diabetes mellitus: review

A Huntley M.D.

Associate Professor, University of California at Davis

ABSTRACT

Diabetes mellitus is a common condition which frequently has skin manifestations. The attachment of glucose to protein may result in a profound effect on structure and function of that protein, and account for clinical manifestations of the disease. It has been suggested that increased crosslinking of collagen in diabetic patients is responsible for the fact that their skin is generally thicker than that of non-diabetics. Advanced glycosylation end products are probably responsible for yellowing of skin and nails. Increased viscosity of blood due to stiff red blood cell membranes results in engorgement of the post-capillary venules in the papillary dermis, detected as erythema of the face, or periungual erythema. It is suggested that these skin changes may eventually be used as a reflection of the patient's current as well as past metabolic status.

INDEX

Cutaneous Infections in Diabetes Mellitus

Dermal Manifestations of Diabetes Mellitus

Vascular Manifestations of Diabetes Mellitus

Other Skin Markers of Diabetes Mellitus

Diabetic Neuropathy and the Skin

Introduction

Skin manifestations in diabetes mellitus are common and expressed in numerous forms. If one considers metabolic effects on microcirculation and changes in skin collagen, prevalence approaches 100 percent. Findings range from the presenting manifestations of the disease to signs of long term involvement, from the mundane to indications of serious, even life-threatening problems. For all of these, recognition is the key to treatment and/or prevention. This review of cutaneous manifestations of diabetes groups findings according to presumed pathophysiology. Since the pathophysiology is not always known, some less common findings are discussed separately at the end.

Biochemical Considerations

In 1968 Rahbar published the observation that patients with diabetes mellitus have oddly behaving hemoglobin.(1) This was subsequently demonstrated to be due to non-enzymatic condensation of glucose with hemoglobin to form stable covalent adducts. Non-enzymatic glycosylation occurs with many proteins including hemoglobin, an attachment that results in changes in the physical and chemical properties.

Glucose in solution exists as a stable pyranose ring in equilibrium with the open chain aldehyde form. The reaction of monosaccharides with proteins consists of the covalent linkage of the double-bonded oxygen of the aldehyde function with an NH2 group, either on the alpha-amino group of the N-terminal amino acid or on the epsilon-amino group of lysine. This condensation results in the formation of a Schiff base or aldimine, and is a reversible reaction. However, following the formation of the Schiff base, there is an internal reconfiguration of the molecule, the so called Amadori rearrangement, resulting in formation of a ketoamine which tends to not revert back to the Schiff base. The rate of reaction of various carbohydrates with protein correlates with the extent to which the sugar exists in the open ring (aldehyde) form.

Following the condensation and reconfiguration, the Amadori products undergo a series of further reactions with amino groups on other proteins to form glucose-derived intermolecular crosslinks. (2) These collagen modifications result in a color change which has been demonstrated by spectrophotometric measurement to correlate with diabetic complications. (3) One of these advanced glycosylation products, a yellow compound, 2-(2- furoyl)-4(5)-(2-furanyl)-1H-imidazole, has been identified. (4) Quantitation of another advanced glycosylation end product in the skin, the amino acid pentosidine, has also been demonstrated to correlate with a cumulative score of diabetic complications. (5)

The process of non-enzymatic glycosylation occurs to a minor extent at normal blood sugar concentrations. This gradual glycosylation of proteins may be responsible for some of the skin changes associated with aging, and this process is apparently accelerated in persons with elevated blood sugars. Most proteins evaluated seem to be involved by this reaction which results in changes in the physical and chemical properties. Glucosylation of the red cell membrane is apparently responsible for the stiffness of diabetic erythrocytes. (6) Glucosylation of collagen results in increased stiffness and resistance to enzymatic degradation, mechanical changes of collagen which are also characteristic for aging.

Protein glycosylation with changes in tertiary structure and solubility of proteins could conceivably be responsible for many of the complications of this disease.

CUTANEOUS INFECTIONS IN DIABETES MELLITUS

In the pre-insulin era the prevalence of common pyodermas such as furunculosis, carbunculosis, and erysipelas was much higher for diabetics than for their non-diabetic counterparts. (7) Today, these infections do not seem to result in much morbidity and diabetics do not even appear to have an increase in the prevalence of skin infection. (8) However, there are several infections which characteristically occur in persons with diabetes mellitus, and some threaten life and limb.

