. (2009) C-elegans as model for the study of high glucose-mediated life span reduction. Diabetes, Vol.58 (No.11). pp. 2450-2456. ISSN 0012-1797

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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-l-dependent methylglyoxal detoxification or preventing mitochondrial dysfunction. Diabetes 58:2450-2456, 2009

Item Type:	Journal Article
Subjects:	R Medicine > RC Internal medicine
Divisions:	Faculty of Medicine > Warwick Medical School > Metabolic and Vascular Health Faculty of Medicine > Warwick Medical School
Journal or Publication Title:	Diabetes
Publisher:	American Diabetes Association
ISSN:	0012-1797
Date:	November 2009
Volume:	Vol.58
Number:	No.11
Number of Pages:	7
Page Range:	pp. 2450-2456
Identification Number:	10.2337/db09-0567
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Restricted or Subscription Access
Funder:	Netzwerk Altersforschung (NAR), Hopp-Stiftung fur Alternsforschung, Juvenile Diabetes Research Foundation, Manfred Lautenschlager Stiftung
URI:	http://wrap.warwick.ac.uk/id/eprint/17021

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