Thrombin stimulates insulin secretion via protease-activated receptor-3

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• dc.contributor.author Hänzelmann, Sonja, 1981-ca
• dc.contributor.author Wang, Jinlingca
• dc.contributor.author Güney, Emre, 1983-ca
• dc.contributor.author Tang, Yunzhaoca
• dc.contributor.author Zhang, Enmingca
• dc.contributor.author Axelsson, Annika S.ca
• dc.contributor.author Nenonen, Hannahca
• dc.contributor.author Salehi, Albert S.ca
• dc.contributor.author Wollheim, Claes B.ca
• dc.contributor.author Zetterberg, Evaca
• dc.contributor.author Berntorp, Erikca
• dc.contributor.author Costa, Ivan G.ca
• dc.contributor.author Castelo Valdueza, Robertca
• dc.contributor.author Rosengren, Anders H.ca
• dc.date.accessioned 2017-03-31T10:44:49Z
• dc.date.available 2017-03-31T10:44:49Z
• dc.date.issued 2015
• dc.description.abstract The disease mechanisms underlying type 2 diabetes (T2D) remain poorly defined. Here we aimed to explore the pathophysiology of T2D by analyzing gene co-expression networks in human islets. Using partial correlation networks we identified a group of co-expressed genes (‘module’) including F2RL2 that was associated with glycated hemoglobin. F2Rl2 is a G-protein-coupled receptor (GPCR) that encodes protease-activated receptor-3 (PAR3). PAR3 is cleaved by thrombin, which exposes a 6-amino acid sequence that acts as a ‘tethered ligand’ to regulate cellular signaling. We have characterized the effect of PAR3 activation on insulin secretion by static insulin secretion measurements, capacitance measurements, studies of diabetic animal models and patient samples. We demonstrate that thrombin stimulates insulin secretion, an effect that was prevented by an antibody that blocks the thrombin cleavage site of PAR3. Treatment with a peptide corresponding to the PAR3 tethered ligand stimulated islet insulin secretion and single β-cell exocytosis by a mechanism that involves activation of phospholipase C and Ca2+ release from intracellular stores. Moreover, we observed that the expression of tissue factor, which regulates thrombin generation, was increased in human islets from T2D donors and associated with enhanced β-cell exocytosis. Finally, we demonstrate that thrombin generation potential in patients with T2D was associated with increased fasting insulin and insulinogenic index. The findings provide a previously unrecognized link between hypercoagulability and hyperinsulinemia and suggest that reducing thrombin activity or blocking PAR3 cleavage could potentially counteract the exaggerated insulin secretion that drives insulin resistance and β-cell exhaustion in T2D.
• dc.description.sponsorship Supported by the NovoNordisk foundation, the Hjelt foundation and the Swedish Research Council. S.H. and R.C. acknowledge support from a Spanish MINECO grant (ref. TIN2011-22826) and S.H. and I.C. acknowledge support from the Interdisciplinary Center for Clinical Research within the faculty of Medicine at the RWTH Aachen University.
• dc.format.mimetype application/pdfca
• dc.identifier.citation Hänzelmann S, Wang J, Güney E, Tang Y, Zhang E, Axelsson AS et al. Thrombin stimulates insulin secretion via protease-activated receptor-3. Islets. 2015;7(4):e1118195. DOI: 10.1080/19382014.2015.1118195
• dc.identifier.doi http://dx.doi.org/10.1080/19382014.2015.1118195
• dc.identifier.issn 1938-2014
• dc.identifier.uri http://hdl.handle.net/10230/28355
• dc.language.iso eng
• dc.publisher Taylor & Francis (Routledge)ca
• dc.relation.ispartof Islets. 2015;7(4):e1118195
• dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/TIN2011-22826
• dc.rights © Taylor & Francis. Sonja Hänzelmann, Jinling Wang, Emre Güney, Yunzhao Tang, Enming Zhang, Annika S Axelsson, Hannah Nenonen, Albert S Salehi, Claes B Wollheim, Eva Zetterberg, Erik Berntorp, Ivan G Costa, Robert Castelo, and Anders H Rosengren. This is an Open Access article distributed under the terms of the Creative Commons Attribution-Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The moral rights of the named author(s) have been asserted.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by-nc/3.0/
• dc.subject.keyword Islets
• dc.subject.keyword Insulin secretion in vitro
• dc.subject.keyword Insulin secretion in vivo
• dc.subject.keyword Pathogenic mechanisms
• dc.title Thrombin stimulates insulin secretion via protease-activated receptor-3ca
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion