Worldwide, diabetes is the most common cause of neuropathy, and diabetic neuropathies are among the most common long-term complications of diabetes [2, 4, 5]. An international consensus group defined diabetic neuropathy (DN) as the “presence of symptoms and/or signs of peripheral nerve dysfunction in people with diabetes after the exclusion of other causes” [6]. Of the several forms of DN (Table 32.1), chronic sensorimotor diabetic peripheral neuropathy and peripheral sympathetic autonomic neuropathy play the greatest role in diabetic foot ulceration [4, 6]. Neuropathy is a major risk factor for developing foot ulceration, and according to Boulton, “in patients with significant neuropathy without a history of ulceration, the annual risk of developing an ulcer is five to seven times higher than in those without neuropathy” [6].

The clinical features of DN may be best recognized by understanding the “painful painless foot.” This term is attributed to Dr. Paul Brand through his work with patients with leprosy. He recognized that neuropathic patients often experience severe painful neuropathic symptoms, but on examination have complete sensory loss to all modalities [6]. Smith describes the clinical features of DN as presenting either “positive” or “negative” sensory symptoms or being asymptomatic. Positive symptoms are described as abnormal excessive sensations such as pricking, tingling, or burning. These sensations may be downright painful. Negative symptoms are characterized by numbness or sensory loss. Some patients are not aware of their sensory loss and may consider themselves as asymptomatic [5].

Typical sensorimotor neuropathy presents with a symmetric stocking distribution sensory loss described by the patients as a feeling of the limb being asleep or numb [4, 6]. Other patients will describe neuropathic painful symptoms such as burning discomfort, electrical sensations, or stabbing pain.

Motor neuropathy is also a component of overall diabetic neuropathy, thus the term sensorimotor neuropathy, and leads to small muscle wasting in the foot and absent ankle reflexes. The clinical presentation of motor nerve dysfunction is wasting of the small muscles in the feet and absent ankle reflexes. This chronic motor denervation results in malfunction of the intrinsic muscles of the foot that distorts foot architecture. Chronic metatarsal flexion, extensor subluxation of the toes, proximal migration of the metatarsal fat pad, and an imbalance in the action of the toe flexors and extensors lead to a “claw foot deformity.” More importantly, with dislocation of the metatarsophalangeal joints, the heads of the metatarsals become more prominent, driven downward, and become the striking surface during ambulation. Other bony prominences become abnormal pressure points as well, and combined with a loss of pain sensation, the overlying skin is subject to repeated injury and ulceration. This so-called claw foot as depicted in Fig. 32.1 is characterized by clawing of the toes, prominent metatarsal heads, and a high arch. The “claw foot” deformity represents a high-risk diabetic neuropathic foot and is associated with increased risk of ulcer formation [7, 8].

Charcot foot (CF) is another form of foot deformity associated with diabetic neuropathy. CF can be acute or chronic. Acute CF can mimic a foot infection where the foot is markedly red, warm, and swollen. Pain is often minimal or absent. The midfoot is usually most affected. Ongoing mechanical stresses lead to ligament strain, fracture-dislocations of the forefoot bones, midfoot collapse, and severe foot deformity and joint instability [9]. Figure 32.2 shows a radiograph of a Charcot foot.

Peripheral autonomic dysfunction affecting the sympathetic nervous system is also present in diabetic neuropathy. Autonomic dysfunction leads to loss of sweat and oil gland function resulting in dry skin prone to cracking and fissure formation . The cracked skin can breakdown and become a portal of entry for bacteria [2, 8].

As one examines diabetic neuropathy, it becomes evident that there is a wide spectrum of presenting symptoms in these patients. Boulton emphasizes that, “neuropathic symptoms correlate poorly with sensory loss and their absence must never be equated with lack of foot ulcer risk.” It has been observed that, “any patient that walks into clinic with a foot ulcer but without a limp must have neuropathy because those with normal pain sensation would not be able to put weight on the lesion” [7]. This observation lead Dr. Paul Brand to state that, “Pain is God’s greatest gift to mankind” as it pertained to the protective nature of foot pain in the prevention of foot ulcers.

