Cutaneous changes in diabetic patients: Primed for aberrant healing?

Cutaneous manifestations affect most patients with diabetes mellitus, clinically presenting with numerous dermatologic diseases from xerosis to diabetic foot ulcers (DFUs). Skin conditions not only impose a significantly impaired quality of life on individuals with diabetes but also predispose patients to further complications. Knowledge of cutaneous biology and the wound healing process under diabetic conditions is largely limited to animal models, and studies focusing on biology of the human condition of DFUs remain limited. In this review, we discuss the critical molecular, cellular, and structural changes to the skin in the hyperglycaemic and insulin-resistant environment of diabetes with a focus specifically on human-derived data. Elucidating the breadth of the cutaneous manifestations coupled with effective diabetes management is important for improving patient quality of life and averting future complications including wound healing disorders.

Patients with diabetes often suffer from dry skin, presenting clinically with irritation, itch, and increased fragility.Skin breakdown further facilitates the route of entry for bacterial or fungal microorganisms and increases the risk of wound formation (Figure 1). 7,17Xerosis develops through several mechanisms related to pathologic hyperglycaemia.Non-enzymatic glycation of collagen fibres increases crosslinking and modifies sidechains to interfere with cell-collagen interactions, causing decreased flexibility and solubility (Table 1). 12onsequently, patients with diabetes have impaired skin elasticity compared with healthy controls. 18,19Structural changes may also be reflected on the gene level, as a whole genome expression analysis of lower leg skin in diabetic patients found downregulated genes in cell adhesion molecule pathways (NCAM1 and L1CAM) and the collagen family members such as type IX collagen and Procollagen C-Endopeptidase Enhancer 2. 20 Interestingly, of 56,318 genes expressed in skin, only 182 are found to be significantly differentially expressed between diabetic and non-diabetic skin.Similarly, transcriptomic analyses of tissue samples collected from non-ulcerated and non-neuropathic diabetic foot skin showed minimal differences in expression levels of mRNA and post-transcriptional regulators microRNA (miRNA) when compared with location matched healthy foot skin controls. 5lthough intact diabetic foot skin shows small differences from non-diabetic foot skin at transcriptional level, its response to challenges (such as wounding, infection, or neuropathy) may be very different.
The impact of diabetes on stratum corneum (SC) function, specifically SC hydration and trans-epidermal water loss (TEWL), reveals conflicting findings. 19,21SC hydration is primarily regulated by a mix of natural moisturising factors (NMFs) that attract and bind water molecules, as well as the physical barrier created by corneocytes and intercellular lamellar lipids such as ceramides, cholesterol, and free fatty acids.The hygroscopic molecules primarily include filaggrin-derived amino acids, lactate, and urea. 22,23Clinically, some studies have observed decreased SC hydration and TEWL in patients with diabetes, associated with poor levels of glycaemic control and older patient age. 21,24These findings correlate with murine models that have demonstrated reduced skin hydration through decrease in hyaluronic acid, decreased epidermal lipid synthesis, and lamellar body number in association with increased serum AGE. 24,25Another clinical study in diabetic patients controlling for age and sex did not observe differences in hydration and TEWL. 19Factors potentially contributing to the contradictory findings are patient age, use of lipid-lowering medications, and presence of obesity between different study populations.Further studies controlling for such confounding factors may better elucidate the impact of diabetes on the SC properties.
