Figure 2: Putative relationship between T2DM and wound healing failure. Hyperglycemia has proved to arrest and perturb fibroblasts and keratinocytes migration as to promote endothelial cells apoptosis under culture conditions. Similar data have emerged from wound bed cells cultured in collagen matrices enriched with AGEs or AGEs precursors. Inflammatory cytokines and ROS spill-over impair mitochondrial function and impose the previously described cellular reactive phenotype so that cells defense reserves are maximally activated. Under this reactive cellular phenotype the pool of growth factors within the wound is reduced. Accordingly, the growth factors-mediated tyrosine kinase activity becomes consequently reduced. This basal constitutive tyrosine kinase receptorsmediated activity ensures the motion of downstream master switches for cells survival, proliferation and anabolism. An example is the PI3K/ Akt/mTOR pathway. This pathway is indispensable for wound repair and tissue growth. The reduced tuning of tyrosine kinase receptors amplifies the pre-existing deficit of growth factors which consequently will reduce the ligands-mediated receptors activation. One of these growth factors is insulin itself. On the other hand, the NF-κB mediated pro-inflammatory cytokine TNF-α downregulates the activity of the most important profibrogenic and pro-granulation growth factor: transforming growth factor-β1 (TGF-β1). The overall consequence for the wound is the onset of a stagnant phenotype based on failure of fibroblasts, endothelial cells, and myofibroblasts to migrate, proliferate, secrete matrix, and induce contraction.