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25 January 2026

Endocrine and Metabolic Modulation of Vascular Dysfunction in the Diabetic Foot: A Narrative Review

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Postgraduate School of Vascular and Endovascular Surgery, University of Milan, Via Festa del Perdono 7, 20122 Milan, Italy
2
Vascular and Endovascular Surgery Unit, IRCCS Ospedale Galeazzi—Sant’Ambrogio, Via Cristina Belgioioso 173, 20157 Milan, Italy
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School of Medicine and Surgery, University of Milan, Via Festa del Perdono 7, 20122 Milan, Italy
4
Department of Diabetes and Podiatric Care, IRCCS Ospedale Galeazzi—Sant’Ambrogio, Via Cristina Belgioioso 173, 20157 Milan, Italy
Endocrines2026, 7(1), 4;https://doi.org/10.3390/endocrines7010004
This article belongs to the Section Obesity, Diabetes Mellitus and Metabolic Syndrome
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Abstract

Diabetic foot complications represent a major global health burden and arise from a multifactorial interaction between neuropathy, ischemia, infection, and impaired wound repair. Increasing evidence suggests that, beyond traditional vascular and metabolic risk factors, endocrine dysregulation plays a central role in shaping vascular dysfunction and tissue vulnerability in patients with diabetes. This narrative review provides an updated overview of the endocrine–vascular axis in the development, progression, and healing of diabetic foot ulcers (DFUs), integrating evidence from experimental and clinical studies identified through targeted searches of PubMed, Embase, and Scopus. We examine how alterations in insulin signaling, relative glucagon excess, adipokine imbalance, dysregulation of stress hormones, and thyroid dysfunction interact with chronic hyperglycemia, dyslipidemia, mitochondrial dysfunction, and low-grade inflammation to impair endothelial homeostasis. These disturbances promote oxidative stress, reduce nitric oxide bioavailability, and compromise microvascular perfusion, thereby creating a pro-ischemic and pro-inflammatory tissue environment that limits angiogenesis, extracellular matrix (ECM) remodeling, immune coordination, and effective wound repair. By linking pathophysiological mechanisms to clinical relevance, this review highlights potential biomarkers of endocrine–vascular dysfunction, implications for risk stratification, and emerging therapeutic perspectives targeting metabolic optimization, endothelial protection, and hormonal modulation. Finally, key knowledge gaps and priority areas for future translational and clinical research are discussed, supporting the development of integrated endocrine-based strategies aimed at improving DFU prevention, healing outcomes, and long-term limb preservation in patients with diabetes.

1. Introduction

Diabetic foot ulcers (DFUs) are among the most severe complications of diabetes, affecting approximately 15% of patients and representing the leading cause of non-traumatic lower-limb amputations worldwide [1,2,3]. With a five-year mortality rate of nearly 50%, DFUs impose a substantial burden on patient survival and healthcare systems [4,5].
The pathogenesis of DFUs is traditionally interpreted through the triad of neuropathy, ischemia, and infection. Peripheral neuropathy, present in nearly half of patients with long-standing diabetes, abolishes protective sensation and predisposes the foot to repetitive, unrecognized trauma [6].
This vulnerability is frequently compounded by peripheral arterial disease (PAD) and diabetes-specific medial arterial calcification, which produce severe distal ischemia and limit adaptive perfusion responses [7]. At a microvascular level, capillary basement membrane thickening and reduced nitric oxide (NO) bioavailability further aggravate tissue hypoxia and impair nutrient delivery to the wound bed [7].
Beyond these structural and hemodynamic deficits, chronic hyperglycemia drives a series of biochemical alterations, including the accumulation of advanced glycation end products (AGEs) and mitochondrial dysfunction, which impair the regenerative capacity of keratinocytes, fibroblasts and endothelial cells [8]. This pro-inflammatory milieu, characterized by macrophage dysregulation and ineffective neutrophil responses, often arrests the wound in a chronic non-healing state [9]. Moreover, even though most of the treated DFUs heal within one year, recurrence rates exceed 60% at three years despite multidisciplinary management [10].
Endocrine factors represent an additional, systemic layer of vulnerability influencing vascular function and tissue repair in diabetes. Dysregulated insulin signaling, relative hyperglucagonemia, altered adipokine secretion, stress hormone activation and thyroid dysfunction exert coordinated effects on endothelial homeostasis, immune regulation, and metabolic efficiency [11,12]. However, these influences are frequently evaluated separately and remain underintegrated within prevailing models of diabetic foot disease. This narrative review aims to synthesize current experimental and clinical evidence on the endocrine–vascular interface, examining how hormonal and metabolic disturbances interact with microvascular dysfunction to promote ischemia and impair wound healing, thereby supporting a more integrated, physiology-driven framework for understanding DFU pathogenesis.