One of the greatest areas of concern with skin fragility is the foot, where DFUs form in the context of advanced diabetes and peripheral neuropathy.Xerotic foot skin in patients with diabetes demonstrated greater stiffness, thinning, and decreased hydration than in non-diabetic patients, without affecting TEWL. 7Clinically, this correlated with an up to three-fold increased number of superficial fissures, as well as severe scaling.Notably, specific markers such as ceramide concentration, amino acids, serine, and total proteins were found elevated in diabetic xerotic foot skin compared with non-diabetic xerotic foot skin. 7The difference could reflect the primary mechanism of dry skin in diabetes arising from additional cofounders such as collagen disruption, rather than simply a decline of NMFs or inter-cellular lipids demonstrated in other conditions such as senile xerosis.Nevertheless, moisturising can improve xerotic changes and multiple randomised controlled trials on foot xerosis in diabetes have demonstrated the enhanced efficacy of moisturisers supplemented with natural moisturising factors such as urea, lactic acid, and amino acids. 26- 28Recent evidence also suggests foot hydration levels could be a non-invasive indicator for foot sole deterioration.Using a Terahertz radiation, pulsed laser-based imaging approach, patients with diabetes demonstrated decreased water content in foot skin, particularly in the heel centre, and lower levels further correlated with degree of diabetic peripheral neuropathy. 29Methods to measure foot skin hydration could be future diagnostic tool to predict neurological deterioration and therefore risk of developing DFU.

| Effects of diabetes on keratinocytes
1][32][33] Cutaneous disorders like xerosis underscore the systemic changes caused by diabetes as well as the multifunctional activity of keratinocytes in reflecting diabetic pathology.
1][32] During skin repair, keratinocyte motility is achieved by shifting keratin (K) expression to K6, K16, and K17, facilitating increased cellular flexibility to migrate. 34Motility is also supported by overall loss of cell-to-cell adhesions and matrix-metalloproteinase (MMP) proteolysis of extracellular matrix (ECM) proteins. 35The hyperglycaemic environment of diabetes inhibits keratinocyte migration by reduced MMP activity in the context of increased tissue inhibitor of metalloproteinase (TIMP) and TGF-β secretion. 6Keratinocytes can further exacerbate hyperglycaemia by autoregulating glucose transporters and thereby uptake. 36Although hyperglycaemic conditions of cell culture in vitro and diabetic murine models in vivo demonstrate altered keratinocyte morphology and number, 5,37 histological evaluation of human diabetic foot skin and normal foot skin reveals no observable differences in epidermal morphology, dermal collagen orientation, fibres composition, skin thickness, or leptin receptor signal, with the upregulation of S100 calcium binding protein A9 (S100A9) detected in some (33%) but not all diabetic foot skin samples. 5,36,38Conversely, hyperglycaemia, not hyperinsulinemia, was found to be associated with suppressed keratinocyte proliferation in T1D mouse model in vivo, 38 suggesting limited translation to the human condition.
Despite these functional and morphological changes to keratinocytes in diabetic conditions, some skin pathologies associated with diabetes exhibit opposite, hyper-proliferative effects.Acanthosis nigricans, an associated skin disorder causing hyper-pigmented, thickened plaques in intertriginous body areas, arises from hyperinsulinemia stimulating insulin-like growth factor, with other potential mediators such as epidermal and fibroblast growth factor receptors stimulating keratinocyte and fibroblast proliferation. 39DFUs are characterised by a hyper-proliferative but non-migratory epidermis, with several factors contributing to keratinocyte dysfunction.[44][45][46] In keratinocytes, hyperglycaemic conditions cause mitochondrial reactive oxygen species (ROS) overproduction and a decrease in endogenous antioxidant production in a dosedependent manner, leading to oxidative damage, accelerated keratinocyte apoptosis, and mitochondrial DNA damage (Table 1). 47,48ROS such as nitric oxide has potent regulatory effects on keratinocyte proliferation and differentiation, but the point at which ROS or other signalling molecules transition from functional and necessary to destructively dysfunctional Both tissue-resident and bone marrow-derived macrophages in diabetic patients have an impaired phenotype transition from M1 to M2 like, favouring an M1 pro-inflammatory phenotype that contributes to the persistent inflammatory state (Table 2). 