Candida Infections

Yeast infections are common in diabetic patients. Involvement of the glans penis and of the vulva appear common in type II diabetes. Vaginal candidiasis is almost universal among women with long term diabetes, and yeast infections may even be the presenting manifestation of diabetes.(9)

Vulvo-vaginal candida infection is an especially common problem for the diabetic woman. (10) It is a common cause of pruritus vulvae during glycosuria. Presenting signs include vulvar erythema which may be accompanied by fissuring with or without satellite pustules. Vaginitis is usually accompanied by a white discharge. Traditional treatment involves normalizing blood sugar, treating both the vagina and vulva with topical medication. Since these patients often have a reservoir of Candida in the colon, oral nystatin may also be administered. Another option for vaginal candidiasis is oral administration of one dose 150 of mg of fluconazole.

Angular stomatitis due to Candida is a classic complication in diabetic children and an occasional complication in diabetic adults. Increased concentrations of salivary glucose reportedly accounts for its occurrence, (11) but not for the predilection for younger patients. Clinically it is appreciated as white, curd- like material which adheres to erythematous, fissured areas at the angle of the mouth or as white patches on the buccal mucosa and palate. Diagnosis is readily confirmed by examination of a potassium hydroxide preparation. Success in treatment may depend on normalization of blood sugar and the supplemental use of anticandidal lozenges.

The prevalence of Candida infection of the hands and feet does not appear to be significantly different for the diabetic population as compared to controls. (12) When it does occur, it usually has one of three presentations. Candida paronychia usually involves the hands but it may occur on the feet. It often begins at the lateral nail folds as erythema, swelling, and separation of the fold from the lateral margin of the nail. Further infection may result in involvement of the proximal nail fold and separation of the cuticle from the nail. Moisture trapped in the resultant space favors further growth of the yeast and repeated episodes of inflammation. At times there may be a purulent discharge from involved nail fold, a clinical finding suggesting bacterial paronychia. But the diagnosis of yeast infection can usually be established by performing a KOH preparation on extruded serous material from this space.

Candida infection of the web spaces usually involves the 3-4 web space of the hands or the 4-5 web-space of the toes. This area has a tendency to retain moisture due to occlusion from apposing surfaces of skin. Presumably the increased sugar content of the skin encourages the establishment of this infection. The clinical appearance is a white patch of skin, often with central peeling. Toe web space involvement is often mistaken for a dermatophyte infection, but the diagnosis can be confirmed on potassium hydroxide preparation.

The third presentation of Candida infection of the extremities is involvement in the toe nail plates. Although dystrophic toe nails are often assumed to be the result of dermatophyte infection, nail plate cultures demonstrate the pathogen to be Candida species about five percent of the time. One needs to be careful about making the diagnosis of primary Candida infection, however, because cultures may only reflect contaminants or secondary involvement.Clinically, nail plate infections with either dermatophyte or Candida sp. present with distal yellowing or whitening and thickening of the toe nail. Living tissue does not appear to be involved. If there is a special risk to the diabetic host to have this nail plate infection, it has not been demonstrated.

Phycomycetes Infections

Hyperglycemia can allow usually nonpathogenic organisms to establish an infection in traumatized skin, occasionally resulting in gangrene and loss of limb. Diabetic patients with leg ulcers, or non-healing surgical wounds, especially those of the lower extremities, may have a complicating Phycomycetes infection. Such an infection should be suspected when lower extremity ulcers or post-traumatic lesions are not responding to therapy. Diagnosis can be confirmed by culture and by histologic demonstration of fungal elements invading vascular channels.

Patients with uncontrolled diabetes with ketosis may be predisposed to deep mycotic infections such as the rare but serious forms of mucormycosis. The characteristic presentation is black crusting or pus on the turbinates, septum, or palate. Without treatment the infection may extend to the maxillary and ethmoid sinuses, the palate, and the orbit. Cerebral involvement occurs in about two thirds of these patients. (13) Treatment consists of correction of acid-base imbalance, aggressive debridement of necrotic tissue, and intravenous amphotericin.

Pseudomonas Infections

Malignant external otitis, an uncommon, but serious, infection of the external ear canal by Pseudomonas, characteristically presents as and severe external ear canal pain and purulent discharge in an elderly diabetic patient. (14,15) The infection is thought to begin as a cellulitis of the ear canal, but natural cleavage planes allow progression through the osseous cartilaginous junction. With further extension the cranial nerves may be involved, especially the facial nerve. About half the affected individuals die of this infection. Treatment of choice consists of surgical debridement and administration of anti-pseudomonas antibiotics. .

