| Home | E-Submission | Sitemap | Editorial Office |  
Journal of Wound Management and Research > Volume 19(3); 2023 > Article
Kim: Investigating Diabetic Foot Pathophysiology and Amputation Prevention Strategies through Behavioral Modification


Diabetic foot complications stem from intricate interactions between macrovascular and microvascular changes, neuropathy, inflammation, immune responses, hyperglycemia, oxidative stress, and infection susceptibility. Macrovascular factors like atherosclerosis lead to tissue ischemia, while microvascular dysfunction worsens perfusion deficits. Neuropathy contributes significantly to such complications, causing sensory loss, motor problems, and autonomic dysfunction. This results in unnoticed injuries, muscle atrophy, deformities, and dry skin, elevating the risk of non-healing wounds and infections. Inflammation and immune responses amplify tissue damage and hinder healing. Chronic hyperglycemia generates advanced glycation end products, stiffening tissues, while oxidative stress exacerbates damage. Mitochondrial dysfunction further compromises cellular energy production, worsening tissue repair challenges. These multifaceted factors collectively contribute to diabetic foot complications. The impact of modifiable behavior factors such as smoking, heavy alcohol consumption, and exercise on the risk of lower extremity amputation (LEA) in diabetic patients is also not to be ignored. Substantial data had identified increased LEA risk from smoking and heavy alcohol intake and reduced risk from regular exercise. The cumulative impact of these behaviors underscores the significance of behavior modification in preventing LEA and enhancing the well-being of diabetic patients. Understanding these mechanisms is vital for developing effective preventive strategies, diagnostics, and treatments, addressing the impact of diabetic foot complications on individuals and healthcare systems.


Diabetic foot is a complication of diabetes brought on by multiple factors including peripheral neuropathy and vasculopathy due to complex metabolic pathways [1-3], with rising prevalence linked to increased diabetes rates and longer life expectancy [2]. Foot ulcers affect 15% to 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 Korea, the prevalence of diabetes is approximately 14.4% and is especially higher among the elderly, incurring healthcare expenses of 16.2 trillion Korean won (over 12 billion US dollars) a year and approximately 7.7% of total health insurance costs. This study delves into the pathophysiology of diabetic foot and explores ways to prevent amputations through behavioral modifications. Through an extensive literature review, I aim to illuminate this condition’s complexities and propose effective strategies for mitigation and prevention.

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 (Fig. 1).

Macrovascular changes

Macrovascular changes in the diabetic foot are primarily characterized by atherosclerosis, a chronic disease affecting larger blood vessels [11]. The process begins with hyperglycemia, a hallmark of diabetes that triggers a cascade of events that culminate in endothelial dysfunction [12]. Elevated blood glucose levels cause damage to the delicate endothelial cells lining the arterial walls. This damage sets the stage for inflammation, which leads to the deposition of fatty plaques within the arterial walls [13,14]. Over time, these plaques accumulate and harden, narrowing the arteries and reducing blood flow to the lower extremities. The consequences of macrovascular changes are profound. Reduced blood flow to the feet can result in chronic ischemia, depriving tissues of the oxygen and nutrients they need to function properly [15]. This impaired circulation contributes to tissue damage and increases the risk of complications such as ulcers and infections. Moreover, macrovascular changes can also lead to thrombosis within the arteries, further exacerbating the issue by obstructing blood flow.

Microvascular changes

Microvascular changes in the diabetic foot are equally significant, if not more so, than macrovascular changes. These changes predominantly affect small blood vessels including arterioles, capillaries, and venules [12]. One of the hallmark features of microvascular changes is diabetic microangiopathy. Chronic hyperglycemia again plays a pivotal role in initiating and perpetuating these changes. In diabetic microangiopathy, the basement membranes of small blood vessels thicken with an increase in capillary permeability [16]. This results in a loss of normal vascular regulation and function. Oxygen and nutrient delivery to the tissues become compromised, and waste product removal is impaired [17]. The result is tissue hypoxia, which can lead to cell dysfunction and death. The implications of microvascular changes are significant. Reduced blood supply to the foot tissues increases vulnerability to injury and hampers the body’s ability to heal wounds [18]. This diminished perfusion contributes to tissue breakdown, ulcers, and poor wound healing and impairs the normal function of sweat glands and skin, making the skin more prone to dryness and cracking.


