The Journal of Bone & Joint Surgery

The Journal of Bone & Joint Surgery, Volume 83, Issue 7

Instructional Course Lecture | July 01, 2001

The Diabetic Foot : Basic Mechanisms of Disease

Gregory P. Guyton, MD; Charles L. Saltzman, MD

An Instructional Course Lecture, American Academy of Orthopaedic Surgeons
Gregory P. Guyton, MD
Department of Orthopaedics, University of North Carolina at Chapel Hill, CB #7055, Chapel Hill, NC 27599-7055. E-mail address: guyton@med.unc.edu

Charles L. Saltzman, MD
Department of Orthopaedics, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, IA 52242. E-mail address: charles-saltzman@uiowa.edu

The authors did not receive grants or outside funding in support of their research or preparation of this manuscript. They did not receive payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, educational institution, or other charitable or nonprofit organization with which the authors are affiliated or associated.

Printed with permission of the American Academy of Orthopaedic Surgeons. This article, as well as other lectures presented at the Academy’s Annual Meeting, will be available in March 2002 in Instructional Course Lectures, Volume 51. The complete volume can be ordered online at www.aaos.org, or by calling 800-626-6726 (8 a.m.-5 p.m., Central time).

J Bone Joint Surg Am, 2001 Jul 01;83(7):1083-1096

5 Recommendations (Recommend) | 3 Comments | Saved by 3 Users Save Case

Article

Comments (0)

text A A A

Extract

Diabetic foot disease is usually thought of in simple terms: neuropathy leads to ulceration and neuroarthropathy. However, a number of more subtle aspects are critical in the development of the disorder. For practical purposes, the diabetic neuropathy cannot be altered, but the additional causes of the disease are often amenable to treatment, tipping the balance back in favor of healing.

Figures in this Article

Introduction

In the absence of large-vessel disease, diabetic foot disease is predicated on two inexorably linked factors: neuropathy and an abnormal mechanical environment. A freely floating foot will not ulcerate, and most patients with a deformed foot will not use it to the point of ulceration if sensory feedback instructs them not to do so. Both factors require closer examination.

View Large | Download Slide(.ppt)
Add to My JBJS

Fig. 1:: Diabetic neuropathy can present in a wide variety of patterns. An individual patient may have any combination of the general syndromes listed above.

View Large | Download Slide(.ppt)
Add to My JBJS

Fig. 2:: The results of the Diabetes Control and Complications Trial (DCCT) indicated that the percentage of patients in whom abnormalities developed was significantly lower in association with intensive glucose control, according to the findings of both neurologic examination and objective nerve-conduction studies. (Adapted, with permission, from: The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med. 1993;329:982. Copyright " 1993 Massachusetts Medical Society. All rights reserved.)

View Large | Download Slide(.ppt)
Add to My JBJS

Fig. 3:: Photograph of the foot of a patient with neuropathic claw toes, showing ulcerations over the prominent dorsal aspects of the proximal interphalangeal joints where the toes rubbed against the shoe.

View Large | Download Slide(.ppt)
Add to My JBJS

Fig. 4-A:: Figs. 4-A and 4-B A radiograph and clinical photograph of the foot of a patient with a midfoot ulceration from Charcot arthropathy with subsequent collapse. Osseous deformity resulting from neuroarthropathy is one of the strongest risk factors for the development of ulceration.

View Large | Download Slide(.ppt)
Add to My JBJS

Fig. 4-B:: Figs. 4-A and 4-B A radiograph and clinical photograph of the foot of a patient with a midfoot ulceration from Charcot arthropathy with subsequent collapse. Osseous deformity resulting from neuroarthropathy is one of the strongest risk factors for the development of ulceration.

View Large | Download Slide(.ppt)
Add to My JBJS

Fig. 5:: A patient with diabetic cheiropathy (limited joint mobility) exhibits the "prayer sign." Subtle contractures at the interphalangeal and metacarpophalangeal joints prevent the fingers from fully opposing each other. A space is visible between the fingers when a praying posture is attempted.

View Large | Download Slide(.ppt)
Add to My JBJS

Fig. 6:: The hallux of a patient with severe autonomic neuropathy. In this disorder, the normal sweat function is disrupted, resulting in dry, cracked skin that can serve as a portal for infection.

View Large | Download Slide(.ppt)
Add to My JBJS

Fig. 7:: A diagram representing a partial explanation of the pathogenesis of microangiopathy.

View Large | Download Slide(.ppt)
Add to My JBJS

Fig. 8:: Diabetic patients with autonomic dysfunction often have engorged vasculature when the foot is dependent (left). Disordered autoregulation allows the blood to drain rapidly when the foot is elevated, and the color of the leg fades (right). This phenomenon of "dependent rubor" is especially common in patients with neuroarthropathy.

View Large | Download Slide(.ppt)
Add to My JBJS

Fig. 9:: Mönckeberg sclerosis (medial arterial calcification) is readily apparent on radiographs and is strongly associated with autonomic failure and Charcot arthropathy, as it was in this patient. Note the smooth, diffuse pattern of calcification (arrows) instead of the irregular intimal calcifications characteristic of common atherosclerosis.

Diabetic Neuropathy

The heterogeneous nature of diabetic neuropathy produces the variable course of diabetic foot disease. All components of the nervous system can be affected, including sensation, motor control, pain, proprioception, and autonomic functions, but, in any given patient, the mix of components that are affected determines how and when complications will develop (Fig. 1).

Somatic neuropathy is the most widely recognized pattern and affects both sensory and motor components. This pattern begins with the classic "stocking-and-glove" distribution; as nerve function diminishes along the length of the axon, the longest nerves are affected first. Diminished distal sensation is the hallmark of this neuropathy, and several methods have been developed for quantification. The Semmes-Weinstein monofilaments are the easiest to apply and the most widely used^1,2. Each monofilament is a piece of nylon line of a precise diameter that is applied end-on to the skin until the line begins to bend, providing a reproducible, metered sensory stimulus. The level of sensation for a specific patient is recorded as the smallest size of monofilament felt by the patient. Recognition of the 5.07 monofilament represents the threshold of "protective sensation"—that is, the amount of sensation required to avoid the possibility of unrecognized injury. In approximately 90% of diabetic patients who can feel the 5.07 monofilament, ulceration does not develop¹.

The disease does not confine itself to classic patterns, however. Proximal diabetic neuropathy, also known as diabetic amyotrophy, is a relatively uncommon variant of somatic neuropathy that primarily affects the motor component and causes profound weakness in the proximal muscles of the lower extremity³. Clinically, it is more reminiscent of a muscular dystrophy than a classic neuropathy. The etiology of amyotrophy is not clear, but early evidence suggests an autoimmune-mediated vasculopathy involving the vasa nervorum.

Diabetic mononeuropathy, another rare form of the disease^4,5, is an acute event involving a single peripheral nerve at a single site, and it is believed to originate from an occlusive event or vasculitis in the microvasculature supplying the nerve. Fortunately, the clinical effects are usually self-limited, and recovery is common.

Autonomic neuropathy represents one of the most underrecognized components of the disease. Direct measurement of sympathetic nerve activity in unmyelinated postganglionic C fibers is possible with use of intraneural microelectrodes⁶. Fagius showed that sympathetic nerve impulses were absent in 64% of patients with diabetic neuropathy compared with 19% of patients who had other types of polyneuropathy⁷. Autonomic dysfunction can manifest primarily as failure of the parasympathetic system, with a loss of heart-rate regulation and gastrointestinal motility, or as failure of the sympathetic system, with disordered neurogenic control of blood flow. Parasympathetic or sympathetic dysfunction may predominate in any given patient⁸.

Evidence that diabetic neuropathy may extend to the central nervous system is also emerging. To date, this research has focused on diabetes-related impotence, and specific forms of cognitive dysfunction and impaired central pathways have been discovered in patients with that condition^9-11. It is certainly possible that future research may uncover a central component that is relevant to abnormalities of the foot.

Why diabetic neuropathy has so many different clinical patterns is not at all clear. The answer must lie in the factors that cause the nerve injury itself¹². The 1993 Diabetes Control and Complications Trial demonstrated that the progression of all components of neuropathy was clearly and directly related to glycemic control¹³ (Fig. 2). Diabetes affects tissues that do not require insulin-mediated glucose transport pumps, including the retina, kidney, and nerves, which glucose enters by diffusion. Unlike retinopathy and nephropathy, however, neuropathy originates primarily from the direct effects of glucose rather than from the indirect effects of microangiopathy.

The most commonly proposed mechanism of damage is called the "sorbitol theory." Normally, glucose is broken down, and ATP (adenosine triphosphate) is produced through the hexokinase pathway. In the presence of extremely high levels of glucose, the enzymes controlling the hexokinase pathway become saturated. The excess glucose goes into an alternative metabolic pathway and is converted to sorbitol through a series of reactions controlled by the enzyme aldose reductase. An unfortunate by-product of this "sorbitol pathway" is that the redox potential of the cell is lowered. This, in turn, impairs fatty acid metabolism, reducing axonal transport¹⁴. With use of aldose reductase inhibitors, which keep glucose from entering this pathway, the progression of neuropathy has been ameliorated in animal models of diabetes^15,16.

