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Diabetologia
Published in: Diabetologia 2/2015

01-02-2015 | Article

daf-16/FOXO and glod-4/glyoxalase-1 are required for the life-prolonging effect of human insulin under high glucose conditions in Caenorhabditis elegans

Authors: Michael Mendler, Andreas Schlotterer, Youssef Ibrahim, Georgi Kukudov, Thomas Fleming, Angelika Bierhaus, Christin Riedinger, Vedat Schwenger, Stephan Herzig, Markus Hecker, Jens Tyedmers, Peter P. Nawroth, Michael Morcos

Published in: Diabetologia | Issue 2/2015

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Abstract

Aims/hypothesis

The aim of this study was to determine the protective effects of human insulin and its analogues, B28Asp human insulin (insulin aspart) and B29Lys(ε-tetradecanoyl),desB30 human insulin (insulin detemir), against glucose-induced lifespan reduction and neuronal damage in the model organism Caenorhabditis elegans and to elucidate the underlying mechanisms.

Methods

Nematodes were cultivated under high glucose (HG) conditions comparable with the situation in diabetic patients and treated with human insulin and its analogues. Lifespan was assessed and neuronal damage was evaluated with regard to structural and functional impairment. Additionally, the activity of glyoxalase-1 and superoxide dismutase (SOD) and the formation of reactive oxygen species (ROS) and AGEs were determined.

Results

Insulin and its analogues reversed the life-shortening effect of HG conditions and prevented the glucose-induced neuronal impairment. Insulin treatment under HG conditions was associated with reduced concentration of glucose, as well as a reduced formation of ROS and AGEs, and increased SOD activity. These effects were dependent on the Forkhead box O (FOXO) homologue abnormal dauer formation (DAF)-16. Furthermore, glyoxalase-1 activity, which was impaired under HG conditions, was restored by human insulin. This was essential for the insulin-induced lifespan extension under HG conditions, as no change in lifespan was observed following either suppression or overexpression of glyoxalase-1.

Conclusions/interpretation

Human insulin and its analogues prevent the reduction in lifespan and neuronal damage caused by HG conditions. The effect of human insulin is mediated by a daf-2/insulin receptor and daf-16/FOXO-dependent pathway and is mediated by upregulation of detoxifying mechanisms.
Appendix
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Metadata
Title
daf-16/FOXO and glod-4/glyoxalase-1 are required for the life-prolonging effect of human insulin under high glucose conditions in Caenorhabditis elegans
Authors
Michael Mendler
Andreas Schlotterer
Youssef Ibrahim
Georgi Kukudov
Thomas Fleming
Angelika Bierhaus
Christin Riedinger
Vedat Schwenger
Stephan Herzig
Markus Hecker
Jens Tyedmers
Peter P. Nawroth
Michael Morcos
Publication date
01-02-2015
Publisher
Springer Berlin Heidelberg
Published in
Diabetologia / Issue 2/2015
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-014-3415-5

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