9,57,58In vitro mechanistic studies have demonstrated that high glucose primes macrophages for increased expression of pro-inflammatory cytokines (tumor necrosis factor-α [TNF-α], interleukin-1 [IL-1], IL-6), further exacerbated with macrophage activation or with a hypoxic environment. 59,60Epigenetic modifications also sustain the pro-inflammatory disposition. 46Patients with T2D have serum peripheral monocytes with elevated levels of histone methyltransferase MLL1, which upregulates pro-inflammatory cytokine IL-6. 61,622D patients display elevated cell-free mtDNA serum levels as well, which induces AIM2 inflammasome-mediated inflammation, and IL-1β and IL-18 secretion in macrophages. 63,64acrophages also demonstrate decreased phagocytic ability in diabetic patients, contributing to impaired host defence.A hyperglycaemic environment suppresses genes involved in mediating bacterial phagocytosis, and efferocytosis, the phagocytic clearance of apoptotic cells. 59In diabetic murine models, efferocytosis by macrophages is impaired. 65Monocytes and macrophages from diabetic patients also demonstrate impaired phagocytic activity in correlation to glycaemic control (Table 2). 9,107][68][69][70] Interestingly, several recent studies have shown that decreased macrophage recruitment contributes to DFUs, suggesting that inflammatory response does not recapitulate the response typically detected in acute wound healing or in murine models of diabetes. 71This was further confirmed by single-cell transcriptomic analyses of DFUs that showed increase of M1 macrophages in healing DFUs, suggesting that activation of acute-like inflammatory response supports the progression of healing. 72[75][76]

| Monocytes
Monocytes recruited to the tissue play key roles during inflammation and pathogen challenge, as monocyte-derived macrophages directing inflammatory response and as antigen-presenting cells. 77Alteration in sympathetic innervation and activation in the bone marrow are known to impact the haematopoietic stem cell niche and disrupts stem cell mobilisation and differentiation. 53,78,79Murine models have established that lowgrade chronic inflammation in diabetes induces myeloid bias in haematopoietic stem and progenitor cells, increasing monocyte production in the bone marrow. 80Diabetic patients also reflect elevated levels of circulating inflammatory monocytes (CD14+ CD16−). 79,81hemotaxis and activation of monocytes in diabetes are also modified, as hyperglycaemia contributes to resistance of vascular endothelial growth factor-induced chemotaxis (Table 2). 11,82-84A genomic assay of forearm skin biopsies in diabetic patients revealed an impaired migratory profile of immune cells, including dysregulated migration of monocytes, dendritic cells, and antigen-presenting cells. 56Elevated glucose also promotes NADPHoxidase mediated toll-like receptor expression and activity in monocyte activation, as well as increased pro-inflammatory cytokine production, contributing to increased inflammatory responses. 85,86

| Mast cells
Mast cells participate in several processes of inflammation, neovascularisation, and wound healing via degranulation, release of mediators, and recruitment and interaction with other cells including macrophages, neutrophils, endothelial cells, and fibroblasts. 58Mast cell activation response to stimuli vary based on tissue location and age, and shift from regenerative to tissue repair mechanism during mammalian development is associated with maturation and activation of mast cells. 87[89] In diabetes, mast cells play a role in disease progression.T1D patients demonstrated increased mast cells infiltration in the pancreatic islets with induced β-cell death. 90Mast cells also help progress lipid retention, vascular remodelling, and atherosclerosis in T2D through promoting adipose tissue inflammation, although activity depends on the adipose anatomical location. 90Unwounded skin in diabetic patients revealed increased numbers of degranulated mast cells associated with inflammatory infiltrates in the dermis (Table 2). 56,58hile the absence of mast cells impairs early skin wound healing in mice, non-degranulated mast cells in skin are essential for proper adult wound healing. 58,90Therefore, therapies towards mast cell stabilisation and regulation of degranulation have been proposed to improve the wound healing capacity of diabetic skin. 58,90

| Neutrophils
Neutrophils play a vital role in first line defence during early inflammatory response, clearing foreign debris and bacteria upon barrier breach and coordinating immune response.