2. Overview of Diabetic Foot Pathophysiology

DFU pathophysiology results from the synergistic interplay of metabolic, vascular and neuropathic abnormalities. Chronic hyperglycemia drives endothelial dysfunction and oxidative stress, compromising the vascular networks that sustain lower-limb perfusion. This creates a pro-inflammatory, hypoxic, and mechanically vulnerable environment that predisposes to ulceration and arrests the healing process.

2.1. Macrovascular Disease and Peripheral Arterial Impairment

Macrovascular disease is a central determinant of ischemia in the diabetic foot. Hyperglycemia and pro-atherogenic lipid profiles accelerate plaque development and medial arterial calcification, resulting in reduced arterial compliance and compromised perfusion, particularly in infrapopliteal vessels [13,14]. Limited collateral formation further restricts distal blood flow, while the frequent coexistence of peripheral neuropathy delays the recognition of ischemic symptoms, contributing to late presentation and more advanced tissue involvement [15].

2.2. Microvascular Dysfunction and Endothelial Failure

Microvascular alterations critically amplify macrovascular deficits. Structural abnormalities, including capillary basement membrane thickening and degradation of the endothelial glycocalyx, reduce microvascular compliance and impair capillary exchange [16]. Functionally, diminished NO bioavailability and dysregulated autoregulation result in inadequate nutritive perfusion [17]. Furthermore, capillary rarefaction and functional impairment of endothelial progenitor cells (EPCs) limit microvascular repair and neovascularization, creating a chronic low-perfusion state that reduces tissue resilience [18].

2.3. Neuropathy, Biomechanical Stress, and Tissue Breakdown

Neuropathy contributes to DFU pathogenesis by interfering with vascular and metabolic disturbances. Sensory loss abolishes protective feedback against mechanical trauma, while motor neuropathy alters intrinsic foot muscle function, leading to deformities and gait changes that redistribute plantar pressures [19]. Autonomic neuropathy further compromises tissue integrity by impairing sweat secretion and skin hydration, increasing susceptibility to microtears [20].
Once tissue integrity is compromised, hyperglycemia-driven biochemical abnormalities—AGEs and reactive oxygen species (ROS)—disrupt keratinocyte and fibroblast signaling, reducing angiogenic capacity and extracellular matrix (ECM) remodeling [21]. The convergence of mechanical stress, microvascular failure and impaired immune coordination establishes a microenvironment prone to chronic ulceration and recurrence (Figure 1).
Figure 1. Multisystem pathophysiological processes driving diabetic foot ulcer development.

3. The Endocrine Influence on Vascular Health in Diabetes

Endocrine dysregulation is a systemic driver of vascular impairment in the diabetic foot. Beyond hyperglycemia, alterations in insulin signaling, adipokine secretion and stress hormone activation modulate endothelial homeostasis, inflammatory responses and angiogenic capacity. These hormonal imbalances interact with oxidative stress and AGE–receptor for AGEs (RAGE) signaling to exacerbate tissue ischemia and delay repair by creating a pro-ischemic and pro-inflammatory vascular phenotype.