Much more common than malignant external otitis, however, is Pseudomonas infection of the toe web spaces or colonization under the toenails. Often, persons who have onychomycosis develop a lifting of the nail plate form the bed (onycholysis). The resulting space between plate and bed may become colonized with Pseudomonas resulting in a green discoloration of this area.

Pseudomonas may cause web space infection on the feet similar to that due to dermatophytosis, but this assumption may be incorrect. The differential diagnosis includes candidiasis, infection due to Pseudomonas, but a Wood's lamp examination often yields a green fluorescence. Soaks with dilute vinegar may eradicate superficial infection, with more advanced cellulitis, oral Ciprofloxacin appears to be the treatment of choice.

Dermatophytosis

Although dermatophyte infections are probably not more common in the diabetic population, (16) they are of special concern. Toe web space infections may lead to inflammation and fissuring that can serve as a portal of entry for bacterial infection in a compromised diabetic foot. The oxygen demand of the subsequent inflammation may exceed the ability of the diabetic microcirculation, leading to gangrene. It is for that reason that tinea pedis should be aggressively managed in patients with neurovascular compromise.

Involvement of the toe-nails by dermatophytes (onychomycosis) is common among elderly diabetics as it is in the population at large. The infection itself is of little consequence, but the nail dystrophy which results may make proper nail care more difficult for the patient. Currently the most promising (but not FDA approved) treatment appears to be itraconazole 400 mg/day for one week a month for 4-6 months.

DERMAL MANIFESTATIONS OF DIABETES MELLITUS

Diabetic Thick Skin

Persons with diabetes tend to have thicker skin than their non-diabetic counterparts. There are three aspects to this observation. First, diabetics in general have a clinically inapparent but measurable increase in skin thickness unassociated with symptoms and goes unnoticed by patients and physicians. Second is a clinically apparent thickening of skin involving the fingers and hands ranging from pebbled skin to scleroderma-like skin changes. And third is an infrequent syndrome of diabetic scleredema in which the patient develops markedly thickened dermis on the upper back region.

The presence of diabetes mellitus is generally associated with measurably thickened skin. Using pulsed ultrasound, it can be demonstrated that diabetics have thicker forearm skin than their age and sex-matched nondiabetic counterparts.(17) Contrary to the pattern in non-diabetics, skin thickness may increase with age (apparently associated with increased duration of diabetes.) Most studies have used the upper extremity skin in evaluating skin thickness, and it may not be a valid conclusion that diabetic skin is thickened at other sites. We have also demonstrated an increased skin thickness on the dorsum of the feet, but not the back, suggesting that increased skin thickness is not necessarily universal in diabetes.(18) It appears to be a safe observation that patients with diabetes mellitus have thicker skin on their extremities.

Hand Skin Thickening

Thickening of skin of the hand is a common occurrence, with a range of manifestation from simple pebbling of the knuckles to the diabetic hand syndrome. The diabetic hand syndrome consists of thickened skin over the dorsum of the digits and limited joint mobility, especially of the interphalangeal joints.(19) The earliest description of this phenomenon was apparently the observation that insulin- dependent diabetes was occasionally complicated by painful stiff hands.(20) Subsequently, Rosenbloom and Frais described three adolescent patients with the syndrome of long-standing diabetes mellitus, restricted joint mobility, thick tight waxy skin, growth impairment, and maturational delay.(21) Rosenbloom et al later reported in a study of 309 mostly juvenile diabetics that 30 percent had joint limitation and one third of these had thick tight, waxy skin that the examiner could not tent, mostly involving the dorsum of the hands.(22) This work has been confirmed by other authors and these observations have been extended to patients with type II diabetes mellitus.(23)

More common is simple thickening of the skin on the dorsum of the hands. At least thirty percent of diabetic patients have hand skin thickening, and some have demonstrable involvement of the dorsum of the feet. Clinical clues which suggest such a thickening include difficulty in tenting the skin, pebbled or rough skin on the knuckles or periungual region,(24) and decreased skin wrinkling following immersion in water.(25)

FIG 1: Knuckle Pebbles. Thickening of the skin on the dorsum of the hand due to many causes, diabetes among them, is often manifest by a pebbling of the skin on the knuckle area. This patient with insulin dependent diabetes mellitus also has palpably thick skin when tenting is attempted.

