Glucose Toxic Effects on Granulation Tissue Productive Cells: The Diabetics’ Impaired Healing

Abstract

Type 2 diabetes mellitus is a metabolic noncommunicable disease with an expanding pandemic magnitude. Diabetes predisposes to lower extremities ulceration and impairs the healing process leading to wound chronification. Diabetes also dismantles innate immunity favoring wound infection. Amputation is therefore acknowledged as one of the disease's complications. Hyperglycemia is the proximal detonator of systemic and local toxic effectors including proinflammation, acute-phase proteins elevation, and spillover of reactive oxygen and nitrogen species. Insulin axis deficiency weakens wounds' anabolism and predisposes to inflammation. The systemic accumulation of advanced glycation end-products irreversibly impairs the entire physiology from cells-to-organs. These factors in concert hamper fibroblasts and endothelial cells proliferation, migration, homing, secretion, and organization of a productive granulation tissue. Diabetic wound bed may turn chronically inflammed, procatabolic, and an additional source of circulating pro-inflammatory cytokines, establishing a self-perpetuating loop. Diabetic fibroblasts and endothelial cells may bear mitochondrial damages becoming prone to apoptosis, which impairs granulation tissue cellularity and perfusion. Endothelial progenitor cells recruitment and tubulogenesis are also impaired. Failure of wound reepithelialization remains a clinical challenge while it appears to be biologically multifactorial. Ulcer prevention by primary care surveillance, education, and attention programs is of outmost importance to reduce worldwide amputation figures.

Hyperglycemia is associated with lower levels of urokinase-type plasminogen activator and urokinase-type plasminogen activator receptor in wound fluid

“…The extracellular matrix represents the granulation tissue that provides support for inflammatory cells, fibroblasts, and endothelial cells, and allows for the chemotaxis of epithelial cells (Hanson et al, 2005). Fibroblasts and endothelial cells are main targets of hyperglycemia in the granulation tissue (Berlanga-Acosta et al, 2013). Studies have shown that high glucose disrupt normal fibroblast physiology and derange the secretion of extracellular matrix ingredients (Hehenberger & Hansson, 1997;Rowe, Starman, Fujimoto, & Williams, 1977;Yevdokimova, 2003).…”

“…Studies have shown that high glucose disrupt normal fibroblast physiology and derange the secretion of extracellular matrix ingredients (Hehenberger & Hansson, 1997;Rowe, Starman, Fujimoto, & Williams, 1977;Yevdokimova, 2003). As depicted for fibroblasts, high glucose exerts a toxic effect on endothelial cells (Berlanga-Acosta et al, 2013). High glucose concentrations has been shown to disturb endothelial cell cycle, increase DNA damage, and delay endothelial cells replication, as inducing excessive cell death (Busik, Mohr, & Grant, 2008;Callaghan, Ceradini, & Gurtner, 2005;Hink et al, 2001;Rai et al, 2005).…”

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

“…At the long term response (21 days after initiation) EGF induces the expression of a constellation of other growth factors that contribute to the healing process. In other words, the locally infiltrated EGF restores the deficit of growth factors brought about by diabetes and resumes the activity of tyrosine kinase receptors which appear crucial for the healing process, especially in the diabetic context where they are depressed [145].…”

Neuronal pathways in tendon healing and tendinopathy - update

“…However, a compromised inflammatory response associated with diseases such as diabetes (a prevalent co-morbidity particularly in the older population with type 2 diabetes; discussed in Purkayastha and Cai, 2013 (12); Hellman et al, 2012 (13); Mirza et al, 2013 (14)), can exert a negative effect on healing, leading to chronic wounds and life-threatening complications (15). Oppositely, excessive or unregulated inflammation may result in abnormal healing, with fibrosis or disruption of the integrity of the tissue function (16).…”