3.1. Insulin and Glucagon Imbalance

Insulin resistance selectively disrupts vasoprotective signaling by impairing the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway in endothelial cells, which reduces NO production [22,23]. Conversely, the mitogen-activated protein kinase (MAPK) pathway remains preserved, leading to an imbalance that favors vasoconstrictive and pro-inflammatory forces [24,25].
Since glucagon primarily regulates hepatic glucose, dysregulated secretion exacerbates hyperglycemia and may indirectly reduce endothelial nitric oxide synthase (eNOS) expression [26,27]. Hence, this hormonal imbalance reduces microvascular adaptability and perfusion reserve, increasing ischemic vulnerability in the diabetic foot.

3.2. Adipokines (Leptin, Adiponectin, Resistin)

In obesity and type 2 diabetes, dysregulated adipokine profiles significantly drive endothelial inflammation [28,29]. Adiponectin provides anti-inflammatory and vasoprotective effects by enhancing NO bioavailability and suppressing adhesion molecule expression; thus, its reduction in diabetes is directly linked to impaired perfusion and delayed healing [30,31]. In contrast, hyperleptinemia upregulates caveolin-1 and inhibits NO signaling, while resistin enhances endothelin-1 release and pro-inflammatory cytokine production, such as Tumor Necrosis Factor alpha (TNF-α) and interleukin-12 (IL-12) [32,33,34]. Furthermore, resistin-induced vascular smooth muscle cell proliferation may contribute to progressive vascular narrowing and restenosis [35].

3.3. Stress Hormones (Cortisol, Catecholamines)

Chronic activation of the hypothalamic–pituitary–adrenal axis (HPA axis) and sympathetic nervous system facilitates metabolic and vascular damage [36]. Prolonged catecholamine exposure activates β-adrenergic receptors on endothelial cells, downregulating eNOS activity and increasing oxidative stress [37]. In adipose tissue, catecholamines stimulate lipolysis, increasing free fatty acids that promote insulin resistance and endothelial inflammation [38].
Simultaneously, chronic hypercortisolemia, often driven by increased 11β-HSD1 activity, elevates pro-inflammatory cytokines (IL-1, IL-6, TNF-α), impairing microvascular repair and wound healing [39,40]. Elevated cortisol is also associated with diabetic neuropathy through neural demyelination, further increasing the risk of unrecognized tissue injury [41].

3.4. Thyroid Hormones

Thyroid hormones, triiodothyronine (T3) and thyroxine (T4), play a central role in regulating systemic metabolism, vascular tone, and tissue perfusion [42,43,44]. At a vascular level, thyroid hormones enhance endothelial NO production, reduce systemic vascular resistance and support adequate microcirculatory flow [43,44]. Thyroid dysfunction, particularly hypothyroidism, is highly prevalent in patients with diabetes and has been associated with worse metabolic and vascular outcomes [42,45].
Hypothyroidism contributes to endothelial dysfunction through multiple mechanisms, including impaired erythropoiesis, increased blood viscosity, oxidative stress and reduced metabolic efficiency, thereby aggravating tissue hypoxia and microvascular injury in the diabetic foot [42]. In addition, thyroid hormones regulate angiogenesis through both non-genomic and genomic pathways. Rapid non-genomic signaling via integrin αvβ3 activates MAPK pathways, promoting endothelial proliferation and migration, while genomic mechanisms regulate the transcription of angiogenic factors such as vascular endothelial growth factor (VEGF) and angiopoietins [46].
In hypothyroid states, attenuation of these pathways results in impaired neovascularization, reduced granulation tissue formation and delayed wound repair [46]. Clinical evidence indicates that both overt and subclinical hypothyroidism are associated with increased prevalence and severity of DFUs, including higher Wagner grades and complication rates [47]. These observations support routine assessment of thyroid function in patients with diabetic foot disease as part of a comprehensive endocrine–vascular evaluation (Table 1).
Table 1. Endocrine factors involved in vascular dysfunction and impaired wound healing in the diabetic foot.

