C. elegans as model for the study of high glucose-mediated life span reduction

Andreas Schlotterer, Georgi Kukudov, Farastuk Bozorgmehr, Harald Hutter, Xueliang Du, Dimitrios Oikonomou, Youssef Ibrahim, Friederike Pfisterer, Naila Rabbani, Paul Thornalley, Ahmed Sayed, Thomas Fleming, Per Humpert, Vedat Schwenger, Martin Zeier, Andreas Hamann, David Stern, Michael Brownlee, Angelika Bierhaus, Peter NawrothMichael Morcos

Research output: Contribution to journalArticle

168 Scopus citations

Abstract

OBJECTIVE - Establishing Caenorhabditis elegans as a model for glucose toxicity-mediated life span reduction. RESEARCH DESIGN AND METHODS - C. elegans were maintained to achieve glucose concentrations resembling the hyperglycemic conditions in diabetic patients. The effects of high glucose on life span, glyoxalase-1 activity, advanced glycation end products (AGEs), and reactive oxygen species (ROS) formation and on mitochondrial function were studied. RESULTS - High glucose conditions reduced mean life span from 18.5 ± 0.4 to 16.5 ± 0.6 days and maximum life span from 25.9 ± 0.4 to 23.2 ± 0.4 days, independent of glucose effects on cuticle or bacterial metabolization of glucose. The formation of methylglyoxal-modified mitochondrial proteins and ROS was significantly increased by high glucose conditions and reduced by mitochondrial uncoupling and complex IIIQo inhibition. Overexpression of the methylglyoxal- detoxifying enzyme glyoxalase-1 attenuated the life-shortening effect of glucose by reducing AGE accumulation (by 65%) and ROS formation (by 50%) and restored mean (16.5 ± 0.6 to 20.6 ± 0.4 days) and maximum life span (23.2 ± 0.4 to 27.7 ± 2.3 days). In contrast, inhibition of glyoxalase-1 by RNAi further reduced mean (16.5 ± 0.6 to 13.9 ± 0.7 days) and maximum life span (23.2 ± 0.4 to 20.3 ± 1.1 days). The life span reduction by glyoxalase-1 inhibition was independent from the insulin signaling pathway because high glucose conditions also affected daf-2 knockdown animals in a similar manner. CONCLUSIONS - C. elegans is a suitable model organism to study glucose toxicity, in which high glucose conditions limit the life span by increasing ROS formation and AGE modification of mitochondrial proteins in a daf-2 independent manner. Most importantly, glucose toxicity can be prevented by improving glyoxalase-1- dependent methylglyoxal detoxification or preventing mitochondrial dysfunction.

Original languageEnglish (US)
Pages (from-to)2450-2456
Number of pages7
JournalDiabetes
Volume58
Issue number11
DOIs
StatePublished - Nov 2009

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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    Schlotterer, A., Kukudov, G., Bozorgmehr, F., Hutter, H., Du, X., Oikonomou, D., Ibrahim, Y., Pfisterer, F., Rabbani, N., Thornalley, P., Sayed, A., Fleming, T., Humpert, P., Schwenger, V., Zeier, M., Hamann, A., Stern, D., Brownlee, M., Bierhaus, A., ... Morcos, M. (2009). C. elegans as model for the study of high glucose-mediated life span reduction. Diabetes, 58(11), 2450-2456. https://doi.org/10.2337/db09-0567