title: Proinsulin c-peptide exerts beneficial effects in endotoxic shock in mice.
abstract: OBJECTIVE
  Insulin connecting peptide (c-peptide) aids the folding of proinsulin and has been considered to have little biological activity. Recently, c-peptide has been shown to improve diabetic neuropathy and nephropathy as well as vascular inflammation. In vitro studies have reported that c-peptide may activate peroxisome proliferator-activated receptor-gamma, a nuclear transcription factor that plays a regulatory role in inflammation. This study was designed to investigate the biological effects of c-peptide during endotoxemia.
  
  
  METHODS
  Prospective, randomized laboratory investigation that used an established murine model of endotoxic shock.
  
  
  METHODS
  University hospital laboratory.
  
  
  METHODS
  Mice were subjected to endotoxic shock by intraperitoneal administration of Escherichia coli lipopolysaccharide.
  
  
  METHODS
  Mice received vehicle or c-peptide (70-140 nmol/kg) intraperitoneally at 3 hrs and 6 hrs after lipopolysaccharide. Mortality was monitored for 96 hrs. In a separate experiment, mice were killed at 4, 7, and 18 hrs after lipopolysaccharide administration. Lungs and plasma were collected for biochemical assays.
  
  
  RESULTS
  In vehicle-treated mice, endotoxic shock resulted in lung injury and was associated with a 41% survival rate and elevation in plasma tumor necrosis factor-alpha, macrophage inflammatory protein-1alpha, monocyte chemoattractant protein-1, and keratinocyte-derived chemokine levels. Lung nuclear levels of phosphorylated extracellular signal-regulated kinases 1 and 2 were significantly increased in vehicle-treated mice. On the other hand, lung nuclear expression and DNA binding of proliferator-activated receptor-gamma were decreased in comparison to control animals. Treatment with c-peptide (140 nmol/kg) improved survival rate (68%) and reduced plasma levels of tumor necrosis factor-alpha, macrophage inflammatory protein-1alpha, and monocyte chemoattractant protein-1, but it did not exert hypoglycemic effects. Treatment with c-peptide also up-regulated lung nuclear expression and DNA binding of proliferator-activated receptor-gamma and reduced phosphorylation of extracellular signal-regulated kinases 1 and 2 in comparison to vehicle-treated mice.
  
  
  CONCLUSIONS
  Our data show that c-peptide has beneficial effects in endotoxic shock, and this therapeutic effect is associated with activation of proliferator-activated receptor-gamma.
authors.affiliation: Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, OH, USA.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Vish
authors.forename: Prajakta
authors.initials: P
authors.lastname: Mangeshkar
authors.forename: Giovanna
authors.initials: G
authors.lastname: Piraino
authors.forename: Alvin
authors.initials: A
authors.lastname: Denenberg
authors.forename: Paul W
authors.initials: PW
authors.lastname: Hake
authors.forename: Michael
authors.initials: M
authors.lastname: O'Connor
authors.forename: Basilia
authors.initials: B
authors.lastname: Zingarelli
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D002096:C-Peptide / Q000494:pharmacology / Q000627:therapeutic use*; D018932:Chemokine CCL2 / Q000097:blood / Q000187:drug effects; D054407:Chemokine CCL4; D018925:Chemokines / Q000097:blood; D004195:Disease Models, Animal; D019446:Endotoxemia / Q000378:metabolism / Q000401:mortality / Q000628:therapy*; D004926:Escherichia coli; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D008070:Lipopolysaccharides; D008168:Lung / Q000187:drug effects* / Q000473:pathology; D019402:Macrophage Inflammatory Proteins / Q000097:blood; D008297:Male; D051379:Mice; D047495:PPAR gamma / Q000378:metabolism*; D011897:Random Allocation; D015996:Survival Rate; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D001786:Blood Glucose; D002096:C-Peptide; D018932:Chemokine CCL2; D054407:Chemokine CCL4; D018925:Chemokines; D008070:Lipopolysaccharides; D019402:Macrophage Inflammatory Proteins; D047495:PPAR gamma; D014409:Tumor Necrosis Factor-alpha; C074302:keratinocyte-derived chemokines; D048049:Extracellular Signal-Regulated MAP Kinases