3.5. Vitamin D as a Neuro-Endocrine Modulator of Wound Healing

Vitamin D, acting as a pleiotropic steroid hormone, has emerged as a crucial player in the endocrine–vascular axis of the diabetic foot. Beyond its role in calcium homeostasis, vitamin D exerts significant extraskeletal effects by binding to the Vitamin D Receptor (VDR) expressed on endothelial cells, keratinocytes and immune cells [48]. In patients with diabetes, vitamin D deficiency is highly prevalent and has been independently associated with an increased risk of DFU development and impaired healing rates [49].
At a vascular level, 1,25-dihydroxyvitamin D3 enhances the endothelial barrier function by modulating tight junction proteins and reducing vascular permeability. Furthermore, vitamin D is a primary inducer of the antimicrobial peptide cathelicidin (LL-37), which is essential for the innate immune defense against opportunistic infections in the ulcer bed [50]. Finally, in the later stages of repair, vitamin D promotes the transition from a pro-inflammatory to a pro-regenerative macrophage phenotype, facilitating re-epithelialization and granulation tissue maturation. Correcting vitamin D deficiency, thus, may represent a targeted endocrine strategy to strengthen the immune response and promote wound healing in the diabetic foot [51,52] (Figure 2).
Figure 2. Endocrine modulation of vascular integrity. (A) Representation of physiological signaling pathways supporting vascular homeostasis. (B) Pathological disruption of these pathways in diabetes. The figure illustrates how the interplay between insulin resistance, hypercortisolemia, and thyroid dysfunction promotes oxidative stress and inflammation, driving both microvascular and macrovascular failure and the development of diabetic foot ulcer. Created in BioRender. Galassi, L. (2026) https://BioRender.com/g0vf5dt (accessed on 4 January 2026). VEGF = Vascular endothelial growth factor, FGF-2 = fibroblast growth factor, ET-1 = endothelin 1, IL-6 = interleukin 6, TNF-α = Tumor necrosis factor alpha.

4. Metabolic and Endocrine Determinants of Ischemia and Impaired Wound Progression in the Diabetic Foot

In the diabetic foot, ischemia and chronic wound failure are strongly determined by metabolic and endocrine dysregulation and sustained inflammatory stress. Hyperglycemia, dyslipidemia and mitochondrial dysfunction interact to disrupt endothelial homeostasis, blunt angiogenic responsiveness and compromise tissue repair. Rather than acting as independent insults, these factors reinforce one another, establishing a self-perpetuating state of microvascular insufficiency and tissue fragility that predisposes to ulcer persistence and recurrence.

4.1. Hyperglycemia, the AGE–RAGE Axis, and Endothelial Injury

Engagement of the RAGE activates Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB)-dependent transcriptional programs that sustain a pro-inflammatory and proteolytic environment characterized by cytokine release, adhesion molecule expression and matrix metalloproteinase (MMP) upregulation [14,53].
Beyond sustaining inflammation, AGE–RAGE signaling destabilizes hypoxia-inducible factor-1α (HIF-1α) and attenuates VEGF responsiveness, effectively inducing a state of angiogenic resistance despite persistent ischemic stimuli [54,55]. This blunted response limits endothelial cell proliferation and impairs the mobilization and function of EPCs, which are essential for microvascular repair in DFUs.

4.2. Dyslipidemia, Cytoskeletal Stiffening, and Mitochondrial Convergence

The atherogenic lipid profile typical of type 2 diabetes, characterized by elevated triglycerides and reduced high-density lipoprotein cholesterol (HDL-C), amplifies endothelial injury in the diabetic foot [56]. In an oxidative milieu, oxidized low-density lipoprotein (oxLDL) activates CD36-dependent RhoA/ROCK signaling, inducing cytoskeletal stiffening and reducing endothelial compliance [26,57,58]. These biomechanical alterations further impair capillary recruitment and nutritive perfusion, exacerbating local ischemia.
Mitochondrial dysfunction represents a critical convergence point for hyperglycemia- and dyslipidemia-driven stress. Chronic nutrient overload disrupts mitochondrial dynamics and suppresses mitophagy through impairment of the PINK1/Parkin pathway [59,60]. The accumulation of dysfunctional mitochondria increases ROS production, damages mitochondrial DNA, and promotes endothelial apoptosis, supporting microvascular rarefaction and limiting cellular survival within the wound bed [61,62]. As a result, the diabetic microvasculature becomes trapped in a state of reduced angiogenic competence and diminished reparative capacity.

