Perspective Chapter: Diabetic Foot Pathophysiology and Prevention of Amputation through Behavioral Modification

Abstract

Diabetic foot complications are the result of a complex interplay involving various physiological factors, including macrovascular and microvascular alterations, neuropathy, inflammation, immune responses, hyperglycemia, oxidative stress, and susceptibility to infection. Macrovascular elements, such as atherosclerosis, give rise to tissue ischemia, while microvascular dysfunction exacerbates impairments in perfusion. Neuropathy plays a pivotal role in the development of these complications, manifesting as sensory loss, motor impairments, and autonomic dysfunction. These neurological deficits lead to the occurrence of unnoticed injuries, muscle atrophy, deformities, and dry skin, thereby increasing the vulnerability to nonhealing wounds and infections. Inflammation and immune responses intricately augment tissue damage while concurrently impeding the healing process. The persistent elevation of blood glucose levels in diabetes leads to the formation of advanced glycation end products, which contribute to tissue stiffening. Additionally, oxidative stress exacerbates the extent of damage. Mitochondrial dysfunction further exacerbates these challenges by compromising cellular energy production, thereby exacerbating the difficulties in tissue repair. These multifaceted factors collectively form a significant contributory framework for the onset and progression of diabetic foot complications. Moreover, with regard to modifiable factors, an examination of the influence of behaviors such as smoking, excessive alcohol consumption, and physical activity on the likelihood of lower extremity amputation (LEA) among individuals with diabetes becomes evident. Comprehensive data analysis discerns an elevated risk of LEA associated with smoking and heavy alcohol consumption, while regular exercise is associated with a decreased risk. The cumulative effect of these behaviors underscores the paramount importance of behavior modification in the prevention of LEA and the enhancement of the overall well-being of diabetic patients. Profound comprehension of these mechanisms is imperative for the formulation of efficacious preventive measures, diagnostic protocols, and therapeutic interventions, thereby addressing the considerable impact of diabetic foot complications on both individuals and healthcare systems.

1. Introduction

The diabetic foot represents a multifaceted complication associated with diabetes, characterized by concurrent peripheral neuropathy and vasculopathy driven by intricate metabolic pathways, as indicated in prior research [1, 2, 3]. The escalating prevalence of this condition is intricately connected to the growing incidence of diabetes and the extension of life expectancy [2]. Foot ulcers affect 15–25% of diabetic patients [4, 5], significantly impacting their lives and mortality rates [6, 7]. Remarkably, 28% of these ulcers lead to lower limb amputations [8], with a 5-year mortality rate ranging from 42 to 79% [9, 10]. In the Korean population, the prevalence of diabetes stands at approximately 14.4%, with a notable concentration among the elderly demographic. This condition imposes substantial healthcare expenditures, accounting for an estimated 12 billion dollars and representing approximately 7.7% of the total health insurance costs.

This study undertakes an in-depth examination of the pathophysiological mechanisms underpinning diabetic foot complications and investigates the potential for amputation prevention through behavioral interventions. Leveraging a comprehensive review of existing literature, our objective is to elucidate the intricate facets of this condition and proffer pragmatic strategies for its mitigation and prevention.

2. Pathophysiology of diabetic foot

Diabetic foot complications arise from complex interplay between macrovascular and microvascular alterations, neuropathic changes, inflammatory processes, immune responses, persistent hyperglycemia, oxidative stress, and an increased susceptibility to infections

2.1 Macrovascular changes

Macrovascular alterations in the context of diabetic foot complications are principally characterized by atherosclerosis, a persistent malady afflicting larger blood vessels [11]. This intricate process commences with hyperglycemia, a defining feature of diabetes, initiating a sequence of events culminating in endothelial dysfunction [12]. Elevated levels of blood glucose precipitate harm to the fragile endothelial cells that line the arterial walls, providing a foundation for ensuing inflammation and the deposition of lipid-laden plaques within the arterial walls [13, 14]. Over time, these plaques accumulate and undergo rigidification, constricting the arteries and diminishing blood flow to the lower extremities.

The repercussions of macrovascular modifications are of significant consequence. The diminished blood flow to the feet can lead to chronic ischemia, resulting in the deprivation of tissues from the requisite oxygen and nutrients for proper function [15]. This compromised circulation contributes to tissue damage and amplifies the susceptibility to complications, such as ulcers and infections. Furthermore, macrovascular changes can also incite arterial thrombosis, compounding the issue by obstructing blood flow.

2.2 Microvascular changes

Microvascular alterations within the diabetic foot are, if not more so, of equal importance when compared to macrovascular changes. These modifications predominantly affect the small blood vessels, encompassing arterioles, capillaries, and venules [12]. A distinctive hallmark of these microvascular changes is diabetic microangiopathy, with chronic hyperglycemia serving as a pivotal initiator and perpetuator of these alterations.

