• Michael G Vish, Prajakta Mangeshkar, Giovanna Piraino, Alvin Denenberg, Paul W Hake, Michael O'Connor, and Basilia Zingarelli.
• Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, OH, USA.
• Crit. Care Med. 2007 May 1; 35 (5): 1348-55.

ObjectiveInsulin 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.DesignProspective, randomized laboratory investigation that used an established murine model of endotoxic shock.SettingUniversity hospital laboratory.SubjectsMice were subjected to endotoxic shock by intraperitoneal administration of Escherichia coli lipopolysaccharide.InterventionsMice 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.Measurements And Main ResultsIn 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.ConclusionsOur data show that c-peptide has beneficial effects in endotoxic shock, and this therapeutic effect is associated with activation of proliferator-activated receptor-gamma.

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