title: daf-16/FOXO and glod-4/glyoxalase-1 are required for the life-prolonging effect of human insulin under high glucose conditions in Caenorhabditis elegans.
abstract: OBJECTIVE
  The aim of this study was to determine the protective effects of human insulin and its analogues, B28Asp human insulin (insulin aspart) and B29Lys(ε-tetradecanoyl),desB30 human insulin (insulin detemir), against glucose-induced lifespan reduction and neuronal damage in the model organism Caenorhabditis elegans and to elucidate the underlying mechanisms.
  
  
  METHODS
  Nematodes were cultivated under high glucose (HG) conditions comparable with the situation in diabetic patients and treated with human insulin and its analogues. Lifespan was assessed and neuronal damage was evaluated with regard to structural and functional impairment. Additionally, the activity of glyoxalase-1 and superoxide dismutase (SOD) and the formation of reactive oxygen species (ROS) and AGEs were determined.
  
  
  RESULTS
  Insulin and its analogues reversed the life-shortening effect of HG conditions and prevented the glucose-induced neuronal impairment. Insulin treatment under HG conditions was associated with reduced concentration of glucose, as well as a reduced formation of ROS and AGEs, and increased SOD activity. These effects were dependent on the Forkhead box O (FOXO) homologue abnormal dauer formation (DAF)-16. Furthermore, glyoxalase-1 activity, which was impaired under HG conditions, was restored by human insulin. This was essential for the insulin-induced lifespan extension under HG conditions, as no change in lifespan was observed following either suppression or overexpression of glyoxalase-1.
  
  
  CONCLUSIONS
  Human insulin and its analogues prevent the reduction in lifespan and neuronal damage caused by HG conditions. The effect of human insulin is mediated by a daf-2/insulin receptor and daf-16/FOXO-dependent pathway and is mediated by upregulation of detoxifying mechanisms.
authors.affiliation: Department of Medicine 1 and Clinical Chemistry, University of Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany, michael.mendler@med.uni-heidelberg.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Mendler
authors.forename: Andreas
authors.initials: A
authors.lastname: Schlotterer
authors.forename: Youssef
authors.initials: Y
authors.lastname: Ibrahim
authors.forename: Georgi
authors.initials: G
authors.lastname: Kukudov
authors.forename: Thomas
authors.initials: T
authors.lastname: Fleming
authors.forename: Angelika
authors.initials: A
authors.lastname: Bierhaus
authors.forename: Christin
authors.initials: C
authors.lastname: Riedinger
authors.forename: Vedat
authors.initials: V
authors.lastname: Schwenger
authors.forename: Stephan
authors.initials: S
authors.lastname: Herzig
authors.forename: Markus
authors.initials: M
authors.lastname: Hecker
authors.forename: Jens
authors.initials: J
authors.lastname: Tyedmers
authors.forename: Peter P
authors.initials: PP
authors.lastname: Nawroth
authors.forename: Michael
authors.initials: M
authors.lastname: Morcos
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism*; D004249:DNA Damage; D004260:DNA Repair; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D061386:Insulin, Regular, Human / Q000494:pharmacology*; D007791:Lactoylglutathione Lyase / Q000378:metabolism*; D008136:Longevity; D015398:Signal Transduction
chemical_list: D029742:Caenorhabditis elegans Proteins; D051858:Forkhead Transcription Factors; D061386:Insulin, Regular, Human; C108831:daf-16 protein, C elegans; D007791:Lactoylglutathione Lyase