. What is the significance of thick skin on the hands and feet in diabetes mellitus? The literature suggests that digital sclerosis (very thick skin) is a marker for retinal microvascular disease. But there is a spectrum of thickening of the skin which ranges from that which is only detectable by ultrasound to the more obvious. For less than digital sclerosis, the significance of thick skin in diabetes is uncertain at this time.

Scleredema of Diabetes

FIG 2: Scleredema of Diabetes. This patient with Type II diabetes gave an incidental complaint of limitation of motion of his upper extremities. To examination, this appeared to be due to the shield-like involvement of the upper back, neck, and shoulders with marked dermal thickening. The examiner is demonstrating the inability to tent the skin on the dorsum of the neck.

Scleredema adultorum of diabetes is a syndrome characterized by a marked increase in dermal thickness on the posterior back and upper neck in middle aged, overweight, poorly controlled type II diabetic subjects. It is not recognized a being related to digital sclerosis, and we found no correlation by ultrasound measurements of back skin and hand skin thickness. It has a reported prevalence of 2.5 percent in patients with type II diabetes.(26) Histologically one finds a thickened dermis with large collagen bundles that are separated by wide, clear spaces. There may be increased numbers of mast cells. (27) There are reports of increased, normal, and decreased glycosaminoglycans in affected dermis.(28)

Are there any known treatments for the thick skin syndromes? There is one study which suggests that tight control of blood sugar helps. Lieberman et al reported that four diabetic patients with thick skin had a decrease of skin thickness following pump administration of insulin and achievement of tighter control.(29) In that study skin thickness was measured ultrasonically on six body areas and the sums of pre- and post- treatment determinations were compared. However, they did not report thickness measurements for any one area. There is no known treatment for diabetic scleredema.

Yellow Skin

Diabetic skin often has a yellow hue. Traditionally considered to be carotenemia, recent evaluations indicate that serum carotene levels are not elevated as they had been years ago when the standard diabetic diet involved heavy consumption of vegetables.(30)

One possible cause of yellow skin might be glycosylation end products. It is known that proteins which have a long turnover time, such as dermal collagen, undergo glycosylation and become yellow. One of the advanced glycosylation products which has been identified, 2-(2-furoyl)-4(5)-(2-furanyl)-1H-imidazole, has a distinctly yellow hue (see the earlier section on Biochemical Considerations).

Yellow skin is a common finding among patients with diabetes, probably best appreciated on the palms and soles because of sparse competition with melanocytic pigment in these areas. There is currently no significance associated with this finding other than that of a time proven observation.

VASCULAR MANIFESTATIONS OF DIABETES MELLITUS

Macroangiopathy

Diabetics have a higher incidence and prevalence of large vessel disease,(31) and develop myocardial infarctions and strokes at a much younger age than their non-diabetic counterparts. Large vessel disease (atherosclerosis) may also be present in the lower extremities and result in skin atrophy, hair loss, coldness of the toes, nail dystrophy, pallor upon elevation, and mottling on dependence. (32)

Microangiopathy

Microangiopathy is one of the major complications of diabetes mellitus. The small blood vessel changes affecting the retinal and renal vasculature are responsible for blindness and kidney failure. Microvascular pathology has also been assumed to play a role in diabetic neuropathy, and in the so-called diabetic foot. Microangiopathy is clinically detected by an eye ground examination which demonstrates the presence of microaneurysms. More severe involvement may demonstrate hemorrhages, exudates, and even some devascularized areas as well.

The histology of affected diabetic tissue reveals a PAS positive, thickened capillary basement membrane. Electron microscopy of skeletal muscle capillaries reveals reduplication of the basal lamina. The skin has not been thought to be a good sample source in evaluation of patients microangiopathy because small blood vessels of the dermis develop less basal lamina thickening than is found in skeletal muscle (which is also easily accessed using a needle biopsy).

The structural changes which occur in the microcirculation do not seem to account for all the full extent of the disease, leading to the concept of functional microangiopathy. Some patients with severe microcirculatory problems such as gangrene of the foot have normal capillaries on skin or skeletal muscle biopsy. Sluggish microcirculation resulting in micro-venular dilatation is considered "functional" in that it may be reversed with improved control of diabetes. The clinical manifestations associated with this include retinal venous dilatation, red face, and periungual telangiectasia, all of which may be very early manifestations of the disease and which may improve with control of diabetes.