4.3. Systemic Inflammation, EPC Dysfunction, and Angiogenic Failure

Local vascular injury, partly due to metabolic dysregulation, contributes to determining a systemic pro-inflammatory phenotype. Persistent NF-κB activation drives sustained release of inflammatory mediators such as IL-6 and TNF-α, which accelerate endothelial senescence and apoptosis [14,63,64]. In this inflammatory context, ischemia-induced reparative signals fail to elicit an adequate regenerative response.
In diabetes, circulating EPCs, which normally contribute to neovascularization and endothelial repair, are reduced in number and functionally impaired [65,66]. EPC mobilization, homing and incorporation into damaged microvessels is collectively inhibited by oxidative stress, inflammatory cytokines and impaired NO signaling. This defect contributes to persistent capillary rarefaction and maintains a chronic low-perfusion state, limiting tissue resilience and wound healing.

4.4. Failure of Wound Progression: Inflammation, ECM Dysregulation and Structural Inferiority

The combined effects of metabolic and endocrine stress decouple the strictly regulated phases of inflammation and wound healing, resulting in the formation of structurally inferior repair tissue. DFUs are frequently arrested in a state of unresolved inflammation, characterized by persistent RAGE activation and dominance of pro-inflammatory M1 macrophage phenotypes [67,68]. This polarization impairs efferocytosis and prevents the transition toward reparative M2 macrophages, sustaining tissue injury and susceptibility to infection [69,70].
As far as fibroblasts and keratinocytes are involved, they acquire a senescent phenotype with reduced migratory and proliferative capacity because of exposure to chronic hyperglycemia, oxidative stress and inflammatory cytokines [61,71,72]. Excessive TNF-α disrupts cytoskeletal organization, while AGE-mediated collagen cross-linking increases matrix stiffness and impairs cellular traction forces necessary for wound contraction [61,73].
Pro-inflammatory signaling disrupts the balance between matrix metalloproteinases and their inhibitors, particularly through upregulation of MMP-9 and suppression of tissue inhibitor of metalloproteinases-1 (TIMP-1), leading to degradation of growth factors and ECM components [71,72]. Concurrent reductions in insulin-like growth factor-1 (IGF-1) and transforming growth factor-β1 (TGF-β1), compounded by chronic hypercortisolemia, suppress type I collagen synthesis and impair matrix maturation [74,75].
Failure to transition from type III to type I collagen results in scar tissue with reduced tensile strength, poor load tolerance and a high risk of ulcer recurrence [76,77]. In this context, wound closure, when achieved, often represents a fragile equilibrium rather than durable tissue restoration, explaining the high rates of re-ulceration observed in patients with diabetes.

5. The Endocrine–Metabolic Convergence Driving Microvascular Failure

Collectively, these metabolic and endocrine disturbances converge on a limited number of shared downstream nodes that cause microvascular failure in the diabetic foot. Reduced NO bioavailability, persistent oxidative stress, mitochondrial dysfunction and chronic inflammatory signaling represent common final pathways through which hyperglycemia, dyslipidemia and hormonal imbalance impair endothelial adaptability and angiogenic competence. Rather than acting as an independent insult, endocrine dysregulation amplifies pre-existing vascular injury by lowering the threshold for ischemia, interfering with reparative signaling and limiting the capacity of ischemic tissues to respond to regenerative stimuli. Within this framework, impaired wound healing derives not solely from inadequate perfusion or local tissue damage, but also from a systemic failure of endocrine–vascular coordination that compromises tissue resilience and repair durability.
This mechanistic convergence provides the biological rationale for interpreting DFUs not only through anatomical severity, but also through the systemic endocrine–vascular context that shapes tissue tolerance, reparative capacity and clinical trajectory.

6. Clinical Stratification and Endocrine–Vascular Contextualization in Diabetic Foot Disease

The clinical trajectory of DFUs reflects the interaction between local tissue injury and systemic biological vulnerability. While ulcer morphology, infection status and macrovascular perfusion remain central to clinical staging, markers of metabolic activity, inflammation and vascular integrity have been consistently associated with impaired healing and adverse limb outcomes, suggesting that systemic endocrine–vascular status may provide critical information for contextual DFU assessment [14,78,79].

