Figure 1: Negative impact of high glucose levels on cutaneous fibroblasts biology. Short- or long-term exposure to high glucose concentrations is toxic for cutaneous fibroblasts suppressing the cells’ biological activities. The fibroblasts become reactive but not active. The high glucose burden engenders and uncontrolled production of ROS within the mitochondria with three major consequences: detriment on the OXPHOS reactions, depletion of the cells antioxidant reserves, and amplification of the mitochondrial dysfunction due to ROS-mediated attack to its DNA. Under this scenario apoptosis may prevail. ROS also may lead to cell cycle arrest due to p53 and p21 upregulation and nuclear compartmentalization. Alternatively, high glucose concentrations may impose a proinflammatory program within the wound by perpetuating a special population of macrophages (M1) so that fibroblasts become intoxicated and suppress the secretion of ECM ingredients. Conversely, the inflammation mediators fuel the secretion of MMPs. The negative balance of ECM inhibits fibroblasts chemotaxis, homing, anchoring, and proliferation. The proinflammatory environment inhibits the secretion of numerous growth factors with fibro angiogenic potential as TGF-β, PDF, EGF, and so forth and interferes with the signaling pathways of the TK-R’s. Inhibition of the TK-R’s downstream networking entails the suppression of positive forces for a balanced control of granulation tissue repopulation with productive cells. The accumulation of AGEs activates the AGE/RAGE axis, which further amplifies local inflammation and reactivity by increasing the secretion of TNF-alpha and adhesion molecules. This cytokine interferes with insulin and growth factors signaling, TGF-β1 for instance, which further amplifies the obstruction of the PI3K/Akt/mTOR/Cyclin D axis. The balance against this vital axis promotes the nuclear compartmentalization of representative of the FOXO family members, which contributes to catabolism, senescence, arrest, and apoptosis. In this prooxidative environment, it is common to activate cells autophagy in response to the accumulation of missfolded proteins. Thus, all these factors converge to slow down granulation tissue outgrowth.