Neutrophils in diabetic patients exhibit increased release of pro-inflammatory cytokines (TNF-α, IL-8, IL-1β), dysregulated ROS generation, and inflammatory cell death with increased release of neutrophil extracellular traps (NETosis) measured by increased marker citrullinated histone H3 (Table 2). 86,91,92Increased NETosis continues to be present in DFUs, along with decreased neutrophil number at wound edge and deregulation of transcriptional networks involving FOXM1, STAT3, and TREM1 that support neutrophils and other immune cells. 71,93The diabetic environment also alters neutrophil function, contributing to a weakened response against infection. 94

| Fibroblasts
][97][98][99][100] Although advances of high-resolution -omic technologies revealed complexity and plethora of fibroblast phenotypes and their function, little is known about how diabetes affects these distinct populations.Hyperglycaemia exacerbates the inhibitory effect of ischemia on myofibroblast differentiation. 101Fibroblasts incubated in hyperglycaemic conditions exhibit senescence and accelerated apoptosis. 102Recent single-cell transcriptomic identified a unique population of fibroblasts associated with healing of DFUs. 72erging evidence points to the involvement of miRNAs in the complex wound microenvironment and a potential major point of differentiation between diabetic and normal wound healing. 5,103miRNA profiling of primary dermal fibroblasts from diabetic and healthy human foot skin identified subtle changes in the regulation of miRNAs between diabetic and healthy foot skin. 5Fibroblasts isolated from diabetic wounds express miR-27-3p, a miRNA associated with promoting insulin resistance and diabetic retinopathy, at significantly higher levels than fibroblasts isolated from normal wounds. 104miR-27-3p suppresses fibroblast proliferation and migration, increases apoptosis in vitro, and delays wound healing. 104Furthermore, paired mRNA-miRNA transcriptomic analyses of human fibroblasts derived from DFUs revealed reveals impairments in cellular functions such as cell migration, proliferation, activation of cell differentiation, and senescence (Table 1), 103 features that can be re-programmed using induced pluripotent stem cells approach from a non-healing diabetic to pro-regenerative fetal-like healing phenotype. 103,105,106abetes is also known to increase the amount of AGE (Table 1 and Figure 1), present in many tissues including skin. 107Glucose, among other reducing sugars, reacts with amino groups on proteins, lipids, and nucleic acids via the Maillard reaction, eventually leading to the accumulation of AGE. 108AGE receptors (RAGE) and post-receptor signalling pathways have been identified, and mechanisms involving RAGE have been implicated in the tissue changes and damage consequential to diabetes. 109AGE-derived oxidant stress, tissue-specific inflammation, growth, and apoptosis enhanced by the hyperglycaemic environment have been shown to contribute to pathogenesis of long-term diabetic complications. 110Prominent AGE signal was found in the dermis of diabetic skin combined with an increase in RAGE -positive fibroblasts compared with healthy non-diabetic skin. 110Additionally, AGE levels in diabetic skin are higher in individuals with distal sensorimotor polyneuropathy (DSP) and are associated with DSP severity. 111In vitro treatment of human fibroblasts with glyoxal, a glycation reaction product, revealed a decrease in fibroblast proliferation, increased tensile strength, increased adherence to ECM, downregulated focal adhesion kinase and exhibited failure to extend filipodia, demonstrating multiple points of hindrance to fibroblast migration and proliferation as a result of AGE treatment. 112Treatment of fibroblasts with rosiglitazone, a peroxisome proliferator-activated receptor-gamma ligand, attenuated the effects of AGE in vitro. 113Connective tissue growth factor (CTGF), a key player in fibroblast-ECM production and angiogenic factor, has been identified as a potential mediator between increased AGE and tissue fibrosis in diabetes. 114Human skin fibroblasts cultured in the presence of AGE show upregulation of CTGF compared with control fibroblasts. 114A separate study showed that apoptosis is induced in human fibroblasts cultured with the most abundant type of AGE, known as N ϵ -(carboxymethyl)lysine. 115

| Extracellular matrix