The pathogenesis of diabetic neuropathy is not completely understood and is likely multifactorial involving hyperglycemia, duration of diabetes, age-related neuronal degeneration, and other common factors such as hypertension, hyperlipidemia, and obesity [4]. According to Smith, “neuropathy likely results from a combination of direct axonal injury due to the metabolic consequences of hyperglycemia, insulin resistance, and toxic adiposity, and endothelial injury and microvascular dysfunction leading to nerve ischemia” [5]. The multiple biochemical pathways involved in the development of neuropathy may include increased mitochondrial production of free radicals, increased formation of glycation end products, downregulation of the soluble receptor for glycation end products, increased activity of the polyol or sorbitol pathway with accumulation of protein kinase C, activation of poly(ADP ribose) polymerase, cyclooxygenase 2 activation, endothelial dysfunction , peroxynitrite and protein nitration, and altered Na⁺/K⁺-ATPase pump function. These pathways alter neuronal activity, mitochondrial function, membrane permeability, and endothelial function. Ultimately these changes promote segmental demyelination, Wallerian degeneration, and microangiopathy and induce neuronal apoptosis leading to axonal and neuronal degeneration [4, 5]. In Fig. 32.3 Smith depicts this complex interaction of multiple pathways leading to neuropathy and the reader is referred to his thorough review of the mechanisms for further details [4].

Initial understanding of PSD in the diabetic population was mistakenly ascribed to the theory of small vessel disease or microvascular occlusion of the arterioles. This led to the assumption that diabetics with arterial insufficiency causing ulcers could not be revascularized and would need amputations. Subsequent decades of experience and research have shown that the predominant cause of ischemia in diabetic patients is macrovascular occlusion of the leg arteries, most commonly the tibial arteries, due to atherosclerosis [8].

PAD in diabetes alters vascular function at the macrovascular and microvascular levels. On a macrovascular level, the formation of standard atheromatous plaques in diabetics is similar to nondiabetics. The pattern of involvement has some unique characteristics in diabetics with the larger iliac and femoral arteries commonly spared of hemodynamically significant disease. However, the popliteal and tibial arteries are more frequently involved compared to nondiabetics. While atherosclerosis affects the femoral and popliteal arteries in both diabetics and nondiabetics, the infragenicular occlusive disease in the anterior tibial, posterior tibial, and peroneal arteries is the classic distribution in diabetic patients (Fig. 32.4). It is not unusual to see diabetic patients with ischemic foot lesions having a palpable popliteal pulse with occlusive disease isolated to the infragenicular arteries. Fortunately, the foot vessels are often spared in diabetics, even in the face of severe tibial level disease, which is important to the success of distal revascularization. A study based on arteriography showed no difference in occlusive disease in the arterial system of the foot when diabetics were compared to nondiabetics [10]. Diabetes can also lead to a hypercoagulable state through alterations in platelet function, coagulation, and blood rheology, thus potentially adding to arterial occlusive disease.

On a microvascular level, the arterial disease in diabetics is best described as nonocclusive microcirculatory impairment. This should not be confused with the term “small vessel disease” that refers to the common misconception of an untreatable occlusive lesion in the microcirculation. The concept of diabetic small vessel occlusive disease often leads to inappropriate management of diabetic patients with nonhealing foot lesions. The formation of these lesions in the presence of normal palpable foot pulses led to the misconception that diabetic patients have microvascular occlusive disease, which causes skin ischemia and formation of foot lesions. Dispelling the notion of “small vessel disease” has been fundamental to diabetic limb salvage, because arterial reconstruction is almost always possible and successful in these patients. In the presence of foot ischemia, the restoration of pulsatile blood flow using vein bypass may be necessary to heal the lesion. In this situation diabetic patients showed the same propensity to healing as nondiabetics. Infrainguinal vein bypasses in diabetics have comparable patency and limb salvage rates to those performed in nondiabetics [11].

Whereas there is no occlusive disease in the microcirculation, multiple structural and physiologic abnormalities result in functional microvascular impairment [12]. Endothelial cell dysfunction as a result of hyperglycemia and hyperinsulinemia plays a major role in this functional defect [13]. Nitric oxide (NO) is the main vasodilator released by the endothelium and causes vasodilation by diffusing into the vascular smooth muscle cells (VSMC) thereby stimulating cyclic guanosine 3′5′-monophosphate-mediated relaxation. NO is synthesized in the endothelial cell through the action of an endothelial-specific NO synthase (ecNOS) . The expression of ecNOS is reduced in response to hyperglycemia and hyperinsulinemia [13]. Also, loss of NO homeostasis at the microcirculatory level creates a proinflammatory environment with damaging oxygen-free radical species released into the vasculature and surrounding tissues.

