C. elegans as Model for the Study of High Glucose– Mediated Life Span Reduction

  1. Andreas Schlotterer1,
  2. Georgi Kukudov1,
  3. Farastuk Bozorgmehr1,
  4. Harald Hutter2,
  5. Xueliang Du3,
  6. Dimitrios Oikonomou1,
  7. Youssef Ibrahim1,
  8. Friederike Pfisterer1,
  9. Naila Rabbani4,
  10. Paul Thornalley4,
  11. Ahmed Sayed1,
  12. Thomas Fleming1,
  13. Per Humpert1,
  14. Vedat Schwenger1,
  15. Martin Zeier1,
  16. Andreas Hamann1,5,
  17. David Stern6,
  18. Michael Brownlee3,
  19. Angelika Bierhaus1,
  20. Peter Nawroth1 and
  21. Michael Morcos1
  1. 1Department of Medicine I and Clinical Chemistry, University of Heidelberg, Heidelberg, Germany;
  2. 2Simon Fraser University, Department of Biological Sciences, Burnaby, Canada;
  3. 3Departments of Medicine and Pathology, Albert Einstein College of Medicine, Bronx, New York;
  4. 4Warwick Medical School, Clinical Sciences Research Institute, University of Warwick, University Hospital, Coventry, U.K.;
  5. 5Diabetes-Clinic, Center for Vascular Medicine, Bad Nauheim, Germany;
  6. 6College of Medicine, University of Cincinnati, Cincinnati, Ohio.
  1. Corresponding author: Andreas Schlotterer, andreas.schlotterer{at}med.uni-heidelberg.de.
  1. A.S., G.K., and F.B. contributed equally to this study.

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.

Footnotes

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Received April 22, 2009.
    • Accepted July 22, 2009.
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This Article

  1. Diabetes vol. 58 no. 11 2450-2456
  1. All Versions of this Article:
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