Within the realm of diabetic microangiopathy, there is observed thickening of the basement membranes of small blood vessels coupled with an escalation in capillary permeability [16]. This culminates in an impairment of normal vascular regulation and functionality. Consequently, the delivery of oxygen and nutrients to the tissues becomes compromised, while the removal of waste products is hindered [17]. The end result is tissue hypoxia, which can lead to cellular dysfunction and eventual demise.

The ramifications of these microvascular changes are substantial. The reduced blood supply to the foot tissues heightens susceptibility to injury and impedes the body’s natural wound healing processes [18]. This diminished perfusion contributes to tissue deterioration, the formation of ulcers, and delayed wound healing. Furthermore, it impairs the regular functionality of sweat glands and the skin, rendering the skin more prone to dryness and fissures.

2.3 Neuropathy

Neuropathy represents another pivotal facet of diabetic foot pathophysiology, profoundly influencing both the somatic and autonomic nervous systems [19]. Sensory neuropathy, arguably the most recognized variant of neuropathy in the context of diabetes, results in the loss of protective sensation, rendering patients less attuned to injuries or trauma to their feet [20]. Patients may inadvertently step on sharp objects, develop blisters, or sustain minor injuries without perceptible awareness [21]. This absence of pain perception underscores the propensity for the development of neuropathic ulcers, a characteristic hallmark of diabetic foot complications.

Conversely, motor neuropathy can lead to muscle weakness and the emergence of foot deformities [22]. Muscles may undergo atrophy, and patients may exhibit altered gait patterns that accentuate pressure on specific regions of the foot [23]. This aberrant mechanical stress further heightens the diabetic foot’s predisposition to injury and ulceration.

Autonomic neuropathy exerts its impact on the autonomic nervous system, regulating functions such as blood pressure, heart rate, and sweat production [20]. Within the diabetic foot, autonomic neuropathy may result in fluctuations in skin blood vessel tone, giving rise to erratic changes in blood flow. These fluctuations can induce episodes of hyperemia or ischemia, both of which significantly contribute to the risk of foot-related complications [21].

2.4 Hyperglycemia

Hyperglycemia stands as the cardinal hallmark of diabetes, serving as the foundational factor underpinning a multitude of the pathophysiological alterations evident in the diabetic foot [24]. Elevated blood glucose levels facilitate the onset of oxidative stress and inflammation, disrupt vital metabolic pathways, and compromise cellular function.

One of the central mechanisms through which hyperglycemia imparts its deleterious impact is via the generation of advanced glycation end-products (AGEs) [25]. AGEs result from nonenzymatic reactions between glucose and proteins or lipids and accumulate within tissues, thereby contributing to processes of inflammation, oxidative stress, and tissue damage. Within the diabetic foot, there is a notable increase in AGEs, which, in turn, can catalyze the development of ulcers while impeding the physiological course of wound healing [26].

2.5 Inflammation

Inflammation is a hallmark of diabetic foot pathophysiology. Elevated glucose levels in diabetes activate proinflammatory pathways, leading to the release of cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) [27]. These cytokines promote inflammation and immune cell recruitment in the affected tissues.

The chronic inflammatory state observed in the diabetic foot has several detrimental consequences. It compromises the immune system’s ability to mount an effective defense against pathogens. Immune cells may become less responsive, impairing the body’s ability to control infections [28]. Additionally, chronic inflammation contributes to tissue damage and the development of fibrosis, further hindering tissue repair and regeneration.

2.6 Immune responses

In diabetes, immune responses are often compromised due to the chronic inflammatory state and impaired immune cell function. Hyperglycemia impairs the function of immune cells, such as neutrophils and macrophages, making them less effective at combating infections [29].

Neutrophils, which play a crucial role in fighting bacterial infections, exhibit reduced chemotaxis and impaired phagocytosis in the presence of high blood sugar levels. This impaired neutrophil function increases susceptibility to bacterial infections, which are common in diabetic foot ulcers [30].

Macrophages, important in wound healing and infection control, also experience dysfunction in the hyperglycemic environment [31]. They may exhibit delayed or impaired wound healing responses, contributing to the chronic nature of diabetic foot ulcers.

2.7 Oxidative stress

Hyperglycemia in diabetes leads to oxidative stress, a condition where there is an imbalance between the production of reactive oxygen species (ROS) and the body’s ability to detoxify them [32]. ROS are highly reactive molecules that can damage cellular components, including proteins, lipids, and DNA [33].

Oxidative stress plays a multifaceted role in the pathophysiology of the diabetic foot. It contributes to endothelial dysfunction, impairing the function of blood vessels and reducing blood flow [34]. Additionally, oxidative stress can damage peripheral nerves, exacerbating neuropathy [35]. It also damages tissue repair processes, hindering wound healing.

2.8 Infection susceptibility

One of the most concerning aspects of the diabetic foot is its heightened susceptibility to infections. The combination of neuropathy, impaired circulation, hyperglycemia, inflammation, and immune dysfunction creates an environment conducive to microbial invasion [36].

