c-peptide and Skin-Ulcer

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.

Topics: Animals; C-Peptide; Cell Movement; Cell Proliferation; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Endothelial Cells; Human Umbilical Vein Endothelial Cells; Humans; Male; MAP Kinase Signaling System; Mice, Inbred C57BL; Neovascularization, Physiologic; Skin Ulcer; Wound Healing

Recent studies have demonstrated that C-peptide is biologically active and might have a beneficial effect on late complications in diabetes mellitus. The aim of this study was to investigate the effects of systemically given C-peptide on dermal wound healing in diabetic mice.. Experiments were carried out in male SKH-1 hr hairless mice. Dermal wounds were created (diameter 2.5mm) in streptozotozin-diabetic and normal control mice. Mice were randomized into three treatment groups (n = 10 each): Normal controls, diabetic mice with PBS or C-peptide injection twice daily. At various time points (prior wounding as well as days 4, 7, 10 and 15) microcirculation was quantitatively analyzed by intravital fluorescent microscopy to determine wound surface area, vessel diameter, red blood cell velocity, plasma leakage, functional capillary density. In addition, leukocyte/endothelium interaction was quantified by in vivo visualization of leukocytes.. Systemic administration of C-peptide showed no influence on wound healing or standard microcirculatory parameters. The leukocyte/ endothelium interaction revealed a significant (p<0.05) increase in the number of adherent leukocytes 15 days after wound creation in C-peptide treated diabetic mice.. Except for the significantly increased number of leukocytes adherent to venular endothelium in the C-peptide group no alteration was observed in wound healing and microcirculation. Neutrophil recruitment after C-peptide injection is of interest because it may reduce the risk of infection in diabetes mellitus.

Topics: Animals; Blood Glucose; C-Peptide; Dextrans; Diabetes Mellitus, Experimental; Fluorescein-5-isothiocyanate; Male; Mice; Mice, Hairless; Microcirculation; Microscopy, Fluorescence; Skin; Skin Ulcer; Wound Healing