Another commonly cited metabolic role of hyperglycemia is nonenzymatic glycosylation, a phenomenon active in a wide variety of tissues, including nerve, vascular basement-membrane, and connective tissue^17,18. The long-term exposure of long-lived proteins, including nerve myelin, to high glucose levels eventually leads to the covalent bonding of an advanced glycation end product, disrupting protein function¹⁹. While the theory appears to explain the effects of diabetes on connective tissue (as will be discussed), experiments with aminoguanidine, an inhibitor of nonenzymatic glycation, have shown only mixed results in animal models of diabetic neuropathy²⁰.

Recent reports have also indicated that autoimmunity may play a role, particularly in the autonomic component of diabetic neuropathy^21,22. Vernino et al. recently described autoantibodies to ganglionic acetylcholine receptors in patients with a wide variety of autonomic neuropathies, including diabetic dysautonomia²¹. Differing roles of autoimmunity may ultimately explain a great deal of the pattern variation seen among neuropathic patients.

The Abnormal Mechanical Environment

Overuse

Static and dynamic deformities contribute to the development of diabetic foot disease, but these structural deformities are likely less important than subtle overuse. Neither extraordinarily high pressures nor abnormal shear forces are necessary to cause ulceration; ordinarily tolerable pressures lead to ulceration if the exposure is repeated too many times. This concept was first explained by Brand, whose early efforts were focused not on diabetes but on leprosy²³. He demonstrated that "repetitive moderate stress" (as a light pressure stimulus) applied to a sensate rat forepaw at a rate of 10,000 repetitions per day could reliably lead to blistering in one week and to ulceration in ten days. The initial areas of necrosis developed in the densely innervated regions of the deep layers of dermis and underlying subcutaneous tissue. Modestly dropping the rate to 8000 repetitions per day and pausing on weekends allowed the rats to continue indefinitely without ulceration. When denervated rat forepaws were tested, the number of repetitions that could be tolerated at any given pressure was reduced. Brand hypothesized that subtle repositioning of the forepaw by the sensate rats provided just enough intermittent mechanical relief to stave off tissue necrosis, while the insensate rats simply had no feedback telling them to do so. The same process is almost certainly at work in humans. Notably, the prevalence of ulceration is remarkably low in patients who have rheumatoid arthritis and other diseases that create severe foot deformity and locally elevated plantar pressures in the absence of neuropathy²⁴.

Shear Stress

In addition to the number of loading events, the direction of loading is thought to influence the development and healing of plantar ulcers. Measuring stress parallel to the skin surface is difficult, and direct data on shear stress in the diabetic foot are sparse. However, indirect evidence for the importance of shear is highlighted by the unique anatomy of the soles and the palms. The sole of the human foot has evolved into a complex architecture of fat embedded in a network of fine, but collectively strong, collagen fibrils that span from the skin to the underlying osteotendinous structures to absorb shock and resist shear²⁵. Shear has long been implicated in the development of blisters and has been shown experimentally to occur as a result of repetitive friction²⁶. The interaction of sweating, sebum secretion, and the skin’s coefficient of friction suggests that local biological activity, including function of the sympathetic nervous system, influences susceptibility to blister formation from exposure to repetitive shear²⁷. In diabetic patients with healed foot ulcerations, maximal shear occurs in regions of maximal vertical force²⁸. Therefore, until improved shear-sensing devices with increased resolution, reliability, and speed are available, normal stress serves as a reasonable surrogate for direct measurements of shear stress.

Static Deformity

Any deformity that increases pressure on any one portion of the foot can instigate ulceration in a patient with diabetic neuropathy. In a patient with a hallux valgus deformity, an ulcer may develop along the medial border of the pronated, deviated hallux or underneath the second metatarsal head as a transfer lesion. Similarly, ulcerations may develop underneath the lateral border of the midfoot in a patient who has a varus hindfoot resulting from a mild cavovarus foot. Diabetic neuropathy can transform previously manageable foot deformities into major sources of disease. It is beyond the scope of this review to discuss the gamut of fixed foot deformities; however, there are two special cases in which diabetic neuropathy contributes not only to the consequences of the deformity but also to their very origin.

Claw Toes

Any lesion that denervates the intrinsic muscles of the foot while preserving the long flexors and extensors can lead to claw toes. Without the modifying force of the intrinsics to flex the metatarsophalangeal joints and extend the interphalangeal joints, the opposite deformities develop, with an extended posture of the metatarsophalangeal joints and a flexion posture of the interphalangeal joints. The anatomic principle is homologous to the clawing seen after distal nerve lesions in the upper extremity. In a convincing demonstration of this principle, Mann photographed the claw-toe deformities that resulted when force was applied to only the long flexors and extensors in a fresh cadaveric limb²⁹. The motor component of diabetic neuropathy, which is often overlooked, selectively affects the intrinsic muscles of the foot while preserving the more proximally innervated long motor units³⁰.

The claw-toe deformity creates several sites of increased pressure, particularly after the deformity has been present for some time and has become fixed. Ulcers can occur under the tip of the toe where it strikes the floor or over the dorsum of the proximal interphalangeal joint where it strikes the shoe (Fig. 3). In addition, dorsiflexion of the metatarsophalangeal joint causes the metatarsal fat pad to be pulled distally through its attachments to the proximal phalanx, leaving only a thin layer of tissue between the metatarsal head and the floor. This leads to increases in peak pressures under the metatarsal heads and an increased risk of ulceration³¹.

Charcot Arthropathy

While the mechanical problems associated with hammer toes are subtle and slow to develop, the deformities of Charcot arthropathy can be sudden and dramatic. Neuroarthropathy is one of the most difficult and intractable sources of excess mechanical pressure in the diabetic foot and can create large osseous prominences in various locations. Ulceration and rapid progression to osteomyelitis can follow (Figs. 4-A and 4-B). A large prospective study of risk factors for ulcerations in a population of male diabetic patients showed that the presence of Charcot arthropathy carried the highest relative risk of all of the factors examined, eclipsing even the absence of protective sensation and a history of amputation³².

Soft-Tissue Contractures

Diabetes acts on the foot not only through the indirect mechanisms of neuropathy but also by direct impact upon the tissues themselves. Initially, high glucose concentrations lead to the formation of reversible breakdown products of glucose that bind to free amino groups on proteins. Prolonged exposure of long-lived proteins to this environment initiates a series of poorly understood dehydrations and rearrangements, yielding an irreversibly bound advanced glycation end product, or AGE¹⁹. The theory that these end products are important factors is supported by the experimental finding, in animal models, that diabetic complications were prevented by the administration of aminoguanidine, a potent inhibitor of nonenzymatic glycation¹⁷. Collagen appears to be particularly susceptible because cross-links derived from advanced glycation end products occur along the entire length of the molecule, dramatically stiffening its construct^17,18. Joint contractures in the hand (presumably from type-I collagen involvement) are strongly correlated with the microvascular complications of diabetes such as retinopathy and nephropathy^33-35. In addition, the development of joint contracture has been shown to correlate directly with glycemic control, a result that would be expected if the contracture were due to the nonenzymatic accumulation of advanced glycation end products^36,37.

In a diabetic patient, progressive stiffening of the collagen-containing tissues manifests itself in a number of ways and can be implicated, in part, in the syndromes of adhesive capsulitis in the shoulder, flexor tenosynovitis about the hand and wrist, Dupuytren contracture, and "limited joint mobility."³⁸ The last syndrome, consisting of multiple contractures of the small joints, originally was called "diabetic cheiropathy" and has been increasingly recognized since its original description in 1957³⁹. This syndrome can be detected clinically with use of the "prayer sign," in which the patient is asked to flatten the hands together as if to pray (Fig. 5). If the patient has limited joint mobility, the combined effects of small flexion contractures at both the interphalangeal joints and the metacarpophalangeal joints do not allow the palms to flatten and a small space is visible between the fingers.

Although easily seen in the hand, limited joint mobility has been identified in the foot as well⁴⁰. Delbridge et al. identified a substantial impairment in the subtalar range of motion in diabetic patients with a history of ulceration compared with that in control populations of both nondiabetic and diabetic subjects without a history of foot disease⁴¹. Limited subtalar motion was also associated with limited joint mobility in the hand. Mueller et al. found that subtalar motion in diabetic patients with a history of ulceration was diminished compared with that in controls⁴². Fernando et al. reported elevated plantar pressures in the forefoot and limited subtalar joint motion in patients who had limited joint mobility as assessed by measurements of metacarpophalangeal and interphalangeal joint motion in the hand⁴³.

In addition to capsular contractures of the joints, increasing stiffness can occur in the motor units powering the foot. This is particularly true in the gastrocnemius-soleus complex. Yosipovitch and Sheskin, in a study of neuropathic patients with leprosy, proposed that a stiff gastrocnemius-soleus complex forces the heel up earlier in the gait cycle, placing increased loads on the forefoot⁴⁴. Subsequent reports have confirmed the presence of a tight heel cord and limited ankle dorsiflexion in diabetic patients with a history of ulceration^42,45. Lin et al. successfully used percutaneous lengthening of the Achilles tendon to treat ulcers that previously had been recalcitrant to treatment with a total-contact cast alone and also found a reduced rate of ulcer recurrence after lengthening⁴⁶. Similarly, Armstrong et al. observed that percutaneous lengthening of the Achilles tendon reduced forefoot pressures in neuropathic diabetic patients with a history of ulceration⁴⁷.

