Purpose. The insulin/ insulin-receptor pathway elicits signals shortening lifespan in various organisms under standard conditions. However, in patients with diabetes mellitus treatment with insulin prolongs life of patients with diabetes mellitus under standard conditions and prevents late complications. Therefore, we speculated that under high glucose (HG) conditions, insulin receptor dependent signals could target a life prolonging instead of a life shortening pathway. Methods. C. elegans were maintained under standard and HG conditions, with or without addition of human insulin. Lifespan was analyzed using Kaplan-Meier-survival curves, expression of insulin homologs and
glod-4 was determined by QRT-PCR. Neuronal structure was visualized using a pan-neuronal YFP-expressing strain, motility was measured by video analysis. Nematodes were stained for reactive oxygen species (ROS) using ethidium-staining and for methylglyoxal-derived advanced glycated endproducts (MG-derived AGEs), using a specific antibody. Enzymatic activity of glyoxalase-1 was determined photometrically. Results. HG conditions reduced lifespan and correlated with
ins-7 expression. Human insulin, insulin aspart and insulin detemir increased lifespan, exclusively under HG conditions in a
daf-2 dependent manner. Moreover, insulin normalized ROS formation, restored HG-mediated reduction of GLOD-4 activity, and normalized accumulation of MG-derived AGEs, thus resulting in protection of neuronal structure and normalization of lifespan. Lifespan normalization by insulin in HG conditions was dependent on
glod-4. Conclusion. The metabolic status influences downstream effects of
daf-2 dependent signaling. While human insulin elicits DAF-2 dependent signals, resulting in a glyoxalase-1 dependent normalization of lifespan under HG conditions, there is no effect exerted by human insulin on C. elegans under standard conditions. Therefore, insulin action might prevent posttranslational modifications of GLOD-4 caused by excess glucose, which in turn prevents further accumulation of MG-derived AGEs.