Functional microangiopathy may result from nonenzymatic glycosylation which affects many blood components including hemoglobin, red blood cell membrane, fibronectin, fibrinogen, and platelets. Glucosylation of the red blood cell has been shown to inhibit the cell pliability and to decrease the ability of this cell to pass through pores smaller than 7 microns. The lumen of some capillaries may be as narrow as 3 microns and ordinarily red blood cells will elongate into a more sausage like configuration to traverse this loop. Stiffened membranes will certainly inhibit or limit this passage.

In addition to stiffened red blood cells, diabetics also have increased plasma concentration of fibrinogen and capillary leakage leading to loss of albumen and water. There is an increased tendency for diabetic platelets to aggregate. The end result is increased whole blood or plasma viscosity and sluggish microcirculation.

In summary, it appears that microangiopathy can be attributed to both structural and functional abnormalities in these vessels. The following discussion will review some of the cutaneous manifestations which may be linked to this microangiopathy.

Diabetic Dermopathy

FIG 3: Diabetic Dermopathy. The presence of many hyperpigmented atrophic macules on the shins is said to be a relatively common finding in patients with diabetes. Antecedent trauma may or may not be recalled by the patient.

Atrophic hyperpigmented macules on the shins, so-called diabetic dermopathy, has been termed the most common cutaneous finding in diabetes.(33) It is usually noted as irregularly round or oval, circumscribed, shallow lesions vary in number from few to many, which are usually bilateral but not symmetrically distributed. They are asymptomatic and often overlooked.

The genesis of these lesions is unclear. Some authors describe a preceding, distinct, red papular eruption which is independent of trauma to the skin.(34) However, Lithner has been able to duplicate these lesions by local thermal trauma.(35) We observe that many patients who develop these depressed hyperpigmented lesions relate antecedent trauma or mild pyoderma such as folliculitis. "Diabetic dermopathy" probably represents post-traumatic atrophy and post-inflammatory hyperpigmentation in poorly vascularized skin.

Do these lesions represent the cutaneous manifestation of structural microangiopathy? Histologic characteristics of acute lesions are edema of the epidermis and papillary dermis, extravasated erythrocytes and a mild lymphohistiocytic infiltrate.(36) Older lesions have thick-walled capillaries in the upper dermis, occasional extravasated erythrocytes and a positive Perl stain for iron. However, one electron microscopic study demonstrated only in some patients the presence of thickened basal lamina.(37) Based on the available studies, there appear to be structural components and some suggestion of a functional factors as well.

The significance and prevalence of diabetic dermopathy depends on the operational definition of this entity. Defined as one or more spots, the original description reported their presence in 55% of 293 diabetics (65% of males and 29% of females).(38) But with this definition, it has also been shown to occur in 20% of control patients with normal glucose tolerance tests.(39) Thus, defining diabetic dermopathy as one or more spots results in high sensitivity but low specificity for diabetes. However, in a study which defined dermopathy as the presence of four or more lesions, they were absent in non-diabetics and present in about 14% of diabetics (24% of men and 3% of women).(40) The multilesional definition also found a high correlation with retinovascular disease.

Pigmented Purpura

FIG 4: Pigmented Purpura. Salt and Pepper type of yellow-tan hyperpigmentation of the shins in the absence of atrophy is characteristic for pigmented purpura, a common finding especially in elderly diabetics. Patients need not be diabetic to demonstrate this finding. This finding is often seen in conjunction with diabetic dermopathy so there are some areas of focal atrophy and wide areas of non-atrophic pigmentation.

Pigmented purpuric dermatosis is a condition involving the skin on the lower extremities resulting from red blood cell extravasation from the superficial vascular plexus. It is characterized by multiple tan to reddish small macules (so-called cayenne pepper spots) which coalesce into tan to orange patches. It often extends down to involve the ankles and the dorsum of the feet. It was described as a manifestation in older diabetic patients, about half of whom had diabetic dermopathy.(41) In most of these patients, cardiac decompensation with edema of the legs was determined to be a precipitating factor for the purpura. Except for the frequent association with diabetic dermopathy, this condition appears clinically consistent with Schambergs disease. Again, with little insight into the pathophysiology, this condition appears to be a marker of structural microangiopathy.