Gait Abnormality

Perhaps the most compelling argument for gait abnormalities as a factor in the pathogenesis of the diabetic foot is that deformity alone still fails to explain why ulceration develops in some patients but not in others. While ulcers clearly occur at sites of high loading in some diabetic patients, the lesions never develop in a great many patients with high focal pressures^24,32,48-50. Smith et al. reported that the maximal pressures under the sites of previous ulceration in patients with a history of ulceration were higher than those in matched diabetic control patients with no history of ulceration⁵⁰. However, the pressure patterns were identical to those on the contralateral side, even when the contralateral foot had never had an ulcer. Veves et al., in a prospective study of eighty-six diabetic patients with documented high pressures in the plantar aspect of the foot, reported that ulcerations developed in 35% of the patients within thirty months⁴⁹, a finding that had been noted in earlier small studies as well²⁴. Although that figure is substantial, it is difficult to explain why ulcerations do not develop in even more patients. While behavioral factors and shoe-wear may hold much of the answer, subtle gait changes in patients with diabetic neuropathy have also been proposed as an additional etiology.

Altered proprioception and postural instability have been reported in patients with diabetic neuropathy and a history of ulceration⁵¹. These observations imply that, not surprisingly, posterior column function and proprioception as well as the other components of the somatic nervous system are affected in diabetic neuropathy. It is still unclear how these findings translate into abnormalities of gait. Cavanagh et al. suggested that an absence of afferent feedback during gait in neuropathic subjects leads to increased variability of gait kinematics in the sagittal plane, although the effect proved difficult to elicit when the subjects walked on a treadmill^52,53. Other investigators have found that patients with diabetic neuropathy subtly use the hip flexors to assist in bringing the leg forward rather than pushing off with the gastrocnemius-soleus muscles⁵⁴, have a slower overall walking speed⁵⁵, and have increased peak plantar-flexor moments. All of these effects are due to increased passive stiffness of the gastrocnemius-soleus complex⁵⁶. Taken as a whole, the weight of evidence in the literature suggests that there is indeed a gait abnormality in these patients, but its exact nature remains to be clearly defined.

Additional Factors

In addition to the requisite etiologies of neuropathy and an abnormal mechanical environment seen in all patients with diabetic foot disease, there are other factors that can contribute. While these factors are certainly not universal, they may play a dominant role in some patients.

Sweat

Sweating represents a unique autonomic function in that it has a mixture of both sympathetic and parasympathetic components. Although the nerve fibers that stimulate sweat glands run with the sympathetic outflow, the fibers themselves are entirely cholinergic with the exception of a few adrenergic fibers to the palms and the soles⁵⁷. Parasympathetic centers in the hypothalamus are ultimately responsible for the stimulation of sweat production; therefore, sweating is best viewed as a unique parasympathetic function that is anatomically segregated in the sympathetic pathways. In this way, altered sweat function represents the only clear mechanism by which failure of a parasympathetic, rather than a sympathetic, system can lead to disease in the diabetic foot. Sweat function can be assessed with use of the quantitative sudomotor axon reflex test (QSART), in which sweating is induced by iontophoresis of a metered dose of acetylcholine and a sweat cell is used to calculate the resultant volume of sweat produced per unit area of skin⁵⁸. Ahmed and Le Quesne found sweat production to be well below the nondiabetic control range in 75% of patients with a history of a neuropathic ulcer⁵⁹. A similar result was reported by Ryder et al.⁶⁰. As the stimulation of sweating is lost, the resulting dry skin becomes scaly and fissures develop (Fig. 6). The crevices can run deep into the dermis and serve as a portal for infection. It is for this reason that long-term lubrication is an important component of preventive care of a diabetic foot.

Vascular Disease

Arteriosclerotic disease is more prevalent, occurs at an earlier age, is more diffuse, accelerates faster, and is more extensive in patients with diabetes than in patients without diabetes. Pathologically, the arterial intima and media show changes. In a diabetic patient, plaques develop circumferentially along the length of the vessel and calcification occurs within the tunica media. A commonly affected area for diabetic patients is the popliteal trifurcation and the distal runoff of these vessels. The underlying reasons for the diffuse development of diabetic angiopathy remain unclear and may be different between patients with type-I and type-II diabetes. Both mechanical and biological factors have been implicated. A chronic decrease in shear stress abnormalities has been found to contribute to endothelial dysfunction in patients with hypertension, although this effect has not been demonstrated in patients with diabetes⁶¹.

Biological mediators of endothelium-dependent vasodilation have been implicated in the development of diabetic macrovascular disease. The chief putative causes involve abnormalities of signal transduction mechanisms, alterations in cell-membrane fluidity that change the expression or presentation of a wide range of receptors, or changes in oxidative stress⁶². Of these potential disturbances, the strongest evidence points to an intrinsic dysfunction of nitric oxide (NO)⁶³. Nitric oxide is an important cellular mediator that interferes with monocyte and leukocyte adhesion to the endothelium, platelet-vessel wall interaction, smooth muscle proliferation, and vascular tone, all key events in the development of atherosclerosis. Chronic hyperglycemia appears to lead to the local formation of reactive oxygen species such as superoxide or hydrogen peroxide, which bind nitric oxide, reducing its local bioavailability. In addition, excessive postprandial lipidemia induces enhanced oxidative stress and a diminished action of nitric oxide⁶⁴.

Diabetic retinopathy and nephropathy are almost entirely due to microvascular disease, and almost certainly the same microvascular disease plays a role in the development and persistence of ulcers by impairing the skin’s nutritive blood-flow reserve⁶⁵. The pathognomonic histological feature of diabetic microangiopathy is a generalized basement-membrane thickening in capillaries, arterioles, and venules⁶⁶. The pathophysiology of microangiopathy is complex. Recent-onset diabetes is characterized by an increase in tissue blood flow that is partially normalized by glycemic control. However, as the duration of diabetes increases, microvascular blood flow decreases and autoregulation is lost^67,68. This pattern can be observed in diverse microvascular beds, including the eye⁶⁹, kidney^70,71, and skin^65,72, supporting the concept that a fundamental microvascular control mechanism is disturbed in patients with diabetes. There is now convincing evidence that the increased peripheral blood flow in patients with diabetes is due to precapillary vasodilatation^67,73,74 that leads to capillary hyperperfusion and capillary hypertension⁷⁶ (Fig. 7). The precapillary vasodilatation that appears to be instrumental in starting the process could result from a variety of different factors, including hyperglycemia, altered blood-flow mechanics, vascular smooth-muscle dysfunction, or endothelial dysfunction, but autonomic neuropathy is the mostly likely initiator^67,76. Excessive pressure stimulates the endothelial cells to produce more extracellular matrix proteins, leading to a thickening of the capillary basement membrane⁷⁷. In addition, the formation of advanced glycation end products and the abnormal cross-linking of type-IV collagen may contribute to the process^17-19,33-35. Capillary sclerosis ultimately results and is accompanied by limited microvascular blood flow, dysfunctional autoregulation, and impaired oxygen and nutrient exchange.

The sympathetic nervous system is known to play an important role in the control of microvascular function^78,79. Neurogenic control of the microcirculation permits global metabolic needs to be fulfilled and is balanced with local autoregulation of the microcirculation, which reflects local tissue requirements. Dysfunctional sympathetic neurovascular control can produce a profound microcirculatory disturbance with capillary hypertension, impaired postural vasoconstriction, increased arteriovenous shunting, and abnormal inflammatory responses to tissue injury^80-82. With time, the resulting capillary hypertension and microangiopathy can add to the pathological process by impairing blood flow through the vasa nervorum, thereby adding an ischemic component to the neuropathy itself⁸³.

Abnormal Wound-Healing of Established Diabetic Ulcers

When approaching diabetic foot ulceration, the first question to be addressed is: "Why do diabetic ulcers occur?" Equally important, though, is the question: "Why don’t they heal?" The answer to the second question involves some unexpected subtlety. There are several additional factors related to the wound environment itself that cannot necessarily be implicated in the creation of ulcers but that clearly act to perpetuate them once they are established.

Tissue oxygen tensions of 20 to 30 mm Hg are required for the secretion of collagen by fibroblasts, and low tissue-oxygen concentrations reduce the secretion of collagen by fibroblasts⁸⁴. Oxygen is also necessary for energy-dependent metabolic processes, fibroblast proliferation, and epithelialization^85-88. Normal tissue oxygenation is also vital for combating bacterial infection, and an impaired oxygen supply increases the risk of infection^85,86,88. Extramolecular oxygen, when reduced to superoxide, has potent bactericidal effects, and oxygen is critical to the functioning of granulocytes, which use oxygen to produce free radical oxidants to control bacteria by oxidizing cell membranes and by interfering with protein enzymatic processes⁸⁹. White blood cells accelerate oxygen consumption during phagocytosis and intracellular killing, and their killing capacity is severely limited in low-oxygen environments^90,91.

The degree to which tissue oxygen influences the healing of diabetic foot ulcers in the context of other intrinsic and extrinsic variables in the healing environment remains equivocal. Most randomized, controlled trials of diabetic foot ulcers have excluded patients whose transcutaneous oxygen tension (TcPO2) is <30 mm Hg^92,93, so that the impact of tissue oxygen levels on healing cannot be analyzed. An exception is the study by Boyko et al.⁹⁴, who compared dry and moist dressings and reported that TcPO2 on the dorsum of the affected foot was significantly higher for subjects in whom the ulcer had healed than for subjects in whom it had not healed over a four-week period, regardless of dressing type.