Fibrosis of the heart, kidney, and liver are well-established forms of diabetes-related end-organ damage, and diabetic skin also responds to systemic pro-fibrotic signals. 116- 118Hyperglycaemia, lipotoxic injury, and insulin resistance promote fibrosis through the stimulation of fibroblasts, immune cells, and vascular cells, and may activate a fibroblast-like phenotype in epithelial and endothelial cells. 119The MMP/TIMP ratio is also unbalanced in diabetic skin, potentially due to chronic pro-inflammatory and fibrotic signals released in the presence of high glucose (Table 1). 120in autofluorescence, which correlates with advanced glycation, is significantly higher in individuals with both T1D and T2D compared with age-matched non-diabetic patients. 121n individuals with T1D, autofluorescence was also found to predict development of DFU and limb amputations across 10 years of observation. 122Pentosidine amount and 370/440 nm fluorescence intensity in skin collagen as parameters of AGE accumulation are also tightly correlated with diabetes duration and have demonstrated capacity as predictors of long-term complications like retinopathy and elevated creatinine. 123Advanced glycation is a long-term process thus predominantly affecting long-living proteins like collagen and other ECM structural components. 108Incubation of fibroblasts with AGE-bovine serum albumin revealed upregulations in RAGE, TGF-β1, collagen I, and collagen III as well as MMP-2 activation. 124Chronic stimulation of fibroblasts demonstrated that collagen I synthesis is a result of RAGE upregulation, whereas collagen III synthesis is a result of both TGF-β1 and RAGE upregulation. 124The tensile strength of diabetic skin, measured by average maximum stress and average modulus, is significantly lower than normal skin and can be attributed to the biomechanical effects of glycation. 125 addition to endogenous AGE accumulated via diabetes-related metabolic damage, AGE content in skin is also correlated with lifestyle factors such as diet, smoking, and sun exposure. 126The development and progression of T2D specifically are associated with dietary factors, and the potential benefit of lifestyle modifications in preventing major diabetes complications may also benefit the skin in attenuating AGE accumulation. 127he involvement of adipose tissue systemically in diabetes is extensive and reviewed elsewhere [128][129][130] clearly demonstrating that diabetes impacts both visceral and subcutaneous adipose fat tissue (Figure 1).Adipose tissue that accumulates around abdominal viscera and intra-abdominal solid organs contributes to metabolic obesity and is functionally distinct from subcutaneous adipose tissue.2][133][134][135] Diabetes medications such as the thiazolidinedione family may induce fat redistribution as a mechanism of action in their treatment of diabetes. 136The distribution ratio of visceral to subcutaneous fat is also affected by sex and race/ethnicity. 137ere is conflicting evidence regarding diabetes-induced changes to the subcutaneous adipose tissue, which may point to redistribution and body site-specific changes in diabetes rather than a universal thinning or thickening of adipose tissue.9][140] Studies have found diabetic patients exhibit thinned skin and thinned subcutaneous layers such as on the foot, back, and hand, whereas other studies using the same method of measurement found that slightly thicker subcutaneous layers on the foot and back, as well as the anterior abdominal wall. 141- 143Additional evidence supports thinned subcutaneous layers independent of sex, race/ ethnicity, and visceral-subcutaneous ratio in diabetic patients. 144Conflicting observations of subcutaneous adipose tissue thickness warrants further investigation into the factors involved such as demographics and comorbidities.
Diabetic patients demonstrate key characteristics of adipose tissue dysfunction within subcutaneous fat including enlarged adipocytes, increased inflammatory markers such as M1/M2 macrophage ratio, TNF-α secretion, as well as increased lipolysis and deregulation of adipogenesis and morphology. 37,145,146Similarly, healthy patients genetically predisposed to T2D demonstrate adipocyte hypertrophy independent of body mass index, associated with increased Wnt signalling activity indicating impaired adipocyte differentiation.They also reveal increased markers of inflammation (IL1-β, IL10, TNF-α) and macrophage infiltration, and early signs of adipose tissue remodelling and fibrosis, suggesting adipose tissue dysfunction may predate disease onset.8][149] Furthermore, adipocyte-derived cells at the wound edge can also differentiate into myofibroblasts, the dominant ECM-producing cell type during the proliferative stage of wound healing. 1496][157] While changes in distribution of subcutaneous layers remain unclear, diabetic patients experience adipose tissue redistribution and dysfunction that promote insulin resistance, fat storage, and deregulated inflammation and remodelling processes.Further advancements towards reversal, replacement, or supplementation of healthy adipocyte function may prove promising in attenuating adipocyte-driven pathology in diabetic complications including cutaneous wound healing.