6.1. Endocrine–Metabolic Biomarkers as Indicators of Biological Vulnerability

Systemic endocrine–metabolic dysfunction identifies phenotypes characterized by reduced reparative reserve, which may not be fully captured by anatomical or hemodynamic parameters alone [80]
Among routinely available biomarkers, dyslipidemia has been consistently associated with impaired reparative signaling and adverse limb outcomes, with an increased risk of major amputation in patients with unfavorable lipid profiles [81]; specifically, decreased HDL-C values may be associated with a 2.5-fold risk of major amputation [82]. Surrogate indices of insulin resistance, such as the triglyceride–glucose index (TyG index), further reflect reduced metabolic flexibility and increased vascular stiffness, both of which are associated with prolonged or unstable healing trajectories [83,84]. These abnormalities frequently coexist with renal disease, which independently amplifies ischemic susceptibility and delays wound resolution [85,86].
Inflammatory and nutritional markers, including the C-reactive protein (CRP)-to-albumin ratio, may offer additional insight into systemic biological fragility. Persistent inflammation together with poor nutritional status antagonize pro-regenerative signaling and have been associated with an increase in limb amputation [87,88].
Systemic hormonal status, including hypothyroidism, vitamin D deficiency and markers of stress hormone activation, has been associated with variability in ulcer healing outcomes [89,90,91], further suggesting that hormonal status potentially contributes to interindividual variability in healing capacity. Importantly, current evidence is largely observational, and, to date, routine hormonal screening in all DFU patients is not supported by interventional data [92].
From a biomechanical perspective, endocrine–metabolic derangements adversely affect collagen organization, microvascular perfusion and tissue viscoelastic properties. As a result, the wound bed may exhibit reduced tolerance to repetitive mechanical stress, partially explaining the limited effectiveness of off-loading strategies in patients with unfavorable systemic profiles [93]. Integrating endocrine–vascular context with foot-specific variables, such as plantar pressure distribution and response to off-loading [94], may yield a more nuanced understanding of healing potential and recurrence risk [95].
While omics-based approaches offer future opportunities for refined phenotyping, limited validation currently supports the pragmatic use of accessible endocrine–metabolic markers within integrated prognostic frameworks [96,97].

6.2. Integrating Endocrine–Vascular Status into Risk Stratification Paradigms

Conventional DFU risk stratification primarily emphasizes ulcer depth, infection severity and macrovascular inflow, providing a primarily structural assessment of disease burden [98]. However, while these models are essential for guiding revascularization and surgical decision-making, they may not fully capture the systemic biological vulnerability.
Within this framework, endocrine and metabolic dysfunctions [99] currently should be interpreted as risk modifiers rather than standalone risk predictors, contributing to lowering the threshold for tissue injury and limiting recovery in response to mechanical load and ischemic stress even when macroscopic perfusion appears adequate.
Current evidence supports a modular, multidisciplinary framework in which podiatric, vascular and endocrine assessments are complementary rather than hierarchical [100,101]. Within this paradigm, systemic endocrine–vascular status defines the biological substrate upon which local and vascular interventions act, [102] helping to explain interindividual variability in outcomes without duplicating therapeutic decision-making [103,104] (Table 2).
Table 2. Risk stratification and classification in diabetic foot 1.