Neuropathy is another critical aspect of diabetic foot pathophysiology. Diabetic neuropathy affects both the somatic and autonomic nervous systems [19]. Sensory neuropathy is perhaps the most well-known form of neuropathy in diabetes and results in loss of protective sensation, making patients less aware of injuries or trauma to their feet [20]. Patients may step on sharp objects, develop blisters, or sustain minor injuries without realizing it [21]. This lack of pain perception can lead to the development of neuropathic ulcers, a hallmark feature of diabetic foot complications. Motor neuropathy, on the other hand, can lead to muscle weakness and deformities in the feet [22]. Muscles may atrophy, and patients can develop altered gait patterns that increase pressure on specific areas of the foot [23]. This abnormal mechanical stress further predisposes the diabetic foot to injury and ulceration. Autonomic neuropathy impacts the autonomic nervous system, which controls functions such as blood pressure, heart rate, and sweat production [20]. In the diabetic foot, autonomic neuropathy can lead to alterations in skin blood vessel tone, causing unpredictable changes in blood flow. This can result in episodes of hyperemia or ischemia, both of which contribute to the risk of foot complications [21].


Hyperglycemia is the defining feature of diabetes and underlies many of the pathophysiological changes observed in the diabetic foot [24]. Elevated blood glucose levels promote oxidative stress and inflammation, disrupt metabolic pathways, and impair cellular function. One of the key mechanisms through which hyperglycemia exerts its damaging effects is the formation of advanced glycation end-products (AGEs) [25]. AGEs are products of non-enzymatic reactions between glucose and proteins or lipids. They accumulate in tissues, where they contribute to inflammation, oxidative stress, and tissue damage. In the diabetic foot, AGEs are increased in number and can promote the development of ulcers and hinder wound healing [26].


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 and interleukin-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.

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.

Oxidative stress

In the context of diabetes, elevated blood glucose levels precipitate oxidative challenges, stemming from an incongruity between the generation of reactive oxygen species (ROS) and the physiological capacity for their detoxification [32]. It is worth noting that ROS are potent entities with the capability to impair cellular structures, encompassing 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.

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 [39].

Modifiable behavioral factors to prevent LEAs in diabetic patients

A comprehensive study conducted on a Korean population demonstrated that in diabetic individuals, the likelihood of lower extremity amputations (LEAs) escalated with active tobacco use and significant alcohol intake [40]. Conversely, consistent physical activity appeared to mitigate this risk. Modifying current smoking habits, reducing heavy alcohol intake, and incorporating regular exercise can help prevent LEA in diabetic patients (Fig. 2) [40]. Additionally, the risk of LEA increases synergistically with the addition of unhealthy behaviors, with the highest risk observed in individuals who lack exercise, engage in current smoking, and consume heavy amounts of alcohol.
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].
Furthermore, sustained and even moderate intake of alcohol in diabetic patients can result in elevated blood glucose levels and peripheral nerve damage. Such conditions can promote diabetic ulcers and heighten 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].


The pathophysiology of the diabetic foot is a complex and multifaceted process that involves a combination of macrovascular and microvascular changes, neuropathy, inflammation, immune responses, hyperglycemia, oxidative stress, and increased susceptibility to infections. These factors interact and amplify each other, creating a hostile environment within the foot tissues. Understanding the intricate interplay of these pathophysiological mechanisms is essential for healthcare providers to effectively prevent, diagnose, and manage diabetic foot complications, ultimately improving the quality of life for individuals living with diabetes. In addition, modification of behaviors of current smoking, heavy alcohol intake, and exercise can help prevent LEA and can improve the physical, emotional, and social qualities of life in diabetic patients.

