Paracrine regulation and improvement of β-cell function by thioredoxin.

Eva-Maria Hanschmann, Sebastian Friedrich Petry, Susanne Eitner, Constanze Christin Maresch, Neelam Lingwal, Christopher Horst Lillig, Thomas Linn

Redox biology 2020 Jul

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The failure of insulin-producing β-cells is the underlying cause of hyperglycemia in diabetes mellitus. β-cell decay has been linked to hypoxia, chronic inflammation, and oxidative stress. Thioredoxin (Trx) proteins are major actors in redox signaling and essential for signal transduction and the cellular stress response. We have analyzed the cytosolic, mitochondrial, and extracellular Trx system proteins in hypoxic and cytokine-induced stress using β-cell culture, isolated pancreatic islets, and pancreatic islet transplantation modelling low oxygen supply. Protein levels of cytosolic Trx1 and Trx reductase (TrxR) 1 significantly decreased, while mitochondrial Trx2 and TrxR2 increased upon hypoxia and reoxygenation. Interestingly, Trx1 was secreted by β-cells during hypoxia. Moreover, murine and human pancreatic islet grafts released Trx1 upon glucose stimulation. Survival of transplanted islets was substantially impaired by the TrxR inhibitor auranofin. Since a release was prominent upon hypoxia, putative paracrine effects of Trx1 on β-cells were examined. In fact, exogenously added recombinant hTrx1 mitigated apoptosis and preserved glucose sensitivity in pancreatic islets subjected to hypoxia and inflammatory stimuli, dependent on its redox activity. Human subjects were studied, demonstrating a transient increase in extracellular Trx1 in serum after glucose challenge. This increase correlated with better pancreatic islet function. Moreover, hTrx1 inhibited the migration of primary murine macrophages. In conclusion, our study offers evidence for paracrine functions of extracellular Trx1 that improve the survival and function of pancreatic β-cells. Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.

Citation

Eva-Maria Hanschmann, Sebastian Friedrich Petry, Susanne Eitner, Constanze Christin Maresch, Neelam Lingwal, Christopher Horst Lillig, Thomas Linn. Paracrine regulation and improvement of β-cell function by thioredoxin. Redox biology. 2020 Jul;34:101570