Human C-peptide antagonises high glucose-induced endothelial dysfunction through the nuclear factor-kappaB pathway

Diabetologia. 2008 Aug;51(8):1534-43. doi: 10.1007/s00125-008-1032-x. Epub 2008 May 21.


Aims/hypothesis: Endothelial dysfunction in diabetes is predominantly caused by hyperglycaemia leading to vascular complications through overproduction of oxidative stress and activation of the transcription factor nuclear factor-kappaB (NF-kappaB). Many studies have suggested that decreased circulating levels of C-peptide may play a role in diabetic vascular dysfunction. To date, the possible effects of C-peptide on endothelial cells and intracellular signalling pathways are largely unknown. We therefore investigated the effect of C-peptide on several biochemical markers of endothelial dysfunction in vitro. To gain insights into potential intracellular signalling pathways affected by C-peptide, we tested NF-kappaB activation, since it is known that inflammation, secondary to oxidative stress, is a key component of vascular complications and NF-kappaB is a redox-dependent transcription factor.

Methods: Human aortic endothelial cells (HAEC) were exposed to 25 mmol/l glucose in the presence of C-peptide (0.5 nmol/l) for 24 h and tested for expression of the gene encoding vascular cell adhesion molecule-1 (VCAM-1) by RT-PCR and flow cytometry. Secretion of IL-8 and monocyte chemoattractant protein-1 (MCP-1) was measured by ELISA. NF-kappaB activation was analysed by immunoblotting and ELISA.

Results: Physiological concentrations of C-peptide affect high glucose-induced endothelial dysfunction by: (1) decreasing VCAM-1 expression and U-937 cell adherence to HAEC; (2) reducing secretion of IL-8 and MCP-1; and (3) suppressing NF-kappaB activation.

Conclusions/interpretation: During hyperglycaemia, C-peptide directly affects VCAM-1 expression and both MCP-1 and IL-8 HAEC secretion by reducing NF-kappaB activation. These effects suggest a physiological anti-inflammatory (and potentially anti-atherogenic) activity of C-peptide on endothelial cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aorta
  • C-Peptide / pharmacology*
  • Cell Culture Techniques
  • Chemokine CCL2 / metabolism
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / metabolism
  • Endothelium, Vascular / physiopathology*
  • Glucose / antagonists & inhibitors
  • Glucose / pharmacology*
  • Humans
  • Interleukin-8 / metabolism
  • NF-kappa B / physiology*
  • Oxidative Stress / drug effects
  • Reverse Transcriptase Polymerase Chain Reaction
  • Vascular Cell Adhesion Molecule-1 / drug effects
  • Vascular Cell Adhesion Molecule-1 / genetics


  • C-Peptide
  • CCL2 protein, human
  • Chemokine CCL2
  • Interleukin-8
  • NF-kappa B
  • Vascular Cell Adhesion Molecule-1
  • Glucose