Thrombin stimulates insulin secretion via protease-activated receptor-3

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...

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Authors: Hänzelmann, Sonja, 1981-, Wang, Jinling, Güney, Emre, 1983-, Tang, Yunzhao, Zhang, Enming, Axelsson, Annika S., Nenonen, Hannah, Salehi, Albert S., Wollheim, Claes B., Zetterberg, Eva, Berntorp, Erik, Costa, Ivan G., Castelo Valdueza, Robert, Rosengren, Anders H.
Format: article
Status:Published version
Publication Date:2015
Country:España
Institution:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repository:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:10230/28355
Online Access:http://hdl.handle.net/10230/28355
http://dx.doi.org/10.1080/19382014.2015.1118195
Access Level:Open access
Keyword:Islets
Insulin secretion in vitro
Insulin secretion in vivo
Pathogenic mechanisms
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spelling Thrombin stimulates insulin secretion via protease-activated receptor-3Hänzelmann, Sonja, 1981-Wang, JinlingGüney, Emre, 1983-Tang, YunzhaoZhang, EnmingAxelsson, Annika S.Nenonen, HannahSalehi, Albert S.Wollheim, Claes B.Zetterberg, EvaBerntorp, ErikCosta, Ivan G.Castelo Valdueza, RobertRosengren, Anders H.IsletsInsulin secretion in vitroInsulin secretion in vivoPathogenic mechanismsThe 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.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.Taylor & Francis (Routledge)201720172015info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/28355http://dx.doi.org/10.1080/19382014.2015.1118195reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésIslets. 2015;7(4):e1118195info:eu-repo/grantAgreement/ES/3PN/TIN2011-22826© 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.http://creativecommons.org/licenses/by-nc/3.0/info:eu-repo/semantics/openAccessoai:recercat.cat:10230/283552026-05-29T05:05:01Z
dc.title.none.fl_str_mv Thrombin stimulates insulin secretion via protease-activated receptor-3
title Thrombin stimulates insulin secretion via protease-activated receptor-3
spellingShingle Thrombin stimulates insulin secretion via protease-activated receptor-3
Hänzelmann, Sonja, 1981-
Islets
Insulin secretion in vitro
Insulin secretion in vivo
Pathogenic mechanisms
title_short Thrombin stimulates insulin secretion via protease-activated receptor-3
title_full Thrombin stimulates insulin secretion via protease-activated receptor-3
title_fullStr Thrombin stimulates insulin secretion via protease-activated receptor-3
title_full_unstemmed Thrombin stimulates insulin secretion via protease-activated receptor-3
title_sort Thrombin stimulates insulin secretion via protease-activated receptor-3
dc.creator.none.fl_str_mv Hänzelmann, Sonja, 1981-
Wang, Jinling
Güney, Emre, 1983-
Tang, Yunzhao
Zhang, Enming
Axelsson, Annika S.
Nenonen, Hannah
Salehi, Albert S.
Wollheim, Claes B.
Zetterberg, Eva
Berntorp, Erik
Costa, Ivan G.
Castelo Valdueza, Robert
Rosengren, Anders H.
author Hänzelmann, Sonja, 1981-
author_facet Hänzelmann, Sonja, 1981-
Wang, Jinling
Güney, Emre, 1983-
Tang, Yunzhao
Zhang, Enming
Axelsson, Annika S.
Nenonen, Hannah
Salehi, Albert S.
Wollheim, Claes B.
Zetterberg, Eva
Berntorp, Erik
Costa, Ivan G.
Castelo Valdueza, Robert
Rosengren, Anders H.
author_role author
author2 Wang, Jinling
Güney, Emre, 1983-
Tang, Yunzhao
Zhang, Enming
Axelsson, Annika S.
Nenonen, Hannah
Salehi, Albert S.
Wollheim, Claes B.
Zetterberg, Eva
Berntorp, Erik
Costa, Ivan G.
Castelo Valdueza, Robert
Rosengren, Anders H.
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Islets
Insulin secretion in vitro
Insulin secretion in vivo
Pathogenic mechanisms
topic Islets
Insulin secretion in vitro
Insulin secretion in vivo
Pathogenic mechanisms
description 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.
publishDate 2015
dc.date.none.fl_str_mv 2015
2017
2017
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10230/28355
http://dx.doi.org/10.1080/19382014.2015.1118195
url http://hdl.handle.net/10230/28355
http://dx.doi.org/10.1080/19382014.2015.1118195
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Islets. 2015;7(4):e1118195
info:eu-repo/grantAgreement/ES/3PN/TIN2011-22826
dc.rights.none.fl_str_mv http://creativecommons.org/licenses/by-nc/3.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by-nc/3.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Taylor & Francis (Routledge)
publisher.none.fl_str_mv Taylor & Francis (Routledge)
dc.source.none.fl_str_mv reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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