Detrimental impact of acute and chronic glucose burden in wound-healing cells: fibroblasts, myofibroblasts and vascular precursor cells

Abstract

Type 2 diabetes mellitus comprises a group of non-communicable metabolic diseases with an expanding pandemic magnitude. Diabetes predisposes to lower extremities ulceration and impairs the healing process leading to wounds chronification. Diabetes also dismantles innate immunity favoring wound infection. Amputation is therefore acknowledged as one of the disease's complications. Hyperglycemia appears as the proximal detonator of toxic effectors including pro-inflammation, spillover of reactive oxygen and nitrogen species. The systemic accumulation of advanced glycation end-products irreversibly impairs the entire physiology from cells-to-organs. Insulin axis deficiency weakens wounds' anabolism and predisposes to inflammation. These factors converge to hamper fibroblasts and endothelial cells proliferation, migration, homing, secretion and organization of a productive granulation tissue. Diabetic wound bed may turn chronically inflamed, pro-catabolic and a superimposed source of circulating pro-inflammatory cytokines, establishing a self-perpetuating loop. Diabetic toxicity breadth includes mitochondrial damages in fibroblasts and endothelial cells becoming prone to apoptosis thus hindering granulation. Endothelial progenitor cells recruitment and tubulogenesis are also impaired. Failure of wound re-epithelialization remains as a clinical challenge while it appears to be biologically multifactorial. Novel medical interventions as the local intra-ulcer infiltration of epidermal growth factor have emerged to hopefully reduce the current worldwide amputation rates.

Keywords

• diabetes
• granulation
• ulcer
• re-epithelialization
• growth factors