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Paracrine regulation and improvement of β-cell function by thioredoxin
- The failure of insulin-producingβ-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 haveanalyzed the cytosolic, mitochondrial, and extracellular Trx system proteins in hypoxic and cytokine-induced stress usingβ-cell culture, isolated pancreatic islets, andpancreatic 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 reox-ygenation. Interestingly, Trx1 was secreted byβ-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 onβ-cells were examined. In fact, exogenously added recombinant hTrx1 mitigatedapoptosis and preserved glucose sensitivity in pancreatic islets subjected to hypoxia and inflammatory stimuli, dependent on its redox activity. Human subjects werestudied, 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 pancreaticβ-cells.
Author: | Eva-Maria Hanschmann, Sebastian Friedrich Petry, Susanne Eitner, Constanze Christin Maresch, Neelam Lingwal, Christopher Horst LilligORCiD, Thomas Linn |
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URN: | urn:nbn:de:gbv:9-opus-43895 |
DOI: | https://doi.org/https://doi.org/10.1016/j.redox.2020.101570 |
ISSN: | 2213-2317 |
Parent Title (German): | Redox Biology |
Publisher: | Elsevier |
Place of publication: | London |
Document Type: | Article |
Language: | English |
Date of first Publication: | 2020/05/16 |
Release Date: | 2021/03/10 |
Volume: | 34 |
Page Number: | 11 |
Faculties: | Universitätsmedizin / Institut für Med. Biochemie u. Molekularbiologie |
Collections: | Artikel aus DFG-gefördertem Publikationsfonds |
Licence (German): | Creative Commons - Namensnennung-Nicht kommerziell-Keine Bearbeitung |