If local oxygenation is poor enough to cause tissue necrosis, the negative effects are amplified and necrotic tissue is associated with wound infection^95,96. Endotoxins that are released from dying cells can kill or injure nearby healthy cells, and high levels of endotoxins prevent fibroblasts and keratinocytes from reaching the wound site. Sapico et al. reported that foot ulcers demonstrated large numbers of both aerobes and anaerobes only when necrotic tissue was present and that the density of all organisms was greater in wounds with necrotic tissue than in those without it⁹⁶. Robson et al., in their seminal study of pressure ulcers, established that a bacterial level of >10⁵ organisms per gram of tissue resulted in delayed healing⁹⁷. The notable exception was β-hemolytic streptococci, as a lower level of such organisms (10³ per gram of tissue) was sufficient to produce the effect⁹⁷. Soft-tissue or bone infection can prolong the inflammatory phase of wound-healing, destroy surrounding tissue, increase protease activity, and retard epithelialization and collagen deposition. Steed et al. showed that débridement may enhance the healing of diabetic foot ulcers by lowering the bacterial burden and eradicating growth-factor inhibitors from the wound environment⁹⁸. Therefore, débridement of necrotic tissue in an ulcer has a sound biological basis.

Overt malnutrition, as well as subtle nutritional deficits, can affect wound repair and resistance to infection. Wound-healing abnormalities usually are associated with protein-calorie malnutrition rather than with depletion of a single nutrient^99,100, and preliminary work by Wipke-Tevis and Stotts suggested that nutritional deficiencies are present in a large proportion of patients with vascular ulcers¹⁰¹. The data are sparser for diabetic foot ulcers, but nutrition has been implicated in the pathogenesis of the broad spectrum of chronic wounds, and it is doubtful that diabetic ulcers would be an exception¹⁰².

Competent immune function is vital to the wound-healing process and is necessary for the synthesis, release, and regulation of the numerous endogenous growth factors, inflammatory cells, and proliferative cells involved in wound repair. In patients with foot ulcers, the influence of chronic hyperglycemia on leukocyte function has important implications for healing¹⁰³. Diminished chemotaxis, phagocytosis, and intracellular bacterial killing lead to impaired healing because of a less efficient inflammatory response. Even in the absence of infection, however, the altered function of neutrophils, macrophages, and lymphocytes can further limit healing by decreasing fibroblast proliferation and collagen deposition. The extent to which hyperglycemia-related immunopathy limits the healing of diabetic foot ulcers has not been delineated completely.

The role of short-term glucose control in wound-healing is complex and is not fully understood. Goodson and Hung demonstrated significantly reduced tensile strength and hydroxyproline content when wounds in animals with acute experimental diabetes were compared with wounds in control animals¹⁰⁴. Insulin treatment for the first eleven days following wounding corrected the hyperglycemia and improved healing. If insulin administration was not begun until the eleventh postoperative day and was continued thereafter, the impaired healing was not corrected. On the other hand, Barr and Joyce reported that re-endothelialization of an experimental microarterial anastomosis was slowed in rats with streptozotocin-induced diabetes and that impaired healing was not alleviated by treatment with insulin starting at the time of the operation and continuing postoperatively¹⁰⁵. Seifter et al. found that supplemental vitamin A given to rats with streptozotocin-induced diabetes alleviated the impaired healing without affecting the hyperglycemia, suggesting that its effects were independent of glucose control¹⁰⁶. It has been suggested that high glucose levels interfere with cellular transport of ascorbic acid into various cells, including fibroblasts, and cause decreased leukocyte chemotaxis¹⁰⁷. Glucose is similar in structure to ascorbic acid and may competitively inhibit its transport across cell membranes¹⁰⁷. In the context of other intrinsic and extrinsic factors that influence the wound-healing environment of diabetic foot ulcers, the role of short-term glucose control remains uncertain.

The Special Case of Charcot Arthropathy

Neuroarthropathy, or "Charcot arthropathy," is a diagnosis that predates the modern era of long-term survival with diabetes, having been first described in patients with tertiary syphilis¹⁰⁸. Despite a history of 130 years in the medical literature, the disorder remains an enigma that deserves special consideration.

Shortly after Charcot’s original description of neuroarthropathy, a school of thought evolved that implicated repetitive, unrecognized microtrauma to the anesthetic joint as the sole etiology. In 1917, Eloesser concluded, from a series of experiments on cat knees, that both an anesthetic joint and an element of trauma were required for joint destruction¹⁰⁹. In reality, he did not demonstrate the primary onset of neuroarthropathy but rather the acceleration of posttraumatic arthrosis. Similarly modern animal models have been inappropriately cited as models of Charcot arthropathy¹¹⁰. This "neurotraumatic" hypothesis entered the literature and served as the mainstream view for over half a century^111,112. A challenge to this hypothesis is based on a number of troubling anecdotal observations that have lent support to the notion that something more than unrecognized repetitive trauma is involved. For example, Schwarz et al. described a diabetic patient in whom a Charcot foot developed immediately following a surgical sympathectomy¹¹³, neuropathic joints are occasionally seen in the lower extremities of paraplegic patients, and Norman et al.¹¹⁴ and Knaggs¹¹⁵ independently reported neuropathic arthropathy of the hip in patients managed with complete bed rest.

The origin of the alternative "neurovascular" hypothesis is commonly attributed to Leriche, who noted concurrent osseous hyperemia and osseous resorption following sympathetic nerve damage¹¹⁶. This hypothesis was concisely articulated by Watkins and Edmonds as follows:

Sympathetic denervation of arterioles causes an increased blood flow, which in turn causes rarefaction of bone, making it prone to damage even after minor trauma. Loss of sensation from somatic neuropathy, in particular reduction of pain sensation, permits abnormal stresses that would normally be prevented by pain. Relatively minor trauma can therefore cause major destructive changes in susceptible bones¹¹⁷.

This hypothesis has been accepted, at least in part, by the authors of many studies^117-119, for it offers an alternative explanation for some of the questions left unsolved by the neurotraumatic hypothesis. Alterations in blood flow following the sympathetic dysfunction brought on by diabetic neuropathy are well documented^117,120. The phenomenon of "dependent rubor," in which the dependent leg is markedly engorged with blood that drains rapidly when the leg is elevated, is common in patients with neuroarthropathy (Fig. 8). Even in the absence of radiographic abnormalities, increased blood flow to bone has been demonstrated directly in the neuropathic foot by radioisotope uptake studies¹²¹. Some global measurements of autonomic function correlate with blood flow measurements. Uccioli et al., in a study of diabetic patients, correlated the results of a series of cardiovascular tests with the prevalence of arteriovenous shunting as assessed with use of the albumin microsphere technique¹²². They found direct correlations between the shunt fraction (an implied measure of the effect of the sympathetic outflow on the vasculature of the foot) and two global sympathetically mediated phenomena (postural hypotension and sustained hand grip) as well as one parasympathetic phenomenon (deep-breathing heart-rate variation). More directly, Young et al. found evidence of autonomic dysfunction in a significantly higher proportion of patients with Charcot arthropathy than in matched neuropathic patients without arthropathy¹²³. Anecdotal evidence in support of the neurovascular hypothesis was provided by Edelman et al., who reported the cases of three patients in whom neuroarthropathy developed immediately following the restoration of blood flow by surgical revascularization¹²⁴. Although it was not determined if the restored blood flow was supranormal, these cases suggest that at least adequate blood flow is necessary for Charcot changes to occur.

Sympathetic denervation has been implicated in structural as well as physiologic alterations in the vasculature¹¹⁷. Kerper and Collier first demonstrated foci of medial necrosis in arteries following sympathectomy in 1926¹²⁵, and structural changes can occur in arterial smooth muscle after long-term denervation¹²⁶. Clinically, Edmonds et al. demonstrated a strong correlation between diffuse medial vascular calcifications (Mönckeberg sclerosis) and the presence of diabetic neuropathy¹²⁷. This correlation is strong enough that the radiographic appearance of smooth vascular calcifications can be used as a marker for sympathetic dysfunction in the extremity (Fig. 9).

Some animal studies have also lent support to the neurovascular hypothesis. Verhas et al. noted striking correlations between increased bone blood flow (as assessed with microsphere techniques) and bone resorption in paraplegic rats¹²⁸. McClugage and McCuskey used direct observation of marrow changes to demonstrate osseous resorption around venules in high flow-high volume states¹²⁹.

While the neurovascular hypothesis has gained wide acceptance in recent years, it has failed, upon close examination, to provide a fundamental mechanism linking increased bone blood flow and bone resorption. There is no a priori reason why this should be so. Only McClugage and McCuskey addressed the issue directly, when they theorized that the hydrostatic pressure in postcapillary venules led to bone resorption¹²⁹. It is important to remember that other physiologic conditions (such as fracture-healing) can increase bone blood flow dramatically and lead to a net deposition of bone. For the time being, the absence of a mechanism remains the weak link in an otherwise compelling neurovascular argument.

