Proinsulin C-peptide prevents impaired wound healing by activating angiogenesis in diabetes

J Invest Dermatol. 2015 Jan;135(1):269-278. doi: 10.1038/jid.2014.285. Epub 2014 Jul 9.


Diabetes mellitus disrupts wound repair and leads to the development of chronic wounds, likely due to impaired angiogenesis. We previously demonstrated that human proinsulin C-peptide can protect against vasculopathy in diabetes; however, its role in impaired wound healing in diabetes has not been studied. We investigated the potential roles of C-peptide in protecting against impaired wound healing by inducing angiogenesis using streptozotocin-induced diabetic mice and human umbilical vein endothelial cells. Diabetes delayed wound healing in mouse skin, and C-peptide supplement using osmotic pumps significantly increased the rate of skin wound closure in diabetic mice. Furthermore, C-peptide induced endothelial cell migration and tube formation in dose-dependent manners, with maximal effect at 0.5 nM. These effects were mediated through activation of extracellular signal-regulated kinase 1/2 and Akt, as well as nitric oxide formation. C-peptide-enhanced angiogenesis in vivo was demonstrated by immunohistochemistry and Matrigel plug assays. Our findings highlight an angiogenic role of C-peptide and its ability to protect against impaired wound healing, which may have significant implications in reparative and therapeutic angiogenesis in diabetes. Thus, C-peptide replacement is a promising therapy for impaired angiogenesis and delayed wound healing in diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • C-Peptide / metabolism*
  • Cell Movement / physiology
  • Cell Proliferation / physiology
  • Diabetes Mellitus, Experimental* / metabolism
  • Diabetes Mellitus, Experimental* / pathology
  • Diabetes Mellitus, Experimental* / physiopathology
  • Diabetes Mellitus, Type 1 / metabolism
  • Diabetes Mellitus, Type 1 / pathology
  • Diabetes Mellitus, Type 1 / physiopathology
  • Diabetes Mellitus, Type 2 / metabolism
  • Diabetes Mellitus, Type 2 / pathology
  • Diabetes Mellitus, Type 2 / physiopathology
  • Endothelial Cells / metabolism
  • Endothelial Cells / pathology
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • MAP Kinase Signaling System / physiology
  • Male
  • Mice, Inbred C57BL
  • Neovascularization, Physiologic / physiology*
  • Skin Ulcer / metabolism
  • Skin Ulcer / pathology
  • Skin Ulcer / physiopathology
  • Wound Healing / physiology*


  • C-Peptide