The impaired sensation resulting from sensory neuropathy means that patients may not notice small injuries or infections until they have progressed significantly [37]. Even minor cuts or blisters can become entry points for bacteria. Furthermore, the compromised immune responses and reduced blood flow make it difficult for the body to control and resolve infections [38].

Chronic hyperglycemia also provides a favorable environment for microbial growth. Elevated glucose levels can serve as a source of nutrients for pathogens, further promoting infection.

3. Modifiable behavioral factors to prevent lower extremity amputations in diabetic patients

A thorough investigation carried out within a Korean population unveiled compelling evidence that among individuals with diabetes the probability of lower extremity amputations (LEA) exhibited a pronounced increase in the presence of active tobacco use and substantial alcohol consumption. In contrast, the consistent engagement in physical activity appeared to serve as a mitigating factor in this risk [39]. Interventions encompassing the modification of current smoking habits, the reduction of heavy alcohol consumption, and the incorporation of regular exercise regimens present themselves as prospective strategies for averting LEA among diabetic patients.

Furthermore, it is essential to acknowledge that the risk of LEA exhibits a synergistic escalation in the presence of unhealthy behaviors. This phenomenon is most strikingly manifested in individuals who are concurrently devoid of exercise, engage in current smoking, and indulge in heavy alcohol consumption as they exhibit the highest risk profile for LEA.

This result originated from the NHIS database, encompassing nearly 97% of the Korean populace who undergo biennial medical examinations subsidized by the Korean government [40]. Out of the entire cohort of 2,644,440 diabetic patients, 0.33% (n = 8778) individuals underwent LEA. A multivariate analysis revealed that the risk of LEA was found to be higher among current cigarette smokers and heavy alcohol consumers (hazard ratio [HR], 1.503 and 1.187), while it was reduced among individuals engaged in regular exercise (HR, 0.865). The scoring system, based on lifestyle choices, assigned zero points for healthy habits (smoking cessation, no alcohol consumption, and regular exercise), one point for each worsening lifestyle choice, and three points for the combination of current smoking, heavy drinking, and lack of exercise. After adjusting for the mentioned variables, an increase in LEA risk was observed with each one-point increment (Score 1: HR, 1.366; Score 2: HR, 1.752; and Score 3: HR, 2.448) [39].

A comprehensive meta-analysis incorporating five cohort studies and three case-control studies highlighted the significant association between cigarette smoking and increased risk of LEA in diabetic patients without publication bias [41]. The pathophysiology of smoking-induced damage lies in the reduced oxygen-carrying capacity of the blood due to harmful cigarette by-products, resulting in tissue hypoxia and arteriospasm [42]. This, in turn, leads to compensatory erythrocytosis, increasing blood viscosity while decreasing tissue perfusion, ultimately inhibiting diabetic ulcer healing, and elevating the risk of LEA [43].

Additionally, chronic and even moderate alcohol consumption among individuals with diabetes can lead to hyperglycemia and peripheral neuropathy, contributing to diabetic ulcer, and increasing the risk of LEA [44]. This highlights the adverse effect of heavy alcohol consumption on LEA risk. Chronic alcohol intake with diabetes often correlates with poor compliance regarding diet and medication, which further hampers glycemic control [45].

On a positive note, evidence from six controlled clinical trials suggests that regular physical activity and exercise can significantly improve diabetic foot outcomes and help prevent complications, including diabetic ulcers, infections, and LEA [46]. Exercise in diabetic patients has shown benefits in terms of improved glycemic control, enhanced nerve velocity conduction, and better gait function [47, 48]. Furthermore, it delays the onset of diabetic peripheral neuropathy, a pivotal risk factor for diabetic ulcers, by enhancing sensory and motor nerve velocity conduction in the lower limbs [49, 50]. Regular exercise also improves balance, foot rollover, dynamic plantar loading, and overall quality of life in diabetic patients [47, 50]. Remarkably, weight-bearing from physical activity does not pose an increased risk of diabetic foot re-ulceration [51].

4. Conclusion

The pathophysiology of diabetic foot complications represents an intricate and multifaceted process, underpinned by a confluence of macrovascular and microvascular alterations, neuropathy, inflammation, immune responses, hyperglycemia, oxidative stress, and an augmented susceptibility to infections. These elements intricately intertwine and mutually potentiate one another, culminating in an inhospitable milieu within the foot tissues. Gaining a profound comprehension of this intricate interplay among these pathophysiological mechanisms is of paramount importance for healthcare professionals to proficiently engage in the prevention, diagnosis, and management of diabetic foot complications. This, in turn, enhances the overall quality of life for individuals grappling with diabetes.

Furthermore, the modification of behaviors encompassing the cessation of current smoking, the reduction of heavy alcohol consumption, and the incorporation of regular exercise regimens represent a fundamental approach in preventing lower extremity amputation, concurrently enhancing the physical, emotional, and social dimensions of life for individuals afflicted with diabetes.

Conflicts of interest

The authors declare no conflicts of interest.

Competing interests

The authors have declared that no competing interests exist.