Abstract
Lower limb ulcers in type-2 diabetic patients are a frequent complication that tributes to amputation and reduces survival. We hypothesized that diabetic healing impairment and other histopathologic hallmarks are mediated by a T2DM-induced tissue priming/metabolic memory that can be transferred from humans to healthy recipient animals and consequently reproduce diabetic donor's phenotypes. We examined the effect of human T2DM tissue homogenates injected into non-diabetic rat excisional wounds. Fresh granulation tissue, popliteal artery, and peroneal nerve of patients with T2DM were obtained following amputation. Post-mammoplasty granulation and post-traumatic amputation-tissue of normal subjects acted as controls. The homogenates were intralesionally injected for 6-7 days into rats' excisional thickness wounds. Infiltration with the different homogenates caused impaired wound closure, inflammation, nerve degeneration, and arterial thickening (all P < 0.01 vs relevant control) resembling histopathology of diabetic donor tissues. Control materials caused marginal inflammation only. Infiltration with glycated bovine albumin provoked inflammation and wound healing delay but did not induce arterial thickening. The reproduction of human diabetic traits in healthy recipient animals through a tissue homogenate support the notion on the existence of tissue metabolic memory-associated and transmissible factors, involved in the pathogenesis of diabetic complications. These may have futuristic clinical implications for medical interventions.
Highlights
Diabetes mellitus (DM) is a heterogeneous group of chronic metabolic conditions of pandemic magnitude, characterized by elevated blood glucose levels, resulting from the inability to produce insulin, resistance to insulin action, or both [1].A torpid healing process along with chronic ulceration and ulcer recurrence constitute a single pathogenic unit and a frequent diabetic complication, which have rendered alarming figures of lower extremity amputations along the history [2]
Infiltration with granulation tissue from the type 2 diabetes mellitus (T2DM) subject resulted in delayed wound healing, a marked inflammatory infiltrate mainly based on lymphocytes, and a constellation of abnormal vascular histological changes that mirrored those of the human donor T2DM granulation tissue
Despite the limitations of this work, it demonstrates for the first time that the torpid healing phenotype and cutaneous histopathological hallmarks of diabetes can be experimentally reproduced in a laboratory animal species through the injection of Cells-Free Filtrate (CFF) obtained from human diabetic tissue samples
Summary
A torpid healing process along with chronic ulceration and ulcer recurrence constitute a single pathogenic unit and a frequent diabetic complication, which have rendered alarming figures of lower extremity amputations along the history [2]. Regardless of the pathogenic differences between the two main clinical forms of diabetes, they both share systemic vascular and nerves damages [5]. The histopathological hallmarks of diabetic skin angiopathy include perivascular inflammation and collagenization, arterial wall thickening; media layer fibrohyaline degeneration, luminal obliteration, and vascular rarefaction [6, 7]. Peripheral diabetic neuropathy is predominantly characterized by different degrees of nerve fascicles edema, Wallerian degeneration, and myelin fragmentation [8, 9]
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