dc.contributor.author | Ma, ZH | |
dc.contributor.author | Moruzzi, N | |
dc.contributor.author | Catrina, SB | |
dc.contributor.author | Hals, Ingrid Katrin | |
dc.contributor.author | Oberholzer, J. | |
dc.contributor.author | Grill, Valdemar | |
dc.contributor.author | Björklund, A. | |
dc.date.accessioned | 2015-11-20T10:19:49Z | |
dc.date.accessioned | 2016-05-18T14:00:18Z | |
dc.date.available | 2015-11-20T10:19:49Z | |
dc.date.available | 2016-05-18T14:00:18Z | |
dc.date.issued | 2013 | |
dc.identifier.citation | PLoS ONE 2013, 8(7) | nb_NO |
dc.identifier.issn | 1932-6203 | |
dc.identifier.uri | http://hdl.handle.net/11250/2389643 | |
dc.description.abstract | Objective: Beta cells of pancreatic islets are susceptible to functional deficits and damage by hypoxia. Here we aimed to characterize such effects and to test for and pharmacological means to alleviate a negative impact of hypoxia.
Methods and Design: Rat and human pancreatic islets were subjected to 5.5 h of hypoxia after which functional and viability parameters were measured subsequent to the hypoxic period and/or following a 22 h re-oxygenation period. Preconditioning with diazoxide or other agents was usually done during a 22 h period prior to hypoxia.
Results: Insulin contents decreased by 23% after 5.5 h of hypoxia and by 61% after a re-oxygenation period. Preconditioning with diazoxide time-dependently alleviated these hypoxia effects in rat and human islets. Hypoxia reduced proinsulin biosynthesis (3H-leucine incorporation into proinsulin) by 35%. Preconditioning counteracted this decrease by 91%. Preconditioning reduced hypoxia-induced necrosis by 40%, attenuated lowering of proteins of mitochondrial complexes I–IV and enhanced stimulation of HIF-1-alpha and phosphorylated AMPK proteins. Preconditioning by diazoxide was abolished by co-exposure to tolbutamide or elevated potassium (i.e. conditions which increase Ca2+ inflow). Preconditioning with nifedipine, a calcium channel blocker, partly reproduced effects of diazoxide. Both diazoxide and nifedipine moderately reduced basal glucose oxidation whereas glucose-induced oxygen consumption (tested with diazoxide) was unaffected. Preconditioning with diaxoxide enhanced insulin contents in transplants of rat islets to non-diabetic rats and lowered hyperglycemia vs. non-preconditioned islets in streptozotocin-diabetic rats. Preconditioning of human islet transplants lowered hyperglycemia in streptozotocin-diabetic nude mice.
Conclusions: 1) Prior blocking of Ca2+ inflow associates with lesser hypoxia-induced damage, 2) preconditioning affects basal mitochondrial metabolism and accelerates activation of hypoxia-reactive and potentially protective factors, 3) results indicate that preconditioning by K+-ATP-channel openers has therapeutic potential for islet transplantations. | nb_NO |
dc.language.iso | eng | nb_NO |
dc.publisher | Public Library of Science | nb_NO |
dc.rights | Navngivelse 3.0 Norge | * |
dc.rights.uri | http://creativecommons.org/licenses/by/3.0/no/ | * |
dc.title | Preconditioning with Associated Blocking of Ca2+ Inflow Alleviates Hypoxia-Induced Damage to Pancreatic β-Cells | nb_NO |
dc.type | Journal article | nb_NO |
dc.type | Peer reviewed | nb_NO |
dc.date.updated | 2015-11-20T10:19:49Z | |
dc.source.volume | 8 | nb_NO |
dc.source.journal | PLoS ONE | nb_NO |
dc.source.issue | 7 | nb_NO |
dc.identifier.doi | 10.1371/journal.pone.0067498 | |
dc.identifier.cristin | 1058654 | |
dc.description.localcode | © 2013 Ma et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. | nb_NO |