dc.contributor.author |
Sorrenson, Brie |
en |
dc.contributor.author |
Cognard, E |
en |
dc.contributor.author |
Lee, Kathryn |
en |
dc.contributor.author |
Dissanayake, Waruni |
en |
dc.contributor.author |
Fu, Y |
en |
dc.contributor.author |
Han, W |
en |
dc.contributor.author |
Hughes, WE |
en |
dc.contributor.author |
Shepherd, Peter |
en |
dc.date.accessioned |
2017-01-26T02:25:25Z |
en |
dc.date.issued |
2016-12-09 |
en |
dc.identifier.citation |
Journal of Biological Chemistry, 9 December 2016, 291 (50), 25888 - 25900 |
en |
dc.identifier.issn |
0021-9258 |
en |
dc.identifier.uri |
http://hdl.handle.net/2292/31684 |
en |
dc.description.abstract |
The processes regulating glucose-stimulated insulin secretion (GSIS) and its modulation by incretins in pancreatic β-cells are only partly understood. Here we investigate the involvement of β-catenin in these processes. Reducing β-catenin levels using siRNA knockdown attenuated GSIS in a range of β-cell models and blocked the ability of GLP-1 agonists and the depolarizing agent KCl to potentiate this. This could be mimicked in both β-cell models and isolated islets by short-term exposure to the β-catenin inhibitory drug pyrvinium. In addition, short-term treatment with a drug that increases β-catenin levels results in an increase in insulin secretion. The timing of these effects suggests that β-catenin is required for the processes regulating trafficking and/or release of pre-existing insulin granules rather than for those regulated by gene expression. This was supported by the finding that the overexpression of the transcriptional co-activator of β-catenin, transcription factor 7-like 2 (TCF7L2), attenuated insulin secretion, consistent with the extra TCF7L2 translocating β-catenin from the plasma membrane pool to the nucleus. We show that β-catenin depletion disrupts the intracellular actin cytoskeleton, and by using total internal reflectance fluorescence (TIRF) microscopy, we found that β-catenin is required for the glucose- and incretin-induced depletion of insulin vesicles from near the plasma membrane. In conclusion, we find that β-catenin levels modulate Ca2+-dependent insulin exocytosis under conditions of glucose, GLP-1, or KCl stimulation through a role in modulating insulin secretory vesicle localization and/or fusion via actin remodeling. These findings also provide insights as to how the overexpression of TCF7L2 may attenuate insulin secretion. |
en |
dc.description.uri |
https://www.ncbi.nlm.nih.gov/pubmed/27777306 |
en |
dc.language |
English |
en |
dc.publisher |
American Society for Biochemistry and Molecular Biology |
en |
dc.relation.ispartofseries |
Journal of Biological Chemistry |
en |
dc.rights |
Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. Details obtained from http://www.sherpa.ac.uk/romeo/issn/0021-9258/
http://www.jbc.org/site/misc/Copyright_Permission.xhtml |
en |
dc.rights.uri |
https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm |
en |
dc.title |
A Critical Role for β-catenin in Modulating Levels of Insulin Secretion from β-cells by Regulating Actin Cytoskeleton and Insulin Vesicle Localization |
en |
dc.type |
Journal Article |
en |
dc.identifier.doi |
10.1074/jbc.M116.758516 |
en |
pubs.issue |
50 |
en |
pubs.begin-page |
25888 |
en |
pubs.volume |
291 |
en |
dc.description.version |
AM - Accepted Manuscript |
en |
dc.identifier.pmid |
27777306 |
en |
pubs.author-url |
http://www.jbc.org/content/291/50/25888 |
en |
pubs.end-page |
25900 |
en |
pubs.publication-status |
Published |
en |
dc.rights.accessrights |
http://purl.org/eprint/accessRights/OpenAccess |
en |
pubs.subtype |
Article |
en |
pubs.elements-id |
544158 |
en |
pubs.org-id |
Medical and Health Sciences |
en |
pubs.org-id |
Medical Sciences |
en |
pubs.org-id |
Molecular Medicine |
en |
pubs.org-id |
Science |
en |
pubs.org-id |
Science Research |
en |
pubs.org-id |
Maurice Wilkins Centre (2010-2014) |
en |
dc.identifier.eissn |
1083-351X |
en |
pubs.record-created-at-source-date |
2017-01-26 |
en |
pubs.online-publication-date |
2016-10-24 |
en |
pubs.dimensions-id |
27777306 |
en |