Type 2 Diabetes Mellitus (T2DM): Biological Overview from Pathways to Organelles and its Translation toward a Torpid Wound Healing Process

Abstract

T2DM is a heterogeneous group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. Hyperglycemia may simply represent the tip of a broad series of molecular events from mitochondrial damages, to epigenetic and metabolic pathways deregulations. At the same time, hyperglycemia appears as the most proximal trigger for the onset and perpetual progression of multi-organ complications even under normoglycemic conditions. Thus, the initial hyperglycemic hit translates into a permanently harmful cellular imprinting as has been demonstrated in diabetic donors’ cells after several passages and cultured in ideal conditions. The wound healing failure along with the inability of the innate immunity to control peripheral infections is the hybrid that determines that 85% of all non-traumatic lower extremity amputations are practiced in diabetic subjects. Diabetic wounds exhibit a complex networking of inflammatory cytokines, local proteases, cytotoxic reactive oxygen and nitrogen species and a polymicrobial biofilm that impose a stagnant phenotype. All these ingredients negatively impact on fibroblasts, endothelial cells and keratinocytes while paradoxically perpetuate the immuno-inflammatory infiltrate. Although the molecular fundamentals toward chronification have not been elucidated, it seems that different gene simultaneously converge to impose the wound cells a pro-senescent, pro-catabolic and pro-apoptotic phenotype given the lack of a “physiological tuning” of tyrosine kinase-dependent receptors due to their limited activation by insulin and local growth factors. Although recombinant growth factors and smart devices have been introduced during the last years the figures of amputations are still discouraging. Faults have been committed while selecting the appropriate growth factor and because of the “chronic” instinct to treat the chronic wounds topically, where bioavailability of the active principle is compromised by wound and bacterial biofilm proteases. The periodic intralesional infiltration of epidermal growth factor has proved to overcome this hurdle. Granulation tissue growth stimulation and wound healing capacity has been restored in diabetic patients by this procedure in several clinical trials and common clinical practice studies.