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Figure 5: Impact of hyperglycemia on granulation tissue biology. The onset of a systemic pro-inflammatory program due to sustained hyperglycemia is associated with the elevation of circulating levels of TNF-α. The cytokine release is further amplified by the agonistic interaction AGE/RAGE and the generation of ROS. This preliminary triad amplifies insulin receptor resistance and a multiorgan toxicity. Excess TNF-α perpetuates the inflammatory infiltrate into the wound bed hindering the onset of the fibroangiogenic phase in part by abrogating TGF-β1 release. This TNF-α related growth factors deficit within the wound bed may act as a vulnerability factor for granulation tissue productive cells apoptosis.