Charcot himself initially attributed neuropathic arthropathy to the absence of "trophic" factors supplied to the bone by the peripheral nerves. Their absence, he believed, led to rapid bone destruction and eventual dissolution of the joint in only a matter of weeks¹⁰⁸. No direct evidence in support of this hypothesis has emerged, but it remains an important potential alternative. Bone does indeed have a nerve supply at the ultrastructural level as described by Cooper¹³⁰. Moore et al. recently described the presence of adrenergic receptors on osteoblasts and found that beta agonists could stimulate bone resorption in vitro, although their activity in vivo remains unproven¹³¹. Perhaps of greater interest, though, is the very recent evidence that osteoclasts have receptors for neuropeptides. Gough et al. found up-regulated serum levels of carboxyterminal type-I collagen telopeptide (a marker of osteoclast activity) in the absence of increases in serum procollagen carboxyterminal propeptide (a marker of osteoblastic bone formation) when patients with an acute Charcot arthropathy of the foot were compared with controls¹³². Evidence is accumulating that osteoclasts express mRNA for receptors of several small neuropeptides, including vasoactive intestinal peptide-1 (VIP1) and the related pituitary adenylate cyclase activating polypeptide (PACAP)¹³³, both of which have been shown to down-regulate bone resorption in isolated osteoclast preparations¹³⁴. A real possibility exists that modern molecular biology may yet prove Charcot’s long-ignored neurotrophic hypothesis to be correct.

Just as in the pathophysiology of ulcers, one of the principal challenges faced by any theory of neuroarthropathy is explaining why the disease develops in some patients with apparently similar circumstances and with similar patterns of neuropathy but not in others. There are suggestions that the underlying metabolic changes in bone may in fact be more systemic than previously thought. Young et al. found marked distal osteopenia on both the involved and the uninvolved side in patients with Charcot arthropathy¹²³, and Gough et al. found no difference between measurements of serum markers of bone turnover in samples drawn from the dorsal veins of involved feet and from the veins of upper extremities¹³². Although additional work is clearly needed, both pieces of evidence suggest that there may in fact be a relatively large number of diabetic patients with a systemic disorder of bone metabolism awaiting only a relatively minor perturbation to trigger an episode of neuroarthropathy.

Overview

There remains vast truth in the statement "neuropathy causes diabetic foot pathology." However, if it were really that straightforward and if our understanding were complete, it is doubtful that ulceration and neuroarthropathy would be the public-health problems that they are today. Diabetes is an insidious disease, and almost every component of the spectrum of hyperglycemic complications is active in creating foot lesions. These include dramatic alterations in all components of the peripheral nerves, the mechanical characteristics of bones and soft tissues, gait kinematics, the vasculature at both a microscopic and a macroscopic level, the immune system, and the fundamental processes of wound-healing. Clinical treatments that address the biological aspects of the problem without considering the mechanics, or vice versa, can sometimes be effective but fail to take advantage of all of the potential means to succeed. The greatest potential for future clinical advance lies in understanding and simultaneously addressing the many synergistic factors that cause both ulceration and neuroarthropathy.

References

Olmos PR; Cataland S; O’Dorisio TM; Casey CA; Smead WL; and Simon SR: The Semmes-Weinstein monofilament as a potential predictor of foot ulceration in patients with noninsulin-dependent diabetes. Am J Med Sci,1995.309: 76-82., 30976 1995 [PubMed][CrossRef]

Pham H; Armstrong DG; Harvey C; Harkless LB; Giurini JM; and Veves A: Screening techniques to identify people at high risk for diabetic foot ulceration: a prospective multicenter trial. Diabetes Care,2000.23: 606-11., 23606 2000 [PubMed][CrossRef]

Kelkar P; Masood M; and Parry GJ: Distinctive pathologic findings in proximal diabetic neuropathy (diabetic amyotrophy). Neurology,2000.55: 83-8., 5583 2000 [PubMed]

O’Brian JT, and Massey EW: Mononeuropathy in diabetes mellitus: a phenomenon easily overlooked. Postgrad Med,1979.65: 128,130-2,135-6., 65128 1979 [PubMed]

Shahani B, and Spalding JM: Diabetes mellitus presenting with bilateral foot-drop. Lancet,1969.2: 930-1., 2930 1969 [PubMed][CrossRef]

Vallbo AB; Hagbarth KE; Torebjork HE; and Wallin BG: Somatosensory, proprioceptive, and sympathetic activity in human peripheral nerves. Physiol Rev,1979.59: 919-57., 59919 1979 [PubMed]

Fagius J: Microneurographic findings in diabetic polyneuropathy with special reference to sympathetic nerve activity. Diabetologia,1982.23: 415-20., 23415 1982 [PubMed]

Low PA; Zimmerman BR; and Dyck PJ: Comparison of distal sympathetic and vagal function in diabetic neuropathy. Muscle Nerve,1986.9: 592-6., 9592 1986 [PubMed][CrossRef]

Ryan CM, and Geckle MO: Circumscribed cognitive dysfunction in middle-aged adults with type 2 diabetes. Diabetes Care,2000.23: 1486-93., 231486 2000 [PubMed][CrossRef]

Sartucci F; Piaggesi A; Logi F; Bonfiglio L; Bongioanni P; Pellegrinetti A; Baccetti F; Navalesi R; and Murri L: Impaired ascendant central pathways conduction in impotent diabetic subjects. Acta Neurol Scand,1999.99: 381-6., 99381 1999 [PubMed][CrossRef]

Biessels GJ: Cerebral complications of diabetes: clinical findings and pathogenetic mechanisms. Neth J Med,1999.54: 35-45., 5435 1999 [PubMed][CrossRef]

Thomas PK, Tomlinson DR. Diabetic and hypoglycemic neuropathy. In: Dyck PJ, Thomas PK, Griffin JW, Low PA, Poduslo JF, editors. Peripheral neuropathy. 3rd ed, vol 2. Philadelphia: WB Saunders; 1993. p 1219-50.

The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med,1993.329: 977-86., 329977 1993 [PubMed][CrossRef]

Tomlinson DR: Future prevention and treatment of diabetic neuropathy. Diabetes Metab,1998.24 Suppl 3: 79-83., 24 Suppl 379 1998 [PubMed]

Shimoshige Y; Ikuma K; Yamamoto T; Takakura S; Kawamura I; Seki J; Mutoh S; and Goto T: The effects of zenarestat, an aldose reductase inhibitor, on peripheral neuropathy in Zucker diabetic fatty rats. Metabolism,2000.49: 1395-9., 491395 2000 [PubMed][CrossRef]

Sundkvist G; Dahlin LB; Nilsson H; Eriksson KF; Lindgarde F; Rosen I; Lattimer SA; Sima AA; Sullivan K; and Greene DA: Sorbitol and myo-inositol levels and morphology of sural nerve in relation to peripheral nerve function and clinical neuropathy in men with diabetic, impaired, and normal glucose tolerance. Diabet Med,2000.17: 259-68., 17259 2000 [PubMed][CrossRef]

Brownlee M; Vlassara H; Kooney A; Ulrich P; and Cerami A: Aminoguanidine prevents diabetes-induced arterial wall protein cross-linking. Science,1986.232: 1629-32., 2321629 1986 [PubMed][CrossRef]

Kent MJ; Light ND; and Bailey AJ: Evidence for glucose-mediated covalent cross-linking of collagen after glycosylation in vitro. Biochem J,1985.225: 745-52., 225745 1985 [PubMed]

Brownlee M: Glycation products and the pathogenesis of diabetic complications. Diabetes Care,1992.15: 1835-43., 151835 1992 [PubMed][CrossRef]

Wada R; Sugo M; Nakano M; and Yagihashi S: Only limited effects of aminoguanidine treatment on peripheral nerve function, (Na+,K+)-ATPase activity and thrombomodulin expression in streptozotocin-induced diabetic rats. Diabetologia,1999.42: 743-7., 42743 1999 [PubMed][CrossRef]

Vernino S; Low PA; Fealey RD; Stewart JD; Farrugia G; and Lennon VA: Autoantibodies to ganglionic acetylcholine receptors in autoimmune autonomic neuropathies. N Engl J Med,2000.343: 847-55., 343847 2000 [PubMed][CrossRef]

Morano S; Tiberti C; Cristina G; Sensi M; Cipriani R; Guidobaldi L; Torresi P; Medici F; Anastasi E; and Di Mario U: Autoimmune markers and neurological complications in non-insulin-dependent diabetes mellitus. Hum Immunol,1999.60: 848-54., 60848 1999 [PubMed][CrossRef]

Brand PW. The insenstitive foot (including leprosy). In: Jahss MH, editor. Disorders of the foot and ankle. Medical and surgical management. 2nd ed. Philadelphia: WB Saunders; 1991. p 2170-86.

Masson EA; Hay EM; Stockley I; Veves A; Betts RP; and Boulton AJ: Abnormal foot pressures alone may not cause ulceration. Diabet Med,1989.6: 426-8., 6426 1989 [PubMed][CrossRef]

Bojsen-Moller F, and Flagstad KE: Plantar aponeurosis and internal architecture of the ball of the foot. J Anat,1976.121: 599-611., 121599 1976 [PubMed]

Naylor PFD: Experimental friction blisters. Br J Dermatol,1955.67: 327-42., 67327 1955 [PubMed][CrossRef]

Cua AB; Wilhelm KP; and Maibach HI: Frictional properties of human skin: relation to age, sex and anatomical region, stratum corneum hydration and transepidermal water loss. Br J Dermatol,1990.123: 473-9., 123473 1990 [PubMed][CrossRef]

Pollard JP; Le Quesne LP; and Tappin JW: Forces under the foot. J Biomed Eng,1983.5: 37-40., 537 1983 [PubMed][CrossRef]

Coughlin MJ, Mann RA. Lesser toe deformities. In: Coughlin MJ, Mann RA, editors. Surgery of the foot and ankle. 7th ed, vol 1. St. Louis: Mosby; 1999. p 320-91.