7. Therapeutic and Clinical Implications

Management of the diabetic foot traditionally relies on a combination of revascularization, infection control and advanced wound care techniques. While these interventions are indispensable for limb salvage, their effectiveness is strongly modulated by the systemic endocrine and metabolic environment, which influences endothelial function, microvascular responsiveness and tissue reparative capacity [112].
Revascularization remains a cornerstone of therapy; however, restoration of macroscopic blood flow does not invariably result in effective microcirculatory reperfusion. Persistent endothelial dysfunction, impaired angiogenic signaling and depletion or dysfunction of EPCs may limit functional tissue perfusion and contribute to delayed or incomplete wound healing, even after technically successful procedures [112].
Beyond glycemic control, metabolic interventions that improve insulin sensitivity may exert indirect vasculoprotective effects by enhancing endothelial NO signaling, reducing oxidative stress and modulating inflammatory pathways. Glucose-lowering agents with pleiotropic cardiovascular effects, such as glucagon-like peptide-1 receptor agonists and sodium–glucose cotransporter-2 inhibitors, have demonstrated beneficial effects on endothelial function and systemic inflammation, although their specific impact on diabetic foot outcomes warrants further investigation [113,114].
From a clinical standpoint, these observations support an even more integrated approach to diabetic foot management, in which endocrine assessment complements vascular and podiatric evaluation. Identification of endocrine dysfunction may aid in risk stratification, help predict wound healing potential and identify patients less likely to benefit from isolated revascularization or local treatment strategies [115].
More broadly, reframing the diabetic foot as a consequence of disrupted endocrine–vascular crosstalk encourages a shift toward personalized, mechanism-driven care. Addressing systemic endocrine dysregulation alongside vascular and local therapies may represent a critical step toward improving therapeutic responsiveness, enhancing wound healing and ultimately increasing rates of limb preservation in patients with diabetes [116,117].

8. Future Directions and Research Gaps

Despite the growing recognition of the endocrine–vascular axis in DFU pathophysiology, substantial gaps remain limiting the translation of mechanistic insights into clinically actionable strategies. Current clinical assessment of the diabetic foot relies predominantly on anatomical, hemodynamic and neurological evaluations, which offer a relatively “static” view of a microenvironment that is instead dynamically regulated by systemic metabolic and endocrine fluctuations [118]. Integrated biomarker profiles linking systemic hormonal dysfunction to local vascular activity may allow for the early identification of ulcers at high risk of stagnation [80]. However, a major unmet need lies in the lack of longitudinal studies capable of defining the temporal relationship between endocrine variability, such as chronic dysregulation of the HPA axis, and long-term tissue durability or ulcer recurrence.
A promising but insufficiently explored research frontier is the concept of “metabolic memory,” whereby prior exposure to a dysregulated diabetic milieu induces persistent epigenetic and cellular alterations that may undermine healing even after glycemic optimization [119]. Furthermore, while interventional research has extensively evaluated local strategies, including stem cell-based therapies, growth factor delivery, and oxygen-based treatments, most clinical trials do not incorporate systemic endocrine or metabolic profiling [120,121]. As a result, the lack of systemic endocrine and metabolic profiling may limit mechanistic stratification of therapeutic response, constraining efforts to identify biologically defined responder phenotypes linked to hormonal or metabolic dysregulation.
Finally, the role of endocrine-targeted therapies as specific modifiers of vascular repair in the diabetic foot remains largely unexplored. Although glucose-lowering and lipid-modifying agents have been extensively studied for macrovascular outcomes, prospective trials evaluating their direct effects on microcirculatory recruitment, wound healing trajectories, and limb-related endpoints are scarce [122,123].
Although glucose-lowering and lipid-modifying therapies have been extensively evaluated for their effects on cardiovascular and macrovascular outcomes in patients with diabetes [124], their potential role as modulators of microvascular repair processes in diabetic foot disease has been less systematically investigated [124,125]. Current evidence is mainly derived from experimental models, mechanistic studies and observational or post hoc clinical analyses. In contrast, prospective clinical trials specifically designed to assess microcirculatory recruitment-related outcomes such as wound-healing trajectories and limb preservation in the context of diabetic foot complications remain limited [80].

9. Conclusions

The diabetic foot represents the final clinical expression of a progressive disruption of vascular and reparative homeostasis driven not only by atherosclerosis and microangiopathy, but also by systemic endocrine dysregulation. This review highlights how alterations in insulin signaling, adipokine balance, stress hormone activity and thyroid function act as amplifiers of endothelial dysfunction, microvascular failure and impaired tissue resilience in diabetes.
These endocrine disturbances converge on shared downstream mechanisms, including reduced NO bioavailability, mitochondrial dysfunction, chronic inflammation and defective angiogenic responses, linking systemic metabolic imbalance to local ischemia and non-healing wounds. Rather than introducing distinct pathogenic pathways, endocrine dysfunction exacerbates pre-existing vascular injury and limits the capacity of ischemic tissues to mount effective reparative responses, helping to explain the frequent failure of wound healing despite adequate revascularization.
Recognizing the endocrine–vascular interface may have further important clinical and research implications. Integrating endocrine assessment into multidisciplinary diabetic foot care may improve risk stratification and support more personalized therapeutic strategies, while future research should focus on targeting shared downstream nodes to restore microvascular competence and promote durable wound healing.