Red Skin and Rubeosis Facei

The prototype functional microangiopathy is facial involvement, the so-called rubeosis facei. The intensity of red coloration which can be appreciated in one's 'complexion' is a function of the degree of engorgement of the superficial venous plexus. Hyperglycemia predisposes to sluggish microcirculation and affected individuals develop a functional microangiopathy which is clinically evident by venous dilatation.(42) This venous dilatation can be demonstrated in the eye grounds and skin. It may be evident in newly diagnosed diabetics and, more importantly, the vascular engorgement may return to normal when the blood sugar is controlled. In a prospective study of 150 medical hospital admissions, comparing facial redness (none, slightly red, or markedly red) with diabetic parameters (persistent fasting hyperglycemia or a diabetic glucose tolerance curve), of sixty one patients with diabetes, thirty-six (59%) had markedly red faces.(43) Because of normal variation in complexion, this sign is difficult to use as a marker of functional microangiopathy.

Periungual Telangiectasia

FIG 5: Periungual Telangiectasia. The nail fold is an excellent site for viewing functional and structural changes in the microvascular of the skin. This patient illustrates microvascular engorgement and tortuosity involving the proximal nail fold.

One may directly examine the skin to survey the superficial microcirculation. Any area of skin may be examined, but because nailfold capillary loops are in a horizontal axis relative to the skin surface, this area offers an excellent view of the entire microvascular loop. In order to see past the stratum corneum, it is helpful to first apply mineral oil to the skin surface and wait a few minutes until this layer becomes translucent. One may use a low power microscope or simply an ophthalmoscope (+40 lens for 10X magnification). In general, the microcirculation of less pigmented individuals is often easier to visualize.

One study found venous capillary dilatation in the nail folds of 49% of seventy-five diabetic patients compared to 10% of sixty-five controls.(44) It is important to note that connective tissue diseases may also result in periungual vessel changes, but that these changes are morphologically different. In diabetes one sees isolated homogeneous engorgement of the venular limbs. In connective tissue diseases, the patterns seen are megacapillaries or irregularly enlarged loops.(45)

Venous dilatation of the periungual microcirculation appears to be an excellent indicator of functional microangiopathy. The structural changes of this area are probably represented by venous tortuosity. Thus a newly diagnosed patient is likely do have simple capillary loops with a dilated venous portion. A long term diabetic patient who had poor control for a number of years, but who now has excellent control, may exhibit venous tortuosity without dilatation. More extensive microangiopathy can be heralded by small hemorrhages and by drop-out of areas of the microcirculation.

Erysipelas-Like Erythema

Another reported phenomenon of microcirculatory compromise in diabetic patients is the development of well demarcated erythema on the lower leg or dorsum of the foot that correlates with radiological evidence of underlying bone destruction, and incipient gangrene. (46,47) The condition was at first mistaken for erysipelas (hence the name erysipelas-like erythema), but there was no associated pyrexia, elevated erythrocyte sedimentation rate, or leukocytosis. This erythema would seem to be functional microangiopathy localized to an area of macrocirculation compromise.

OTHER SKIN MARKERS OF DIABETES MELLITUS

Yellow Nails

FIG 6: Yellow nails of diabetes. For comparison, the examiners thumbnail is photographed alongside the yellow nail of a person with diabetes. Another illustration of the nail of the hallux of a person with diabetes is also given.

As pointed out by Lithner, diabetics tend to have yellow nails.(47) He noted this phenomenon in half of 36 diabetics and in none of nine controls. Our patients have a similar prevalence of yellow nails, except we also see it occasionally in elderly controls, and in some patients with onychomycosis. Although this phenomenon may occur on all the nails, it is most often evident on the distal aspect of the nail of the hallux.

What might account for this coloration? Clinically the yellow color is not usually the result of underlying dermatophytosis. Similar to the yellow color observed in diabetic skin, yellowing of the nails probably represents glycosylation end products. Whereas keratin of the epidermis is only present for one month before being shed, that of the nail plate may be present for greater than a year. The protein- glucose reaction presumably continues to evolve in the aging nail resulting in the most yellow pigment at the distal aspect of the slowest growing nail. The presence of the yellow glycosylation end products in the nail plate has not been confirmed to date, but one study of fingernails has demonstrated that diabetics have high levels of fructose-lysine, another marker of nonenzymatic glycosylation.(48)

Clinically one appreciates yellow nails of diabetes best on examination of the toe-nails. Most diabetic patients have some aspect of this yellowing. Minimal involvement consists of distal yellow or yellow-brown discoloration of the hallux nail plate. Marked involvement consists of canary yellow discoloration of all toe- and finger-nails. It is not a specific finding in diabetes mellitus since it can be occasionally observed with normal aging. Like the yellow hue appreciated generally in the skin of persons with diabetes, the significance of this observation is undetermined. The obvious question is whether or not yellow nails and yellow skin can be used as an quantifiable indicator of the degree of nonenzymatic glycosylation for other tissues of the body.

