Exendin-4 protects hypoxic islets from oxidative stress and improves islet transplantation outcome

M. Padmasekar, N. Lingwal, Balaji Samikannu, C. Chen, H. Sauer, T. Linn

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Oxidative stress produced during pancreatic islet isolation leads to significant β-cell damage. Homeostatic cytokines secreted subsequently to islet transplantation damage β-cells by generating oxygen free radicals. In this study, exendin-4, a glucagon-like peptide-1 analog improved islet transplantation outcome by increasing the survival of diabetic recipient mice from 58% to 100%. We hypothesized that this beneficial effect was due to the ability of exendin-4 to reduce oxidative stress. Further experiments showed that it significantly reduced the apoptotic rate of cultured β-cells subjected to hypoxia or to IL-1β. Reduction of apoptotic events was confirmed in pancreatic islet grafts of exendin-4-treated mice. Exendin-4 enhanced Akt phosphorylation of β-cells and insulin released from them. It even augmented insulin secretion from islets cultivated at hypoxic conditions. Exposure to hypoxia led to a decrease in the activation of Akt, which was reversed when β-cells were pretreated with exendin-4. Moreover, exendin-4 increased the activity of redox enzymes in a hypoxia-treated β-cell line and reduced reactive oxygen species production in isolated pancreatic islets. Recovery from diabetes in mice transplanted with hypoxic islets was more efficient when they received exendin-4. In conclusion, exendin-4 rescued islets from oxidative stress caused by hypoxia or due to cytokine exposure. It improved the outcome of syngenic and xenogenic islet transplantation.

Original languageEnglish
Pages (from-to)1424-1433
Number of pages10
JournalEndocrinology
Volume154
Issue number4
DOIs
Publication statusPublished - 1 Apr 2013
Externally publishedYes

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Islets of Langerhans Transplantation
Oxidative Stress
Islets of Langerhans
Reactive Oxygen Species
Insulin
Cytokines
Glucagon-Like Peptide 1
exenatide
Interleukin-1
Oxidation-Reduction
Free Radicals
Cultured Cells
Phosphorylation
Transplants
Cell Line
Hypoxia
Enzymes

ASJC Scopus subject areas

  • Endocrinology

Cite this

Exendin-4 protects hypoxic islets from oxidative stress and improves islet transplantation outcome. / Padmasekar, M.; Lingwal, N.; Samikannu, Balaji; Chen, C.; Sauer, H.; Linn, T.

In: Endocrinology, Vol. 154, No. 4, 01.04.2013, p. 1424-1433.

Research output: Contribution to journalArticle

Padmasekar, M. ; Lingwal, N. ; Samikannu, Balaji ; Chen, C. ; Sauer, H. ; Linn, T. / Exendin-4 protects hypoxic islets from oxidative stress and improves islet transplantation outcome. In: Endocrinology. 2013 ; Vol. 154, No. 4. pp. 1424-1433.
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