliation: Oxford Centre for Diabetes, Endocrinology & Metabolism, Radcliffe Department of Medicine, Oxford, U.K. Henry Wellcome Centre for Gene Function, Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, U.K.
authors.forename: Juris
authors.initials: J
authors.lastname: Galvanovskis
authors.affiliation: Oxford Centre for Diabetes, Endocrinology & Metabolism, Radcliffe Department of Medicine, Oxford, U.K.
authors.forename: Mahdieh
authors.initials: M
authors.lastname: Godazgar
authors.affiliation: Henry Wellcome Centre for Gene Function, Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, U.K.
authors.forename: Sheena
authors.initials: S
authors.lastname: Lee
authors.affiliation: Mammalian Genetics Unit, MRC Harwell, Oxfordshire, U.K.
authors.forename: Michelle
authors.initials: M
authors.lastname: Goldsworthy
authors.affiliation: Lund University Diabetes Centre, Department of Clinical Sciences, Skåne University Hospital Malmö, Lund University, Malmö, Sweden Department of Neuroscience and Physiology, University of Göteborg, Göteborg, Sweden.
authors.forename: Albert
authors.initials: A
authors.lastname: Salehi
authors.affiliation: Oxford Centre for Diabetes, Endocrinology & Metabolism, Radcliffe Department of Medicine, Oxford, U.K. Oxford National Institute of Health Research, Biomedical Research Centre, Churchill Hospital, Oxford, U.K.
authors.forename: Andrei I
authors.initials: AI
authors.lastname: Tarasov
authors.affiliation: Lund University Diabetes Centre, Department of Clinical Sciences, Skåne University Hospital Malmö, Lund University, Malmö, Sweden.
authors.forename: Anders H
authors.initials: AH
authors.lastname: Rosengren
authors.affiliation: Mammalian Genetics Unit, MRC Harwell, Oxfordshire, U.K.
authors.forename: Roger
authors.initials: R
authors.lastname: Cox
authors.affiliation: Oxford Centre for Diabetes, Endocrinology & Metabolism, Radcliffe Department of Medicine, Oxford, U.K. Department of Neuroscience and Physiology, University of Göteborg, Göteborg, Sweden Oxford National Institute of Health Research, Biomedical Research Centre, Churchill Hospital, Oxford, U.K.
authors.forename: Patrik
authors.initials: P
authors.lastname: Rorsman
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D005089:Exocytosis / Q000502:physiology*; D020868:Gene Silencing; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism*; D008297:Male; D051379:Mice; D055751:SOXC Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D002352:Carrier Proteins; D007328:Insulin; D055751:SOXC Transcription Factors; C489990:Sox4 protein, mouse; D002118:Calcium