10. Limitations

This review has several limitations that should be acknowledged. First, the present work is a narrative review and therefore does not follow a systematic methodology or predefined inclusion criteria. Although the literature search was conducted across major databases and focused on recent and high-impact studies, the selection of evidence may be subject to selection bias, and some relevant studies may not have been included.
Second, much of the mechanistic evidence linking endocrine dysregulation to vascular dysfunction and impaired wound healing in diabetes is derived from experimental, preclinical, or observational studies. While these data provide important pathophysiological insights, their direct clinical translatability to DFU prevention and treatment remains incompletely established. In several domains, particularly regarding glucagon signaling, stress hormones and thyroid dysfunction, human interventional data are limited, and causal relationships cannot be definitively inferred.
Third, endocrine and metabolic abnormalities frequently coexist and interact in patients with diabetes, making it difficult to isolate the independent contribution of individual hormones or metabolic pathways to DFU development and healing outcomes. As a result, the effects described in this review likely reflect complex, multifactorial interactions rather than linear cause–effect relationships.
Finally, the review focuses primarily on pathophysiological mechanisms and does not provide a quantitative comparison of therapeutic interventions or clinical outcomes. Consequently, the proposed endocrine–vascular framework should be viewed as hypothesis-generating, intended to support future translational and clinical research rather than to define evidence-based treatment recommendations.
Despite these limitations, this review integrates emerging evidence across endocrinology, vascular biology, and wound healing, offering a comprehensive conceptual model that may inform future mechanistic studies and interdisciplinary approaches to diabetic foot management.

Author Contributions

Conceptualization, L.G. and K.N.; methodology, L.G., M.L.R. and K.N.; investigation, E.A., E.G., B.F. and N.L.D.; data curation, E.A. and E.G.; writing—original draft preparation, E.A. and E.G.; writing—review and editing, L.G., M.L.R., K.N., B.F. and N.L.D.; section writing (volume management), G.C.; supervision, K.N.; project administration, L.G. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Data Availability Statement

No new data were created or analyzed in this study. Data sharing is not applicable to this article.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

AGEsAdvanced glycation end products
AKTProtein kinase B
CRPC-reactive protein
DFUDiabetic foot ulcer
DFUsDiabetic foot ulcers
ECMExtracellular matrix
eNOSEndothelial nitric oxide synthase
EPCsEndothelial progenitor cells
ET-1Endothelin-1
FGF-2Fibroblast Growth Factor-2
HDL-CHigh-density lipoprotein cholesterol
HIF-1αHypoxia-inducible factor-1 alpha
HPA axisHypothalamic–pituitary–adrenal axis
IGF-1Insulin-like growth factor-1
ILInterleukin
LL-37Cathelicidin antimicrobial peptide
MAPKMitogen-activated protein kinase
MMPMatrix metalloproteinase
MMP-9Matrix metalloproteinase-9
NF-κBNuclear factor kappa-light-chain-enhancer of activated B cells
NONitric oxide
oxLDLOxidized low-density lipoprotein
PADPeripheral arterial disease
PI3KPhosphoinositide 3-kinase
RAGEReceptor for advanced glycation end products
ROSReactive oxygen species
T3Triiodothyronine
T4Thyroxine
TGF-β1Transforming growth factor beta 1
TIMP-1Tissue inhibitor of metalloproteinases-1
TNF-αTumor necrosis factor alpha
TyG indexTriglyceride–glucose index
VCAM-1Vascular cell adhesion molecule 1
VEGFVascular endothelial growth factor
VDRVitamin D receptor

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