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Thrombin stimulates...
Thrombin stimulates insulin secretion via protease-activated receptor-3.
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- Hänzelmann, Sonja (författare)
- Lund University,Lunds universitet,Diabetes - öpatofysiologi,Forskargrupper vid Lunds universitet,Diabetes - Islet Patophysiology,Lund University Research Groups,Hospital del Mar Medical Research Institute
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- Wang, Jinling (författare)
- Lund University,Lunds universitet,Diabetes - öpatofysiologi,Forskargrupper vid Lunds universitet,Diabetes - Islet Patophysiology,Lund University Research Groups
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- Güney, Emre (författare)
- Pompeu Fabra University
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- Tang, Yunzhao (författare)
- Lund University,Lunds universitet,Diabetes - öpatofysiologi,Forskargrupper vid Lunds universitet,Diabetes - Islet Patophysiology,Lund University Research Groups
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- Zhang, Enming (författare)
- Lund University,Lunds universitet,Diabetes - öpatofysiologi,Forskargrupper vid Lunds universitet,Diabetes - Islet Patophysiology,Lund University Research Groups
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- Axelsson, Annika (författare)
- Lund University,Lunds universitet,Diabetes - öpatofysiologi,Forskargrupper vid Lunds universitet,Diabetes - Islet Patophysiology,Lund University Research Groups
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- Nenonen, Hannah (författare)
- Lund University,Lunds universitet,-lup-obsolete,Forskargrupper vid Lunds universitet,LUDC (Lund University Diabetes Centre)-lup-obsolete,Lund University Research Groups
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- Salehi, S Albert (författare)
- Lund University,Lunds universitet,Islet cell physiology,Forskargrupper vid Lunds universitet,Lund University Research Groups
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- Wollheim, Claes (författare)
- Lund University,Lunds universitet,Genomik, diabetes och endokrinologi,Forskargrupper vid Lunds universitet,Genomics, Diabetes and Endocrinology,Lund University Research Groups
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- Zetterberg, Eva (författare)
- Lund University,Lunds universitet,Klinisk koagulationsmedicin, Malmö,Forskargrupper vid Lunds universitet,Clinical Coagulation, Malmö,Lund University Research Groups
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- Berntorp, Erik (författare)
- Lund University,Lunds universitet,Klinisk koagulationsmedicin, Malmö,Forskargrupper vid Lunds universitet,Clinical Coagulation, Malmö,Lund University Research Groups
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- Costa, Ivan G (författare)
- Helmholtz-Institute for Biomedical Engineering,RWTH Aachen University
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- Castelo, Robert (författare)
- Pompeu Fabra University,Hospital del Mar Medical Research Institute
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- Rosengren, Anders (författare)
- Lund University,Lunds universitet,Diabetes - öpatofysiologi,Forskargrupper vid Lunds universitet,Diabetes - Islet Patophysiology,Lund University Research Groups
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(creator_code:org_t)
- 2016-01-19
- 2015
- Engelska.
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Ingår i: Islets. - : Informa UK Limited. - 1938-2022 .- 1938-2014. ; 7:4, s. 1118195-1118195
- Relaterad länk:
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http://www.ncbi.nlm....
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http://dx.doi.org/10... (free)
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https://www.tandfonl...
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https://lup.lub.lu.s...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Fysiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Physiology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
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Hänzelmann, Sonj ...
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Wang, Jinling
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Güney, Emre
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Tang, Yunzhao
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Zhang, Enming
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Axelsson, Annika
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Nenonen, Hannah
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Salehi, S Albert
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Wollheim, Claes
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Zetterberg, Eva
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Berntorp, Erik
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Costa, Ivan G
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Castelo, Robert
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Rosengren, Ander ...
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