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.

DESIGN:

Prospective, randomized laboratory investigation that used an established murine model of endotoxic shock.

SETTING:

University hospital laboratory.

SUBJECTS:

Mice were subjected to endotoxic shock by intraperitoneal administration of Escherichia coli lipopolysaccharide.

INTERVENTIONS:

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.

MEASUREMENTS AND MAIN 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: Michael G Vish, Prajakta Mangeshkar, Giovanna Piraino, Alvin Denenberg, Paul W Hake, Michael O'Connor, Basilia Zingarelli
• Journal: Critical care medicine (Crit Care Med) Vol. 35 Issue 5 Pg. 1348-55 (May 2007) ISSN: 0090-3493 [Print] United States
• PMID: 17414724 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Blood Glucose
• C-Peptide
• Chemokine CCL2
• Chemokine CCL4
• Chemokines
• Lipopolysaccharides
• Macrophage Inflammatory Proteins
• PPAR gamma
• Tumor Necrosis Factor-alpha
• keratinocyte-derived chemokines
• Extracellular Signal-Regulated MAP Kinases

Topics

• Animals
• Blood Glucose (drug effects)
• C-Peptide (pharmacology, therapeutic use)
• Chemokine CCL2 (blood, drug effects)
• Chemokine CCL4
• Chemokines (blood)
• Disease Models, Animal
• Endotoxemia (metabolism, mortality, therapy)
• Escherichia coli
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Lipopolysaccharides
• Lung (drug effects, pathology)
• Macrophage Inflammatory Proteins (blood)
• Male
• Mice
• PPAR gamma (metabolism)
• Random Allocation
• Survival Rate
• Tumor Necrosis Factor-alpha (blood)