Conflict of Interest

No potential conflict of interest relevant to this article was reported.

Fig. 1.
Schema of diabetic foot pathophysiology
Fig. 2.
Cumulative incidence of lower extremity amputation in diabetic patients. Demonstrating the role of behavioral factors.


1. Apelqvist J. Diagnostics and treatment of the diabetic foot. Endocrine 2012;41:384-97.
crossref pmid pdf
2. Zhang P, Lu J, Jing Y, et al. Global epidemiology of diabetic foot ulceration: a systematic review and meta-analysis †. Ann Med 2017;49:106-16.
crossref pmid
3. Mishra SC, Chhatbar KC, Kashikar A, et al. Diabetic foot. BMJ 2017;359:j5064.
crossref pmid pmc
4. Lavery LA, Armstrong DG, Wunderlich RP, et al. Diabetic foot syndrome: evaluating the prevalence and incidence of foot pathology in mexican americans and non-hispanic whites from a diabetes disease management cohort. Diabetes Care 2003;26:1435-8.
5. Reiber GE. The epidemiology of diabetic foot problems. Diabet Med 1996;13 Suppl 1:S6-11.
crossref pmid pdf
6. Kerr M, Rayman G, Jeffcoate WJ. Cost of diabetic foot disease to the national health service in england. Diabet Med 2014;31:1498-504.
crossref pmid pdf
7. Armstrong DG, Boulton AJ, Bus SA. Diabetic foot ulcers and their recurrence. N Engl J Med 2017;376:2367-75.
crossref pmid
8. Armstrong DG, Lavery LA, Harkless LB. Validation of a diabetic wound classification system: the contribution of depth, infection, and ischemia to risk of amputation. Diabetes Care 1998;21:855-9.
crossref pmid pdf
9. Moulik PK, Mtonga R, Gill GV. Amputation and mortality in new-onset diabetic foot ulcers stratified by etiology. Diabetes Care 2003;26:491-4.
crossref pmid pdf
10. Ikonen TS, Sund R, Venermo M, et al. Fewer major amputations among individuals with diabetes in finland in 1997-2007: a population-based study. Diabetes Care 2010;33:2598-603.
pmid pmc
11. Thiruvoipati T, Kielhorn CE, Armstrong EJ. Peripheral artery disease in patients with diabetes: epidemiology, mechanisms, and outcomes. World J Diabetes 2015;6:961-9.
crossref pmid pmc
12. Chawla A, Chawla R, Jaggi S. Microvasular, macrovascular complications in diabetes mellitus. distinct or continuum? Indian J Endocrinol Metab 2016;20:546-51.
pmid pmc
13. Johnstone MT, Creager SJ, Scales KM, et al. Impaired endothelium-dependent vasodilation in patients with insulin-dependent diabetes mellitus. Circulation 1993;88:2510-6.
crossref pmid
14. Steinberg HO, Tarshoby M, Monestel R, et al. Elevated circulating free fatty acid levels impair endothelium-dependent vasodilation. J Clin Invest 1997;100:1230-9.
crossref pmid pmc
15. Bandyk DF. The diabetic foot: pathophysiology, evaluation, and treatment. Semin Vasc Surg 2018;31:43-8.
crossref pmid
16. Lefrandt JD, Bosma E, Oomen PH, et al. Sympathetic mediated vasomotion and skin capillary permeability in diabetic patients with peripheral neuropathy. Diabetologia 2003;46:40-7.
crossref pmid pdf
17. Korzon-Burakowska A, Edmonds M. Role of the microcirculation in diabetic foot ulceration. Int J Low Extrem Wounds 2006;5:144-8.
crossref pmid pdf
18. Jeffcoate WJ, Harding KG. Diabetic foot ulcers. Lancet 2003;361:1545-51.
crossref pmid
19. Boulton AJ, Hardisty CA, Betts RP, et al. Dynamic foot pressure and other studies as diagnostic and management aids in diabetic neuropathy. Diabetes Care 1983;6:26-33.
crossref pmid pdf
20. Rathur HM, Boulton AJ. The diabetic foot. Clin Dermatol 2007;25:109-20.
21. Bakker K, Apelqvist J, Schaper NC, et al. Practical guidelines on the management and prevention of the diabetic foot 2011. Diabetes Metab Res Rev 2012;28 Suppl 1:225-31.
22. Volmer-Thole M, Lobmann R. Neuropathy and diabetic foot syndrome. Int J Mol Sci 2016;17:917.
crossref pmid pmc
23. Katoulis EC, Ebdon-Parry M, Lanshammar H, et al. Gait abnormalities in diabetic neuropathy. Diabetes Care 1997;20:1904-7.
crossref pmid pdf
24. Marston WA. Dermagraft diabetic foot ulcer study group. Risk factors associated with healing chronic diabetic foot ulcers: the importance of hyperglycemia. Ostomy Wound Manage 2006;52:26-32.

