Etiology

Various factors increase the risk of developing a diabetic foot ulcer.[15] These factors fall into three main categories:

  • Abnormal distribution of plantar pressures due to structural/biomechanical abnormalities (e.g., bunions, hammer or mallet toes, midfoot deformities as a result of Charcot neuro-osteoarthropathy), impaired joint mobility, gait abnormalities, and motor neuropathies

  • Impaired protective mechanisms (e.g., dry skin, immune system abnormalities, peripheral artery disease)

  • Impaired recognition due to sensory neuropathy and/or visual impairments.

In most patients, epithelial ulceration results from repetitive trauma from the shoe contacting various prominent skin surfaces of the foot during ambulation. This, in addition to various combinations of the above factors, leads to a portal of entry for bacterial inoculation into the foot. Moreover, puncture wounds, along with these various risk factors, may also lead to bacterial inoculation and subsequent infection.

Pathophysiology

A healthy, intact viscoelastic and supple epithelium is the most important protection against foot infection. When various combinations of risk factors are present, ulceration or puncture injuries occur. The longer a wound has been present, the higher the risk of both soft-tissue and bone infection. Infection often spreads along anatomic planes in the foot and will often cause hyperglycemia. Chronic hyperglycemia may lead to sensory neuropathy and immune system dysfunction, but hyperglycemia does not directly affect the development of foot infections.

Untreated macrovascular (typically popliteal- and tibial-level) atherosclerotic disease poses a higher risk for foot infections among those with unhealed foot ulcers and increases the risk for amputation.[14][16]

Although microvascular abnormalities (including abnormal arteriovenous shunting and basement membrane thickening) are often present in patients with diabetes mellitus, there has been no evidence that occlusive phenomena in the microvasculature of the foot (i.e., small-vessel disease) contributes significantly to ulcer development, infection, or poor healing. Indeed, it was pointed out decades ago that a belief in the concept of small-vessel disease often leads to inappropriate pessimism toward the treatment of diabetic foot infections.[17]

There is significant overlap between the risk factors for macro- and microvascular disease, but in general hypercholesterolemia and hypertension are more often associated with macrovascular disease development, whereas hyperglycemia is most often associated with microvascular disease, according to a 2023 scientific statement on diabetic foot ulcers by the American Heart Association.[18]​ Many cardiovascular risk factors, such as tobacco use, are strongly associated with worsening of both macro- and microvascular disease, and both processes contribute to nonhealing of diabetic foot ulcers. Cellular dysfunction is also thought to play a significant role in delayed wound healing, in particular dysregulation of immune cells causing chronic inflammation, and damage to endothelial and smooth muscle cells which impairs angiogenesis.[18]

The pathophysiological factors contributing to diabetes-related foot disease can be further compounded by societal and ethnic health disparities: US studies have found higher amputation rates among communities with economic hardship and rural-dwelling populations, and among black and African-American, Hispanic and Latino, and Native American populations.[18] In the UK, by contrast, studies have found lower amputation rates in African and Caribbean men and in people of South Asian origin, compared to other ethnic groups, suggesting these discrepancies are driven more by socio-economic and regional variations than genetic factors.[19][20]​​

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