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Glial cell-line derived neurotrophic factor protects human islets from nutrient deprivation and endoplasmic reticulum stress induced apoptosis
Oslo Univ Hosp, Sect Transplant Surg, Oslo, Norway.;Oslo Univ Hosp, Inst Surg Res, Oslo, Norway.;Univ Oslo, Inst Clin Med, Oslo, Norway..
AstraZeneca R&D Gothenburg, Dept CVMD Biosci, Gothenburg, Sweden..
Oslo Univ Hosp, Sect Transplant Surg, Oslo, Norway.;Oslo Univ Hosp, Inst Surg Res, Oslo, Norway.;Univ Oslo, Inst Clin Med, Oslo, Norway..
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.ORCID iD: 0000-0002-8524-9547
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2017 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 1575Article in journal (Refereed) Published
Abstract [en]

One of the key limitations to successful human islet transplantation is loss of islets due to stress responses pre- and post-transplantation. Nutrient deprivation and ER stress have been identified as important mechanisms leading to apoptosis. Glial Cell-line Derived Neurotrophic Factor (GDNF) has recently been found to promote islet survival after isolation. However, whether GDNF could rescue human islets from nutrient deprivation and ER stress-mediated apoptosis is unknown. Herein, by mimicking those conditions in vitro, we have shown that GDNF significantly improved glucose stimulated insulin secretion, reduced apoptosis and proinsulin: insulin ratio in nutrient deprived human islets. Furthermore, GDNF alleviated thapsigargin-induced ER stress evidenced by reduced expressions of IRE1 alpha and BiP and consequently apoptosis. Importantly, this was associated with an increase in phosphorylation of PI3K/AKT and GSK3B signaling pathway. Transplantation of ER stressed human islets pre- treated with GDNF under kidney capsule of diabetic mice resulted in reduced expressions of IRE1 alpha and BiP in human islet grafts with improved grafts function shown by higher levels of human C-peptide post-transplantation. We suggest that GDNF has protective and anti-apoptotic effects on nutrient deprived and ER stress activated human islets and could play a significant role in rescuing human islets from stress responses.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP , 2017. Vol. 7, article id 1575
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Medical and Health Sciences
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URN: urn:nbn:se:uu:diva-325337DOI: 10.1038/s41598-017-01805-1ISI: 000400874500015PubMedID: 28484241OAI: oai:DiVA.org:uu-325337DiVA, id: diva2:1119395
Available from: 2017-07-04 Created: 2017-07-04 Last updated: 2017-07-04Bibliographically approved

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