25. Huijberts MS, Schaper NC, Schalkwijk CG. Advanced glycation end products and diabetic foot disease. Diabetes Metab Res Rev 2008;24 Suppl 1:S19-24.
crossref pmid
26. Vouillarmet J, Maucort-Boulch D, Michon P, et al. Advanced glycation end products assessed by skin autofluorescence: a new marker of diabetic foot ulceration. Diabetes Technol Ther 2013;15:601-5.
crossref pmid
27. Zubair M, Ahmad J. Role of growth factors and cytokines in diabetic foot ulcer healing: a detailed review. Rev Endocr Metab Disord 2019;20:207-17.
crossref pmid pdf
28. Davis FM, Kimball A, Boniakowski A, et al. Dysfunctional wound healing in diabetic foot ulcers: new crossroads. Curr Diab Rep 2018;18:2.
crossref pmid pdf
29. Xiu F, Stanojcic M, Diao L, et al. Stress hyperglycemia, insulin treatment, and innate immune cells. Int J Endocrinol 2014;2014:486403.
crossref pmid pmc pdf
30. Turina M, Miller FN, Tucker C, et al. Effects of hyperglycemia, hyperinsulinemia, and hyperosmolarity on neutrophil apoptosis. Surg Infect (Larchmt) 2006;7:111-21.
crossref pmid
31. Iida KT, Suzuki H, Sone H, et al. Insulin inhibits apoptosis of macrophage cell line, THP-1 cells, via phosphatidylinositol-3-kinase-dependent pathway. Arterioscler Thromb Vasc Biol 2002;22:380-6.
crossref pmid
32. Bolajoko EB, Mossanda KS, Adeniyi F, et al. Antioxidant and oxidative stress status in type 2 diabetes and diabetic foot ulcer. S Afr Med J 2008;98:614-7.
33. Deng L, Du C, Song P, et al. The role of oxidative stress and antioxidants in diabetic wound healing. Oxid Med Cell Longev 2021;2021:8852759.
crossref pmid pmc pdf
34. Goldberg RB. Cytokine and cytokine-like inflammation markers, endothelial dysfunction, and imbalanced coagulation in development of diabetes and its complications. J Clin Endocrinol Metab 2009;94:3171-82.
crossref pmid
35. Babizhayev MA, Strokov IA, Nosikov VV, et al. The role of oxidative stress in diabetic neuropathy: generation of free radical species in the glycation reaction and gene polymorphisms encoding antioxidant enzymes to genetic susceptibility to diabetic neuropathy in population of type I diabetic patients. Cell Biochem Biophys 2015;71:1425-43.
crossref pmid pdf
36. Bader MS. Diabetic foot infection. Am Fam Physician 2008;78:71-9.
37. Chantelau E, Tanudjaja T, Altenhofer F, et al. Antibiotic treatment for uncomplicated neuropathic forefoot ulcers in diabetes: a controlled trial. Diabet Med 1996;13:156-9.
crossref pmid
38. Cunha BA. Antibiotic selection for diabetic foot infections: a review. J Foot Ankle Surg 2000;39:253-7.
crossref pmid
39. Sohail MU, Mashood F, Oberbach A, et al. The role of pathogens in diabetes pathogenesis and the potential of immunoproteomics as a diagnostic and prognostic tool. Front Microbiol 2022;13:1042362.
crossref pmid pmc