PATIENTS
Resulting from the low-grade chronic inflammatory state, diabetes promotes inappropriate immune function that places patients at increased risk of infection.A dysfunctional skin barrier from glycaemic changes to collagen and SC may also present easier entry of pathogens for infection.Diabetic patients report about a two-fold increased risk of skin and soft tissue infections, most commonly including cellulitis and infected ulcers, with decreased resolution rates and increased complications associated with poor glycaemic control. 158,159ertain antimicrobial peptides such as RNAse7 are downregulated in the skin of diabetic patients regardless of ulcer presence, 160 decreasing host defence against infection.
Evidence indicates that the skin microbiome composition is altered in diabetic patients (Figure 1).A case-control study of cutaneous foot microbiome in T2D patients demonstrated increased abundance of Staphylococcus aureus and decrease in commensal Staphylococcus epidermidis compared with healthy skin. 161Increased abundance of S. aureus may arise from the epidermal barrier defects and hyperglycaemia, which increases glucose nutrient availability for S. aureus to enhance expression of virulence factors. 162,163This is in line with the complex microbiome characterised with antibiotic-resistant S. aureus and anaerobic bacteria associated with the non-healing outcomes in DFU. 164Another study of foot skin microbiome found that diabetic patients had a different microbiome composition, with increased Trichophyton rubrum and decreased fungal diversity. 165T. rubrum is a common dermatophyte contributing to onychomycosis and tinea pedis, reflecting the increased prevalence of fungal manifestations among the diabetic patient population. 166,167

| MICROVASCULATURE CHANGES AND PERIPHERAL NEUROPATHY DUE TO DIABETES
Hyperglycaemia is believed to cause microvascular disease in diabetes, with synergistic contribution from hypertension, dyslipidaemia, smoking, and duration of diabetes. 168ot limited to diabetes, microvascular and macrovascular dysfunction are independently associated with prediabetes and hyperglycaemia as well. 169Free fatty acid-derived endothelial injury causes insulin resistance and inflammation in insulin target tissues, resulting in inhibition of nitric oxide-mediated vasodilation. 8Vascular response to heat stress is also impaired in diabetes compared with both young and old non-diabetic individuals, indicating that the slowed, less prominent response may contribute to poor wound healing of burns in diabetic individuals. 141,1702][173] The cumulative effects of macroangiopathy due to atherosclerosis, vasculitis and microangiopathy contribute to skin atrophy and nail abnormalities due to chronic lack of oxygen. 173Prostacyclin I2 analogue increases blood flow in the foot skin of diabetic patients in correlation with reducing plasma thrombomodulin levels, an endothelial cell surface receptor for thrombin important in protein C-regulated coagulation. 174Peripheral hypercoagulation contributing to inadequate tissue perfusion may also promote the dysregulated wound healing cascade observed in DFUs.
