A. J. Whittam1, Z. N. Maan1, D. Duscher1, L. H. Fischer1, N. Ho1, M. Rodrigues1, M. S. Hu1, G. G. Walmsley1, M. Januszyk1, J. Barrera1, A. J. Whitmore1, G. C. Gurtner1 1Stanford University,Surgery,Palo Alto, CA, USA
Introduction:
Chronic diabetic wounds are thought to result from impairments in the cellular and molecular mechanisms of wound repair in diabetic patients. Clinically, these wounds can result in significant disability, amputation, and increased mortality. Poor neovascularization in response to ischemia has been discovered to be fundamental to this problem, resulting from a high glucose induced defect in the transactivation of hypoxia-inducible factor-1α (HIF-1α). This leads to impairment of HIF-1α mediated expression of vascular endothelial growth factor (VEGF) and stromal-derived factor-1 (SDF-1). In particular, diabetic patients are known to be deficient in SDF-1, and it has been shown that in non-diabetic cells inhibiting DPP-4, which cleaves SDF-1, enhances the chemotaxis of murine and human HSCs and hematopoietic progenitor cells in vitro via SDF-1 induction. To explore the potential therapeutic benefits of DPP-4 inhibition for diabetic wounds, we utilized the DPP-4 inhibitor MK0626 and tested its effect on wound healing and cell behavior.
Methods:
Wild-type mice were either treated with streptozocin or fed a high fat diet to induce type 1 and 2 diabetes, respectively, which was confirmed via glucose tolerance test. Type 1 and type 2 diabetic mice were treated for 6 weeks with either: vehicle (high fat chow), glipizide (hypoglycemic agent), or MK0626. Humanized excisional wounds were subsequently created on the dorsum of treated type 1 and type 2 diabetic mice, with wounds being photographed and assessed at two-day intervals. Tissue was harvested for histology and qRT-PCR.
Results:
MK0626 significantly accelerated wound healing compared to both control and glipizide groups (*p= <0.05). This effect became evident by day 4, with significantly reduced mean wound area relative to original size (MK0626 = 79%, Control = 90%, Glipizide = 87%, *p= <0.05). qRT-PCR demonstrated increased transcription of SDF-1 (*p= <0.05), and vascular endothelial growth factor (VEGF) (*p= <0.05) in MK0626 treated v control mice. Immunohistochemistry studies demonstrated increased expression of SDF-1 (*p=0.008) and CD31 (*p=0.02) in MK0626 v control groups.
Conclusion:
DPP-4 inhibition has the potential to play a pivotal role in diabetic wound healing. The administration of MK0626 enhances wound healing more effectively than reducing hyperglycemia alone. Furthermore, a low concentration of MK0626 (1mg/kg/BW in chow) seems to be the optimal dosage for oral administration.