Negrin P, and Fardin P: Multiple role of peripheral neuropathy in the pathogenesis of the so-called "diabetic foot." Clinical and electromyographical (EMG) study of 42 cases of "mutilating acropathy." Electromyogr Clin Neurophysiol. 1986.26: 533-40., 26533 1986

Brodsky JW. The diabetic foot. In: Coughlin MJ, Mann RA, editors. Surgery of the foot and ankle. 7th ed, vol 2. St. Louis: Mosby; 1999. p 895-969.

Boyko EJ; Ahroni JH; Stensel V; Forsberg RC; Davignon DR; and Smith DG: A prospective study of risk factors for diabetic foot ulcer. The Seattle Diabetic Foot Study. Diabetes Care,1999.22: 1036-42., 221036 1999 [PubMed][CrossRef]

Jennings AM; Milner PC; and Ward JD: Hand abnormalities are associated with the complications of diabetes in type 2 diabetes. Diabet Med,1989.6: 43-7., 643 1989 [PubMed][CrossRef]

Rosenbloom AL; Silverstein JH; Lezotte DC; Richardson K; and McCallum M: Limited joint mobility in childhood diabetes mellitus indicates increased risk for microvascular disease. N Engl J Med,1981.305: 191-4., 305191 1981 [PubMed][CrossRef]

Arkkila PE; Kantola IM; Viikari JS; Ronnemaa T; and Vahatalo MA: Limited joint mobility is associated with the presence but does not predict the development of microvascular complications in type 1 diabetes. Diabet Med,1996.13: 828-33., 13828 1996 [PubMed][CrossRef]

Silverstein JH; Gordon G; Pollock BH; and Rosenbloom AL: Long-term glycemic control influences the onset of limited joint mobility in type 1 diabetes. J Pediatr,1998.132: 944-7., 132944 1998 [PubMed][CrossRef]

Arkkila PE; Kantola IM; and Viikari JS: Limited joint mobility in non-insulin-dependent diabetic (NIDDM) patients: correlation to control of diabetes, atherosclerotic vascular disease, and other diabetic complications. J Diabetes Complications,1997.11: 208-17., 11208 1997 [PubMed][CrossRef]

Rosenbloom AL, and Silverstein JH: Connective tissue and joint disease in diabetes mellitus. Endocrinol Metab Clin North Am,1996.25: 473-83., 25473 1996 [PubMed][CrossRef]

Lundbaek K: Stiff hands in long term diabetes. Acta Med Scand,1957.158: 447-51., 158447 1957 [PubMed]

Campbell RR; Hawkins SJ; Maddison PJ; and Reckless JP: Limited joint mobility in diabetes mellitus. Ann Rheum Dis,1985.44: 93-7., 4493 1985 [PubMed][CrossRef]

Delbridge L; Perry P; Marr S; Arnold N; Yue DK; Turtle JR; and Reeve TS: Limited joint mobility in the diabetic foot: relationship to neuropathic ulceration. Diabet Med,1988.5: 333-7., 5333 1988 [PubMed][CrossRef]

Mueller MJ; Diamond JE; Delitto A; and Sinacore DR: Insensitivity, limited joint mobility, and plantar ulcers in patients with diabetes mellitus. Phys Ther,1989.69: 453-62., 69453 1989 [PubMed]

Fernando DJ; Masson EA; Veves A; and Boulton AJ: Relationship of limited joint mobility to abnormal foot pressures and diabetic foot ulceration. Diabetes Care,1991.14: 8-11., 148 1991 [PubMed][CrossRef]

Yosipovitch Z, and Sheskin J: Subcutaneous Achilles tenotomy in the treatment of perforating ulcer of the foot in leprosy. . Int J Lepr Other Mycobact Dis,1971.39: 631-2., 39631 1971 [PubMed]

Bennett PJ; Stocks AE; and Whittam DJ: Analysis of risk factors for neuropathic foot ulceration in diabetes mellitus. J Am Podiatr Med Assoc,1996.86: 112-6., 86112 1996 [PubMed]

Lin SS; Lee TH; and Wapner KL: Plantar forefoot ulceration with equinus deformity of the ankle in diabetic patients: the effect of tendo-Achilles lengthening and total contact casting. Orthopedics,1996.19: 465-75., 19465 1996 [PubMed]

Armstrong DG; Stacpoole-Shea S; Nguyen H; and Harkless LB: Lengthening of the Achilles tendon in diabetic patients who are at high risk for ulceration of the foot. J Bone Joint Surg Am,1999.81: 535-8., 81535 1999 [PubMed]

Frykberg RG; Lavery LA; Pham H; Harvey C; Harkless L; and Veves A: Role of neuropathy and high foot pressures in diabetic foot ulceration. Diabetes Care,1998.21: 1714-9., 211714 1998 [PubMed][CrossRef]

Veves A; Murray HJ; Young MJ; and Boulton AJ: The risk of foot ulceration in diabetic patients with high foot pressure: a prospective study. Diabetologia,1992.35: 660-3., 35660 1992 [PubMed][CrossRef]

Smith L; Plehwe W; McGill M; Genev N; Yue DK; and Turtle JR: Foot bearing pressure in patients with unilateral diabetic foot ulcers. Diabet Med,1989.6: 573-5., 6573 1989 [PubMed][CrossRef]

Katoulis EC; Ebdon-Parry M; Hollis S; Harrison AJ; Vileikyte L; Kulkarni J; and Boulton AJ: Postural instability in diabetic neuropathic patients at risk of foot ulceration. Diabet Med,1997.14: 296-300., 14296 1997 [PubMed][CrossRef]

Cavanagh PR, Simoneau GG, Ulbrecht JS: Ulceration, unsteadiness, and uncertainty: the biomechanical consequences of diabetes mellitus. J Biomech,1993.26 Suppl 1: 23-40., 26 Suppl 123 1993 [PubMed][CrossRef]

Dingwell JB; Ulbrecht JS; Boch J; Becker MB; O’Gorman JT; and Cavanagh PR: Neuropathic gait shows only trends towards increased variability of sagittal plane kinematics during treadmill locomotion. Gait Posture,1999.10: 21-9., 1021 1999 [PubMed][CrossRef]

Mueller MJ; Minor SD; Sahrmann SA; Schaaf JA; and Strube MJ: Differences in the gait characteristics of patients with diabetes and peripheral neuropathy compared with age-matched controls. Phys Ther,1994.74: 299-313., 74299 1994 [PubMed]

Katoulis EC; Ebdon-Parry M; Lanshammar H; Vileikyte L; Kulkarni J; and Boulton AJ: Gait abnormalities in diabetic neuropathy. Diabetes Care,1997.20: 1904-7., 201904 1997 [PubMed][CrossRef]

Salsich GB, and Mueller MJ: Effect of plantar flexor muscle stiffness on selected gait characteristics. Gait Posture,2000.11: 207-16., 11207 2000 [PubMed][CrossRef]

Guyton AC. Textbook of medical physiology. 7th ed. Philadelphia: WB Saunders; 1986. p 774.

Low PA; Caskey PE; Tuck RR; Fealey RD; and Dyck PJ: Quantitative sudomotor axon reflex test in normal and neuropathic subjects. Ann Neurol,1983.14: 573-80., 14573 1983 [PubMed][CrossRef]

Ahmed ME, and Le Quesne PM: Quantitative sweat test in diabetics with neuropathic foot lesions. J Neurol Neurosurg Psychiatry,1986.49: 1059-62., 491059 1986 [PubMed][CrossRef]

Ryder RE; Kennedy RL; Newrick PG; Wilson RM; Ward JD; and Hardisty CA: Autonomic denervation may be a prerequisite of diabetic neuropathic foot ulceration. Diabet Med,1990.7: 726-30., 7726 1990 [PubMed][CrossRef]

Khder Y; Briancon S; Petermann R; Quilliot D; Stoltz JF; Drouin P; and Zannad F: Shear stress abnormalities contribute to endothelial dysfunction in hypertension but not in type II diabetes. J Hypertens,1998.16: 1619-25., 161619 1998 [PubMed][CrossRef]

Tooke JE: Possible pathophysiological mechanisms for diabetic angiopathy in type 2 diabetes. J Diabetes Complications,2000.14: 197-200., 14197 2000 [PubMed][CrossRef]

Cosentino F, and Luscher TF: Endothelial dysfunction in diabetes mellitus. J Cardiovasc Pharmacol,1998.32 Suppl 3: 54-61., 32 Suppl 354 1998

Evans M; Khan N; and Rees A: Diabetic dyslipidaemia and coronary heart disease: new perspectives. Curr Opin Lipidol,1999.10: 387-91., 10387 1999 [PubMed][CrossRef]

Rendell M, and Bamisedun O: Diabetic cutaneous microangiopathy. Am J Med,1992.93: 611-8., 93611 1992 [PubMed][CrossRef]