6][177] Diabetic peripheral neuropathy is estimated to affect 30% of diabetic patients, a greater proportion of those with T2D. 178Multiple studies have shown reductions in intraepidermal nerve fibres density in skin biopsies from diabetic patients. 179,180As a diabetes complication associated with increased cardiovascular mortality and severe systemic manifestations, peripheral neuropathy also causes dry skin, loss of sweating, and loss of skin barrier function. 181hese cutaneous changes can contribute to the development of skin fissures, producing susceptibility to microorganisms in the context of an already deregulated immune system. 181ome studies suggest altered leukocyte composition in association with development of diabetic peripheral neuropathy, with increased neutrophil-to-lymphocyte ratio and increased basophil and CD4+ T-cell populations. 182,183Diabetic patients demonstrate significantly decreased periglandular nerve terminals, 184 and various neuropathy screening methods have found asymmetry of sensorimotor neuropathy between extremities to correlate with disease severity and DFUs. 185,186

| PHYSIOLOGICAL ACUTE WOUND HEALING IN DIABETIC INDIVIDUALS
8][189] Frequent reference is made to impaired post-operative wound healing in diabetic patients, for example, poor healing of post-surgical wounds, yet clinical evidence supporting this assertion is scant.Interestingly, surgical site infection was the only outcome found to be significantly increased post-operatively in diabetic patients as compared with non-diabetic individuals. 190,191To this end, meta-analysis revealed a significant association between diabetes and incidence of surgical site infection across multiple types of surgeries independent from body mass index, and this association was maintained independent from perioperative hyperglycaemia. 192Even this association has not been consistently reproduced; for example, no association between diabetes and postoperative infection was found on analysis of infection risk factors in patients undergoing bariatric surgery. 193Notably, studies have not supported a difference in post-surgical clinical healing outcomes-including delayed wound closure and abnormal scarring-in diabetic and non-diabetic wounds. 190,191For example, while AGE accumulation in diabetic skin impeding normal dermal function wound be expected to affect wound healing and the mechanical properties of scars, there are few reports to support that significantly impacts clinical wound healing outcomes in patients. 14Comorbidities, indications for surgery, and types of surgery impact not only the nature of the wound but also the systemic environment in which the wound is required to heal.Future studies are needed to observe the postoperative healing of diabetic and non-diabetic individuals to document patterns in healing rates, complication risks, and abnormal scarring.

| CONCLUSIONS AND CLOSING REMARKS
Diabetes causes significant structural and molecular changes to the skin, priming for development of cutaneous complications such as DFU (Figure 1).Pathologic uncontrolled hyperglycaemia contributes to impaired epidermal barrier and skin fragility.Altered keratinocyte and fibroblast activity reflect the early properties identified in impaired wound healing, and a dysregulated immune system promotes chronic inflammation with impaired function.Together these changes increase patient susceptibility to barrier breach, impaired healing, and persistent infection.Current clinical trials aiming to address these early cutaneous changes include moisturisers targeting foot xerosis [26][27][28] suggesting that improved management with therapies that target these early changes in non-injured diabetic skin may help reduce further complications.
There has been insufficient research on acute wound healing processes in diabetic patients to support clinical differences in healing, with the majority of clinical evidence demonstrating increased infection risk.Considering the lack of epidemiologic literature supporting the role of diabetes impairing acute wound healing, additional significant factors leading to the formation and persistence of wounds developing into DFU should be considered, such as location-based neuropathy and lack of surveillance/management of the wound site.Future clinical studies aiming to elucidate potential disparities between diabetic and non-diabetic acute wounding should consider surgery type, wound area and size, glycaemic control, patient comorbidities, and age, as well as increase their scope to measure additional aspects of healing including scarring and wound re-innervation.It may be challenging to collect and control for such data retrospectively, and large prospective studies of surgical procedures would be important to compare the acute wound healing process between diabetic and non-diabetic patients.Of note, many of the reviewed clinical studies focus on patients with T2D, possibly due to its greater incidence and prevalence as compared with T1D.In addition, epidemiologic studies suggest an increased prevalence of DFU in T2D patients compared to T1D. 194 The additive influence of common comorbidities of T2D, such as obesity, that also alter cutaneous microenvironment and immunity as risk factors for DFU development, should be considered as well. 195Nevertheless, the pathophysiology of glucose intolerance affecting cutaneous properties and neuropathy is universal across both types of diabetes, and related targeted therapies will aid in addressing the multifactorial emergence of diabetic complications.Representation of diabetes-induced cutaneous changes affecting epidermis, dermis, peripheral nerves, immune cells and subcutaneous tissue.AGE, advanced glycation end products.