Diabetic Bullae

FIG 7: Diabetic bullae. This adult onset diabetic patient had spontaneous onset of multiple bullae on his lower extremities, one of which is illustrated here. These lesions were not secondary to trauma or infection and they healed without special intervention.

Another curious phenomenon in diabetes mellitus is the spontaneous appearance of blisters on the extremities (usually confined to hands or feet). These lesions are not the result of trauma or infection. They tend to heal without treatment.

On the basis of cleavage level, there appears to be three types of these blisters. The most common type is spontaneous and nonscarring. They present as clear, sterile blisters on the tips of the toes or fingers and less frequently on the dorsal and lateral surfaces of the feet, legs, hands, and forearms. Spontaneous healing occurs within 2 to 5 weeks.(49) These patients were reported to have good circulation to the affected extremity and tended to have diabetic peripheral neuropathy. In those patients in whom histopathology has been performed, there is an intraepidermal cleavage without acantholysis.(50,51) The second type of diabetic bullae involves lesions that may be hemorrhagic and heal with scarring and atrophy.(52,53 The reported cleavage plane is below the dermoepidermal junction.

A third type described in a case report consists of multiple tender nonscarring blisters on sun-exposed and deeply tanned skin, on the feet, legs, and arms. Immunofluorescence and porphyrin studies were negative. Electron microscopy placed the cleavage plane at the lamina lucida. (54)

Necrobiosis Lipoidica

FIG 8: Necrobiosis Lipoidica. This patient has waxy tan plaques on both shins. This lesions demonstrates the translucency in the center portion with visibility of underlying blood vessels.

Necrobiosis lipoidica diabeticorum (NLD) is an uncommon manifestation of diabetes mellitus, occurring in about 0.3% of these patients.(55) This skin manifestation is not pathognomonic for diabetes mellitus since less than two thirds of patients with necrobiosis lipoidica are diabetic. Necrobiosis lipoidica has been documented to occur prior to the onset of diabetes mellitus.(56) Certainly any patient who presents with necrobiosis lipoidica should be evaluated for diabetes.

The initial lesions of NLD begin as well-circumscribed erythematous papules. Evolving radially, the sharply defined lesions have depressed, waxy, yellow-brown, atrophic telangiectatic centers through the underlying dermal vessels can be visualized. The periphery is slightly raised and erythematous and there may be partial or complete anesthesia of the lesion.(57) Ulceration is reported in about one third of leg lesions, mostly in large lesions following minor trauma. Lesions of NLD sometimes spontaneously resolve, but more often they do not. They seem to occur and persist independent of degree of control of hyperglycemia.

Whereas most lesions of NLD occur on the legs, about 15 percent of lesions are found elsewhere, including on the hands, forearms, abdomen, face, or scalp. When necrobiosis lipoidica occurs in areas other than the lower extremities, the patient is less likely to have diabetes mellitus.(58)

The histopathology of NLD reveals neutrophilic necrotizing vasculitis in early lesions.(59 With progression there is collagen degeneration and destruction of adnexal structures. Lesions evolve through granulomatous and sclerotic stages, with most of the sclerosis occurring in the lower reticular dermis. The upper dermis contains fatty deposits that give the lesions their yellow color.

Electron microscopy of necrobiosis lipoidica reveals striking changes involving dermal blood vessels consisting of focal degeneration of the endothelial cells lining the microvasculature.(60) These cells have electron lucency and loss of intracellular organelles.

Treatment is used to arrest the progression of the disease. This is most commonly achieved by application of high potency topical steroids or intralesional injection of steroids into the active margin. Other agents reported include pentoxifylline, high dose oral nicotinamide(61), aspirin and dipyridamole(62,63,64) Currently the most impressive therapeutic option may be oral corticosteroids. Five weeks of oral corticosteroid treatment was described as resulting in complete disease cessation for all of six patients treated.(65). Since the pathophysiology of necrobiosis is not understood, it is difficult to design rational therapy.