Williamson JR, and Kilo C: Vascular complications in diabetes mellitus. N Engl J Med,1980.302: 399-400., 302399 1980 [PubMed][CrossRef]

Tooke JE: Microvascular function in human diabetes. A physiological perspective. Diabetes,1995.44: 721-6., 44721 1995 [PubMed][CrossRef]

Ditzel J: Functional microangiopathy in diabetes mellitus. Diabetes,1968.17: 388-97., 17388 1968 [PubMed]

Sinclair SH; Grunwald JE; Riva CE; Braunstein SN; Nichols CW; and Schwartz SS: Retinal vascular autoregulation in diabetes mellitus. Ophthalmology,1982.89: 748-50., 89748 1982 [PubMed]

Christiansen JS: Glomerular hyperfiltration in diabetes mellitus. Diabet Med,1985.2: 235-9., 2235 1985 [PubMed]

Parving HH; Kastrup H; Smidt UM; Andersen AR; Feldt-Rasmussen B; and Christiansen JS: Impaired autoregulation of glomerular filtration rate in type 1 (insulin-dependent) diabetic patients with nephropathy. Diabetologia,1984.27: 547-52., 27547 1984 [PubMed][CrossRef]

Kastrup J; Norgaard T; Parving HH; Henriksen O; and Lassen NA: Impaired autoregulation of blood flow in subcutaneous tissue of long-term type 1 (insulin-dependent) diabetic patients with microangiopathy: an index of arteriolar dysfunction. Diabetologia,1985.28: 711-7., 28711 1985 [PubMed]

Parving HH; Viberti GC; Keen H; Christiansen JS; and Lassen NA: Hemodynamic factors in the genesis of diabetic microangiopathy. Metabolism,1983.32: 943-9., 32943 1983 [PubMed][CrossRef]

Zatz R, and Brenner BM: Pathogenesis of diabetic microangiopathy. The hemodynamic view. Am J Med,1986.80: 443-53., 80443 1986 [PubMed][CrossRef]

Sandeman DD; Shore AC; and Tooke JE: Relation of skin capillary pressure in patients with insulin-dependent diabetes mellitus to complications and metabolic control. N Engl J Med,1992.327: 760-4., 327760 1992 [PubMed][CrossRef]

Flynn MD, and Tooke JE: Diabetic neuropathy and the microcirculation. Diabet Med,1995.12: 298-301., 12298 1995 [PubMed][CrossRef]

Riser BL; Cortes P; Zhao X; Bernstein J; Dumler F; and Narino RG: Intraglomerular pressure and mesangial stretching stimulate extracellular matrix formation in the rat. J Clin Invest,1992.90: 1932-43., 901932 1992 [PubMed][CrossRef]

Gaskell P, and Buton AC: Local postural venomotor reflexes arising from the limb veins. Circ Res,1953.1: 27-39., 127 1953 [PubMed]

Renkin EM: Regulation of the microcirculation. Microvasc Res,1985.30: 251-63., 30251 1985 [PubMed][CrossRef]

Rayman G; Hassan A; and Tooke JE: Blood flow in the skin of the foot related to posture in diabetes mellitus. Br Med J (Clin Res Ed),1986.292: 87-90., 29287 1986 [PubMed][CrossRef]

Flynn MD; Hassan AA; and Tooke JE: Effect of postural change and thermoregulatory stress on the capillary microcirculation of the human toe. Clin Sci,1989.76: 231-6., 76231 1989 [PubMed]

Belcaro G; Nicolaides AN; Volteas N; and Leon M: Skin flow the venoarteriolar response and capillary filtration in diabetics. A 3-year follow-up. Angiology,1992.43: 490-5., 43490 1992 [PubMed][CrossRef]

Faberberg SE: Diabetic neuropathy: a clinical and histological study of the significance of vascular affections. Acta Med Scand,1959.164 (Suppl 345): 1-97., 164 (Suppl 345)1 1959

Hunt TK, and Pai MP: The effect of varying ambient oxygen tensions on wound metabolism and collagen synthesis. Surg Gynecol Obstet,1972.135: 561-7., 135561 1972 [PubMed]

Hunt TK, Hussain Z. Wound microenvironment. In: Cohen IK, Diegelmann RF, Lindblad WJ, editors. Wound healing. Biochemical and clinical aspects. Philadelphia: WB Saunders; 1992. p 274-81.

Ehrlichman RJ; Seckel BR; Bryan DJ; and Moschella CJ: Common complications of wound healing. Prevention and management. Surg Clin North Am,1991.71: 1323-51., 711323 1991 [PubMed]

Paquet P, Lapiére CM. Causes of delayed wound healing and optimization of the patient’s condition. In: Westerhof W, editor. Leg ulcers: diagnosis and treatment. New York: Elsevier Science; 1993. p 281-90.

Lawrence WT. Clinical management of nonhealing wounds. In: Cohen IK, Diegelmann RF, Lindblad WJ, editors. Wound healing. Biochemical and clinical aspects. Philadelphia: WB Saunders; 1992. p 541-61.

White MJ, and Heckler FR: Oxygen free radicals and wound healing. Clin Plast Surg,1990.17: 473-84., 17473 1990 [PubMed]

Hohn DC. Host resistance of infection: established and emerging concepts. In: Hunt TK, editor. Wound healing and wound infection. Theory and surgical practice. New York: Appleton-Century-Crofts; 1980. p 264-80.

LaVan FB, Hunt TK: Oxygen and wound healing. Clin Plast Surg,1990.17: 463-72., 17463 1990 [PubMed]

Steed DL; Goslen JB; Holloway GA; Malone JM; Bunt TJ; and Webster MW: Randomized prospective double-blind trial in healing chronic diabetic foot ulcers. CT-102 activated platelet supernatant, topical versus placebo. Diabetes Care,1992.15: 1598-604., 151598 1992 [PubMed][CrossRef]

Steed DL: Clinical evaluation of recombinant human platelet-derived growth factor for the treatment of lower extremity diabetic ulcers. Diabetic Ulcer Study Group. J Vasc Surg,1995.21: 71-81., 2171 1995 [PubMed][CrossRef]

Boyko EJ; Ahroni JH; Stensel VL; Smith DG; Davignon DR; and Pecoraro RE: Predictors of transcutaneous oxygen tension in the lower limbs of diabetic subjects. Diabet Med,1996.13: 549-54., 13549 1996 [PubMed][CrossRef]

Dhingra U; Schauerhamer RR; and Wangensteen OW: Peripheral dissemination of bacteria in contaminated wounds; role of devitalized tissue: evaluation of therapeutic measures. Surgery,1976.80: 535-43., 80535 1976 [PubMed]

Sapico FL; Ginunas VJ; Thornhill-Joynes M; Canawati HN; Capen DA; Klein NE; Khawam S; and Montgomerie JZ: Quantitative microbiology of pressure sores in different stages of healing. Diagn Microbiol Infect Dis,1986.5: 31-8., 531 1986 [PubMed][CrossRef]

Robson MC; Stenberg BD; and Heggers JP: Wound healing alterations caused by infection. Clin Plast Surg,1990.17: 485-92., 17485 1990 [PubMed]

Steed DL; Donohoe D; Webster MW; and Lindsley L: Effect of extensive debridement and treatment on the healing of diabetic foot ulcers. Diabetic Ulcer Study Group. J Am Coll Surg,1996.183: 61-4., 18361 1996 [PubMed]

Goodson WH, Hunt TK. Wound healing. In: Kinney JM, Jeejeebhoy KN, et al., editors. Nutrition and metabolism in patient care. Philadelphia: WB Saunders; 1988. p 635-42.

100

Daly JM; Vars HM; and Dudrick SJ: Effects of protein depletion on strength of colonic anastomoses. Surg Gynecol Obstet,1972.134: 15-21., 13415 1972 [PubMed]

101

Wipke-Tevis DD, and Stotts NA: Nutrition, tissue oxygenation, and healing of venous leg ulcers. J Vasc Nurs,1998.16: 48-56., 1648 1998 [PubMed][CrossRef]

102

Falanga V: Chronic wounds: pathophysiologic and experimental considerations. J Invest Dermatol,1993.100: 721-5., 100721 1993 [PubMed][CrossRef]

103

Carrico TJ; Mehrhof AI Jr; and Cohen IK: Biology of wound healing. Surg Clin North Am,1984.64: 721-33., 64721 1984 [PubMed]

104

Goodson WH 3rd, and Hung TK: Studies of wound healing in experimental diabetes mellitus. J Surg Res,1977.22: 221-7., 22221 1977 [PubMed][CrossRef]

105

Barr LC, and Joyce AD: Microvascular anastomoses in diabetes: an experimental study. Br J Plast Surg,1989.42: 50-3., 4250 1989 [PubMed]

106

Seifter E; Rettura G; Padawer J; Stratford F; Kamposos D; and Levenson SM: Impaired wound healing in streptozotocin diabetes. Prevention by supplemental vitamin. A Ann Surg,1981.194: 42-50., 19442 1981 [CrossRef]

107

Mann GV, and Newton P: The membrane transport of ascorbic acid. Ann N Y Acad Sci,1975.258: 243-52., 258243 1975 [PubMed][CrossRef]

