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

Abstract

OBJECTIVEEstablishing Caenorhabditis elegans as a model for glucose toxicity–mediated life span reduction.RESEARCH DESIGN AND METHODSC. 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.RESULTSHigh 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.CONCLUSIONSC. 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.

O-Linked-N-Acetylglucosamine Cycling and Insulin Signaling Are Required for the Glucose Stress Response inCaenorhabditis elegans

“…As the animals aged, exposure to glucose concentrations below the toxicity threshold caused no change in pumping rates, whereas concentrations at (250 mm) or above (333 mm) the threshold caused a slight reduction in pumping rates (20% decrease compared to control; Figure 1C and data not shown). Because glucose stress leads to shortened life span in C. elegans (Schulz et al 2007;Lee et al 2009;Schlotterer et al 2009), this pumping decline may be a general symptom of sick and dying animals, consistent with our own observations on the effects of glucose toxicity on life span.…”

“…In addition, the frequency of infertility, developmental defects, pregnancy complications, and perinatal mortality is higher in obese and diabetic patients (reviewed in Tsoi et al 2010;Vimaleswaran and Loos 2010). Like mammals, C. elegans is subject to glucose toxicity, as high levels of glucose lead to reductions in fertility (Lu and Goetsch 1993;Lee et al 2009) (Figure 1) and life span (Schulz et al 2007;Lee et al 2009;Schlotterer et al 2009). The conservation of glucose-responsive pathways, including the insulin-like signaling pathway and the hexosamine signaling pathway, coupled with the ability to control diet and genetic background, make C. elegans an excellent model system for studying the glucose stress response and the genes that determine the threshold for glucose toxicity.…”

“…Several laboratories have demonstrated that supplemental glucose shortens C. elegans life span, at both high and low levels of insulin signaling (Schulz et al 2007;Lee et al 2009;Schlotterer et al 2009). Recently, the glucose disaccharide trehalose, which is elevated in daf-2 and age-1 mutants (Lamitina and Strange 2005;Honda et al 2010), has been shown to extend C. elegans life span in a DAF-2-dependent manner (Honda et al 2010).…”

Glucose Induces Sensitivity to Oxygen Deprivation and Modulates Insulin/IGF-1 Signaling and Lipid Biosynthesis inCaenorhabditis elegans

“…Although ceramides are also implicated in ischemic responses, the functional role ceramides have in anoxia survival is not well understood (Argraves et al 2011;Novgorodov and Gudz 2011). Of interest are the recent findings that ceramides are associated with impaired insulin action and the incidence of type 2 diabetes (Galadari et al 2013;Lopez et al 2013;Larsen and Tennagels 2014;Turpin et al 2014).Several studies have shown that a high glucose diet impacts the metabolism, development, and stress responses of C. elegans (Lee et al 2009;Schlotterer et al 2009;Choi 2011;Mondoux et al 2011) and that pathways and cellular processes involving glucose metabolism are conserved in metazoans (Berninsone 2006;Forsythe et al 2006;Hashmi et al 2013;Kitaoka et al 2013). Here, we use C. elegans to examine the impact a glucose diet has on oxygen deprivation responses and gene expression.…”

Diabetes-related adduct formation and retinopathy

“…This has been shown in endothelial cells transfected to overexpress GLO1 which accumulate less MGO and subsequently contain less AGEs [62,83]. Nematode worms engineered to overexpress GLO1 also contain fewer MGO-derived AGE adducts, and the worms demonstrate increased life-span [52,61]. More recently it has been shown that overexpression of GLO1 in diabetic rats is significantly protective against key retinopathy lesions including Müller glia damage and formation of acellular capillaries [91].…”