DIABETIC NEUROPATHY AND THE SKIN

Autonomic Neuropathy

It has been suggested that nonmyelinated nerve fibers, such as those of the autonomic nervous system, may be the first nervous tissue affected in diabetics.(66) In clinical practice, evidence of autonomic neuropathy is common as manifested by disturbance of sweating (usually anhidrosis) of the feet. Occasionally patients complain of over-sweating elsewhere, a compensatory mechanism for loss of the ability to temperature regulate in the involved area. It has also been reported that autonomic neuropathy (as measured by quantitation of the sweating deficiency) correlates well with the severity of sensory neuropathy.(67) One might safely assume that patients who have diabetic sensory neuropathy also have accompanying autonomic involvement.

The clinical manifestations of peripheral autonomic neuropathy vary from absence of symptoms to complaints that the feet are abnormally cold, burning, or pruritic. But there is also a problem due to absence of sweating. Perspiration on the feet maintains hydration of the stratum corneum: callosities without hydration tend to become brittle and may fissure serving as a portal for infection. Thus symptoms and signs of autonomic peripheral neuropathy in the diabetic patient indicate the need for extra attention to foot care.

Motor Neuropathy

Diabetic motor neuropathy most often affects the foot. The clinical presentation is wasting of the interosseous foot muscles resulting in two major mechanical problems. The foot tends to splay upon weight bearing, resulting in a wider foot. The toes tend to draw upward, and the plantar fat pads move forward leaving the metatarsal heads riding on the plantar skin without the benefit of padding.

Motor neuropathy may appear suddenly or occur gradually over several years. Acute and reversible motor neuropathy may follow an episode of ketoacidosis,(68) or as the result of insulin excess. More usual is an insidious progression of motor nerve deterioration over many years.

Motor neuropathy in diabetes mellitus is almost always accompanied by a sensory involvement. Changes in the shape of the foot follow the imbalance of its internal musculature and result in ill-fitting shoes. If the changes go unnoticed, the patient may continue to wear shoes which can now traumatize the foot. Because of the accompanying sensory loss, displacement of the plantar fat pads can result in uncushioned weight bearing at the metatarsal heads. Callosities and eventually ulceration of the weight-bearing skin or of the skin being rubbed by the now ill fitting shoes result (neuropathic ulcers). The presence of motor neuropathy of the foot often necessitates the use of special widened shoes with molded inserts to redistribute weight bearing, to accommodate and to protect the compromised foot.

Sensory Neuropathy

FIG 9: The erosion with callus on the tip of the toe is typical of the type of injury which results with sensory neuropathy of diabetes.

Diabetics often develop sensory neuropathy on the feet, especially with long-standing disease. The clinical presentation usually involves tingling and numbness starting in the toes. The level of neuropathy may vary from mild numbness of the distal toes to profound anesthesia and neuropathic ulcers. Thermal sensitivity is also affected. (69)

What is the clinical significance of sensory neuropathy? Although tingling and numbness tend to be the complaint, the lack of sensation may allow trauma to go unnoticed and result in a traumatic ulceration. Depending upon the status of the microcirculation, these ulcers may present difficult therapeutic problems. Neuropathic patients who walk barefoot may sustain damage when during routine ambulation because they have inadequate sensation to withdraw the foot when it encounters noxious stimuli. Occasionally this unsensed trauma during ambulation results in fracturing the bones of the feet, eventuating into a Charcot foot.

FIG 10: Charcot Foot. This patient, with diabetic motor and sensory neuropathy, developed multiple midfoot fractures while running a short distance barefoot. The result is a misshapen foot as seen here.

Patients with sensory neuropathy need to be instructed to make sure their shoes are devoid of foreign objects before the shoes are worn. As simple as it sounds, patients who do not follow this rule occasionally sustain severe damage by wearing shoes which, unknown to them, had objects (especially children's toys) included.

SUMMARY

Diabetes Mellitus is a common ailment and virtually all persons with diabetes develop skin manifestations of this disease. Many of these manifestations, especially the more common ones, might be explained on the basis of the attachment of glucose to proteins, and the subsequent metabolism of this combination, which results in changes in structure, function, and color. Hopefully, the common skin findings described here may eventually be used as indicators of the patient's current and past metabolic status.

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