Another effect of hyperglycemia is the nonspecific glycosylation of proteins, so-called advanced glycosylation end products (AGEs) . AGEs impair the actions of NO by stimulating the formation of free oxygen radicals that react with NO and convert it to a prooxidant. AGEs also displace disulfide cross-linkages in collagen proteins thereby diminishing the charge in the capillary basement membrane and altering its diffusion properties [14]. These basement membrane alterations contribute to increased vascular permeability and inflammation. AGEs activate and upregulate the expression of endothelial AGE receptors—these add to the local inflammatory state by increasing leukocyte chemotaxis and transformation into foam cells which contribute to increasing local oxidative stress [15]. One result of this increase in inflammation is an increase in C-reactive protein (CRP) which is strongly related to widespread acceleration of atherosclerosis and promotion of endothelial cell apoptosis [16]. These and other mechanisms result in the impaired microvasculature marked by a characteristic thickening of the capillary basement membran e which does not affect arteriolar luminal diameter or blood flow but does impair nutrient and substrate flow into the adjacent tissues. This, coupled with autonomic dysfunction at the capillary level described earlier, severely hinders the hyperemic response to injury, inflammation, and infection.

The macrovascular component of PAD in diabetics is due to atherosclerosis. The atheromatous changes occur in a similar fashion as in nondiabetics, but in an accelerated way. This acceleration could be due to the previously described diabetes-driven increases in inflammation that worsen the course of “normal” plaque pathophysiology , changes in platelet and coagulation system function, and the high coincidence of hypertension among diabetics due to diabetic nephropathy.

Another common finding among diabetics is extensive medial calcification of the arteries. This is a process that can occur either at or separate from sites of atheromatous plaque and in diabetics is characteristically found throughout the arteries of the legs. There are several different disease states and proposed pathways for this abnormal calcification of the media; in diabetics both hyperinsulinemia and hyperglycemia are implicated. Both have been shown to alter gene and protein expression in endothelial and vascular smooth muscle cell (VSMC) that directly result in “osteoblast-like” activity of the VSMC and pericyte cells of the artery [17]. An example is the abnormal expression of proteins like osteopontin by these cells. Osteopontin coupled with chronic inflammation and high presence of oxygen-free radicals and C-reactive protein within the vessel wall leads to the deposition of calcium-phosphate complexes that mineralize within the media. Although this is generally a nonobstructive lesion, it leads to noncompliant arteries unable to augment flow in response to increased demand and, depending on the luminal diameter of the vessel, long segmental stenoses that disturb normal blood flow.

As mentioned before, the formation of atheromatous plaques in diabetics is similar in most regards to nondiabetics, but the pattern of involvement has a unique characteristic in diabetics. Despite sometimes widespread calcinosis, the larger iliofemoral arteries are commonly spared of hemodynamically significant disease. However, in diabetics the popliteal and infra-popliteal vessels are more frequently involved than the larger arteries and more frequently diseased compared to nondiabetics [18]. The foot vessels are relatively spared in diabetics, even in the face of severe tibioperoneal level disease, which is important to the success of revascularization [19].

In addition to the effects on the endothelium and VSMC, diabetes also leads to a hypercoagulable state through alterations in platelet function, coagulation, and blood rheology. Platelet uptake of glucose is unregulated in hyperglycemia and results in increased oxidative stress which enhances platelet aggregation. These platelets also have increased expression of glycoprotein Ib and IIb/IIIa receptors which are important in thrombosis and platelet adhesion. The coagulation system is affected by diabetic-related increases in tissue factor expression by VSMC and endothelial cells and increases in plasma concentrations of factor VII. Hyperglycemia is also associated with a decreased concentration of antithrombin and protein C, impaired fibrinolytic function, and excess plasminogen activator inhibitor-1 [20]. Blood rheology is altered as a consequence of an increase in viscosity and fibrinogen content due to hyperglycemia.

In summary, the effects of PAD in diabetics confer alterations in the microvascular functioning and macrovascular supply that lead to ischemia. Because of the synergistic consequences of both processes, the actual degree of ischemia can be greater than suspected, and even relatively minor trauma or infection can be made worse due to vascular insufficiency. The contribution of neuropathy with even moderate levels of ischemia is particularly worrisome as these “neuroischemic” feet are more prone to ulceration and infection [21, 22].

As previously mentioned, infection is more a result of than a true cause of diabetic foot ulceration . The structural and functional alterations of the arteriole and capillary walls, most notably, membrane basement thickening, associated with diabetes add to the likelihood of an ulcer becoming infected. The thickened basement membran e blocks leukocyte migration and hinders hyperemic and vasodilatory response to injury. This may block the normal inflammatory signs associated with infection. Erythema, rubor, cellulitis, and tenderness may be absent. The normal systemic signs of infection like fever, tachycardia, and leukocytosis may be absent as well [8]. Failure by the diabetic patient to recognize the onset of infection in an ulcer can have dire consequences. The risk of amputation correlates directly with increasing severity of infection as confirmed by Lavery in 2007 [23]. This study of 1666 diabetic patients showed increased risk of amputation, higher level amputation, and lower extremity-related hospitalization in patients with increased severity of infection based on the Infectious Disease Society of America (IDSA) classification of wound infection.