108

Charcot J-M: Sur quelques arthropathies qui paraissant dépendre d’une lesion du cerveau ou de la moelle épinierè. Arch Physiol Norm Pathol,1868.1: 161-78., 1161 1868

109

Eloesser L: On the nature of neuropathic affections of the joints. Ann Surg,1917.66: 201-7., 66201 1917 [PubMed][CrossRef]

110

O’Connor BL; Palmoski MJ; and Brandt KD: Neurogenic acceleration of degenerative joint lesions. J Bone Joint Surg Am,1985.67: 562-72., 67562 1985 [PubMed]

111

Delano PJ: The pathogenesis of Charcot’s joint. Am J Roentgenol,1946.56: 189-200., 56189 1946

112

Johnson JT: Neuropathic fractures and joint injuries. Pathogenesis and rationale of prevention and treatment. J Bone Joint Surg Am,1967.49: 1-30., 491 1967 [PubMed]

113

Schwarz GS; Berenyi MR; and Siegel MW: Atrophic arthropathy and diabetic neuritis. Am J Roentgenol Radium Ther Nucl Med,1969.106: 523-9., 106523 1969 [PubMed]

114

Norman A; Robbins H; and Milgram JE: The acute neuropathic arthropathy—a rapid, severely disorganizing form of arthritis. Radiology,1968.90: 1159-64., 901159 1968 [PubMed]

115

Knaggs RL.Inflammatory and toxic diseases of bone: a textbook for senior students. New York: William Wood; 1926. Charcot joints; p 105-19.

116

Leriche R: Sur quelques maladies osseuses et articulares d’origine vasomotrice et sur leur traitment. Bull et mém Soc nat de chir,1927.53: 1022-30., 531022 1927

117

Watkins PJ, and Edmonds ME: Sympathetic nerve failure in diabetes. Diabetologia,1983.25: 73-7., 2573 1983 [PubMed]

118

Brower AC, and Allman RM: Pathogenesis of the neurotrophic joint: neurotraumatic vs. neurovascular. Radiology,1981.139: 349-54., 139349 1981 [PubMed]

119

Brooks AP: The neuropathic foot in diabetes. Part II: Charcot’s neuroarthropathy. Diabet Med,1986.3: 116-8., 3116 1986 [PubMed][CrossRef]

120

Edmonds ME: The neuropathic foot in diabetes. Part I: Blood flow. Diabet Med,1986.3: 111-5., 3111 1986 [PubMed][CrossRef]

121

Watkins PJ, Edmonds ME. Autonomic neuropathy: blood flow in the diabetic foot. In: Bostrom H, Ljungstedt N, editors. Recent trends in diabetic research. Stockholm: Almqvist and Wiksell; 1981. p 221-4.

122

Uccioli L; Mancini L; Giordano A; Solini A; Magnani P; Manto A; Cotroneo P; Greco AV; and Ghirlanda G: Lower limb arterio-venous shunts, autonomic neuropathy and the diabetic foot. Diabetes Res Clin Pract,1992.16: 123-30., 16123 1992 [PubMed][CrossRef]

123

Young MJ; Marshall A; Adams JE; Selby PL; and Boulton AJ: Osteopenia, neurological dysfunction, and the development of Charcot neuroarthropathy. Diabetes Care,1995.18: 34-8., 1834 1995 [PubMed][CrossRef]

124

Edelman SV; Kosofsky EM; Paul RA; and Kozak GP: Neuro-osteoarthropathy (Charcot’s joint) in diabetes mellitus following revascularization surgery. Three case reports and a review of the literature. Arch Intern Med,1987.147: 1504-8., 1471504 1987 [PubMed][CrossRef]

125

Kerper AH, and Collier WD: Pathological changes in arteries following partial denervation. Proc Soc Exp Biol Med,1926.24: 493-4., 24493 1926

126

Bevan RD, and Tsuru H: Long-term denervation of vascular smooth muscle causes not only functional but structural change. Blood Vessels,1979.16: 109-12., 16109 1979 [PubMed]

127

Edmonds ME; Morrison N; Laws JW; and Watkins PJ: Medical arterial calcification and diabetic neuropathy. Br Med J (Clin Res Ed),1982.284: 928-30., 284928 1982 [PubMed][CrossRef]

128

Verhas M; Martinello Y; Mone M; Heilporn A; Bergmann P; Tricot A; and Schoutens A: Demineralization and pathological physiology of the skeleton in paraplegic rats. Calcif Tissue Int,1980.30: 83-90., 3083 1980 [PubMed][CrossRef]

129

McClugage SG Jr, and McCuskey RS: Relationship of the microvascular system to bone resorption and growth in situ. Microvasc Res,1973.6: 132-4., 6132 1973 [PubMed][CrossRef]

130

Cooper RR: Nerves in cortical bone. Science,1968.160: 327-8., 160327 1968 [PubMed][CrossRef]

131

Moore RE; Smith CK 2nd; Bailey CS; Voelkel EF; and Tashjian AH Jr: Characterization of beta-adrenergic receptors on rat and human osteoblast-like cells and demonstration that beta-receptor agonists can stimulate bone resorption in organ culture. Bone Miner,1993.23: 301-15., 23301 1993 [PubMed][CrossRef]

132

Gough A; Abraha H; Li F; Purewal TS; Foster AV; Watkins PJ; Moniz C; and Edmonds ME: Measurement of markers of osteoclast and osteoblast activity in patients with acute and chronic diabetic Charcot neuroarthropathy. Diabet Med,1997.14: 527-31., 14527 1997 [PubMed][CrossRef]

133

Ransjo M; Lie A; Mukohyama H; Lundberg P; and Lerner UH: Microisolated mouse osteoclasts express VIP-1 and PACAP receptors. Biochem Biophys Res Commun,2000.274: 400-4., 274400 2000 [PubMed][CrossRef]

134

Winding B; Wiltink A; and Foged NT: Pituitary adenylyl cyclase-activating polypeptides and vasoactive intestinal peptide inhibit bone resorption by isolated rabbit osteoclasts. Exp Physiol,1997.82: 871-86., 82871 1997 [PubMed]

Topics

diabetes mellitus, type 1 ; diabetic neuropathy ; diabetic foot ulcer ; ulcer ; arthropathy, neurogenic ; contracture ; foot ; neuropathy

First Page Preview

View Large

Username

Password

Access for Patients

Forgot Password?

Have a subscription to the print edition?

Not a Subscriber?

Buy this Article

Get online access for 30 days for $35

New to JBJS?

Subscribe to the online edition for 30 days for $75

Register for a FREE limited account to get full access to all CME activities, to comment on public articles, or to sign up for alerts.

Have a subscription to the print edition?

Current subscribers to The Journal of Bone & Joint Surgery in either the print or quarterly DVD formats receive free online access to JBJS.org.

Activate your online account now

Forgot your password?

Enter your username and email address. We'll send you a reminder to the email address on record.

Username:*

Email Address:*

Forgot your username or need assistance? Please contact customer service at subs@jbjs.org. If your access is provided
by your institution, please contact you librarian or administrator for username and password information. Institutional
administrators, to reset your institution's master username or password, please contact subs@jbjs.org

References

Accreditation Statement

These activities have been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Academy of Orthopaedic Surgeons and The Journal of Bone and Joint Surgery, Inc. The American Academy of Orthopaedic Surgeons is accredited by the ACCME to provide continuing medical education for physicians.

CME Activities Associated with This Article

Submit a Comment

Please read the other comments before you post yours. Contributors must reveal any conflict of interest.
Comments are moderated and will appear on the site at the discretion of JBJS editorial staff.

* = Required Field

Comment Author(s) * (if multiple authors, separate names by comma)

Example: John Doe

Affiliation & Institution*

Disclosure

Comment Title*

Comment*

Cancel

Print
PDF
Email

Recipient(s) will receive an email with a link (good for 5 days) to 'The Diabetic Foot : Basic Mechanisms of Disease'.
Your Name:*
Example: John Doe

Email Address:* CC Me:
Enter your valid email address. Example: jdoe@example.com

Recipient's Email Address:*

Separate multiple email address with semi-colons (up to 5).

Subject:* 's The Journal of Bone & Joint Surgery: 'The Diabetic Foot : Basic Mechanisms of Disease'
Subject for your email.

Message:

(Optional, message will truncate at 1000 characters)

Processing your request... Please Wait...

Copyright © in the material you requested is held by The Journal of Bone & Joint Surgery, Inc. (unless otherwise noted). This email ability is provided as a courtesy, and by using it you agree that that you are requesting the material solely for personal, non-commercial use, and that it is subject to Journal of Bone & Joint Surgery, Inc.'s Terms of Use. The information provided in order to email this topic will not be used to send unsolicited email, nor will it be furnished to third parties. Please refer to The Journal of Bone & Joint Surgery Inc.'s Privacy Policy for further information.

Copyright © The Journal of Bone & Joint Surgery Inc. All rights reserved.
Share
Get Citation

Gregory P. Guyton, Charles L. Saltzman; The Diabetic Foot Basic Mechanisms of Disease. The Journal of Bone & Joint Surgery. 2001 Jul;83(7):1083-1096.

Download citation file:

RIS (Zotero)

EndNote

BibTex

Medlars

ProCite

RefWorks

Reference Manager

Copyright © The Journal of Bone and Joint Surgery, Inc.
Rights & Permissions
Article Alerts

Processing your request... Please Wait.
Submit a Comment