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Anders Rosengren

Postdoctoral research fellow

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

Author

  • Sonja Hänzelmann
  • Jinling Wang
  • Emre Güney
  • Yunzhao Tang
  • Enming Zhang
  • Annika Axelsson
  • Hannah Nenonen
  • S Albert Salehi
  • Claes Wollheim
  • Eva Zetterberg
  • Erik Berntorp
  • Ivan G Costa
  • Robert Castelo
  • Anders Rosengren

Summary, in English

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.

Department/s

  • Diabetes - Islet Patophysiology
  • Islet cell physiology
  • Genomics, Diabetes and Endocrinology
  • Clinical Coagulation, Malmö
  • EXODIAB: Excellence of Diabetes Research in Sweden

Publishing year

2015

Language

English

Pages

1118195-1118195

Publication/Series

Islets

Volume

7

Issue

4

Document type

Journal article

Publisher

Landes Bioscience

Topic

  • Physiology
  • Cell and Molecular Biology

Status

Published

Research group

  • Diabetes - Islet Patophysiology
  • LUDC (Lund University Diabetes Centre)
  • Islet cell physiology
  • Genomics, Diabetes and Endocrinology
  • Clinical Coagulation, Malmö

ISBN/ISSN/Other

  • ISSN: 1938-2022