40. Lee YJ, Han KD, Kim JH. Association among current smoking, alcohol consumption, regular exercise, and lower extremity amputation in patients with diabetic foot: nationwide population-based study. Endocrinol Metab (Seoul) 2022;37:770-80.
crossref pmid pmc pdf
41. Liu M, Zhang W, Yan Z, et al. Smoking increases the risk of diabetic foot amputation: a meta-analysis. Exp Ther Med 2018;15:1680-5.
crossref pmid pmc
42. Kourembanas S, Marsden PA, McQuillan LP, et al. Hypoxia induces endothelin gene expression and secretion in cultured human endothelium. J Clin Invest 1991;88:1054-7.
crossref pmid pmc
43. Lee FS. Genetic causes of erythrocytosis and the oxygensensing pathway. Blood Rev 2008;22:321-32.
crossref pmid pmc
44. Ben G, Gnudi L, Maran A, et al. Effects of chronic alcohol intake on carbohydrate and lipid metabolism in subjects with type II (non-insulin-dependent) diabetes. Am J Med 1991;90:70-6.
crossref pmid
45. Pal B, Raveender N, Sudipta P. A study on the impact of smoking and alcoholism as determinant factors in the prognosis and outcome of diabetic foot ulcer disease. Int J Res Med Sci 2016;4:1720-4.
46. Matos M, Mendes R, Silva AB, et al. Physical activity and exercise on diabetic foot related outcomes: a systematic review. Diabetes Res Clin Pract 2018;139:81-90.
crossref pmid
47. Sartor CD, Hasue RH, Cacciari LP, et al. Effects of strengthening, stretching and functional training on foot function in patients with diabetic neuropathy: results of a randomized controlled trial. BMC Musculoskelet Disord 2014;15:137.
crossref pmid pmc pdf
48. Tran MM, Haley MN. Does exercise improve healing of diabetic foot ulcers? A systematic review. J Foot Ankle Res 2021;14:19.
crossref pmid pmc pdf
49. Balducci S, Iacobellis G, Parisi L, et al. Exercise training can modify the natural history of diabetic peripheral neuropathy. J Diabetes Complications 2006;20:216-23.
crossref pmid
50. Ahn S, Song R. Effects of Tai Chi exercise on glucose control, neuropathy scores, balance, and quality of life in patients with type 2 diabetes and neuropathy. J Altern Complement Med 2012;18:1172-8.
crossref pmid pmc
51. Lemaster JW, Mueller MJ, Reiber GE, et al. Effect of weight-bearing activity on foot ulcer incidence in people with diabetic peripheral neuropathy: feet first randomized controlled trial. Phys Ther 2008;88:1385-98.
crossref pmid pdf
PDF Links  PDF Links
PubReader  PubReader
ePub Link  ePub Link
XML Download  XML Download
Full text via DOI  Full text via DOI
Download Citation  Download Citation
Related article
Editorial Office
Department of Plastic & Reconstructive Surgery, Dankook University Hospital
201 Manghyang-ro, Dongnam-gu, Cheonan 31116, Korea
TEL: +82-41-550-6285   FAX: +82-41-556-0524   E-mail: office@jwmr.org
About |  Browse Articles |  Current Issue |  For Authors and Reviewers
Copyright © Korean Wound Management Society.                 Developed in M2PI
Close layer
prev next