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Thrombin stimulates insulin secretion via protease-activated receptor-3.

Hänzelmann, Sonja LU ; Wang, Jinling LU ; Güney, Emre; Tang, Yunzhao LU ; Zhang, Enming LU ; Axelsson, Annika LU ; Nenonen, Hannah LU ; Salehi, S Albert LU ; Wollheim, Claes LU and Zetterberg, Eva LU , et al. (2015) In Islets 7(4). p.1118195-1118195
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... (More)
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 Ca(2+) 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. (Less)
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organization
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type
Contribution to journal
publication status
published
subject
in
Islets
volume
7
issue
4
pages
1118195 - 1118195
publisher
Landes Bioscience
external identifiers
  • pmid:26742564
  • wos:000368712100002
  • scopus:84964043425
ISSN
1938-2022
DOI
10.1080/19382014.2015.1118195
language
English
LU publication?
yes
id
c46ae0f8-76c2-4249-a046-91cb2db70b2b (old id 8592792)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/26742564?dopt=Abstract
date added to LUP
2016-02-10 11:03:32
date last changed
2017-03-28 08:56:56
@article{c46ae0f8-76c2-4249-a046-91cb2db70b2b,
  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 Ca(2+) 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.},
  author       = {Hänzelmann, Sonja and Wang, Jinling and Güney, Emre and Tang, Yunzhao and Zhang, Enming and Axelsson, Annika and Nenonen, Hannah and Salehi, S Albert and Wollheim, Claes and Zetterberg, Eva and Berntorp, Erik and Costa, Ivan G and Castelo, Robert and Rosengren, Anders},
  issn         = {1938-2022},
  language     = {eng},
  number       = {4},
  pages        = {1118195--1118195},
  publisher    = {Landes Bioscience},
  series       = {Islets},
  title        = {Thrombin stimulates insulin secretion via protease-activated receptor-3.},
  url          = {http://dx.doi.org/10.1080/19382014.2015.1118195},
  volume       = {7},
  year         = {2015},
}